Po Wang

All Publications

• Antidepressants have complex associations with longitudinal depressive burden in bipolar disorder JOURNAL OF AFFECTIVE DISORDERS Hooshmand, F., Do, D., Shah, S., Gershon, A., Park, D., Yuen, L. D., Dell'Osso, B., Wang, P. W., Miller, S., Ketter, T. A. 2019; 246: 836–42

  View details for DOI 10.1016/j.jad.2018.12.074

  View details for Web of Science ID 000457276200102

• Depressive symptoms carry an increased risk for suicidal ideation and behavior in bipolar disorder without any additional contribution of mixed symptoms JOURNAL OF AFFECTIVE DISORDERS Fiedorowicz, J. G., Persons, J. E., Assari, S., Ostacher, M. J., Zandi, P., Wang, P. W., Thase, M. E., Frye, M. A., Coryell, W., Natl Network Depression Ctr 2019; 246: 775–82

  View details for DOI 10.1016/j.jad.2018.12.057

  View details for Web of Science ID 000457276200093

• Antidepressants have complex associations with longitudinal depressive burden in bipolar disorder. Journal of affective disorders Hooshmand, F., Do, D., Shah, S., Gershon, A., Park, D. Y., Yuen, L. D., Dell'Osso, B., Wang, P. W., Miller, S., Ketter, T. A. 2019; 246: 836–42

  Abstract

  Antidepressants are common in bipolar disorder (BD), but controversial due to questionable efficacy/tolerability. We assessed baseline antidepressant use/depression associations in BD.Stanford BD Clinic outpatients, enrolled during 2000-2011, assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation, were monitored up to two years with the STEP-BD Clinical Monitoring Form while receiving naturalistic expert treatment. Prevalence/correlates of baseline antidepressant use in recovered (euthymic ≥8 weeks)/depressed patients were assessed. Kaplan-Meier survival analyses assessed times to depressive recurrence/recovery in patients with/without baseline antidepressant use, and Cox Proportional Hazard regression analyses assessed covariate effects.Baseline antidepressant use was significantly (albeit without Bonferroni multiple comparison correction) less among 105 recovered (31.4%) versus 153 depressed (44.4%) patients, and among recovered patients (again without Bonferroni correction), associated with Caucasian race, earlier onset, worse Clinical Global Impression scores, and hastened depressive recurrence (only if mood elevation episodes were not censored), driven by lifetime anxiety disorder, and more (even with Bonferroni correction) bipolar II disorder, lifetime anxiety and eating disorders, and core psychotropics. Baseline antidepressant use among depressed patients was associated with significantly (again without Bonferroni correction) older age, female gender, and more (even with Bonferroni correction) anxiolytics/hypnotics, complex pharmacotherapy, and core psychotropics, but no other unfavorable illness characteristic/current mood symptom, and not time to depressive recovery.Tertiary BD clinic referral sample receiving open naturalistic expert treatment. Analyses without/with Bonferroni correction.Additional research is required to assess the complex associations between baseline antidepressant use and longitudinal depressive burden in BD.

  View details for PubMedID 30795488

• Depressive symptoms carry an increased risk for suicidal ideation and behavior in bipolar disorder without any additional contribution of mixed symptoms. Journal of affective disorders Fiedorowicz, J. G., Persons, J. E., Assari, S., Ostacher, M. J., Zandi, P., Wang, P. W., Thase, M. E., Frye, M. A., Coryell, W., of the National Network of Depression Centers Bipolar Disorders Interest Group 2018; 246: 775–82

  Abstract

  OBJECTIVES: To determine whether the risk of suicidal ideation or behavior during mixed states exceeds that attributable to the depressive components of these states alone in bipolar disorder.METHODS: We utilized real-world, longitudinal clinical data collected on 290 patients with bipolar disorders (bipolar I, bipolar II, and bipolar not otherwise specified (NOS)) from the National Network of Depression Centers (NNDC) Clinical Care Registry (CCR) seen for 891 visits over a mean of 27.5 weeks. Depressive symptoms were measured with the Patient Health Questionnaire-9 (PHQ-9), manic symptoms with the Altman Self-Rating Mania (ASRM), and suicidal ideation and behavior with the Columbia-Suicide Severity Rating Scale (C-SSRS), obtained as part of the routine, measurement-based care provided across the NNDC. The relations between depressive symptoms, manic symptoms, and the interaction thereof (mixed symptoms) on coinciding suicidal ideation and behavior were modeled in generalized linear mixed models.RESULTS: Depressive symptoms, as measured by the PHQ-9, were strongly associated with suicidal ideation and behavior (p < 0.0001), while there was no significant association with manic symptoms as measured by the ASRM or the interaction between depressive and manic symptoms. Similar results were observed when the outcome was restricted to suicidal behavior and when mood was modeled categorically. There was evidence of a gender by ASRM interaction (p = 0.011) and risk of suicidal ideation or behavior was significant for women, but not men with manic symptoms.LIMITATIONS: Diagnoses were based on clinician assessment and not structured interview. Mood assessments were self-reported rather than clinician-administered. Suicidal ideation was more frequently observed than suicidal behavior (23/272 visits where outcome positive).CONCLUSIONS: Depression represents the primary mood state accounting for suicide risk in bipolar disorder. Co-occurring symptoms of mania (mixed symptoms) do not appear to convey an elevated risk for suicidal ideation or behavior beyond that explained by the depressive symptoms alone.

  View details for PubMedID 30623823

• Differential prevalence and demographic and clinical correlates of antidepressant use in American bipolar I versus bipolar II disorder patients JOURNAL OF AFFECTIVE DISORDERS Hooshmand, F., Do, D., Shah, S., Gershon, A., Park, D., Kim, H., Yuen, L. D., Dell'Osso, B., Wang, P. W., Ketter, T. A., Miller, S. 2018; 234: 74–79

  View details for DOI 10.1016/j.jad.2018.02.091

  View details for Web of Science ID 000429308000012

• Differential prevalence and demographic and clinical correlates of antidepressant use in American bipolar I versus bipolar II disorder patients. Journal of affective disorders Hooshmand, F., Do, D., Shah, S., Gershon, A., Park, D. Y., Kim, H., Yuen, L. D., Dell'Osso, B., Wang, P. W., Ketter, T. A., Miller, S. 2018; 234: 74–79

  Abstract

  AIMS: Antidepressant use is controversial in bipolar disorder (BD) due to questionable efficacy/psychiatric tolerability. We assessed demographic/clinical characteristics of baseline antidepressant use in BD patients.METHODS: Prevalence and correlates of baseline antidepressant use in 503 BD I and BD II outpatients referred to the Stanford Bipolar Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation.RESULTS: Antidepressant use was 39.0%, overall, and was higher in BD II versus BD I (46.9% versus 30.5%, p = 0.0002). Both BD I and BD II antidepressant compared to non-antidepressant users had higher rates of complex pharmacotherapy (≥ 4 mood stabilizers, antipsychotics, and/or antidepressants) and use of other psychotropics. Antidepressant use in BD II versus BD I was higher during euthymia (44.0% vs. 28.0%) and subsyndromal symptoms (56.1% vs. 28.6%), but not depression or mood elevation.LIMITATIONS: American tertiary BD clinic referral sample receiving open naturalistic treatment.CONCLUSIONS: In our sample, antidepressant use was higher in BD II versus BD I patients, and was associated with markers of heightened illness severity in both BD I and BD II patients. Additional research is warranted to investigate these complex relationships.

  View details for PubMedID 29524749

• Longer-Term Effectiveness and Tolerability of Adjunctive Open Lurasidone in Patients With Bipolar Disorder. Journal of clinical psychopharmacology Miller, S., Do, D., Gershon, A., Wang, P. W., Hooshmand, F., Chang, L. S., Ketter, T. A. 2018; 38 (3): 207–11

  Abstract

  PURPOSE: To retrospectively assess lurasidone effectiveness/efficacy/tolerability in bipolar disorder (BD) patients.METHODS: Outpatients assessed with Systematic Treatment Enhancement Program for BD Affective Disorders Evaluation received naturalistically administered (primarily adjunctive) open lurasidone while monitored at visits with the Systematic Treatment Enhancement Program for BD Clinical Monitoring Form.RESULTS: Sixty-one patients (32 type I, 26 type II, 3 type not otherwise specified; mean ± SD age, 45.1 ± 14.0 years; 63.9% were female) received lurasidone with 3.1 ± 1.4 (≥2 in 88.5%, monotherapy in only 3.3%) other nonanxiolytic/hypnotic prescription psychotropics, started during syndromal depression in 57.4%, subsyndromal depression in 23.0%, and euthymia in 19.7%. Lurasidone was taken for median 126 days, with final dose 55.6 ± 30.8 mg/d. By final visit taking lurasidone, syndromal depression rate decreased by nearly one-half to 31.1%, and euthymia rate more than doubled to 42.6%, whereas subsyndromal depression rate was unchanged at 23.0%. Clinical Global Impressions-BD-Overall Severity improved significantly only in patients with baseline syndromal depression. Seventy-seven percent of patients discontinued lurasidone after median 103 days, because of adverse events in 54.1% (most often akathisia, sedation/somnolence, nausea, and weight gain), inefficacy in 16.4%, and other reasons in 6.6%; 12.1% had equal to or greater than 7% weight gain, and 3.3% developed hypomania. Limitations to this study were the open design and demographically homogeneous (relatively affluent, predominantly white female) small sample taking complex pharmacotherapy.CONCLUSIONS: In American specialty clinic BD outpatients, adjunctive longer-term lurasidone commonly relieved syndromal depression and maintained euthymia, suggesting possible effectiveness/efficacy. However, lurasidone was discontinued in 54.1% because of adverse events, suggesting tolerability limitations in these challenging patients, nearly 90% of whom were already taking at least 2 other nonanxiolytic/hypnotic prescription psychotropics.

  View details for PubMedID 29620693

• Longer-Term Effectiveness and Tolerability of Adjunctive Open Lurasidone in Patients With Bipolar Disorder JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Miller, S., Do, D., Gershon, A., Wang, P. W., Hooshmand, F., Chang, L. S., Ketter, T. A. 2018; 38 (3): 207–11

  View details for DOI 10.1097/JCP.0000000000000867

  View details for Web of Science ID 000431001500008

• Do we have evidence for differentiating pharmacological treatment of bipolar I from bipolar ii disorder (Bp)? Ketter, T., Arici, C., Cremaschi, L., Miller, S., Hooshmand, F., Wang, P., Do, D., Shah, S., Gershon, A., Holsinger, A., Park, D. Y. WILEY. 2018: 28–29

  View details for Web of Science ID 000426605800058

• Episode accumulation associated with hastened recurrence and delayed recovery in bipolar disorder JOURNAL OF AFFECTIVE DISORDERS Park, D., Do, D., Chang, L., Shah, S., Yuen, L. D., Hooshmand, F., Wang, P. W., Miller, S., Ketter, T. A. 2018; 227: 657–64

  Abstract

  Assess episode accumulation (≥ 10 prior mood episodes) associations with demographic/baseline clinical characteristics and mood episode recurrence/recovery in bipolar disorder (BD).Stanford BD Clinic outpatients enrolled during 2000-2011 were assessed with Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation. Among recovered and syndromal mood episode patients, we assessed episode accumulation associations with demographic/baseline clinical characteristics and with recurrence/recovery (by Kaplan-Meier survival analyses, with mediators assessed with Cox Proportional Hazard Ratio (HR) analyses).Among all 450 BD outpatients, almost twice as many had versus lacked episode accumulation (65.8% versus 34.2%), which was less common among 92 recovered versus 193 syndromal mood episode patients (51.1% versus 69.9%). Among recovered patients, episode accumulation was associated with 14/18 (77.7%) demographic/other baseline clinical characteristics, and hastened mood episode recurrence. Among syndromal mood episode patients, episode accumulation was associated with 13/18 (72.2%) demographic/other baseline clinical characteristics, and delayed mood episode recovery.American tertiary BD clinic referral sample.Studies are needed to confirm episode accumulation is associated with hastened mood episode recurrence and delayed mood episode recovery in BD, and to further explore its' associations with hastened mood elevation recurrence and delayed recovery from depressive and mood elevation episodes, considered separately.

  View details for PubMedID 29174739

• American tertiary clinic-referred bipolar II disorder versus bipolar I disorder associated with hastened depressive recurrence. International journal of bipolar disorders Dell'Osso, B., Shah, S., Do, D., Yuen, L. D., Hooshmand, F., Wang, P. W., Miller, S., Ketter, T. A. 2017; 5 (1): 2-?

  Abstract

  Bipolar disorder (BD) is a chronic, frequently comorbid condition characterized by high rates of mood episode recurrence and suicidality. Little is known about prospective longitudinal characterization of BD type II (BD II) versus type I (BD I) in relation to time to depressive recurrence and recovery from major depressive episode. We therefore assessed times to depressive recurrence/recovery in tertiary clinic-referred BD II versus I patients.Outpatients referred to Stanford BD Clinic during 2000-2011 were assessed with Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation and with Clinical Monitoring Form during up to 2 years of naturalistic treatment. Prevalence and clinical correlates of bipolar subtype in recovered (euthymic ≥8 weeks) and depressed patients were assessed. Kaplan-Meier analyses assessed the relationships between bipolar subtype and longitudinal depressive severity, and Cox proportional hazard analyses assessed the potential mediators.BD II versus BD I was less common among 105 recovered (39.0 vs. 61.0%, p = 0.03) and more common among 153 depressed (61.4 vs. 38.6%, p = 0.006) patients. Among recovered patients, BD II was associated with 6/25 (24.0%) baseline unfavorable illness characteristics/mood symptoms/psychotropics and hastened depressive recurrence (p = 0.015). Among depressed patients, BD II was associated with 8/25 (33.0%) baseline unfavorable illness characteristics/mood symptoms/psychotropics, but only non-significantly associated with delayed depressive recovery.BD II versus BD I was significantly associated with current depression and hastened depressive recurrence, but only non-significantly associated with delayed depressive recovery. Research on bipolar subtype relationships with depressive recurrence/recovery is warranted to enhance clinical management of BD patients.

  View details for DOI 10.1186/s40345-017-0072-x

  View details for PubMedID 28124233

  View details for PubMedCentralID PMC5267582

• Lifetime eating disorder comorbidity associated with delayed depressive recovery in bipolar disorder. International journal of bipolar disorders Balzafiore, D. R., Rasgon, N. L., Yuen, L. D., Shah, S., Kim, H., Goffin, K. C., Miller, S., Wang, P. W., Ketter, T. A. 2017; 5 (1): 25-?

  Abstract

  Although eating disorders (EDs) are common in bipolar disorder (BD), little is known regarding their longitudinal consequences. We assessed prevalence, clinical correlates, and longitudinal depressive severity in BD patients with vs. without EDs.Outpatients referred to Stanford University BD Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) affective disorders evaluation, and while receiving naturalistic treatment for up to 2 years, were monitored with the STEP-BD clinical monitoring form. Patients with vs. without lifetime EDs were compared with respect to prevalence, demographic and unfavorable illness characteristics/current mood symptoms and psychotropic use, and longitudinal depressive severity.Among 503 BD outpatients, 76 (15.1%) had lifetime EDs, which were associated with female gender, and higher rates of lifetime comorbid anxiety, alcohol/substance use, and personality disorders, childhood BD onset, episode accumulation (≥10 prior mood episodes), prior suicide attempt, current syndromal/subsyndromal depression, sadness, anxiety, and antidepressant use, and earlier BD onset age, and greater current overall BD severity. Among currently depressed patients, 29 with compared to 124 without lifetime EDs had significantly delayed depressive recovery. In contrast, among currently recovered (euthymic ≥8 weeks) patients, 10 with compared to 95 without lifetime EDs had only non-significantly hastened depressive recurrence.Primarily Caucasian, insured, suburban, American specialty clinic-referred sample limits generalizability. Small number of recovered patients with EDs limited statistical power to detect relationships between EDs and depressive recurrence.Further studies are warranted to explore the degree to which EDs impact longitudinal depressive illness burden in BD.

  View details for DOI 10.1186/s40345-017-0094-4

  View details for PubMedID 28480483

• Lifetime anxiety disorder and current anxiety symptoms associated with hastened depressive recurrence in bipolar disorder. Journal of affective disorders Shah, S., Kim, J. P., Park, D. Y., Kim, H., Yuen, L. D., Do, D., Dell'Osso, B., Hooshmand, F., Miller, S., Wang, P. W., Ketter, T. A. 2017; 219: 165-171

  Abstract

  To assess differential relationships between lifetime anxiety disorder/current anxiety symptoms and longitudinal depressive severity in bipolar disorder (BD).Stanford BD Clinic outpatients enrolled during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation and followed with the STEP-BD Clinical Monitoring Form while receiving naturalistic treatment for up to two years. Baseline unfavorable illness characteristics/current mood symptoms and times to depressive recurrence/recovery were compared in patients with versus without lifetime anxiety disorder/current anxiety symptoms.Among 105 currently recovered patients, lifetime anxiety disorder was significantly associated with 10/27 (37.0%) demographic/other unfavorable illness characteristics/current mood symptoms/current psychotropics, hastened depressive recurrence (driven by earlier onset age), and a significantly (> two-fold) higher Kaplan-Meier estimated depressive recurrence rate, whereas current anxiety symptoms were significantly associated with 10/27 (37.0%) demographic/other unfavorable illness characteristics/current mood symptoms/current psychotropics and hastened depressive recurrence (driven by lifetime anxiety disorder), but only a numerically higher Kaplan-Meier estimated depressive recurrence rate. In contrast, among 153 currently depressed patients, lifetime anxiety disorder/current anxiety symptoms were not significantly associated with time to depressive recovery or depressive recovery rate.American tertiary BD clinic referral sample, open naturalistic treatment.Research is needed regarding differential relationships between lifetime anxiety disorder and current anxiety symptoms and hastened/delayed depressive recurrence/recovery - specifically whether lifetime anxiety disorder versus current anxiety symptoms has marginally more robust association with hastened depressive recurrence, and whether both have marginally more robust associations with hastened depressive recurrence versus delayed depressive recovery, and related clinical implications.

  View details for DOI 10.1016/j.jad.2017.05.007

  View details for PubMedID 28558363

• Abnormal sleep duration associated with hastened depressive recurrence in bipolar disorder. Journal of affective disorders Gershon, A., Do, D., Satyanarayana, S., Shah, S., Yuen, L. D., Hooshmand, F., Miller, S., Wang, P. W., Ketter, T. A. 2017; 218: 374-379

  Abstract

  Abnormal sleep duration (ASD, <6 or ≥9h) is common in bipolar disorder (BD), and often persists beyond acute mood episodes. Few longitudinal studies have examined the ASD's impact upon BD illness course. The current study examined the longitudinal impact of ASD upon bipolar depressive recurrence/recovery.Outpatients referred to the Stanford BD Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation at baseline, and with the Clinical Monitoring Form at monthly follow-ups for up to two years of naturalistic treatment. Prevalence and clinical correlates of ASD in 93 recovered (euthymic ≥8 weeks) and 153 depressed BD patients were assessed. Kaplan-Meier analyses (Log-Rank tests) assessed relationships between baseline ASD and longitudinal depressive severity, with Cox Proportional Hazard analyses assessing potential mediators.ASD was only half as common among recovered versus depressed BD outpatients, but was significantly associated with hastened depressive recurrence (Log-Rank p=0.007), mediated by lifetime anxiety disorder and attenuated by lifetime history of psychosis, and had only a non-significant tendency towards association with delayed depressive recovery (Log-Rank p=0.07). In both recovered and depressed BD outpatients, baseline ASD did not have significant association with any baseline BD illness characteristic.Self-reported sleep duration. Limited generalizability beyond our predominately white, female, educated, insured American BD specialty clinic sample.Baseline ASD among recovered BD patients may be a risk marker for hastened depressive recurrence, suggesting it could be an important therapeutic target between mood episodes.

  View details for DOI 10.1016/j.jad.2017.05.015

  View details for PubMedID 28500982

• Abnormal sleep duration associated with hastened depressive recurrence in bipolar disorder Journal of Affective Disorders Gershon, A., Do, D., Satyanarayana, S., Shah, S., Yuen, L., Hooshmand, F., Miller, S., Wang, P., Ketter, T. 2017; 218: 374–79

  Abstract

  Abnormal sleep duration (ASD, <6 or ≥9h) is common in bipolar disorder (BD), and often persists beyond acute mood episodes. Few longitudinal studies have examined the ASD's impact upon BD illness course. The current study examined the longitudinal impact of ASD upon bipolar depressive recurrence/recovery.Outpatients referred to the Stanford BD Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation at baseline, and with the Clinical Monitoring Form at monthly follow-ups for up to two years of naturalistic treatment. Prevalence and clinical correlates of ASD in 93 recovered (euthymic ≥8 weeks) and 153 depressed BD patients were assessed. Kaplan-Meier analyses (Log-Rank tests) assessed relationships between baseline ASD and longitudinal depressive severity, with Cox Proportional Hazard analyses assessing potential mediators.ASD was only half as common among recovered versus depressed BD outpatients, but was significantly associated with hastened depressive recurrence (Log-Rank p=0.007), mediated by lifetime anxiety disorder and attenuated by lifetime history of psychosis, and had only a non-significant tendency towards association with delayed depressive recovery (Log-Rank p=0.07). In both recovered and depressed BD outpatients, baseline ASD did not have significant association with any baseline BD illness characteristic.Self-reported sleep duration. Limited generalizability beyond our predominately white, female, educated, insured American BD specialty clinic sample.Baseline ASD among recovered BD patients may be a risk marker for hastened depressive recurrence, suggesting it could be an important therapeutic target between mood episodes.

  View details for DOI 10.1016/j.jad.2017.05.015

• Current irritability associated with hastened depressive recurrence and delayed depressive recovery in bipolar disorder. International journal of bipolar disorders Yuen, L. D., Shah, S., Do, D., Miller, S., Wang, P. W., Hooshmand, F., Ketter, T. A. 2016; 4 (1): 15-?

  Abstract

  Current irritability is associated with greater retrospective and current bipolar disorder (BD) illness severity; less is known about prospective longitudinal implications of current irritability. We examined relationships between current irritability and depressive recurrence and recovery in BD.Outpatients referred to the Stanford BD Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation at baseline, and with the Clinical Monitoring Form during follow-up during up to 2 years of naturalistic treatment. Prevalence and clinical correlates of any current irritability in depressed and recovered (euthymic ≥8 weeks) BD patients were assessed. Kaplan-Meier analyses (Log-Rank tests) assessed relationships between current irritability and longitudinal depressive severity, with Cox Proportional Hazard analyses assessing potential mediators.Recovered BD outpatients with vs. without current irritability had significantly higher rates of 13/19 (68.4 %) other baseline unfavorable illness characteristics/current mood symptoms and hastened depressive recurrence (Log-Rank p = 0.020), driven by lifetime history of anxiety disorder and prior year rapid cycling, and attenuated by history of psychosis. Depressed BD outpatients with vs. without current irritability had significantly higher rates of 7/19 (36.8 %) other unfavorable illness characteristics/current mood symptoms and delayed depressive recovery (Log-Rank p = 0.034), NOT mediated by any assessed parameter.Limited generalizability beyond our predominately white, female, educated, insured American BD specialty clinic sample.Current irritability was associated with hastened depressive recurrence and delayed depressive recovery in BD. Treatment studies targeting irritability may yield strategies to mitigate increased longitudinal depressive burden.

  View details for DOI 10.1186/s40345-016-0056-2

  View details for PubMedID 27473754

  View details for PubMedCentralID PMC4967068

• Longer-Term Lurasidone Efficacy and Tolerability in an American Bipolar Disorder Specialty Clinic Ketter, T., Do, D., Gershon, A., Holsinger, A., Hooshmand, F., Wang, P., Miller, S. NATURE PUBLISHING GROUP. 2016: S493

  View details for Web of Science ID 000440366400059

• More inclusive bipolar mixed depression definition by permitting overlapping and non-overlapping mood elevation symptoms. Acta psychiatrica Scandinavica Kim, H., Kim, W., Citrome, L., Akiskal, H. S., Goffin, K. C., Miller, S., HOLTZMAN, J. N., Hooshmand, F., Wang, P. W., Hill, S. J., Ketter, T. A. 2016; 134 (3): 199-206

  Abstract

  The objective of this study was to assess the strengths and limitations of a mixed bipolar depression definition made more inclusive than that of the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) by counting not only 'non-overlapping' mood elevation symptoms (NOMES) as in DSM-5, but also 'overlapping' mood elevation symptoms (OMES, psychomotor agitation, distractibility, and irritability).Among bipolar disorder (BD) out-patients assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation, we assessed prevalence, demographics, and clinical correlates of mixed vs. pure depression, using more inclusive (≥3 NOMES/OMES) and less inclusive DSM-5 (≥3 NOMES) definitions.Among 153 depressed BD, counting not only NOMES but also OMES yielded a three-fold higher mixed depression rate (22.9% vs. 7.2%) and important statistically significant clinical correlates for mixed compared to pure depression (more lifetime anxiety disorder comorbidity, more current irritability, and less current antidepressant use), which were not significant using the DSM-5 threshold.To conclude, further studies with larger numbers of patients with DSM-5 bipolar mixed depression assessing strengths and limitations of more inclusive mixed depression definitions are warranted, including efforts to ascertain whether or not OMES should count toward mixed depression.

  View details for DOI 10.1111/acps.12580

  View details for PubMedID 27137894

• More inclusive bipolar mixed depression definitions by requiring fewer non-overlapping mood elevation symptoms. Acta psychiatrica Scandinavica Kim, W., Kim, H., Citrome, L., Akiskal, H. S., Goffin, K. C., Miller, S., HOLTZMAN, J. N., Hooshmand, F., Wang, P. W., Hill, S. J., Ketter, T. A. 2016; 134 (3): 189-198

  Abstract

  Assess strengths and limitations of mixed bipolar depression definitions made more inclusive than that of the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) by requiring fewer than three 'non-overlapping' mood elevation symptoms (NOMES).Among bipolar disorder (BD) out-patients assessed with Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation, we assessed prevalence, demographics, and clinical correlates of mixed vs. pure depression, using less inclusive (≥3 NOMES, DSM-5), more inclusive (≥2 NOMES), and most inclusive (≥1 NOMES) definitions.Among 153 depressed BD, compared to less inclusive DSM-5 threshold, our more and most inclusive thresholds, yielded approximately two- and five-fold higher mixed depression rates (7.2%, 15.0%, and 34.6% respectively), and important statistically significant clinical correlates for mixed compared to pure depression (e.g. more lifetime anxiety disorder comorbidity, more current irritability), which were not significant using the DSM-5 threshold.Further studies assessing strengths and limitations of more inclusive mixed depression definitions are warranted, including assessing the extent to which enhanced statistical power vs. other factors contributes to more vs. less inclusive mixed bipolar depression thresholds having more statistically significant clinical correlates, and whether 'overlapping' mood elevation symptoms should be counted.

  View details for DOI 10.1111/acps.12563

  View details for PubMedID 26989836

• Current irritability robustly related to current and prior anxiety in bipolar disorder JOURNAL OF PSYCHIATRIC RESEARCH Yuen, L. D., Miller, S., Wang, P. W., Hooshmand, F., Holtzman, J. N., Goffin, K. C., Shah, S., Ketter, T. A. 2016; 79: 101-107

  Abstract

  Although current irritability and current/prior anxiety have been associated in unipolar depression, these relationships are less well understood in bipolar disorder (BD). We investigated relationships between current irritability and current/prior anxiety as well as other current emotions and BD illness characteristics.Outpatients referred to the Stanford Bipolar Disorders Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation. Prevalence and clinical correlates of current irritability and current/prior anxiety and other illness characteristics were examined.Among 497 BD outpatients (239 Type I, 258 Type II; 58.1% female; mean ± SD age 35.6 ± 13.1 years), 301 (60.6%) had baseline current irritability. Patients with versus without current irritability had significantly higher rates of current anxiety (77.1% versus 42.9%, p < 0.0001) and history of anxiety disorder (73.1% versus 52.6%, p < 0.0001). Current irritability was more robustly related to current anxiety than to current anhedonia, sadness, or euphoria (all p < 0.001), and current irritability-current anxiety associations persisted across current predominant mood states. Current irritability was more robustly related to past anxiety than to all other assessed illness characteristics, including 1° family history of mood disorder, history of alcohol/substance use disorder, bipolar subtype, and current syndromal/subsyndromal depression (all p < 0.05).Limited generalizability beyond our predominately white, female, educated, insured American BD specialty clinic sample.In BD, current irritability was robustly related to current/prior anxiety. Further studies are warranted to assess longitudinal clinical implications of relationships between irritability and anxiety in BD.

  View details for DOI 10.1016/j.jpsychires.2016.05.006

  View details for Web of Science ID 000378179000015

  View details for PubMedID 27218815

• Gender by onset age interaction may characterize distinct phenotypic subgroups in bipolar patients JOURNAL OF PSYCHIATRIC RESEARCH Holtzman, J. N., Miller, S., Hooshmand, F., Wang, P. W., Chang, K. D., Goffin, K. C., Hill, S. J., Ketter, T. A., Rasgon, N. L. 2016; 76: 128-135

  Abstract

  Although bipolar disorder (BD) is a common recurrent condition with highly heterogeneous illness course, data are limited regarding clinical implications of interactions between gender and onset age. We assessed relationships between onset age and demographic/illness characteristics among BD patients stratified by gender.Demographic and unfavorable illness characteristics, descriptive traits, and clinical correlates were compared in 502 patients from Stanford University BD Clinic patients enrolled in the Systematic Treatment Enhancement Program for BD between 2000 and 2011, stratified by gender, across pre-, peri-, and post-pubertal (<12, 13-16, and >17 years, respectively) onset-age subgroups.Among 502 BD patients, 58.2% were female, of whom 21.9% had pre-pubertal, 30.7% peri-pubertal, and 47.4% post-pubertal onset. Between genders, although demographics, descriptive characteristics, and most clinical correlates were statistically similar, there were distinctive onset-age related patterns of unfavorable illness characteristics. Among females, rates of 6/8 primary unfavorable illness characteristics were significantly higher in pre-pubertal and peri-pubertal compared to post-pubertal onset patients. However, among males, rates of only 3/8 unfavorable illness characteristics were significantly higher in only pre-pubertal versus post-pubertal onset patients, and none between peri-pubertal versus post-pubertal onset patients.Caucasian, insured, suburban, American specialty clinic-referred sample limits generalizability, onset age based on retrospective recall.We describe different phenotypic presentations across age at illness onset groups according to gender. Among females and males, peri-pubertal and post-pubertal onset age groups were more different and more similar, respectively. Further investigation is warranted to assess implications of gender-by-onset-age interactions to more accurately delineate distinctive BD phenotypes.

  View details for DOI 10.1016/j.jpsychires.2016.02.009

  View details for PubMedID 26926801

• Differential prevalence and demographic and clinical correlates of second-generation antipsychotic use in bipolar I versus bipolar II disorder JOURNAL OF PSYCHIATRIC RESEARCH Park, D. Y., Goffin, K. C., Shah, S., Yuen, L. D., Holtzman, J. N., Hooshmand, F., Miller, S., Wang, P. W., Ketter, T. A. 2016; 76: 52-58

  Abstract

  To assess second-generation antipsychotic (SGA) use, demographics, and clinical correlates in patients with bipolar I disorder (BDI) versus bipolar II disorder (BDII).Stanford Bipolar Disorder (BD) Clinic outpatients enrolled during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation. Current SGA use, demographics, and clinical correlates were assessed for BDI versus BDII.Among 503 BD outpatients, in BDI versus BDII, SGA use was more than twice as common (44.0% versus 21.2%), and doses were approximately twice as high. BDI patients taking (N = 107) versus not taking (N = 136) SGAs less often had current full time employment and college degree; and more often had lifetime psychiatric hospitalization, current depression, and current complex pharmacotherapy, and had a higher mean current Clinical Global Impression for Bipolar Version Overall Severity score, and these persisted significantly after covarying for employment and education. Prior psychiatric hospitalization was the most robust correlate of SGA use in BDI patients. In contrast, these demographic and clinical correlates of SGA use were not statistically significant among patients with BDII, although BDII (but not BDI) patients taking (N = 55) versus not taking (N = 205) SGAs were more likely to have current mood stabilizer use (67.3% versus 51.7%).American tertiary bipolar disorder clinic referral sample, cross-sectional design.Current SGA use was robustly associated with prior psychiatric hospitalization in BDI and to a more limited extent with current mood stabilizer use in BDII. SGA use associations with other unfavorable illness characteristics in BDI were less robust.

  View details for DOI 10.1016/j.jpsychires.2016.01.016

  View details for Web of Science ID 000373412400007

  View details for PubMedID 26874463

• Different characteristics associated with suicide attempts among bipolar I versus bipolar II disorder patients JOURNAL OF PSYCHIATRIC RESEARCH Goffin, K. C., Dell'Osso, B., Miller, S., Wang, P. W., Holtzman, J. N., Hooshmand, F., Ketter, T. A. 2016; 76: 94-100

  Abstract

  Suicide attempts are common in patients with bipolar disorder (BD), and consistently associated with female gender and certain unfavorable BD illness characteristics. Findings vary, however, regarding effects of BD illness subtype and yet other illness characteristics upon prior suicide attempt rates. We explored the effects of demographics and BD illness characteristics upon prior suicide attempt rates in patients stratified by BD illness subtype (i.e., with bipolar I disorder (BDI) versus bipolar II disorder (BDII)).Outpatients referred to the Stanford BD Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD Affective Disorders Evaluation. Rates of prior suicide attempt were compared in patients with and without diverse demographic and BD illness characteristics stratified by BD subtype.Among 494 BD outpatients (mean ± SD age 35.6 ± 13.1 years; 58.3% female; 48.6% BDI, 51.4% BDII), overall prior suicide attempt rates in were similar in BDI versus BDII patients, but approximately twice as high in BDI (but not BDII) patients with compared to without lifetime eating disorder, and in BDII (but not BDI) patients with compared to without childhood BD onset. In contrast, current threshold-level suicidal ideation and lifetime alcohol use disorder robustly but less asymmetrically increased prior suicide attempt risk across BD subtypes.American tertiary bipolar disorder clinic referral sample, cross-sectional design.Further studies are needed to assess the extent to which varying clinical characteristics of samples of patients with BDI and BDII could yield varying prior suicide attempt rates in patients with BDI versus BDII.

  View details for DOI 10.1016/j.jpsychires.2016.02.006

  View details for Web of Science ID 000373412400012

  View details for PubMedID 26921874

• Treatment of bipolar disorder: Review of evidence regarding quetiapine and lithium JOURNAL OF AFFECTIVE DISORDERS Ketter, T. A., Miller, S., Dell'Osso, B., Wang, P. W. 2016; 191: 256-273

  Abstract

  Lithium, the prototypical mood stabilizer, and quetiapine, a second-generation antipsychotic, are widely used acute and maintenance pharmacotherapies for bipolar disorder. The Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE) study was the first comparative effectiveness assessment of lithium versus quetiapine (in combination with adjunctive personalized treatment), and found no overall significant differences in efficacy and safety/tolerability outcomes between lithium and quetiapine. Completion of Bipolar CHOICE offers a timely opportunity to review the evidence regarding lithium and quetiapine for bipolar disorder.Controlled clinical trials and real-world observational studies that included quetiapine and lithium as monotherapy or as combination therapy were identified by literature search. Selected studies were reviewed in detail.Review of the available trials suggested comparable efficacy of quetiapine and lithium in acute mania, and possibly greater efficacy for quetiapine compared with lithium in acute bipolar depression and in prevention of recurrent (particularly depressive) episodes. Combination therapy including quetiapine and lithium was generally more effective than either agent alone in acute mania and bipolar maintenance, although adding lithium to quetiapine did not increase efficacy in acute bipolar depression. Safety data for quetiapine and lithium were consistent with the established profiles of the two treatments.Limitations include those of the available efficacy and effectiveness trial data.Quetiapine and lithium have overlapping but distinctive roles in different phases of bipolar disorder, and further studies of these agents (particularly in combination with one another) are warranted.

  View details for DOI 10.1016/j.jad.2015.11.002

  View details for Web of Science ID 000368253400033

• Treatment of bipolar disorder: Review of evidence regarding quetiapine and lithium. Journal of affective disorders Ketter, T. A., Miller, S., Dell'Osso, B., Wang, P. W. 2016; 191: 256–73

  Abstract

  Lithium, the prototypical mood stabilizer, and quetiapine, a second-generation antipsychotic, are widely used acute and maintenance pharmacotherapies for bipolar disorder. The Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE) study was the first comparative effectiveness assessment of lithium versus quetiapine (in combination with adjunctive personalized treatment), and found no overall significant differences in efficacy and safety/tolerability outcomes between lithium and quetiapine. Completion of Bipolar CHOICE offers a timely opportunity to review the evidence regarding lithium and quetiapine for bipolar disorder.Controlled clinical trials and real-world observational studies that included quetiapine and lithium as monotherapy or as combination therapy were identified by literature search. Selected studies were reviewed in detail.Review of the available trials suggested comparable efficacy of quetiapine and lithium in acute mania, and possibly greater efficacy for quetiapine compared with lithium in acute bipolar depression and in prevention of recurrent (particularly depressive) episodes. Combination therapy including quetiapine and lithium was generally more effective than either agent alone in acute mania and bipolar maintenance, although adding lithium to quetiapine did not increase efficacy in acute bipolar depression. Safety data for quetiapine and lithium were consistent with the established profiles of the two treatments.Limitations include those of the available efficacy and effectiveness trial data.Quetiapine and lithium have overlapping but distinctive roles in different phases of bipolar disorder, and further studies of these agents (particularly in combination with one another) are warranted.

  View details for PubMedID 26688495

• American tertiary clinic-referred bipolar II disorder compared to bipolar I disorder: More severe in multiple ways, but less severe in a few other ways JOURNAL OF AFFECTIVE DISORDERS Dell'Osso, B., Holtzman, J. N., Goffin, K. C., Portillo, N., Hooshmand, F., Miller, S., Dore, J., Wang, P. W., Hill, S. J., Ketter, T. A. 2015; 188: 257-262

  Abstract

  Prevalence and relative severity of bipolar II disorder (BDII) vs. bipolar I disorder (BDI) are controversial.Prevalence, demographics, and illness characteristics were compared among 260 BDII and 243 BDI outpatients referred to the Stanford University BD Clinic and assessed with the Systematic Treatment Enhancement Program for Bipolar Disorder Affective Disorders Evaluation.BDII vs. BDI outpatients had statistically similar prevalence (51.7% vs. 48.3%), and in multiple ways had more severe illness, having significantly more often: lifetime comorbid anxiety (70.8% vs. 58.4%) and personality (15.4% vs. 7.4%) disorders, first-degree relative with mood disorder (62.3% vs. 52.3%), at least 10 prior mood episodes (80.0% vs. 50.9%), current syndromal/subsyndromal depression (52.3% vs. 38.4%), current antidepressant use (47.3% vs. 31.3%), prior year rapid cycling (33.6% vs. 13.4%), childhood onset (26.2% vs. 16.0%), as well as earlier onset age (17.0±8.6 vs. 18.9±8.1 years), longer illness duration (19.0±13.0 vs. 16.1±13.0), and higher current Clinical Global Impression for Bipolar Disorder-Overall Severity (4.1±1.4 vs. 3.7±1.5). However, BDII vs. BDI patients significantly less often had prior psychosis (14.2% vs. 64.2%), psychiatric hospitalization (10.0% vs. 67.9%), and current prescription psychotropic use, (81.5% vs. 93.0%), and had a statistically similar rate of prior suicide attempt (29.5% vs. 32.1%).American tertiary bipolar disorder clinic referral sample, cross-sectional design.Further studies are warranted to determine the extent to which BDII, compared to BDI, can be more severe in multiple ways but less severe in a few other ways, and contributors to occurrence of more severe forms of BDII.

  View details for DOI 10.1016/j.jad.2015.09.001

  View details for Web of Science ID 000364168100036

  View details for PubMedID 26378735

• Childhood-compared to adolescent-onset bipolar disorder has more statistically significant clinical correlates JOURNAL OF AFFECTIVE DISORDERS Holtzman, J. N., Miller, S., Hooshmand, F., Wang, P. W., Chang, K. D., Hill, S. J., Rasgon, N. L., Ketter, T. A. 2015; 179: 114-120

  Abstract

  The strengths and limitations of considering childhood-and adolescent-onset bipolar disorder (BD) separately versus together remain to be established. We assessed this issue.BD patients referred to the Stanford Bipolar Disorder Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD Affective Disorders Evaluation. Patients with childhood- and adolescent-onset were compared to those with adult-onset for 7 unfavorable bipolar illness characteristics with replicated associations with early-onset patients.Among 502 BD outpatients, those with childhood- (<13 years, N=110) and adolescent- (13-18 years, N=218) onset had significantly higher rates for 4/7 unfavorable illness characteristics, including lifetime comorbid anxiety disorder, at least ten lifetime mood episodes, lifetime alcohol use disorder, and prior suicide attempt, than those with adult-onset (>18 years, N=174). Childhood- but not adolescent-onset BD patients also had significantly higher rates of first-degree relative with mood disorder, lifetime substance use disorder, and rapid cycling in the prior year. Patients with pooled childhood/adolescent - compared to adult-onset had significantly higher rates for 5/7 of these unfavorable illness characteristics, while patients with childhood- compared to adolescent-onset had significantly higher rates for 4/7 of these unfavorable illness characteristics.Caucasian, insured, suburban, low substance abuse, American specialty clinic-referred sample limits generalizability. Onset age is based on retrospective recall.Childhood- compared to adolescent-onset BD was more robustly related to unfavorable bipolar illness characteristics, so pooling these groups attenuated such relationships. Further study is warranted to determine the extent to which adolescent-onset BD represents an intermediate phenotype between childhood- and adult-onset BD.

  View details for DOI 10.1016/j.jad.2015.03.019

  View details for PubMedID 25863906

• Bipolar therapeutics update 2014: A tale of 3 treatments. journal of clinical psychiatry Ketter, T. A., Wang, P. W., Miller, S. 2015; 76 (1): 69-70

  Abstract

  In the 2010s, advances in the treatment of bipolar disorder slowed, with only 1 agent approved by the US Food and Drug Administration (FDA) for acute bipolar I depression (in 2013), compared to the robust progress in the 2000s, during which 7 agents were approved for acute mania, 2 for acute bipolar depression, and 6 for bipolar disorder preventive treatment. This slowing of progress may have been in part due to decreased pharmaceutical company enthusiasm for developing compounds for psychiatric indications, as well as the tendency for periods of consolidation (development of derivative and better-tolerated treatments) to follow periods of rapid advances (development of efficacious novel treatments) in pharmacotherapy advancement.

  View details for DOI 10.4088/JCP.14ac09649

  View details for PubMedID 25650673

• Trends in pharmacotherapy in patients referred to a bipolar specialty clinic, 2000-2011 JOURNAL OF AFFECTIVE DISORDERS Hooshmand, F., Miller, S., Dore, J., Wang, P. W., Hill, S. J., Portillo, N., Ketter, T. A. 2014; 155: 283-287

  Abstract

  To assess mood stabilizer (MS) and second-generation antipsychotic (SGA) prescribing trends in bipolar disorder (BD) outpatients referred to a bipolar disorder specialty clinic over the past 12 years.BD outpatients referred to the Stanford University Bipolar Disorder Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation. Prescription rates for MSs and SGAs were compared during the first (2000-2005) and second (2006-2011) six years.Among 597 BD patients (mean±SD age 35.4±8.6 years; 58.1% female; 40.7% Type I, 43.6% Type II, and 15.7% Type Not Otherwise Specified; taking 2.6±1.7 prescription psychotropic medications), lamotrigine, quetiapine, and aripiprazole usage more than doubled, from 14.7% to 37.2% (p<0.0001), 7.2% to 19.7% (p<0.0001), and 3.1% to 10.9% (p=0.0003), respectively, while olanzapine and risperidone use decreased by more than half from 15.0% to 6.6% (p=0.0043), and from 8.7% to 3.8% (p=0.039), respectively. SGA use increased from 34.1% to 44.8% (p=0.013), although MS use continued to be more common (in 65.2% for 2006-2011). Use of other individual MSs and SGAs and MSs as a class did not change significantly.Over 12 years, in patients referred to a BD specialty clinic, lamotrigine, quetiapine, and aripiprazole use more than doubled, and olanzapine and risperidone use decreased by more than half. Tolerability (for lamotrigine, aripiprazole, olanzapine, and risperidone) more than efficacy (for quetiapine) differences may have driven these findings. Additional studies are needed to explore the relative influences of enhanced tolerability versus efficacy upon prescribing practices in BD patients.

  View details for DOI 10.1016/j.jad.2013.10.054

  View details for Web of Science ID 000329574500041

  View details for PubMedID 24314912

• Evaluation of reproductive function in women treated for bipolar disorder compared to healthy controls. Bipolar disorders Reynolds-May, M. F., Kenna, H. A., Marsh, W., Stemmle, P. G., Wang, P., Ketter, T. A., Rasgon, N. L. 2014; 16 (1): 37-47

  Abstract

  The purpose of the present study was to investigate the reproductive function of women with bipolar disorder (BD) compared to healthy controls.Women diagnosed with BD and healthy controls with no psychiatric history, aged 18-45 years, were recruited from a university clinic and surrounding community. Participants completed a baseline reproductive health questionnaire, serum hormone assessment, and ovulation tracking for three consecutive cycles using urine luteinizing hormone (LH)-detecting strips with a confirmatory luteal-phase serum progesterone.Women with BD (n = 103) did not differ from controls (n = 36) in demographics, rates of menstrual abnormalities (MAs), or number of ovulation-positive cycles. Of the women with BD, 17% reported a current MA and 39% reported a past MA. Dehydroepiandrosterone sulfate and 17-hydroxyprogesterone levels were higher in controls (p = 0.052 and 0.004, respectively), but there were no other differences in biochemical levels. Medication type, dose, or duration was not associated with MA or biochemical markers, although those currently taking an atypical antipsychotic agent indicated a greater rate of current or past MA (80% versus 55%, p = 0.013). In women with BD, 22% reported a period of amenorrhea associated with exercising or stress, versus 8% of controls (p = 0.064). Self-reported rates of bulimia and anorexia nervosa were 10% and 5%, respectively.Rates of MA and biochemical levels did not significantly differ between women with BD and controls. Current atypical antipsychotic agent use was associated with a higher rate of current or past MA and should be further investigated. The incidence of stress-induced amenorrhea should be further investigated in this population, as should the comorbid incidence of eating disorders.

  View details for DOI 10.1111/bdi.12149

  View details for PubMedID 24262071

• Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE): A pragmatic trial of complex treatment for a complex disorder. Clinical trials Nierenberg, A. A., Sylvia, L. G., Leon, A. C., Reilly-Harrington, N. A., Shesler, L. W., McElroy, S. L., Friedman, E. S., Thase, M. E., Shelton, R. C., Bowden, C. L., Tohen, M., Singh, V., Deckersbach, T., Ketter, T. A., Kocsis, J. H., McInnis, M. G., Schoenfeld, D., Bobo, W. V., Calabrese, J. R. 2014; 11 (1): 114-127

  Abstract

  Classic and second-generation antipsychotic mood stabilizers are recommended for treatment of bipolar disorder, yet there are no randomized comparative effectiveness studies that have examined the 'real-world' advantages and disadvantages of these medications.We describe the strategic decisions in the design of the Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE). This article outlines the key issues and solutions the investigators faced in designing a clinical trial that would maximize generalizability and inform real-world clinical treatment of bipolar disorder.Bipolar CHOICE was a 6-month, multi-site, prospective, randomized clinical trial of outpatients with bipolar disorder. This study compares the effectiveness of quetiapine versus lithium, each with adjunctive personalized treatments (APTs). The co-primary outcomes selected are the overall benefits and harms of the study medications (as measured by the Clinical Global Impression-Efficacy Index) and the Necessary Clinical Adjustments (a measure of the number of medication changes). Secondary outcomes are continuous measures of mood, the Framingham General Cardiovascular Risk Score, and the Longitudinal Interval Follow up Evaluation Range of Impaired Functioning Tool (LIFE-RIFT).The final study design consisted of a single-blind, randomized comparative effectiveness trial of quetiapine versus lithium, plus APT, across 10 sites. Other important study considerations included limited exclusion criteria to maximize generalizability, flexible dosing of APT medications to mimic real-world treatment, and an intent-to-treat analysis plan. In all, 482 participants were randomized to the study, and 364 completed the study.The potential limitations of the study include the heterogeneity of APT, selection of study medications, lack of a placebo-control group, and participants' ability to pay for study medications.We expect that this study will inform our understanding of the benefits and harms of lithium, a classic mood stabilizer, compared to quetiapine, a second-generation antipsychotic with broad-spectrum activity in bipolar disorder, and will provide an example of a well-designed and well-conducted randomized comparative effectiveness clinical trial.

  View details for DOI 10.1177/1740774513512184

  View details for PubMedID 24346608

• 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

• Long-term aripiprazole effectiveness in bipolar disorder patients decreases with pharmacotherapeutic complexity and degree of baseline mood disturbance ASIAN BIOMEDICINE Ittasakul, P., Miller, S., Wang, P. W., Hill, S. J., Childers, M. E., Ketter, T. A. 2013; 7 (4): 537-544

  View details for DOI 10.5372/1905-7415.0704.209

  View details for Web of Science ID 000341273400010

• 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

  View details for PubMedCentralID PMC3529984

• 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

• DSM-5 mixed features specifier may increase complexity without enhancing milder mixed symptom detection in bipolar disorder patients: a 36 case series 9th International Conference on Bipolar Disorder (ICBD) Ketter, T. A., Srivastava, S., Wang, P. W., Childers, M. E., Hill, S. J., Keller, K. L. WILEY-BLACKWELL. 2011: 62–62

  View details for Web of Science ID 000300102400142

• Pilot study of the effectiveness of double-blind, placebo-controlled brief olanzapine therapy in heterogeneous symptomatic bipolar disorder patients 9th International Conference on Bipolar Disorder (ICBD) Srivastava, S., Wang, P. W., Childers, M. E., Hill, S. J., Keller, K. L., Ketter, T. A. WILEY-BLACKWELL. 2011: 93–94

  View details for Web of Science ID 000300102400232

• Effectiveness of Aripiprazole in Bipolar Disorder Patients Primarily Taking Complex Pharmacotherapy 66th Annual Meeting of the Society-of-Biological-Psychiatry Ittasakul, P., Srivastava, S., Wang, P. W., Hill, S. J., Childers, M. E., Ketter, T. A. ELSEVIER SCIENCE INC. 2011: 92S–92S

  View details for Web of Science ID 000290641800295

• 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

  View details for DOI 10.1111/j.1758-5872.2010.00080.x

  View details for Web of Science ID 000282375900079

• 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

  View details for PubMedCentralID PMC2941396

• 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

• Management of Bipolar Disorders in Children and Adolescents HANDBOOK OF DIAGNOSIS AND TREATMENT OF BIPOLAR DISORDERS Chang, K. D., Singh, M. K., Wang, P. W., Howe, M., Ketter, T. A. 2010: 389–424

  View details for Web of Science ID 000294220800011

• 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

  View details for PubMedCentralID PMC3265395

• 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

  View details for PubMedCentralID PMC2677624

• 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

  View details for DOI 10.1016/j.jpsychires.2008.04.015

  View details for Web of Science ID 000262747100002

• Divalproex-extended release monotherapy and adjunctive therapy in bipolar II depression 7th International Conference on Bipolar Disorder Keffer, T. A., Wang, P. W., Nowakowska, C., Chandler, R. A., Hill, S. J., Nam, J. Y., Culver, J. L., Keller, K. L. WILEY-BLACKWELL. 2007: 58–58

  View details for Web of Science ID 000253284000160

• 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

• 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

• 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

• Regional cerebral gray matter density changes associated with creativity in healthy volunteers 62nd Annual Meeting of the Society-of-Biological-Psychiatry Bonner, J. C., Ketter, T. A., Wang, P. W., Garcia-Amador, M., Brooks, J. O. ELSEVIER SCIENCE INC. 2007: 113S–114S

  View details for Web of Science ID 000245698100361

• Gray matter density changes associated with bipolar depression Brooks, J. O., Bonner, J. C., Rosen, A. C., Wang, P. W., Ketter, T. A. ELSEVIER SCIENCE INC. 2007: 56S

  View details for Web of Science ID 000245698100177

• Differential global cerebral metabolism changes with sadness induction between creative bipolar patients and healthy controls Wang, P. W., Sachs, N., Brooks, J. O., Bonner, J., Ketter, T. A. ELSEVIER SCIENCE INC. 2007: 230S

  View details for Web of Science ID 000245698100736

• Bipolar disorders: Mixed states, rapid cycling, and atypical forms (Book Review) JOURNAL OF NERVOUS AND MENTAL DISEASE Book Review Authored by: Wang, P. W. 2007; 195 (4): 360–61

  View details for DOI 10.1097/01.nmd.0000260110.22780.94

  View details for Web of Science ID 000245790400017

• 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

  View details for DOI 10.1016/j.jpyschires.2006.01.007

  View details for Web of Science ID 000241915500010

  View details for PubMedID 16516926

• Effectiveness of quetiapine in a clinical setting 45th Annual Meeting of the American-College-of-Neuropsychopharmacology Ketter, T. A., Holland, A. A., Nam, J. Y., Culver, J. L., Wang, P. W., Marsh, W. K., Bonner, J. C. NATURE PUBLISHING GROUP. 2006: S234–S234

  View details for Web of Science ID 000242215900616

• 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

• Commonalities and dissociations of cerebral metabolism with divalproex response in bipolar disorder Wang, P. W., Brooks, J. O., Bonner, J. C., Hill, S., Chandler, R. A., Ketter, T. A. ELSEVIER SCIENCE INC. 2006: 252S

  View details for Web of Science ID 000236767301396

• Effects of depression on cerebral metabolism in bipolar disorder Brooks, J. O., Wang, P. W., Bonner, J. C., Ketter, T. A. ELSEVIER SCIENCE INC. 2006: 168S

  View details for Web of Science ID 000236767301124

• Voxel-based morphometric analysis of gray matter in bipolar depression Bonner, J. C., Rosen, A. C., Wang, P. W., Ketter, T. A., Hill, S. J., Brooks, J. O. ELSEVIER SCIENCE INC. 2006: 174S

  View details for Web of Science ID 000236767301145

• 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

  Abstract

  Animal models of depression and psychopharmacological mechanisms of action suggest the importance of the gamma-amino butyric acid (GABA) system in the pathophysiology of mood disorders. Mood stabilizers have overlapping effects on GABAergic neurotransmission, and antidepressant use has been associated with alterations in GABAB receptor function. Magnetic resonance spectroscopy (MRS) provides an opportunity to noninvasively assess cerebral GABA concentrations in anterior paralimbic circuits that have been implicated in mood disorders.In bipolar disorder patients and healthy control subjects, we used MRS with a modified GABA-edited point resolved spectroscopy sequence (TE 68 ms, TR 1500 ms, 512 averages, total scan time 26 min) to assess GABA in an 18-cm3 occipital voxel. In addition, in another cohort of bipolar disorder patients and healthy control subjects, we similarly assessed GABA in a 12.5-cm3 medial prefrontal/anterior cingulate (MPF/AC) voxel. The concentration of GABA was referenced to creatine (Cr) from unedited spectra.In bipolar patients and controls, we consistently detected 3.0 p.p.m. GABA peaks in occipital lobe and MPF/AC. In 16 bipolar (nine bipolar I and seven bipolar II) disorder patients, compared with six healthy control subjects, mean occipital GABA/Cr concentration was 61% higher. In addition, in 15 bipolar (five bipolar I, nine bipolar II, and one bipolar not otherwise specified) disorder patients, compared with six healthy control subjects, mean MPF/AC GABA/Cr concentration tended to be 41% higher.Patients with bipolar disorders may have increased cerebral GABA concentrations. Although this was more evident in the occipital lobe, MPC/AC GABA disturbance may be of greater potential interest in view the more established role of MPF/AC in affective processing. Additional studies are warranted to assess changes in GABAergic neurotransmission and the influences of diagnosis, mood state, and medication status in bipolar disorder patients.

  View details for Web of Science ID 000237985900009

• 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): 120–26

  Abstract

  Animal models of depression and psychopharmacological mechanisms of action suggest the importance of the gamma-amino butyric acid (GABA) system in the pathophysiology of mood disorders. Mood stabilizers have overlapping effects on GABAergic neurotransmission, and antidepressant use has been associated with alterations in GABAB receptor function. Magnetic resonance spectroscopy (MRS) provides an opportunity to noninvasively assess cerebral GABA concentrations in anterior paralimbic circuits that have been implicated in mood disorders.In bipolar disorder patients and healthy control subjects, we used MRS with a modified GABA-edited point resolved spectroscopy sequence (TE 68 ms, TR 1500 ms, 512 averages, total scan time 26 min) to assess GABA in an 18-cm3 occipital voxel. In addition, in another cohort of bipolar disorder patients and healthy control subjects, we similarly assessed GABA in a 12.5-cm3 medial prefrontal/anterior cingulate (MPF/AC) voxel. The concentration of GABA was referenced to creatine (Cr) from unedited spectra.In bipolar patients and controls, we consistently detected 3.0 p.p.m. GABA peaks in occipital lobe and MPF/AC. In 16 bipolar (nine bipolar I and seven bipolar II) disorder patients, compared with six healthy control subjects, mean occipital GABA/Cr concentration was 61% higher. In addition, in 15 bipolar (five bipolar I, nine bipolar II, and one bipolar not otherwise specified) disorder patients, compared with six healthy control subjects, mean MPF/AC GABA/Cr concentration tended to be 41% higher.Patients with bipolar disorders may have increased cerebral GABA concentrations. Although this was more evident in the occipital lobe, MPC/AC GABA disturbance may be of greater potential interest in view the more established role of MPF/AC in affective processing. Additional studies are warranted to assess changes in GABAergic neurotransmission and the influences of diagnosis, mood state, and medication status in bipolar disorder patients.

  View details for PubMedID 26989801

• 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

• Psychotic bipolar disorders: dimensionally similar to or categorically different from schizophrenia? Conference on Non Schizophrenic Psychoses Ketter, T. A., Wang, P. W., Becker, O. V., Nowakowska, C., Yang, Y. S. PERGAMON-ELSEVIER SCIENCE LTD. 2004: 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 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

• 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 Conference on the Role of GABA in Neuropsychiatric Disorders Ketter, T. A., Wang, P. W. PHYSICIANS POSTGRADUATE PRESS. 2003: 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

  View details for Web of Science ID 000179723500007

• 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

• 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

• 3 Tesla 1h-magnetic resonance spectroscopic measurements of prefrontal cortical gamma-aminobutyric acid (GABA) levels in bipolar disorder patients and healthy volunteers Wang, P. W., Dieckmann, N., Sailasuta, N., Adalsteinsson, E., Spielman, D., Ketter, T. A. ELSEVIER SCIENCE INC. 2002: 197S–197S

  View details for Web of Science ID 000174980400553

• Predictors of treatment response in bipolar disorders: Evidence from clinical and brain imaging studies 50th Annual Meeting of the Canadian-Psychiatric-Association 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

• 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

• 3 Tesla 1H-magnetic resonance spectroscopic (MRS) detection of cerebral gamma-aminobutyric acid (GABA) in bipolar disorder patients and healthy volunteers Wang, P. W., Sachs, N., Sailasuta, N., Adalsteinsson, E., Spielman, D., Ketter, T. A. ELSEVIER SCIENCE INC. 2001: 27S–27S

  View details for Web of Science ID 000168163000093

• 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