Bio

Clinical Focus


  • Psychopharmacology
  • Bipolar Disorder
  • Psychiatry

Academic Appointments


Professional Education


  • Medical Education:Washington University School Of Medicine (1995) MO
  • Residency:Stanford University Medical Center (1999) CA
  • Board Certification: Psychiatry, American Board of Psychiatry and Neurology (2001)
  • Internship:Stanford University Medical Center (1996) CA

Research & Scholarship

Current Research and Scholarly Interests


Bipolar Disorders, Psychopharmacology, Treatment, Anticonvulsants, Mood stabilizers

Clinical Trials


  • Safety and Efficacy Study of ELND005 as an Adjunctive Maintenance Treatment in Bipolar I Disorder Recruiting

    The primary purpose of this study is to determine whether ELND005 is effective in the maintenance treatment of bipolar 1 disorder when added to other therapies.

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Teaching

2010-11 Courses


Publications

Journal Articles


  • Superior chronic tolerability of adjunctive modafinil compared to pramipexole in treatment-resistant bipolar disorder JOURNAL OF AFFECTIVE DISORDERS Dell'Osso, B., Timtim, S., Hooshmand, F., Miller, S., Wang, P. W., Hill, S. J., Portillo, N., Ketter, T. A. 2013; 150 (1): 130-135

    Abstract

    Suboptimal outcomes are common in bipolar disorder (BD) pharmacotherapy, and may be mitigated with novel adjunctive agents such as modafinil (a low-affinity dopamine transport inhibitor) and pramipexole (a dopamine D2/D3 receptor agonist). While uncontrolled long-term effectiveness data have been reported for these treatments, reports specifically assessing their comparative acute versus chronic tolerability in BD are lacking. Such information, particularly in relation to discontinuation causes, has substantial relevance, providing initial indications to clinicians which treatment may be better tolerated, and to researchers which agent ought to be assessed in longer-term controlled trials.BD outpatients assessed with the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) Affective Disorders Evaluation, and followed with the STEP-BD Clinical Monitoring Form, were naturalistically prescribed adjunctive modafinil or pramipexole, and somatic/psychiatric intolerability discontinuation rates were compared.Among 63 BD outpatients (mean±SD age 43.5±14.3 years, 60.3% female, 42.9% type I, 44.4% type II, 12.7% type not otherwise specified), taking 3.5±1.5 (median 3) concurrent prescription psychotropics, adjunctive modafinil (n=24) for 626.9±863.9 (286) days versus pramipexole (n=39) for 473.7±613.4 (214; p=0.51) days yielded a 26.0% lower somatic/psychiatric intolerability discontinuation rate (12.5% vs. 38.5%; p<0.05), with most of the difference accounted for by more pramipexole somatic intolerability discontinuations, due to nausea and sedation, after the first 12 weeks of treatment.No placebo comparison group. Small sample of predominantly female Caucasian insured outpatients, taking complex concurrent medication regimens.Further studies are warranted to assess our preliminary observation that modafinil, compared to pramipexole, may be better tolerated for longer-term BD treatment.

    View details for DOI 10.1016/j.jad.2012.11.030

    View details for Web of Science ID 000322762600019

    View details for PubMedID 23261131

  • Brain-derived neurotrophic factor val66met genotype and early life stress effects upon bipolar course JOURNAL OF PSYCHIATRIC RESEARCH Miller, S., Hallmayer, J., Wang, P. W., Hill, S. J., Johnson, S. L., Ketter, T. A. 2013; 47 (2): 252-258

    Abstract

    Gene-environment interactions may contribute to bipolar disorder (BD) clinical course variability. We examined effects of brain-derived neurotrophic factor (BDNF) val66met genotype and early life stress (ELS) upon illness severity and chronicity in adult BD patients.80 patients (43 BD I, 33 BD II, 4 BD not otherwise specified, mean ± SD age 46.4 ± 14.0 years, 63.7% female) receiving open evidence-based and measurement-based care in the Stanford Bipolar Disorders Clinic for at least 12 months underwent BDNF val66met genotyping and completed the Childhood Trauma Questionnaire. BDNF met allele carrier genotype and history of childhood sexual and physical abuse were evaluated in relation to mean prior-year Clinical Global Impressions-Bipolar Version-Overall Severity of Illness (MPY-CGI-BP-OS) score and clinical and demographic characteristics.BDNF met allele carriers (but not non-met allele carriers) with compared to without childhood sexual abuse had 21% higher MPY-CGI-BP-OS scores (3.5 ± 0.7 versus 2.9 ± 0.7, respectively, t = -2.4, df = 28, p = 0.025) and 35% earlier BD onset age (14.6 ± 5.7 versus 22.8 ± 7.9 years, respectively, t = 3.0, df = 27, p = 0.006). Regression analysis, however, was non-significant for a BDNF-childhood sexual abuse interaction.small sample of predominantly female Caucasian insured outpatients taking complex medication regimens; only one gene polymorphism considered.Between group comparisons suggested BDNF met allele carrier genotype might amplify negative effects of ELS upon BD illness severity/chronicity, although with regression analysis, there was not a significant gene-environment interaction. Further studies with larger samples are warranted to assess whether BDNF met allele carriers with ELS are at risk for more severe/chronic BD illness course.

    View details for DOI 10.1016/j.jpsychires.2012.10.015

    View details for Web of Science ID 000314330100016

    View details for PubMedID 23182421

  • Enhanced Ziprasidone Combination Therapy Effectiveness in Obese Compared to Nonobese Patients With Bipolar Disorder JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Miller, S., Ittasakul, P., Wang, P. W., Hill, S. J., Childers, M. E., Rasgon, N., Ketter, T. A. 2012; 32 (6): 814-819

    Abstract

    To assess longer-term ziprasidone effectiveness in obese and non-obese patients with bipolar disorder (BD).Outpatients assessed with the Systematic Treatment Enhancement Program for BD Affective Disorders Evaluation and monitored with the Systematic Treatment Enhancement Program for BD Clinical Monitoring Form received open ziprasidone.Eighty-two patients (39 patients with BD I, 39 patients with BD II, and 4 patients with BD not otherwise specified; mean age, 41.1 years; females, 78.0%; obese, 48.8%) received ziprasidone combined with an average of 3.6 (in 74.4% at least 3) other prescription psychotropics and 1.2 prescription nonpsychotropics. Mean (median) ziprasidone final dose and duration were 134.3 (150) mg/d and 489 (199.5) days, respectively. Ziprasidone yielded in obese compared to nonobese patients less discontinuation (42.5% vs 71.4%, P = 0.01), albeit with a higher rate of addition of subsequent psychotropic medication (62.5% vs 35.7%, P = 0.03). Moreover, obese compared to nonobese patients had a higher rate of shift to final-visit euthymia (27.5% vs 0.0%, P = 0.0002), and more weight loss (-20.7 lbs vs -0.6 lbs, P = 0.001), and obese (but not nonobese) patients had significant improvements in mean Clinical Global Impression-Severity of Illness (decreased 0.6 points; P = 0.03) and Global Assessment of Functioning (increased 3.3 points, P = 0.01) scores. Weight change correlated significantly with Global Assessment of Functioning change (P = 0.047) but not with Clinical Global Impression-Severity of Illness change. Limitations are small sample size and open-label, uncontrolled, observational design.Controlled and additional observational studies seem warranted to confirm our preliminary findings suggesting ziprasidone may be more effective in obese compared to nonobese patients with BD already receiving combination pharmacotherapy.

    View details for DOI 10.1097/JCP.0b013e318270dea9

    View details for Web of Science ID 000310923500014

    View details for PubMedID 23131875

  • Pilot study of the efficacy of double-blind, placebo-controlled one-week olanzapine stabilization therapy in heterogeneous symptomatic bipolar disorder patients JOURNAL OF PSYCHIATRIC RESEARCH Srivastava, S., Wang, P. W., Hill, S. J., Childers, M. E., Keller, K. L., Ketter, T. A. 2012; 46 (7): 920-926

    Abstract

    Olanzapine has demonstrated efficacy in acute mania and bipolar I disorder (BDI) maintenance, but efficacy in brief therapy in more diverse populations, including patients with bipolar II disorder (BDII)/bipolar disorder not otherwise specified (BDNOS) with syndromal/subsyndromal depressive/mood elevation symptoms and taking/not taking concurrent medications remains to be established.Fifty adult outpatients (24 BD1, 22 BDII, 4 BDNOS, mean ± SD age 40.8 ± 11.5 years, 28.1% female, already taking 1.1 ± 1.2 [median 1] prescription psychotropics) with 17-item Hamilton Depression Rating Scale (HDRS) ?10 and/or Young Mania Rating Scale (YMRS) ?10 and ?24, were randomized to double-blind olanzapine (2.5-20 mg/day) versus placebo for one week.Among 45 patients with post-baseline ratings, olanzapine (9.0 ± 5.8 mg/day, n = 23) compared to placebo (n = 22) tended to yield greater Clinical Global Impressions-Bipolar Version-Overall Severity of Illness (-1.4 ± 0.9 versus -0.8 ± 1.1, p = 0.08) and Hamilton Anxiety Scale (-7.9 ± 6.3 versus -3.8 ± 6.1, p = 0.07) improvements, and YMRS/HDRS remission rate (47.8% versus 22.7%, p = 0.08), but significantly increased median weight (+2 versus -1 lbs, p = 0.001), and rates of excessive appetite (54.2% versus 22.7%, p = 0.04) and tremor (50.0% versus 9.1% p = 0.004). Number Needed to Treat and 95% Confidence Interval for YMRS/HDRS remission were 4 (1-?). Numbers Needed to Harm for excessive appetite and tremor were 4 (1-21) and 3 (1-6), respectively.Olanzapine tended to yield affective improvement and significantly increased weight, appetite, and tremor. Larger controlled studies appear feasible and warranted to assess brief olanzapine therapy in heterogeneous symptomatic bipolar disorder patients.

    View details for DOI 10.1016/j.jpsychires.2012.04.004

    View details for Web of Science ID 000306536100012

    View details for PubMedID 22579071

  • Open adjunctive ziprasidone associated with weight loss in obese and overweight bipolar disorder patients JOURNAL OF PSYCHIATRIC RESEARCH Wang, P. W., Hill, S. J., Childers, M. E., Chandler, R. A., Rasgon, N. L., Ketter, T. A. 2011; 45 (8): 1128-1132

    Abstract

    To assess effectiveness and tolerability of open adjunctive ziprasidone for weight loss in obese/overweight patients with bipolar disorders (BD) in diverse mood states, taking weight gain-implicated psychotropic medications.22 obese and three overweight BD patients (20 female; 10 BD-I, 14 BD-II, 1 BD-NOS) with mean ± SD baseline body mass index (BMI) of 31.8 ± 2.5 kg/m2 received ZIP (mean final dose 190 ± 92 mg/day) for mean of 79.2 ± 23.2 days. Weight was assessed at six weekly and three biweekly visits. Subjects entered the study in diverse mood states. At baseline, 21 were taking second-generation antipsychotics, 7 lithium, and 1 valproate, which could be reduced/discontinued at investigators' discretion.Weight and BMI decreased from baseline to endpoint by 4.5 ± 3.4 kg and 1.6 ± 1.2 kg/m2, respectively, at weekly rates of 0.37 kg and 0.13 kg/m2, respectively (all p < 0.00001). 48% of patients had at least 5% weight loss. Obesity rate decreased from 88% to 35% (p < 0.0001). Waist circumference decreased 1.6 inches (p = 0.0001). Overall, mood did not change. Patients with at least moderate baseline mood symptoms experienced significant mood improvement, despite 72% patients decreasing/discontinuing weight gain-implicated psychotropic medications. Seven patients discontinued ZIP early: 3 for weight loss inefficacy, and 1 each for viral gastroenteritis, loss of consciousness, pneumonia with hypomania, and lost to follow up.Open adjunctive ziprasidone may be effective for weight loss in obese/overweight BD patients taking weight gain-implicated psychotropic medications. These preliminary data should be considered with caution due to the open uncontrolled design, small sample size, and brief duration.

    View details for DOI 10.1016/j.jpsychires.2011.01.019

    View details for Web of Science ID 000293938900019

    View details for PubMedID 21371718

  • Gender-specific lipid profiles in patients with bipolar disorder JOURNAL OF PSYCHIATRIC RESEARCH Vemuri, M., Kenna, H. A., Wang, P. W., Ketter, T. A., Rasgon, N. L. 2011; 45 (8): 1036-1041

    Abstract

    High rates of dyslipidemia and insulin resistance (IR) are reported in patients with bipolar disorder (BD). We assessed gender effects upon rates of dyslipidemia/IR in outpatients with BD.Data from 491 outpatients (ages 18-88) seen in the Stanford Bipolar Disorders clinic between 2000 and 2007 were evaluated. Patients were followed longitudinally and received naturalistic treatment. BD patients (n = 234; 61% female; 42% Type I, 47% Type II, 11% NOS) with a mean age of 40.3 ± 14.0 years, mean BMI 26.8 ± 6.4, and 81% Caucasian, who had one of four lipid measures (total cholesterol, LDL, HDL, TG) at clinicians' discretion, a psychiatry clinic visit within 2 months of laboratory, and were not medicated for dyslipidemia were included. IR was imputed from TG/HDL ratio.Women, compared with men, had significantly lower mean triglycerides (105.58 ± 64.12 vs. 137.99 ± 105.14, p = 0.009), higher mean HDL cholesterol (60.17 ± 17.56 vs. 46.07 ± 11.91 mg/dl, p < 0.001), lower mean LDL cholesterol (109.84 ± 33.47 vs. 123.79 ± 35.96 mg/dl, p = 0.004), and lower TG/HDL ratio (1.98 ± 1.73 vs. 3.59 ± 3.14 p < 0.001). Compared to men, women had a significantly lower prevalence of abnormal total cholesterol, LDL, TG, HDL, and TG/HDL ratio. No significant differences were found between men and women with regard to age, BMI, ethnicity, educational attainment, smoking habits, bipolar illness type, illness severity or duration, or weight-liable medication exposure.In outpatients with BD, women had more favorable lipid profiles than men despite similar demographic variables. This sample of primarily Caucasian and educated patients, receiving vigilant clinical monitoring, may represent a relatively healthy psychiatric population demonstrating gender differences similar to those in the general population.

    View details for DOI 10.1016/j.jpsychires.2011.02.002

    View details for Web of Science ID 000293938900006

    View details for PubMedID 21377167

  • Treatments for bipolar disorder: can number needed to treat/harm help inform clinical decisions? ACTA PSYCHIATRICA SCANDINAVICA Ketter, T. A., Citrome, L., Wang, P. W., Culver, J. L., Srivastava, S. 2011; 123 (3): 175-189

    Abstract

    To compare bipolar treatment interventions, using number needed to treat (NNT) and number needed to harm (NNH).Results of randomized controlled clinical trials were used to assess efficacy (NNT for response and relapse/recurrence prevention vs. placebo) and tolerability (e.g. NNH for weight gain and sedation vs. placebo).United States Food and Drug Administration-approved bipolar disorder pharmacotherapies all have single-digit NNTs (i.e. > 10% advantage over placebo), but NNHs for adverse effects that vary widely. Some highly efficacious agents are as likely to yield adverse effects as therapeutic benefit, but may be interventions of choice in more acute severe illness. In contrast, some less efficacious agents with better tolerability may be interventions of choice in more chronic mild-moderate illness.Clinical trials can help inform clinical decision making by quantifying the likelihood of benefit vs. harm. Integrating such data with individual patient circumstances, values, and preferences can help optimize treatment choices.

    View details for DOI 10.1111/j.1600-0447.2010.01645.x

    View details for Web of Science ID 000286890300002

    View details for PubMedID 21133854

  • Higher prevalence of bipolar I disorder among Asian and Latino compared to Caucasian patients receiving treatment ASIA-PACIFIC PSYCHIATRY Hwang, S. H., Childers, M. E., Wang, P. W., Nam, J. Y., Keller, K. L., Hill, S. J., Ketter, T. A. 2010; 2 (3): 156-165
  • Toward interaction of affective and cognitive contributors to creativity in bipolar disorders: A controlled study JOURNAL OF AFFECTIVE DISORDERS Srivastava, S., Childers, M. E., Baek, J. H., Strong, C. M., Hill, S. J., Warsett, K. S., Wang, P. W., Akiskal, H. S., Akiskal, K. K., Ketter, T. A. 2010; 125 (1-3): 27-34

    Abstract

    Enhanced creativity in bipolar disorder patients may be related to affective and cognitive phenomena.32 bipolar disorder patients (BP), 21 unipolar major depressive disorder patients (MDD), 22 creative controls (CC), and 42 healthy controls (HC) (all euthymic) completed the Revised Neuroticism Extraversion Openness Personality Inventory (NEO), the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A), the Myers-Briggs Type Inventory (MBTI); the Barron-Welsh Art Scale (BWAS), the Adjective Check List Creative Personality Scale, and the Figural and Verbal Torrance Tests of Creative Thinking. Mean scores were compared across groups, and relationships between temperament/personality and creativity were assessed with bivariate correlation and hierarchical multiple linear regression.BP and CC (but not MDD) compared to HC had higher BWAS-Total (46% and 42% higher, respectively, p<0.05) and BWAS-Dislike (83% and 93% higher, p<0.02) scores, and higher MBTI-Intuition preference type rates (78% vs. 50% and 96% vs. 50%, p<0.05). BP, MDD, and CC, compared to HC, had increased TEMPS-A-Cyclothymia scores (666%, 451% and 434% higher, respectively, p<0.0001), and NEO-Neuroticism scores (60%, 57% and 51% higher, p<0.0001). NEO-Neuroticism and TEMPS-A Cyclothymia correlated with BWAS-Dislike (and BWAS-Total), while MBTI-Intuition continuous scores and NEO-Openness correlated with BWAS-Like (and BWAS-Total).Relatively small sample size.We replicate the role of cyclothymic and related temperaments in creativity, as well as that of intuitive processes. Further studies are needed to clarify relationships between creativity and affective and cognitive processes in bipolar disorder patients.

    View details for DOI 10.1016/j.jad.2009.12.018

    View details for Web of Science ID 000281377100004

    View details for PubMedID 20085848

  • Metabolic dysfunction in women with bipolar disorder: the potential influence of family history of type 2 diabetes mellitus BIPOLAR DISORDERS Rasgon, N. L., Kenna, H. A., Reynolds-May, M. F., Stemmle, P. G., Vemuri, M., Marsh, W., Wang, P., Ketter, T. A. 2010; 12 (5): 504-513

    Abstract

    Overweight/obesity, insulin resistance (IR), and other types of metabolic dysfunction are common in patients with bipolar disorder (BD); however, the pathophysiological underpinnings of metabolic dysfunction in BD are not fully understood. Family history of type 2 diabetes mellitus (FamHxDM2), which has been shown to have deleterious effects on metabolic function in the general population, may play a role in the metabolic dysfunction observed in BD.Using multivariate analysis of variance, the effects of BD illness and/or FamHxDM2 were examined relative to metabolic biomarkers in 103 women with BD and 36 healthy, age-matched control women.As a group, women with BD had higher levels of fasting plasma insulin (FPI) and fasting plasma glucose (FPG), higher homeostatic assessment of IR (HOMA-IR) scores, body mass index (BMI), waist circumference (WC), and hip circumference (HC) compared to control women. FamHxDM2 was associated with significantly worse metabolic biomarkers among women with BD but not among healthy control women. Among women with BD, there was a significant main effect of FamHxDM2 on FPI, HOMA-IR, BMI, WC, and HC, even after controlling for type of BD illness, duration of medication exposure, and depression severity. Metabolic biomarkers were not influenced by use of weight-liable psychotropic medication (WLM), even after controlling for type of BD illness, duration of medication exposure, and depression severity.Women with BD have overall worse metabolic biomarkers than age-matched control women. The use of WLM, duration of medication use, type of BD illness, and depression severity did not appear to be associated with more pronounced metabolic dysfunction. FamHxDM2 may represent a risk factor for the development of IR in women with BD. Further, focused studies of the endocrine profiles of families of BD patients are needed.

    View details for DOI 10.1111/j.1399-5618.2010.00839.x

    View details for Web of Science ID 000280987800005

    View details for PubMedID 20712751

  • Divalproex extended-release in acute bipolar II depression JOURNAL OF AFFECTIVE DISORDERS Wang, P. W., Nowakowska, C., Chandler, R. A., Hill, S. J., Nam, J. Y., Culver, J. L., Keller, K. L., Ketter, T. A. 2010; 124 (1-2): 170-173

    Abstract

    Divalproex extended-release (divalproex-ER) is effective in acute mania, and limited data suggest divalproex may have efficacy in acute bipolar depression.A 7-week, open-label trial of divalproex-ER monotherapy or adjunctive therapy was conducted in 28 outpatients (15 female, mean age 36.7+/-9.1, and mean duration of illness 22.1+/-11.1 years) with bipolar II depression (39% with rapid cycling course of illness within the prior year). Divalproex-ER was generally given as a single dose at bedtime, starting at 250mg and increased by 250mg every 4 days to symptom relief or adverse effects. Efficacy was assessed using weekly prospective Montgomery Asberg Depression Rating Scale (MADRS) scores.Overall, mean divalproex-ER final doses and serum concentrations were 1469mg/day and 80.1microg/mL, respectively. Mean MADRS scores (last observation carried forward) decreased significantly from baseline in patients in the overall group (from 30.1 to 15.2, p<.00001). The overall response rate was 54%. Divalproex-ER therapy was generally well tolerated, with no early discontinuations due to adverse events.This study is limited by a small sample size and an open-label study design with no placebo control.Divalproex-ER as monotherapy and adjunctive therapy was well tolerated and yielded an overall response rate of 54% in bipolar II depression. Based on the results of this pilot study, randomized, double-blind, placebo-controlled studies of divalproex-ER in bipolar II depression are warranted.

    View details for DOI 10.1016/j.jad.2009.10.021

    View details for Web of Science ID 000278787400022

    View details for PubMedID 19923006

  • Dorsolateral and dorsomedial prefrontal gray matter density changes associated with bipolar depression PSYCHIATRY RESEARCH-NEUROIMAGING Brooks, J. O., Bonner, J. C., Rosen, A. C., Wang, P. W., Hoblyn, J. C., Hill, S. J., Ketter, T. A. 2009; 172 (3): 200-204

    Abstract

    Mood states are associated with alterations in cerebral blood flow and metabolism, yet changes in cerebral structure are typically viewed in the context of enduring traits, genetic predispositions, or the outcome of chronic psychiatric illness. Magnetic resonance imaging (MRI) scans were obtained from two groups of patients with bipolar disorder. In one group, patients met criteria for a current major depressive episode whereas in the other no patient did. No patient in either group met criteria for a current manic, hypomanic, or mixed episode. Groups were matched with respect to age and illness severity. Analyses of gray matter density were performed with Statistical Parametric Mapping software (SPM5). Compared with non-depressed bipolar subjects, depressed bipolar subjects exhibited lower gray matter density in the right dorsolateral and bilateral dorsomedial prefrontal cortices and portions of the left parietal lobe. In addition, gray matter density was greater in the left temporal lobe and right posterior cingulate cortex/parahippocampal gyrus in depressed than in non-depressed subjects. Our findings highlight the importance of mood state in structural studies of the brain-an issue that has received insufficient attention to date. Moreover, our observed differences in gray matter density overlap metabolic areas of change and thus have implications for the conceptualization and treatment of affective disorders.

    View details for DOI 10.1016/j.pscychresns.2008.06.007

    View details for Web of Science ID 000266580800005

    View details for PubMedID 19351579

  • Sleep functioning in relation to mood, function, and quality of life at entry to the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) JOURNAL OF AFFECTIVE DISORDERS Gruber, J., Harvey, A. G., Wang, P. W., Brooks, J. O., Thase, M. E., Sachs, G. S., Ketter, T. A. 2009; 114 (1-3): 41-49

    Abstract

    Sleep disturbance in bipolar disorder can be both a risk factor and symptom of mood episodes. However, the associations among sleep and clinical characteristics, function, and quality of life in bipolar disorder have not been fully investigated.The prevalence of sleep disturbance, duration, and variability, as well as their associations with mood, function, and quality of life, was determined from 2024 bipolar patients enrolled in the National Institute of Mental Health Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).Analyses indicated that 32% of patients were classified as short sleepers, 38% normal sleepers, and 23% long sleepers. Overall, short sleepers demonstrated greater mood elevation, earlier age at onset, and longer illness duration compared to both normal and long sleepers. Both short and long sleepers had greater depressive symptoms, poorer life functioning, and quality of life compared to normal sleepers.Short sleep duration in bipolar disorder was associated with a more severe symptom presentation, whereas both short and long sleep duration are associated with poorer function and quality of life compared to normal sleep duration. Sleep disturbance could be a trait marker of bipolar disorder, though longitudinal assessments are warranted to assess potential causal relations and the longer-term implications of sleep disturbance in bipolar disorder.

    View details for DOI 10.1016/j.jad.2008.06.028

    View details for Web of Science ID 000264223900004

    View details for PubMedID 18707765

  • Insulin resistance and hyperlipidemia in women with bipolar disorder. Journal of psychiatric research Stemmle, P. G., Kenna, H. A., Wang, P. W., Hill, S. J., Ketter, T. A., Rasgon, N. L. 2009; 43 (3): 341-343

    View details for DOI 10.1016/j.jpsychires.2008.04.003

    View details for PubMedID 18490029

  • Decreased prefrontal, anterior cingulate, insula, and ventral striatal metabolism in medication-free depressed outpatients with bipolar disorder. Journal of psychiatric research Brooks, J. O., Wang, P. W., Bonner, J. C., Rosen, A. C., Hoblyn, J. C., Hill, S. J., Ketter, T. A. 2009; 43 (3): 181-188

    Abstract

    This study explored whether cerebral metabolic changes seen in treatment resistant and rapid cycling bipolar depression inpatients are also found in an outpatient sample not specifically selected for treatment resistance or rapid cycling. We assessed 15 depressed outpatients with bipolar disorder (six type I and nine type II) who were medication-free for at least 2 weeks and were not predominantly rapid cycling. The average 28-item Hamilton Depression Scale (HAM-D) total score was 33.9. The healthy control group comprised 19 age-matched subjects. All participants received a resting quantitative 18F-fluoro-deoxyglucose positron emission tomography scan. Data analyses were performed with Statistical Parametric Mapping (SPM5). Analyses revealed that depressed patients exhibited similar global metabolism, but decreased absolute regional metabolism in the left much more than right dorsolateral prefrontal cortex, bilateral (left greater than right) insula, bilateral subgenual prefrontal cortex, anterior cingulate, medial prefrontal cortex, ventral striatum, and right precuneus. No region exhibited absolute hypermetabolism. Moreover, HAM-D scores inversely correlated with absolute global metabolism and regional metabolism in the bilateral medial prefrontal gyrus, postcentral gyrus, and middle temporal gyrus. Analysis of relative cerebral metabolism yielded a similar, but less robust pattern of findings. Our findings confirm prefrontal and anterior paralimbic metabolic decreases in cerebral metabolism outside of inpatients specifically selected for treatment resistant and rapid cycling bipolar disorder. Prefrontal metabolic rates were inversely related to severity of depression. There was no evidence of regional hypermetabolism, perhaps because this phenomenon is less robust or more variable than prefrontal hypometabolism.

    View details for DOI 10.1016/j.jpsychires.2008.04.015

    View details for PubMedID 18582900

  • A new US-UK diagnostic project: mood elevation and depression in first-year undergraduates at Oxford and Stanford universities ACTA PSYCHIATRICA SCANDINAVICA Chandler, R. A., Wang, P. W., Ketter, T. A., Goodwin, G. M. 2008; 118 (1): 81-85

    Abstract

    To investigate differences in prevalence of mood elevation, distress and depression among first-year undergraduates at Oxford and Stanford universities.An online survey was sent to Oxford and Stanford first-year undergraduate students for two consecutive years in the winter of 2005 and 2006. Students completed a survey that assessed mood symptoms and medication use.Both universities had similar rates of distress by General Health Questionnaire (Oxford - 42.4%; Stanford - 38.3%), depression by Primary Care Evaluation of Mental Disorders (Oxford - 6.2%; Stanford - 6.6%), and psychotropic and non-psychotropic medication usage (psychotropic: Oxford - 1.5%; Stanford 3.5%; nonpsychotropic: Oxford - 13.3%; Stanford - 18%). Oxford had higher rates of mood elevation by Mood Disorder Questionnaire (MDQ) (Oxford - 4%; Stanford - 1.7%).Oxford and Stanford students have similar rates of mood distress, depression and general medication usage. Students at Oxford have a higher prevalence of MDQ scores that possibly indicate a bipolar disorder, while Stanford students are prescribed more psychotropics.

    View details for DOI 10.1111/j.1600-0447.2008.01193.x

    View details for Web of Science ID 000256684000011

    View details for PubMedID 18595178

  • Adjunctive zonisamide for weight loss in euthymic bipolar disorder patients: A pilot study JOURNAL OF PSYCHIATRIC RESEARCH Wang, P. W., Yang, Y., Chandler, R. A., Nowakowska, C., Alarcon, A. M., Culver, J., Ketter, T. A. 2008; 42 (6): 451-457

    Abstract

    To assess the effectiveness and tolerability of open adjunctive zonisamide in treatment of obesity in euthymic bipolar disorder (BD) patients.Zonisamide was administered to recovered, overweight BD outpatients assessed with the Systematic Treatment Enhancement Program for Bipolar Disorders (STEP-BD) Affective Disorders Evaluation and followed with the STEP-BD Clinical Monitoring Form. Weight changes (Body Mass Index (BMI) and BMI percentage changes) were assessed prospectively at four weekly visits, one bi-weekly visit, and then five monthly visits, for a maximal duration of six months. Weight loss was assessed with random effects modeling to maximize all available data for analysis.Twenty-five BD (10 BD-type I, 15 BD-type II) patients (mean age 41.0+/-10.4 years, 64% female, 96% Caucasian) on a mean of 2.8+/-1.5 prescription psychotropic and 1.3+/-1.4 prescription non-psychotropic medications received zonisamide for a mean duration of 14.2+/-8.5 weeks, with a mean final dose of 375+/-206 (range 75-800) mg/day. Slope of weight loss was 0.078 BMI points per week, and non-zero (p<0.0005). Mean weight loss was 1.2+/-1.9 BMI points (baseline BMI 34.2+/-3.1 to final BMI 33.0+/-3.5, p<0.003). Eighteen patients (72%) discontinued study participation early, 11/25 (44%) due to emergent mood symptoms (eight depression, two mania, one subsyndromal mixed symptoms) requiring treatment intervention, 5/25 (20%) due to adverse physical events, and 2/25 (8%) due to patient choice, but none due to weight loss inefficacy.Adjunctive zonisamide appeared effective and generally physically tolerated, but had high rates of mood adverse events, in obese BD patients. Controlled trials are warranted to systematically explore these preliminary naturalistic observations.

    View details for DOI 10.1016/j.jpsychires.2007.05.005

    View details for Web of Science ID 000254720300004

    View details for PubMedID 17628595

  • Decreased prefrontal, anterior cingulate, insula, and ventral striatal metabolism in medication-free depressed outpatients with bipolar disorder JOURNAL OF PSYCHIATRIC RESEARCH Brooks, J. O., Wang, P. W., Bonner, J. C., Rosen, A. C., Hoblyn, J. C., Hill, S. J., Ketter, T. A. 2008; 43 (3): 181-188
  • Temperament-creativity relationships in mood disorder patients, healthy controls and highly creative individuals JOURNAL OF AFFECTIVE DISORDERS Strong, C. M., Nowakowska, C., Santosa, C. M., Wang, P. W., Kraemer, H. C., Ketter, T. A. 2007; 100 (1-3): 41-48

    Abstract

    To investigate temperament-creativity relationships in euthymic bipolar (BP) and unipolar major depressive (MDD) patients, creative discipline controls (CC), and healthy controls (HC).49 BP, 25 MDD, 32 CC, and 47 HC (all euthymic) completed three self-report temperament/personality measures: the Revised NEO Personality Inventory (NEO-PI-R), the Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A), and the Temperament and Character Inventory (TCI); and four creativity measures yielding six parameters: the Barron-Welsh Art Scale (BWAS-Total, BWAS-Like, and BWAS-Dislike), the Adjective Check List Creative Personality Scale (ACL-CPS), and the Torrance Tests of Creative Thinking--Figural (TTCT-F) and Verbal (TTCT-V) versions. Factor analysis was used to consolidate the 16 subscales from the three temperament/personality measures, and the resulting factors were assessed in relationship to the creativity parameters.Five personality/temperament factors emerged. Two of these factors had prominent relationships with creativity measures. A Neuroticism/Cyclothymia/Dysthymia Factor, comprised mostly of NEO-PI-R-Neuroticism and TEMPS-A-Cyclothymia and TEMPS-A-Dysthymia, was related to BWAS-Total scores (r=0.36, p<0.0001) and BWAS-Dislike subscale scores (r=0.39, p<0.0001). An Openness Factor, comprised mostly of NEO-PI-R-Openness, was related to BWAS-Like subscale scores (r=0.28, p=0.0006), and to ACL-CPS scores (r=0.46, p<0.0001). No significant relationship was found between temperament/personality and TTCT-F and TTCT-V scores.Neuroticism/Cyclothymia/Dysthymia and Openness appear to have differential relationships with creativity. The former could provide affective (Neuroticism, i.e. access to negative affect, and Cyclothymia, i.e. changeability of affect) and the latter cognitive (flexibility) advantages to enhance creativity. Further studies are indicated to clarify mechanisms of creativity and its relationships to affective processes and bipolar disorders.

    View details for DOI 10.1016/j.jad.2006.10.015

    View details for Web of Science ID 000247704400006

    View details for PubMedID 17126408

  • Enhanced creativity in bipolar disorder patients: A controlled study JOURNAL OF AFFECTIVE DISORDERS Santosa, C. A., Strong, C. M., Nowakowska, C., Wang, P. W., Rennicke, C. M., Ketter, T. A. 2007; 100 (1-3): 31-39

    Abstract

    Associations between eminent creativity and bipolar disorders have been reported, but there are few data relating non-eminent creativity to bipolar disorders in clinical samples. We assessed non-eminent creativity in euthymic bipolar (BP) and unipolar major depressive disorder (MDD) patients, creative discipline controls (CC), and healthy controls (HC).49 BP, 25 MDD, 32 CC, and 47 HC (all euthymic) completed four creativity measures yielding six parameters: the Barron-Welsh Art Scale (BWAS-Total, and two subscales, BWAS-Dislike and BWAS-Like), the Adjective Check List Creative Personality Scale (ACL-CPS), and the Torrance Tests of Creative Thinking--Figural (TTCT-F) and Verbal (TTCT-V) versions. Mean scores on these instruments were compared across groups.BP and CC (but not MDD) compared to HC scored significantly higher on BWAS-Total (45% and 48% higher, respectively) and BWAS-Dislike (90% and 88% higher, respectively), but not on BWAS-Like. CC compared to MDD scored significantly higher (12% higher) on TTCT-F. For all other comparisons, creativity scores did not differ significantly between groups.We found BP and CC (but not MDD) had similarly enhanced creativity on the BWAS-Total (driven by an increase on the BWAS-Dislike) compared to HC. Further studies are needed to determine the mechanisms of enhanced creativity and how it relates to clinical (e.g. temperament, mood, and medication status) and preclinical (e.g. visual and affective processing substrates) parameters.

    View details for DOI 10.1016/j.jad.2006.10.013

    View details for Web of Science ID 000247704400005

    View details for PubMedID 17126406

  • Improving the pedagogy associated with the teaching of psychopharmacology ACADEMIC PSYCHIATRY Glick, I. D., Salzman, C., Cohen, B. M., Klein, D. F., Moutier, C., Nasrallah, H. A., Ongur, D., Wang, P., Zisook, S. 2007; 31 (3): 211-217

    Abstract

    The authors summarize two special sessions focused on the teaching of psychopharmacology at the 2003 and 2004 annual meeting of the American College of Neuropsychopharmacology (ACNP). The focus was on whether "improving the teaching-learning process" in psychiatric residency programs could improve clinical practice.Problems of strategies and pedagogic techniques that have been used were presented from multiple perspectives (e.g., from a dean, department chair, training director, and former students).There was a consensus that action involving psychopharmacology organizations and the American Association of Directors of Residency Training in Psychiatry (AADPRT) was necessary to improve "evidence-based" competencies before graduation and to follow prescribing patterns into clinical practice to determine whether the standards of care could be improved.

    View details for Web of Science ID 000246445500009

    View details for PubMedID 17496178

  • Overweight and obesity in bipolar disorders JOURNAL OF PSYCHIATRIC RESEARCH Wang, P. W., Sachs, G. S., Zarate, C. A., Marangell, L. B., Calabrese, J. R., Goldberg, J. F., Sagduyu, K., Miyahara, S., Ketter, T. A. 2006; 40 (8): 762-764
  • Adjunctive aripiprazole in treatment-resistant bipolar depression. Annals of clinical psychiatry Ketter, T. A., Wang, P. W., Chandler, R. A., Culver, J. L., Alarcon, A. M. 2006; 18 (3): 169-172

    Abstract

    There are limited management options for treatment-resistant depression in bipolar disorder (BD) patients.Open adjunctive aripiprazole was administered to outpatients with treatment-resistant depression assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation, and followed with the STEP-BD Clinical Monitoring Form.Thirty BD (11 type I, 15 type II, 4 NOS) patients (mean age 44.4 +/- 17.0 years, 70% female) on a mean of 3.2 +/- 1.6 other psychotropic and 2.3 +/- 1.6 nonpsychotropic prescription medications received aripiprazole for a mean duration of 84 +/- 69 days, with a mean final dose of 15.3 +/- 11.2 (range 2.5-40) mg/day. Fourteen patients (47%) discontinued aripiprazole; due to inefficacy in 5/30 (17%), patient choice in 3/30 (10%), and adverse effects in 6/30 (20%). Aripiprazole yielded improvement in Clinical Global Impression-Severity (CGI-S, 4.4 +/- 1.1 to 3.8 +/- 1.2, p < 0.01), with 8/30 (27%) patients responding (CGI-S improvement > or = 2), including 4/30 (13%) who remitted (final CGI-S < or = 2). Global Assessment of Function, and depressed mood and suicidal ideation ratings also improved. Aripiprazole was generally well tolerated, with no significant change in mean adverse effect ratings or mean weight.Aripiprazole appeared effective and generally well tolerated in treatment-resistant bipolar depression. Controlled trials are warranted to systematically explore these preliminary naturalistic observations.

    View details for PubMedID 16923655

  • Preliminary evidence of differential relations between prefrontal cortex metabolism and sustained attention in depressed adults with bipolar disorder and healthy controls BIPOLAR DISORDERS Brooks, J. O., Wang, P. W., Strong, C., Sachs, N., Hoblyn, J. C., Fenn, R., Ketter, T. A. 2006; 8 (3): 248-254

    Abstract

    To assess the relations between sustained attention as assessed by the Continuous Performance Test (CPT) and subgenual and dorsolateral prefrontal cortex metabolism in depressed patients with bipolar disorders and healthy controls.Cross-sectional case-control design.Cerebral metabolic rates were assessed with 18F-fluoro-deoxyglucose and positron emission tomography (PET) in the regions of interest defined on co-registered structural magnetic resonance images in eight medication-free, depressed bipolar disorder patients and 27 healthy control participants. PET scans were obtained in a resting state and the CPT was administered within 1 week of the PET scan.Although there were no statistically significant differences in performance on the CPT or in cerebral metabolism between the two groups, our analyses revealed differential relations between the CPT and metabolism across the groups. Decreased subgenual prefrontal metabolism was associated with slower hit rate reaction time and more omission errors in the bipolar group, but not the control group. Decreased dorsolateral prefrontal metabolism in the bipolar group, but not the control group, was associated with more commission errors.This study extends previous neuroimaging findings of structural and functional relevance of the prefrontal region with attention to include depressed states in bipolar disorder. The results are consistent with interpretations that decreased prefrontal activity may represent failure to activate some areas of inhibitory control. Decreasing subgenual prefrontal cortex metabolism appears to relate to decreased attention whereas the decreased dorsolateral prefrontal cortex metabolism relates more to decreased inhibitory control.

    View details for Web of Science ID 000237515900005

    View details for PubMedID 16696826

  • Magnetic resonance spectroscopic measurement of cerebral gamma-aminobutyric acid concentrations in patients with bipolar disorders ACTA NEUROPSYCHIATRICA Wang, P. W., Sailasuta, N., Chandler, R. A., Ketter, T. A. 2006; 18 (2): 120-126
  • Clinical use of carbamazepine for bipolar disorders EXPERT OPINION ON PHARMACOTHERAPY Wang, P. W., Ketter, T. A. 2005; 6 (16): 2887-2902

    Abstract

    Two recently completed large, randomised, double-blind, placebo-controlled trials supporting the efficacy of carbamazepine (CBZ) extended-release capsules (ERC) for the treatment of acute manic and mixed episodes have resulted in US FDA approval of CBZ-ERC, and have reinvigorated the importance of understanding the role of CBZ in bipolar disorder (BD) pharmacotherapy. Additional data suggest that CBZ may have a use in BD maintenance treatment and possibly in acute BD depression. Optimal use of CBZ requires sound knowledge of adverse effects and pharmacokinetic interactions with this agent. Adverse effects commonly involve benign side effects but can rarely include serious haematological, dermatological and hepatic manifestations. On the other hand, metabolic adverse effects (thyroid, glucose, lipid disturbances and significant weight gain) can be less problematic with CBZ, compared with lithium, valproate and atypical antipsychotics. Pharmacokinetic considerations (cytochrome P450 3A3/4 metabolism, active epoxide metabolite and catabolic enzyme induction) can influence the clinical use of CBZ. Managing adverse effects and pharmacokinetic complexities is important for optimising pharmacotherapy with CBZ in patients with BD. This paper reviews the chemistry, pharmacodynamics and pharmacokinetics of CBZ, as well as reviews of the controlled trials of CBZ in acute bipolar mania, acute bipolar depression and bipolar maintenance treatment.

    View details for DOI 10.1517/14656566.6.16.2887

    View details for Web of Science ID 000233901000011

    View details for PubMedID 16318439

  • Dermatology precautions and slower titration yield low incidence of lamotrigine treatment-emergent rash JOURNAL OF CLINICAL PSYCHIATRY Ketter, T. A., Wang, P. W., Chandler, R. A., Alarcon, A. M., Becker, O. V., Nowakowska, C., O'Keeffe, C. M., Schumacher, M. R. 2005; 66 (5): 642-645

    Abstract

    To assess treatment-emergent rash incidence when using dermatology precautions (limited antigen exposure) and slower titration during lamotrigine initiation.We assessed rash incidence in 100 patients with DSM-IV bipolar disorder instructed, for their first 3 months taking lamotrigine, to avoid other new medicines and new foods, cosmetics, conditioners, deodorants, detergents, and fabric softeners, as well as sunburn and exposure to poison ivy/oak. Lamotrigine was not started within 2 weeks of a rash, viral syndrome, or vaccination. In addition, lamotrigine was titrated more slowly than in the prescribing information. Patients were monitored for rash and clinical phenomena using the Systematic Treatment Enhancement Program for Bipolar Disorder Clinical Monitoring Form. Descriptive statistics were compiled.No patient had serious rash. Benign rash occurred in 5 patients (5%) and resolved uneventfully in 3 patients discontinuing and 2 patients continuing lamotrigine. Two patients with rash were found to be not adherent to dermatology precautions. Therefore, among the remaining patients, only 3/98 (3.1%) had benign rashes.The observed rate of benign rash was lower than the 10% incidence in other clinical studies. The design of this study confounds efforts to determine the relative contributions of slower titration versus dermatology precautions to the low rate of rash. Systematic studies are needed to confirm these preliminary findings, which suggest that adhering to dermatology precautions with slower titration may yield a low incidence of rash with lamotrigine.

    View details for Web of Science ID 000229302900016

    View details for PubMedID 15889953

  • Temperamental commonalities and differences in euthymic mood disorder patients, creative controls, and healthy controls JOURNAL OF AFFECTIVE DISORDERS Nowakowska, C., Strong, C. M., Santosa, C. M., Wang, P. W., Ketter, T. A. 2005; 85 (1-2): 207-215

    Abstract

    Understanding of mood disorders can be enhanced through assessment of temperamental traits. We explored temperamental commonalities and differences among euthymic bipolar (BP) and unipolar (MDD) mood disorder patients, creative discipline graduate student controls (CC), and healthy controls (HC).Forty-nine BP, 25 MDD, 32 CC, and 47 HC completed self-report temperament/personality measures including: The Affective Temperament Evaluation of Memphis, Pisa, Paris and San Diego (TEMPS-A); the Revised NEO Personality Inventory (NEO-PI-R); and the Temperament and Character Inventory (TCI).Euthymic BP, MDD, and CC, compared to HC, had significantly increased cyclothymia, dysthymia and irritability scores on TEMPS-A; increased neuroticism and decreased conscientiousness on NEO-PI-R; and increased harm avoidance and novelty seeking as well as decreased self-directedness on TCI. TEMPS-A cyclothymia scores were significantly higher in BP than in MDD. NEO-PI-R openness was increased in BP and CC, compared to HC, and in CC compared to MDD. TCI self-transcendence scores in BP were significantly higher than in MDD, CC, and HC.Most of the subjects were not professional artists, and represented many fields; temperament might be different in different art fields.Euthymic BP, MDD, and CC compared to HC, had prominent temperamental commonalities. However, BP and CC had the additional commonality of increased openness compared to HC. BP had particularly high Cyclothymia scores that were significantly higher then those of MDD. The prominent BP-CC overlap suggests underlying neurobiological commonalities between people with mood disorders and individuals involved in creative disciplines, consistent with the notion of a temperamental contribution to enhanced creativity in individuals with bipolar disorders.

    View details for DOI 10.1016/j.jad.2003.11.012

    View details for Web of Science ID 000228409400022

    View details for PubMedID 15780691

  • New medication treatment options for bipolar disorders ACTA PSYCHIATRICA SCANDINAVICA Ketter, T. A., Wang, P. W., Nowakowska, C., Marsh, W. K. 2004; 110: 18-33

    Abstract

    To assess new treatment options for bipolar disorders.Controlled studies of new treatments for bipolar disorders were identified by computerized searches and reviews of scientific meeting proceedings, and were compiled by drug category.Two main categories of medications, newer anticonvulsants and newer antipsychotics, are yielding emerging new treatment options for bipolar disorders. Newer anticonvulsants have diverse psychotropic profiles, and although not generally effective for acute mania, may have utility for other aspects of bipolar disorders (e.g. lamotrigine for maintenance or acute bipolar depression), or for comorbid conditions (e.g. gabapentin for anxiety or pain, topiramate for obesity, bulimia, alcohol dependence, or migraine, and zonisamide for obesity). In contrast, newer antipsychotics generally appear effective for acute mania, and some may ultimately prove effective in acute depression (e.g. olanzapine combined with fluoxetine, quetiapine) and maintenance (e.g. olanzapine).Emerging research is yielding new treatment options for bipolar disorders and comorbid conditions.

    View details for Web of Science ID 000224297000003

    View details for PubMedID 15330935

  • Psychotic bipolar disorders: dimensionally similar to or categorically different from schizophrenia? JOURNAL OF PSYCHIATRIC RESEARCH Ketter, T. A., Wang, P. W., Becker, O. V., Nowakowska, C., Yang, Y. S. 2004; 38 (1): 47-61

    Abstract

    For over a century, clinicians have struggled with how to conceptualize the primary psychoses, which include psychotic mood disorders and schizophrenia. Indeed, the nature of the relationship between mood disorders and schizophrenia is an area of ongoing controversy. Psychotic bipolar disorders have characteristics such as phenomenology, biology, therapeutic response, and brain imaging findings, suggesting both commonalities with and dissociations from schizophrenia. Taken together, these characteristics are in some instances most consistent with a dimensional view, with psychotic bipolar disorders being intermediate between non-psychotic bipolar disorders and schizophrenia spectrum disorders. However, in other instances, a categorical approach appears useful. Although more research is clearly necessary to address the dimensional versus categorical controversy, it is feasible that at least in the interim, a mixed dimensional/categorical approach could provide additional insights into pathophysiology and management options, which would not be available utilizing only one of these models.

    View details for DOI 10.1016/S0022-3956(03)00099-2

    View details for Web of Science ID 000220190700006

    View details for PubMedID 14690770

  • New anticonvulsant medication uses in bipolar disorder CNS SPECTRUMS Wang, P. W., Ketter, T. A., Becker, O. V., Nowakowska, C. 2003; 8 (12): 930-?

    Abstract

    Therapy of bipolar disorders is a rapidly evolving field. Lithium has efficacy in classic bipolar disorders whereas divalproex sodium and carbamazepine may have broader spectrum efficacy that includes non-classic bipolar disorder. In the last 10 years, a series of anticonvulsants have been approved for marketing in the United States. Gabapentin has indirect g-aminobuytric acid-ergic actions, is generally well tolerated, and appears to have anxiolytic, analgesic, and hypnotic effects. Lamotrigine has antiglutamatergic actions and is generally well tolerated (aside from rash in 1 in 10, and serious rash in 1 in 1,000 patients). Lamotrigine is indicated for maintenance treatment in bipolar disorder. Emerging evidence suggests lamotrigine may have utility in bipolar disorder patients with depression and treatment-refractory rapid cycling, as well as analgesic effects. Topiramate and zonisamide may allow both weight loss, while topiramate may have specific efficacy in bulimia, binge eating disorder, and alcohol dependence. Two small studies found oxcarbazepine had similar efficacy to lithium and haloperidol in acute mania. Phenytoin, an older anticonvulsant, may have adjunctive acute mania efficacy. Levetiracetam, a newer anticonvulsant, may be worth exploring and has minimal drug-drug interactions. None of these newer agents has been shown effective in a large placebo controlled trial for acute mania. Although the clinical profiles of these newer anticonvulsants do not appear to overlap markedly with divalproex and carbamazepine (except perhaps for oxcarbazepine), these novel agents may still offer important new options in relieving a variety of specific target symptoms in patients with bipolar disorder.

    View details for Web of Science ID 000226890300014

    View details for PubMedID 14978468

  • Safety of antidepressants in the elderly. Expert opinion on drug safety Sommer, B. R., Fenn, H., Pompei, P., DeBattista, C., Lembke, A., Wang, P., Flores, B. 2003; 2 (4): 367-383

    Abstract

    Until the 1980s, the two major classes of antidepressants, the tricyclics and the monoamine oxidase inhibitors (MAOIs), were effective but had severe side effects, requiring monitoring by psychiatrists. The past several years have brought new classes of antidepressants that are safer for the patient to take and far easier for the non-psychiatrist to prescribe. Whilst this is of enormous value, it leaves the physician with the dilemma of which one to prescribe. These new antidepressants cannot safely be used interchangeably. This paper will discuss each of the antidepressants presently available, with particular emphasis on safety in the elderly. Drug interactions, side effects and particular challenges to the older patient will be described. The authors will then advise a general strategy for prescribing antidepressants.

    View details for PubMedID 12904093

  • The diverse roles of anticonvulsants in bipolar disorders. Annals of clinical psychiatry Ketter, T. A., Wang, P. W., Becker, O. V., Nowakowska, C., Yang, Y. 2003; 15 (2): 95-108

    Abstract

    Anticonvulsant drugs (ACs) have diverse antiseizure, psychotropic, and biochemical effects. Carbamazepine and valproate have mood-stabilizing actions, benzodiazepines and gabapentin have anxiolytic actions, lamotrigine is useful in rapid cycling and acute treatment and prophylaxis of bipolar depression, and topiramate and zonisamide can yield weight loss. Limited controlled data suggest the carbamazepine keto derivative oxcarbazepine has antimanic effects. A categorical approach to the diverse roles of ACs in bipolar disorders is proposed, using broad categories of ACs, on the basis of their predominant psychotropic profiles. Thus, some ACs have "sedating" profiles that may include sedation, cognitive difficulties, fatigue, weight gain, and possibly antimanic and/or anxiolytic effects. In contrast, some newer ACs have "activating" profiles that may include improved energy, weight loss, and possibly antidepressant and even anxiogenic effects. Still other newer ACs have novel "mixed" profiles, combining sedation and weight loss. A categorical-mechanistic extension of this approach is also presented, with hypotheses that "sedating" profiles might be related to prominent potentiation of gamma-aminobutyric acid (GABA) inhibitory neurotransmission, "activating" profiles could be related to prominent attenuation of glutamate excitatory neurotransmission, and for "mixed" profiles, sedation and weight loss might be related to concurrent GABAergic and antiglutamatergic actions, respectively. The categorical approach may have utility as an aid to clinicians in reinforcing the heterogeneity ACs, and recalling psychotropic profiles of individual ACs, but is limited as it fails to address the etiology of the heterogeneity of AC psychotropic effects. The categorical-mechanistic extension strives to address this issue, but requires systematic clinical investigation of more precise relationships between psychotropic profiles and discrete mechanisms of action to assess its merits.

    View details for PubMedID 12938867

  • The emerging differential roles of GABAergic and antiglutamatergic agents in bipolar disorders JOURNAL OF CLINICAL PSYCHIATRY Ketter, T. A., Wang, P. W. 2003; 64: 15-20

    Abstract

    Treatment options to relieve the diverse symptoms encountered in patients with bipolar disorders include not only mood stabilizers, but also anxiolytics, new anticonvulsants, antidepressants, and antipsychotics. These agents have widely varying mechanisms of action, which could contribute to the heterogeneity of clinical effects seen in practice. Several of these medications, especially those with anticonvulsant effects, enhance gamma-aminobutyric acid (GABA) inhibitory neurotransmission and/or attenuate glutamate excitatory neurotransmission. We review the efficacy and tolerability of these diverse treatment options in bipolar disorders and explore possible relationships between clinical effects and GABAergic and antiglutamatergic mechanisms of action.

    View details for Web of Science ID 000181811400003

    View details for PubMedID 12662129

  • The emerging role of olanzapine in bipolar disorders PSYCHIATRIC ANNALS Ketter, T. A., Wang, P. W., Janenawasin, S., Becker, O. V., Wang, A. 2002; 32 (12): 753-762
  • Gabapentin augmentation therapy in bipolar depression BIPOLAR DISORDERS Wang, P. W., Santosa, C., Schumacher, M., Winsberg, M. E., Strong, C., Ketter, T. A. 2002; 4 (5): 296-301

    Abstract

    Gabapentin (GBP) may be useful in bipolar disorders, including as adjunctive therapy for bipolar depression, although controlled studies suggest inefficacy as primary treatment for mania or treatment-resistant rapid cycling.We performed a 12-week trial of open GBP (mean dose 1725 mg/day) added to stable doses of mood stabilizers or atypical antipsychotics in 22 (10 women, mean age 38.4 years) depressed (28-item Hamilton Depression Rating Scale (HDRS) > 18] bipolar (10 bipolar I, 12 bipolar II) disorder outpatients. Mean illness duration was 18.6 years, current depressive episode duration was 18.0 weeks. Prospective 28-item HDRS, Young Mania Rating Scale (YMRS) and Clinical Global Impression-Severity (CGI-S) ratings were obtained.Overall, HDRS ratings decreased 53% from 32.5 +/- 7.7 at baseline to 16.5 +/- 12.8 at week 12 (p < 0.0001). Twelve of 22 (55%) patients had moderate to marked improvement (HDRS decrease = 50%) with HDRS decreasing 78% from 27.9 +/- 6.2 to 6.2 +/- 4.5 (p < 0.0001). Eight of 22 (36%) patients remitted (HDRS > or = 8). In non-responders, HDRS decreased from 38.0 +/- 5.4 to 28.9 +/- 6.7 (p = 0.005). Ten of 13 (77%) mild to moderately depressed (baseline HDRS > 18 and <35) patients responded, while only two of nine patients (22%) with severe depression (HDRS > or = 35) responded (p < 0.03). Both groups, however, had similar, statistically significant HDRS decreases. GBP was well tolerated.Open adjunctive GBP was effective and well tolerated in patients with mild to moderate bipolar depression. This open pilot study must be viewed with caution, and randomized controlled studies are warranted.

    View details for Web of Science ID 000178520500004

    View details for PubMedID 12479661

  • Olanzapine in diverse syndromal and subsyndromal exacerbations of bipolar disorders BIPOLAR DISORDERS Janenawasin, S., Wang, P. W., Lembke, A., Schumacher, M., Das, B., Santosa, C. M., Mongkolcheep, J., Ketter, T. A. 2002; 4 (5): 328-334

    Abstract

    To evaluate effects of olanzapine in diverse exacerbations of bipolar disorders.Twenty-five evaluable bipolar disorder [14 bipolar I (BPI), 10 bipolar II (BPII) and one bipolar disorder not otherwise specified (BP NOS)] outpatients received open olanzapine (15 adjunctive, 10 monotherapy). Thirteen had elevated (11 syndromal, two subsyndromal) and 12 depressed (four syndromal, eight subsyndromal) mood symptoms of at least mild severity, with Clinical Global Impression-Severity (CGI-S) scores of at least 3. Only one had psychotic symptoms.With open olanzapine (15 adjunctive, 10 monotherapy), overall symptom severity (CGI-S) as well as mood elevation (Young Mania Rating Scale), depression (Hamilton and Montgomery-Asberg Depression Rating Scales), and anxiety (Hamilton Anxiety Rating Scale), rapidly decreased (significantly by days 2-3). Patients with the greatest baseline severity (CGI-S) had the greatest improvement. Fifteen of 25 (60%) patients responded. Time to consistent response was bimodal, with five early (by 0.5 +/- 0.3 weeks) and 10 late (by 7.0 +/- 1.9 weeks) responders. Early compared with late responders had 51% lower final olanzapine doses. Olanzapine was generally well tolerated, with sedation and weight gain the most common adverse effects.Olanzapine was effective in diverse exacerbations of bipolar disorders. The bimodal distribution of time to response and different final doses are consistent with differential mechanisms mediating early compared with late responses. Controlled studies are warranted to further explore these preliminary observations.

    View details for Web of Science ID 000178520500009

    View details for PubMedID 12479666

  • Pharmacokinetics of mood stabilizers and new anticonvulsants. Psychopharmacology bulletin Wang, P. W., Ketter, T. A. 2002; 36 (1): 44-66

    Abstract

    Mechanisms of action, efficacy spectra, pharmacokinetics, and adverse effects differentiate the mood stabilizers lithium, carbamazepine (CBZ), and valproate (VPA). Lithium, which has a low therapeutic index, is excreted through the kidneys, resulting in renally mediated, but not hepatically mediated, drug-drug interactions. CBZ also has a low therapeutic index and is metabolized primarily by a single isoform (CYP3A3/4). It has an active epoxide metabolite, is susceptible to CYP3A3/4 or epoxide hydrolase inhibitors, and is able to induce drug metabolism (both via cytochrome P450 oxidation and conjugation). CBZ thus has multiple problematic drug-drug interactions. In contrast, VPA has less prominent neurotoxicity and three principal metabolic pathways, and it is less susceptible to pharmacokinetic drug interactions. Still, VPA can increase plasma concentrations of some drugs by inhibiting metabolism and can increase the free fractions of certain medications by displacing them from plasma proteins. The newer anticonvulsants lamotrigine, topiramate, and tiagabine have different, generally less problematic, hepatically mediated drug-drug interactions. Gabapentin, which is renally excreted, lacks hepatic drug-drug interactions, though bioavailability may be reduced at higher doses. Recently approved anticonvulsants, including oxcarbazepine, zonisamide, and levetiracetam, may have improved pharmacokinetic profiles compared to older agents. Novel psychotropic effects of these drugs may also be demonstrated, based on their mechanisms of action and preliminary clinical data.

    View details for PubMedID 12397847

  • Biology and recent brain imaging studies in affective psychoses. Current psychiatry reports Wang, P. W., Ketter, T. A. 2000; 2 (4): 298-304

    Abstract

    Psychosis is a cardinal symptom of schizophrenia, but also occurs in other psychiatric conditions, including mood disorders. In many instances, brain abnormalities in psychotic and mood disorders appear to be on a spectrum, with the most marked changes in schizophrenia, followed by psychotic mood disorders, followed by nonpsychotic mood disorders. Such observations are consistent with the notion that mood disorders and schizophrenia represent a continuum of disease. However, in some instances, cerebral changes with psychosis may be qualitatively different, rather than merely more severe than those seen in mood disorders, more consistent with the theory that they are discrete entities. We review brain imaging studies that have advanced our knowledge of psychosis in mood disorders, with respect to the continuum versus discrete entity hypotheses.

    View details for PubMedID 11122972

Conference Proceedings


  • Predictors of treatment response in bipolar disorders: Evidence from clinical and brain imaging studies Ketter, T. A., Wang, P. W. PHYSICIANS POSTGRADUATE PRESS. 2002: 21-25

    Abstract

    The clinical features of bipolar disorders can be correlated with responses to medications. Patients who respond to lithium, for example, often present differently from those who respond to divalproex or carbamazepine, but the correlations are relatively modest. Brain-imaging tools, such as positron emission tomography (PET), single photon emission computed tomography (SPECT), and functional magnetic resonance imaging (fMRI), can relate brain function to clinical features and medication responses. For example, in depression, it appears that prefrontal cortical function is decreased while subcortical anterior paralimbic activity is increased. Preliminary evidence suggests that baseline metabolism increases and decreases in the left insula may be associated with carbamazepine and nimodipine responses, respectively, and that cerebral lithium concentrations may correlate with antimanic effects. Although it is not yet a clinical tool for bipolar disorders, brain imaging provides useful research data to understand the fundamental neurobiology of mood disorders and to more effectively target therapeutics.

    View details for Web of Science ID 000174419600005

    View details for PubMedID 11908918

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