Trisha Suppes, MD, PhD

All Publications

• Prevalence of axis II comorbidities in bipolar disorder: relationship to mood state BIPOLAR DISORDERS Post, R. M., Leverich, G. S., McElroy, S., Kupka, R., Suppes, T., Altshuler, L., Nolen, W., Frye, M., Keck, P., Grunze, H., Hellemann, G. 2018; 20 (4): 303–12

  Abstract

  A high incidence of Axis II personality disorders is described in patients with bipolar disorder; however, their relationship to mood state remains uncertain.A total of 966 outpatients with bipolar disorder gave informed consent and filled out the Personality Disorder Questionnaire, 4th edition (PDQ4) and a questionnaire on demographics and course of illness prior to Bipolar Treatment Outcome Network entry at average age 41 years. Patients were rated at each visit for depression on the Inventory of Depressive Symptoms-Clinician version (IDS-C) and for mania on the Young Mania Rating Scale (YMRS). In a subgroup, the PDQ4 was retaken during periods of depression and euthymia.Patients met criteria for most personality disorders at a much higher rate when they took the PDQ4 while depressed compared to while euthymic, and scores were significantly related to the severity of depression (IDS) and of mania (YMRS) assessed within 2 weeks of taking the PDQ. Even when euthymic, more than quarter to half of the patients met criteria for a cluster A, B or C personality disorder.A wide range of personality disorders occur in bipolar patients, but are highly dependent on filling out the form while depressed compared to while euthymic. How this relates to having a personality disorder assessed using a structured clinical interview remains to be tested. However, higher PDQ4 scores are related to an earlier age of onset of bipolar disorder and other factors portending a more difficult course of bipolar disorder, and the optimal treatment of these patients remains to be illuminated.

  View details for PubMedID 29369448

• UNDERSTANDING TREATMENT RESPONSE TO INTEGRATED BEHAVIOR THERAPY FOR COMORBID OBESITY AND DEPRESSION IN PRIMARY CARE Ma, J., Lv, N., Rosas, L., Xiao, L., Lavori, P., Venditti, E., Lewis, M., Snowden, M., Ward, E., Smyth, J., Suppes, T., Goldstein-Piekarski, A., Williams, L. OXFORD UNIV PRESS INC. 2018: S129

  View details for Web of Science ID 000431185200292

• Bipolar disorders NATURE REVIEWS DISEASE PRIMERS Vieta, E., Berk, M., Schulze, T. G., Carvalho, A. F., Suppes, T., Calabrese, J. R., Gao, K., Miskowiak, K. W., Grande, I. 2018; 4: 18008

  Abstract

  Bipolar disorders are chronic and recurrent disorders that affect >1% of the global population. Bipolar disorders are leading causes of disability in young people as they can lead to cognitive and functional impairment and increased mortality, particularly from suicide and cardiovascular disease. Psychiatric and nonpsychiatric medical comorbidities are common in patients and might also contribute to increased mortality. Bipolar disorders are some of the most heritable psychiatric disorders, although a model with gene-environment interactions is believed to best explain the aetiology. Early and accurate diagnosis is difficult in clinical practice as the onset of bipolar disorder is commonly characterized by nonspecific symptoms, mood lability or a depressive episode, which can be similar in presentation to unipolar depression. Moreover, patients and their families do not always understand the significance of their symptoms, especially with hypomanic or manic symptoms. As specific biomarkers for bipolar disorders are not yet available, careful clinical assessment remains the cornerstone of diagnosis. The detection of hypomanic symptoms and longtudinal clinical assessment are crucial to differentiate a bipolar disorder from other conditions. Optimal early treatment of patients with evidence-based medication (typically mood stabilizers and antipsychotics) and psychosocial strategies is necessary.

  View details for PubMedID 29516993

• A randomized controlled trial of moodswings 2.0: An internet-based self-management program for bipolar disorder Gliddon, E., Cosgrove, V., Berk, L., Lauder, S., Mohebbi, M., Grimm, D., Dodd, S., Coulson, C., Raju, K., Suppes, T., Berk, M. WILEY. 2018: 60

  View details for Web of Science ID 000426605800141

• Bipolar patients in the us are quadrupally vulnerable and sensitized to a poor outcome: A national public health emergency should be declared Post, R., Frye, M., Kupka, R., Nolen, W., Altshuler, L., McElroy, S., Suppes, T., Grunze, H., Keck, P., Row, M. WILEY. 2018: 87

  View details for Web of Science ID 000426605800209

• Efficacy and tolerability of divalproex sodium plus adjunctive quetiapine, lithium, or placebo for hypomanic or manic episodes in outpatients with bipolar I disorder Fischer, E. G., Cosgrove, V., Suppes, T., Lange, N. K., Gwizdowski, I., Doan, G., Ostacher, M. WILEY. 2018: 116

  View details for Web of Science ID 000426605800284

• Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder BIPOLAR DISORDERS Yatham, L. N., Kennedy, S. H., Parikh, S. V., Schaffer, A., Bond, D. J., Frey, B. N., Sharma, V., Goldstein, B. I., Rej, S., Beaulieu, S., Alda, M., MacQueen, G., Milev, R. V., Ravindran, A., O'Donovan, C., McIntosh, D., Lam, R. W., Vazquez, G., Kapczinski, F., McIntyre, R. S., Kozicky, J., Kanba, S., Lafer, B., Suppes, T., Calabrese, J. R., Vieta, E., Malhi, G., Post, R. M., Berk, M. 2018; 20 (2): 97–170

  Abstract

  The Canadian Network for Mood and Anxiety Treatments (CANMAT) previously published treatment guidelines for bipolar disorder in 2005, along with international commentaries and subsequent updates in 2007, 2009, and 2013. The last two updates were published in collaboration with the International Society for Bipolar Disorders (ISBD). These 2018 CANMAT and ISBD Bipolar Treatment Guidelines represent the significant advances in the field since the last full edition was published in 2005, including updates to diagnosis and management as well as new research into pharmacological and psychological treatments. These advances have been translated into clear and easy to use recommendations for first, second, and third- line treatments, with consideration given to levels of evidence for efficacy, clinical support based on experience, and consensus ratings of safety, tolerability, and treatment-emergent switch risk. New to these guidelines, hierarchical rankings were created for first and second- line treatments recommended for acute mania, acute depression, and maintenance treatment in bipolar I disorder. Created by considering the impact of each treatment across all phases of illness, this hierarchy will further assist clinicians in making evidence-based treatment decisions. Lithium, quetiapine, divalproex, asenapine, aripiprazole, paliperidone, risperidone, and cariprazine alone or in combination are recommended as first-line treatments for acute mania. First-line options for bipolar I depression include quetiapine, lurasidone plus lithium or divalproex, lithium, lamotrigine, lurasidone, or adjunctive lamotrigine. While medications that have been shown to be effective for the acute phase should generally be continued for the maintenance phase in bipolar I disorder, there are some exceptions (such as with antidepressants); and available data suggest that lithium, quetiapine, divalproex, lamotrigine, asenapine, and aripiprazole monotherapy or combination treatments should be considered first-line for those initiating or switching treatment during the maintenance phase. In addition to addressing issues in bipolar I disorder, these guidelines also provide an overview of, and recommendations for, clinical management of bipolar II disorder, as well as advice on specific populations, such as women at various stages of the reproductive cycle, children and adolescents, and older adults. There are also discussions on the impact of specific psychiatric and medical comorbidities such as substance use, anxiety, and metabolic disorders. Finally, an overview of issues related to safety and monitoring is provided. The CANMAT and ISBD groups hope that these guidelines become a valuable tool for practitioners across the globe.

  View details for PubMedID 29536616

• User engagement within the moodswings 2.0 online self-guided intervention for bipolar disorder Cosgrove, V., Gliddon, E., Berk, L., Lauder, S., Grimm, D., Dodd, S., Suppes, T., Berk, M. WILEY. 2018: 30

  View details for Web of Science ID 000426605800062

• The association between mood state and chronobiological characteristics in bipolar I disorder: a naturalistic, variable cluster analysis-based study INTERNATIONAL JOURNAL OF BIPOLAR DISORDERS Gonzalez, R., Suppes, T., Zeitzer, J., McClung, C., Tamminga, C., Tohen, M., Forero, A., Dwivedi, A., Alvarado, A. 2018; 6: 5

  Abstract

  Multiple types of chronobiological disturbances have been reported in bipolar disorder, including characteristics associated with general activity levels, sleep, and rhythmicity. Previous studies have focused on examining the individual relationships between affective state and chronobiological characteristics. The aim of this study was to conduct a variable cluster analysis in order to ascertain how mood states are associated with chronobiological traits in bipolar I disorder (BDI). We hypothesized that manic symptomatology would be associated with disturbances of rhythm.Variable cluster analysis identified five chronobiological clusters in 105 BDI subjects. Cluster 1, comprising subjective sleep quality was associated with both mania and depression. Cluster 2, which comprised variables describing the degree of rhythmicity, was associated with mania. Significant associations between mood state and cluster analysis-identified chronobiological variables were noted. Disturbances of mood were associated with subjectively assessed sleep disturbances as opposed to objectively determined, actigraphy-based sleep variables. No associations with general activity variables were noted. Relationships between gender and medication classes in use and cluster analysis-identified chronobiological characteristics were noted. Exploratory analyses noted that medication class had a larger impact on these relationships than the number of psychiatric medications in use.In a BDI sample, variable cluster analysis was able to group related chronobiological variables. The results support our primary hypothesis that mood state, particularly mania, is associated with chronobiological disturbances. Further research is required in order to define these relationships and to determine the directionality of the associations between mood state and chronobiological characteristics.

  View details for PubMedID 29457195

• The ENGAGE study: Integrating neuroimaging, virtual reality and smartphone sensing to understand self-regulation for managing depression and obesity in a precision medicine model. Behaviour research and therapy Williams, L. M., Pines, A., Goldstein-Piekarski, A. N., Rosas, L. G., Kullar, M., Sacchet, M. D., Gevaert, O., Bailenson, J., Lavori, P. W., Dagum, P., Wandell, B., Correa, C., Greenleaf, W., Suppes, T., Perry, L. M., Smyth, J. M., Lewis, M. A., Venditti, E. M., Snowden, M., Simmons, J. M., Ma, J. 2018; 101: 58–70

  Abstract

  Precision medicine models for personalizing achieving sustained behavior change are largely outside of current clinical practice. Yet, changing self-regulatory behaviors is fundamental to the self-management of complex lifestyle-related chronic conditions such as depression and obesity - two top contributors to the global burden of disease and disability. To optimize treatments and address these burdens, behavior change and self-regulation must be better understood in relation to their neurobiological underpinnings. Here, we present the conceptual framework and protocol for a novel study, "Engaging self-regulation targets to understand the mechanisms of behavior change and improve mood and weight outcomes (ENGAGE)". The ENGAGE study integrates neuroscience with behavioral science to better understand the self-regulation related mechanisms of behavior change for improving mood and weight outcomes among adults with comorbid depression and obesity. We collect assays of three self-regulation targets (emotion, cognition, and self-reflection) in multiple settings: neuroimaging and behavioral lab-based measures, virtual reality, and passive smartphone sampling. By connecting human neuroscience and behavioral science in this manner within the ENGAGE study, we develop a prototype for elucidating the underlying self-regulation mechanisms of behavior change outcomes and their application in optimizing intervention strategies for multiple chronic diseases.

  View details for PubMedID 29074231

• Anxiety, irritability, and agitation as indicators of bipolar mania with depressive symptoms: a post hoc analysis of two clinical trials INTERNATIONAL JOURNAL OF BIPOLAR DISORDERS Suppes, T., Eberhard, J., Lemming, O., Young, A. H., McIntyre, R. S. 2017; 5: 36

  Abstract

  Symptoms of anxiety, irritability, and agitation (AIA) are prevalent among patients with bipolar I disorder (BD-I) mania with depressive symptoms, and could potentially be used to aid physicians in the identification of this more severe form of BD-I. Using data from two clinical trials, the aims of this post hoc analysis were to describe the phenomenology of bipolar mania in terms of AIA and depressive symptoms, and to evaluate the influence of these symptoms on the likelihood of remission during treatment.Patients with a BD-I manic or mixed episode (Diagnostic and Statistical Manual of Mental Disorders IV criteria) were randomised to 3 weeks of double-blind treatment with asenapine, placebo, or olanzapine (active comparator). Anxiety was defined as a score of ≥3 on the Positive and Negative Syndrome Scale 'anxiety' item, irritability as a score of ≥4 on the Young Mania Rating Scale (YMRS) 'irritability' item, and agitation as a score of ≥3 on the YMRS 'increased motor activity-energy' item. Depressive symptoms were defined as a score of ≥1 on three or more individual Montgomery-Åsberg Depression Rating Scale (MADRS) items, or a MADRS Total score of ≥20.A total of 960 patients with BD-I were analysed, 665 with a manic episode and 295 with a mixed episode. At baseline, 61.4% had anxiety, 62.4% had irritability, 76.4% had agitation, and 34.0% had all three AIA symptoms ('severe AIA'); 47.3% had three or more depressive symptoms, and 13.5% had a MADRS total score of ≥20. Anxiety, irritability, and severe AIA (but not agitation) were statistically significantly more common in patients with depressive symptoms. Patients with anxiety or severe AIA at baseline were statistically significantly less likely to achieve remission (YMRS total <12). In general, remission rates were higher with asenapine and olanzapine than with placebo, irrespective of baseline AIA or depressive symptoms.Assessment of AIA symptoms in bipolar mania could enable physicians to identify patients with more severe depressive symptoms, allowing for appropriate intervention. Assessment and monitoring of AIA may help physicians to predict which patients may be harder to treat and at risk for self-harm. Trial registration ClinicalTrials.gov NCT00159744, NCT00159796. Registered 8 September 2005 (retrospectively registered).

  View details for PubMedID 29105003

• Increased Suicidal Ideation in Patients with Co-Occurring Bipolar Disorder and Post-Traumatic Stress Disorder. Archives of suicide research Carter, J. M., Arentsen, T. J., Cordova, M. J., Ruzek, J., Reiser, R., Suppes, T., Ostacher, M. J. 2016: 1-12

  Abstract

  Suicide risk increases for those with Bipolar Disorder or PTSD, however little research has focused on risk for co-occurring Bipolar Disorder and PTSD. The aim of this article was to evaluate increased suicide risk in co-occurring disorders, and differences in suicide risk for patients with Bipolar I versus Bipolar II. This study evaluated suicide risk in patients with co-occurring PTSD and Bipolar Disorder (n = 3,158), using the MADRS and Suicide Questionnaire. Those with history of PTSD had significantly higher suicidal ideation than those without (U = 1063375.00, p < .0001). Those with Bipolar I had higher risk than those with Bipolar II. Patients with Bipolar I and PTSD were at higher risk for suicidal ideation, implying the importance of diagnosis and risk assessment.

  View details for PubMedID 27310106

• More illness in offspring of bipolar patients from the US compared to Europe JOURNAL OF AFFECTIVE DISORDERS Post, R. M., Altshuler, L. L., Kupka, R., McElroy, S. L., Frye, M. A., Rowe, M., Grunze, H., Suppes, T., Keck, P. E., Leverich, G. S., Nolen, W. A. 2016; 191: 180-186

  Abstract

  Evidence suggests that patients with bipolar disorder from the United States have an earlier age of onset and a more difficult course of illness than those from Germany and the Netherlands. These characteristics were related to a greater family burden of psychiatric illness and the experience of more psychosocial adversity in childhood. We hypothesized that this greater illness burden would extend to the offspring of the US patients.968 outpatients (average age 41) with bipolar illness gave informed consent for participation in a treatment outcome network and filled out a detailed questionnaire about their illness and family history of illness, including whether their offspring had a diagnosis of depression, bipolar disorder, alcohol or substance abuse, suicide attempt or "other" illness. Of those with children, 356 were from the US and 132 were from Europe.Compared to the Europeans, offspring of patients from the US had significantly (p<0.001) more depression, bipolar disorder, drug abuse, and "other" illnesses. The number of illnesses in the offspring was related to the bipolar parent being from the US, having had childhood adversity, more than 20 prior episodes, and more parental psychiatric illness.While the findings are limited by their basis on self report, the distribution of the percentages in the US offspring are similar to those of Axelson et al. (2015) who used direct interviews. The higher burden of illness in the offspring and their in direct progenitors from the US compared to Europe warrant new attempts at better treatment and prevention.

  View details for DOI 10.1016/j.jad.2015.11.038

  View details for Web of Science ID 000368253400025

• Toward a Valid Animal Model of Bipolar Disorder: How the Research Domain Criteria Help Bridge the Clinical-Basic Science Divide. Biological psychiatry Cosgrove, V. E., Kelsoe, J. R., Suppes, T. 2016; 79 (1): 62-70

  Abstract

  Bipolar disorder is a diagnostically heterogeneous disorder, although mania emerges as a distinct phenotype characterized by elevated mood and increased activity or energy. While bipolar disorder's cyclicity is difficult to represent in animals, models of mania have begun to decode its fundamental underlying neurobiology. When psychostimulants such as amphetamine or cocaine are administered to rodents, a resulting upsurge of motor activity is thought to share face and predictive validity with mania in humans. Studying black Swiss mice, which inherently exhibit proclivity for reward seeking and risk taking, also has yielded some insight. Further, translating the biology of bipolar disorder in humans into animal models has led to greater understanding of roles for candidate biological systems such as the GRIK2 and CLOCK genes, as well as the extracellular signal-related kinase pathway involved in the pathophysiology of the illness. The National Institute of Mental Health Research Domain Criteria initiative seeks to identify building blocks of complex illnesses like bipolar disorder in hopes of uncovering the neurobiology of each, as well as how each fits together to produce syndromes like bipolar disorder or why so many mental illnesses co-occur together. Research Domain Criteria-driven preclinical models of isolated behaviors and domains involved in mania and bipolar disorder will ultimately inform movement toward nosology supported by neurobiology.

  View details for DOI 10.1016/j.biopsych.2015.09.002

  View details for PubMedID 26531027

• Evaluating discussion board engagement in the MoodSwings online self-help program for bipolar disorder: protocol for an observational prospective cohort study BMC PSYCHIATRY Gliddon, E., Lauder, S., Berk, L., Cosgrove, V., Grimm, D., Dodd, S., Suppes, T., Berk, M. 2015; 15

  Abstract

  Online, self-guided programs exist for a wide range of mental health conditions, including bipolar disorder, and discussion boards are often part of these interventions. The impact engagement with these discussion boards has on the psychosocial well-being of users is largely unknown. More specifically we need to clarify the influence of the type and level of engagement on outcomes. The primary aim of this exploratory study is to determine if there is a relationship between different types (active, passive or none) and levels (high, mid and low) of discussion board engagement and improvement in outcome measures from baseline to follow up, with a focus on self-reported social support, stigma, quality of life and levels of depression and mania. The secondary aim of this study is to identify any differences in demographic variables among discussion users.The present study is a sub-study of the MoodSwings 2.0 3-arm randomised controlled trial (discussion board only (arm 1), discussion board plus psychoeducation (arm 2), discussion board, psychoeducation plus cognitive behavioural therapy-based tools (arm 3)). Discussion engagement will be measured via online participant activity monitoring. Assessments include online self-report as well as blinded phone interviews at baseline, 3, 6, 9 and 12 months follow up.The results of this study will help to inform future programs about whether or not discussion boards are a beneficial inclusion in online self-help interventions. It will also help to determine if motivating users to actively engage in online discussion is necessary, and if so, what level of engagement is optimal to produce the most benefit. Future programs may benefit through being able to identify those most likely to poorly engage, based on demographic variables, so motivational strategies can be targeted accordingly.ClinicalTrials.gov NCT02118623 registered April 15 2014 and NCT02106078 registered May 16 2013.

  View details for DOI 10.1186/s12888-015-0630-7

  View details for Web of Science ID 000363120700001

  View details for PubMedID 26462799

  View details for PubMedCentralID PMC4604761

• Increases in multiple psychiatric disorders in parents and grandparents of patients with bipolar disorder from the USA compared with The Netherlands and Germany PSYCHIATRIC GENETICS Post, R. M., Leverich, G. S., Kupka, R., Keck, P. E., McElroy, S. L., Altshuler, L. L., Frye, M. A., Rowe, M., Grunze, H., Suppes, T., Nolen, W. A. 2015; 25 (5): 194-200

  Abstract

  We previously found that compared with Europe more parents of the USA patients were positive for a mood disorder, and that this was associated with early onset bipolar disorder. Here we examine family history of psychiatric illness in more detail across several generations.A total of 968 outpatients (average age 41) with bipolar disorder from four sites in the USA and three in the Netherlands and Germany (abbreviated as Europe) gave informed consent and provided detailed demographic and family history information on a patient questionnaire. Family history of psychiatric illness (bipolar disorder, unipolar depression, suicide attempt, alcohol abuse, substance abuse, and other illness) was collected for each parent, four grandparents, siblings, and children.Parents of the probands with bipolar disorder from the USA compared with Europe had a significantly higher incidence of both unipolar and bipolar mood disorders, as well as each of the other psychiatric conditions listed above. With a few exceptions, this burden of psychiatric disorders was also significantly greater in the grandparents, siblings, and children of the USA versus European patients.The increased complexity of psychiatric illness and its occurrence over several generations in the families of patients with bipolar disorder from the USA versus Europe could be contributing to the higher incidence of childhood onsets and greater virulence of illness in the USA compared with Europe. These data are convergent with others suggesting increased both genetic and environmental risk in the USA, but require replication in epidemiologically-derived populations with data based on interviews of the family members.

  View details for DOI 10.1097/YPG.0000000000000093

  View details for Web of Science ID 000360658100002

• Increases in multiple psychiatric disorders in parents and grandparents of patients with bipolar disorder from the USA compared with The Netherlands and Germany. Psychiatric genetics Post, R. M., Leverich, G. S., Kupka, R., Keck, P. E., McElroy, S. L., Altshuler, L. L., Frye, M. A., Rowe, M., Grunze, H., Suppes, T., Nolen, W. A. 2015; 25 (5): 194-200

  Abstract

  We previously found that compared with Europe more parents of the USA patients were positive for a mood disorder, and that this was associated with early onset bipolar disorder. Here we examine family history of psychiatric illness in more detail across several generations.A total of 968 outpatients (average age 41) with bipolar disorder from four sites in the USA and three in the Netherlands and Germany (abbreviated as Europe) gave informed consent and provided detailed demographic and family history information on a patient questionnaire. Family history of psychiatric illness (bipolar disorder, unipolar depression, suicide attempt, alcohol abuse, substance abuse, and other illness) was collected for each parent, four grandparents, siblings, and children.Parents of the probands with bipolar disorder from the USA compared with Europe had a significantly higher incidence of both unipolar and bipolar mood disorders, as well as each of the other psychiatric conditions listed above. With a few exceptions, this burden of psychiatric disorders was also significantly greater in the grandparents, siblings, and children of the USA versus European patients.The increased complexity of psychiatric illness and its occurrence over several generations in the families of patients with bipolar disorder from the USA versus Europe could be contributing to the higher incidence of childhood onsets and greater virulence of illness in the USA compared with Europe. These data are convergent with others suggesting increased both genetic and environmental risk in the USA, but require replication in epidemiologically-derived populations with data based on interviews of the family members.

  View details for DOI 10.1097/YPG.0000000000000093

  View details for PubMedID 26146875

• Verbal abuse, like physical and sexual abuse, in childhood is associated with an earlier onset and more difficult course of bipolar disorder BIPOLAR DISORDERS Post, R. M., Altshuler, L. L., Kupka, R., McElroy, S. L., Frye, M. A., Rowe, M., Leverich, G. S., Grunze, H., Suppes, T., Keck, P. E., Nolen, W. A. 2015; 17 (3): 323-330

  Abstract

  Physical or sexual abuse in childhood is known to have an adverse effect on the course of bipolar disorder, but the impact of verbal abuse has not been well elucidated.We examined the occurrence and frequency (never to frequently) of each type of abuse in childhood in 634 US adult outpatients (average age 40 years). Patients gave informed consent and provided information about their age of onset and course of illness prior to study entry.Verbal abuse alone occurred in 24% of the patients. Similar to a history of physical or sexual abuse, a history of verbal abuse was related to an earlier age of onset of bipolar disorder and other poor prognosis characteristics, including anxiety and substance abuse comorbidity, rapid cycling, and a deteriorating illness course as reflected in ratings of increasing frequency or severity of mania and depression.A lasting adverse impact of the experience of verbal abuse in childhood is suggested by its relationship to an earlier age of onset of bipolar disorder, other poor prognosis factors, and a deteriorating course of illness. Verbal abuse is a common confound in comparison groups defined by a lack of physical or sexual abuse. Ameliorating the impact of verbal abuse on the unfolding course of bipolar disorder appears to be an important target of therapeutics and worthy of attempts at primary and secondary prophylaxis. Family-based treatments that focus on psychoeducation, enhancing intra-family communication, and coping skills may be particularly helpful.

  View details for DOI 10.1111/bdi.12268

  View details for Web of Science ID 000353402800009

  View details for PubMedID 25307301

• Relationship of clinical course of illness variables to medical comorbidities in 900 adult outpatients with bipolar disorder. Comprehensive psychiatry Post, R. M., Altshuler, L., Leverich, G. S., Frye, M. A., Suppes, T., McElroy, S. L., Keck, P. E., Nolen, W. A., Kupka, R. W., Grunze, H., Rowe, M. 2015; 56: 21-28

  Abstract

  Medical illnesses are highly comorbid with bipolar disorder, but their relationship to illness characteristics has not been previously delineated.The incidence of 34 medical conditions and 6 poor prognosis factors (PPFs) was derived from answers to a questionnaire in over 900 outpatients with bipolar disorder who gave informed consent. The relationship of PPFs to the number of medical comorbidities was examined by Mann-Whitney U, Pearson r, and logistic regression.When examined individually, each of the 6 PPFs associated with an adverse course of bipolar disorder was significantly related to the number of medical comorbidities patients had. When age, gender, and independence of their relationships to each other were controlled for via regression, 3 of the PPFs remained significant (anxiety disorder, childhood abuse, and age of onset), and having 20 or more prior episodes was a strong trend. The number of PPFs was correlated with the number of comorbidities, although the above 3 PPFs show a similar magnitude of relationship.A history of childhood adversity, early age of onset of bipolar disorder, and an anxiety comorbidity were independently related to the number of medical comorbidities that patients experienced as adults. While the nature and mechanisms of this linkage remain to be further explored, the findings indicate the need for greater attention to and treatment of these 3 PPFs in hopes of ameliorating both the adverse course of bipolar illness and the burden of medical comorbidities with which they are associated.

  View details for DOI 10.1016/j.comppsych.2014.08.050

  View details for PubMedID 25284280

• Evaluating discussion board engagement in the MoodSwings online self-help program for bipolar disorder: protocol for an observational prospective cohort study. BMC psychiatry Gliddon, E., Lauder, S., Berk, L., Cosgrove, V., Grimm, D., Dodd, S., Suppes, T., Berk, M. 2015; 15: 243-?

  Abstract

  Online, self-guided programs exist for a wide range of mental health conditions, including bipolar disorder, and discussion boards are often part of these interventions. The impact engagement with these discussion boards has on the psychosocial well-being of users is largely unknown. More specifically we need to clarify the influence of the type and level of engagement on outcomes. The primary aim of this exploratory study is to determine if there is a relationship between different types (active, passive or none) and levels (high, mid and low) of discussion board engagement and improvement in outcome measures from baseline to follow up, with a focus on self-reported social support, stigma, quality of life and levels of depression and mania. The secondary aim of this study is to identify any differences in demographic variables among discussion users.The present study is a sub-study of the MoodSwings 2.0 3-arm randomised controlled trial (discussion board only (arm 1), discussion board plus psychoeducation (arm 2), discussion board, psychoeducation plus cognitive behavioural therapy-based tools (arm 3)). Discussion engagement will be measured via online participant activity monitoring. Assessments include online self-report as well as blinded phone interviews at baseline, 3, 6, 9 and 12 months follow up.The results of this study will help to inform future programs about whether or not discussion boards are a beneficial inclusion in online self-help interventions. It will also help to determine if motivating users to actively engage in online discussion is necessary, and if so, what level of engagement is optimal to produce the most benefit. Future programs may benefit through being able to identify those most likely to poorly engage, based on demographic variables, so motivational strategies can be targeted accordingly.ClinicalTrials.gov NCT02118623 registered April 15 2014 and NCT02106078 registered May 16 2013.

  View details for DOI 10.1186/s12888-015-0630-7

  View details for PubMedID 26462799

  View details for PubMedCentralID PMC4604761

• Patterns of response to aripiprazole, lithium, haloperidol, and placebo across factor scores of mania. International journal of bipolar disorders Ostacher, M. J., Suppes, T., Swann, A. C., Eudicone, J. M., Landsberg, W., Baker, R. A., Carlson, B. X. 2015; 3: 11-?

  Abstract

  A previous factor analysis of Young Mania Rating Scale and Montgomery-Åsberg Depression Rating Scale items identified composite factors of depression, mania, sleep disturbance, judgment/impulsivity, and irritability/hostility as major components of psychiatric symptoms in acute mania or mixed episodes in a series of trials of antipsychotics. However, it is unknown whether these factors predict treatment outcome.Data from six double-blind, randomized, controlled clinical trials with aripiprazole in acute manic or mixed episodes in adults with bipolar I disorder were pooled for this analysis and the previously identified factors were examined for their value in predicting treatment outcome. Treatment efficacy was assessed for aripiprazole (n = 1,001), haloperidol (n = 324), lithium (n = 155), and placebo (n = 694) at baseline, days 4, 7, and 10, and then weekly to study end. Mean change in factor scores from baseline to week 3 was assessed by receiver operating characteristics curves for percentage factor change at day 4 and week 1.Subjects receiving aripiprazole, haloperidol, and lithium significantly improved mania factor scores versus placebo. Factors most predictive of endpoint efficacy for aripiprazole were judgment/impulsivity at day 4 and mania at week 1. Optimal factor score improvement for outcome prediction was approximately 40% to 50%. Early efficacy predicted treatment outcome across all factors; however, response at week 1 was a better predictor than response at day 4.This analysis confirms clinical benefits in early treatment/assessment for subjects with bipolar mania and suggests that certain symptom factors in mixed or manic episodes may be most predictive of treatment response.

  View details for DOI 10.1186/s40345-015-0026-0

  View details for PubMedID 25945321

• Effectiveness of the extended release formulation of quetiapine as monotherapy for the treatment of acute bipolar depression. Journal of affective disorders Suppes, T., Datto, C., Minkwitz, M., Nordenhem, A., Walker, C., Darko, D. 2014; 168: 485-493

  Abstract

  Background: To evaluate the effectiveness of quetiapine extended release once daily in bipolar depression. Methods: Double-blind, placebo-controlled study in acutely depressed adults with bipolar I or II disorder, with or without rapid cycling.Patients were randomized to 8 weeks of quetiapine extended release(XR) 300 mg daily monotherapy or placebo.The primary out come measure was changed from baseline to Week 8 in MADRS total score. Results: Quetiapine XR 300 mg once daily(N=133)showed significantly greater improvement in depressive symptoms compared with placebo (N=137) from Week 1(p<0.001)through to Week 8 (p<0.001).Mean change in MADRS total score at Week 8 was 17.4 in the quetiapine XR group and -11.9 in the placebo group(p<0.001). Response (≥ 50% reduction in MADRS total score)and remission (MADRS total score ≤12)rates at Week 8 were significantly higher with quetiapine XR compared with placebo (p<0.001 and p<0.05, respectively).Quetiapine XR improved core symptoms of depression. The most common adverse events associated with quetiapine XR were dry mouth, somnolence,and sedation. Greater weight gain was observed inpatients on quetiapine XR relative to placebo. Limitations: Fewer patients with bipolar II disorder included, only one fixed dose tested and the lack of an active comparator. Conclusions: Quetiapine XR(300 mg)once daily monotherapy was significantly more effective than placebo for treating episodes of depression in bipolar I disorder, throughout the 8-week study,with significance observed as early as Day 7.Adverse events were consistent with the known effects of quetiapine.

  View details for PubMedID 25538990

• Increased parental history of bipolar disorder in the United States: association with early age of onset. Acta psychiatrica Scandinavica Post, R. M., Leverich, G. S., Kupka, R., Keck, P., McElroy, S., Altshuler, L., Frye, M. A., Luckenbaugh, D. A., Rowe, M., Grunze, H., Suppes, T., Nolen, W. A. 2014; 129 (5): 375-382

  Abstract

  Early-onset bipolar (BP) disorder and other poor prognosis characteristics are more prevalent in patients from the United States than from the Netherlands and Germany (abbreviated as Europe). We explored the impact of parental loading for affective illness on onset and other characteristics of BP disorder.Parental history for unipolar (UP) and bipolar (BP) depression and course of illness characteristics were obtained from self-report in adults (average age 42) with BP disorder. Illness characteristics were examined by χ(2) and multinomial logistic regression in relationship to the degree of parental loading: i) both parents negative; ii) one UP disorder; iii) one with BP disorder; and iv) both affected.After controlling for many poor prognosis factors, compared with those from Europe, patients from the United States had more iii) one parent with BP disorder and iv) both parents affected. An early age of onset of BP disorder was independently associated with this increased parental loading for affective disorder.Parental history of BP disorder and both parents with a mood disorder were more common in the United States than Europe and were associated with an early onset of bipolar disorder and other poor prognosis characteristics. These findings deserve replication and exploration of the potential mechanisms involved and their therapeutic implications.

  View details for DOI 10.1111/acps.12208

  View details for PubMedID 24138298

• More pernicious course of bipolar disorder in the United States than in many European countries: Implications for policy and treatment. Journal of affective disorders Post, R. M., Altshuler, L., Kupka, R., McElroy, S., Frye, M. A., Rowe, M., Leverich, G. S., Grunze, H., Suppes, T., Keck, P. E., Nolen, W. A. 2014; 160: 27-33

  Abstract

  There is some controversy but growing evidence that childhood onset bipolar disorder may be more prevalent and run a more difficult course in the United States than some European countries.We update and synthesize course of illness data from more than 960 outpatients with bipolar disorder (average age 40) from 4 sites in the U.S. and 3 sites in Netherlands and Germany. After giving informed consent, patients reported on parental history, childhood and lifetime stressors, comorbidities, and illness characteristics.Almost all aspects of bipolar disorder were more adverse in patients from the US compared with Europe, including a significantly higher prevalence of: bipolar disorder in one parent and a mood disorder in both parents; childhood verbal, physical, or sexual abuse; stressors in the year prior to illness onset and the last episode; childhood onsets of bipolar illness; delay to first treatment; anxiety disorder, substance abuse, and medical comorbidity; mood episodes and rapid cycling; and nonresponse to prospective naturalistic treatment.Selection bias in the recruit of patients cannot be ruled out, but convergent data in the literature suggest that this does not account for the findings. Potential mechanisms for the early onset and more adverse course in the U.S. have not been adequately delineated and require further investigation.The data suggest the need for earlier and more effective long-term treatment intervention in an attempt to ameliorate this adverse course and its associated heavy burden of psychiatric and medical morbidity.

  View details for DOI 10.1016/j.jad.2014.02.006

  View details for PubMedID 24709019

• The relationship between affective state and the rhythmicity of activity in bipolar disorder. journal of clinical psychiatry Gonzalez, R., Tamminga, C. A., Tohen, M., Suppes, T. 2014; 75 (4): e317-22

  Abstract

  The aim of this study was to test the relationships between mood state and rhythm disturbances as measured via actigraphy in bipolar disorder by assessing the correlations between manic and depressive symptoms as measured via Young Mania Rating Scale (YMRS) and 30-item Inventory for Depressive Symptomatology, Clinician-Rated (IDS-C-30) scores and the actigraphic measurements of rhythm, the 24-hour autocorrelation coefficient and circadian quotient.The research was conducted at the University of Texas Southwestern Medical Center at Dallas from February 2, 2009, to March 30, 2010. 42 patients with a DSM-IV-TR diagnosis of bipolar I disorder were included in the study. YMRS and the IDS-C-30 were used to determine symptom severity. Subjects wore the actigraph continuously for 7 days. The 24-hour autocorrelation coefficient was used as an indicator of overall rhythmicity. The circadian quotient was used to characterize the strength of a circadian rhythm.A greater severity of manic symptoms correlated with a lower degree of rhythmicity and less robust rhythms of locomotor activity as indicated by lower 24-hour autocorrelation (r = -0.3406, P = .03) and circadian quotient (r = -0.5485, P = .0002) variables, respectively. No relationship was noted between the degree of depression and 24-hour autocorrelation scores (r = -0.1190, P = .45) or circadian quotient (r = 0.0083, P = .96). Correlation was noted between the 24-hour autocorrelation and circadian quotient scores (r = 0.6347, P < .0001).These results support the notion that circadian rhythm disturbances are associated with bipolar disorder and that these disturbances may be associated with clinical signatures of the disorder. Further assessment of rhythm disturbances in bipolar disorder is warranted.

  View details for DOI 10.4088/JCP.13m08506

  View details for PubMedID 24500063

  View details for PubMedCentralID PMC4038338

• More medical comorbidities in patients with bipolar disorder from the United States than from the Netherlands and Germany. journal of nervous and mental disease Post, R. M., Altshuler, L. L., Leverich, G. S., Frye, M. A., Suppes, T., McElroy, S. L., Keck, P. E., Nolen, W. A., Kupka, R. W., Grunze, H., Rowe, M. 2014; 202 (4): 265-270

  Abstract

  Medical comorbidities are common in patients with bipolar (BP) disorder but have not been previously examined for differences between United States and Europe. More than 900 outpatients with BP I and BP II disorder (mean age, 41 years) filled out a questionnaire including the occurrence of 30 listed medical conditions. The patients from the United States were from Los Angeles, Dallas, Cincinnati, and Bethesda, whereas those from Europe were from Utrecht, Freiberg, and Munich. Those from the United States had a significantly higher incidence of obesity and nine other medical comorbidities than those from Europe, who had only more cases of hyperthyroidism. The burden of medical comorbidities in patients with BP disorder from the United States seems higher than in patients from Europe. Given the adversities, morbidity, and early mortality associated with these conditions and their interaction with the morbidity and lethality of BP disorder itself, greater efforts at treatment and prevention of these medical comorbidities would seem indicated.

  View details for DOI 10.1097/NMD.0000000000000116

  View details for PubMedID 24647213

• Letter to the editor in response to 2012 article by Frances and Jones. Bipolar disorders Suppes, T., Frank, E., DePaulo, J. R., Davis, L., Zarate, C. A., Angst, J., Fawcett, J. 2014; 16 (2): 214-215

  View details for DOI 10.1111/bdi.12176

  View details for PubMedID 24597757

• A randomized, double-blind, placebo-controlled study of ziprasidone monotherapy in bipolar disorder with co-occurring lifetime panic or generalized anxiety disorder. journal of clinical psychiatry Suppes, T., McElroy, S. L., Sheehan, D. V., Hidalgo, R. B., Cosgrove, V. E., Gwizdowski, I. S., Feldman, N. S. 2014; 75 (1): 77-84

  Abstract

  Bipolar disorder often co-occurs with anxiety disorders. Evidence suggests that second-generation antipsychotics (SGAs) may be useful in treating both conditions. This study examined the efficacy of ziprasidone in the treatment of these disorders.This 3-site, randomized, double-blind, placebo-controlled, parallel group, 8-week trial of ziprasidone monotherapy examined 49 subjects with bipolar disorder and lifetime panic disorder (with or without agoraphobia) or generalized anxiety disorder (GAD) experiencing moderately severe anxiety symptoms at entrance into the study. Both bipolar disorder and anxiety diagnoses were based on DSM-IV-TR criteria. Patients were screened and randomized from June 25, 2010, through August 23, 2011. Primary outcome measures were the Clinical Global Impressions-21 Anxiety Scale (CGI-21 Anxiety) and the Sheehan Disability Scale (SDS), with secondary measures monitoring anxiety and mood symptoms.Last-observation-carried-forward analyses demonstrated that patients in the ziprasidone group did not improve significantly more than those in the placebo group on the CGI-21 Anxiety (F1 = 0.34; P = .564) or SDS (F1 = 0.26; P = .611). Secondary analysis using hierarchical linear modeling found similar results (CGI-21 Anxiety: F1 = 1.82; P = .178; and SDS: F1 = 0.70; P = .408). Regardless of group, time in the study was associated with significant decrease in anxiety (F1 = 11.08; P = .001) and total disability (F1 = 26.16; P < .001). Patients in the ziprasidone group showed a greater increase in abnormal involuntary movement, and 81.8% (n = 9) of the subjects who withdrew from the study due to adverse events, serious adverse events, or side effects were in the ziprasidone group.Results suggest that ziprasidone monotherapy was not associated with a clinically significant improvement in anxiety symptoms or improved function for patients with bipolar disorder, lifetime panic disorder or GAD, and concurrent moderately severe anxiety symptoms, and it was associated with a more negative side-effect profile relative to placebo.ClinicalTrials.gov identifier: NCT01172652.

  View details for DOI 10.4088/JCP.12m08297

  View details for PubMedID 24345758

• Illness progression as a function of independent and accumulating poor prognosis factors in outpatients with bipolar disorder in the United States. The primary care companion for CNS disorders Post, R. M., Altshuler, L. L., Leverich, G. S., Nolen, W. A., Kupka, R., Grunze, H., Frye, M. A., Suppes, T., McElroy, S. L., Keck, P. E., Rowe, M. 2014; 16 (6)

  Abstract

  Many patients with bipolar disorder in the United States experience a deteriorating course of illness despite naturalistic treatment in the community. We examined a variety of factors associated with this pattern of illness progression.From 1995 to 2002, we studied 634 adult outpatients with bipolar disorder (mean age of 40 years) emanating from 4 sites in the United States. Patients gave informed consent and completed a detailed questionnaire about demographic, vulnerability, and course-of-illness factors and indicated whether their illness had shown a pattern of increasing frequency or severity of manic or depressive episodes. Fifteen factors previously linked in the literature to a poor outcome were examined for their relationship to illness progression using Kruskal-Wallis test, followed by a 2-sample Wilcoxon rank sum (Mann-Whitney) test, χ(2), and logistical regression.All of the putative poor prognosis factors occurred with a high incidence, and, with the exception of obesity, were significantly (P < .05) associated with illness progression. These factors included indicators of genetic and psychosocial risk and loss of social support, early onset, long delay to first treatment, anxiety and substance abuse comorbidity, rapid cycling in any year, and the occurrence of more than 20 prior episodes prior to entering the network. A greater number of factors were linearly associated with the likelihood of a progressively worsening course.Multiple genetic, psychosocial, and illness factors were associated with a deteriorating course of bipolar disorder from onset to study entry in adulthood. The identification of these factors provides important targets for earlier and more effective therapeutic intervention in the hope of achieving a more benign course of bipolar disorder.

  View details for DOI 10.4088/PCC.14m01677

  View details for PubMedID 25834764

• More stressors prior to and during the course of bipolar illness in patients from the United States compared with the Netherlands and Germany. Psychiatry research Post, R. M., Altshuler, L., Leverich, G., Nolen, W., Kupka, R., Grunze, H., Frye, M., Suppes, T., McElroy, S., Keck, P., Rowe, M. 2013; 210 (3): 880-886

  Abstract

  Considerable data suggest that compared to some European countries, in the U.S. there are more childhood onset bipolar disorders, more adverse courses of illness, and greater treatment resistance. Psychosocial variables related to these findings have not been adequately explored. Therefore we analyzed psychosocial stressors in three time domains: childhood; the year prior to illness Onset; and the Last Episode from questionnaires in 968 outpatients (mean age 41) with bipolar I or II disorder; 676 from four sites in the U.S. and 292 from three in the Netherlands and Germany (abbreviated here as Europe). Compared to the Europeans, those from the U.S. had significantly more stressors in childhood and prior to the last episode. Stressors prior to the last episode were related to: childhood stressors; an earlier age at illness onset; anxiety and substance abuse comorbidity; lower income; both parents having an affective illness; and feeling more stigma. These data suggest a greater prevalence of adverse life events in childhood and over the course of bipolar illness in the U.S. compared to the Netherlands and Germany. Clinical, therapeutic, and public health approaches to these illness-relevant stressors require further exploration.

  View details for DOI 10.1016/j.psychres.2013.08.007

  View details for PubMedID 24021999

• MAINTENANCE TREATMENT WITH QUETIAPINE WHEN COMBINED WITH EITHER LITHIUM OR DIVALPROEX IN BIPOLAR I DISORDER: ANALYSIS OF TWO LARGE RANDOMIZED, PLACEBO-CONTROLLED TRIALS DEPRESSION AND ANXIETY Suppes, T., Vieta, E., Gustafsson, U., Ekholm, B. 2013; 30 (11): 1089-1098

  Abstract

  BACKGROUND: To determine the efficacy and safety of quetiapine combined with lithium or divalproex for preventing mood events in patients with bipolar I disorder. In this pooled analysis of two similar long-term studies (D1447C00126 [NCT00107731] and D1447C00127 [NCT00081380]), lithium and divalproex treatment groups were analyzed separately. METHODS: Patients received open-label quetiapine (400-800 mg/d) plus lithium or divalproex to achieve ≥12 weeks of clinical stability before being randomized to double-blind combination treatment with quetiapine (400-800 mg/d) or placebo plus lithium or divalproex for up to 104 weeks. The primary endpoint was time to first mood event postrandomization following open stabilization. RESULTS: Of 3,414 patients in the stabilization phase, 1,326 were randomized. There were no differences in the risk of recurrence of mood, mania, or depression between quetiapine plus lithium or quetiapine plus divalproex. Among patients co-treated with placebo and lithium, the risk of recurrence of a mania event was significantly higher than among patients co-treated with placebo and divalproex. In patients with an index episode of mania, placebo plus lithium was associated with a significantly higher risk of recurrence of a mania event than placebo plus divalproex. Safety data were generally consistent with recognized safety profiles. CONCLUSIONS: In patients with bipolar I disorder previously stabilized on quetiapine and lithium or divalproex, maintenance therapy with quetiapine significantly increased the time to recurrence of a mood event (mania or depression) versus placebo, regardless of whether it was combined with lithium or divalproex.

  View details for DOI 10.1002/da.22136

  View details for PubMedID 23761037

• Presentation and prevalence of PTSD in a bipolar disorder population: A STEP-BD examination JOURNAL OF AFFECTIVE DISORDERS Hernandez, J. M., Cordova, M. J., Ruzek, J., Reiser, R., Gwizdowski, I. S., Suppes, T., Ostacher, M. J. 2013; 150 (2): 450-455

  Abstract

  BACKGROUND: Co-occurring psychiatric diagnoses have a negative impact on quality of life and change the presentation and prognosis of bipolar disorder (BD). To date, comorbidity research on patients with BD has primarily focused on co-occurring anxiety disorders and trauma history; only recently has there been a specific focus on co-occurring PTSD and BD. Although rates of trauma and PTSD are higher in those with bipolar disorder than in the general population, little is known about differences across bipolar subtypes. METHODS: Using the NIMH STEP-BD dataset (N=3158), this study evaluated whether there were baseline differences in the prevalence of PTSD between participants with bipolar disorder I (BDI) and bipolar disorder II (BDII), using the MINI and the Davidson Trauma Scale. Differences in PTSD symptom clusters between patients with BDI and BDII were also evaluated. RESULTS: A significantly greater proportion of participants with BDI had co-occurring PTSD at time of study entry (Χ(2)(1)=12.6; p<.001). BDI and BDII subgroups did not significantly differ in re-experiencing, avoidance, or arousal symptoms. LIMITATIONS: The analysis may suggest a correlational relationship between PTSD and BD, not a causal one. Further, it is possible this population seeks treatment more often than individuals with PTSD alone. Finally, due to the episodic nature of BD and symptom overlap between the two disorders, misdiagnosis is possible. CONCLUSIONS: PTSD may be more prevalent in patients with BDI. However, the symptom presentation of PTSD appears similar across BD subtypes. Individuals should be thoroughly assessed for co-occurring diagnoses in an effort to provide appropriate treatment.

  View details for DOI 10.1016/j.jad.2013.04.038

  View details for Web of Science ID 000323563300039

  View details for PubMedID 23706842

• First controlled treatment trial of bipolar II hypomania with mixed symptoms: Quetiapine versus placebo. Journal of affective disorders Suppes, T., Ketter, T. A., Gwizdowski, I. S., Dennehy, E. B., Hill, S. J., Fischer, E. G., Snow, D. E., Gonzalez, R., Sureddi, S., Shivakumar, G., Cosgrove, V. E. 2013; 150 (1): 37-43

  Abstract

  OBJECTIVES: To compare the efficacy and safety of adjunctive quetiapine (QTP) versus placebo (PBO) for patients with bipolar II disorder (BDII) currently experiencing mixed hypomanic symptoms in a 2-site, randomized, placebo-controlled, double-blind, 8-week investigation. METHODS: Participants included 55 adults (age 18-65 years) who met criteria for BDII on the Structured Clinical Interview for DSM-IV-TR (SCID). Entrance criteria included a stable medication regimen for ≥2 weeks and hypomania with mixed symptoms (>12 on the Young Mania Rating Scale [YMRS] and >15 on the Montgomery Asberg Depression Rating Scale [MADRS] at two consecutive visits 1-3 days apart). Participants were randomly assigned to receive adjunctive quetiapine (n=30) or placebo (n=25). RESULTS: Adjunctive quetiapine demonstrated significantly greater improvement than placebo in Clinical Global Impression for Bipolar Disorder Overall Severity scores (F(1)=10.12, p=.002) and MADRS scores (F(1)=6.93, p=.0138), but no significant differences were observed for YMRS scores (F(1)=3.68, p=.069). Side effects of quetiapine were consistent with those observed in previous clinical trials, with sedation/somnolence being the most common, occurring in 53.3% with QTP and 20.0% with PBO. CONCLUSIONS: While QTP was significantly more effective than PBO for overall and depressive symptoms of BDII, there was no significant difference between groups in reducing symptoms of hypomania. Hypomania improved across both groups throughout the study.

  View details for DOI 10.1016/j.jad.2013.02.031

  View details for PubMedID 23521871

• Comparison of objective and subjective assessments of sleep time in subjects with bipolar disorder JOURNAL OF AFFECTIVE DISORDERS Gonzalez, R., Tamminga, C., Tohen, M., Suppes, T. 2013; 149 (1-3): 363-366

  Abstract

  Sleep disturbance is a core feature of bipolar disorder. To date there are a limited number of studies that compare subjective and objective measures of sleep in populations of subjects with mood disorders. This study evaluated the relationship between subjective and objective measurements of total sleep time (TST) in a bipolar type I disorder (BD I) population.Thirty-nine subjects diagnosed with BD I participated in the study. Mood symptoms were assessed via YMRS and IDS-30-C. Subjects wore an actigraph device and maintained a sleep diary for seven consecutive days. Differences between TST as estimated via sleep diaries and actigraphy were calculated.Objective and subjective measures of TST were significantly correlated (r=0.5151, p=0.0008). Secondary analysis revealed that the severity of depressive symptoms did correlate to this discrepancy (t=2.65, p=0.01).The impact that medications have on the accuracy of TST reported was not investigated. Also, sleep diaries may have acted to prompt subjects to pay closer attention to their sleep habits and therefore more accurately report TST than in the average clinical setting.The results of the current study demonstrate a significant correlation between the estimation of TST as measured objectively via actigraphy and subjectively via sleep diaries in BD patients. Mood symptomotology might impact the accuracy of TST reported. Further study is warranted.

  View details for DOI 10.1016/j.jad.2013.02.013

  View details for Web of Science ID 000320593000048

  View details for PubMedID 23489400

• An online intervention for bipolar disorder Moodswings 2.0: www.moodswings.net.au 10th International Conference on Bipolar Disorder of the International-Society-for-Bipolar-Disorders Cosgrove, V., Fischer, E., Lauder, S., Gwizdowski, I., Feldman, N., Berk, M., Gliddon, E., Suppes, T. WILEY-BLACKWELL. 2013: 97–97

  View details for Web of Science ID 000319826800221

• A randomized, double-blind, placebo-controlled study of ziprasidone in bipolar disorder with co-occurring lifetime panic or generalized anxiety disorder 10th International Conference on Bipolar Disorder of the International-Society-for-Bipolar-Disorders Suppes, T., McElroy, S., Cosgrove, V., Gwizdowski, I., Feldman, N. WILEY-BLACKWELL. 2013: 102–102

  View details for Web of Science ID 000319826800232

• Role of childhood adversity in the development of medical co-morbidities associated with bipolar disorder JOURNAL OF AFFECTIVE DISORDERS Post, R. M., Altshuler, L. L., Leverich, G. S., Frye, M. A., Suppes, T., McElroy, S. L., Keck, P. E., Nolen, W. A., Kupka, R. W., Grunze, H., Rowe, M. 2013; 147 (1-3): 288-294

  Abstract

  A role for childhood adversity in the development of numerous medical conditions in adults has been described in the general population, but has not been examined in patients with bipolar disorder who have multiple medical comorbidities which contribute to their premature mortality.More than 900 outpatients (average age 41) with bipolar disorder completed questionnaires that included information about the occurrence of verbal, physical, or sexual abuse in childhood and whether their parents had a mood or substance abuse disorder, or a history of suicidality. These factors were combined to form a total childhood adversity score, which was then related to one or more of 30 medical conditions patients rated as present or absent.The child adversity score was significantly related to the total number of medical comorbidities a patient had (p<.001), as well as to 11 specific medical conditions that could be modeled in a logistic regression (p<.03). These included: asthma, arthritis, allergies, chronic fatigue syndrome, chronic menstrual irregularities, fibromyalgia, head injury (without loss of consciousness), hypertension, hypotension, irritable bowel syndrome, and migraine headaches.The contribution of parental diagnosis to childhood adversity is highly inferential.These data link childhood adversity to the later occurrence of multiple medical conditions in adult outpatients with bipolar disorder. Recognition of these relationships and early treatment intervention may help avert a more severe course of not only bipolar disorder but also of its prominent medical comorbidities and their combined adverse effects on patients'health, wellbeing, and longevity.

  View details for DOI 10.1016/j.jad.2012.11.020

  View details for Web of Science ID 000316790400041

  View details for PubMedID 23337654

• Characteristics of responders and non-responders to risperidone monotherapy or placebo in co-occurring bipolar disorder and anxiety disorder EUROPEAN PSYCHIATRY Seo, J. S., Jamieson, K., Cosgrove, V., Gwizdowski, I. S., Yang, H., Sheehan, D. V., McElroy, S. L., Suppes, T. 2013; 28 (3): 190-196

  Abstract

  Clinical characteristics predicting response and remission to psychopharmacological treatment of bipolar disorder (BD) and co-occurring anxiety disorders have been understudied. We hypothesized that non-response to risperidone or placebo in individuals with co-occurring BD and anxiety symptoms would be associated with a more severe clinical course of BD, and certain demographic variables. This study was a secondary analysis of a randomized, double-blind, parallel, 8-week study comparing risperidone monotherapy and placebo in individuals with BD plus current panic disorder, current generalized anxiety disorder (GAD), or lifetime panic disorder (n=111) [31]. We compared clinical characteristics of responders (50% improvement on the Hamilton Anxiety Scale [HAM-A]) and non-responders as well as remitters (HAM-A<7) and non-remitters in risperidone treatment (n=54) and placebo (n=57) groups. For non-responders in the risperidone group, co-occurring lifetime panic disorder was significantly more common than for non-responders in the placebo group. Apart from this, no significant differences in course of illness or demographics were found either between or across groups for patients with BD and co-occurring anxiety symptoms receiving risperidone or placebo in this acute phase study.

  View details for DOI 10.1016/j.eurpsy.2011.08.001

  View details for PubMedID 22130178

• Randomized, placebo-controlled trial of quetiapine XR and divalproex ER monotherapies in the treatment of the anxious bipolar patient JOURNAL OF AFFECTIVE DISORDERS Sheehan, D. V., Harnett-Sheehan, K., Hidalgo, R. B., Janavs, J., McElroy, S. L., Amado, D., Suppes, T. 2013; 145 (1): 83-94

  Abstract

  Anxiety disorders complicate the treatment of bipolar disorder but are seldom the focus of bipolar treatment studies.The anxiolytic effect of quetiapine XR 50-300 mg/day compared to divalproex ER (500-3000 mg/day) was tested in an 8-week, double-blind, placebo-controlled, randomized clinical trial in 149 patients with bipolar disorder and a co-occurring panic disorder or GAD. The primary efficacy measure was the Clinician Global Improvement-21 Anxiety Scale (CGI-21). Secondary measures included the Hamilton Anxiety Scale (HAM-A) and Sheehan Panic Disorder Scale (SPS).Repeated measures last-observation-carried-forward (LOCF) analyses of variance demonstrated significant treatment-by-time interaction effects on 3 of the 4 anxiety measures. Quetiapine XR at a mean endpoint dose of 186 mg/day produced rapid sustained improvements relative to baseline, divalproex ER and placebo on anxiety. Mean baseline-to-endpoint improvement was significantly greater for quetiapine XR compared to divalproex ER and placebo on the HAM-A and SPS. Both active medications were well tolerated, but weight gain was higher on quetiapine XR.The study was limited to 8 weeks and to patients with bipolar disorder and comorbid panic disorder or GAD. The results may not be applicable to quetiapine XR as an add-on treatment to mood stabilizers or to bipolar disorder comorbid with other anxiety disorders.Quetiapine XR in a dose range of 50-300 mg/day appears to reduce anxiety in bipolar patients with comorbid panic disorder or GAD treated for 8 weeks. The efficacy of other second-generation antipsychotics and mood stabilizers in patients with bipolar disorder and a co-occurring anxiety disorder should be investigated in double-blind, placebo-controlled studies.

  View details for DOI 10.1016/j.jad.2012.07.016

  View details for Web of Science ID 000314091800012

  View details for PubMedID 22920718

• Multivariate analysis of bipolar mania: Retrospectively assessed structure of bipolar I manic and mixed episodes in randomized clinical trial participants JOURNAL OF AFFECTIVE DISORDERS Swann, A. C., Suppes, T., Ostacher, M. J., Eudicone, J. M., McQuade, R., Forbes, A., Carlson, B. X. 2013; 144 (1-2): 59-64

  Abstract

  Manic episodes are heterogeneous. Mixed states may differ in important clinical characteristics from other manic episodes. However, it has not been established whether mixed states are a distinct type of episodes, or a common basic structure exists across manic episodes.Using 2179 well-characterized subjects in the pretreatment phase of six randomized, clinical trials, we conducted rotated factor analysis followed by cluster analysis, using all items from the Young Mania Rating Scale and the Montgomery-Åsberg Depression Scale. Analyses were conducted for all subjects (n=2179) and for those in Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM-IV) mixed (n=644) and non-mixed (n=1535) episodes separately.There were five factors characterized (in order of variance accounted for) as depression, mania, sleep disturbance, judgment/impulsivity and irritability/hostility. Cluster analysis identified five clusters. Three were predominately manic, with depression scores below average for the overall group. Two had high average depression scores; these clusters differed in irritability/hostility. Judgment/impulsivity scores were similar across factors. Essentially identical factors and clusters existed whether analyses were done in all subjects or only in subjects classified by DSM-IV as mixed or non-mixed.Exclusion criteria of studies may limit generalizability of findings.All manic episodes, whether mixed or non-mixed, shared a similar structure according to factor/cluster analysis. Patients with high depression factor scores were heterogeneous with respect to irritability. These data suggest that depressive symptoms should be considered a dimensional property across manic episodes, rather than as defining a specific type of episode.

  View details for DOI 10.1016/j.jad.2012.05.061

  View details for Web of Science ID 000311640300008

  View details for PubMedID 22858209

• Informing DSM-5: biological boundaries between bipolar I disorder, schizoaffective disorder, and schizophrenia. BMC medicine Cosgrove, V. E., Suppes, T. 2013; 11: 127-?

  Abstract

  The fifth version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) opted to retain existing diagnostic boundaries between bipolar I disorder, schizoaffective disorder, and schizophrenia. The debate preceding this decision focused on understanding the biologic basis of these major mental illnesses. Evidence from genetics, neuroscience, and pharmacotherapeutics informed the DSM-5 development process. The following discussion will emphasize some of the key factors at the forefront of the debate.Family studies suggest a clear genetic link between bipolar I disorder, schizoaffective disorder, and schizophrenia. However, large-scale genome-wide association studies have not been successful in identifying susceptibility genes that make substantial etiological contributions. Boundaries between psychotic disorders are not further clarified by looking at brain morphology. The fact that symptoms of bipolar I disorder, but not schizophrenia, are often responsive to medications such as lithium and other anticonvulsants must be interpreted within a larger framework of biological research.For DSM-5, existing nosological boundaries between bipolar I disorder and schizophrenia were retained and schizoaffective disorder preserved as an independent diagnosis since the biological data are not yet compelling enough to justify a move to a more neurodevelopmentally continuous model of psychosis.

  View details for DOI 10.1186/1741-7015-11-127

  View details for PubMedID 23672587

  View details for PubMedCentralID PMC3653750

• Quetiapine monotherapy in bipolar II depression: combined data from four large, randomized studies. International journal of bipolar disorders Young, A. H., Calabrese, J. R., Gustafsson, U., Berk, M., McElroy, S. L., Thase, M. E., Suppes, T., Earley, W. 2013; 1: 10-?

  Abstract

  Despite being present in up to 1% of the population, few controlled trials have examined the efficacy of treatments for bipolar II depression. Pooled data are presented from four placebo-controlled studies (BOLDER I [5077US/0049] and II [D1447C00135]; EMBOLDEN I [D1447C00001] and II [D1447C00134]) that evaluated the efficacy of quetiapine monotherapy for depressive episodes in patients with bipolar II disorder.All studies included an 8-week, double-blind treatment phase in which patients were randomly assigned to treatment with quetiapine 300 mg/day, quetiapine 600 mg/day, or placebo. Outcome measures included the change from baseline in MADRS total score at week 8, effect sizes, and MADRS response and remission rates.Improvements in mean MADRS total scores from baseline to week 8 were significantly greater with quetiapine 300 and 600 mg/day (-15.58 [n = 283] and -14.88 [n = 289]; p < 0.001) compared with placebo (-11.61 [n = 204]). The MADRS effect sizes were 0.44 for quetiapine 300 mg/day and 0.47 for 600 mg/day (p < 0.001 vs placebo). Significantly higher proportions of patients receiving quetiapine, at both doses, than placebo-treated patients achieved response and remission at week 8 (p < 0.01). Common adverse events associated with quetiapine (both doses) included dry mouth, somnolence, sedation, dizziness, and headache. Rates of mania and hypomania were similar for quetiapine and placebo. Quetiapine monotherapy demonstrated significant efficacy compared with placebo and was generally well tolerated in the treatment of bipolar II depression.

  View details for DOI 10.1186/2194-7511-1-10

  View details for PubMedID 25505677

  View details for PubMedCentralID PMC4230312

• Bipolar Mixed States: An International Society for Bipolar Disorders Task Force Report of Symptom Structure, Course of Illness, and Diagnosis AMERICAN JOURNAL OF PSYCHIATRY Swann, A. C., Lafer, B., Perugi, G., Frye, M. A., Bauer, M., Bahk, W., Scott, J., Ha, K., Suppes, T. 2013; 170 (1): 31-42

  Abstract

  Episodes of bipolar disorder are defined as depressive or manic, but depressive and manic symptoms can combine in the same episode. Coexistence or rapid alternation of depressive and manic symptoms in the same episode may indicate a more severe form of bipolar disorder and may pose diagnostic and treatment challenges. However, definitions of mixed states, especially those with prominent depression, are not well established.The authors performed literature searches for bipolar disorder, multivariate analyses, and the appearance of the terms "mixed" in any field; references selected from the articles found after the search were combined after a series of conferences among the authors.The authors reviewed the evolution of the concept of mixed states and examined the symptom structure of mixed states studied as predominantly manic, predominantly depressive, and across both manic and depressive episodes, showing essentially parallel structures of mixed states based on manic or depressive episodes. The authors analyzed the relationships between mixed states and a severely recurrent course of illness in bipolar disorder, with early onset and increased co-occurring anxiety-, stress-, and substance-related disorders, and they used this information to derive proposed diagnostic criteria for research or clinical use.The definitions and properties of mixed states have generated controversy, but the stability of their characteristics over a range of clinical definitions and diagnostic methods shows that the concept of mixed states is robust. Distinct characteristics related to the course of illness emerge at relatively modest opposite polarity symptom levels in depressive or manic episodes.

  View details for DOI 10.1176/appi.ajp.2012.12030301

  View details for Web of Science ID 000313086200007

  View details for PubMedID 23223893

• Long-term efficacy of quetiapine in combination with lithium or divalproex on mixed symptoms in bipolar I disorder JOURNAL OF AFFECTIVE DISORDERS Vieta, E., Suppes, T., Ekholm, B., Udd, M., Gustafsson, U. 2012; 142 (1-3): 36-44

  Abstract

  To evaluate quetiapine in patients with bipolar I disorder with mixed symptoms. Methods: Data from 2 studies (D1447C00126, D1447C00127) were pooled and mixed events analyzed separately. Patients received quetiapine (400-800mg/day) plus lithium/divalproex to achieve ≥12 weeks of clinical stability, followed by double-blind quetiapine (400-800mg/day) or placebo, plus lithium/divalproex, for up to 104 weeks. Primary endpoint was time to first mood event post-randomization. Results: The ITT population included 1326 patients, of whom 445 had a mixed episode at study entry, 219 received quetiapine plus lithium/divalproex, and 226 received placebo plus lithium/divalproex. Mood events were reported by fewer quetiapine-plus-lithium/divalproex than placebo-plus-lithium/divalproex-treated patients (21.0% vs 54.0%), and included mixed (6.4% vs 22.1%), pure manic (5.0% vs 13.3%), and pure depressed events (9.6% vs 18.6%). Hazard ratios (HR) for time to recurrence were longer for quetiapine plus lithium/divalproex than placebo plus lithium/divalproex for mixed (HR=0.23; 95% CI: 0.13-0.42; p<0.0001), pure manic (HR=0.30; 95% CI: 0.15-0.60; p=0.0007), and pure depressed events (HR=0.38; 95% CI: 0.22-0.64; p=0.0003). No new safety concerns were noted.The post hoc nature of the analyses as patients were not randomized according to index symptom status.In stable patients with bipolar I disorder, quetiapine plus lithium/divalproex significantly increased time to recurrence of mood events versus placebo in patients with mixed symptoms at study entry and time to occurrence of mixed-mood events in patients with any mood episode at study entry.

  View details for DOI 10.1016/j.jad.2012.04.014

  View details for Web of Science ID 000310565900006

  View details for PubMedID 23062763

• Relationship of Prior Antidepressant Exposure to Long-Term Prospective Outcome in Bipolar I Disorder Outpatients JOURNAL OF CLINICAL PSYCHIATRY Post, R. M., Leverich, G. S., Altshuler, L. L., Frye, M. A., Suppes, T., McElroy, S. L., Keck, P. E., Nolen, W. A., Rowe, M., Kupka, R. W., Grunze, H., Goodwin, F. K. 2012; 73 (7): 924-930

  Abstract

  The long-term impact of prior antidepressant exposure on the subsequent course of bipolar illness remains controversial.139 outpatients (mean age, 42 years) with bipolar I disorder diagnosed by DSM-IV criteria had a detailed retrospective examination of their prior course of illness on the National Institute of Mental Health Life Chart Method. Number of prior antidepressant trials and total duration of antidepressant exposure were assessed. Prospective long-term response (for at least 6 months) to naturalistic treatment in the network from 1996 through 2002 was the primary outcome measure as it related to prior antidepressant exposure (and other illness variables) by logistic regression, with P < .05 used for statistical significance in this post hoc analysis.Greater number of antidepressant trials, but not duration of antidepressant exposure, was related to prospective nonresponse (P = .0051) whether or not antidepressants were covered by concurrent treatment with a mood stabilizer or atypical antipsychotic. Poor prospective response was also independently related to having had an anxiety disorder and 20 or more prior affective episodes.That the number of antidepressant trials, but not duration of antidepressant treatment, was associated with prospective nonresponse suggests that it is the repeated use of antidepressants to treat episodes of depression that is related to poor prospective response to naturalistic treatment. The direction of causality is unclear as to whether more antidepressant trials led to this increased treatment resistance or whether a difficult course of illness with more episodes and anxiety comorbidity engendered more attempts at antidepressant treatment.

  View details for DOI 10.4088/JCP.11m07396

  View details for Web of Science ID 000315000200003

  View details for PubMedID 22480597

• Co-occurrence of Serious or Undiagnosed Medical Conditions With Bipolar Disorder Preventing Clinical Trial Randomization: A Case Series JOURNAL OF CLINICAL PSYCHIATRY Feldman, N. S., Gwizdowski, I. S., Fischer, E. G., Yang, H., Suppes, T. 2012; 73 (6): 874-877

  Abstract

  Studies have shown that patients with bipolar disorder have high rates of serious and/or untreated co-occurring general medical conditions. This case series examined reports of co-occurring medical conditions with bipolar disorder in potential clinical study participants, and in particular the percentage of these individuals who were previously unaware of their conditions.Patients were potential participants in 1 of 2 medication trials who met DSM-IV criteria for bipolar disorder and were excluded from those studies just prior to randomization from May 2009 through July 2011. Patients were compared with each other on a number of demographic criteria, including age, race, gender, reason for exclusion from the trial, and psychiatric diagnoses.Of the patients excluded from the studies just prior to randomization, 31% (n = 10) were excluded because of medical conditions previously unreported by the patient during screening for these studies. Seventy percent of those excluded patients (n = 7) had no prior knowledge of their conditions.These results suggest that patients with bipolar disorder may not only have high rates of co-occurring medical conditions but also frequently remain unaware of those conditions. These findings indicate that co-occurring general medical conditions may be a more serious problem in the treatment of bipolar disorder than previously appreciated and that more stringent monitoring and guidelines are needed regardless of medication regimen. This case series asserts that, regardless of a patient's claim of having no medical conditions, more general medical screening may be needed in outpatient psychiatric settings.

  View details for DOI 10.4088/JCP.11m07331

  View details for Web of Science ID 000315000100014

  View details for PubMedID 22480536

• Clinical predictors of response vs. non-response to risperidone: CGI-21 scores after 1 week of treatment in a bipolar disorder population with co-occurring panic disorder or generalized anxiety disorder 5th Biennial Conference of the International-Society-for-Bipolar-Disorders Raudabaugh, B. J., Hernandez, J. M., Seo, J. S., Jamison, K., Cosgrove, V., Gwizdowski, I. S., Yang, H., Sheehan, D. V., McElroy, S. L., Suppes, T. WILEY-BLACKWELL. 2012: 115–116

  View details for Web of Science ID 000301531000282

• Differential clinical characteristics, medication usage, and treatment response of bipolar disorder in the US versus The Netherlands and Germany INTERNATIONAL CLINICAL PSYCHOPHARMACOLOGY Post, R. M., Leverich, G. S., Altshuler, L. L., Frye, M. A., Suppes, T., Keck, P. E., McElroy, S. L., Nolen, W. A., Kupka, R., Grunze, H., Walden, J., Rowe, M. 2011; 26 (2): 96-106

  Abstract

  Increased early-onset bipolar illness was seen in the US compared with the Netherlands and Germany (abbreviated here as Europe), but other clinical characteristics, medication use, and treatment response have not been systematically explored. Outpatients with bipolar disorder were treated naturalistically and followed prospectively at four sites in the US and three in Europe. Data and clinical characteristics were collected from patient questionnaires, and medication usage and good-to-excellent response to treatment for at least 6 months ascertained from daily clinician ratings on the National Institutes of Mental Health-Life Chart Method. Almost all clinical characteristics earlier associated with a poor treatment response were more prevalent in the US than in Europe, including early onset, environmental adversity, rapid cycling, more than 20 prior episodes, comorbid anxiety and substance abuse disorders, and a positive parental history for an affective disorder. Lithium was used more frequently in Europe than in the US and had a higher rate of success, whereas valproate was used more in the US, with a trend toward higher success in Europe. Antidepressants were used more in the US, but had extremely low success rates. Many other agents were deployed differently on the two continents, but success rates were consistently lower in the US than in Europe. In conclusion, clinical characteristics and patterns of medication usage and effectiveness differed markedly in the two continents suggesting the need for uncovering explanations and considering the two populations as heterogeneous in the future pharmacological studies.

  View details for DOI 10.1097/YIC.0b013e3283409419

  View details for Web of Science ID 000286658300006

  View details for PubMedID 21178634

• Prevalence and correlates of eating disorders in 875 patients with bipolar disorder JOURNAL OF AFFECTIVE DISORDERS McElroy, S. L., Frye, M. A., Hellemann, G., Altshuler, L., Leverich, G. S., Suppes, T., Keck, P. E., Nolen, W. A., Kupka, R., Post, R. M. 2011; 128 (3): 191-198

  Abstract

  Relatively little is known about the co-occurrence of bipolar and eating disorders. We therefore assessed the prevalence and clinical correlates of eating disorders in 875 patients with bipolar disorder.875 outpatients with DSM-IV bipolar I or II disorder were evaluated with structured diagnostic interviews and clinician- and self-administered questionnaires to determine bipolar and eating disorder diagnoses, other comorbid Axis I disorder diagnoses, and demographic and historical illness characteristics.125 (14.3%) patients met DSM-IV criteria for at least one comorbid lifetime Axis I eating disorder, with binge eating disorder (N=77) being more common than bulimia nervosa (n=42) and anorexia nervosa (N=27). There were no significant eating disorder comorbidity differences between bipolar I and bipolar II patients. Presence of a lifetime comorbid eating disorder was associated with female gender, younger age, earlier age of onset of mood symptoms and of bipolar disorder, presentation in a mixed episode, greater number of prior mood episodes, history of rapid cycling and suicide attempts, greater mean BMI, obesity and severe obesity, and family history of depression, bipolar disorder, alcoholism, and drug abuse. When the three eating disorder groups were compared, lifetime anorexia nervosa was associated with normal weight and a lifetime anxiety disorder, lifetime bulimia nervosa was associated with overweight, and lifetime binge eating disorder was associated with obesity and severe obesity.Patients with bipolar disorder, especially women, not infrequently have comorbid eating disorders, and this comorbidity is associated with an earlier age of onset and more severe course of bipolar illness.

  View details for DOI 10.1016/j.jad.2010.06.037

  View details for Web of Science ID 000289014000002

  View details for PubMedID 20674033

• Advances in bipolar disorder: selected sessions from the 2011 International Conference on Bipolar Disorder 9th International Conference on Bipolar Disorder (ICBD) Kupfer, D. J., Angst, J., Berk, M., Dickerson, F., Frangou, S., Frank, E., Goldstein, B. I., Harvey, A., Laghrissi-Thode, F., Leboyer, M., Ostacher, M. J., Sibille, E., Strakowski, S. M., Suppes, T., Tohen, M., Yolken, R. H., Young, L. T., Zarate, C. A. BLACKWELL SCIENCE PUBL. 2011: 1–25

  Abstract

  Recently, the 9(th) International Conference on Bipolar Disorder (ICBD) took place in Pittsburgh, PA, June 9-11, 2011. The conference focused on a number of important issues concerning the diagnosis of bipolar disorders across the life span, advances in neuroscience, treatment strategies for bipolar disorders, early intervention, and medical comorbidity. Several of these topics were discussed in four plenary sessions. This meeting report describes the major points of each of these sessions and included (1) strategies for moving biology forward; (2) bipolar disorder and the forthcoming new DSM-5 nomenclature; (3) management of bipolar disorders-both theory and intervention, with an emphasis on the medical comorbidities; and, (4) a review of several key task force reports commissioned by the International Society for Bipolar Disorder (ISBD).

  View details for DOI 10.1111/j.1749-6632.2011.06336.x

  View details for Web of Science ID 000301290100001

  View details for PubMedID 22191553

• Complexity of Pharmacologic Treatment Required for Sustained Improvement in Outpatients With Bipolar Disorder JOURNAL OF CLINICAL PSYCHIATRY Post, R. M., Altshuler, L. L., Frye, M. A., Suppes, T., Keck, P. E., McElroy, S. L., Leverich, G. S., Luckenbaugh, D. A., Rowe, M., Pizzarello, S., Kupka, R. W., Grunze, H., Nolen, W. A. 2010; 71 (9): 1176-1186

  Abstract

  To evaluate the clinical correlates of and types of naturalistic treatments associated with sustained improvement/remission for at least 6 months in outpatients with bipolar disorder.Five hundred twenty-five outpatients with bipolar disorder (77.7% bipolar I) gave informed consent, had their mood rated daily on the National Institute of Mental Health Life Chart Method for a minimum of at least 1 year, and recorded all medications. Demographics and clinical characteristics of patients with a "sustained response" (ratings of "improved" or "very much improved" on the Clinical Global Impressions-Bipolar Version for a period of at least 6 months) versus nonresponders were compared. The study was conducted from 1996 to 2002.Of the 429 patients who were ill at study entry, 195 (45.5%) showed a sustained response; 54.5% showed no or insufficient response. A mean of 2.98 medications was given at time of improvement, which occurred after a mean of 18 months of participation in the study. Lithium and valproate were the medications most frequently prescribed at the time of improvement and had among the highest overall success rates. Equally complex regimens were employed in the nonresponders who, however, had a more adverse clinical course prior to network entry. Nonresponders were ultimately exposed to more antidepressants and antipsychotics than the sustained responders.A mean of 1.5 years and at times highly complex medication regimens were required to achieve a sustained response for 6 months during naturalistic outpatient treatment of bipolar disorder. Delineating the clinical and biologic correlates of individual response to combination treatment is a very high clinical research priority, as is developing new treatment strategies for the large proportion of patients who fail to respond in a sustained fashion.

  View details for DOI 10.4088/JCP.08m04811yel

  View details for Web of Science ID 000282705700010

  View details for PubMedID 20923622

• Early-Onset Bipolar Disorder and Treatment Delay Are Risk Factors for Poor Outcome in Adulthood JOURNAL OF CLINICAL PSYCHIATRY Post, R. M., Leverich, G. S., Kupka, R. W., Keck, P. E., McElroy, S. L., Altshuler, L. L., Frye, M. A., Luckenbaugh, D. A., Rowe, M., Grunze, H., Suppes, T., Nolen, W. A. 2010; 71 (7): 864-872

  Abstract

  We examined the influence of age at onset of illness and the delay in time to first treatment on morbidity in adulthood.529 adult outpatients with a mean age of 42 years, who entered our research network from 1996 through 2001 and who were diagnosed with bipolar disorder according to DSM-IV criteria, were rated prospectively on a daily basis with the National Institute of Mental Health-Life Chart Method during naturalistic treatment for up to 4 years.Fifty percent of patients had illness onset in childhood (<13 years of age) or adolescence (13-18 years of age). In year 1 of follow-up, these patients, compared to those with adult onset, showed significantly (P<.05) greater severity of depression and mania, greater number of episodes, more days depressed, more days of ultradian cycling, and fewer days euthymic. After 4 years, the mean severity and duration of depression remained greater and the number of days euthymic fewer in those with childhood compared to adult onset (P<.05). The delays to first treatment correlated inversely with age at onset of illness. Independently, delay to first treatment was associated with more time depressed, greater severity of depression, greater number of episodes, more days of ultradian cycling, and fewer days euthymic (all P<.05).These data converge with other evidence that onset of bipolar disorder in childhood is common and often associated with extraordinarily long delays to first pharmacologic treatment. Both childhood onset and treatment delay were associated with a persistently more adverse course of illness rated prospectively in adults. These data should help foster efforts to ensure earlier and more effective treatment of bipolar illness in children and adolescents. It is hoped that appropriate early intervention would result in a more benign illness and a better prognosis in adulthood.

  View details for DOI 10.4088/JCP.08m04994yel

  View details for Web of Science ID 000280470700006

  View details for PubMedID 20667291

• Is There a Role for Antidepressants in the Treatment of Bipolar II Depression? AMERICAN JOURNAL OF PSYCHIATRY Suppes, T. 2010; 167 (7): 738-740

  View details for DOI 10.1176/appi.ajp.2010.10040590

  View details for Web of Science ID 000279429300003

  View details for PubMedID 20595424

• Gender and Depressive Symptoms in 711 Patients With Bipolar Disorder Evaluated Prospectively in the Stanley Foundation Bipolar Treatment Outcome Network AMERICAN JOURNAL OF PSYCHIATRY Altshuler, L. L., Kupka, R. W., Hellemann, G., Frye, M. A., Sugar, C. A., McElroy, S. L., Nolen, W. A., Grunze, H., Leverich, G. S., Keck, P. E., Zermeno, M. 2010; 167 (6): 708-715

  Abstract

  The authors assessed gender differences in the proportion of clinical visits spent depressed, manic, or euthymic in patients with bipolar disorder.Data were analyzed from 711 patients with bipolar I or II disorder who were followed prospectively over 7 years (13,191 visits). The main outcome measures were the presence of symptoms of depression or of hypomania or mania, measured by the Inventory of Depressive Symptomatology and the Young Mania Rating Scale. Data were analyzed using three separate repeated-measures regressions with a logistic link function to model the probability that an individual was depressed, manic, or euthymic. The models controlled for bipolar I or bipolar II diagnosis, rapid cycling, age, time in the study, comorbid anxiety disorders, and comorbid substance use disorders.In approximately half of visits, patients had depressive, manic, or hypomanic symptoms. The likelihood of having depressive symptoms was significantly greater for women than for men. This was accounted for by higher rates in women of rapid cycling and anxiety disorders, each of which was associated with increased rates of depression. All patient groups showed an increase in number of euthymic visits and a decrease in number of visits with depressive and manic symptoms with increased time in study.Bipolar patients spend a substantial proportion of their time ill. Significant gender differences exist, with women spending a greater proportion of their visits in the depressive pole. This finding appears to be related to the corresponding differences in rates of rapid cycling and anxiety disorders.

  View details for Web of Science ID 000278269500016

  View details for PubMedID 20231325

• The Quick Inventory of Depressive Symptomatology (Clinician and Self-Report Versions) in Patients With Bipolar Disorder CNS SPECTRUMS Bernstein, I. H., Rush, A. J., Suppes, T., Kyotoku, Y., Warden, D. 2010; 15 (6): 367-373

  Abstract

  The clinical and self-report versions of the Quick Inventory of Depressive Symptomatology (QIDS-C16 and QIDS-SR16) have been well studied in patients with major depressive disorder and in one recent study using patients with bipolar disorder. This article examines these measures in a second sample of 141 outpatients with bipolar disorder in different phases of the illness.At baseline, 61 patients were depressed and 30 were euthymic; at exit, 50 were depressed and 52 were euthymic. The remaining patients (at baseline or exit) were in either a manic or mixed phase and were pooled for statistical reasons.Similar results were found for the QIDS-C16 and QIDS-SR16. Scores were reasonably reliable to the extent that variability within groups permitted. As expected, euthymic patients showed less depressive symptomatology than depressed patients. Sad mood and general interest were the most discriminating symptoms between depressed and euthymic phases. Changes in illness phase (baseline to exit) were associated with substantial changes in scores. The relation of individual depressive symptoms to the overall level of depression was consistent across phases.Both the QIDS-SR16 and QIDS-C16 are suitable measures of depressive symptoms in patients with bipolar disorder.

  View details for Web of Science ID 000279618600007

  View details for PubMedID 20625369

• Genetics and intermediate phenotypes of the schizophrenia bipolar disorder boundary NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS Ivleva, E. I., Morris, D. W., Moates, A. F., Suppes, T., Thaker, G. K., Tamminga, C. A. 2010; 34 (6): 897-921

  Abstract

  Categorization of psychotic illnesses into schizophrenic and affective psychoses remains an ongoing controversy. Although Kraepelinian subtyping of psychosis was historically beneficial, modern genetic and neurophysiological studies do not support dichotomous conceptualization of psychosis. Evidence suggests that schizophrenia and bipolar disorder rather present a clinical continuum with partially overlapping symptom dimensions, neurophysiology, genetics and treatment responses. Recent large scale genetic studies have produced inconsistent findings and exposed an urgent need for re-thinking phenomenology-based approach in psychiatric research. Epidemiological, linkage and molecular genetic studies, as well as studies in intermediate phenotypes (neurocognitive, neurophysiological and anatomical imaging) in schizophrenia and bipolar disorders are reviewed in order to support a dimensional conceptualization of psychosis. Overlapping and unique genetic and intermediate phenotypic signatures of the two psychoses are comprehensively recapitulated. Alternative strategies which may be implicated into genetic research are discussed.

  View details for DOI 10.1016/j.neubiorev.2009.11.022

  View details for Web of Science ID 000277352400013

  View details for PubMedID 19954751

• Effectiveness of the extended release formulation of quetiapine as monotherapy for the treatment of acute bipolar depression JOURNAL OF AFFECTIVE DISORDERS Suppes, T., Datto, C., Minkwitz, M., Nordenhem, A., Walker, C., Darko, D. 2010; 121 (1-2): 106-115

  Abstract

  To evaluate the effectiveness of quetiapine extended release once daily in bipolar depression.Double-blind, placebo-controlled study in acutely depressed adults with bipolar I or II disorder, with or without rapid cycling. Patients were randomized to 8 weeks of quetiapine extended release (XR) 300 mg daily monotherapy or placebo. The primary outcome measure was change from baseline to Week 8 in MADRS total score.Quetiapine XR 300 mg once daily (N=133) showed significantly greater improvement in depressive symptoms compared with placebo (N=137) from Week 1 (p<0.001) through to Week 8 (p<0.001). Mean change in MADRS total score at Week 8 was -17.4 in the quetiapine XR group and -11.9 in the placebo group (p<0.001). Response (>or=50 reduction in MADRS total score) and remission (MADRS total score

  View details for DOI 10.1016/j.jad.2009.10.007

  View details for PubMedID 19903574

• Mood Stabilization and Destabilization During Acute and Continuation Phase Treatment for Bipolar I Disorder With Lamotrigine or Placebo JOURNAL OF CLINICAL PSYCHIATRY Goldberg, J. F., Calabrese, J. R., Saville, B. R., Frye, M. A., Ketter, T. A., Suppes, T., Post, R. M., Goodwin, F. K. 2009; 70 (9): 1273-1280

  Abstract

  During post-acute phase pharmacotherapy for bipolar disorder, there has been little empirical study to establish when emerging mania symptoms (1) are of clinical significance and (2) reflect iatrogenic events versus the natural course of illness.Secondary analyses were conducted in a previously studied group of bipolar I disorder (DSM-IV) outpatients randomly assigned to lamotrigine monotherapy (n=171) or placebo (n=121), and a larger prerandomization group (N=966) during open-label titration of lamotrigine, following an index depressive episode. Time until the emergence of mania symptoms, at varying severity thresholds, was examined over 6 months for lamotrigine versus placebo, while controlling for potential confounding factors in Cox proportional hazard models. Subject enrollment occurred between July 1997 and August 2001.Rates of mood elevation during both acute open-label and randomized continuation phases of lamotrigine treatment were comparable to those seen with placebo during the randomized phase. The hazard ratio for the emergence of mania symptoms with lamotrigine was not significantly different from placebo (hazard ratio=0.79; 95% CI, 0.53 to 1.16), with an upper bound that suggests no meaningful increase in susceptibility toward mania with lamotrigine. By contrast, clinically meaningful rises in mania symptom severity were predicted by baseline residual manic symptoms prerandomization and by the number of manic, hypomanic, or mixed episodes in the past year.Based on a composite definition of mood destabilization involving a range of severity thresholds for emerging signs of mania, lamotrigine confers no meaningful elevated risk relative to placebo for mood destabilization in bipolar I disorder. Rather, illness burden related to residual or lifetime mania features may hold greater importance for explaining mania relapses or breakthrough manic features during lamotrigine continuation pharmacotherapy.

  View details for DOI 10.4088/JCP.08m04381

  View details for Web of Science ID 000270246700010

  View details for PubMedID 19689918

• The International Society for Bipolar Disorders (ISBD) Task Force report on the nomenclature of course and outcome in bipolar disorders BIPOLAR DISORDERS Tohen, M., Frank, E., Bowden, C. L., Colom, F., Ghaemi, S. N., Yatham, L. N., Malhi, G. S., Calabrese, J. R., Nolen, W. A., Vieta, E., Kapczinski, F., Goodwin, G. M., Suppes, T., Sachs, G. S., Chengappa, K. N., Grunze, H., Mitchell, P. B., Kanba, S., Berk, M. 2009; 11 (5): 453-473

  Abstract

  Via an international panel of experts, this paper attempts to document, review, interpret, and propose operational definitions used to describe the course of bipolar disorders for worldwide use, and to disseminate consensus opinion, supported by the existing literature, in order to better predict course and treatment outcomes.Under the auspices of the International Society for Bipolar Disorders, a task force was convened to examine, report, discuss, and integrate findings from the scientific literature related to observational and clinical trial studies in order to reach consensus and propose terminology describing course and outcome in bipolar disorders.Consensus opinion was reached regarding the definition of nine terms (response, remission, recovery, relapse, recurrence, subsyndromal states, predominant polarity, switch, and functional outcome) commonly used to describe course and outcomes in bipolar disorders. Further studies are needed to validate the proposed definitions.Determination and dissemination of a consensus nomenclature serve as the first step toward producing a validated and standardized system to define course and outcome in bipolar disorders in order to identify predictors of outcome and effects of treatment. The task force acknowledges that there is limited validity to the proposed terms, as for the most part they represent a consensus opinion. These definitions need to be validated in existing databases and in future studies, and the primary goals of the task force are to stimulate research on the validity of proposed concepts and further standardize the technical nomenclature.

  View details for Web of Science ID 000267874900001

  View details for PubMedID 19624385

• Depressive relapse during lithium treatment associated with increased serum thyroid-stimulating hormone: results from two placebo-controlled bipolar I maintenance studies ACTA PSYCHIATRICA SCANDINAVICA Frye, M. A., Yatham, L., Ketter, T. A., Goldberg, J., Suppes, T., Calabrese, J. R., Bowden, C. L., Bourne, E., Bahn, R. S., Adams, B. 2009; 120 (1): 10-13

  Abstract

  To assess the relationship between depressive relapse and change in thyroid function in an exploratory post hoc analysis from a controlled maintenance evaluation of bipolar I disorder.Mean thyroid-stimulating hormone (TSH) and outcome data were pooled from two 18-month, double-blind, placebo-controlled, maintenance studies of lamotrigine and lithium monotherapy. A post hoc analysis of 109 subjects (n = 55 lamotrigine, n = 32 lithium, n = 22 placebo) with serum TSH values at screening and either week 52 (+/-14 days) or study drop-out was conducted.Lithium-treated subjects who required an intervention for a depressive episode had a significantly higher adjusted mean TSH level (4.4 microIU/ml) compared with lithium-treated subjects who did not require intervention for a depressive episode (2.4 microIU/ml).Lithium-related changes in thyroid function are clinically relevant and should be carefully monitored in the maintenance phase of bipolar disorder to maximize mood stability and minimize the risk of subsyndromal or syndromal depressive relapse.

  View details for DOI 10.1111/j.1600-0447.2008.01343.x

  View details for Web of Science ID 000266636100002

  View details for PubMedID 19183414

• Randomized, placebo-controlled trial of risperidone for acute treatment of bipolar anxiety JOURNAL OF AFFECTIVE DISORDERS Sheehan, D. V., McElroy, S. L., Harnett-Sheehan, K., Keck, P. E., Janavs, J., Rogers, J., Gonzalez, R., Shivakumar, G., Suppes, T. 2009; 115 (3): 376-385

  Abstract

  The treatment of bipolar disorder is often complicated by the presence of a co-occuring anxiety disorder. Although second generation antipsychotics are being used with increasing frequency in bipolar patients, their anxiolytic effects have not been well studied in this population.The anxiolytic effect of risperidone 0.5-4 mg/day was tested in an 8-week, double-blind, placebo-controlled, randomized clinical trial in 111 patients with bipolar disorder and a co-occuring panic disorder or generalized anxiety disorder (GAD). The primary outcome measure was the Clinician Global Improvement-21 Anxiety scale (CGI-21 Anxiety). Secondary measures included the Hamilton Anxiety Scale (HAM-A) and the Sheehan Panic Disorder Scale.On the last-observation-carried forward analysis of repeated measures analysis of variance (ANOVA), risperidone was not more effective than placebo for the CGI-21 Anxiety score or the other anxiety outcome measures. Risperidone was well tolerated, with only two patients withdrawing because of adverse events.The risperidone treated group had more patients with mixed states and lifetime panic disorder at randomization than the placebo group. The study was limited to 8 weeks and to individuals with bipolar and comorbid panic disorder or GAD. The results may not be applicable to risperidone as an add-on treatment to mood stabilizers, or to bipolar disorder comorbid with anxiety disorders other than panic disorder or GAD.Risperidone monotherapy was not an effective anxiolytic for bipolar patients with comorbid panic disorder or GAD in doses of 0.5-4 mg/day over 8 weeks of treatment. The efficacy of other second generation antipsychotics and mood stabilizers on anxiety in patients with bipolar disorder and a co-occuring anxiety disorder should be investigated in double-blind, placebo-controlled studies.

  View details for DOI 10.1016/j.jad.2008.10.005

  View details for Web of Science ID 000266347600012

  View details for PubMedID 19042026

• A psychometric evaluation of the clinician-rated Quick Inventory of Depressive Symptomatology (QIDS-C-16) in patients with bipolar disorder INTERNATIONAL JOURNAL OF METHODS IN PSYCHIATRIC RESEARCH Bernstein, I. H., Rush, A. J., Suppes, T., Trivedi, M. H., Woo, A., Kyutoku, Y., Crismon, M. L., Dennehy, E., Carmody, T. J. 2009; 18 (2): 138-146

  Abstract

  The clinician-rated, 16-item Quick Inventory of Depressive Symptomatology (QIDS-C16) has been extensively evaluated in patients with major depressive disorder (MDD). This report assesses the psychometric properties of the QIDS-C16 in outpatients with bipolar disorder (BD, N = 405) and MDD (N = 547) and in bipolar patients in the depressed phase only (BD-D) (N = 99) enrolled in the Texas Medication Algorithm Project (TMAP) using classical test theory (CTT) and the Samejima graded item response theory (IRT) model. Values of coefficient alpha were very similar in BD, MDD, and BD-D groups at baseline (alpha = 0.80-0.81) and at exit (alpha = 0.82-0.85). The QIDS-C16 was unidimensional for all three groups. MDD and BD-D patients (n = 99) had comparable symptom levels. The BD-D patients (n = 99) had the most, and bipolar patients in the manic phase had the least depressive symptoms at baseline. IRT analyses indicated that the QIDS-C16 was most sensitive to the measurement of depression for both MDD patients and for BD-D patients in the average range. The QIDS-C16 is suitable for use with patients with BD and can be used as an outcome measure in trials enrolling both BD and MDD patients.

  View details for DOI 10.1002/mpr.285

  View details for Web of Science ID 000267387200007

  View details for PubMedID 19507161

• The Safety, Acceptability, and Effectiveness of Acupuncture as an Adjunctive Treatment for Acute Symptoms in Bipolar Disorder 6th International Conference on Bipolar Disorder Dennehy, E. B., Schnyer, R., Bernstein, I. H., Gonzalez, R., Shivakumar, G., Kelly, D. I., Snow, D. E., Sureddi, S., Suppes, T. PHYSICIANS POSTGRADUATE PRESS. 2009: 897–905

  Abstract

  There is growing interest in the utility of nonpharmacologic treatments for mood symptoms, including mood elevation and depression associated with bipolar disorders. The purpose of this research was to provide preliminary data on the safety, effectiveness, and acceptability of adjunctive acupuncture in the acute treatment of hypomania and depression associated with bipolar disorder.Two randomized trials were conducted to assess the benefits of adjunctive acupuncture for symptoms of depression and hypomania in patients with bipolar disorder (DSM-IV criteria). For 20 patients experiencing symptoms of hypomania, targeted acupuncture (points specific to symptoms) was compared to acupuncture points off the acupuncture meridian over 12 weeks (from May 2000 through May 2003). For patients experiencing symptoms of depression (n = 26), targeted acupuncture was compared to acupuncture for nonpsychiatric health concerns over 8 weeks (from November 2001 through May 2003). Preexisting psychotropic medications were maintained at stable doses throughout study participation.Regardless of acupuncture assignment or symptom pattern at entry, all patients experienced improvement over the course of study participation. There was evidence that acupuncture treatment did target the symptom dimension of interest (mood elevation in Study I, depression in Study II). There were few negative side effects and no attrition directly associated with adjunctive acupuncture.Novel methodologies are needed to assess the utility of acupuncture as adjunctive treatment of mood episodes associated with bipolar disorder. We observed similar benefits associated with "placebo" acupuncture experiences and active treatment. Further studies are warranted. TRIAL REGISTRATION (STUDY II): (ClinicalTrials.gov) Identifier: NCT00071669.

  View details for Web of Science ID 000267502100014

  View details for PubMedID 19422756

• Maintenance Treatment for Patients With Bipolar I Disorder: Results From a North American Study of Quetiapine in Combination With Lithium or Divalproex (Trial 127) 46th Annual Meeting of the American-College-of-Neuropsychopharmacology Suppes, T., Vieta, E., Liu, S., Brecher, M., Paulsson, B. AMER PSYCHIATRIC PUBLISHING, INC. 2009: 476–88

  Abstract

  The authors evaluated the efficacy and safety of quetiapine plus lithium or divalproex in the prevention of recurrent mood events in patients with stabilized bipolar I disorder.A total of 1,953 patients received open-label quetiapine (400-800 mg/day in flexible, divided doses) with either lithium or divalproex (target serum concentrations 0.5-1.2 meq/liter and 50-125 microg/ml, respectively) for up to 36 weeks. After at least 12 weeks of clinical stability, 628 patients were randomly assigned to double-blind treatment with quetiapine or placebo, in combination with lithium or divalproex, for up to 104 weeks. The primary efficacy measure was time to recurrence of any mood event (mania, depression, or a mixed episode).Fewer patients in the quetiapine group experienced a mood event compared with the placebo group (20.3% versus 52.1%). The hazard ratio for time to recurrence of a mood event was 0.32. Hazard ratios were similar for mania and depression events (0.30 and 0.33, respectively). Sedation, weight increase, and hypothyroidism occurred more frequently in the quetiapine group, as did discontinuations due to adverse events. The incidence and incidence density of a single emergent blood glucose value > or =126 mg/dl were higher in the quetiapine group (12.6% versus 5.4%; 18.44 versus 9.56 patients per 100 patient-years). Adverse events were generally consistent with the known tolerability profile of quetiapine.In patients stabilized on quetiapine plus lithium or divalproex, continued treatment was associated with a significant risk reduction in the time to recurrence of any mood event compared with placebo and lithium or divalproex.

  View details for DOI 10.1176/appi.ajp.2008.08020189

  View details for Web of Science ID 000264784100016

  View details for PubMedID 19289454

• Impact of Antidepressant Continuation After Acute Positive or Partial Treatment Response for Bipolar Depression: A Blinded, Randomized Study JOURNAL OF CLINICAL PSYCHIATRY Altshuler, L. L., Post, R. M., Hellemann, G., Leverich, G. S., Nolen, W. A., Frye, M. A., Keck, P. E., Kupka, R. W., Grunze, H., McElroy, S. L., Sugar, C. A., Suppes, T. 2009; 70 (4): 450-457

  Abstract

  To assess long-term outcome in bipolar disorder, subjects were prospectively followed after receiving acute treatment for bipolar depression.Eighty-three outpatients with DSM-IV bipolar depression who were enrolled between March 1996 and November 2002 and were treated in a 10-week acute double-blind antidepressant treatment trial agreed to participate in a 1-year double-blind continuation of their medication. In the acute antidepressant treatment trial, subjects were treated with a mood stabilizer plus 1 of 3 randomly assigned antidepressants. Sixty-one subjects had attained an acute positive antidepressant response (50% improvement on the Inventory for Depressive Symptomatology [IDS] or 2-point improvement on the Clinical Global Impression for Bipolar Disorder [CGI-BP]) and 22 subjects achieved only acute partial improvement at the end of the 10-week acute trial. In the blinded continuation phase immediately following the acute trial, subjects continued on the same medications and were rated monthly for up to 1 year using the IDS, CGI-BP, and the Young Mania Rating scale.At study endpoint, 42 (69%) of the 61 acute positive responders maintained positive response and 32 (53%) achieved remission. Compared to the acute positive responders, 6 (27%) of the 22 acute partial responders had achieved positive treatment response at study endpoint (p < .001). Eight acute positive responders (13%) and 5 acute partial responders (22%) developed mania.Patients who achieve a positive acute antidepressant response to 10 weeks of antidepressant treatment adjunctive to a mood stabilizer will probably maintain response with the same continued treatment. Patients who achieve only a partial acute antidepressant response are less likely to further improve when the same treatment is sustained. The switch rate into mania for patients being treated with an antidepressant adjunctive to a mood stabilizer is not higher than the reported rate for patients on mood stabilizer monotherapy.

  View details for Web of Science ID 000265550200002

  View details for PubMedID 19358785

• Methyltestosterone Add-On in Bipolar Depression: A Case Report KLINIK PSIKOFARMAKOLOJI BULTENI-BULLETIN OF CLINICAL PSYCHOPHARMACOLOGY Ozcan, M. E., Suppes, T. 2009; 19: S166-S167

  View details for Web of Science ID 000209020900050

• Correlates of Treatment-Emergent Mania Associated With Antidepressant Treatment in Bipolar Depression AMERICAN JOURNAL OF PSYCHIATRY Frye, M. A., Helleman, G., McElroy, S. L., Altshuler, L. L., Black, D. O., Keck, P. E., Nolen, W. A., Kupka, R., Leverich, G. S., Grunze, H., Mintz, J., Post, R. M., Suppes, T. 2009; 166 (2): 164-172

  Abstract

  Treatment-emergent mania can have substantial negative impact on overall mood and psychosocial stability in patients receiving treatment for bipolar depression. This study examined the correlates associated with treatment-emergent mania in patients receiving adjunctive antidepressant treatment for bipolar depression.A total of 176 adult outpatients with bipolar disorder in a 10-week trial of adjunctive antidepressant treatment for depression were categorized into three groups based on the Clinical Global Impression Scale for Bipolar Disorder: those who responded to antidepressant treatment (N=85), those who did not respond to antidepressant treatment (N=45), and those who had treatment-emergent mania or hypomania (N=46). Symptom severity was measured with the Inventory of Depressive Symptomatology and the Young Mania Rating Scale (YMRS) at baseline and bimonthly intervals. Factor analysis was used to examine correlates of treatment-emergent mania.Baseline YMRS scores were significantly different between groups. Otherwise, there were no significant between-group differences in demographic or clinical characteristics. Factor analysis showed that a subset of the YMRS items predicted treatment-emergent mania in this sample: increased motor activity, speech, and language-thought disorder.These data suggest that minimal manic symptoms at baseline coexisting with otherwise full syndromal bipolar depression are associated with antidepressant treatment-emergent mania or hypomania. A careful examination of motor activation, pressured speech, and racing thoughts is warranted before starting antidepressant treatment in bipolar depression.

  View details for DOI 10.1176/appi.ajp.2008.08030322

  View details for Web of Science ID 000263031500009

  View details for PubMedID 19015231

• A single blind comparison of lithium and lamotrigine for the treatment of bipolar II depression JOURNAL OF AFFECTIVE DISORDERS Suppes, T., Marangell, L. B., Bernstein, I. H., Kelly, D. I., Fischer, E. G., Zboyan, H. A., Snow, D. E., Martinez, M., Al Jurdi, R., Shivakumar, G., Sureddi, S., Gonzalez, R. 2008; 111 (2-3): 334-343

  Abstract

  Treatment studies are lacking for patients with bipolar II disorder (BDII). The objective of this study was to compare lamotrigine (LTG) and lithium (Li) monotherapy for the treatment of BDII depression.Patients with BDII acute depression were randomized to open-label monotherapy with LTG or Li, and evaluated by trained raters blinded to treatment. Patients were titrated to 200 mg/day of LTG over 8 weeks or at least 900 mg/day of Li over 2 weeks (serum level 0.6-1.2 mEq/L), and seen biweekly for 16 weeks. The primary outcome variable was change in the Hamilton Depression Rating Scale 17-item (Ham-D(17)), evaluated using mixed effects random regression.Both groups showed significant improvement from baseline to endpoint on the Ham-D(17) (p<0.0001), with no between group differences (p=0.95). Seventy-two percent of the population was rapid cycling by DSM-IV criteria. No differences in response were noted between rapid cyclers and non-rapid cyclers. Early termination for any cause was 42%. The Li group reported significantly more side effects, although drop-out due to side effects did not differ between groups.This study was limited by an open treatment design, a lack of placebo arm, and uneven treatment groups.Lamotrigine and lithium were effective monotherapy for BDII depression, with comparable response and remission rates. Naturalistic design and lack of placebo limit conclusions, though patient history indicated long standing depression unlikely to be alleviated by time. Patients who received Li reported more side effects, but this did not appear to impact drop-out rates.

  View details for DOI 10.1016/j.jad.2008.02.004

  View details for Web of Science ID 000261273900024

  View details for PubMedID 18358540

• Efficacy and safety of quetiapine in combination with lithium or divalproex for maintenance of patients with bipolar I disorder (international trial 126) JOURNAL OF AFFECTIVE DISORDERS Vieta, E., Suppes, T., Eggens, I., Persson, I., Paulsson, B., Brecher, M. 2008; 109 (3): 251-263

  Abstract

  This study examined the efficacy and safety of quetiapine in combination with lithium or divalproex compared with placebo with lithium or divalproex in the prevention of recurrent mood events in bipolar I patients, most recent episode mania, depression, or mixed.Patients received open-label quetiapine (400-800 mg/day; flexible, divided doses) with lithium or divalproex (target serum concentrations 0.5-1.2 mEq/L and 50-125 microg/mL, respectively) for up to 36 weeks to achieve at least 12 weeks of clinical stability. Patients were subsequently randomized to double-blind treatment with quetiapine (400-800 mg/day) plus lithium/divalproex or placebo plus lithium/divalproex for up to 104 weeks. The primary endpoint was time to recurrence of any mood event.Treatment with quetiapine in combination with lithium/divalproex significantly increased the time to recurrence of any mood event compared with placebo plus lithium/divalproex. The proportion of patients having a mood event was markedly lower in the quetiapine than in the placebo group (18.5% versus 49.0%). The hazard ratio for time to recurrence of a mood event was 0.28 (P<0.001), a mania event 0.30 (P<0.001), and a depression event 0.26 (P<0.001) corresponding to risk reductions of 72%, 70%, and 74%, respectively. During the randomization phase, the most common adverse events occurring in > or =5% in the quetiapine group were somnolence, nasopharyngitis, and headache. Insomnia was more common in the placebo group. During the randomization phase, there was an increase in weight of 0.5 kg in the quetiapine group and a reduction of 1.9 kg in the placebo group. The incidence and incidence density of a single emergent fasting blood glucose value> or =126 mg/dL was higher with quetiapine than with placebo (9.3% versus 4.1%; 17.6 versus 9.5 patients per 100 patient-years).This was an enriched sample of patients with bipolar I disorder responding to treatment with quetiapine plus lithium/divalproex.Maintenance treatment with quetiapine in combination with lithium/divalproex significantly increased time to recurrence of any event (mania, depression, or mixed) irrespective of the polarity of the index episode compared with placebo with lithium/divalproex. Long-term treatment with quetiapine was generally well-tolerated. Quetiapine with lithium/divalproex can provide an effective long-term treatment option for bipolar I disorder to prevent recurrences not only of mania but also depression.

  View details for DOI 10.1016/j.jad.2008.06.001

  View details for Web of Science ID 000258011400003

  View details for PubMedID 18579216

• Efficacy of quetiapine monotherapy for the treatment of depressive episodes in bipolar I disorder: A post hoc analysis of combined results from 2 double-blind, randomized, placebo-controlled studies 5th European-Stanley-Foundation Conference on Bipolar Disease Weisler, R. H., Calabrese, J. R., Thase, M. E., Arvekvist, R., Stening, G., Paulsson, B., Suppes, T. PHYSICIANS POSTGRADUATE PRESS. 2008: 769–82

  Abstract

  To investigate the efficacy and tolerability of quetiapine monotherapy for the treatment of major depressive episodes in patients with bipolar I disorder, as a post hoc analysis of data from 2 large studies, the BipOLar DEpRession (BOLDER) I and II studies, which investigated the overall efficacy of quetiapine in both bipolar I and II disorder.A combined cohort of patients with depressive episodes in bipolar I disorder (DSM-IV criteria) (N = 694) from 2 nearly identical double-blind, randomized, placebo-controlled studies that each randomly assigned patients with bipolar I and II disorder to 8 weeks of treatment with quetiapine 300 or 600 mg/day or placebo was analyzed. The primary efficacy measure was change from baseline to end of treatment (week 8) in the Montgomery-Asberg Depression Rating Scale (MADRS) total scores.In the combined cohort of patients with depressive episodes in bipolar I disorder from 2 studies, there were significantly greater clinical improvements in mean MADRS total scores among patients who received quetiapine compared with placebo from baseline to week 1 and through week 8 (at week 8: quetiapine 300 mg/day = -19.4; 600 mg/day = -19.6; placebo = -12.6; p < .001 for each dose), providing effect sizes of 0.78 and 0.80, respectively. Changes in MADRS were unrelated to reports of sedation and somnolence. The most common adverse events (AEs) with quetiapine were dry mouth, somnolence, sedation, dizziness, and constipation. Rates of withdrawal because of these AEs were relatively low.Quetiapine monotherapy (300 and 600 mg/day) is more effective than placebo and generally well tolerated for the treatment of depressive episodes in patients with bipolar I disorder.

  View details for Web of Science ID 000256279600010

  View details for PubMedID 18452345

• Awareness of metabolic concerns in patients with bipolar disorder: A survey of European psychiatrists EUROPEAN PSYCHIATRY Bauer, M., Lecrubier, Y., Suppes, T. 2008; 23 (3): 169-177

  Abstract

  An online survey of European psychiatrists assessed awareness of the metabolic syndrome and its influence on the management of bipolar disorder.Psychiatrists in the United Kingdom, France, Germany, Spain, and Italy were surveyed from April to June 2006. Eligibility criteria w ere 4-30 years in practice, >or=50% of time in direct patient care, had seen >or=10 bipolar patients in the preceding month. Aggregate data were weighted to represent the practicing physician population per country.Of 718 respondents, 56% had diagnosed metabolic syndrome. Respondents reported that metabolic syndrome prevalence was higher in bipolar patients (25%) than in the general population (20%). Seventy-two percent felt that metabolic syndrome poses significant health risks, warranting monitoring/treatment, and were most concerned with the bipolar medication adverse effects of weight gain, cognitive impairment, and glucose intolerance. Survey respondents recognized clear differences among psychotropic agents in the propensity to induce metabolic adverse effects. Sixty-five percent of respondents indicated that they had made interviewing and monitoring changes in the past three years as a result of metabolic concerns.European psychiatrists view metabolic syndrome as highly prevalent in the general population and in bipolar patients; two-thirds have changed their management of bipolar patients because of metabolic health concerns.

  View details for DOI 10.1016/j.eurpsy.2007.10.007

  View details for Web of Science ID 000254884100002

  View details for PubMedID 18160267

• Efficacy and safety of aripiprazole in subpopulations with acute manic or mixed episodes of bipolar I disorder JOURNAL OF AFFECTIVE DISORDERS Suppes, T., Eudicone, J., McQuade, R., Pikalov, A., Carlson, B. 2008; 107 (1-3): 145-154

  Abstract

  This analysis was designed to assess the efficacy and safety of aripiprazole compared with placebo in subpopulations of patients with acute manic or mixed episodes of bipolar I disorder.Acutely manic patients experiencing DSM-IV manic/mixed episodes of bipolar I disorder were pooled from two randomized, three-week, flexible-dose, double-blind, placebo-controlled trials (N=516) and stratified by disease severity (Young Mania Rating Scale, YMRS), episode type, presence or absence of psychotic features, episode frequency, age, gender, and baseline severity of depressive symptoms. Safety and treatment-emergent adverse-event analyses were also performed.Aripiprazole significantly reduced mean YMRS total scores at end point compared with placebo in patients with more severe or less severe illness, with mixed or manic episodes, with or without psychotic features, or with a history of rapid or non-rapid cycling (p<0.01 for each subpopulation); in men and women (p=0.001 for both); in patients in the 18-40 and 41-55 year age groups (por=5% of patients aged 18-40 years receiving aripiprazole were similar to those reported for the overall population.This post hoc analysis utilized pooled data from two short-term studies.Efficacy of the second-generation antipsychotic aripiprazole was noted across a broad range of subpopulations often associated with treatment resistance in patients experiencing manic or mixed episodes of bipolar I disorder.

  View details for DOI 10.1016/j.jad.2007.08.015

  View details for Web of Science ID 000254546000016

  View details for PubMedID 17904226

• Are bipolar mood symptoms affected by the phase of the menstrual cycle? JOURNAL OF WOMENS HEALTH Shivakumar, G., Bernstein, I. H., Suppes, T. 2008; 17 (3): 473-478

  Abstract

  Evidence suggests gender differences may exist in bipolar disorder, and a review of the literature shows that more women than men may experience rapid-cycling bipolar disorder. The issues contributing to these gender differences are unknown; a number of case reports have indicated the possibility of mood changes secondary to hormonal influences during the menstrual cycle. We sought to examine the relationship between bipolar disorder and menstrual cycle-related mood changes. To our knowledge, this is one of the largest samples in the literature addressing this issue.Outpatient women with bipolar disorder I, bipolar disorder II, and not otherwise specified (NOS), between the ages of 18 and 45, were evaluated. The National Institute of Mental Health Life Chart Method-p (NIMH-LCM-p) was used for daily mood ratings of depression and mania. Repeated measures of ANOVA and t tests were conducted separately for depressive and for manic symptom scores.One hundred nineteen women met the age criterion, and only 41 women met the rest of the inclusion criteria. In this sample of 41 women, there was no significant relationship between phases of the menstrual cycle (early and late follicular and early and late luteal phases) and changes in depression or mania. In an exploratory examination, 8 of 41 women showed a numerically higher mean depression score in the luteal phase than in the follicular phase; 5 of 41 women showed a numerically higher mean mania score in the luteal phase than in the follicular phase of the menstrual cycle.Different phases of the menstrual cycle were unrelated to depression and mania in a heterogeneous group of women with bipolar disorder. Prospective studies are needed to identify a vulnerable subpopulation in a homogeneous clinical sample.

  View details for DOI 10.1089/jwh.2007.0466

  View details for Web of Science ID 000254734800016

  View details for PubMedID 18328012

• Incidence of childhood-onset bipolar illness in the USA and Europe BRITISH JOURNAL OF PSYCHIATRY Post, R. M., Luckenbaugh, D. A., Leverich, G. S., Altshuler, L. L., Frye, M. A., Suppes, T., Keck, P. E., McElroy, S. L., Nolen, W. A., Kupka, R., Grunze, H., Walden, J. 2008; 192 (2): 150-151

  Abstract

  The relative incidence of childhood-onset bipolar illness in the USA compared with that in Europe is controversial. We examined this issue in more than 500 out-patients (average age 42 years) with bipolar illness who reported age at onset of first episode, family history, and childhood physical or sexual abuse. Childhood or adolescent onset of bipolar illness was reported by 61% of those in the US cohort but by only 30% of those in The Netherlands or Germany. In the USA there was also twice the incidence of childhood adversity and genetic/familial risk for affective disorder. The findings deserve replication and further exploration.

  View details for DOI 10.1192/bjp.bp.107.037820

  View details for Web of Science ID 000253410700013

  View details for PubMedID 18245035

• A 1-year pilot study of vagus nerve stimulation in treatment-resistant rapid-cycling bipolar disorder JOURNAL OF CLINICAL PSYCHIATRY Marangell, L. B., Suppes, T., Zboyan, H. A., Prashad, S. J., Fischer, G., Snow, D., Sureddi, S., Allen, J. C. 2008; 69 (2): 183-189

  Abstract

  Vagus nerve stimulation (VNS) appears to be an effective treatment option for patients with treatment-resistant unipolar and bipolar depression. The aim of the present study was to investigate the efficacy of VNS in a group of patients with treatment-resistant rapid-cycling bipolar disorder (RCBD) who were excluded from previous trials.Nine outpatients with a DSM-IV-TR diagnosis of treatment-resistant RCBD were treated for 40 weeks with open-label VNS. The first patient was enrolled in June 2001, and the last patient completed the study in July 2005. Patients recorded their depression and mania mood symptoms on a daily basis throughout the study using the National Institute of Mental Health prospective life charting methodology and daily mood ratings. Patients were assessed every 2 weeks during the 2-month baseline period before device activation, every 2 weeks for the remaining 40 weeks of the study, and at the end of the study with the 24-item Hamilton Rating Scale for Depression (HAM-D-24), the 10-item Montgomery-Asberg Depression Rating Scale (MADRS), the Young Mania Rating Scale (YMRS), the Clinical Global Impressions (CGI) scale, the Global Assessment of Functioning (GAF) scale, and the 30-item Inventory of Depressive Symptomatology Self-Report (IDS-SR-30). Any adverse events or device complications were also recorded at each visit. The prospective life charts were analyzed by calculating the area under the curve. Statistical analysis was performed with a mixed-model repeated-measures regression analysis for repeated measures of the various rating scales. Significant p values were < or = .05.Over the 12-month study period, VNS was associated with a 38.1% mean improvement in overall illness as compared to baseline (p = .012), as well as significant reductions in symptoms as measured by the HAM-D-24 (p = .043), MADRS (p = .003), CGI (p = .013), and GAF (p < .001) rating scales. Common adverse events were voice alteration during stimulation and hoarseness.These data suggest that VNS may be an efficacious and well-tolerated treatment option for patients with treatment-resistant RCBD. Currently, no comparison is available in the literature. Larger randomized trials are needed to verify these findings.

  View details for Web of Science ID 000253506300003

  View details for PubMedID 18211128

• Bipolar II disorder: arguments for and against a distinct diagnostic entity BIPOLAR DISORDERS Vieta, E., Suppes, T. 2008; 10 (1): 163-178

  Abstract

  As a commitment to the International Society for Bipolar Disorders (ISBD), a Task Force was developed to investigate the diagnostic value of bipolar II disorder.Task Force members worked jointly reviewing all relevant literature (original articles, reviews, letters, book chapters and congress presentations) that included 'bipolar II disorder' and/or 'hypomania' as key words.Bipolar II disorder appears to be a reasonably valid and reliable diagnostic category yet often underdiagnosed or misdiagnosed as unipolar disorder or personality disorder. Moreover, it is officially recognized as a mental disorder in DSM-IV-TR but not in ICD-10, and many clinicians still regard it as a milder form of manic-depressive illness, despite data supporting high morbidity and mortality rates. In fact, bipolar II may be the most prevalent bipolar phenotype, although current diagnostic boundaries are seen as quite restrictive concerning the required duration for hypomania (4 days), the exclusion of hypomanic episodes potentially triggered by antidepressants and other substances, and the negligence of hypomanic mixed states. The course of bipolar II disorder is characterized by depressive predominant polarity, and its treatment is still controversial and poorly evidence-based.Bipolar II disorder is supported as a distinct category within mood disorders, but the definition and boundaries deserve a greater clarification in the DSM-V and ICD-11.

  View details for Web of Science ID 000252319400006

  View details for PubMedID 18199235

• An investigation of water lithium concentrations and rates of violent acts in 11 texas counties: Can an association be easily shown? JOURNAL OF CLINICAL PSYCHIATRY Gonzalez, R., Bernstein, I., Suppes, T. 2008; 69 (2): 325-326

  View details for Web of Science ID 000253506300021

  View details for PubMedID 18363457

• Six-month prospective life charting of mood symptoms with lamotrigine monotherapy versus placebo in rapid cycling bipolar disorder 59th Annual Meeting of the Society-of-Biological-Psychiatry Goldberg, J. F., Bowden, C. L., Calabrese, J. R., Ketter, T. A., Dann, R. S., Frye, M. A., Suppes, T., Post, R. M. ELSEVIER SCIENCE INC. 2008: 125–30

  Abstract

  Fluctuations in mood are quintessential features of bipolar disorder; however, previous studies have seldom examined the extent to which pharmacotherapies for bipolar disorder may reduce or ameliorate daily or weekly mood variability. The anticonvulsant lamotrigine has demonstrated efficacy for relapse prevention in bipolar disorder, but its possible mood-stabilizing properties on a day-to-day or week-to-week basis have not previously been investigated.Weekly mood shifts were examined over 26 weeks using patients' self-reported prospective Life Chart Method (LCM) data obtained as part of a previously reported randomized relapse prevention comparison of lamotrigine monotherapy or placebo in 182 bipolar patients with DSM-IV rapid cycling. Generalized estimating equation (GEE) analyses were used to compare treatment arms for subjects who achieved euthymia across weeks.After adjusting for potential confounding factors, a final GEE model revealed that subjects taking lamotrigine were 1.8 times more likely than those taking placebo to achieve euthymia, as measured by LCM, at least once per week over 6 months (95% confidence interval [CI] = 1.03-3.13). Subjects taking lamotrigine had an increase of .69 more days per week euthymic as compared with those taking placebo (p = .014).Achievement of euthymia across weeks represents a novel paradigm shift in gauging the mood-stabilizing properties of a psychotropic agent. The present findings demonstrate the utility of the prospective Life Chart Method for assessing longitudinal mood stability during randomized clinical trials for bipolar disorder. The results lend support to the potential mood-stabilizing properties of lamotrigine monotherapy for bipolar disorder.

  View details for DOI 10.1016/j.biopsych.2006.12.031

  View details for Web of Science ID 000251864000020

  View details for PubMedID 17543894

• Awareness of the metabolic syndrome in patients with bipolar disorder: A comparison of US and European psychiatrists INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE Lecrubier, Y., Bauer, M., Hirschfeld, R., McElroy, S., Suppes, T. 2008; 12 (3): 187-195

  View details for DOI 10.1080/13651500701827671

  View details for Web of Science ID 000258018400005

• Quetiapine for the treatment of bipolar II depression: Analysis of data from two randomized, double-blind, placebo-controlled studies 5th European-Stanley-Foundation Conference on Bipolar Disease Suppes, T., Hirschfeld, R. M., Vieta, E., Raines, S., Paulsson, B. TAYLOR & FRANCIS LTD. 2008: 198–211

  Abstract

  To investigate the efficacy and tolerability of quetiapine monotherapy for depressive episodes in patients with bipolar II disorder.A post-hoc evaluation was conducted in 351 patients with bipolar II depression combined from two similarly designed double-blind, randomized, placebo-controlled, 8-week studies of quetiapine (300 or 600 mg/day) that included patients with bipolar I or II disorder (DSM-IV) exhibiting moderate to severe depression. The primary endpoint was change from baseline to week 8 in MADRS total score. Secondary endpoints included HAM-D, HAM-A, and CGI.In patients with bipolar II disorder, improvement in mean MADRS total score from baseline was significantly greater with quetiapine 300 (n = 107) and 600 mg/day (n = 106) from the first assessment (week 1) through week 8 compared with placebo (n = 108). The mean change from baseline at week 8 for quetiapine 300 and 600 mg/day versus placebo was -17.1 and -17.9 versus -13.3 (P = 0.005 and P = 0.001 versus placebo), respectively. Change in HAM-D, HAM-A, and CGI were also significantly greater for quetiapine groups versus placebo. Common adverse events in the quetiapine groups included dry mouth, sedation, and somnolence.Quetiapine demonstrated significant efficacy as monotherapy, compared with placebo, for the treatment of acute depressive episodes in bipolar II disorder.

  View details for DOI 10.1080/15622970701317265

  View details for Web of Science ID 000258019600006

  View details for PubMedID 17853277

• Clinical implications of anti psychotic-induced hyperprolactinemia in patients with schizophrenia spectrum or bipolar spectrum disorders - Recent developments and current perspectives JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Byerly, M., Suppes, T., Tran, Q., Baker, R. A. 2007; 27 (6): 639-661

  Abstract

  Hyperprolactinemia is increasingly studied as a frequent and potentially important consequence of antipsychotic medication treatment. Some individuals presenting with hyperprolactinemia remain asymptomatic, but others may exhibit a wide range of clinical symptoms resulting from either the direct effects of prolactin on body tissues (galactorrhea, gynecomastia) or endocrine-related secondary effects (sexual and reproductive dysfunction in the short term, and possibly the risk of tumorigenesis and osteoporosis in the longer term). Short-term side effects may negatively impact medication compliance, and long-term effects have the potential for serious health consequences. Antipsychotic medications have differing propensities to cause prolactin elevation. The first-generation antipsychotics, as well as the second-generation antipsychotic risperidone and its active metabolite paliperidone, have been shown to cause marked and sustained elevations in prolactin levels, whereas others of the second-generation antipsychotics appear to have little or no effect on prolactin levels or may decrease prolactin. A comprehensive overview of antipsychotics and hyperprolactinemia is presented together with a review of emerging evidence about the short- and long-term health risks of hyperprolactinemia.

  View details for DOI 10.1097/jcp.0b013e31815ac4e5

  View details for Web of Science ID 000251181600013

  View details for PubMedID 18004132

• Quetiapine for the continuation treatment of bipolar depression: naturalistic prospective case series from the Stanley Bipolar Treatment Network INTERNATIONAL CLINICAL PSYCHOPHARMACOLOGY Suppes, T., Kelly, D. I., Keck, P. E., McElroy, S. L., Altshuler, L. L., Mintz, J., Frye, M. A., Nolen, W. A., Luckenbaugh, D. A., Post, R. M., Leverich, G. S., Kupka, R. W., Grunze, H. 2007; 22 (6): 376-381

  Abstract

  Continuation treatment for bipolar disorder often consists of a mood stabilizer and a second-generation antipsychotic. Quetiapine has been shown to be an effective treatment for acute mania and acute bipolar depression, but there are limited data for its use in continuation treatment. This study examined the effectiveness of open-label adjunctive quetiapine therapy for continuation treatment in patients with bipolar disorder. Prospectively collected life chart data from 63 outpatients with bipolar disorders, most recent episodes depressed, manic, or cycling, who received adjunctive quetiapine therapy as part of standard acute treatment were analyzed. Patients had 4 or more weeks of prequetiapine baseline data and at least 2 weeks of quetiapine treatment with no other medication changes. Patients were grouped by baseline symptoms; depression only, mania only, or both mania and depression (cycling group). Owing to small mania and well groups (n=4), differences between depression and cycling groups were examined and mania and well groups excluded. Fifty-five patients were included in the analyses. The primary outcome measure was change in mood severity from baseline to change in treatment regimen, as measured by the NIMH Life Charting Method. Patients received adjunctive quetiapine for a mean of 122 (SD=149) days. Both groups showed significant improvement in depression ratings and time spent depressed by week 10. Both groups showed significant improvement in overall mood. No between-group differences in improvement were found. Adjunctive quetiapine may be useful as continuation treatment in bipolar populations with both pure depressive and cycling symptoms. Further controlled studies are warranted.

  View details for Web of Science ID 000250315000009

  View details for PubMedID 17917557

• Three times more days depressed than manic or hypomanic in both bipolar I and bipolar II disorder BIPOLAR DISORDERS Kupka, R. W., Altshuler, L. L., Nolen, W. A., Suppes, T., Luckenbaugh, D. A., Leverich, G. S., Frye, M. A., Keck, P. E., McElroy, S. L., Grunze, H., Post, R. M. 2007; 9 (5): 531-535

  Abstract

  To assess the proportion of time spent in mania, depression and euthymia in a large cohort of bipolar subjects studied longitudinally, and to investigate depression/mania ratios in patients with bipolar I versus bipolar II disorder.Clinician-adjusted self-ratings of mood were completed daily for one year for naturalistically treated outpatients with bipolar I (n = 405) or bipolar II (n = 102) disorder. Ratings were analyzed for mean time spent euthymic, depressed, manic, hypomanic, and cycling, and the percentages of time spent ill were compared between the two groups.Percentages of time spent ill for bipolar I versus II patients were: euthymia 47.7% versus 50.2%; depression 36.0% versus 37.0%; hypomania 11.5% versus 9.8%; mania 1.0% versus 0.2%; and cycling 3.7% versus 2.8%. The depression/mania ratio was 2.9 in the bipolar I and 3.8 in bipolar II sub-groups.Depression represents the predominant abnormal mood state for treated outpatients with bipolar I and II disorder. In contrast to other studies, we found that depression/mania ratios were of a similar magnitude, suggesting the same tendency towards mood instability in both sub-groups.

  View details for Web of Science ID 000248590500013

  View details for PubMedID 17680925

• Open-label aripiprazole in the treatment of acute bipolar depression: A prospective pilot trial JOURNAL OF AFFECTIVE DISORDERS McElroy, S. L., Suppes, T., Frye, M. A., Altshuler, L. L., Stanford, K., Martens, B., Leverich, G. S., Post, R. M., Keck, P. E. 2007; 101 (1-3): 275-281

  Abstract

  Increasing evidence indicates that some second-generation antipsychotics are efficacious in bipolar depression, but there are few data on this illness for the novel agent aripiprazole.Aripiprazole response was prospectively assessed for 8 weeks with the Montgomery-Asberg Depression Rating Scale (MADRS), the Clinical Global Impression Scale Modified for Bipolar Illness (CGI-BP), and the Young Mania Rating Scale (YMRS) in 31 bipolar patients with acute depression inadequately responsive to 1 mood stabilizer. Side effects and body weight were also evaluated. Outcome measures were analyzed with repeated measures ANOVAs.Patients showed a significant decrease in mean MADRS total and CGI-BP-Depression Severity scores, but only 14 (45%) completed the 8-week trial. Thirteen (42%) patients met criteria for response (> or =50% reduction in MADRS total score), 11 (35%) patients met criteria for remission (final MADRS total score < or =12), and 9 (29%) patients discontinued aripiprazole for side effects, most commonly akathisia (N=4). As a group, patients showed statistically insignificant weight gain (0.8+/-2.5 kg) over the 8-week trial.Aripiprazole was associated with beneficial effects on mood in some patients with bipolar depression, but also had a high discontinuation rate, primarily due to side effects. Double-blind, placebo-controlled studies are necessary to determine aripiprazole's efficacy, tolerability, and safety in bipolar depression.

  View details for DOI 10.1016/j.jad.2006.11.025

  View details for Web of Science ID 000247860000033

  View details for PubMedID 17229469

• Alcoholism and anxiety in bipolar illness: Differential lifetime anxiety comorbidity in bipolar I women with and without alcoholism 4th European-Stanley-Foundation Conference on Bipolar Disorder Levander, E., Frye, M. A., McElroy, S., Suppes, T., Grunze, H., Nolen, W. A., Kupka, R., Keck, P. E., Leverich, G. S., Altshuler, L. L., Hwang, S., Mintz, J., Post, R. M. ELSEVIER SCIENCE BV. 2007: 211–17

  Abstract

  This study was undertaken to evaluate the prevalence rate of anxiety comorbidity in bipolar subjects with and without alcohol use disorders (AUD).Bipolar men and women who entered the Stanley Foundation Bipolar Network (SFBN) underwent a Structured Clinical Interview for DSM-IV (SCID-IV) and were divided into those subjects meeting current or lifetime criteria for an alcohol use disorder (AUD=213) vs. those subjects who did not (non-AUD=137). Lifetime rates of comorbid anxiety disorder were evaluated between groups.Of 350 subjects, 163 (46.5%) met criteria for an anxiety disorder. Panic disorder and OCD were the most common anxiety disorders in the AUD and non-AUD groups. OCD and specific phobia were significantly less prevalent in BP I patients with AUD compared to those without. Bipolar women with AUD had a significantly higher rate of PTSD than those without.These data highlight the added liability of anxiety comorbidity in BP disorder. Specifically, the greater amount of PTSD and lesser amount of OCD in bipolar women with alcohol comorbidity may have important diagnostic and treatment implications beyond dual diagnosis. Further study in comorbidity patterns is encouraged to not only better understand illness burden, but to maximize pattern-specific treatment outcomes.

  View details for DOI 10.1016/j.jad.2006.11.023

  View details for Web of Science ID 000247860000022

  View details for PubMedID 17254638

• A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression 44th Annual Meeting of the American-College-Neuropsychopharmacology Frye, M. A., Grunze, H., Suppes, T., McElroy, S. L., Keck, P. E., Walden, J., Leverich, G. S., Altshuler, L. L., Nakelsky, S., Hwang, S., Mintz, J., Post, R. M. AMER PSYCHIATRIC PUBLISHING, INC. 2007: 1242–49

  Abstract

  Modafinil is approved by the U.S. Food and Drug Administration for improving wakefulness in patients with excessive sleepiness associated with narcolepsy, obstructive sleep apnea, and shift-work sleep disorder. This study was conducted to evaluate the efficacy and safety of adjunctive modafinil in bipolar depression, which is often characterized by excessive sleepiness and fatigue.Eighty-five patients with bipolar depression that was inadequately responsive to a mood stabilizer with or without concomitant antidepressant therapy were randomly assigned to receive adjunctive modafinil (N=41) or placebo (N=44) for 6 weeks. The primary outcome measure was baseline-to-endpoint change in score on the Inventory of Depressive Symptoms--Clinician Rated (IDS).The baseline-to-endpoint change in IDS score was significantly greater in the modafinil group (mean dose, 177 mg/day) compared with the placebo group. Improvement in depressive symptoms was significantly greater in the modafinil group by week 2, and this greater improvement was maintained at weeks 4, 5, and 6. Both the response and remission rates were significantly higher in the modafinil group (44% and 39%) compared with the placebo group (23% and 18%). During the 6-week study period, there was no difference between groups in treatment-emergent hypomania or mania (six patients in the modafinil group and five in the placebo group) or hospitalization for mania (one in each group).These data suggest that adjunctive modafinil at doses of 100-200 mg a day may improve depressive symptoms in patients with bipolar disorder.

  View details for DOI 10.1176/appi.ajp.2007.06060981

  View details for Web of Science ID 000248727200020

  View details for PubMedID 17671288

• Dimensions and the psychosis phenotype Conference on Dimensional Approaches to Psychiatric Classification Allardyce, J., Suppes, T., van Os, J. JOHN WILEY & SONS LTD. 2007: S34–S40

  Abstract

  In this paper, we discuss the conceptual background for including a dimensional component to the DSM V diagnoses for psychoses. We review the evidence for a continuous distribution of psychosis like symptoms in the general population and summarise the research validating the clinical usefulness of psychopathological dimensions. We conclude that diagnostic models using both categorical and dimensional representations of psychosis have better predictive validity than either model independently. Dimensions do not appear to be diagnosis specific so a flexible scoring of dimensions across all psychotic and major affective disorders may be potentially more informative than a system where categorical diagnoses are kept artificially dimension-specific.

  View details for DOI 10.1002/mpr.214

  View details for Web of Science ID 000247880500006

  View details for PubMedID 17623393

• A 24-week, randomized, controlled trial of adjunctive sibutramine versus topiramate in the treatment of weight gain in overweight or obese patients with bipolar disorders 6th International Conference on Bipolar Disorder McElroy, S. L., Frye, M. A., Altshuler, L. L., Suppes, T., Hellemann, G., Black, D., Mintz, J., Kupka, R., Nolen, W., Leverich, G. S., Denicoff, K. D., Post, R. M., Keck, P. E. WILEY-BLACKWELL. 2007: 426–34

  Abstract

  Patients with bipolar disorder (BD) have an increased risk of obesity as well as psychotropic-associated weight gain. The objective of this study was to compare sibutramine and topiramate as adjunctive treatments for psychotropic-associated weight gain in overweight or obese outpatients with BD.In this 24-week, open-label, flexible-dose, comparison trial, 46 outpatients with bipolar disorders who had a body mass index (BMI) > or =30 kg/m(2), or > or =27 kg/m(2) with obesity-related comorbidities, and psychotropic-associated weight gain were randomly assigned to receive sibutramine (n = 18; 5-15 mg/day) or topiramate (n = 28; 25-600 mg/day). The primary outcome measure was weight loss. Secondary measures included changes in BMI, percent body weight loss, and mood symptoms.Patients randomized either to sibutramine or topiramate lost comparable amounts of weight (4.1 +/- 5.7 and 2.8 +/- 3.5 kg, respectively) and displayed similar rates of weight loss (0.85 and 0.82 kg/week, respectively). However, only four (22%) patients receiving sibutramine and six (21%) patients receiving topiramate completed the 24-week trial. In addition, the attrition patterns for the two drugs were different, with patients discontinuing topiramate doing so early in treatment and patients discontinuing sibutramine doing so throughout treatment. Also, higher ratings of manic and depressive symptoms significantly increased risk for early topiramate discontinuation compared to that for sibutramine.Adjunctive sibutramine and topiramate may have comparable weight loss effects in overweight or obese bipolar patients with psychotropic-associated weight gain, but are each associated with similarly high discontinuation rates. In addition, they may have different attrition profiles. Compared to sibutramine, discontinuation of topiramate may be more likely to occur early in treatment and may be more dependent upon manic and depressive symptoms.

  View details for Web of Science ID 000247110600012

  View details for PubMedID 17547588

• Tranylcypromine vs. lamotrigine in the treatment of refractory bipolar depression: a failed but clinically useful study ACTA PSYCHIATRICA SCANDINAVICA Nolen, W. A., Kupka, R. W., Hellemann, G., Frye, M. A., Altshuler, L. L., Leverich, G. S., Suppes, T., Keck, P. E., McElroy, S., Grunze, H., Mintz, J., Post, R. M. 2007; 115 (5): 360-365

  Abstract

  To compare the efficacy and tolerability of tranylcypromine vs. lamotrigine in bipolar depression not responding to conventional antidepressants.Bipolar depressed patients received open randomized treatment with tranylcypromine or lamotrigine as add-on to a mood stabilizer during 10 weeks. In a second treatment phase, non-responding patients could receive the opposite drug. Outcome criteria were response (measured with CGI-BP and IDS-C), switch into mania, and completion of the study.Only 20 of 70 planned patients were randomized, due to problems with recruitment, and 19 patients received any medication. During the first treatment phase 5/8 patients (62.5%) responded to tranylcypromine without switch into mania, compared with 4/11 patients (36.4%) on lamotrigine with two switches (statistically not significant). Over both treatment phases, 8/10 patients (80%) receiving tranylcypromine completed the study vs. 5/13 (38.5%) on lamotrigine (likelihood 0.02).There still appears to be a role for tranylcypromine in the treatment of refractory bipolar depression. Larger controlled studies are demanded.

  View details for DOI 10.1111/j.1600-0447.2007.00993.x

  View details for Web of Science ID 000245390100004

  View details for PubMedID 17430413

• The poor prognosis of childhood-onset bipolar disorder JOURNAL OF PEDIATRICS Leverich, G. S., Post, R. M., Keck, P. E., Altshuler, L. L., Frye, M. A., Kupka, R. W., Nolen, W. A., Suppes, T., McElroy, S. L., Grunze, H., Denicoff, K., Moravec, M. K., Luckenbaugh, D. 2007; 150 (5): 485-490

  Abstract

  We examined age of onset of bipolar disorder as a potential course-of-illness modifier with the hypothesis that early onset will engender more severe illness.A total of 480 carefully diagnosed adult outpatients with bipolar disorder (mean age, 42.5 +/- 11.6 years) were retrospectively rated for age of illness onset, time to first pharmacotherapy, and course of illness. Clinicians prospectively rated daily mood fluctuations over 1 year.Of the 480 patients, 14% experienced onset in childhood (12 years or younger); 36% in adolescence (13 to 18 years); 32% in early adulthood (19 to 29 years); and 19% in late adulthood (after 30 years). Childhood-onset bipolar illness was associated with long delays to first treatment, averaging more than 16 years. The patients with childhood or adolescent onset reported more episodes, more comorbidities, and rapid cycling retrospectively; prospectively, they demonstrated more severe mania, depression, and fewer days well.This study demonstrates that childhood onset of bipolar disorder is common and is associated with long delays to first treatment. Physicians and clinicians should be alert to a possible bipolar diagnosis in children in hopes of shortening the time to initiating treatment and perhaps ameliorating the otherwise adverse course of illness.

  View details for DOI 10.1016/j.jpeds.2006.10.070

  View details for Web of Science ID 000246245600012

  View details for PubMedID 17452221

• Comparison of two anticonvulsants in a randomized, single-blind treatment of hypomanic symptoms in patients with bipolar disorder AUSTRALIAN AND NEW ZEALAND JOURNAL OF PSYCHIATRY Suppes, T., Kelly, D. I., Hlynan, L. S., Snow, D. E., Sureddi, S., Foster, B., Curley, E. 2007; 41 (5): 397-402

  Abstract

  Oxcarbazepine was compared to divalproex to assess clinical effectiveness of a proven agent, divalproex, against a newer, less studied agent, oxcarbazepine, in the treatment of hypomania.Thirty patients with bipolar disorder, currently hypomanic, were randomized to receive oxcarbazepine or divalproex as add-on or monotherapy for 8 weeks. A rater blind to treatment assignment performed all symptom ratings. Hypomania and depression were rated using the Young Mania Rating Scale (YMRS) and the Inventory of Depressive Symptoms-Clinician Version (IDS-C). Random regression models were used to assess clinical symptom scores.There were no significant differences of YMRS or IDS-C scores between groups. Mean YMRS scores at baseline were 22.07+/-5.86 and 20.53+/-6.02 for the oxcarbazepine and the divalproex groups, respectively. Mean percent reduction from baseline to week 8 for the YMRS was 63.8% and 79.0% for oxcarbazepine and divalproex groups, respectively. Mean percent reduction from baseline to week 8 for the IDS-C was 48.7% versus 19.7% for oxcarbazepine and divalproex groups, respectively. Significant antimanic efficacy was noted for each medication. Both medications were generally well tolerated.In this pilot study, oxcarbazepine was as effective as divalproex in the treatment of hypomania. Further controlled trials are warranted.

  View details for Web of Science ID 000246619500004

  View details for PubMedID 17464731

• Awareness of Metabolic Concerns and Perceived Impact of Pharmacotherapy in Patients with Bipolar Disorder: A Survey of 500 US Psychiatrists PSYCHOPHARMACOLOGY BULLETIN Suppes, T., McElroy, S. L., Hirschfeld, R. 2007; 40 (2): 22-37

  Abstract

  An online survey was conducted to assess psychiatrists' familiarity with the metabolic syndrome and its components in patients with bipolar disorder, and characterize their perspectives and practices regarding its impact on patient management.Participants were US psychiatrists from a random sample of those in the AMA database. Qualified respondents practiced 4-30 years, spent > or = 50% of their time in direct patient care, and treated > or = 25 bipolar patients in the last month. Results were collected and tabulated by Harris Interactive from Nov-Dec 2005.Five hundred psychiatrists qualified and completed the survey, and 50 respondents also participated in follow-up interviews. Most respondents (94%) viewed metabolic syndrome as a significant health risk requiring monitoring and treatment. While 76% have diagnosed it, only 28% correctly identified the five NCEP diagnostic criteria. Medication adverse effects of greatest concern were weight gain, glucose intolerance, and dyslipidemia. During treatment, 78% of respondents reported monitoring weight, 69% glucose, 61% lipids, and 52% blood pressure. Most respondents (92%) reported referring patients to specialists or primary care for metabolic abnormalities. Changes in metabolic profile were reported to prompt many psychiatrists (85%) to stop or switch bipolar medications, especially those who treat a large number of bipolar patients (89%). The follow-up interviews supported a change in practice patterns over the last 5 years.Nearly all respondents have metabolic concerns with medical therapies used to treat bipolar disorder. Many now routinely monitor weight and other metabolic parameters. Most have referred patients for medical management and adjusted bipolar therapies due to metabolic abnormalities.

  View details for Web of Science ID 000207792600002

  View details for PubMedID 17514184

• Longitudinal follow-up of reproductive and metabolic features of valproate-associated polycystic ovarian syndrome features: A preliminary report 87th Annual Meeting of the Endocrine-Society Joffe, H., Cohen, L. S., Suppes, T., Hwang, C. H., Molay, F., Adams, J. M., Sachs, G. S., Hall, J. E. ELSEVIER SCIENCE INC. 2006: 1378–81

  Abstract

  In the Systematic Treatment Enhancement Program for Bipolar Disorder, we showed that valproate is associated with new-onset menstrual-cycle irregularities and hyperandrogenism in 10.5% of 86 women. We now determine whether polycystic ovarian syndrome (PCOS) features reverse on valproate discontinutation.Women with valproate-associated PCOS and those at risk for PCOS (valproate use < or =6 months) were re-evaluated for PCOS.Follow-up (mean 17 months) assessments were completed in 14 women (5 with treatment-emergent PCOS, 9 on valproate < or =6-month). Of seven women who developed valproate-associated PCOS, PCOS reproductive features remitted in three of four discontinuing valproate and persisted in all 3 continuing valproate. Menstrual-cycle irregularities improved among valproate-discontinuers whose PCOS features remitted (p = 0.01). There was a trend toward lower serum testosterone (p = 0.06). Body-weight and polycystic ovarian morphology did not change.In the first longitudinal bipolar-disorder study of valproate-associated PCOS, most valproate-discontinuers had improved reproductive features of PCOS despite static body-weight.

  View details for DOI 10.1016/j.biopsych.2006.05.027

  View details for Web of Science ID 000242735700016

  View details for PubMedID 16950230

• New findings from the Bipolar Collaborative Network: clinical implications for therapeutics. Current psychiatry reports Post, R. M., Altshuler, L. L., Frye, M. A., Suppes, T., McElroy, S., Keck, P. E., Leverich, G. S., Kupka, R., Nolen, W. A., Grunze, H. 2006; 8 (6): 489-497

  Abstract

  In this article, we highlight recent Bipolar Collaborative Network data. We found that childhood-onset bipolar illness is common, often goes untreated for more than a decade, and carries a poor prognosis. During randomized studies of adjunctive medications in depression: 1) Venlafaxine showed higher switch rates than bupropion or sertraline; 2) Tranylcypromine was as well tolerated as lamotrigine; and 3) Modafinil was more effective than placebo. Finally, in treatment of overweight and obesity, topiramate and sibutramine showed equal efficacy but poor tolerability, and zonisamide data showed that it may be useful for mood and weight loss.

  View details for PubMedID 17162830

• Double-blind, randomized, placebo-controlled trials of ethyl-eicosapentanoate in the treatment of bipolar depression and rapid cycling bipolar disorder Conference on Pediatric Bipolar Disorder Keck, P. E., Mintz, J., McElroy, S. L., Freeman, M. P., Frye, T. S., Altshuler, L. L., Kupka, R., Nolen, W. A., Leverich, G. S., Denicoff, K. D., Grunze, H., Duan, N., Post, R. M. ELSEVIER SCIENCE INC. 2006: 1020–22

  Abstract

  The results of pilot trials suggest that omega-3 fatty acids may have efficacy in the treatment of mood symptoms in bipolar disorder.We conducted a 4-month, randomized, placebo-controlled, adjunctive trial of ethyl-eicosapentanoate (EPA) 6 g/day in the treatment of bipolar depression and rapid cycling bipolar disorder. Subjects were receiving mood-stabilizing medications at therapeutic doses or plasma concentrations. The measures of efficacy were early study discontinuation, changes from baseline in depressive symptoms (Inventory for Depressive Symptomology total score) and in manic symptoms (Young Mania Rating Scale total score), and manic exacerbations ("switches"). We also measured side effects and bleeding time, a biomarker of drug action.Overall, there were no significant differences on any outcome measure between the EPA and placebo groups.This study did not find overall evidence of efficacy for adjunctive treatment with EPA 6 g/day in outpatients with bipolar depression or rapid cycling bipolar disorder.

  View details for DOI 10.1016/j.biopsych.2006.03.056

  View details for Web of Science ID 000241691600017

  View details for PubMedID 16814257

• Incidence and time course of subsyndromal symptoms in patients with bipolar I disorder: An evaluation of 2 placebo-controlled maintenance trials JOURNAL OF CLINICAL PSYCHIATRY Frye, M. A., Yatham, L. N., Calabrese, J. R., Bowden, C. L., Ketter, T. A., Suppes, T., Adams, B. E., Thompson, T. R. 2006; 67 (11): 1721-1728

  Abstract

  Subsyndromal symptoms in bipolar disorder can cause significant functional impairment and are associated with relapse.In this post hoc analysis from 2 randomized, double-blind, 18-month, placebo-controlled maintenance trials for bipolar I disorder (both trials were conducted between August 1997 and August 2001 and used DSM-IV criteria), the incidence, time course, and impact of pharmacotherapy on subsyndromal symptoms were examined.Subsyndromal symptoms occurred in approximately 25% of all visits. Compared with placebo (54.8%), a significantly higher mean percentage of visits in remission were observed with lamotrigine treatment (63.0%, p = .020) but not with lithium treatment (60.0%, p = .165). The median time to onset of subsyndromal symptoms for lamotrigine (N = 223), lithium (N = 164), and placebo (N = 188) was 15, 15, and 9 days, respectively. Compared with placebo, both lamotrigine and lithium significantly delayed the time from randomization to onset of subsyndromal symptoms (p = .046, lamotrigine vs. placebo; p = .033, lithium vs. placebo; p = .763, lamotrigine vs. lithium) and the time from onset of subsyndromal symptoms to subsequent mood episode (p = .037, lamotrigine vs. placebo; p = .023, lithium vs. placebo; p = .845, lamotrigine vs. lithium). Agreement between the polarities of the first-observed subsyndromal symptom and subsequent intervention for mood episode was statistically significant (p < .001).Subsyndromal symptoms are common during maintenance treatment and appear to be associated with relapse into an episode of the same polarity. Both lithium and lamotrigine delayed the onset of subsyndromal symptoms and the time from onset of subsyndromal symptoms to subsequent relapse. Further study to assess whether treatment intervention can minimize subsyndromal symptoms or prevent relapse is encouraged.

  View details for Web of Science ID 000242432300008

  View details for PubMedID 17196051

• Subsyndromal depressive symptoms are associated with functional impairment in patients with bipolar disorder: Results of a large, multisite study JOURNAL OF CLINICAL PSYCHIATRY Altshuler, L. L., Post, R. M., Black, D. O., Keck, P. E., Nolen, W. A., Frye, M. A., Suppes, T., Grunze, H., Kupka, R. W., Leverich, G. S., McElroy, S. L., Walden, J., Mintz, J. 2006; 67 (10): 1551-1560

  Abstract

  Studies of patients with unipolar depression have demonstrated a relationship between subthreshold depressive symptoms and impairment in role functioning. Research examining this relationship in persons with bipolar disorder is rare. This study sought to evaluate the association between subsyndromal depressive symptoms and role functioning in subjects with bipolar disorder.759 adult outpatients with a DSM-IV diagnosis of bipolar disorder were entered into this study at 7 different sites in the Stanley Foundation Bipolar Network (SFBN) beginning in March 1996 and ending in November 2002 and were followed longitudinally for assessment of their course of illness. Subsyndromal depression was operationalized using cutoff scores on the Inventory for Depressive Symptomatology-Clinician Rated (IDS-C), and patients were divided into 3 groups: not depressed (IDS-C score < 13), subsyndromally depressed (IDS-C score 13 to 27), and syndromally depressed (IDS-C score >or= 28). Groups were compared using a series of chi(2) analyses on degree of role function impairment across 4 role domains (work, home duties, family life, and friendships) from the Life Functioning Questionnaire. Logistic regression was used to estimate the probability of any impairment in life functioning based on severity of depressive symptoms.Subsyndromally depressed patients were significantly more likely than those not depressed to report impairment in their work and home functioning roles, as well as impairment in relations with family and friends (p < .001). Across all domains of role function, the proportion of patients impaired in the subsyndromally depressed group was more similar to the syndromally depressed group than to the not depressed group.These findings clearly demonstrate the public health significance of subsyndromal depression in the bipolar population. The most appropriate interventions for subsyndromal depressive symptoms in patients with bipolar disorder remain to be determined.

  View details for Web of Science ID 000241964300009

  View details for PubMedID 17107246

• Omega-3 fatty acids in bipolar disorder: Clinical and research considerations PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS Marangell, L. B., Suppes, T., Ketter, T. A., Dennehy, E. B., Zboyan, H., Kertz, B., Nierenberg, A., Calabrese, J., Wisniewski, S. R., Sachs, G. 2006; 75 (4-5): 315-321

  Abstract

  Several lines of evidence suggest that omega-3 fatty acids may be important in the pathophysiology, treatment or prevention of bipolar disorder (BD). Electronic and manual searches were conducted in order to review the literature relevant to the etiology and treatment of BDs with omega-3 fatty acids. We also present data from a randomized, double-blind, placebo-controlled pilot study conducted at three sites (N = 10) comparing an omega-3 fatty acid (docosahexaenoic acid, DHA) versus placebo, added to psychosocial treatment for women with BD who chose to discontinue standard pharmacologic treatment while attempting to conceive. While some epidemiologic and preclinical data support the role of omega-3 fatty acids in BD, clinical trials to date have yielded conflicting results. In our pilot study of 10 Caucasian women taking DHA while attempting to conceive (BP1 = 9, BPII = 1), age 27-42 years, DHA was well tolerated and suggests that a larger study would be feasible. The elucidation of the potential role of omega-3 fatty acids as a treatment for BD requires further study. The current data are not sufficient to support a recommendation of monotherapy treatment as a substitute for standard pharmacologic treatments. However, judicious monotherapy in selected clinical situations, or adjunctive use, may be warranted pending further data from adequately powered controlled clinical trials. Our pilot trial of DHA in women who plan to stop conventional psychotropics in order to conceive suggests that such trials are feasible.

  View details for DOI 10.1016/j.plefa.2006.07.008

  View details for Web of Science ID 000241423400010

  View details for PubMedID 16928441

• Implementation of the texas medication algorithm project patient and family education program JOURNAL OF CLINICAL PSYCHIATRY Toprac, M. G., Dennehy, E. B., Carmody, T. J., Crismon, M. L., Miller, A. L., Trivedi, M. H., Suppes, T., Rush, A. J. 2006; 67 (9): 1362-1372

  Abstract

  This article describes the implementation and utilization of the patient and family education program (PFEP) component of the Texas Medication Algorithm Project (TMAP). The extent of participation, types of psychoeducation received, and predictors of receiving at least a minimum level of education are presented.TMAP included medication guidelines, a dedicated clinical coordinator, standardized assessments of symptoms and side effects, uniform documentation, and a PFEP. The PFEP includes phased, multimodal, disorder-specific educational materials for patients and families. Participants were adult outpatients of 1 of 7 community mental health centers in Texas that were implementing the TMAP disease management package. Patients had DSM-IV clinical diagnoses of major depressive disorder, with or without psychotic features; bipolar I disorder or schizoaffective disorder, bipolar type; or schizophrenia or schizoaffective disorder. Assessments were administered by independent research coordinators. Study data were collected between March 1998 and March 2000, and patients participated for at least 1 year.Of the 487 participants, nearly all (95.1%) had at least 1 educational encounter, but only 53.6% of participants met criteria for "minimum exposure" to individual education interventions. Furthermore, only 31.0% participated in group education, and 42.5% had a family member involved in at least 1 encounter. Participants with schizophrenia were less involved in the PFEP across multiple indicators of utilization. Diagnosis, intensity of symptoms, age, and receipt of public assistance were related to the likelihood of exposure to minimum levels of individual education.Despite adequate resources and infrastructure to provide PFEP, utilization was less than anticipated. Although implementation guidelines were uniform across diagnoses, participants with schizophrenia experienced less exposure to psychoeducation. Recommendations for improving program implementation and modification of materials are discussed.

  View details for Web of Science ID 000241339100006

  View details for PubMedID 17017822

• Mood switch in bipolar depression: comparison of adjunctive venlafaxine, bupropion and sertraline BRITISH JOURNAL OF PSYCHIATRY Post, R. M., Altshuler, L. L., Leverich, G. S., Frye, M. A., Nolen, W. A., Kupka, R. W., Suppes, T., McElroy, S., Keck, P. E., Denicoff, K. D., Grunze, H., Kitchen, C. M., Mintz, J. 2006; 189: 124-131

  Abstract

  Few studies have examined the relative risks of switching into hypomania or mania associated with second-generation antidepressant drugs in bipolar depression.To examine the relative acute effects of bupropion, sertraline and venlafaxine as adjuncts to mood stabilisers.In a 10-week trial, participants receiving out-patient treatment for bipolar disorder (stratified for rapid cycling) were randomly treated with a flexible dose of one of the antidepressants, or their respective matching placebos, as adjuncts to mood stabilisers.A total of 174 adults with bipolar disorder I, II or not otherwise specified, currently in the depressed phase, were included. All three antidepressants were associated with a similar range of acute response (49-53%) and remission (34-41%). There was a significantly increased risk of switches into hypomania or mania in participants treated with venlafaxine compared with bupropion or sertraline.More caution appears indicated in the use of venlafaxine rather than bupropion or sertraline in the adjunctive treatment of bipolar depression, especially if there is a prior history of rapid cycling.

  View details for Web of Science ID 000239836800006

  View details for PubMedID 16880481

• Recurrence in bipolar I disorder: A post hoc analysis excluding relapses in two double-blind maintenance studies BIOLOGICAL PSYCHIATRY Calabrese, J. R., Goldberg, J. F., Ketter, T. A., Suppes, T., Frye, M., White, R., DeVeaugh-Geiss, A., Thompson, T. R. 2006; 59 (11): 1061-1064

  Abstract

  To assess the efficacy of lamotrigine or lithium in preventing mood recurrence (i.e., a new mood episode) in bipolar disorder.Data from bipolar I patients with relapses (i.e., mood episodes having the same polarity as the index episode within 90 or 180 days of randomization) were excluded from post hoc efficacy analyses of two 18-month, placebo-controlled maintenance trials of lamotrigine and lithium.Both lamotrigine and lithium were more effective than placebo in delaying the time to intervention for any mood episode (depression, mania, hypomania, or mixed) when relapses that occurred in the first 90 days were excluded from the analyses (p = .002, lamotrigine vs. placebo; p = .010, lithium vs. placebo). Results were similar when patients with mood episodes within 180 days of randomization were excluded.Both lamotrigine and lithium maintenance therapy protected against mood episode recurrence in bipolar I disorder.

  View details for DOI 10.1016/j.biopsych.2006.02.034

  View details for Web of Science ID 000238416000011

  View details for PubMedID 16769295

• Valproate is associated with new-onset oligoamenorrhea with hyperandrogenism in women with bipolar disorder BIOLOGICAL PSYCHIATRY Joffe, H., Cohen, L. S., Suppes, T., McLaughlin, W. L., Lavori, P., Adams, J. M., Hwang, C. H., Hall, J. E., Sachs, G. S. 2006; 59 (11): 1078-1086

  Abstract

  Preliminary evidence suggests that valproate is associated with isolated features of polycystic ovarian syndrome (PCOS), while contradictory data support an association between epilepsy and PCOS. The development of PCOS features after initiation of valproate was therefore examined in women with bipolar disorder using a standardized definition of PCOS.Three hundred women 18 to 45 years old with bipolar disorder were evaluated for PCOS at 16 Systematic Treatment Enhancement for Bipolar Disorder sites. A comparison was made between the incidence of hyperandrogenism (hirsutism, acne, male-pattern alopecia, elevated androgens) with oligoamenorrhea that developed while taking valproate versus other anticonvulsants (lamotrigine, topiramate, gabapentin, carbamazepine, oxcarbazepine) and lithium. Medication and menstrual cycle histories were obtained, and hyperandrogenism was assessed.Among 230 women who could be evaluated, oligoamenorrhea with hyperandrogenism developed in 9 (10.5%) of 86 women on valproate and in 2 (1.4%) of 144 women on a nonvalproate anticonvulsant or lithium (relative risk 7.5, 95% confidence interval [CI] 1.7-34.1, p = .002). Oligoamenorrhea always began within 12 months of valproate use.Valproate is associated with new-onset oligoamenorrhea with hyperandrogenism. Monitoring for reproductive-endocrine abnormalities is important when starting and using valproate in reproductive-aged women. Prospective studies are needed to elucidate risk factors for development of PCOS on valproate.

  View details for DOI 10.1016/j.biopsych.2005.10.017

  View details for Web of Science ID 000238416000014

  View details for PubMedID 16448626

• An empirical analysis of cost outcomes of the Texas medication algorithm project PSYCHIATRIC SERVICES Kashner, T. M., Rush, A. J., Crismon, M. L., Toprac, M., Carmody, T. J., Miller, A. L., Trivedi, M. H., Wicker, A., Suppes, T. 2006; 57 (5): 648-659

  Abstract

  Disease management systems that incorporate medication algorithms have been proposed as cost-effective means to offer optimal treatment for patients with severe and chronic mental illnesses. The Texas Medication Algorithm Project was designed to compare health care costs and clinical outcomes between patients who received algorithm-guided medication management or usual care in 19 public mental health clinics.This longitudinal cohort study for patients with major depression (N=350), bipolar disorder (N=267), and schizophrenia (N=309) applied a multi-part declining-effects cost model. Outcomes were assessed by the Inventory of Depressive Symptomatology and the Brief Psychiatric Rating Scale.Compared with patients in usual care, patients in algorithm-based care incurred higher medication costs and had more frequent physician visits, although these differences often became smaller with time. For major depression, algorithm-based care achieved better outcomes sustainable with time but at higher agency and non-agency costs (mixed cost-effective). For bipolar disorder, patients in algorithm-based management achieved better outcomes at lower agency costs (cost-effective). For schizophrenia, patients in algorithm-based care achieved better outcomes that diminished with time, with no detectable difference in health care costs (cost-effective).Cost outcomes of algorithm-based care and usual care varied by disorder and over time. For bipolar disorder and schizophrenia, algorithm-based care improved outcomes without higher costs for health care services. For major depression, substantively better and sustained outcomes were obtained but at greater costs.

  View details for Web of Science ID 000237301500010

  View details for PubMedID 16675759

• Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and Bupropion as adjuncts to mood stabilizers AMERICAN JOURNAL OF PSYCHIATRY Leverich, G. S., Altshuler, L. L., Frye, M. A., Suppes, T., McElroy, S. L., Keck, P. E., Kupka, R. W., Denicoff, K. D., Nolen, W. A., Grunze, H., Martinez, M. I., Post, R. M. 2006; 163 (2): 232-239

  Abstract

  The authors examined the comparative risks of switches in mood polarity into hypomania or mania during acute and continuation trials of adjunctive antidepressant treatment of bipolar depression.One hundred fifty-nine patients with bipolar I disorder or bipolar II disorder participated in a total of 228 acute (10-week) randomized trials of bupropion, sertraline, or venlafaxine as an adjunct to a mood stabilizer. Patients in 87 of these trials entered continuation treatment for up to 1 year. Antidepressant response and the occurrence of subthreshold brief hypomania (emergence of brief hypomania [at least 1 but <7 days] or recurrent brief hypomania) and threshold switches (emergence of full-duration hypomania [> or =7 days] or mania) were blindly assessed by using clinician-rated daily reports of mood-associated dysfunction on the National Institute of Mental Health Life Chart Method.Threshold switches into full-duration hypomania and mania occurred in 11.4% and 7.9%, respectively, of the acute treatment trials and in 21.8% and 14.9%, respectively, of the continuation trials. The rate of threshold switches was higher in the 169 trials in patients with bipolar I disorder (30.8%) than the 59 trials in patients with bipolar II disorder (18.6%). The ratio of threshold switches to subthreshold brief hypomanias was higher in both the acute (ratio=3.60) and continuation trials (ratio=3.75) of venlafaxine than in the acute and continuation trials of bupropion (ratios=0.85 and 1.17, respectively) and sertraline (ratios=1.67 and 1.66, respectively). In only 37 (16.2%) of the original 228 acute antidepressant trials, or in only 23.3% of the patients, was there a sustained antidepressant response in the continuation phase in the absence of a threshold switch.Adjunctive treatment with antidepressants in bipolar depression was associated with substantial risks of threshold switches to full-duration hypomania or mania in both acute and long-term continuation treatment. Of the three antidepressants included in the study, venlafaxine was associated with the highest relative risk of such switching and bupropion with the lowest risk.

  View details for Web of Science ID 000235031000013

  View details for PubMedID 16449476

• Lower switch rate in depressed patients with bipolar II than bipolar I disorder treated adjunctively with second-generation antidepressants AMERICAN JOURNAL OF PSYCHIATRY Altshuler, L. L., Suppes, T., Black, D. O., Nolen, W. A., Leverich, G., Keck, P. E., Frye, M. A., Kupka, R., McElroy, S. L., Grunze, H., Kitchen, C. M., Post, R. 2006; 163 (2): 313-315

  Abstract

  The authors compared the switch rate into hypomania/mania in depressed patients treated with second-generation antidepressants who had either bipolar I or bipolar II disorder.In a 10-week trial, 184 outpatients with bipolar depression (134 with bipolar I disorder, 48 with bipolar II disorder, two with bipolar disorder not otherwise specified) were treated with one of three antidepressants as an adjunct to mood stabilizers. The patients' switch rates were assessed. Switch was defined as a Young Mania Rating Scale (YMRS) score >13 or a Clinical Global Impression (CGI) mania score > or =3 (mildly ill).Depressed subjects with bipolar II disorder had a significantly lower acute switch rate into hypomania/mania when either YMRS or CGI criteria were used to define switch.These data suggest that depressed patients with bipolar II disorder are less vulnerable than those with bipolar I disorder to switch into hypomania/mania when treated with an antidepressant adjunctive to a mood stabilizer.

  View details for Web of Science ID 000235031000024

  View details for PubMedID 16449487

• Rapid versus non-rapid cycling as a predictor of response to olanzapine and divalproex sodium for bipolar mania and maintenance of remission: Post hoc analyses of 47-week data JOURNAL OF AFFECTIVE DISORDERS Suppes, T., Brown, E., Schuh, L. M., Baker, R. W., Tohen, M. 2005; 89 (1-3): 69-77

  Abstract

  Rapid cycling in bipolar disorder has been associated with greater morbidity. We examine whether rapid cycling affects treatment response to olanzapine or divalproex in acute mania.A post hoc analysis of a 47-week, randomized, double-blind study compared olanzapine (5-20 mg/day) to divalproex sodium (500-2500 mg/day) for bipolar manic or mixed episodes (N=251). Young Mania Rating Scale (YMRS) scores > or = 20 were required for inclusion. Patients were classified at study entry as "rapid cyclers" if they experienced > or = 4 episodes within the last year. A repeated measures analysis of variance was used to analyze YMRS change from baseline.A significant three-way interaction (cycling frequency by medication by visit) was found when modeling change in YMRS total scores. For patients with bipolar I disorder identified as rapid cyclers, mania improvement across the trial did not differ significantly between treatment groups (p=0.181). Among non-rapid cyclers, olanzapine-treated patients had significantly greater YMRS improvement than divalproex-treated patients across the trial (p<0.001) and at most time points. Among olanzapine-treated patients, non-rapid cyclers experienced numerically greater YMRS improvement than rapid cyclers throughout the trial; statistically significant differences occurred at weeks 11, 15 and 39. In contrast, among divalproex-treated patients, YMRS scores were significantly better in rapid cyclers than non-rapid cyclers during the first two study weeks but were comparable thereafter. A similar pattern was seen in Clinical Global Impressions-Mania Severity scores. Hamilton Depression scores in rapid versus non-rapid cycling patients differed at some time points but not over the entire trial and differences by cycling status were not treatment-specific.Apart from the post hoc nature of the analyses, there were high dropout rates in both groups, and cycle frequency was not taken into account.Rapid cycling patients did less well over long-term treatment than non-rapid cycling patients. Among rapid cycling patients, olanzapine and divalproex appear similarly effective against manic symptoms; however, among non-rapid cycling patients, olanzapine-treated patients experienced superior mania improvement. Olanzapine-treated, non-rapid cyclers experienced greater mania improvement than rapid cyclers. The converse was true of divalproex-treated patients early in treatment.

  View details for DOI 10.1016/j.jad.2005.07.011

  View details for Web of Science ID 000234355500007

  View details for PubMedID 16253344

• Does provider adherence to a treatment guideline change clinical outcomes for patients with bipolar disorder? Results from the Texas Medication Algorithm Project PSYCHOLOGICAL MEDICINE Dennehy, E. B., Suppes, T., Rush, A. J., Miller, A. L., Trivedi, M. H., Crismon, M. L., Carmody, T. J., Kashner, T. M. 2005; 35 (12): 1695-1706

  Abstract

  Despite increasing adoption of clinical practice guidelines in psychiatry, there is little measurement of provider implementation of these recommendations, and the resulting impact on clinical outcomes. The current study describes one effort to measure these relationships in a cohort of public sector out-patients with bipolar disorder.Participants were enrolled in the algorithm intervention of the Texas Medication Algorithm Project (TMAP). Study methods and the adherence scoring algorithm have been described elsewhere. The current paper addresses the relationships between patient characteristics, provider experience with the algorithm, provider adherence, and clinical outcomes. Measurement of provider adherence includes evaluation of visit frequency, medication choice and dosing, and response to patient symptoms. An exploratory composite 'adherence by visit' score was developed for these analyses.A total of 1948 visits from 141 subjects were evaluated, and utilized a two-stage declining effects model. Providers with more experience using the algorithm tended to adhere less to treatment recommendations. Few patient factors significantly impacted provider adherence. Increased adherence to algorithm recommendations was associated with larger decreases in overall psychiatric symptoms and depressive symptoms over time, but did not impact either immediate or long-term reductions in manic symptoms.Greater provider adherence to treatment guideline recommendations was associated with greater reductions in depressive symptoms and overall psychiatric symptoms over time. Additional research is needed to refine measurement and to further clarify these relationships.

  View details for DOI 10.1017/S0033291705005933

  View details for Web of Science ID 000234059100002

  View details for PubMedID 16194283

• Quality of care measures for the treatment of bipolar disorder PSYCHIATRIC QUARTERLY Duffy, F. F., Narrow, W., West, J. C., Fochtmann, L. J., Kahn, D. A., Suppes, T., Oldham, J. M., McIntyre, J. S., Manderscheid, R. W., Sirovatka, P., Regier, D. 2005; 76 (3): 213-230

  Abstract

  The staff of the American Psychiatric Association (APA), the American Psychiatric Institute for Research and Education (APIRE), and a national panel of experts in bipolar disorder and practice guideline development have collaborated to generate a set of quality of care indicators for the pharmacologic and psychosocial treatment of bipolar disorder. The indicators were derived from APA's evidence-based Practice Guideline for the Treatment of Patients with Bipolar Disorder, 2002 (1) and the Expert Consensus Guideline Series: Medication Treatment of Bipolar Disorder, 2000 (2) These quality indicators can be used for quality monitoring, benchmarking, and quality improvement efforts across health plans, systems of care, and health care providers to improve quality and outcomes of care for patients with bipolar disorder.

  View details for DOI 10.1007/s11126-005-2975-4

  View details for Web of Science ID 000229788600001

  View details for PubMedID 16080418

• Mixed hypomania in 908 patients with bipolar disorder evaluated prospectively in the Stanley Foundation Bipolar Treatment Network - A sex-specific phenomenon 4th European-Stanley-Foundation Conference on Bipolar Disorder Suppes, T., Mintz, J., McElroy, S. L., Altshuler, L. L., Kupka, R. W., Frye, M. A., Keck, P. E., Nolen, W. A., Leverich, G. S., Grunze, H., Rush, A. J., Post, R. M. AMER MEDICAL ASSOC. 2005: 1089–96

  Abstract

  The prevalence of depressive symptoms co-occurring with hypomanic symptoms has not been quantified. Whether there is a greater likelihood for women to experience mixed symptoms has not been resolved.To determine whether mixed hypomania is observed more frequently than euphoric hypomania and whether a sex effect exists in patients with bipolar disorder.Academic research settings in the United States (4 sites) and Europe (3 sites).Subjects were enrolled in a naturalistic prospective study after providing written informed consent.Mixed hypomania was defined at a given visit as a Young Mania Rating Scale score of 12 or higher and an Inventory of Depressive Symptomatology-Clinician-Rated Version score of 15 or higher. Given partial overlap of items from these scales, exploratory analyses were completed assessing instrument overlap affecting the findings.In 908 patients, 14 328 visits over 7 years were evaluated. Patients with bipolar I disorder were significantly more likely to experience hypomania than those with bipolar II disorder. Of all 1044 visits by patients with hypomanic symptoms, 57% met criteria for mixed hypomania. The likelihood of depression was significantly greater for women during hypomania (P<.001). For women, the probability of mixed symptoms increased with the severity of hypomania and then decreased at the most severe levels of hypomania or mania. When a modified Inventory of Depressive Symptomatology-Clinician-Rated Version was evaluated by removing the 5 overlapping Young Mania Rating Scale items, a significant sex effect persisted for women (P<.001) but not for men (P = .95), owing to the elimination of the items "irritability" and "agitation."Mixed hypomania is common in patients with symptoms of hypomania and particularly common in women. Potential overlap of clinical symptom scales should be assessed before study of patients with bipolar disorder symptoms is undertaken.

  View details for Web of Science ID 000232430600004

  View details for PubMedID 16203954

• Comparison of rapid-cycling and non-rapid-cycling bipolar disorder based on prospective mood ratings in 539 outpatients 5th International Conference on Bipolar Disorder Kupka, R. W., Luckenbaugh, D. A., Post, R. M., Suppes, T., Altshuler, L. L., Keck, P. E., Frye, M. A., Denicoff, K. D., Grunze, H., Leverich, G. S., McElroy, S. L., Walden, J., Nolen, W. A. AMER PSYCHIATRIC PUBLISHING, INC. 2005: 1273–80

  Abstract

  To detect risk factors for rapid cycling in bipolar disorder, the authors compared characteristics of rapid-cycling and non-rapid-cycling patients both from a categorical and a dimensional perspective.Outpatients with bipolar I disorder (N=419), bipolar II disorder (N=104), and bipolar disorder not otherwise specified (N=16) were prospectively evaluated with daily mood ratings for 1 year. Subjects were classified as having rapid cycling (defined by the DSM-IV criterion of four or more manic or depressive episodes within 1 year) or not having rapid cycling, and the two groups' demographic and retrospective and prospective illness characteristics were compared. Associated factors were also evaluated in relationship to episode frequency.Patients with rapid cycling (N=206; 38.2%) significantly differed from those without rapid cycling (N=333) with respect to the following independent variables: history of childhood physical and/or sexual abuse, bipolar I disorder subtype, number of lifetime manic or depressive episodes, history of rapid cycling, and history of drug abuse. The prevalence of these characteristics increased progressively with episode frequency. The proportion of women was greater than the proportion of men only among patients with eight or more episodes per year. The average time spent manic/hypomanic increased as a function of episode frequency, but the average time spent depressed was comparable in patients with one episode and in those with more than one episode. Brief episodes were as frequent as full-duration DSM-IV-defined episodes.A number of heterogeneous risk factors were progressively associated with increasing episode frequency. Depression predominated in all bipolar disorder patients, but patients with rapid cycling were more likely to be characterized by manic features. The findings overall suggest that rapid cycling is a dimensional course specifier arbitrarily defined on a continuum of episode frequency.

  View details for Web of Science ID 000230196500008

  View details for PubMedID 15994709

• The Texas Implementation of Medication Algorithms: Update to the algorithms for treatment of bipolar I disorder JOURNAL OF CLINICAL PSYCHIATRY Suppes, T., Dennehy, E. B., Hirschfeld, R. M., Altshuler, L. L., Bowden, C. L., Calabrese, J. R., Crismon, M. L., Ketter, T. A., Sachs, G. S., Swann, A. C. 2005; 66 (7): 870-886

  Abstract

  A panel consisting of academic psychiatrists and pharmacist administrators of the Texas Department of State Health Services (formerly Texas Department of Mental Health and Mental Retardation), community mental health physicians, advocates, and consumers met in May 2004 to review new evidence in the pharmacologic treatment of bipolar I disorder (BDI). The goal of the consensus conference was to update and revise the current treatment algorithm for BDI as part of the Texas Implementation of Medication Algorithms, a statewide quality assurance program for the treatment of major psychiatric illness. The guidelines for evaluating possible medications, the criteria for selection and ranking, and the updated algorithms are described.Principles from previous consensus conferences were reviewed and amended. Medication algorithms for the acute treatment of hypomanic/manic or mixed and depressive episodes in BDI were developed after examining recent efficacy and safety and tolerability data. Recommendations for maintenance treatments were developed.The panel updated the 2 primary algorithms (hypomanic/manic/mixed and depressive) based on clinical evidence for efficacy, tolerability, and safety developed since 2000. Expert consensus was utilized where clinical evidence was limited. Prevention of new episodes or prophylaxis treatment recommendations were developed based on recent data from longer-term trials. Maintenance recommendations are provided as levels versus a specified staged algorithm, as for acute treatment, due to the relatively limited database to inform treatment.These algorithms for the treatment of BDI represent the recommendations based on the most recent evidence available. These recommendations are meant to provide a framework for clinical decision making, not to replace clinical judgment. As with any algorithm, treatment practices will evolve beyond the recommendations of this consensus conference as new evidence and additional medications become available.

  View details for Web of Science ID 000230663800010

  View details for PubMedID 16013903

• Brief Psychiatric Rating Scale Expanded Version: How do new items affect factor structure? PSYCHIATRY RESEARCH Velligan, D., Prihoda, T., Dennehy, E., Biggs, M., Shores-Wilson, K., Crismon, M. L., Rush, A. J., Miller, A., Suppes, T., Trivedi, M., Kashner, T. M., Witte, B., Toprac, M., Carmody, T., Chiles, J., Shon, S. 2005; 135 (3): 217-228

  Abstract

  Our goal was to suggest a factor structure for the Brief Psychiatric Rating Scale Expanded Version (BPRS-E) based upon a large and diverse sample and to determine which of the new items improved the factors derived from the 18-item version of the scale that have been used in clinical research for decades. We investigated the consistency of our proposed model over time and across demographic groups. As part of the Texas Medication Algorithm Project, the BPRS-E was administered to a total of 1440 psychiatric outpatients in three different diagnostic groups on multiple occasions. The sample was randomly split so that exploratory factor analysis could be done with the first half, and the model could be confirmed on the second half. A four-factor structure including factors assessing depression/anxiety, psychosis, negative symptoms, and activation was found. For each factor, we specify items in the expanded version that added to the breadth of the commonly used clinical factors while improving or maintaining goodness of fit and reliability. The final model proposed was consistent over time and across diagnosis, phase of illness, age, gender, ethnicity, and level of education. The BPRS-E has a stable four-factor structure, making it useful as a clinical outcome measure.

  View details for DOI 10.1016/j.psychres.2005.05.001

  View details for Web of Science ID 000230969600006

  View details for PubMedID 15993949

• Reproductive function and risk for PCOS in women treated for bipolar disorder BIPOLAR DISORDERS Rasgon, N. L., Altshuler, L. L., Fairbanks, L., Elman, S., Bitran, J., Labarca, R., Saad, M., Kupka, R., Nolen, W. A., Frye, M. A., Suppes, T., McElroy, S. L., Keck, P. E., Leverich, G., Grunze, H., Walden, J., Post, R., Mintz, J. 2005; 7 (3): 246-259

  Abstract

  This study examined the reproductive function and prevalence of polycystic ovary syndrome (PCOS) in women with bipolar disorder taking antimanic medications.Women aged 18-45 treated for bipolar disorder and not taking steroid contraceptives were recruited to complete questionnaires about their menstrual cycle and to provide blood samples for measurement of a range of reproductive endocrine and metabolic hormone levels. Eighty women participated in completing the questionnaires and 72 of them provided blood samples.Fifty-two of the 80 women (65%) reported current menstrual abnormalities, 40 of which (50%) reported one or more menstrual abnormalities that preceded the diagnosis of bipolar disorder. Fifteen women (38%) reported developing menstrual abnormalities since treatment for bipolar disorder, 14 of which developed abnormalities since treatment with valproate (p = 0.04). Of the 15 patients reporting menstrual abnormalities since starting medication, 12 (80%) reported changes in menstrual flow (heavy or prolonged bleeding) and five (33%) reported changes in cycle frequency. No significant differences were observed between women receiving or not receiving valproate in mean levels of free or total serum testosterone levels. This was true for the total sample and for the sub-group without preexisting menstrual problems. However, within the valproate group, duration of use was significantly correlated with free testosterone levels (r = 0.33, p = 0.02). Three of the 50 women (6%) taking VPA, and 0% of the 22 taking other antimanic medications, met criteria for PCOS (p = 0.20). Other reproductive and metabolic values outside the normal range across treatment groups included elevated 17 alpha-OH progesterone levels, luteinizing hormone: follicle-stimulating hormone ratios, homeostatic model assessment (HOMA) values, and low estrogen and dehydroepiandrosterone sulfate (DHEAS) levels. Preexisting menstrual abnormalities predicted higher levels of 17 alpha-OH progesterone, free testosterone, and estrone as well as development of new menstrual abnormalities. Body mass index (BMI) was significantly positively correlated with free testosterone levels and insulin resistance (HOMA) across all subjects, regardless of medication used.Rates of menstrual disturbances are high in women with bipolar disorder and, in many cases, precede the diagnosis and treatment for the disorder. Treatment with valproate additionally contributes significantly to the development of menstrual abnormalities and an increase in testosterone levels over time. A number of bipolar women, regardless of type of medication treatment received, have reproductive and metabolic hormonal abnormalities, yet the etiology of such abnormalities requires further study. Women with preexisting menstrual abnormalities may represent a group at risk for development of reproductive dysfunction while being treated for bipolar disorder.

  View details for Web of Science ID 000229081100004

  View details for PubMedID 15898962

• Open-label adjunctive zonisamide in the treatment of bipolar disorders: A prospective trial JOURNAL OF CLINICAL PSYCHIATRY McElroy, S. L., Suppes, T., Keck, P. E., Black, D., Frye, M. A., Altshuler, L. L., Nolen, W. A., Kupka, R. W., Leverich, G. S., Walden, J., Grunze, H., Post, R. M. 2005; 66 (5): 617-624

  Abstract

  The response of 62 outpatients with DSM-IV bipolar disorders to open-label adjunctive zonisamide was evaluated in a prospective 8-week acute trial, followed by a 48-week continuation trial, conducted from June 2001 through May 2002.During the acute trial, response to zonisamide was assessed weekly for the first 4 weeks and every 2 weeks for the second 4 weeks with the Clinical Global Impressions scale modified for bipolar illness (CGI-BP), the Young Mania Rating Scale (YMRS), and the Inventory for Depressive Symptomatology (IDS). During the continuation trial, patients were assessed with these scales every 4 weeks. Patients' weights and side effects were also evaluated. Outcome measures were analyzed with repeated-measures analyses of variance.Patients with manic symptoms at study entry (N = 34) displayed significant reductions in CGI-BP-Mania Severity and YMRS scores in the acute and continuation (N = 19) trials (p values < .0001 and < .001, respectively). Patients with depressive symptoms at study entry (N = 22) showed significant decreases in CGI-BP-Depression Severity and IDS scores in the acute trial (p values < .001 and < .05, respectively), but only 9 patients entered the continuation trial. Among these 9 patients, maintenance of anti-depressant response was mostly maintained. Initially euthymic patients (N = 6) showed no change in any rating scale scores acutely, but 2 of 4 patients who entered the continuation trial developed depressive symptoms. The 62 patients as a group showed significant weight loss in both trials (p values < .001). However, 20 patients (32%) discontinued zonisamide for worsening mood symptoms.Adjunctive zonisamide was associated with beneficial effects on mood and body weight in some patients with bipolar disorders, but was also associated with a high discontinuation rate due to worsening mood symptoms. Double-blind, placebo-controlled studies are necessary to determine zonisamide's thymoleptic properties, if any, in bipolar disorders.

  View details for Web of Science ID 000229302900012

  View details for PubMedID 15889949

• The efficacy of light therapy in the treatment of mood disorders: A review and meta-analysis of the evidence 156th Annual Meeting of the American-Psychiatric-Association Golden, R. N., Gaynes, B. N., Ekstrom, R. D., Hamer, R. M., JACOBSEN, F. M., Suppes, T., Wisner, K. L., Nemeroff, C. B. AMER PSYCHIATRIC PUBLISHING, INC. 2005: 656–62

  Abstract

  The purpose of this study was to assess the evidence base for the efficacy of light therapy in treating mood disorders.The authors systematically searched PubMed (January 1975 to July 2003) to identify randomized, controlled trials of light therapy for mood disorders that fulfilled predefined criteria. These articles were abstracted, and data were synthesized by disease and intervention category.Only 13% of the studies met the inclusion criteria. Meta-analyses revealed that a significant reduction in depression symptom severity was associated with bright light treatment (eight studies, having an effect size of 0.84 and 95% confidence interval [CI] of 0.60 to 1.08) and dawn simulation in seasonal affective disorder (five studies; effect size=0.73, 95% CI=0.37 to 1.08) and with bright light treatment in nonseasonal depression (three studies; effect size=0.53, 95% CI=0.18 to 0.89). Bright light as an adjunct to antidepressant pharmacotherapy for nonseasonal depression was not effective (five studies; effect size=-0.01, 95% CI=-0.36 to 0.34).Many reports of the efficacy of light therapy are not based on rigorous study designs. This analysis of randomized, controlled trials suggests that bright light treatment and dawn simulation for seasonal affective disorder and bright light for nonseasonal depression are efficacious, with effect sizes equivalent to those in most antidepressant pharmacotherapy trials. Adopting standard approaches to light therapy's specific issues (e.g., defining parameters of active versus placebo conditions) and incorporating rigorous designs (e.g., adequate group sizes, randomized assignment) are necessary to evaluate light therapy for mood disorders.

  View details for Web of Science ID 000228040600003

  View details for PubMedID 15800134

• Preliminary observations on the effectiveness of levetiracetam in the open adjunctive treatment of refractory bipolar disorder JOURNAL OF CLINICAL PSYCHIATRY Post, R. M., Altshuler, L. L., Frye, M. A., Suppes, T., McElroy, S. L., Keck, P. E., Leverich, G. S., Kupka, R., Nolen, W. A., Luckenbaugh, D. A., Walden, J., Grunze, H. 2005; 66 (3): 370-374

  Abstract

  Levetiracetam is a recently approved, well-tolerated anticonvulsant with a unique mechanism of action yielding efficacy in treatment-refractory seizure disorders and positive effects in an animal model of mania. Given the effectiveness of a range of other anticonvulsants in bipolar disorder, we sought to evaluate levetiracetam in patients with treatment-resistant illness.Thirty-four patients received 500 to 1000 mg of levetiracetam titrated to a target dose of 2000 mg/day (maximum dose = 3000 mg/day) as open, adjunctive treatment for clinically significant symptoms of depression (N = 13), mania (N = 7), or cycling (N = 14) despite ongoing treatment with mood stabilizers. Inventory for Depressive Symptomatology-Clinician version (IDS-C), Young Mania Rating Scale (YMRS), and Clinical Global Impressions scale for use in Bipolar Illness ratings were completed at each visit for 8 weeks, and partial responders were offered continuation treatment. Data were collected from July 2001 to December 2002.Five of 16 (31%; 13 depressed, 3 cycling) patients with initial depressive symptoms met the criterion for remission (IDS-C score of < or = 13) at last observation. All of these patients were less severely ill at baseline, whereas none of those more severely depressed at baseline responded. The majority of the 16 patients (7 manic, 9 cycling) with manic symptoms at baseline showed improvement in the YMRS in the first 2 weeks. While 7 of the 16 (44%) patients met the criterion for manic response and remission at last observation, 4 showed intervening periods of moderate to marked exacerbation. Levetiracetam was weight neutral.Other pilot trials should explore possible areas of psychotropic action of levetiracetam prior to the conduct of more controlled clinical trials.

  View details for Web of Science ID 000227744700013

  View details for PubMedID 15766304

• Low doses of clozapine may stabilize treatment-resistant bipolar patients EUROPEAN ARCHIVES OF PSYCHIATRY AND CLINICAL NEUROSCIENCE Fehr, B. S., Ozcan, M. E., Suppes, T. 2005; 255 (1): 10-14

  Abstract

  Open, uncontrolled studies suggest clozapine can have mood-stabilizing effects in treatment-resistant bipolar disorder. Unfortunately, the side effect profile limits clozapine's use at high doses. We report a series of nine bipolar I disorder patients who improved on relatively low doses of clozapine add-on therapy (250 mg or lower). Retrospectively abstracted clinical data identified nine patients with bipolar I disorder, as defined by DSMIV criteria, treated with low-dose clozapine at inpatient and outpatient settings. Monthly symptom evaluations were collected prospectively using standard assessments. Symptoms of mania and mood lability improved in all patients. Three patients demonstrated striking mood stabilization and returned to previous levels of functioning; five patients evidenced moderate improvement in mood stabilization and functioning; and one patient showed a minimal response. Overall, clozapine did not have a significant antidepressant effect. The mean clozapine dose at the end of the study was 156.3 +/- 77.6 mg/day, and duration of treatment was 12 months. Residual side effects were mild. The symptomatic improvement in these prospectively evaluated patients is consistent with our clinical impression in the majority of patients with bipolar disorder taking clozapine.

  View details for DOI 10.1007/s00406-004-0528-8

  View details for Web of Science ID 000227045700003

  View details for PubMedID 15538596

• Challenges in the management of bipolar depression Roundtable Meeting on the Burden of Bipolar Illness Suppes, T., Kelly, D. I., Perla, J. M. PHYSICIANS POSTGRADUATE PRESS. 2005: 11–16

  Abstract

  Bipolar depression has started to receive more attention in clinical trials only relatively recently, despite the fact that patients spend more time in the depressed phase than in the manic phase of bipolar disorder. The diagnosis and management of bipolar depression are challenging, and many patients are undiagnosed or misdiagnosed due to symptom similarities with unipolar depression or other illnesses and/or comorbidities. Untreated or inappropriately treated bipolar depression adds to the burden of illness and is associated with a greater risk of suicide. Treatment options include lithium, lamotrigine, atypical antipsychotics, and traditional antidepressants, such as the selective serotonin reuptake inhibitors. However, traditional antidepressants are recommended with caution due to their potential risk of switching patients into mania. Some atypical antipsychotics have shown efficacy in bipolar depression, although longer-term studies are warranted. The choice of treatment for different subgroups of patients with bipolar depression, including those with comorbid anxiety, may vary and also needs further study. Other important issues that require further investigation include the recognition of the core features of bipolar depression and the threshold symptoms for treatment, as well as the optimal treatment choices for monotherapy or combination therapy, and acute versus long-term management of bipolar depression.

  View details for Web of Science ID 000230322300003

  View details for PubMedID 16038597

• Atypical antipsychotics in bipolar depression: Potential mechanisms of action Roundtable Meeting on the Burden of Bipolar Illness Yatham, L. N., Goldstein, J. M., Vieta, E., Bowden, C. L., Grunze, H., Post, R. M., Suppes, T., Calabrese, J. R. PHYSICIANS POSTGRADUATE PRESS. 2005: 40–48

  Abstract

  "Conventional" antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs), bupropion, or serotonin-norepinephrine reuptake inhibitors, are not recommended as monotherapy for bipolar depression. Although they are likely to provide effective symptom relief in combination with mood stabilizers, the risk of precipitating a switch to mania often complicates their use even as combination therapy. Recently, 2 psychotropic medications approved for treating acute mania, olanzapine and quetiapine, have also been shown to possess antidepressant activity without destabilizing mood and, as such, are potential mood stabilizers. This article aims to review the mechanism of action of conventional antidepressants and newer agents that are effective in the treatment of bipolar depression. A number of mechanisms have been postulated to play a role in the effective treatment of bipolar depression, including targets as diverse as serotonin (5-HT), norepinephrine, dopamine, gamma-aminobutyric acid (GABA), glutamate, and various second messenger signaling pathways. A review of the data reveals an important point of commonality among the antidepressant treatments, olanzapine, and quetiapine. Antidepressant treatments, such as norepinephrine reuptake inhibitors, SSRIs, and electroconvulsive therapy, induce a reduction of 5-HT(2A) receptors. Both olanzapine and quetiapine not only are antagonists at this receptor but also induce downregulation of 5-HT(2A) receptors. It is possible that the antidepressant efficacy of these agents is mediated by this receptor, while the additional benefit of olanzapine and quetiapine over unimodal antidepressant treatments, in terms of stabilizing mood, may be provided by their concomitant dopamine D(2) antagonism. Further studies should be conducted to examine these hypotheses.

  View details for Web of Science ID 000230322300007

  View details for PubMedID 16038601

• A cautionary note when using zonisamide in youths a case report of association with toxic epidermal necrolysis JOURNAL OF CLINICAL PSYCHIATRY Majeres, K. D., Suppes, T. 2004; 65 (12): 1720-1720

  View details for Web of Science ID 000226074800019

  View details for PubMedID 15641880

• Effects of clozapine on sleep in bipolar and schizoaffective disorders PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY Armitage, R., Cole, D., Suppes, T., Ozcan, M. E. 2004; 28 (7): 1065-1070

  Abstract

  Sleep disturbances are strongly associated with mood disorders, although the majority of data have been obtained in patients with major depressive disorder. Studies reporting results in bipolar disorder are few, and results have not been consistent. Clozapine is a prototype of atypical antipsychotics, which is effective in improving symptoms of manic episodes in patients with bipolar disorder, or schizoaffective disorder, bipolar type and has been shown to influence sleep in other psychiatric disorders. The present study evaluated the sleep effects of clozapine in bipolar and schizoaffective disorders.Participants were 11 women and 4 men (range:28-53 years of age, mean 40.9+/-8.6 years), all with a history of mania by DSM-IV criteria for either bipolar I disorder or schizoaffective disorder, bipolar type. They participated in a sleep study at baseline and again after 6 months initiation of clozapine add-on therapy.Sleep latency was longer on clozapine and the number of awakenings were increased, whereas time in bed (TIB) and total sleep period (TSP) were increased (range: F=6.2-17.9; df=l,12; p<0.05). Although none of the individual sleep stage showed significant treatment changes, both Stage 2 and slow-wave sleep were increased and Stage 2 decreased on clozapine. Subjective sleep measures improved on clozapine with a small but significant improvement in how rested patients felt upon awakening (t=-2.1; df=26; p<0.05).Clozapine prolonged sleep latency, improved restedness, and increased total sleep time. Although lack of a control group limits interpretation of these results, they are in general agreement with studies in other psychiatric populations, and support the view that clozapine is primarily a NREM sleep enhancer. The improvement in restedness may be of positive clinical consequence.

  View details for DOI 10.1016/j.pnpbp.2004.05.048

  View details for Web of Science ID 000225602200001

  View details for PubMedID 15610918

• Treatment of bipolar mania with atypical antipsychotics. Expert review of neurotherapeutics Chengappa, K. N., Suppes, T., Berk, M. 2004; 4 (6): S17-25

  Abstract

  Acute manic episodes in bipolar disorder require rapid and effective relief. Pharmacotherapy has traditionally involved mood stabilizers such as lithium or divalproex. Evidence for the efficacy of atypical antipsychotics to treat bipolar mania, either as monotherapy or in combination with traditional mood-stabilizing agents, has increased in recent years. Since the combination of an atypical agent and a traditional mood stabilizer is generally well tolerated, it represents a first-line approach for the treatment of severe and treatment-resistant mania. Atypical antipsychotics have a superior neurological tolerability profile compared with typical antipsychotics and are preferentially recommended in most treatment guidelines. The atypical agents, olanzapine, risperidone, quetiapine, ziprasidone and aripiprazole, have demonstrated efficacy in bipolar mania in large randomized, controlled studies, and offer efficacy across a broader range of symptoms than typical antipsychotics, and may even have mood-stabilizing properties traditionally associated with lithium and divalproex. Olanzapine, risperidone and quetiapine have been shown to be effective for manic episodes both as monotherapy and in combination with other agents such as lithium and divalproex. Although the tolerability profiles of atypicals as a class are superior to those of conventional antipsychotics, there are differences among the atypical agents in their propensity to cause certain adverse events such as extrapyramidal symptoms (EPS) and weight gain, particularly in the long-term. The ultimate choice of the atypical agent will depend on the patient's individual needs, but atypical antipsychotics are clinically effective options for achieving mood stabilization in the treatment of acute bipolar mania.

  View details for PubMedID 16279862

• Adjunctive stimulant use in patients with bipolar disorder: treatment of residual depression and sedation BIPOLAR DISORDERS Carlson, P. J., Merlock, M. C., Suppes, T. 2004; 6 (5): 416-420

  Abstract

  Residual depression and medication-induced sedation remain significant problems for many patients with bipolar disorder (BD). Some evidence indicates that bipolar depression may be more responsive to dopaminergic agents, suggesting that adjunctive stimulant medication may be an effective treatment for bipolar depression as well as for medication-induced sedation. However, there are few data regarding the use of these medications in BD, likely due in part to concerns regarding potential stimulant-induced switching and stimulant abuse.In order to evaluate the effectiveness and safety of psychostimulants in BD, we retrospectively reviewed the cases of eight consecutive individuals from our clinic (five with bipolar I and three with bipolar II) who received adjunctive stimulants (either methylphenidate or amphetamine) within the last 2 years. Primary target symptoms of stimulant therapy included residual depression and medication-induced sedation. The degree of clinical change in target symptoms was estimated, and the Clinical Global Impression-BP Version scale (CGI-BP) was used to evaluate the overall severity of illness at baseline, 6 months after stimulant initiation, and at last visit.The eight patients generally showed moderate clinical improvement in their target symptoms and substantial improvement of overall bipolar illness (mean change in CGI-BP overall score 2.9). There was no evidence of stimulant-induced switching or abuse. The stimulants were well tolerated.The present case series suggests that adjunctive stimulants may be a reasonable therapeutic option for treating residual depression and medication-induced sedation in some patients. Controlled trials are needed to assess the safety and effectiveness of stimulant augmentation in BD.

  View details for Web of Science ID 000223996200009

  View details for PubMedID 15383134

• Correlates of 1-year prospective outcome in bipolar disorder: Results from the Stanley foundation bipolar network AMERICAN JOURNAL OF PSYCHIATRY Nolen, W. A., Luckenbaugh, D. A., Altshuler, L. L., Suppes, T., McElroy, S. L., Frye, M. A., Kupka, R. W., Keck, P. E., Leverich, G. S., Post, R. M. 2004; 161 (8): 1447-1454

  Abstract

  The purpose of the study was to examine potential correlates of outcome in patients treated for bipolar disorder.During a 1-year period, 258 patients with DSM-IV bipolar disorder or schizoaffective disorder were rated with the prospective NIMH-Life Chart Method, which characterizes each day in terms of the severity of manic and depressive symptoms on the basis of patients' mood-related impairment in their usual educational, social, or occupational roles. Mean ratings for the severity of mania, depression, and overall bipolar illness and the number of manic, depressive, and overall illness episodes were calculated. Potential risk factors were assessed at the start of the study, and multivariate linear regression analysis was used to determine the correlates of the six 1-year outcome measures.Three of the six outcome measures were largely independent of each other and were used in the analysis. The mean rating for severity of mania was associated with comorbid substance abuse, history of more than 10 prior manic episodes, and poor occupational functioning at study entry. The mean rating for severity of depression was associated with a history of more than 10 prior depressive episodes and poor occupational functioning at study entry. The total number of overall illness episodes was associated with a positive family history of drug abuse, a history of prior rapid cycling, and poor occupational functioning. In addition, the mean rating for severity of mania and the total number of overall illness episodes were both initially associated with a history of childhood abuse, but these relationships were lost with the addition of other illness variables to the analysis.Clinicians who treat patients with bipolar disorder should consider a family history of drug abuse, a history of childhood abuse, prior course of illness, comorbid substance abuse, and occupational functioning in determining prognosis and setting goals for further treatment.

  View details for Web of Science ID 000222976400019

  View details for PubMedID 15285972

• Response to clozapine of rapid cycling versus non-cycling patients with a history of mania BIPOLAR DISORDERS Suppes, T., Ozcan, M. E., Carmody, T. 2004; 6 (4): 329-332

  Abstract

  Rapid cycling (RC) bipolar disorder (BD) patients often do not respond fully to mood-stabilizers. Atypical antipsychotics including clozapine may be good candidates as an alternative mood-stabilizer for these patients.Twenty-eight treatment-resistant patients with either Bipolar Disorder Type I (n = 20), or Schizoaffective Disorder Bipolar Type (n = 8) received clozapine add-on therapy. Patients were followed for up to 1 year. Patients were seen monthly and assessed on a number of symptom domains.Fifteen of 28 patients met RC criteria. Differences between groups was non-significant for reported age of onset, age at study entry, past history of treatment or hospitalization, or diagnosis. However, significantly more women were RC. More than 80% of patients in either group showed at least some improvement over the 1-year study. Random regression analyses found the non-rapid cycling (NRC) group experienced significantly greater improvement than RC patients (p < 0.0001).Clozapine is more effective in NRC patients with a history of mania in comparison to patients with a recent history of RC.

  View details for Web of Science ID 000222356100009

  View details for PubMedID 15225152

• Clinical results for patients with major depressive disorder in the Texas medication algorithm project 155th Annual Meeting of the American-Psychiatric-Association Trivedi, M. H., Rush, A. J., Crismon, M. L., Kashner, T. M., Toprac, M. G., Carmody, T. J., Key, T., Biggs, M. M., Shores-Wilson, K., Witte, B., Suppes, T., Miller, A. L., Altshuler, K. Z., Shon, S. P. AMER MEDICAL ASSOC. 2004: 669–80

  Abstract

  The Texas Medication Algorithm Project is an evaluation of an algorithm-based disease management program for the treatment of the self-declared persistently and seriously mentally ill in the public mental health sector.To present clinical outcomes for patients with major depressive disorder (MDD) during 12-month algorithm-guided treatment (ALGO) compared with treatment as usual (TAU).Effectiveness, intent-to-treat, prospective trial comparing patient outcomes in clinics offering ALGO with matched clinics offering TAU.Four ALGO clinics, 6 TAU clinics, and 4 clinics that offer TAU to patients with MDD but provide ALGO for schizophrenia or bipolar disorder. Patients Male and female outpatients with a clinical diagnosis of MDD (psychotic or nonpsychotic) were divided into ALGO and TAU groups. The ALGO group included patients who required an antidepressant medication change or were starting antidepressant therapy. The TAU group initially met the same criteria, but because medication changes were made less frequently in the TAU group, patients were also recruited if their Brief Psychiatric Rating Scale total score was higher than the median for that clinic's routine quarterly evaluation of each patient.Primary outcomes included (1) symptoms measured by the 30-item Inventory of Depressive Symptomatology-Clinician-Rated scale (IDS-C(30)) and (2) function measured by the Mental Health Summary score of the Medical Outcomes Study 12-item Short-Form Health Survey (SF-12) obtained every 3 months. A secondary outcome was the 30-item Inventory of Depressive Symptomatology-Self-Report scale (IDS-SR(30)).All patients improved during the study (P<.001), but ALGO patients had significantly greater symptom reduction on both the IDS-C(30) and IDS-SR(30) compared with TAU. ALGO was also associated with significantly greater improvement in the SF-12 mental health score (P =.046) than TAU.The ALGO intervention package during 1 year was superior to TAU for patients with MDD based on clinician-rated and self-reported symptoms and overall mental functioning.

  View details for Web of Science ID 000222620200005

  View details for PubMedID 15237079

• Development of the Brief Bipolar Disorder Symptom Scale for patients with bipolar disorder PSYCHIATRY RESEARCH Dennehy, E. B., Suppes, T., Crismon, M. L., Toprac, M., Carmody, T. J., Rush, A. J. 2004; 127 (1-2): 137-145

  Abstract

  The Brief Bipolar Disorder Symptom Scale (BDSS) is a 10-item measure of symptom severity that was derived from the 24-item Brief Psychiatric Rating Scale (BPRS24). It was developed for clinical use in settings where systematic evaluation is desired within the constraints of a brief visit. The psychometric properties of the BDSS were evaluated in 409 adult outpatients recruited from 19 clinics within the public mental health system of Texas, as part of the Texas Medication Algorithm Project (TMAP). The selection process for individual items is discussed in detail, and was based on multiple analyses, including principal components analysis with varimax rotation. Selection of the final items considered the statistical strength and factor loading of items within each of those factors as well as the need for comprehensive coverage of critical symptoms of bipolar disorder. The BDSS demonstrated good psychometric properties in this preliminary investigation. It demonstrated a strong association with the BPRS24 and performed similarly to the BPRS24 in its relationship to other symptom measures. The BDSS demonstrated superior sensitivity to symptom change, and an excellent level of agreement for classification of patients as either responders or non-responders with the BPRS24.

  View details for DOI 10.1016/j.psychres.2004.02.009

  View details for Web of Science ID 000222952700014

  View details for PubMedID 15261712

• Quetiapine with lithium or divalproex for the treatment of bipolar mania: a randomized, double-blind, placebo-controlled study BIPOLAR DISORDERS Sachs, G., Chengappa, K. N., Suppes, T., MULLEN, J. A., Brecher, M., Devine, N. A., Sweitzer, D. E. 2004; 6 (3): 213-223

  Abstract

  Evaluate the efficacy and tolerability of quetiapine (QTP) combined with lithium (Li) or divalproex (DVP) in the treatment of acute mania.Patients were randomized to 21 days of double-blind treatment with QTP plus Li/DVP, or placebo (PBO) plus Li/DVP. QTP was rapidly dosed up to a maximum of 800 mg/day; Li was dosed to 0.7-1.0 mEq/L; or DVP to 50-100 microg/mL.Fifty-six of 91 (61.5%) individuals in the QTP + Li/DVP group compared with 49 of 100 (49%) taking PBO + Li/DVP completed the study. A significantly greater mean reduction in total Young Mania Rating Scale (YMRS) score was observed at end-point in patients receiving QTP + Li/DVP compared with those in the PBO + Li/DVP group (-13.76 versus -9.93; p = 0.021). The response rate (> or =50% YMRS improvement) was significantly higher in the QTP + Li/DVP group than in PBO + Li/DVP-treated patients (54.3% versus 32.6%; p = 0.005), as was the proportion of patients achieving clinical remission (YMRS < 12) (45.7% versus 25.8%; p = 0.007). Patients receiving QTP + Li/DVP also had a significantly greater improvement in Clinical Global Impressions-Bipolar (CGI-BP) Severity of Illness scores (-1.38 versus -0.78; p = 0.001). The mean last-week dose of QTP was 584 mg/day in patients meeting response criteria. Common adverse events (at least 10% and twice the rate of Li/DVP) in the QTP + Li/DVP group included somnolence, dry mouth, asthenia, and postural hypotension.Quetiapine combined with either Li or DVP has superior efficacy compared with Li or DVP monotherapy for treating patients with bipolar mania. Combination therapy was well-tolerated and most adverse events were mild, withdrawal because of adverse events being only 5% compared with 6% on Li or DVP monotherapy.

  View details for Web of Science ID 000221525200005

  View details for PubMedID 15117400

• Use of quetiapine in bipolar disorder: a case series with prospective evaluation INTERNATIONAL CLINICAL PSYCHOPHARMACOLOGY Suppes, T., McElroy, S. L., Keck, P. E., Altshuler, L., Frye, M. A., Grunze, H., Leverich, G. S., Nolen, W. A., Chisholm, K., Dennehy, E. B., Post, R. M. 2004; 19 (3): 173-174

  Abstract

  Quetiapine, a new atypical antipsychotic, was added to ongoing treatment of bipolar I outpatients (n=15) for symptoms of illness (mood lability, irritability, psychosis and/or difficulty sleeping). All evaluations were prospectively obtained, with the majority of patients (n=9) showing much or very much improvement on the Clinical Global Impression for Bipolar Disorder (CGI-BP). Somatic complaints were limited. Mean (SD) duration before changes in medication regimens was 134 (100) days. Studies of the use of quetiapine in maintenance treatment of bipolar disorder are warranted.

  View details for DOI 10.1091/01.yic.0000110797.97676.c0

  View details for Web of Science ID 000221282700010

  View details for PubMedID 15107662

• Development of a computerized assessment of clinician adherence to a treatment guideline for patients with bipolar disorder 42nd Annual Meeting of the New-Clinical-Drug-Evaluation-Unit Dennehy, E. B., Suppes, T., Rush, A. J., Crismon, M. L., Witte, B., Webster, J. PERGAMON-ELSEVIER SCIENCE LTD. 2004: 285–94

  Abstract

  The adoption of treatment guidelines for complex psychiatric illness is increasing. Treatment decisions in psychiatry depend on a number of variables, including severity of symptoms, past treatment history, patient preferences, medication tolerability, and clinical response. While patient outcomes may be improved by the use of treatment guidelines, there is no agreed upon standard by which to assess the degree to which clinician behavior corresponds to those recommendations. This report presents a method to assess clinician adherence to the complex multidimensional treatment guideline for bipolar disorder utilized in the Texas Medication Algorithm Project. The steps involved in the development of this system are presented, including the reliance on standardized documentation, defining core variables of interest, selecting criteria for operationalization of those variables, and computerization of the assessment of adherence. The computerized assessment represents an improvement over other assessment methods, which have relied on laborious and costly chart reviews to extract clinical information and to analyze provider behavior. However, it is limited by the specificity of decisions that guided the adherence scoring process. Preliminary findings using this system with 2035 clinical visits conducted for the bipolar disorder module of TMAP Phase 3 are presented. These data indicate that this system of guideline adherence monitoring is feasible.

  View details for DOI 10.1016/j.jpsychires.2003.10.002

  View details for Web of Science ID 000220334800009

  View details for PubMedID 15003434

• Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabiliser v. mood stabiliser alone BRITISH JOURNAL OF PSYCHIATRY Tohen, M., Chengappa, K. N., Suppes, T., Baker, R. W., Zarate, C. A., Bowden, C. L., Sachs, G. S., Kupfer, D. J., Ghaemi, S. N., Feldman, P. D., Risser, R. C., Evans, A. R., Calabrese, J. R. 2004; 184: 337-345

  Abstract

  Few controlled studies have examined the use of atypical antipsychotic drugs for prevention of relapse in patients with bipolar I disorder. Aims To evaluate whether olanzapine plus either lithium or valproate reduces the rate of relapse, compared with lithium or valproate alone.Patients achieving syndromic remission after 6 weeks'treatment with olanzapine plus either lithium (0.6-1.2 mmol/l) or valproate (50-125 microg/ml) received lithium or valproate plus either olanzapine 5-20 mg/day (combination therapy) or placebo (monotherapy), and were followed in a double-masked trial for 18 months.The treatment difference in time to relapse into either mania or depression was not significant for syndromic relapse (median time to relapse: combination therapy 94 days, monotherapy 40.5 days; P=0.742), but was significant for symptomatic relapse (combination therapy 163 days, monotherapy 42 days; P=0.023).Patients taking olanzapine added to lithium or valproate experienced sustained symptomatic remission, but not syndromic remission, for longer than those receiving lithium or valproate monotherapy.

  View details for Web of Science ID 000220754200011

  View details for PubMedID 15056579

• Management of bipolar disorder during pregnancy and the postpartum period AMERICAN JOURNAL OF PSYCHIATRY Yonkers, K. A., Wisner, K. L., Stowe, Z., Leibenluft, E., Cohen, L., Miller, L., Manber, R., Viguera, A., Suppes, T., Altshuler, L. 2004; 161 (4): 608-620

  Abstract

  Bipolar disorder affects 0.5%-1.5% of individuals in the United States. The typical age at onset is late adolescence or early adulthood, placing women at risk for episodes throughout their reproductive years. General guidelines for the treatment of bipolar disorder are available from the American Psychiatric Association, but additional issues arise when these guidelines are applied in the treatment of peripartum women. The authors summarize knowledge regarding the management of bipolar disorder during pregnancy and the postpartum period, with a focus on managing mania, hypomania, and the psychotic components of the illness.An expert panel reviewed articles that address the management of bipolar disorder and the consequences of the use of mood stabilizers during pregnancy, and a consensus document was generated.The treatment of bipolar disorder in pregnant women involves significant challenges. Some mood stabilizers, e.g., sodium valproate and carbamazepine, are human teratogens. On the other hand, the teratogenicity associated with lithium may have been overestimated in the past.Since treatment can be managed most effectively if pregnancy is planned, clinicians should discuss the issue of pregnancy and its management with every bipolar disorder patient who has childbearing potential, regardless of future reproductive plans. Additional research should address the risks of disturbed sleep to pregnant and postpartum women with bipolar disorder, as well as structural and behavioral consequences to offspring when mood stabilizers are used during pregnancy. Longitudinal and cohort studies can promote these efforts. Given the rate of bipolar disorder in the general population, research efforts will need to be broad based and include multiple collaborating centers.

  View details for Web of Science ID 000221276200003

  View details for PubMedID 15056503

• A 52-week, open-label continuation study of lamotrigine in the treatment of bipolar depression JOURNAL OF CLINICAL PSYCHIATRY McElroy, S. L., Zarate, C. A., Cookson, J., Suppes, T., Huffman, R. F., Greene, P., Ascher, J. 2004; 65 (2): 204-210

  Abstract

  Lamotrigine has demonstrated efficacy for the acute treatment of depression in bipolar I patients in a placebo-controlled, monotherapy study. We describe the results of a 52-week, open-label continuation of that trial.Patients meeting DSM-IV criteria for bipolar I disorder with a current major depressive episode who completed a 7-week, double-blind study of bipolar depression were offered 1 year of open-label lamotrigine therapy (flexible doses of 100-500 mg/day) in a continuation study. To maintain the acute study blind, the first 3 weeks of the continuation study remained blinded while patients previously randomly assigned to placebo were titrated to a lamotrigine dose of 50 mg/day. Patients who had been randomly assigned to lamotrigine continued at their fixed doses. Beginning at week 4, all patients received open-label lamotrigine for up to 49 additional weeks. Concomitant psychotropic medications were permitted during the open-label phase. Effectiveness (Montgomery-Asberg Depression Rating Scale [MADRS], Clinical Global Impressions-Improvement scale) and safety assessments were administered at weeks 4, 12, 24, 36, and 52. The study was conducted from June 1996 to December 1998.Of 135 patients completing the acute study, 124 (92%) entered the continuation study: 77 had received lamotrigine and 47 had received placebo in the acute study. The mean duration of lamotrigine exposure was 10.4 months, with a mean modal dose of 187 mg/day. Sixty-nine patients (56%) completed 1 year of treatment. Significant and sustained improvement from baseline was seen in mean observed MADRS scores (p <.05). The proportion of patients achieving remission (MADRS score < or = 11) by week 4 of the study was 81.4%, and episodes of mania/hypomania occurred less frequently than in the preceding year. Headache was the most common drug-related adverse event.During 1 year of open-label therapy with lamotrigine as adjunctive therapy or monotherapy, bipolar I patients experienced sustained improvement in depressive symptoms without evidence of mood destabilization.

  View details for Web of Science ID 000222190200010

  View details for PubMedID 15003074

• Treatment of rapid-cycling bipolar disorder CNS SPECTRUMS Post, R. M., Chang, K. D., Suppes, T., Ginsberg, D. L. 2004; 9 (2): 1-10

  View details for Web of Science ID 000226890700014

  View details for PubMedID 15032235

• Self-reported participation in nonpharmacologic treatments for bipolar disorder JOURNAL OF CLINICAL PSYCHIATRY Dennehy, E. B., GONZALEZ, R., Suppes, T. 2004; 65 (2): 278-278

  View details for Web of Science ID 000222190200028

  View details for PubMedID 15003089

• The Inventory of Depressive Symptomatology, Clinician Rating (IDS-C) and Self-Report (IDS-SR), and the Quick Inventory of Depressive Symptomatology, Clinician Rating (QIDS-C) and Self-Report (QIDS-SR) in public sector patients with mood disorders: a psychometric evaluation PSYCHOLOGICAL MEDICINE Trivedi, M. H., Rush, A. J., Ibrahim, H. M., Carmody, T. J., Biggs, M. M., Suppes, T., Crismon, M. L., Shores-Wilson, K., Toprac, M. G., Dennehy, E. B., Witte, B., Kashner, T. M. 2004; 34 (1): 73-82

  Abstract

  The present study provides additional data on the psychometric properties of the 30-item Inventory of Depressive Symptomatology (IDS) and of the recently developed Quick Inventory of Depressive Symptomatology (QIDS), a brief 16-item symptom severity rating scale that was derived from the longer form. Both the IDS and QIDS are available in matched clinician-rated (IDS-C30; QIDS-C16) and self-report (IDS-SR30; QIDS-SR16) formats.The patient samples included 544 out-patients with major depressive disorder (MDD) and 402 out-patients with bipolar disorder (BD) drawn from 19 regionally and ethnicically diverse clinics as part of the Texas Medication Algorithm Project (TMAP). Psychometric analyses including sensitivity to change with treatment were conducted.Internal consistencies (Cronbach's alpha) ranged from 0.81 to 0.94 for all four scales (QIDS-C16, QIDS-SR16, IDS-C30 and IDS-SR30) in both MDD and BD patients. Sad mood, involvement, energy, concentration and self-outlook had the highest item-total correlations among patients with MDD and BD across all four scales. QIDS-SR16 and IDS-SR30 total scores were highly correlated among patients with MDD at exit (c = 0.83). QIDS-C16 and IDS-C30 total scores were also highly correlated among patients with MDD (c = 0.82) and patients with BD (c = 0.81). The IDS-SR30, IDS-C30, QIDS-SR16, and QIDS-C16 were equivalently sensitive to symptom change, indicating high concurrent validity for all four scales. High concurrent validity was also documented based on the SF-12 Mental Health Summary score for the population divided in quintiles based on their IDS or QIDS score.The QIDS-SR16 and QIDS-C16, as well as the longer 30-item versions, have highly acceptable psychometric properties and are treatment sensitive measures of symptom severity in depression.

  View details for DOI 10.1017/S0033291703001107

  View details for Web of Science ID 000189108300007

  View details for PubMedID 14971628

• The Texas Medication Algorithm Project: Clinical results for schizophrenia 154th Annual Meeting of the American-Psychiatric-Association Miller, A. L., Crismon, M. L., Rush, A. J., Chiles, J., Kashner, T. M., Toprac, M., Carmody, T., Biggs, M., Shores-Wilson, K., Chiles, J., Witte, B., Bow-Thomas, C., Velligan, D. I., Trivedi, M., Suppes, T., Shon, S. OXFORD UNIV PRESS. 2004: 627–47

  Abstract

  In the Texas Medication Algorithm Project (TMAP), patients were given algorithm-guided treatment (ALGO) or treatment as usual (TAU). The ALGO intervention included a clinical coordinator to assist the physicians and administer a patient and family education program. The primary comparison in the schizophrenia module of TMAP was between patients seen in clinics in which ALGO was used (n = 165) and patients seen in clinics in which no algorithms were used (n = 144). A third group of patients, seen in clinics using an algorithm for bipolar or major depressive disorder but not for schizophrenia, was also studied (n = 156). The ALGO group had modestly greater improvement in symptoms (Brief Psychiatric Rating Scale) during the first quarter of treatment. The TAU group caught up by the end of 12 months. Cognitive functions were more improved in ALGO than in TAU at 3 months, and this difference was greater at 9 months (the final cognitive assessment). In secondary comparisons of ALGO with the second TAU group, the greater improvement in cognitive functioning was again noted, but the initial symptom difference was not significant.

  View details for Web of Science ID 000225659100018

  View details for PubMedID 15631256

• A re-evaluation of the role of antidepressants in the treatment of bipolar depression: data from the Stanley Foundation Bipolar Network Symposium on Antidepressant use in Bipolar Disorder Post, R. M., Leverich, G. S., Nolen, W. A., Kupka, R. W., Altshuler, L. L., Frye, M. A., Suppes, T., McElroy, S., Keck, P., Grunze, H., Walden, J. WILEY-BLACKWELL PUBLISHING, INC. 2003: 396–406

  Abstract

  The risk-to-benefit ratio of the use of unimodal antidepressants (ADs) as adjuncts to mood stabilizers continues to be an area of controversy and disagreement among experts in the field. This paper reviews new data on: (1) depression in bipolar illness, (2) switch rates on ADs and (3) risks of AD discontinuation that are pertinent to the ongoing discussion and recommendations.In the first study reviewed, 258 outpatients with bipolar illness were assessed prospectively on a daily basis using the National Institute of Mental Health-Life Chart Method (NIMH-LCM) for 1 year. In the second study, 127 bipolar depressed patients were randomized to 10 weeks of sertraline, bupropion, or venlafaxine, as adjuncts to mood stabilizers; non-responders were re-randomized and responders were offered a year of continuation treatment. In the final study, Altshuler et al. retrospectively and prospectively assessed the risk of depressive relapses in patients who remained on ADs after 2 months of euthymia compared with those who discontinued ADs.Despite intensive naturalistic treatment, the 258 outpatients with bipolar illness followed prospectively for 1 year showed three times as many days depressed as days manic, re-emphasizing the considerable depressive morbidity that remains in bipolar disorder despite the number of treatment options available. In the study of bipolar depressed patients randomized to one of three ADs, a range of severities and durations of hypomanic to manic switches were discerned following 175 trials of AD augmentation of treatment with a mood stabilizer. Of the acute 10-week trials, 9.1% were associated with switches into hypomania or mania and another 9.1% with a week or more of hypomania alone (with no to minimal dysfunction). In 73 continuation phase AD trials, 16.4 and 19.2% were similarly associated with hypomanic to manic and hypomanic switches, respectively. In the Altshuler et al. studies, those who remained well on any AD for more than 2 months (only 15-20% of those initially treated) and who continued on ADs showed a lesser rate of relapse into depression over 1 year (35 and 36% in the first and second study, respectively) compared with those who discontinued their ADs (68 and 70% relapsing into depression). Surprisingly, this continuation of ADs was associated with no increase in the rate of switching into mania compared with those stopping ADs.These data reveal that depression and depressive cycling remain a substantial problem in some two-thirds of intensively treated bipolar outpatients. Acute AD augmentation was associated with a modest response rate and 18.2% switched into a hypomanic to manic episode, and 35.6% of the continuation trials showed these two types of switches. Two separate studies suggest that in the very small subgroup who remain well on ADs for at least 2 months, one should consider continuation of this AD augmentation treatment, because AD discontinuation appears associated with a substantially increased risk of depression relapse over the subsequent year with no reduced risk of switching into mania.

  View details for Web of Science ID 000186869600003

  View details for PubMedID 14636363

• An overview of recent findings of the Stanley Foundation Bipolar Network (Part I) BIPOLAR DISORDERS Post, R. M., Leverich, G. S., Altshuler, L. L., Frye, M. A., Suppes, T. M., Keck, P. E., McElroy, S. L., Kupka, R., Nolen, W. A., Grunze, H., Walden, J. 2003; 5 (5): 310-319

  Abstract

  Selected recent findings of the Stanley Foundation Bipolar Network are briefly reviewed and their clinical implications discussed.Daily prospective ratings on the NIMH-LCM indicate a high degree of residual depressive morbidity (three times that of hypomania or mania) despite active psychopharmacological treatment with a variety of modalities including mood stabilizers, antidepressants, and benzodiazepines, as well as antipsychotics as necessary. The rates of switching into brief to full hypomania or mania during the use of antidepressants is described, and new data suggesting the potential utility of continuing antidepressants in the small group of patients showing an initial acute and persistent response is noted. Bipolar patients with a history of major environmental adversities in childhood have a more severe course of illness and an increased incidence of suicide attempts compared with those without. Preliminary open data suggest useful antidepressant effects of the atypical antipsychotic quetiapine, while a double-blind randomized controlled study failed to show efficacy of omega-3 fatty acids (6 g of eicosapentaenoic acid compared with placebo for 4 months) in the treatment of either acute depression or rapid cycling. The high prevalence of overweight and increased incidence of antithyroid antibodies in patients with bipolar illness is highlighted.Together, these findings suggest a very high degree of comorbidity and treatment resistance in outpatients with bipolar illness treated in academic settings and the need to develop not only new treatment approaches, but also much earlier illness recognition, diagnosis, and intervention in an attempt to reverse or prevent this illness burden.

  View details for Web of Science ID 000185736900002

  View details for PubMedID 14525551

• Psychosis in bipolar disorder: Phenomenology and impact on morbidity and course of illness COMPREHENSIVE PSYCHIATRY Keck, P. E., McElroy, S. L., Havens, J. R., Altshuler, L. L., Nolen, W. A., Frye, M. A., Suppes, T., Denicoff, K. D., Kupka, R., Leverich, G. S., Rush, A. J., Post, R. M. 2003; 44 (4): 263-269

  Abstract

  Although psychosis is common in bipolar disorder, few studies have examined the prognostic significance of psychotic features. In addition, some studies suggest that the presence of mood-incongruent psychosis, in particular, is associated with poorer outcome compared with mood-congruent psychosis. We assesses the phenomenology and prevalence of mood-congruent and mood-incongruent psychotic symptoms in 352 patients with bipolar I disorder participating in the Stanley Foundation Bipolar Treatment Network. We compared the demographic and clinical features, and measures of psychosocial and vocational functioning in patients with and without a history of psychosis. The phenomenology of psychosis in this cohort of patients with bipolar disorder was similar to that reported in earlier studies and supported the lack of diagnostic specificity of any one type of psychotic symptom. There were no significant differences between patients with and without a history of psychosis on any demographic, psychosocial, vocational, or course of illness variables. Only family history of bipolar disorder was significantly more common in patients with nonpsychotic bipolar disorder compared to patients with a history of psychosis. Among bipolar patients with a history of psychosis, only the proportion of women and lifetime prevalence rates of anxiety disorders occurred significantly more in patients with mood-incongruent delusions. In this large cohort of outpatients with bipolar I disorder, neither a history of psychosis nor of mood-incongruent psychosis had prognostic significance at entry into the Network. The lack of observable prognostic impact may have been, in part, due to the relatively high morbidity and poor functional outcome of a substantial portion of the total cohort.

  View details for DOI 10.1016/S0010-440X(03)00089-0

  View details for Web of Science ID 000184311600001

  View details for PubMedID 12923703

• Impact of antidepressant discontinuation after acute bipolar depression remission on rates of depressive relapse at 1-year follow-up AMERICAN JOURNAL OF PSYCHIATRY Altshuler, L., Suppes, T., Black, D., Nolen, W. A., Keck, P. E., Frye, M. A., McElroy, S., Kupka, R., Grunze, H., Walden, J., Leverich, G., Denicoff, K., Luckenbaugh, D., Post, R. 2003; 160 (7): 1252-1262

  Abstract

  While guidelines for treating patients with bipolar depression recommend discontinuing antidepressants within 6 months after remission, few studies have assessed the implications of this strategy on the risk for depressive relapse. This study examined the effect of antidepressant discontinuation or continuation on depressive relapse risk among bipolar subjects successfully treated for an acute depressive episode.Eighty-four subjects with bipolar disorder who achieved remission from a depressive episode with the addition of an antidepressant to an ongoing mood stabilizer regimen were followed prospectively for 1 year. The risk of depressive relapse among 43 subjects who stopped antidepressant treatment within 6 months after remission ("discontinuation group") was compared with the risk among 41 subjects who continued taking antidepressants beyond 6 months ("continuation group").A Cox proportional hazards regression analysis indicated that shorter antidepressant exposure time following successful treatment was associated with a significantly shorter time to depressive relapse. Furthermore, patients who discontinued antidepressant treatment within the first 6 months after remission experienced a significantly shorter period of euthymia before depressive relapse over the length of 1-year follow-up. One year after successful antidepressant response, 70% of the antidepressant discontinuation group experienced a depressive relapse compared with 36% of the continuation group. By the 1-year follow-up evaluation, 15 (18%) of the 84 subjects had experienced a manic relapse; only six of these subjects were taking an antidepressant at the time of manic relapse.The risk of depressive relapse in patients with bipolar illness was significantly associated with discontinuing antidepressants soon after remission. The risk of manic relapse was not significantly associated with continuing use of antidepressant medication and, overall, was substantially less than the risk of depressive relapse. Maintenance of antidepressant treatment in combination with a mood stabilizer may be warranted in some patients with bipolar disorder.

  View details for Web of Science ID 000183957200009

  View details for PubMedID 12832239

• Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of remission: A 47-week study AMERICAN JOURNAL OF PSYCHIATRY Tohen, M., Ketter, T. A., Zarate, C. A., Suppes, T., Frye, M., Altshuler, L., Zajecka, J., Schuh, L. M., Risser, R. C., Brown, E., Baker, R. W. 2003; 160 (7): 1263-1271

  Abstract

  Few double-blind trials have compared longer-term efficacy and safety of medications for bipolar disorder. The authors report a 47-week comparison of olanzapine and divalproex.This 47-week, randomized, double-blind study compared flexibly dosed olanzapine (5-20 mg/day) to divalproex (500-2500 mg/day) for manic or mixed episodes of bipolar disorder (N=251). The only other psychoactive medication allowed was lorazepam for agitation. The primary efficacy instrument was the Young Mania Rating Scale; a priori protocol-defined threshold scores were > or =20 for inclusion, < or =12 for remission, and > or = 15 for relapse. Analytical techniques included mixed model repeated-measures analysis of variance for change from baseline, Fisher's exact test (two-tailed) for categorical comparisons, and Kaplan-Meier estimates of time to events of interest.Over 47 weeks, mean improvement in Young Mania Rating Scale score was significantly greater for the olanzapine group. Median time to symptomatic mania remission was significantly shorter for olanzapine, 14 days, than for divalproex, 62 days. There were no significant differences between treatments in the rates of symptomatic mania remission over the 47 weeks (56.8% and 45.5%, respectively) and subsequent relapse into mania or depression (42.3% and 56.5%). Treatment-emergent adverse events occurring significantly more frequently during olanzapine treatment were somnolence, dry mouth, increased appetite, weight gain, akathisia, and high alanine aminotransferase levels; those for divalproex were nausea and nervousness.In this 47-week study of acute bipolar mania, symptomatic remission occurred sooner and overall mania improvement was greater for olanzapine than for divalproex, but rates of bipolar relapse did not differ.

  View details for Web of Science ID 000183957200010

  View details for PubMedID 12832240

• Morbidity in 258 bipolar outpatients followed for 1 year with daily prospective ratings on the NIMH Life Chart Method JOURNAL OF CLINICAL PSYCHIATRY Post, R. M., Denicoff, K. D., Leverich, G. S., Altshuler, L. L., Frye, M. A., Suppes, T. M., Rush, A. J., Keck, P. E., McElroy, S. L., Luckenbaugh, D. A., Pollio, C., Kupka, R., Nolen, W. A. 2003; 64 (6): 680-690

  Abstract

  A number of recent longitudinal outcome studies have found substantial long-term morbidity in patients with bipolar disorder. The detailed course and pattern of illness emerging despite comprehensive treatment with mood stabilizers and adjunctive agents have previously not been well delineated.258 consecutive outpatients admitted from 1996 to 1999 to the Stanley Foundation Bipolar Network who had a full year of prospective daily clinician ratings on the National Institute of Mental Health-Life Chart Method were included in the analysis. Patients were diagnosed by the Structured Clinical Interview for DSM-IV, with the majority (76%) having bipolar I disorder. They completed a questionnaire on demographics and prior illness course, and variables associated with outcome were examined in a hierarchical multinomial logistic regression analysis. Patients were treated naturalistically with a mean of 4.1 psychotropic medications during the year.Despite comprehensive pharmacologic treatment, mean time depressed (33.2% of the year) was 3-fold higher than time manic (10.8%); 62.8% of patients had 4 or more mood episodes per year. Two thirds of the patients were substantially impacted by their illness; 26.4% were ill for more than three fourths of the year, and 40.7% were intermittently ill with major affective episodes. After logistic regression analysis, those who were ill most of the year, compared with the largely well group, had a significantly greater family history of substance abuse, 10 or more depressive episodes, and limited occupational functioning prior to Network entry.A majority of outpatients with bipolar illness, even with intense monitoring and treatment in specialty clinics, have a considerable degree of residual illness-related morbidity, including a 3-fold greater amount of time spent depressed versus time spent manic. A personal or family history of substance abuse, 10 or more prior depressions, and limited occupational functioning predicted the poorest outcomes. Additional interventions, particularly those targeted at treating depressive phases of bipolar illness, are greatly needed.

  View details for Web of Science ID 000183746400010

  View details for PubMedID 12823083

• How rare is bipolar disorder not otherwise specified? BIPOLAR DISORDERS Ozcan, M. E., Shiekh, M., Suppes, T. 2003; 5 (3): 226-227

  View details for Web of Science ID 000183156800008

  View details for PubMedID 12780876

• The efficacy of olanzapine monotherapy for acute hypomania or mania in an outpatient setting INTERNATIONAL CLINICAL PSYCHOPHARMACOLOGY Dennehy, E. B., Doyle, K., Suppes, T. 2003; 18 (3): 143-145

  Abstract

  Randomized controlled trials have demonstrated the efficacy of olanzapine for treating acute mania or depression symptoms in patients with bipolar disorder. We aimed to evaluate the effectiveness of this medication in more usual care outpatient settings. A consecutive series of 15 patients entered an open, uncontrolled 8-week trial of olanzapine monotherapy. Inclusion criteria included significant hypomanic or manic symptoms greater than or equal to 15 on the Young Mania Rating Scale and no psychotic symptoms. The majority of patients experienced significant decreases in mania ratings and more limited improvement on depression ratings. Most patients reported adverse events consistent with other studies, but few discontinued due to these complaints. This case series highlights the individual variation in response to a proven medication. Furthermore, it highlights that those medications effective at one end of the mood spectrum may not be equally or simultaneously effective with other symptoms, emphasizing the complexity of treating bipolar illness.

  View details for DOI 10.1097/01.yic.0000062801.74434.25

  View details for Web of Science ID 000182963900003

  View details for PubMedID 12702892

• Gender differences in prevalence, risk, and clinical correlates of alcoholism comorbidity in bipolar disorder 2nd European Stanley-Foundation Conference on Bipolar Disorder Frye, M. A., Altshuler, L. L., McElroy, S. L., Suppes, T., Keck, P. E., Denicoff, K., Nolen, W. A., Kupka, R., Leverich, G. S., Pollio, C., Grunze, H., Walden, J., Post, R. M. AMER PSYCHIATRIC PUBLISHING, INC. 2003: 883–89

  Abstract

  The prevalence of lifetime alcohol abuse and/or dependence (alcoholism) in patients with bipolar disorder has been reported to be higher than in all other axis I psychiatric diagnoses. This study examined gender-specific relationships between alcoholism and bipolar illness, which have previously received little systematic study.The prevalence of lifetime alcoholism in 267 outpatients enrolled in the Stanley Foundation Bipolar Network was evaluated by using the Structured Clinical Interview for DSM-IV. Alcoholism and its relationship to retrospectively assessed measures of the course of bipolar illness were evaluated by patient-rated and clinician-administered questionnaires.As in the general population, more men (49%, 57 of 116) than women with bipolar disorder (29%, 44 of 151) met the criteria for lifetime alcoholism. However, the risk of having alcoholism was greater for women with bipolar disorder (odds ratio=7.35) than for men with bipolar disorder (odds ratio=2.77), compared with the general population. Alcoholism was associated with a history of polysubstance use in women with bipolar disorder and with a family history of alcoholism in men with bipolar disorder.This study suggests that there are gender differences in the prevalence, risk, and clinical correlates of alcoholism in bipolar illness. Although this study is limited by the retrospective assessment of illness variables, the magnitude of these gender-specific differences is substantial and warrants further prospective study.

  View details for Web of Science ID 000182610400012

  View details for PubMedID 12727691

• Factors associated with suicide attempts in 648 patients with bipolar disorder in the Stanley Foundation Bipolar Network JOURNAL OF CLINICAL PSYCHIATRY Leverich, G. S., Altshuler, L. L., Frye, M. A., Suppes, T., Keck, P. E., McElroy, S. L., Denicoff, K. D., Obrocea, G., Nolen, W. A., Kupka, R., Walden, J., Grunze, H., Perez, S., Luckenbaugh, D. A., Post, R. M. 2003; 64 (5): 506-515

  Abstract

  Clinical factors related to suicide and suicide attempts have been studied much more extensively in unipolar depression compared with bipolar disorder. We investigated demographic and course-of-illness variables to better understand the incidence and potential clinical correlates of serious suicide attempts in 648 outpatients with bipolar disorder.Patients with bipolar I or II disorder (DSM-IV criteria) diagnosed with structured interviews were evaluated using self-rated and clinician-rated questionnaires to assess incidence and correlates of serious suicide attempts prior to study entry. Clinician prospective ratings of illness severity were compared for patients with and without a history of suicide attempt.The 34% of patients with a history of suicide attempts, compared with those without such a history, had a greater positive family history of drug abuse and suicide (or attempts); a greater personal history of early traumatic stressors and more stressors both at illness onset and for the most recent episode; more hospitalizations for depression; a course of increasing severity of mania; more Axis I, II, and III comorbidities; and more time ill on prospective follow-up. In a hierarchical logistic regression, a history of sexual abuse, lack of confidant prior to illness onset, more prior hospitalizations for depression, suicidal thoughts when depressed, and cluster B personality disorder remained significantly associated with a serious suicide attempt.Our retrospective findings, supplemented by prospective follow-up, indicate that a history of suicide attempts is associated with a more difficult course of bipolar disorder and the occurrence of more psychosocial stressors at many different time domains. Greater attention to recognizing those at highest risk for suicide attempts and therapeutic efforts aimed at some of the correlates identified here could have an impact on bipolar illness-related morbidity and mortality.

  View details for Web of Science ID 000183114500003

  View details for PubMedID 12755652

• Texas Medication Algorithm Project, Phase 3 (TMAP-3): Clinical results for patients with a history of mania 154th Annual Meeting of the American-Psychiatric-Association Suppes, T., Rush, A. J., Dennehy, E. B., Crismon, M. L., Kashner, T. M., Toprac, M. G., Carmody, T. J., Brown, E. S., Biggs, M. M., Shores-Wilson, K., Witte, B. P., Trivedi, M. H., Miller, A. L., Altshuler, K. Z., Shon, S. P. PHYSICIANS POSTGRADUATE PRESS. 2003: 370–82

  Abstract

  The Texas Medication Algorithm Project (TMAP) assessed the clinical and economic impact of algorithm-driven treatment (ALGO) as compared with treatment-as-usual (TAU) in patients served in public mental health centers. This report presents clinical outcomes in patients with a history of mania (BD), including bipolar I and schizoaffective disorder, bipolar type, during 12 months of treatment beginning March 1998 and ending with the final active patient visit in April 2000.Patients were diagnosed with bipolar I disorder or schizoaffective disorder, bipolar type, according to DSM-IV criteria. ALGO was comprised of a medication algorithm and manual to guide treatment decisions. Physicians and clinical coordinators received training and expert consultation throughout the project. ALGO also provided a disorder-specific patient and family education package. TAU clinics had no exposure to the medication algorithms. Quarterly outcome evaluations were obtained by independent raters. Hierarchical linear modeling, based on a declining effects model, was used to assess clinical outcome of ALGO versus TAU.ALGO and TAU patients showed significant initial decreases in symptoms (p =.03 and p <.001, respectively) measured by the 24-item Brief Psychiatric Rating Scale (BPRS-24) at the 3-month assessment interval, with significantly greater effects for the ALGO group. Limited catch-up by TAU was observed over the remaining 3 quarters. Differences were also observed in measures of mania and psychosis but not in depression, side-effect burden, or functioning.For patients with a history of mania, relative to TAU, the ALGO intervention package was associated with greater initial and sustained improvement on the primary clinical outcome measure, the BPRS-24, and the secondary outcome measure, the Clinician-Administered Rating Scale for Mania (CARS-M). Further research is planned to clarify which elements of the ALGO package contributed to this between-group difference.

  View details for Web of Science ID 000182545700003

  View details for PubMedID 12716236

• Texas Medication Algorithm Project, Phase 3 (TMAP-3): Rationale and study design 154th Annual Meeting of the American-Psychiatric-Association Rush, A. J., Crismon, M. L., Kashner, T. M., Toprac, M. G., Carmody, T. J., Trivedi, M. H., Suppes, T., Miller, A. L., Biggs, M. M., Shores-Wilson, K., Witte, B. P., Shon, S. P., Rago, W. V., Altshuler, K. Z. PHYSICIANS POSTGRADUATE PRESS. 2003: 357–69

  Abstract

  Medication treatment algorithms may improve clinical outcomes, uniformity of treatment, quality of care, and efficiency. However, such benefits have never been evaluated for patients with severe, persistent mental illnesses. This study compared clinical and economic outcomes of an algorithm-driven disease management program (ALGO) with treatment-as-usual (TAU) for adults with DSM-IV schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD) treated in public mental health outpatient clinics in Texas.The disorder-specific intervention ALGO included a consensually derived and feasibility-tested medication algorithm, a patient/family educational program, ongoing physician training and consultation, a uniform medical documentation system with routine assessment of symptoms and side effects at each clinic visit to guide ALGO implementation, and prompting by on-site clinical coordinators. A total of 19 clinics from 7 local authorities were matched by authority and urban status, such that 4 clinics each offered ALGO for only 1 disorder (SCZ, BD, or MDD). The remaining 7 TAU clinics offered no ALGO and thus served as controls (TAUnonALGO). To determine if ALGO for one disorder impacted care for another disorder within the same clinic ("culture effect"), additional TAU subjects were selected from 4 of the ALGO clinics offering ALGO for another disorder (TAUinALGO). Patient entry occurred over 13 months, beginning March 1998 and concluding with the final active patient visit in April 2000. Research outcomes assessed at baseline and periodically for at least 1 year included (1) symptoms, (2) functioning, (3) cognitive functioning (for SCZ), (4) medication side effects, (5) patient satisfaction, (6) physician satisfaction, (7) quality of life, (8) frequency of contacts with criminal justice and state welfare system, (9) mental health and medical service utilization and cost, and (10) alcohol and substance abuse and supplemental substance use information. Analyses were based on hierarchical linear models designed to test for initial changes and growth in differences between ALGO and TAU patients over time in this matched clinic design.

  View details for Web of Science ID 000182545700002

  View details for PubMedID 12716235

• Clinician ratings vs. global ratings of symptom severity: a comparison of symptom measures in the bipolar disorder module, phase II, Texas Medication Algorithm Project PSYCHIATRY RESEARCH Brown, E. S., Rush, A. J., Biggs, M. M., Shores-Wilson, K., Carmody, T. J., Suppes, T. 2003; 117 (2): 167-175

  Abstract

  This study compares ratings obtained with an itemized, clinician-rated, symptom severity measure--the 24-item Brief Psychiatric Rating Scale (BPRS(24))--to a Physician Global Rating Scale (PhGRS), a Patient Global Rating Scale (PtGRS) and the clinician-completed Multnomah Community Ability Scale (MCAS) in patients with bipolar disorder (BPD). A total of 69 patients (25 inpatients and 44 outpatients) with BPD were enrolled in a feasibility study of the use of medication algorithms in the treatment of BPD. Clinicians at each visit completed the BPRS(24), PhGRS and MCAS, and patients completed the PtGRS. Analyses compared the BPRS(24) and BPRS subscales with the PtGRS, PhGRS and MCAS. PtGRS scores correlated poorly with BPRS(24) and with PhGRS scores at baseline, although PtGRS change scores correlated moderately with BPRS(24) change scores. Baseline BPRS(24) and PhGRS scores correlated moderately at baseline with somewhat stronger correlations found on change scores for the two measures. MCAS scores showed moderate correlations with BPRS(24) scores both at baseline and with change over time. Global assessments by patients or physicians only moderately or poorly reflected BPRS(24) scores. Itemized symptom measures to gauge severity of illness or change over time are preferred over patient or physician global judgments.

  View details for Web of Science ID 000182132700006

  View details for PubMedID 12606018

• Catching up on health outcomes: The Texas Medication Algorithm Project HEALTH SERVICES RESEARCH Kashner, T. M., Carmody, T. J., Suppes, T., Rush, A. J., Crismon, M. L., Miller, A. L., Toprac, M., Trivedi, M. 2003; 38 (1): 311-331

  Abstract

  To develop a statistic measuring the impact of algorithm-driven disease management programs on outcomes for patients with chronic mental illness that allowed for treatment-as-usual controls to "catch up" to early gains of treated patients.Statistical power was estimated from simulated samples representing effect sizes that grew, remained constant, or declined following an initial improvement. Estimates were based on the Texas Medication Algorithm Project on adult patients (age > or = 18) with bipolar disorder (n = 267) who received care between 1998 and 2000 at 1 of 11 clinics across Texas.Study patients were assessed at baseline and three-month follow-up for a minimum of one year. Program tracks were assigned by clinic.Hierarchical linear modeling was modified to account for declining-effects. Outcomes were based on 30-item Inventory for Depression Symptomatology-Clinician Version.Declining-effect analyses had significantly greater power detecting program differences than traditional growth models in constant and declining-effects cases. Bipolar patients with severe depressive symptoms in an algorithm-driven, disease management program reported fewer symptoms after three months, with treatment-as-usual controls "catching up" within one year.In addition to psychometric properties, data collection design, and power, investigators should consider how outcomes unfold over time when selecting an appropriate statistic to evaluate service interventions. Declining-effect analyses may be applicable to a wide range of treatment and intervention trials.

  View details for Web of Science ID 000181108900016

  View details for PubMedID 12650393

• High numbers of circulating activated T cells and raised levels of serum IL-2 receptor in bipolar disorder BIOLOGICAL PSYCHIATRY Breunis, M. N., Kupka, R. W., Nolen, W. A., Suppes, T., Denicoff, K. D., Leverich, G. S., Post, R. M., Drexhage, H. A. 2003; 53 (2): 157-165

  Abstract

  Previously, we found an increased prevalence of thyroid autoantibodies in patients with bipolar disorder. In the present study, we investigated other signs of immune activation in bipolar patients, in particular an activation of the T cell system.Fluorescence activated cell scanning (FACS) analysis was performed on lymphocytes of 64 outpatients with DSM-IV bipolar disorder using the T cell marker CD3 in combination with the activation markers MHC-class II, CD25, CD69 or CD71. In 34 patients, these assays were repeated after an interval of 2 years. In addition, T cell activation was determined by measuring serum soluble IL-2 receptor (sIL-2R) in 172 bipolar outpatients. Outcomes were compared with a healthy control group.Significantly higher numbers of circulating activated T cells and raised sIL-2R levels were found in euthymic, manic, and depressed bipolar patients when compared with healthy controls. In general, these abnormalities were stable over time. Manic patients showed significantly higher levels of sIL-2R in comparison with depressed patients.The T cell system was found to be activated in both symptomatic and euthymic patients with bipolar disorder. The pathophysiological significance of these findings remains to be explored.

  View details for DOI 10.1016/S0006-3223(02)01452-X

  View details for Web of Science ID 000180518900008

  View details for PubMedID 12547472

• Review of the use of topiramate for treatment of bipolar disorders JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Suppes, T. 2002; 22 (6): 599-609

  Abstract

  Lithium alone or in combination with other psychotherapeutic drugs has long been the gold standard of management for bipolar disorder (BD). Recognition of its limitations in the acute and chronic management of BD has led to the development of alternative therapies. One such approach involves the use of antiepileptic drugs (AEDs). The AED topiramate is currently being studied in the efficacy and management of BD. Topiramate has mechanisms in common with other AEDs, including sodium channel-blocking activity and enhancement of cerebral GABA concentrations. Open-label trials have evaluated topiramate at mean daily doses of 100 to 300 mg in various BD subtypes, including acute mania, depression, rapid-cycling, mixed states, and BD refractory to other medications. Results from these trials suggest topiramate may be efficacious in BD subtypes, particularly in rapid-cycling patients and those refractory to conventional treatment. Its side effect profile appears benign when used as monotherapy or in combination with other mood stabilizers. Placebo-controlled, double-blind studies are warranted to evaluate topiramate further in BD.

  View details for Web of Science ID 000179639500010

  View details for PubMedID 12454560

• Presentations of depression in bipolar illness CLINICAL NEUROSCIENCE RESEARCH Post, R. A., Denicoff, K. D., Leverich, G. S., Altshuler, L. L., Frye, M. A., Suppes, T. M., Keck, P. E., McElroy, S. L., Kupka, R., Nolen, W. A., Grunze, H., Walden, J. 2002; 2 (3-4): 142-157

  View details for Web of Science ID 000180273600004

• Rash in multicenter trials of lamotrigine in mood disorders: Clinical relevance and management 40th Annual Meeting of the American-College-of-Neuropsychopharmacology Calabrese, J. R., Sullivan, J. R., Bowden, C. L., Suppes, T., Goldberg, J. F., Sachs, G. S., Shelton, M. D., Goodwin, F. K., Frye, M. A., Kusumakar, V. PHYSICIANS POSTGRADUATE PRESS. 2002: 1012–19

  Abstract

  The rate of lamotrigine-associated rash in patients with mood disorders has not been well characterized. The objective of this report was to determine rash rates in clinical trials of lamotrigine in DSM-IV unipolar depression or bipolar disorder.A retrospective analysis was conducted of rates of lamotrigine-related rash in 12 multicenter studies, including 1 open study, 7 randomized controlled acute trials, and 4 randomized controlled maintenance trials from 1996 to 2001.A total of 1955 patients were treated with lamotrigine in open-label settings (open-label phases preceding or following randomization and 1 stand-alone open-label study); 1198 patients received lamotrigine in controlled settings, and 1056 patients received placebo. In controlled settings, rates of benign rash were 8.3% and 6.4% in lamotrigine- and placebo-treated patients, respectively. Rates of serious rash were 0% with lamotrigine, 0.1% (N = 1) with placebo, and 0% with comparators. In the open-label setting, the overall rate of rash for lamotrigine was 13.1% (N = 257) and of serious rash, 0.1% (N = 2). One mild case of Stevens-Johnson syndrome not requiring hospitalization occurred in a patient treated with lamotrigine. There were no cases of toxic epidermal necrolysis in any setting.Serious drug eruptions associated with lamotrigine were rare. Although rash is a potentially life-threatening reaction, the risk of serious rash due to lamotrigine should be weighed against more common risks associated with untreated or undertreated bipolar depression.

  View details for Web of Science ID 000179471900010

  View details for PubMedID 12444815

• Tiagabine in treatment refractory bipolar disorder: a clinical case series BIPOLAR DISORDERS Suppes, T., Chisholm, K. A., Dhavale, D., Frye, M. A., Atshuler, L. L., McElroy, S. L., Keck, P. E., Nolen, W. A., Kupka, R., Denicoff, K. D., Leverich, G. S., Rush, A. J., Post, R. M. 2002; 4 (5): 283-289

  Abstract

  Anticonvulsants have provided major treatment advances for patients with bipolar disorder. Many of these drugs, including several with proven efficacy in bipolar mania or depression, enhance the activity of the gamma-amino butyric acid (GABA) neurotransmitter system. A new anticonvulsant, tiagabine, has selective GABAergic activity and is approved for patients with partial epilepsy. Few reports of its potential effectiveness in bipolar disorder, however, have been published. We sought to evaluate the effectiveness of tiagabine added to ongoing medication regimens in patients with bipolar disorder inadequately responsive to or intolerant of usual treatments.Seventeen treatment-refractory patients participating in the Stanley Foundation Bipolar Network (SFBN) long-term follow-up study were offered open treatment with add-on tiagabine after discussion of the risks, benefits, other treatment options and giving informed consent. Patients' clinical symptoms and somatic complaints were closely monitored with SFBN longitudinal and cross-sectional ratings. Four patients discontinued low-dose tiagabine prior to the second visit and were excluded from data analysis.Thirteen patients received a mean of 38 days of treatment at a mean dose of 8.7 mg/day of tiagabine. On the Clinical Global Impression Scale for Bipolar Disorder Overall category, three (23%) patients showed much or very much improvement and 10 (77%) patients showed no change or worsening. Three significant adverse events were noted, including two presumptive seizures.Open add-on tiagabine for treatment-refractory patients with bipolar disorder demonstrated limited efficacy with the majority of patients showing no change or worsening of clinical symptoms. In addition, patients experienced serious side-effects attributed as likely due to the medication, which resolved without lasting consequence when tiagabine was discontinued.

  View details for Web of Science ID 000178520500002

  View details for PubMedID 12479659

• Developing novel treatments for mood disorders: Accelerating discovery BIOLOGICAL PSYCHIATRY Tamminga, C. A., Nemeroff, C. B., Blakely, R. D., Brady, L., Carter, C. S., Davis, K. L., Dingledine, R., Gorman, J. M., Grigoriadis, D. E., Henderson, D. C., Innis, R. B., Killen, J., Laughren, T. P., McDonald, W. M., Murphy, G. M., Paul, S. M., Rudorfer, M. V., Sausville, E., Schatzberg, A. F., SCOLNICK, E. M., Suppes, T. 2002; 52 (6): 589-609

  Abstract

  This review was generated from discussions by the Pharmacologic and Somatic Treatments Section of the National Institute of Mental Health Strategic Plan for Mood Disorders Committee on advancing novel pharmacologic and somatic treatments for mood disorders. The opening section of the article summarizes in broad strokes, current pharmacologic treatments, and new directions in the field. Thereafter the topics focus on specific research initiatives that could advance the current therapeutics for mood disorders including new basic and clinical research in vivo human imaging procedures, somatic therapeutics, and the vast new area of pharmacogenetics. New scientific and technical opportunities exist today based on advances in basic neuroscience, opportunities in clinical testing, industry interest in advancing central nervous system therapeutics, and on active consumer advocacy groups. The question of how to bring all of these positive forces together to accelerate discovery in mood disorder thera-peutics is the topic of this article.

  View details for Web of Science ID 000178297000008

  View details for PubMedID 12361670

• Assessment of beliefs in the effectiveness of acupuncture for treatment of psychiatric symptoms JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE Dennehy, E. B., Webb, A., Suppes, T. 2002; 8 (4): 421-425

  Abstract

  Research has demonstrated that beliefs or expectancies can exert a powerful influence on treatment and/or drug effects. As patients participate in more complementary and/or alternative treatments for psychiatric conditions, it is important to assess the role of belief or expectancy on response to nontraditional treatment approaches. The Acupuncture Beliefs Scale was developed to assess belief in the efficacy of acupuncture for both physical and psychiatric symptoms and conditions. Development and psychometric properties of the scale are described.Research personnel solicited statements regarding the potential experience and effects of acupuncture. These items were collapsed into a set of 36 items, with some rotated to avoid response bias. Outpatients diagnosed with bipolar disorder and undergraduates completed the scale (n = 118).The scale yielded excellent internal consistency (coefficient alpha = 0.97), and item-total score correlations between 0.37 and 0.83. Principal component analysis with a varimax rotation revealed three significant and meaningful factors that were consistent across both subject groups. Factors appeared to capture general endorsement of acupuncture treatment, beliefs in the scientific value and credibility of acupuncture treatment, and beliefs about the procedures and physical experience of acupuncture.The Acupuncture Beliefs Scale is a 36-item self-report scale that may be useful for measurement of beliefs in the effectiveness of acupuncture treatment.

  View details for Web of Science ID 000177855600006

  View details for PubMedID 12230902

• Olanzapine versus divalproex in the treatment of acute mania AMERICAN JOURNAL OF PSYCHIATRY Tohen, M., Baker, R. W., Altshuler, L. L., Zarate, C. A., Suppes, T., Ketter, T. A., Milton, D. R., Risser, R., Gilmore, J. A., Breier, A., Tollefson, G. A. 2002; 159 (6): 1011-1017

  Abstract

  The effects of olanzapine and divalproex for the treatment of mania were compared in a large randomized clinical trial.A 3-week, randomized, double-blind trial compared flexibly dosed olanzapine (5-20 mg/day) to divalproex (500-2500 mg/day in divided doses) for the treatment of patients hospitalized for acute bipolar manic or mixed episodes. The Young Mania Rating Scale and the Hamilton Depression Rating Scale were used to quantify manic and depressive symptoms, respectively. Safety was assessed with several measures.The protocol defined baseline-to-endpoint improvement in the mean total score on the Young Mania Rating Scale as the primary outcome variable. The mean Young Mania Rating Scale score decreased by 13.4 for patients treated with olanzapine (N=125) and 10.4 for those treated with divalproex (N=123). A priori categorizations defined response and remission rates: 54.4% of olanzapine-treated patients responded (> or = 50% reduction in Young Mania Rating Scale score), compared to 42.3% of divalproex-treated patients; 47.2% of olanzapine-treated patients had remission of mania symptoms (endpoint Young Mania Rating Scale < or = 12), compared to 34.1% of divalproex-treated patients. The decrease in Hamilton depression scale score was similar in the two treatment groups. Completion rates for the 3-week study were similar in both groups. The most common treatment-emergent adverse events (incidence >10%) occurring more frequently during treatment with olanzapine were dry mouth, increased appetite, and somnolence. For divalproex, nausea was more frequently observed. The average weight gain with olanzapine treatment was 2.5 kg, compared to 0.9 kg with divalproex treatment.The olanzapine treatment group had significantly greater mean improvement of mania ratings and a significantly greater proportion of patients achieving protocol-defined remission, compared with the divalproex treatment group. Significantly more weight gain and cases of dry mouth, increased appetite, and somnolence were reported with olanzapine, while more cases of nausea were reported with divalproex.

  View details for Web of Science ID 000175951300019

  View details for PubMedID 12042191

• Report of the Texas Consensus Conference Panel on Medication Treatment of Bipolar Disorder 2000 JOURNAL OF CLINICAL PSYCHIATRY Suppes, T., Dennehy, E. B., Swann, A. C., Bowden, C. L., Calabrese, J. R., Hirschfeld, R. M., Keck, P. E., Sachs, G. S., Crismon, M. L., Toprac, M. G., Shon, S. R. 2002; 63 (4): 288-299

  Abstract

  The process and outcome of a consensus conference to develop revised algorithms for treatment of bipolar disorder to be implemented in the public mental health system of Texas are described. These medication algorithms for bipolar disorder are an update of those developed for the Texas Medication Algorithm Project, a research study that tested the clinical and economic impact of treatment guidelines for major psychiatric illnesses treated in the Texas public mental health system (Texas Department of Mental Health and Mental Retardation [TDMHMR]).Academic clinicians and researchers, practicing clinicians in the TDMHMR system, administrators, advocates, and consumers participated in a consensus conference in August 2000. Participants attended presentations reviewing new evidence in the pharmacologic treatment of bipolar disorder and discussed the needs of consumers in the TDMHMR system. Principles were enumerated, including balancing of evidence for efficacy, tolerability, and safety in medication choices. A set of 7 distinct algorithms was drafted. In the following months, a subcommittee condensed this product into 2 primary algorithms.The panel agreed to 2 primary algorithms: treatment of mania/hypomania, including 3 pathways for treatment of euphoric symptoms, mixed or dysphoric symptoms, and psychotic symptoms; and treatment of depressive symptoms. General principles to guide algorithm implementation were discussed and drafted.The revised algorithms are currently being disseminated and implemented within the Texas public mental health system. The goals of the Texas initiative include increasing the consistency of appropriate treatment of bipolar disorder, encouraging systematic and optimal use of available pharmacotherapies, and improving the outcomes of patients with bipolar disorder.

  View details for Web of Science ID 000175017500004

  View details for PubMedID 12004801

• Correlates of overweight and obesity in 644 patients with bipolar disorder JOURNAL OF CLINICAL PSYCHIATRY McElroy, S. L., Frye, M. A., Suppes, T., Dhavale, D., Keck, P. E., Leverich, G. S., Altshuler, L., Denicoff, K. D., Nolen, W. A., Kupka, R., Grunze, H., Walden, J., Post, R. M. 2002; 63 (3): 207-213

  Abstract

  Overweight and obesity are common clinical problems encountered in the treatment of bipolar disorder. We therefore assessed the prevalence and clinical correlates of overweight, obesity, and extreme obesity in 644 bipolar patients.644 outpatients with DSM-IV bipolar disorder in the Stanley Foundation Bipolar Treatment Outcomes Network were evaluated with structured diagnostic interviews and clinician- and self-administered questionnaires to determine bipolar disorder diagnoses, demographic and historical illness characteristics, comorbid Axis I diagnoses, medical histories, health habits, and body mass indices (BMMs).Fifty-eight percent of the patients with bipolar disorder were overweight, 21% were obese, and 5% were extremely obese. American patients had significantly higher mean (p < .0001) BMIs and significantly higher rates of obesity (p < .001) and extreme obesity (p < .001) than European patients. Significant associations (p < or = .001) were found between overweight, obesity. and extreme obesity and gender, age, income level, comorbid binge-eating disorder, hypertension, arthritis, diabetes mellitus, exercise habits, and coffee consumption. Current BMI and weight were each correlated with the number of weight gain-associated psychotropics to which patients had been exposed. Multinomial logistic regression (adjusted for site and eating disorder diagnosis and corrected for multiple comparisons) showed that (1) overweight was significantly associated with male gender and hypertension (p < .001), (2) obesity was significantly associated with hypertension (p < .001), and (3) extreme obesity was significantly associated with hypertension and arthritis (p < .001).Overweight, obesity, and extreme obesity were common in this group of bipolar patients, although it was unclear that their prevalence rates were truly elevated, because overweight and obesity are increasingly common public health problems among the general population. Correlates of overweight and obesity in bipolar disorder include patient and treatment variables such as gender, geographical location, comorbid binge-eating disorder, age, income level, degree of exposure to weight gain-associated psychotropics, medical disorders associated with obesity, and health habits.

  View details for Web of Science ID 000174613400006

  View details for PubMedID 11926719

• High rate of autoimmune thyroiditis in bipolar disorder: Lack of association with lithium exposure BIOLOGICAL PSYCHIATRY Kupka, R. W., Nolen, W. A., Post, R. M., McElroy, S. L., Altshuler, L. L., Denicoff, K. D., Frye, M. A., Keck, P. E., Leverich, G. S., Rush, A. J., Suppes, T., Pollio, C., Drexhage, H. A. 2002; 51 (4): 305-311

  Abstract

  We assessed the prevalence of thyroperoxidase antibodies (TPO-Abs) and thyroid failure in outpatients with bipolar disorder compared with two control groups.The TPO-Abs of outpatients with DSM-IV bipolar disorder (n = 226), a population control group (n = 252), and psychiatric inpatients of any diagnosis (n = 3190) were measured. Thyroid failure was defined as a raised thyroid stimulating hormone level, previously diagnosed hypothyroidism, or both. Subjects were compared with attention to age, gender, and exposure to lithium.The TPO-Abs were more prevalent in bipolar patients (28%) than population and psychiatric controls (3-18%). The presence of TPO-Abs in bipolar patients was associated with thyroid failure, but not with age, gender, mood state, rapid cycling, or lithium exposure. Thyroid failure was present in 17% of bipolar patients and more prevalent in women. It was associated with lithium exposure, especially in the presence of TPO-Abs, but not with current rapid cycling, although an association may have been masked by thyroid hormone replacement.Thyroid autoimmunity was highly prevalent in this sample of outpatients with bipolar disorder and not associated with lithium treatment. These variables appear to be independent risk factors for the development of hypothyroidism, especially in women with bipolar disorder.

  View details for Web of Science ID 000174281200005

  View details for PubMedID 11958781

• Early physical and sexual abuse associated with an adverse course of bipolar illness BIOLOGICAL PSYCHIATRY Leverich, G. S., McElroy, S. L., Suppes, T., Keck, P. E., Denicoff, K. D., Nolen, W. A., Altshuler, L. L., Rush, A. J., Kupka, R., Frye, M. A., Autio, K. A., Post, R. M. 2002; 51 (4): 288-297

  Abstract

  There is growing awareness of the association between physical and sexual abuse and subsequent development of psychopathology, but little is known, however, about their relationship to the longitudinal course of bipolar disorder.We evaluated 631 outpatients with bipolar I or II disorder for general demographics, a history of physical or sexual abuse as a child or adolescent, course of illness variables, and prior suicide attempts, as well as SCID-derived Axis I and patient endorsed Axis II comorbidity.Those who endorsed a history of child or adolescent physical or sexual abuse, compared with those who did not, had a history of an earlier onset of bipolar illness, an increased number of Axis I, II, and III comorbid disorders, including drug and alcohol abuse, faster cycling frequencies, a higher rate of suicide attempts, and more psychosocial stressors occurring before the first and most recent affective episode. The retrospectively reported associations of early abuse with a more severe course of illness were validated prospectively.Greater appreciation of the association of early traumatic experiences and an adverse course of bipolar illness should lead to preventive and early intervention approaches that may lessen the associated risk of a poor outcome.

  View details for Web of Science ID 000174281200003

  View details for PubMedID 11958779

• Mood changes during prednisone bursts in outpatients with asthma JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Brown, E. S., Suppes, T., Khan, D. A., Carmody, T. J. 2002; 22 (1): 55-61

  Abstract

  Corticosteroids, such as prednisone and dexamethasone, are frequently prescribed medications sometimes associated with severe systemic side effects. Currently there are limited data regarding the psychiatric side effects of these medications, although mood changes and even psychoses have been reported. This study was designed to quantify psychiatric changes during brief courses of prednisone in patients with asthma. Outpatients with asthma (N = 32) receiving bursts of prednisone (>40 mg/day) were evaluated before, during, and after corticosteroid therapy by use of the Hamilton Rating Scale for Depression, the Young Mania Scale, the Brief Psychiatric Rating Scale, and the Internal State Scale. A Structured Clinical Interview for DSM-IV disorders was also conducted to examine past psychiatric history. Highly significant increases in the Young Mania Scale and Activation subscale of the Internal State Scale (both measures of mania) were observed with no increase in depression measures during the first 3 to 7 days of prednisone therapy. Mood changes were not correlated with improvement in airway obstruction, suggesting that mood elevations may not be in response to improvement in asthma symptoms. Subjects with past or current symptoms of depression had a significant decrease in depressive symptoms during prednisone therapy compared with those without depression. Some patients with posttraumatic stress disorder reported increases in depression and memories of the traumatic event during prednisone therapy. In summary, statistically significant changes in mood were observed even during brief courses of corticosteroids at modest dosages. The symptoms were primarily manic, not depressive. Persons with depression did not become more depressed during prednisone therapy, and, in fact, some showed improvement.

  View details for Web of Science ID 000173457200009

  View details for PubMedID 11799343

• Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy 153rd Annual Meeting of the American-Psychiatric-Association Tohen, M., Chengappa, K. N., Suppes, T., Zarate, C. A., Calabrese, J. R., Bowden, C. L., Sachs, G. S., Kupfer, D. J., Baker, R. W., Risser, R. C., Keeter, E. L., Feldman, P. D., Tollefson, G. D., Breier, A. AMER MEDICAL ASSOC. 2002: 62–69

  Abstract

  A 6-week double-blind, randomized, placebo-controlled trial was conducted to determine the efficacy of combined therapy with olanzapine and either valproate or lithium compared with valproate or lithium alone in treating acute manic or mixed bipolar episodes.The primary objective was to evaluate the efficacy of olanzapine (5-20 mg/d) vs placebo when added to ongoing mood-stabilizer therapy as measured by reductions in Young Mania Rating Scale (YMRS) scores. Patients with bipolar disorder (n = 344), manic or mixed episode, who were inadequately responsive to more than 2 weeks of lithium or valproate therapy, were randomized to receive cotherapy (olanzapine + mood-stabilizer) or monotherapy (placebo + mood-stabilizer).Olanzapine cotherapy improved patients' YMRS total scores significantly more than monotherapy (-13.11 vs -9.10; P = .003). Clinical response rates (> or = 50% improvement on YMRS) were significantly higher with cotherapy (67.7% vs 44.7%; P< .001). Olanzapine cotherapy improved 21-item Hamilton Depression Rating Scale (HAMD-21) total scores significantly more than monotherapy (4.98 vs 0.89 points; P< .001). In patients with mixed-episodes with moderate to severe depressive symptoms (DSM-IV mixed episode; HAMD-21 score of > or = 20 at baseline), olanzapine cotherapy improved HAMD-21 scores by 10.31 points compared with 1.57 for monotherapy (P< .001). Extrapyramidal symptoms (Simpson-Angus Scale, Barnes Akathisia Scale, Abnormal Involuntary Movement Scale) were not significantly changed from baseline to end point in either treatment group. Treatment-emergent symptoms that were significantly higher for the olanzapine cotherapy group included somnolence, dry mouth, weight gain, increased appetite, tremor, and slurred speech.Compared with the use of valproate or lithium alone, the addition of olanzapine provided superior efficacy in the treatment of manic and mixed bipolar episodes.

  View details for Web of Science ID 000173115800013

  View details for PubMedID 11779284

• Evidence-based long-term treatment of bipolar II disorder Symposium on Long-Term Use of Mood Stabilizers in Bipolar Disorder Suppes, T., Dennehy, E. B. PHYSICIANS POSTGRADUATE PRESS. 2002: 29–33

  Abstract

  Bipolar II disorder is a distinct, lifelong mental illness that affects at least 1.5 million people in the United States, is associated with a high incidence of comorbidity, and ends with completed suicide in 10% to 15% of diagnosed individuals. Bipolar II disorder is characterized by at least 1 major depressive episode with 1 or more hypomanic episodes, as opposed to manic or mixed episodes. While it is expected that there may be similarities in approaches to managing patients with bipolar I and bipolar II disorders, data suggest differential patient responses to pharmacologic treatments, supporting the need for research specifically in patients with bipolar II disorder. Despite the prevalence and severity of the disorder, a well-developed scientific database informing long-term treatment choices for bipolar II disorder as an illness differing from bipolar I disorder and major depressive disorder is virtually absent. A review of the limited and sometimes contradictory information stresses that more research is needed into prophylactic and maintenance treatment of bipolar II disorder.

  View details for Web of Science ID 000178701100006

  View details for PubMedID 12392351

• The Stanley Foundation Bipolar Treatment Outcome Network I. Longitudinal methodology JOURNAL OF AFFECTIVE DISORDERS Leverich, G. S., Nolen, W. A., Rush, A. J., McElroy, S. L., Keck, P. E., Denicoff, K. D., Suppes, T., Altshuler, L. L., Kupka, R., Kramlinger, K. G., Post, R. M. 2001; 67 (1-3): 33-44

  Abstract

  The NIMH-Stanley Foundation Bipolar Treatment Outcome Network, a multisite clinical trials network, has been established to address many of the neglected areas of research in bipolar illness. The Network was designed so that it would be able to conduct randomized clinical trials at several different levels of methodologic rigor (blinded and open-label) both in academic and community practice settings in order to better assess long-term efficacy of existing treatments and develop new ones. In this fashion, large numbers of representative patients with bipolar disorder have been enrolled with an additional focus of elucidating possible clinical and biological predictors of treatment response. The unique focus of the Network is its systematic longitudinal approach to illness so that patients can be assessed comprehensively over the long-term in sequential randomized clinical trials at critical clinical decision points where data on relative efficacy are inadequate. Bipolar I and bipolar II patients with a range of illness variants and comorbidities are included. Daily prospective ratings of severity of mania and depression and associated degree of functional impairment are completed on the NIMH-Life Chart Method and a modified Clinical Global Impressions Scale for Bipolar Illness (CGI-BP) is utilized. More detailed cross-sectional ratings for depression (Inventory of Depressive Symptomatology), mania (Young Mania Rating Scale), and psychosis (Positive and Negative Syndrome Scale) are additionally used at academic centers. This article describes the rationale for the Network, its guiding principles, methods, and study design to systematically assess the highly variable course of bipolar illness and its response to current and future treatments.

  View details for Web of Science ID 000174633800004

  View details for PubMedID 11869751

• The Stanley Foundation Bipolar Treatment Outcome Network II. Demographics and illness characteristics of the first 261 patients JOURNAL OF AFFECTIVE DISORDERS Suppes, T., Leverich, G. S., Keck, P. E., Nolen, W. A., Denicoff, K. D., Altshuler, L. L., McElroy, S. L., Rush, A. J., Kupka, R., Frye, M. A., Bickel, M., Post, R. M. 2001; 67 (1-3): 45-59

  Abstract

  Since recent NIMH Bipolar Disorder Workshops highlighted the dearth of longitudinal and controlled studies of bipolar illness, the Stanley Foundation Bipolar Network (SFBN) has recruited a large cohort of patients with bipolar disorder to begin to address these issues. This report describes the demographics and course of illness characteristics of this study population.The first 261 outpatients to be diagnosed by the Structured Clinical Interview for DSM-IV (SCID) and complete a detailed patient and a brief clinician questionnaire are described. All patients met DSM-IV criteria for bipolar I (n=211), bipolar II (n=42), or NOS (n=5) or schizoaffective (n=3), bipolar type. Chi-square and t-tests were used to examine statistically significant associations among important demographic and descriptive items.The general demographic and illness characteristics were similar to those in many bipolar clinical samples and not dissimilar from those reported in epidemiological surveys. The majority of patients had been hospitalized, with almost half reporting a worsening of illness over time, and two-thirds were not asymptomatic between episodes. First treatment for patients had been delayed by an average of 10 years from illness onset (by SCID). Almost a third of patients had attempted suicide at least once, and 30% reported current suicidal ideation at study entry. A total of 62% reported moderate to severe impact of the illness on occupational functioning. Early onset bipolar illness (< or =17 years old) was associated with increased frequency of mood switches, worsening course of illness, and history of early abuse (physical, verbal, or sexual).The SFBN represents a sample of predominantly BP I patients largely recruited from the community who will be followed in detail longitudinally, participate in clinical trials, and thus help advance our understanding and treatment of this life-threatening medical disorder. While there is a broad range of illness characteristics and severity, the majority of patients have been severely impacted by their illness despite the availability of multiple conventional treatment approaches in the community. These data further underscore the need for development of new and earlier treatment interventions.The SFBN population is limited by the lack of random selection and represents a cohort willing to be treated and followed intensively in academic tertiary referral centers. While its characteristics are similar to many clinical study populations, the generalizability to non-clinic populations remains uncertain.

  View details for Web of Science ID 000174633800005

  View details for PubMedID 11869752

• Rate of switch in bipolar patients prospectively treated with second-generation antidepressants as augmentation to mood stabilizers BIPOLAR DISORDERS Post, R. M., Altshuler, L. L., Frye, M. A., Suppes, T., Rush, A. J., Keck, P. E., McElroy, S. L., Denicoff, K. D., Leverich, G. S., Kupka, R., Nolen, W. A. 2001; 3 (5): 259-265

  Abstract

  Bipolar patients with breakthrough major depressive episodes despite ongoing adequately-dosed mood stabilizer medication were randomized in a double-blind manner to one of three antidepressants with different mechanisms of action: bupropion, sertraline, or venlafaxine. Preliminary data are presented on the switch rates into hypomania or mania for the antidepressants as a group prior to unblinding the specific individual drug efficacy and tolerability data in this ongoing clinical trial.Subjects included 64 bipolar patients who participated at five sites in a 10-week double-blind trial for depression and a 1-year blinded continuation maintenance phase for responders. Nonresponders were re-randomized such that there were 95 acute treatment phases. In the acute phase, doses were titrated to clinical response, side effects, or maximum dose of bupropion (450 mg/day), sertraline (200 mg/day), or venlafaxine (375 mg/day). Daily ratings on the National Institute of Mental Health-Life Chart Methodology (NIMH-LCM) were inspected for the degree of improvement on the Clinical Global Impressions scale as revised for bipolar illness (CGI-BP) and the occurrence of hypomania or mania.Thirty-five (37%) of the 95 acute treatment phases were associated with a much or very much improved rating in depression on the CGI-BP. Thirteen (14%) of these 95 acute trials of antidepressants as adjuncts to mood stabilizers were associated with switches, seven into hypomania and six into mania. Forty-two patients elected to go into the continuation phase in 48 instances. Sixteen (33%) of the continuation phase trials were associated with mood switches, 10 into hypomania and six into mania.In this randomized double-blind prospective study of three second-generation antidepressants (bupropion, sertraline, and venlafaxine) in bipolar patients whose depression broke through ongoing treatment with mood stabilizers, switches into hypomania or mania occurred in 14% of the acute phases and 33% of the continuation phases. Individual data on each drug will be assessed in the next phase of the study after more subjects are recruited and the blind is broken.

  View details for Web of Science ID 000171709900005

  View details for PubMedID 11912569

• Drug abuse and bipolar disorder: comorbidity or misdiagnosis? JOURNAL OF AFFECTIVE DISORDERS Brown, E. S., Suppes, T., Adinoff, B., Thomas, N. R. 2001; 65 (2): 105-115

  Abstract

  Bipolar disorder is a common, severe and cyclic psychiatric illness. A strong association between alcohol dependence and bipolar disorder has been reported in numerous studies. The abuse of other drugs including cocaine, amphetamines, opiates, cannabis, and prescription medications in bipolar patients is also an important public health concern and has been less extensively investigated. This review examines the abuse of drugs other than alcohol or nicotine in people with bipolar disorder. The high rates of milder affective symptoms but not mania observed in patients in drug abuse treatment settings suggests the symptoms may in many cases be associated with the drug use. However, such patients presenting in psychiatric settings might be suffering from cyclothymic and related attenuated bipolar disorders (type II). Substance abuse may be associated with medication non-compliance, more mixed or dysphoric mania and possibly an earlier onset of affective symptoms and more hospitalizations. The pharmacotherapy of patients with bipolar disorder and drug abuse is examined, including evidence on the use of mood stabilizers, neuroleptics and the newer atypical antipsychotics in this population.

  View details for Web of Science ID 000169077900001

  View details for PubMedID 11356233

• The Stanley Foundation Bipolar Network. I. Rationale and methods. The British journal of psychiatry. Supplement Post, R. M., Nolen, W. A., Kupka, R. W., Denicoff, K. D., Leverich, G. S., Keck, P. E., McElroy, S. L., Rush, A. J., Suppes, T., Altshuler, L. L., Frye, M. A., Grunze, H., Walden, J. 2001; 41: s169-76

  Abstract

  The Stanley Foundation Bipolar Network (SFBN) was created to address the paucity of help studies in bipolar illness.To describe the rationale and methods of the SFBN.The SFBN includes five core sites and a number of affiliated sites that have adopted consistent methodology for continuous longitudinal monitoring of patients. Open and controlled studies are performed as patients' symptomatology dictates.The reliability of SFBN raters and the validity of the rating instruments have been established. More than 500 patients are in continuous daily longitudinal follow-up. More than 125 have been randomised to one of three of the newer antidepressants (bupropion, sertraline and venlafaxine) as adjuncts in a study of mood stabilizers and 93 to omega-3 fatty acids. A number of open clinical case series have been published.Well-characterised patients are followed in a detailed continuous longitudinal fashion in both opportunistic case series and double-blind, randomised controlled trials with reliable and validated measures.

  View details for PubMedID 11450179

• The Stanley Foundation Bipolar Network 2. Preliminary summary of demographics, course of illness and response to novel treatments 1st European Stanley-Foundation Symposium on Bipolar Disorder Kupka, R. W., Nolen, W. A., Altshuler, L. L., Denicoff, K. D., Frye, M. A., Leverich, G. S., Keck, P. E., McElroy, S. L., Rush, A. J., Suppes, T., Post, R. M. ROYAL COLLEGE OF PSYCHIATRISTS. 2001: S177–S183

  View details for Web of Science ID 000169351100012

• The Stanley Foundation Bipolar Network I. Rationale and methods 1st European Stanley-Foundation Symposium on Bipolar Disorder Post, R. M., Nolen, W. A., Kupka, R. W., Denicoff, K. D., Leverich, G. S., Keck, P. E., McElroy, S. L., Rush, A. J., Suppes, T., Altshuler, L. L., Frye, M. A., Grunze, H., Walden, J. ROYAL COLLEGE OF PSYCHIATRISTS. 2001: S169–S176

  View details for Web of Science ID 000169351100011

• The Stanley Foundation Bipolar Network. 2. Preliminary summary of demographics, course of illness and response to novel treatments. The British journal of psychiatry. Supplement Kupka, R. W., Nolen, W. A., Altshuler, L. L., Denicoff, K. D., Frye, M. A., Leverich, G. S., Keck, P. E., McElroy, S. L., Rush, A. J., Suppes, T., Post, R. M. 2001; 41: s177-83

  Abstract

  The Stanley Foundation Bipolar Network (SFBN) evaluates treatments, course and clinical and neurobiological markers of response in bipolar illness.To give a preliminary summary of emerging findings in these areas.Studies with established and potentially antimanic, antidepressant and mood-stabilising agents range from open case series to double-blind randomised clinical trials, and use the same core assessment methodology, thereby optimising the comparability of the outcomes. The National Institute of Mental Health Life Chart Method is the core instrument for retrospective and prospective longitudinal illness description.The first groups of patients enrolled show a considerable degree of past and present symptomatology, psychiatric comorbidity and functional impairment. There are associations of both genetic and early environmental factors with more severe courses of illness. Open case series with add-on olanzapine, lamotrigine, gabapentin or topiramate show a differential spectrum of effectiveness in refractory patients.The SFBN provides important new data for the understanding and treatment of bipolar disorder.

  View details for PubMedID 11450180

• Texas Medication Algorithm Project: Development and feasibility testing of a treatment algorithm for patients with bipolar disorder JOURNAL OF CLINICAL PSYCHIATRY Suppes, T., Swann, A. C., Dennehy, E. B., Habermacher, E. D., Mason, M., Crismon, M. L., Toprac, M. G., Rush, A. J., Shon, S. P., Altshuler, K. Z. 2001; 62 (6): 439-447

  Abstract

  Use of treatment guidelines for treatment of major psychiatric illnesses has increased in recent years. The Texas Medication Algorithm Project (TMAP) was developed to study the feasibility and process of developing and implementing guidelines for bipolar disorder, major depressive disorder, and schizophrenia in the public mental health system of Texas. This article describes the consensus process used to develop the first set of TMAP algorithms for the Bipolar Disorder Module (Phase 1) and the trial testing the feasibility of their implementation in inpatient and outpatient psychiatric settings across Texas (Phase 2).The feasibility trial answered core questions regarding implementation of treatment guidelines for bipolar disorder. A total of 69 patients were treated with the original algorithms for bipolar disorder developed in Phase 1 of TMAP.Results support that physicians accepted the guidelines, followed recommendations to see patients at certain intervals, and utilized sequenced treatment steps differentially over the course of treatment. While improvements in clinical symptoms (24-item Brief Psychiatric Rating Scale) were observed over the course of enrollment in the trial, these conclusions are limited by the fact that physician volunteers were utilized for both treatment and ratings. and there was no control group.Results from Phases 1 and 2 indicate that it is possible to develop and implement a treatment guideline for patients with a history of mania in public mental health clinics in Texas. TMAP Phase 3, a recently completed larger and controlled trial assessing the clinical and economic impact of treatment guidelines and patient and family education in the public mental health system of Texas, improves upon this methodology.

  View details for Web of Science ID 000169918900007

  View details for PubMedID 11465521

• Axis I psychiatric comorbidity and its relationship to historical illness variables in 288 patients with bipolar disorder AMERICAN JOURNAL OF PSYCHIATRY McElroy, S. L., Altshuler, L. L., Suppes, T., Keck, P. E., Frye, M. A., Denicoff, K. D., Nolen, W. A., Kupka, R. W., Leverich, G. S., Rochussen, J. R., Rush, A. J., Post, R. M. 2001; 158 (3): 420-426

  Abstract

  Bipolar disorder often co-occurs with other axis I disorders, but little is known about the relationships between the clinical features of bipolar illness and these comorbid conditions. Therefore, the authors assessed comorbid lifetime and current axis I disorders in 288 patients with bipolar disorder and the relationships of these comorbid disorders to selected demographic and historical illness variables.They evaluated 288 outpatients with bipolar I or II disorder, using structured diagnostic interviews and clinician-administered and self-rated questionnaires to determine the diagnosis of bipolar disorder, comorbid axis I disorder diagnoses, and demographic and historical illness characteristics.One hundred eighty-seven (65%) of the patients with bipolar disorder also met DSM-IV criteria for at least one comorbid lifetime axis I disorder. More patients had comorbid anxiety disorders (N=78, 42%) and substance use disorders (N=78, 42%) than had eating disorders (N=9, 5%). There were no differences in comorbidity between patients with bipolar I and bipolar II disorder. Both lifetime axis I comorbidity and current axis I comorbidity were associated with earlier age at onset of affective symptoms and syndromal bipolar disorder. Current axis I comorbidity was associated with a history of development of both cycle acceleration and more severe episodes over time.Patients with bipolar disorder often have comorbid anxiety, substance use, and, to a lesser extent, eating disorders. Moreover, axis I comorbidity, especially current comorbidity, may be associated with an earlier age at onset and worsening course of bipolar illness. Further research into the prognostic and treatment response implications of axis I comorbidity in bipolar disorder is important and is in progress.

  View details for Web of Science ID 000167323000013

  View details for PubMedID 11229983

• Psychopharmacologic treatment strategies for depression, bipolar disorder, and schizophrenia ANNALS OF INTERNAL MEDICINE Glick, I. D., Suppes, T., Debattista, C., Hu, R. J., Marder, S. 2001; 134 (1): 47-60

  Abstract

  Patients with serious psychiatric disorders are frequently treated by primary care physicians, who may have difficulty keeping up with recent advances in psychiatry. This paper presents an updated synopsis for three major psychiatric illnesses: major depression, bipolar disorder, and schizophrenia. Current definitions, updated diagnostic criteria, short- and long-term treatment strategies with algorithms, and special challenges for the clinician are discussed for each of these illnesses. On the basis of each illness's distinct characteristics, five treatment principles are emphasized: 1) Treatment strategies should be long-term and should emphasize adherence, 2) treatment choice should be empirical, 3) combinations of medications may be helpful, 4) a combination of psychosocial and pharmacologic treatments may be more useful than either alone, and 5) the family or "significant others" as well as a consumer organization need to be involved. Some of the new directions in dinical research to refine these strategies and meet these challenges are also described.

  View details for PubMedID 11187420

• Bipolar rapid cycling: Focus on depression as its hallmark Symposium on the Role of Anticonvulsants as Mood Stabilizers Calabrese, J. R., Shelton, M. D., Bowden, C. L., Rapport, D. J., Suppes, T., Shirley, E. R., Kimmel, S. E., Caban, S. J. PHYSICIANS POSTGRADUATE PRESS. 2001: 34–41

  Abstract

  The phenomenon of frequent cycling in bipolar disorder was first recognized by Emil Kraepelin in 1913. More recently, rapid cycling has been reported to be a predictor of nonresponse to treatment. At the time of presentation, most patients with DSM-IV-defined rapid cycling appear to be in the depressed phase of their illness. Frequent and more severe episodes of depression appear to be the hallmark of rapid cycling. Reported in this article are recent preliminary data suggesting that the combination of lithium and divalproex sodium administered continuously over 6 months appears to result in marked acute and continuation antimanic efficacy in 85% of patients and marked antidepressant efficacy in 60%. However, only one half of patients experienced bimodal stabilization. Comorbid alcohol, cannabis, and/or cocaine abuse and/or dependence did not appear to directly affect the spectrum of efficacy of lithium and divalproex or response rates in compliant patients. Comorbidity appeared to alter prognosis by increasing the prevalence of poor compliance. The majority of patients receiving lithium and divalproex who required additional treatment were depressed, suggesting that the frequent recurrence of depression is the primary unmet need in patients with rapid cycling. The use of antidepressants in this population has been discouraged because of concerns about the possibility of cycle acceleration. There exists a need for a pharmacotherapy that not only possesses marked acute antidepressant properties, but that does so without inducing switching or cycle acceleration. A double-blind, placebo-controlled trial of lamotrigine monotherapy in bipolar I depression has demonstrated efficacy without causing switching at a rate exceeding placebo; however, this initial study excluded patients with rapid cycling. To explore the efficacy of lamotrigine in rapid cycling, a recent multicenter study has examined lamotrigine as a maintenance therapy for this population. The results indicate that lamotrigine may be a useful treatment for patients with rapid-cycling bipolar II disorder and that this drug has begun to address this unmet need.

  View details for Web of Science ID 000169642100007

  View details for PubMedID 11469674

• A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder 2nd European Stanley-Foundation Conference on Bipolar Disorder Calabrese, J. R., Suppes, T., Bowden, C. L., Sachs, G. S., Swann, A. C., McElroy, S. L., Kusumakar, V., Ascher, J. A., Earl, N. L., Greene, P. L., Monaghan, E. T. PHYSICIANS POSTGRADUATE PRESS. 2000: 841–50

  Abstract

  Patients with rapid-cycling bipolar disorder are often treatment refractory. This study examined lamotrigine as maintenance monotherapy for rapid-cycling bipolar disorder.Lamotrigine was added to patients' current psychotropic regimens and titrated to clinical effect during an open-label treatment phase. Stabilized patients were tapered off other psychotropics and randomly assigned to lamotrigine or placebo monotherapy for 6 months. Time to additional pharmacotherapy for emerging symptoms was the primary outcome measure. Secondary efficacy measures included survival in study (time to any premature discontinuation), percentage of patients stable without relapse for 6 months, and changes in the Global Assessment Scale and Clinical Global Impressions-Severity scale. Safety was assessed from adverse event, physical examination, and laboratory data.324 patients with rapid-cycling bipolar disorder (DSM-IV criteria) received open-label lamotrigine, and 182 patients were randomly assigned to the double-blind maintenance phase. The difference between the treatment groups in time to additional pharmacotherapy did not achieve statistical significance in the overall efficacy population. However, survival in study was statistically different between the treatment groups (p = .036). Analyses also indicated a 6-week difference in median survival time favoring lamotrigine. Forty-one percent of lamotrigine patients versus 26% of placebo patients (p = .03) were stable without relapse for 6 months of monotherapy. Lamotrigine was well tolerated; there were no treatment-related changes in laboratory parameters, vital signs, or body weight. No serious rashes occurred.This was the largest and only prospective placebo-controlled study of rapid-cycling bipolar disorder patients to date; results indicate lamotrigine monotherapy is a useful treatment for some patients with rapid-cycling bipolar disorder.

  View details for Web of Science ID 000165551400006

  View details for PubMedID 11105737

• Validation of the prospective NIMH-Life-Chart Method (NIMH-LCM (TM)-p) for longitudinal assessment of bipolar illness PSYCHOLOGICAL MEDICINE Denicoff, K. D., Leverich, G. S., Nolen, W. A., Rush, A. J., McElroy, S. L., Keck, P. E., Suppes, T., Altshuler, L. L., Kupka, R., Frye, M. A., Hatef, J., Brotman, M. A., Post, R. M. 2000; 30 (6): 1391-1397

  Abstract

  Systematic and accurate depiction of a patient's course of illness is crucial for assessing the efficacy of maintenance treatments for bipolar disorder. This need to rate the long-term prospective course of illness led to the development of the National Institute of Mental Health prospective Life Chart Methodology (NIMH-LCM-p or LCM). The NIMH-LCM-p allows for the daily assessment of mood and episode severity based on the degree of mood associated functional impairment. We have previously presented preliminary evidence of the reliability and validity of the LCM, and its utility in clinical trials. This study is a further and more extensive validation of the clinician rated NIMH-LCM-p.Subjects included 270 bipolar patients from the five sites participating in the Stanley Foundation Bipolar Network. Daily prospective LCM ratings on the clinician form were initiated upon entry, in addition to at least monthly ratings with the Inventory of Depressive Symptomatology-clinician rated (IDS-C), the Young Mania Rating Scale (YMRS) and the Global Assessment of Functioning (GAF). We correlated appropriate measures and time domains of the LCM with the IDS-C, YMRS and GAF.Severity of depression on the LCM and on the IDS-C were highly correlated in 270 patients (r = -0.785, P < 0.001). Similarly, a strong correlation was found between LCM mania and the YMRS (r = 0.656, P < 0.001) and between the LCM average severity of illness and the GAF (r = -0.732, P < 0.001).These data further demonstrate the validity and potential utility of the NIMH-LCM-p for the detailed daily longitudinal assessment of manic and depressive severity and course, and response to treatment.

  View details for Web of Science ID 000165285000014

  View details for PubMedID 11097079

• Efficacy of divalproex therapy for schizoaffective disorder JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Bogan, A. M., Brown, E. S., Suppes, T. 2000; 20 (5): 520-522

  Abstract

  Schizoaffective disorder is a common, severe, and lifelong illness; however, little is known about the pharmacologic treatment of this mental disorder. Divalproex has proven efficacy in the treatment of bipolar disorder. Therefore, to determine whether divalproex is also effective as adjunctive therapy for schizoaffective disorder, the authors performed a retrospective study of 20 patients in the public mental health system with schizoaffective disorder, bipolar type, who initiated divalproex therapy. The mean maximum dose of divalproex (+/-1 SD) was 1,150 mg (+/-400 mg; range, 500-2,000). The mean peak serum valproic acid level was 61 microg/mL (+/-25 microg/mL; range, 20-92). The overall improvement in Clinical Global Impression Scale scores was observed in 75% (15/20) of the patients (p = 0.0001). None in the sample worsened, and none discontinued divalproex because of side effects. These data suggest that divalproex is well-tolerated and effective as treatment of persistent schizoaffective disorder, bipolar type. Thus, divalproex may be an effective agent in the treatment of schizoaffective disorder as well as bipolar disorder. Controlled prospective trials in patients with schizoaffective disorder are needed to verify these findings.

  View details for Web of Science ID 000089366400004

  View details for PubMedID 11001235

• Methodological issues in developing new acute treatments for patients with bipolar illness Conference on Biopolar Disorder - From Clinical to Clinical, Facing the New Millennium Rush, A. J., Post, R. M., Nolen, W. A., Keck, P. E., Suppes, T., Altshuler, L., McElroy, S. L. ELSEVIER SCIENCE INC. 2000: 615–24

  Abstract

  One important aim of the recent reorganization of the National Institute of Mental Health (NIMH) is to streamline the development of new treatments for patients with severe mental illnesses, such as bipolar disorder. Researching new treatments for patients with bipolar disorder presents specific problems not readily addressed by traditional efficacy trial methodologies that aim to maximize internal validity. This article reexamines several assumptions that have guided the design of these efficacy trials but that also create obstacles for studies of bipolar disorder and suggests potential solutions. This article draws on literature from neurology and psychiatry and discussions at a MacArthur Foundation-sponsored Conference on Longitudinal Methodology in 1992 (David J. Kupfer, M.D., Chair), which brought together investigators to consider alternative designs for patients with severe and persistent mental illness. In addition, we benefited from discussions at two NIMH-sponsored conferences, one held in 1989 (Prien and Potter 1990) and the other in 1994 (Prien and Rush 1996), at which investigators and methodologists discussed issues surrounding the development and conduct of informative efficacy trials for patients with bipolar disorder. Based on these discussions and recent literature reviews, we 1) outline common problems in the development and evaluation of effective acute treatments for bipolar disorder and 2) suggest possible solutions to these impediments. We also discuss alternative designs by which to build a sequence of acute treatment studies from which efficacy, safety, and the comparative value of different treatments can be established.

  View details for Web of Science ID 000089452700021

  View details for PubMedID 11018232

• The McLean-Harvard first-episode project: 6-month symptomatic and functional outcome in affective and noneffective psychosis Conference on Biopolar Disorder - From Clinical to Clinical, Facing the New Millennium Tohen, M., Strakowski, S. M., Zarate, C., Hennen, J., Stoll, A. L., Suppes, T., Faedda, G. L., Cohen, B. M., Gebre-Medhin, P., BALDESSARINI, R. J. ELSEVIER SCIENCE INC. 2000: 467–76

  Abstract

  The McLean-Harvard First-Episode Project recruited affective and nonaffective patients at their first lifetime psychiatric hospitalization.Baseline evaluation and 6-month follow-up in 257 cases yielded recovery outcomes defined by syndromal (absence of DSM-IV criteria for a current episode) and functional (vocational and residential status at least at baseline levels) status. Time to recovery was assessed by survival analysis, and risk factors by multivariate logistic regression.Syndromal recovery was attained by 77% of cases over an average of 84 days. By diagnostic group, syndromal recovery rates ranked (p = .001) major affective disorders (81%) > nonaffective acute psychoses (74%) > schizoaffective disorders (70%) > schizophrenia (36%). Functional recovery was significantly associated to syndromal recovery, diagnosis, shorter hospitalization normalized to year, and older age at onset. Average hospital stay declined across the study period, but recovery did not vary with year of entry.Syndromal recovery was achieved by nearly one half of patients within 3 months of a first lifetime hospitalization for a psychotic illness, but functional recovery was not achieved by 6 months in nearly two thirds of patients who had attained syndromal recovery.

  View details for Web of Science ID 000089452700009

  View details for PubMedID 11018220

• Acute and continuation pharmacological treatment of children and adolescents with bipolar disorders; a summary of two previous studies ACTA NEUROPSYCHIATRICA Kowatch, R. A., Carmody, T. J., Suppes, T., Hume, J. H., Kromelis, M., Emslie, G. J., Weinberg, W. A. 2000; 12 (3): 145-149

  View details for Web of Science ID 000089511500023

• A review of randomized, controlled clinical trials in acute mania 1st International Exchange on Bipolar Disorders Meeting (IEBD) Keck, P. E., Mendlwicz, J., Calabrese, J. R., Fawcett, J., Suppes, T., Vestergaard, P. A., Carbonell, C. ELSEVIER SCIENCE BV. 2000: S31–S37

  Abstract

  This review considers the evidence supporting the use of somatic therapies (medications and electroconvulsive therapy) in the treatment of acute mania associated with bipolar disorder. Data from randomized, controlled clinical trials have established the efficacy of lithium, divalproex sodium, and carbamazepine in the treatment of acute mania. The use of combinations of mood stabilizers in the treatment of acute mania has not been well examined in controlled trials. Conventional antipsychotics and some atypical antipsychotics are frequently used as initial or adjunctive treatment. Similarly, benzodiazepines are frequently used as adjunctive agents. Preliminary data suggest that some calcium channel blockers and several anticonvulsants, e.g., lamotrigine, gabapentin, and topiramate, may have therapeutic value in the treatment of acute mania. In contrast, electroconvulsive therapy is generally accepted as being highly effective despite the lack of controlled evidence.

  View details for Web of Science ID 000166935400003

  View details for PubMedID 11121825

• Open-label adjunctive topiramate in the treatment of bipolar disorders BIOLOGICAL PSYCHIATRY McElroy, S. L., Suppes, T., Keck, P. E., Frye, M. A., Denicoff, K. D., Altshuler, L. L., Brown, E. S., Nolen, W. A., Kupka, R. W., Rochussen, J., Leverich, G. S., Post, R. M. 2000; 47 (12): 1025-1033

  Abstract

  To preliminarily explore the spectrum of effectiveness and tolerability of the new antiepileptic drug topiramate in bipolar disorder, we evaluated the response of 56 bipolar outpatients in the Stanley Foundation Bipolar Outcome Network (SFBN) who had been treated with adjunctive topiramate in an open-label, naturalistic fashion.In this case series, response to topiramate was assessed every 2 weeks for the first 3 months according to standard ratings in the SFBN, and monthly thereafter while patients remained on topiramate. Patients' weights, body mass indices (BMIs), and side effects were also assessed.Of the 54 patients who completed at least 2 weeks of open-label, add-on topiramate treatment, 30 had manic, mixed, or cycling symptoms, 11 had depressed symptoms, and 13 were relatively euthymic at the time topiramate was begun. Patients who had been initially treated for manic symptoms displayed significant reductions in standard ratings scores after 4 weeks, after 10 weeks, and at the last evaluation. Those patients who were initially depressed or treated while euthymic showed no significant changes. Patients as a group displayed significant decreases in weight and BMI from topiramate initiation to week 4, to week 10, and to the last evaluation. The most common adverse side effects were neurologic and gastrointestinal.These preliminary open observations of adjunctive topiramate treatment suggest that it may have antimanic or anticycling effects in some patients with bipolar disorder, and may be associated with appetite suppression and weight loss that is often viewed as beneficial by the patient and clinician. Controlled studies of topiramate's acute and long-term efficacy and side effects in bipolar disorder appear warranted.

  View details for Web of Science ID 000087604100002

  View details for PubMedID 10862801

• Effect size of lithium, divalproex sodium, and carbamazepine in children and adolescents with bipolar disorder JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Kowatch, R. A., Suppes, T., Carmody, T. J., Bucci, J. P., Hume, J. H., Kromelis, M., Emslie, G. J., Weinberg, W. A., Rush, A. J. 2000; 39 (6): 713-720

  Abstract

  To develop effect sizes for 3 mood stabilizers--lithium, divalproex sodium, and carbamazepine--for the acute-phase treatment of bipolar I or II disorder, mixed or manic episode, in children and adolescents aged 8 to 18 years.Forty-two outpatients with a mean age of 11.4 years (20 with bipolar I disorder and 22 with bipolar II disorder) were randomly assigned to 6 weeks of open treatment with either lithium, divalproex sodium, or carbamazepine. The primary efficacy measures were the weekly Clinical Global Impression Improvement scores and the Young Mania Rating Scale (Y-MRS).Using a > or = 50% change from baseline to exit in the Y-MRS scores to define response, the effect size was 1.63 for divalproex sodium, 1.06 for lithium, and 1.00 for carbamazepine. Using this same response measure with the intent-to-treat sample, the response rates were as follows: sodium divalproex, 53%; lithium, 38%; and carbamazepine, 38% (chi 2(2) = 0.85, p = .60). All 3 mood stabilizers were well tolerated, and no serious adverse effects were seen.Divalproex sodium, lithium, and carbamazepine all showed a large effect size in the open treatment of children and adolescents with bipolar I or II disorder in a mixed or manic episode.

  View details for Web of Science ID 000087331200009

  View details for PubMedID 10846305

• Comparison of the Internal State Scale to clinician-administered scales in asthma patients receiving corticosteroid therapy GENERAL HOSPITAL PSYCHIATRY Brown, E. S., Bauer, M. S., Suppes, T., Khan, D. A., Carmody, T. 2000; 22 (3): 180-183

  Abstract

  Mood symptoms are reported frequently in asthma patients, particularly during corticosteroid therapy. This investigation compared the Internal State Scale (ISS), a self-report measure of symptoms of mania and depression, to the Hamilton Rating Scale for Depression (HRSD), Young Mania Rating Scale (YMRS), and Brief Psychiatric Rating Scale (BPRS) in a group of asthma patients (n=60 at baseline) before, during, and after a 1-2 week burst of prednisone. The depression and well being subscales of the ISS correlated well with HDRS scores. The perceived conflict subscale correlated with the BPRS scores. However, none of the ISS subscales correlated consistently and specifically with the YMRS in this population. Possible explanations for differences observed in bipolar versus asthma patients given the ISS are discussed. These data suggest the ISS may be a useful tool for depression symptoms and overall psychopathology in asthma patients and in patients receiving corticosteroid therapy. However, its ability may be attenuated outside of the population for which it was designed.

  View details for Web of Science ID 000088061700007

  View details for PubMedID 10880712

• Forum. What are the mental health complications of steroid therapy? The Harvard mental health letter Brown, E. S., Suppes, T. 2000; 16 (8): 8-?

  View details for PubMedID 10637023

• Switching outpatients between atypical antipsychotics PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY Bogan, A. M., Shellhorn, E., Brown, E. S., Mcdanald, C., Suppes, T. 2000; 24 (2): 351-355

  Abstract

  1. Some reports have suggested an increase in symptoms when switching patients with psychosis from clozapine to other atypical antipsychotics. 2. No data are available on switching between atypical antipsychotics other than clozapine, though this is common in clinical practice. 3. Six patients with schizophrenia or schizoaffective disorder, bipolar type were switched to quetiapine after finishing a clinical trial of sertindole. 4. During the observation period of two to ten weeks no subjects worsened and one improved. Side effects were mild. 5. These preliminary data suggest that switching between some atypical agents may be well tolerated. Larger controlled trials are needed to confirm this observation.

  View details for Web of Science ID 000085836900016

  View details for PubMedID 10800756

• Two-year syndromal and functional recovery in 219 cases of first-episode major affective disorder with psychotic features AMERICAN JOURNAL OF PSYCHIATRY Tohen, M., Hennen, J., Zarate, C. M., BALDESSARINI, R. J., Strakowski, S. M., Stoll, A. L., Faedda, G. L., Suppes, T., Gebre-Medhin, P., Cohen, B. M. 2000; 157 (2): 220-228

  Abstract

  Psychotic affective disorders are the most prevalent idiopathic psychoses, but their outcome from onset has rarely been studied. In this study, the authors determined the rate and latency of syndromal recovery and rates of functional recovery after first lifetime hospitalization in patients with first-episode psychotic affective disorders.From first lifetime hospitalization in 1989-1996, 219 patients with a DSM-IV psychotic affective illness were assessed at intervals over 24 months. Time to syndromal recovery (no longer meeting DSM-IV episode criteria) was assessed by survival analysis, and functional recovery (regaining baseline vocational and residential status) was rated. Factors associated with recovery were identified by bivariate and multivariate methods.By 3, 6, 12, and 24 months after first hospitalization, syndromal recovery was attained by 65.1%, 83.7%, 91.1%, and 97.5%, respectively, of subjects. Time to syndromal recovery (6.1 weeks to 50% of subjects recovered) was shorter for patients who had bipolar disorder, were married, were age 30 or older at onset, lacked comorbidity, required relatively brief hospitalization, and received fewer medicines. Functional recovery by 6 (30.4%) and 24 months (37. 6% of patients) was 2.6-2.7 times less likely than syndromal recovery; 63.1% of those recovering syndromally did not recover functionally by 2 years. Functional recovery was associated with older age at onset and shorter hospitalization. Annual recovery rates remained stable as mean hospital length of stay decreased 3. 6-fold over the 8-year study period.Syndromal recovery was attained by most psychotic affective disorder patients soon after hospitalization, but only one-third recovered functionally by 24 months. The findings suggest that these very common psychotic illnesses can carry a grave functional prognosis from the initial episode and first hospitalization.

  View details for Web of Science ID 000085169000011

  View details for PubMedID 10671390

• The longitudinal course of bipolar disorder JOURNAL OF CLINICAL PSYCHIATRY Suppes, T., Dennehy, E. B., Gibbons, E. W. 2000; 61: 23-30

  Abstract

  Course of illness is central to our focus on bipolar disorder due to the lifelong nature of this illness in the majority of patients. In this overview, we highlight areas of consensus and debate on factors that impact course of illness. Findings on age at onset, psychiatric comorbidity, frequency of episodes, cycle pattern, rapid cycling, mixed symptoms, and precipitants of episodes including use of substances and antidepressants and lithium discontinuation are discussed. The diversity and range of presentation and even course of illness become quickly apparent in this review. Highlighting these factors rather than seeking a unifying theory should be a productive way to refine our ability to identify additive factors contributing to course of illness for patients with bipolar disorder.

  View details for Web of Science ID 000087085500004

  View details for PubMedID 10826657

• Treating bipolar illness: Focus on treatment algorithms and management of the sleep-wake cycle AMERICAN JOURNAL OF PSYCHIATRY Leibenluft, E., Suppes, T. 1999; 156 (12): 1976-1981

  View details for Web of Science ID 000083934800020

  View details for PubMedID 10588413

• Clozapine associated with decreased suicidality in bipolar disorder: a case report. Bipolar disorders Vangala, V. R., Brown, E. S., Suppes, T. 1999; 1 (2): 123-124

  View details for PubMedID 11252659

• Gabapentin in the acute treatment of refractory bipolar disorder. Bipolar disorders Altshuler, L. L., Keck, P. E., McElroy, S. L., Suppes, T., Brown, E. S., Denicoff, K., Frye, M., Gitlin, M., Hwang, S., Goodman, R., Leverich, G., Nolen, W., Kupka, R., Post, R. 1999; 1 (1): 61-65

  Abstract

  Gabapentin, a new anti-epileptic agent, has been anecdotally reported to be effective in the treatment of mania. We systematically assessed the response rate in bipolar patients being treated adjunctively with gabapentin for manic symptoms, depressive symptoms, or rapid cycling not responsive to standard treatments.Twenty-eight bipolar patients experiencing manic (n = 18), depressive (n = 5), or rapid-cycling (n = 5) symptoms inadequately responsive to at least one mood stabilizer were treated in an open fashion with adjunctive gabapentin. Illness response was assessed using the Clinical Global Impression Scale modified for bipolar disorder (CGI-BP). A 'positive response' was operationalized as a CGI response of much or very much improved.Fourteen of the 18 (78%) treated for hypomania or mania had a positive response to a dosage range of 600-3,600 mg/day. Patients with hypomania responded fastest, with a positive response achieved in 12.7 +/- 7.2 days. Patients with classic mania had a mean time to positive response of 25 +/- 12 days, and in patients with mixed mania it was 31.8 +/- 20.9 days. All of the five patients treated for depression had a positive response within 21 +/- 13.9 days. Only one of five patients with rapid cycling had a positive response. Gabapentin was well tolerated by all patients, with the most common side-effect being sedation.Gabapentin appears to have acute anti-manic and anti-depressant properties as an adjunctive agent for refractory bipolar illness. Prospective double-blind studies are needed to further delineate its acute efficacy when used as monotherapy and its prophylactic efficacy as monotherapy or in conjuction with other mood stabilizers.

  View details for PubMedID 11256659

• Clinical outcome in a randomized 1-year trial of clozapine versus treatment as usual for patients with treatment-resistant illness and a history of mania 27th Annual Meeting of the Society-of-Neuroscience Suppes, T., Webb, A., Paul, B., Carmody, T., Kraemer, H., Rush, A. J. AMER PSYCHIATRIC PUBLISHING, INC. 1999: 1164–69

  Abstract

  Case series and follow-up studies suggest that clozapine may have mood-stabilizing properties in addition to antipsychotic action in patients with schizoaffective disorder, bipolar type, and bipolar I disorder, but the generalizability of these findings is limited. This article describes a randomized, open study of clozapine add-on therapy versus treatment as usual for patients with treatment-resistant illness and a history of mania.Thirty-eight patients meeting the DSM-IV criteria for schizoaffective or bipolar disorder that was deemed treatment-resistant were randomly assigned to clozapine add-on treatment (N = 19) or treatment as usual (no clozapine) (N = 19) and followed up for 1 year. Patients received monthly ratings on the Brief Psychiatric Rating Scale, Clinical Global Impression scale, Bech-Rafaelsen Mania Scale, Hamilton Depression Rating Scale, Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms, Abnormal Involuntary Movement Scale, and a 40-item side effect checklist. Differences between treatment groups were assessed according to a pattern-mix random-regression model. An additional analysis compared group differences in rating scale scores against relative time in the study.Significant between-group differences were found in scores on all rating scales except the Hamilton depression scale. Total medication use over 1 year significantly decreased in the clozapine group. No significant differences between groups in somatic complaints were noted. The subjects with nonpsychotic bipolar I disorder who received clozapine showed a degree of improvement similar to that of the entire clozapine-treated group. Clozapine dose was significantly higher for the patients with schizoaffective illness than for those with bipolar disorder.The results of this study support clozapine's independent mood-stabilizing property. They demonstrate that clozapine use was associated with significant clinical improvement relative to treatment as usual.

  View details for Web of Science ID 000081923300006

  View details for PubMedID 10450255

• Lamotrigine in the treatment of bipolar depression 11th European-College-of-Neuropsychopharmacology Congress Bowden, C. L., Mitchell, P., Suppes, T. ELSEVIER SCIENCE BV. 1999: S113–S117

  Abstract

  Several case reports and open studies have reported the efficacy of lamotrigine in bipolar depression. A randomised placebo-controlled 7-week study comparing two doses of lamotrigine with placebo in 195 patients with moderate to severe bipolar depression has now been completed. Lamotrigine was superior to placebo after 3 weeks as assessed by changes in the Montgomery-Asberg Depression Rating Scale (MADRS). A response, defined as more than 50% improvement on the MADRS occurred in 56 and 48% of the lamotrigine 200 and 50 mg/day groups, respectively, compared with 29% for placebo (P<0.05). There was no evidence that lamotrigine destabilised mood or precipitated mania. Tolerability was good and there were no cases of serious rashes. Preliminary results from an ongoing study also indicate that lamotrigine is more effective than gabapentin in bipolar depression. In conclusion, lamotrigine is effective in alleviating bipolar depression, without causing mood destabilisation. Slow dosage escalation yields good tolerability.

  View details for Web of Science ID 000083170000003

  View details for PubMedID 10524837

• Treatment of corticosteroid-induced mood changes with olanzapine AMERICAN JOURNAL OF PSYCHIATRY Brown, E. S., Khan, D. A., Suppes, T. 1999; 156 (6): 968-968

  View details for Web of Science ID 000080698500038

  View details for PubMedID 10360143

• Medication treatment for the severely and persistently mentally ill: The Texas Medication Algorithm Project JOURNAL OF CLINICAL PSYCHIATRY Rush, A. J., Rago, W. V., Crismon, M. L., Toprac, M. G., Shon, S. P., Suppes, T., Miller, A. L., Trivedi, M. H., Swann, A. C., Biggs, M. M., Shores-Wilson, K., Kashner, T. M., Pigott, T., Chiles, J. A., Gilbert, D. A., Altshuler, K. Z. 1999; 60 (5): 284-291

  Abstract

  This article provides an overview of the issues involved in developing, using, and evaluating specific medication guidelines for patients with psychiatric disorders. The potential advantages and disadvantages, as well as the essential elements in the structure of algorithms, are illustrated by experience to date with the Texas Medication Algorithm Project, a public-academic collaboration. Phase 1 entailed assembling research findings on the efficacy of medications for schizophrenic, bipolar, and major depressive disorders. This knowledge was evaluated for its quality and relevance, integrated with expert clinical judgment as well as input by practicing clinicians, family advocates, and patients. Phase 1 (the design and development of the algorithms) was followed by a feasibility test (Phase 2). Phase 3 is an ongoing evaluation comparing the clinical and economic effects of using specific medication guidelines (algorithms) versus treatment as usual in public sector patients with severe and persistent mental illnesses.

  View details for Web of Science ID 000080557300002

  View details for PubMedID 10362434

• Lamotrigine for the treatment of bipolar disorder: a clinical case series JOURNAL OF AFFECTIVE DISORDERS Suppes, T., Brown, E. S., McElroy, S. L., Keck, P. E., Nolen, W., Kupka, R., Frye, M., Denicoff, K. D., Altshuler, L., Leverich, G. S., Post, R. M. 1999; 53 (1): 95-98

  Abstract

  Recently, a number of new agents have become available to treat bipolar disorder, however many patients may not respond fully even when used in combination. Early reports in epilepsy studies suggested mood-related effects of lamotrigine treatment, as have preliminary reports in bipolar patients.Seventeen patients meeting DSM-IV criteria for bipolar I (n = 9) or bipolar II (n = 8) disorder displaying affective symptoms and a past history of inadequate response or tolerability to at least two standard mood stabilizing agents were recruited through the Stanley Foundation Bipolar Network and treated with the new anticonvulsant lamotrigine in an add-on, open-label study. Response to therapy was assessed using the Clinical Global Impression Scale modified for bipolar disorder.The mean dose of lamotrigine was 187+/-157 mg/day (range 50-600 mg/day) for a mean duration of 159+/-109 days (range 14-455 days). Eleven (65%) patients were rated as very much or much improved. Lamotrigine was well tolerated, and may have mood stabilizing and antidepressant properties in some patients with bipolar disorder.The study is hypothesis generating because it was uncontrolled and open. Controlled studies are warranted.This preliminary report supports clinical improvement for both mood cycling and depression in patients with bipolar disorder treated with lamotrigine.

  View details for Web of Science ID 000080305900012

  View details for PubMedID 10363672

• Measuring use of outpatient care among mentally ill individuals: a comparison of self reports and provider records EVALUATION AND PROGRAM PLANNING Kashner, T. M., Suppes, T., Rush, A. J., Altshuler, K. Z. 1999; 22 (1): 31-39

  View details for Web of Science ID 000080053500004

• Mental health care from the public perspective: The Texas Medication Algorithm Project Symposium on Pharmacoeconomic Factors Related to the Treatment of Schizophrenia Shon, S. P., Crismon, M. L., Toprac, M. G., Trivedi, M., Miller, A. L., Suppes, T., Rush, A. J. PHYSICIANS POSTGRADUATE PRESS. 1999: 16–21

  Abstract

  Medication treatment algorithms have been suggested as a strategy to provide uniform care at predictable costs. The Texas Medication Algorithm Project is a 3-phase study designed to provide solid data on the usefulness of medication algorithms. In phase 1, medication algorithms for the treatment of schizophrenia, major depressive disorder, and bipolar disorder were developed. Phase 2 was a feasibility study of these algorithms, and phase 3, now underway, compares the costs and outcome in 3 groups, one using a combination of an algorithm and patient/family education, a second using treatment as usual in a clinic that uses an algorithm for a different disorder, and a third using treatment as usual in a nonalgorithm clinic.

  View details for Web of Science ID 000078825200003

  View details for PubMedID 10073372

• Clinical experience using gabapentin adjunctively in patients with a history of mania or hypomania JOURNAL OF AFFECTIVE DISORDERS Knoll, J., Stegman, K., Suppes, T. 1998; 49 (3): 229-233

  Abstract

  Gabapentin is an anticonvulsant proposed to have mood-stabilizing properties. It has been effective in the add-on treatment of refractory partial seizures and secondary generalized tonic-clonic seizures. It has the advantage of a favorable side effect profile and lack of drug interactions.Twelve consecutive outpatients with persistent, treatment-resistant bipolar spectrum disorders were treated with gabapentin in combination with other medications. Patients were started at 300 mg/day, which was titrated according to clinical response. Response was assessed every 3-4 weeks with a Clinical Global Improvement Scale. Dosage and side effects were noted. The median peak dose was 2400 mg/day.One patient had a marked response to gabapentin; seven, a moderate response; two, mild; and two, no response to treatment. Six patients discontinued treatment due to somatic complaints (i.e., sedation or fatigue). The most frequently reported adverse effect was sedation.Gabapentin was added openly, and rating was nonblind in this case series. The use of concomitant medications could have increased the amount of sedation experienced with gabapentin.Overall, gabapentin was associated with moderate improvement of mood symptoms. Given the severity and chronicity of these patients' illness, a moderate response must be considered a relative success. Controlled studies of gabapentin are needed to clarify its role in the treatment of bipolar disorder.

  View details for Web of Science ID 000073709900008

  View details for PubMedID 9629953

• Olanzapine in treatment-resistant bipolar disorder JOURNAL OF AFFECTIVE DISORDERS McElroy, S. L., Frye, M., Denicoff, K., Altshuler, L., Nolen, W., Kupka, R., Suppes, T., Keck, P. E., Leverich, G. S., Kmetz, G. F., Post, R. M. 1998; 49 (2): 119-122

  Abstract

  We evaluated the response to olanzapine in 14 consecutive patients with bipolar I disorder who were inadequately responsive to standard psychotropic agents.Fourteen patients with bipolar I disorder by DSM-IV criteria experiencing persistent affective symptoms inadequately responsive to at least one standard mood stabilizer were treated with open-label olanzapine by one of the authors. Response was assessed with the Clinical Global Impression Scale modified for use in bipolar disorder (CGI-BP).The 14 patients received olanzapine at a mean (SD dosage of 14.1+/-7.2 (range 5-30) mg/day for a mean+/-SD of 101.4+/-56.3 (range 30-217) days of treatment. Of the 14 patients, 8 (57%) displayed much or very much overall improvement in their illness. In general, olanzapine was well tolerated. The most common side effects were sedation, tremor, dry mouth, and appetite stimulation with weight gain.Data were obtained nonblindly and without a randomized control group, and olanzapine was added to ongoing psychotropic regimens.Olanzapine may have antimanic and mood-stabilizing effects in some patients with bipolar disorder, and is generally well tolerated. Controlled studies of olanzapine in bipolar disorder appear warranted.

  View details for Web of Science ID 000073384500004

  View details for PubMedID 9609675

• What are the new treatments for bipolar disorder? The Harvard mental health letter / from Harvard Medical School Rush, A. J., Suppes, T. 1998; 14 (11): 8-?

  View details for PubMedID 9581536

• Gastrointestinal side-effects after switch to generic valproic acid PHARMACOPSYCHIATRY Brown, E. S., Shellhorn, E., Suppes, T. 1998; 31 (3): 114-114

  View details for Web of Science ID 000074246200007

  View details for PubMedID 9657239

• Treatment algorithm use to optimize management of symptomatic patients with a history of mania 33rd Annual Meeting of the American-College-of-Neuropsychopharmacology Suppes, T., Rush, A. J., Kraemer, H. C., Webb, A. PHYSICIANS POSTGRADUATE PRESS. 1998: 89–96

  Abstract

  While monotherapy has significant limitations in bipolar disorder, few published data addressing alternatives exist. Treatment algorithms have been proposed, but none have undergone empirical evaluation. This study provides a systematic prospective, open evaluation of the effectiveness and tolerability of a treatment algorithm for patients with histories of mania.Twenty-eight symptomatic outpatients from a public mental health facility who were diagnosed as having either bipolar I or schizoaffective illness, bipolar type, entered the study. Minimum blood levels of lithium and divalproex sodium were defined. Medications were pushed to predetermined levels (as tolerated) before proceeding to the next algorithm step. Clinical symptoms were assessed monthly using the Brief Psychiatric Rating Scale (BPRS, 27 item) and Clinical Global Impressions scale.Pretreatment and posttreatment clinical symptoms were compared. Over 50% of patients attained 30% improvement from baseline BPRS after 4 months. Thirty-six percent of patients (N = 10) became mood stable, 46% (N = 13) remained mood unstable, and 18% (N = 5) dropped out before completing the algorithm. Although patients who finished the algorithm were taking more medication, either dosage and/or drugs, somatic complaints did not increase.The potential benefit of a defined treatment algorithm was demonstrated for these complex and persistently ill patients. Despite long treatment histories, patients improved with more frequent visits and addition of medication(s). A randomized controlled trial comparing a similar treatment algorithm with treatment-as-usual is warranted.

  View details for Web of Science ID 000072288800016

  View details for PubMedID 9501899

• A new algorithm for treating schizophrenia PSYCHOPHARMACOLOGY BULLETIN Pearsall, R., Glick, I. D., Pickard, D., Suppes, T., Tauscher, J., Jobson, K. O. 1998; 34 (3): 349-353

  Abstract

  This article presents two algorithms dealing with the management of schizophrenia. One provides a strategy for initiating pharmacologic treatment of schizophrenia and for ongoing medication management. The other covers suggestions for managing several common comorbid psychiatric conditions and some common side effects. The major change from previous algorithms is the suggestion that the newer atypical antipsychotic agents may now be the treatment of choice for initiating therapy in most clinical situations.

  View details for Web of Science ID 000078297300024

  View details for PubMedID 9803768

• Mood symptoms during corticosteroid therapy: A review 1997 Meeting of the Society-of-Biological-Psychiatry / American-Psychiatric-Association Brown, E. S., Suppes, T. TAYLOR & FRANCIS INC. 1998: 239–46

  Abstract

  Corticosteroids such as prednisone are commonly prescribed for a variety of illnesses mediated by the immune system. This paper reviews the available literature on mood symptoms during corticosteroid treatment. Few studies have used well-recognized measures of symptoms or clearly defined diagnostic criteria to characterize such mood changes. The limited data available suggest that symptoms of hypomania, mania, depression, and psychosis are common during therapy. Symptoms appear to be dose dependent and generally begin during the first few weeks of treatment. Risk factors for the development of mood instability or psychosis are not known. The similarities of the psychiatric symptoms resulting from corticosteroid treatment to the symptoms of bipolar disorder are discussed.

  View details for Web of Science ID 000071876500001

  View details for PubMedID 9493946

• The atypical antipsychotic sertindole: A case series JOURNAL OF CLINICAL PSYCHIATRY Lee, A. M., Knoll, J. L., Suppes, T. 1997; 58 (9): 410-416

  Abstract

  Psychotic disorders are often difficult to treat with traditional neuroleptics. Sertindole is a new atypical neuroleptic with a broader CNS receptor profile.Ten patients diagnosed with either schizophrenia or schizoaffective disorder were treated with sertindole for 18 months and observed for changes in Clinical Global Impression scale scores.Nine patients experienced a reduction of symptoms after 12 months of treatment. Eight patients completed 18 months of treatment, all exhibiting overall improvement. Despite side effects of tiredness, weight gain, headache, nausea, and decreased ejaculatory volume, sertindole was generally well tolerated.Sertindole appears to be a useful treatment in psychotic disorders. It may present an advantage over traditional neuroleptics in the form of fewer extrapyramidal symptoms and improvement of negative symptoms.

  View details for Web of Science ID A1997XY69000015

  View details for PubMedID 9378698

• Gabapentin for treatment of bipolar and schizoaffective disorders JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Bennett, J., GOLDMAN, W. T., Suppes, T. 1997; 17 (2): 141-142

  View details for Web of Science ID A1997WQ26500030

  View details for PubMedID 10950494

• Special treatment issues: Maintaining and discontinuing psychotropic medications MOOD DISORDERS Suppes, T., BALDESSARINI, R. J., Motohashi, N., Tondo, L., Viguera, A. C. 1997; 25: 235-254

  View details for Web of Science ID A1997BJ75D00015

  View details for PubMedID 9344380

• Is postictal electrical silence a predictor of response to electroconvulsive therapy? JOURNAL OF AFFECTIVE DISORDERS Suppes, T., Webb, A., Carmody, T., Gordon, E., GUTIERREZESTEINOU, R., Hudson, J. I., Pope, H. G. 1996; 41 (1): 55-58

  Abstract

  Electroconvulsive therapy (ECT) is an established effective treatment modality for patients with severe depression. Recent studies have focused on developing predictors of response. In this prospective study, using percent decrease in Hamilton Depression Scale (21 items) as the outcome measure, we blindly evaluated 33 inpatients with major depression to determine whether postictal suppression, the electrical silence following induced seizure, would predict treatment response to ECT. A significant relationship was observed between degree of postictal suppression and likelihood of clinical improvement. Postictal suppression should be explored in more controlled studies as a predictor of ECT response.

  View details for Web of Science ID A1996VT13600007

  View details for PubMedID 8938205

• Effects of the rate of discontinuing lithium maintenance treatment in bipolar disorders JOURNAL OF CLINICAL PSYCHIATRY BALDESSARINI, R. J., Tondo, L., Faedda, G. L., Suppes, T. R., Floris, G., Rudas, N. 1996; 57 (10): 441-448

  Abstract

  Gradual discontinuation of lithium may reduce high risk of early morbidity in bipolar disorder patients discontinuing successful long-term maintenance on lithium, but previous small samples have limited analyses of subgroups.DSM-IV bipolar disorder patients (N = 161) were pooled from similar samples maintained on lithium for 4.2 +/- 3.1 years. Effects of discontinuing treatment abruptly (1-14 days) or gradually (15-30 days) were compared by survival analysis in clinically closely similar groups.After gradual versus rapid discontinuation, the overall median time to recurrence +/- SE differed by 5.0-fold (20.0 +/- 5.8 vs. 4.0 +/- 0.7 months; p < .0001). After rapid discontinuation, the median time in remission was 2.3 times shorter than the mean cycling interval before lithium (6.3 vs. 14.6 months; p < .0001). The proportion of subjects falling ill/month (recurrence rate) was much higher in the first year after rapid discontinuation (6.5% vs. 2.3%), but similar thereafter (0.4% vs. 0.6%); patients remained stable for 3 years when off lithium treatment 20 times more frequently after gradual than rapid discontinuation (37% vs. 1.8%; p < .0001). Ratios of median survival times after gradual/rapid lithium discontinuation were similar for a first recurrence of mania and depression (4.4 vs. 3.4-fold), insignificantly higher (34%) with rapid or continuous cycling before lithium, and greater in Type II than Type I disorder (9.8- vs. 4.0-fold). The polarity of first off-lithium and first lifetime episodes matched in 70% of cases.These pooled results strengthen the concept or a pharmacodynamic stress factor in early relapse after stopping lithium maintenance and support the conclusion that early recurrence risk can be minimized by discontinuing maintenance treatment gradually in both Type I and II bipolar disorders.

  View details for Web of Science ID A1996VP48700001

  View details for PubMedID 8909329

• Medication optimization during clozapine treatment JOURNAL OF CLINICAL PSYCHIATRY Suppes, T., Rush, A. J. 1996; 57 (7): 307-308

  View details for Web of Science ID A1996UY66200008

  View details for PubMedID 8666574

• Capgras' and Fregoli's syndromes in one family JOURNAL OF CLINICAL PSYCHIATRY Brown, E. S., Thompson, R., Suppes, T. 1996; 57 (3): 137-138

  View details for Web of Science ID A1996UA87300011

  View details for PubMedID 8617702

• Lithium Withdrawal in Bipolar Disorder: Implications for Clinical Practice and Experimental Therapeutics Research. American journal of therapeutics Baldessarini, R. J., Suppes, T., Tondo, L. 1996; 3 (7): 492–96

  Abstract

  Recent clinical research strongly suggests that there is a period of elevated risk of morbidity in the several months following abrupt discontinuation or reduction of doses in maintenance treatments commonly used in the contemporary management of chronic or recurring major psychiatric disorders. This risk is best quantified for the discontinuation of lithium therapy in bipolar disorders, in which risk of mania, depression, and suicidal behavior may rise. Similar symptomatic risks are well known after stopping antianxiety agents, and probably also follow rapid removal of oral neuroleptics in schizophenia and antidepressants in major depression. Morbid risk probably can be limited by slowing the rate of removal of medication. Such responses probably reflect interactions of individual illness diatheses with physiological adaptations to long-term drug treatments. The findings appear to have broad scientific, clinical, and ethical implications for clinical pharmacology in psychiatry as well as in general medicine.

  View details for PubMedID 11862280

• PEDIATRIC-ONSET BIPOLAR DISORDER - A NEGLECTED CLINICAL AND PUBLIC-HEALTH PROBLEM HARVARD REVIEW OF PSYCHIATRY Faedda, G. L., BALDESSARINI, R. J., Suppes, T., Tondo, L., Becker, I., Lipschitz, D. S. 1995; 3 (4): 171-195

  Abstract

  Bipolar disorder (BPD), probably the most prevalent psychotic disorder in adults, has been relatively neglected or controversial in children and adolescents over the past century. We reviewed the literature on early-onset BPD. Estimates of prevalence, particularly before puberty, are limited by historical biases against pediatric mood disorders and by formidable diagnostic complexity and comorbidity. Although clinical features of pediatric and adult BPD have similarities, pediatric cases probably cannot be defined solely by features characteristic of adult cases. Onset was before age 20 years in at least 25% of reported BPD cases, with some increase in this incidence over the past century. Pediatric BPD is familial more often than is adult-onset BPD, may be associated with a premorbid cyclothymic or hyperthymic temperament, and can be precipitated by antidepressant treatment. Pediatric BPD episodes frequently include irritability, dysphoria, or psychotic symptoms; they are commonly chronic and carry high risks of substance abuse and suicide. BPD is often recognized in adolescents, but the syndrome or its antecedents are almost certainly underrecognized and undertreated in children. Controlled studies of short- and long-term treatment, course, and outcome in this disorder remain strikingly limited, and the syndrome urgently requires increased clinical and scientific interest.

  View details for Web of Science ID A1995TJ19200001

  View details for PubMedID 9384947

• A CLINICALLY SIGNIFICANT INTERACTION BETWEEN CLOZAPINE AND VALPROATE JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY COSTELLO, L. E., Suppes, T. 1995; 15 (2): 139-141

  View details for Web of Science ID A1995QN55900010

  View details for PubMedID 7782488

• International psychopharmacology algorithm project report .B. Algorithms for the treatment of bipolar, manic-depressive illness PSYCHOPHARMACOLOGY BULLETIN Suppes, T., Calabrese, J. R., Mitchell, P. B., Pazzaglia, P. J., Potter, W. Z., Zarin, D. A. 1995; 31 (3): 469-474

  View details for Web of Science ID A1995TR74300004

• Clozapine treatment of children and adolescents with bipolar disorder and schizophrenia: A clinical case series JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Kowatch, R. A., Suppes, T., Gilfillan, S. K., Fuentes, R. M., Grannemann, B. D., Emslie, G. J. 1995; 5 (4): 241-253

  View details for Web of Science ID A1995TU67800002

• NEUROLOGIC FACTORS PREDICT A FAVORABLE VALPROATE RESPONSE IN BIPOLAR AND SCHIZOAFFECTIVE DISORDERS JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Stoll, A. L., Banov, M., KOLBRENER, M., Mayer, P. V., Tohen, M., STRAKOWSKI, S. H., Castillo, J., Suppes, T., Cohen, B. M. 1994; 14 (5): 311-313

  Abstract

  The hypothesis that neurologic factors influence the response to valproate (divalproex sodium) in bipolar and schizoaffective disorders was tested. In 115 predominantly lithium-refractory inpatients, neurologic findings were recorded, and blind raters assessed valproate response from the medical record. Patients with a seizure history were much more likely to have a robust response to valproate (70%), when compared with patients without such history (34.6%). History of head injury and abnormal electroencephalographic findings also tended to be more common in those patients with good response. Overall, the group of patients with any neurologic abnormality exhibited a significantly higher rate of good response to valproate (43.6%) than did the neurologically normal group (24.3%). Bipolar or schizoaffective patients with abnormal neurologic features may represent a distinct subtype of illness and appear to be good candidates for valproate therapy.

  View details for Web of Science ID A1994PH78400004

  View details for PubMedID 7806685

• CLOZAPINE TREATMENT OF NONPSYCHOTIC RAPID-CYCLING BIPOLAR DISORDER - A REPORT OF 3 CASES BIOLOGICAL PSYCHIATRY Suppes, T., Phillips, K. A., JUDD, C. R. 1994; 36 (5): 338-340

  View details for Web of Science ID A1994PG03600007

  View details for PubMedID 7993960

• STEREOTYPICAL CHANGES IN THE PATTERN AND DURATION OF LONG-TERM POTENTIATION EXPRESSED AT POSTNATAL DAYS 11 AND 15 IN THE RAT HIPPOCAMPUS JOURNAL OF NEUROPHYSIOLOGY Jackson, P. S., Suppes, T., Harris, K. M. 1993; 70 (4): 1412-1419

  Abstract

  1. Extracellular recordings from hippocampal area CA1 lasting 2-8 h posttetanus were used to evaluate the duration of long-term potentiation (LTP) at two key developmental ages. 2. At day 11 LTP consistently endured for approximately 1 h before declining to baseline by 2.5 h posttetanus. The response could then be repotentiated, and in some cases, the repotentiation lasted longer than the original potentiation. 3. At day 15 two patterns of potentiation were observed. The first pattern was similar to that observed at day 11 in that the potentiation did not persist; however, it did endure for approximately 2-2.5 h before declining to baseline by 4 h posttetanus. In the second pattern the potentiation persisted indefinitely; these responses were monitored for 6-8 h posttetanus. 4. These patterns are similar to the temporal phases of LTP that have been revealed in adult rat hippocampus through pharmacological manipulations. They may reflect developmental changes during which the different cellular mechanisms underlying LTP become sequentially activated. 5. These findings are important for several reasons. First, because the different temporal phases of LTP seem to be added stepwise during development, animals of different ages could be used explicitly to elucidate the underlying cellular mechanisms of these phases in LTP. Second, because LTP is a candidate mechanism for some forms of learning and memory, these results have implications for sequential steps in the ontogeny of learning and memory. Finally, because studies of LTP have used animals of widely varying ages, including these two ages, it is important to consider whether differences in the developmental properties of LTP could influence experimental observations.

  View details for Web of Science ID A1993MC01300012

  View details for PubMedID 7904299

• DISCONTINUATION OF MAINTENANCE TREATMENT IN BIPOLAR DISORDER - RISKS AND IMPLICATIONS HARVARD REVIEW OF PSYCHIATRY Suppes, T., BALDESSARINI, R. J., Faedda, G. L., Tondo, L., Tohen, M. 1993; 1 (3): 131-144

  Abstract

  There is abundant evidence for substantial long-term prophylactic efficacy of lithium in bipolar manic-depressive disorders. Interruption of such treatment carries an extraordinarily high risk of recurrence within several months, even after several years of stability. Even a sharp reduction in dose may carry some risk. Gradual discontinuation of lithium was accompanied by markedly reduced risk of early recurrence. There is suggestive evidence that the phenomenon of high risk of recurrence after abrupt interruption of maintenance treatment may occur with other disorders and treatments, including neuroleptics in schizophrenia and possibly antidepressants in recurrent depression. The phenomenon of discontinuation-associated iatrogenic risk of early recurrence of major psychiatric illness has clear clinical implications. These include the need to evaluate safer methods of interrupting long-term maintenance treatment, particularly when clinical indications for rapid cessation are compelling and gradual discontinuation is not feasible. Questions also arise concerning interpretation of existing experimental studies of maintenance treatments that require interruption of treatment, reduction of dose, or crossover to a placebo, as well as the ethical and scientifically unambiguous design of future studies of this kind.

  View details for Web of Science ID A1993MU38100001

  View details for PubMedID 9384841

• OUTCOME AFTER RAPID VS GRADUAL DISCONTINUATION OF LITHIUM TREATMENT IN BIPOLAR DISORDERS ARCHIVES OF GENERAL PSYCHIATRY Faedda, G. L., Tondo, L., BALDESSARINI, R. J., Suppes, T., Tohen, M. 1993; 50 (6): 448-455

  Abstract

  Withdrawal of bipolar mood disorder (BP-I) patients from prolonged, stable lithium maintenance has a high risk of early recurrence, particularly of mania. We thus compared risks of stopping lithium rapidly vs gradually.Outpatients undergoing clinically determined discontinuation of lithium treatment at different rates were followed up prospectively to 5 years. Risks and timing of new episodes were analyzed.Subjects (N = 64) with a DSM-III-R BP disorder, previously stable on lithium monotherapy for 18 to 120 months (mean, 3.6 years) were followed up clinically after discontinuing lithium (elected in prolonged wellbeing in 67%). None was unavailable for follow-up, and subtyping (BP-I or BP-II) remained stable.Within 5 years, 75% had a recurrent episode; BP-I patients were 1.5-times less likely than BP-II to remain in remission. Polarity of first-recurrent and onset episodes was 80.8% concordant. Overall risk of a new episode of mania was significantly greater after rapid (< 2) than gradual (2 to 4 weeks discontinuation (5-year hazard ratio = 2.8); the difference in risk of depression was even greater hazard ratio = 5.4). Recurrence rate was more elevated within months of rapid discontinuation (12-month hazard ratio = 5.4). Recurrence rate was more elevated within months of rapid discontinuation (12-month hazard ratio = 4.3) than at later times (2 to 5 years), when courses of "survival" over time were nearly parallel in both discontinuation groups.Risk of early recurrence of BP disorder following discontinuation of lithium maintenance is elevated, but may be both predictable (timing and polarity) and modifiable by gradual discontinuation.

  View details for Web of Science ID A1993LF79600004

  View details for PubMedID 8498879

• Combined Clozapine and Electroconvulsive Therapy. Convulsive therapy Frankenburg, F. R., Suppes, T., McLean, P. E. 1993; 9 (3): 176–80

  Abstract

  We reviewed consecutive patients (n = 12) at McLean Hospital from 1990 through 1991 treated with the combination of the atypical antipsychotic agent clozapine and electroconvulsive therapy (ECT). There were no adverse effects. Three patients had a marked clinical improvement, one a moderate response, four a minimal response, two minimal to no response, and two no response. Using daily doses of up to 550 mg clozapine, this combination appears to be safe, and may be useful in some patients with treatment-refractory psychosis.

  View details for PubMedID 11941210

• CLOZAPINE IN THE TREATMENT OF DYSPHORIC MANIA BIOLOGICAL PSYCHIATRY Suppes, T., McElroy, S. L., Gilbert, J., Dessain, E. C., Cole, J. O. 1992; 32 (3): 270-280

  Abstract

  Seven patients with bipolar disorder, characterized by dysphoric mania with psychotic features and chronic disability, refractory to standard treatments and anticonvulsants, all showed marked symptomatic and functional improvement when given the atypical antipsychotic clozapine. During follow-up over 3-5 years, most of the patients sustained substantial gains in psychosocial function; and of the six patients remaining on clozapine, no further hospitalizations were needed. This remarkable improvement in a severely ill group of patients suggests that clozapine may have utility in the treatment of bipolar disorder as well as schizophrenia.

  View details for Web of Science ID A1992JW49200005

  View details for PubMedID 1420643

• RISK OF RECURRENCE FOLLOWING DISCONTINUATION OF LITHIUM TREATMENT IN BIPOLAR DISORDER ARCHIVES OF GENERAL PSYCHIATRY Suppes, T., BALDESSARINI, R. J., Faedda, G. L., Tohen, M. 1991; 48 (12): 1082-1088

  Abstract

  Episode recurrence in bipolar disorder following discontinuation of stable maintenance treatment with lithium salts was analyzed from 14 studies involving 257 patients with bipolar I disorder. More than 50% of new episodes of illness occurred within 10 weeks of stopping an average of 30 months of treatment. By survival analysis of 124 cases in which the time to a new episode was known, the computed time to 50% failure of remission was 5.0 months after stopping therapy; the time to 25% recurrence of mania was 5.2 times earlier than for depression (2.7 vs 14 months). In 16 patients with a mean cycle length before treatment of 11.6 months, the time to a new episode when off lithium therapy was only 1.7 months. Risk of early recurrence of bipolar illness, especially of mania, evidently is increased following discontinuation of lithium use and may exceed that predicted by the course of the untreated disorder. The basis and management of risks associated with discontinuing effective long-term mood-stabilizing treatment require further study.

  View details for Web of Science ID A1991GW65300006

  View details for PubMedID 1845226

• Cellular and synaptic physiology and epileptogenesis of developing rat neocortical neurons in vitro. Brain research Kriegstein, A. R., Suppes, T., Prince, D. A. 1987; 431 (2): 161-171

  Abstract

  The cellular and synaptic physiology of developing rat neocortical neurons was studied using the in vitro slice method. Rats aged 1-28 days were used for analysis. During the first two postnatal weeks several sequential changes occur in membrane properties and evoked synaptic potentials. Immature neurons had higher input resistances, more linear I-V characteristics, longer membrane time constants, and slower rising and falling phases of action potentials. The developmental increase in rate of rise of the action potential suggests an increasing density of voltage-dependent Na+-channels are inserted in neuronal membranes during postnatal development. The higher input resistance of young cells might be due to their small size and differences in membrane properties. The long time constant indicates a higher specific membrane resistivity of immature neurons. Postsynaptic potentials (PSPs) recorded in young neurons were longer in latency, longer in duration, and more fragile during repetitive activation than their mature counterparts. In addition, PSPs evoked in neurons of animals less than 1 week old did not contain inhibitory postsynaptic components. These physiological features of immature neocortical neurons help explain the pattern of epileptogenesis in young animals. When neonatal cortical slices were exposed to the gamma-aminobutyric acid (GABA) antagonists penicillin or bicuculline, the frequency of occurrence of discharges resembling epileptiform depolarization shifts approached that found in mature slices only during the second postnatal week. Depolarization shifts at younger ages were less stereotyped and more sensitive to stimulus parameters than those in mature neurons.

  View details for PubMedID 3040188

• CELLULAR AND SYNAPTIC PHYSIOLOGY AND EPILEPTOGENESIS OF DEVELOPING RAT NEOCORTICAL NEURONS INVITRO DEVELOPMENTAL BRAIN RESEARCH Kriegstein, A. R., Suppes, T., Prince, D. A. 1987; 34 (2): 161-171

  Abstract

  The cellular and synaptic physiology of developing rat neocortical neurons was studied using the in vitro slice method. Rats aged 1-28 days were used for analysis. During the first two postnatal weeks several sequential changes occur in membrane properties and evoked synaptic potentials. Immature neurons had higher input resistances, more linear I-V characteristics, longer membrane time constants, and slower rising and falling phases of action potentials. The developmental increase in rate of rise of the action potential suggests an increasing density of voltage-dependent Na+-channels are inserted in neuronal membranes during postnatal development. The higher input resistance of young cells might be due to their small size and differences in membrane properties. The long time constant indicates a higher specific membrane resistivity of immature neurons. Postsynaptic potentials (PSPs) recorded in young neurons were longer in latency, longer in duration, and more fragile during repetitive activation than their mature counterparts. In addition, PSPs evoked in neurons of animals less than 1 week old did not contain inhibitory postsynaptic components. These physiological features of immature neocortical neurons help explain the pattern of epileptogenesis in young animals. When neonatal cortical slices were exposed to the gamma-aminobutyric acid (GABA) antagonists penicillin or bicuculline, the frequency of occurrence of discharges resembling epileptiform depolarization shifts approached that found in mature slices only during the second postnatal week. Depolarization shifts at younger ages were less stereotyped and more sensitive to stimulus parameters than those in mature neurons.

  View details for Web of Science ID A1987J501200001

• SENSITIVITY OF NEURONAL DOPAMINE RESPONSE IN THE SUBSTANTIA-NIGRA AND VENTRAL TEGMENTUM TO CLOZAPINE, METOCLOPRAMIDE AND SCH 23390 NEUROPHARMACOLOGY Suppes, T., Pinnock, R. D. 1987; 26 (4): 331-337

  Abstract

  The activity of neurones in the substantial nigra and ventral tegmentum was recorded extracellularly in vitro. Dopamine produced depression of spontaneous firing in a dose-dependent manner. Antagonism of these neuronal responses to dopamine by metoclopramide, SCH 23390 and clozapine was examined. Metoclopramide antagonised the responses to dopamine in the manner expected; SCH 23390 had little effect on the response to dopamine as would be predicted for a selective dopamine "D1" antagonist. Clozapine did not produce the expected antagonism of the response to dopamine. The results at the single neurone level are compared with behavioural and biochemical data.

  View details for Web of Science ID A1987G924600007

  View details for PubMedID 3295579

• THE INFLUENCE OF DOPAMINE ON EPILEPTIFORM BURST ACTIVITY IN HIPPOCAMPAL PYRAMIDAL NEURONS BRAIN RESEARCH Suppes, T., Kriegstein, A. R., Prince, D. A. 1985; 326 (2): 273-280

  Abstract

  Dopamine (DA) application to guinea pig hippocampal CA1 neurons in vitro causes hyperpolarization of the resting potential, increase in conductance, and increase in amplitude and duration of the afterhyperpolarization (AHP). Since these changes could influence repetitive firing, we performed experiments to determine whether DA-induced effects would suppress epileptogenesis in the hippocampus. Epileptiform bursts were induced by adding penicillin (3.4 mM) to the perfusion medium. Focal application of DA (40-160 microns) onto CA1 cells (n = 15) produced a hyperpolarization averaging 4.5 mV beginning in 5-20 s and lasting up to 3 min. DA also caused an increase in the amplitude and duration of slow AHPs. The frequency of spontaneous epileptiform events however was not affected. CA3 neurons (n = 6) responded to DA application with an initial 1-3 mV depolarization beginning within 5-30 s and lasting 1-2 min. In 3 cases a small hyperpolarization lasting several minutes subsequently developed. AHP duration increased 70% and amplitude increased 35% (n = 4). Along with these membrane changes the frequency of epileptiform bursting in CA3 cells slowed for 1-3 min. We added DA (10-80 microM) to the perfusion medium to see whether a significant decrease in epileptiform burst frequency might occur in the follower CA1 region if greater numbers of pacemaker CA2 and CA3 cells were exposed to DA. Spontaneous CA1 bursting was reversibly slowed, the interburst interval became variable and increased from a mean of 4 to a mean of 5-7 s (n = 6). These results suggest that DA may play a role in decreasing the incidence or frequency of epileptogenic discharges in vivo.

  View details for Web of Science ID A1985ABY4500008

  View details for PubMedID 2982462

• A LATE SLOW DEPOLARIZATION UNMASKED IN THE PRESENCE OF TETRAETHYLAMMONIUM IN NEONATAL RAT SYMPATHETIC NEURONS INVITRO BRAIN RESEARCH Suppes, T. 1984; 293 (2): 269-278

  Abstract

  Neonatal rat superior cervical ganglia were mechanically dissociated, and the sympathetic neurons grown in dispersed cell cultures. Intracellular microelectrodes were used to study the effects of tetraethylammonium (TEA+), a blocker of outward K+ currents, on the excitable properties of these neurons. Addition of TEA+ to the perfusion media (TEA+-media) caused the resting potential to depolarize and the action potential to increase in duration. In TEA+-media (20-60 mM), a late delayed depolarization (LDD) followed the falling phase of the action potential with a delay of 1.5-2 s (n = 95). The LDD peak amplitude was in the range of 4-26 mV and the duration, to full return of the resting potential, was in the range of 18-90 s. For a given cell the amplitude and duration of the LDD were constant. The LDD was associated with a conductance increase. No LDD could be elicited in the presence of calcium channel blockers. Evidence was found for a Ca2+-dependence of the LDD: increasing the extracellular Ca2+ concentration caused increases in the amplitude and duration of the LDD. The significance of an endogenous LDD-like potential and possible explanations for the origin of the LDD are discussed.

  View details for Web of Science ID A1984SE16200008

  View details for PubMedID 6697220

• CHOLINERGIC ENHANCEMENT OF PENICILLIN-INDUCED EPILEPTIFORM DISCHARGES IN PYRAMIDAL NEURONS OF THE GUINEA-PIG HIPPOCAMPUS BRAIN RESEARCH Kriegstein, A. R., Suppes, T., Prince, D. A. 1983; 266 (1): 137-142

  Abstract

  Acetylcholine (1-20 mM) was applied to guinea pig hippocampal slices bathed in normal and penicillin-containing media. Recordings in the CA 1 pyramidal cell layer in the presence of penicillin showed that acetylcholine caused a prolonged enhancement of the extracellular field potential. Intracellular recordings documented an increase in duration of cell bursting, a decrease in burst afterhyperpolarization, and a membrane depolarization lasting 1-5 min. These results suggest that the actions of acetylcholine to increase membrane excitability interact with penicillin-induced disinhibition to enhance hippocampal epileptogenesis.

  View details for Web of Science ID A1983QM90500013

  View details for PubMedID 6850341