Longer-Term Effectiveness and Tolerability of Adjunctive Open Lurasidone in Patients With Bipolar Disorder.

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.

Differentiating multiple vs single lifetime suicide attempters with bipolar disorders: A retrospective study.

BACKGROUND: The risk of suicide in Bipolar Disorder (BD) has been estimated up to 20-30 times higher compared with the general population. Previous suicide attempts (SAs) represent a well-established risk factor for further attempts and for death by suicide in patients with psychiatric disorders. However, little is known about the socio-demographic and clinical profile of BD patients with a history of multiple SAs (MSAs). The present study sought to characterize BD patients with MSAs versus single suicide attempt (SSA) within a large Italian sample. METHODS: An original sample of 354 bipolar patients, recruited at the University Clinic and related community services at the Department of Psychiatry, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico of Milan (Italy), was screened for the presence of previous SAs (n=95). Socio-demographic and clinical variables were then compared between patients with multiple vs single lifetime suicide attempts. RESULTS: Bipolar patients with MSAs versus SSA had longer bipolar illness duration (26.9±12.6 vs 21.2±12.8years; p=0.05), and more frequently lived alone (38.5% vs 17.2%; p<0.05), had more than one psychiatric comorbidity (39.3% vs 17.5%; p=0.04), and utilized substance ingestion (e.g., overdose) (78.6% vs 47.2%, p=0.009), although the latter was the most common suicide attempt method in both groups. CONCLUSION: Present findings suggest different socio-demographic and clinical characteristics in bipolar patients with MSAs versus SSA. Further investigation is needed to confirm reported data.

Italian Bipolar II vs I patients have better individual functioning, in spite of overall similar illness severity.

Introduction Bipolar disorders (BDs) comprise different variants of chronic, comorbid, and disabling conditions, with relevant suicide and suicide attempt rates. The hypothesis that BD types I (BDI) and II (BDII) represent more and less severe forms of illness, respectively, has been increasingly questioned over recent years, justifying additional investigation to better characterize related sociodemographic and clinical profiles. METHODS: A sample of 217 outpatients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR)-described BD (141 BDI, 76 BDII), without a current syndromal mood episode, was recruited, and sociodemographic and clinical characteristics of BDI and II patients were compared. RESULTS: BDII patients had significantly more favorable sociodemographics, in relation to occupational stability, cohabitation, and marital status. However, BDII compared with BDI patients had significantly longer duration of untreated illness, more frequent lifetime anxiety disorders comorbidity, longer most recent episode duration, higher rate of depressive first/most recent episode, and more current antidepressant use. In contrast, BDI compared with BDII patients had significantly more severe illness in terms of earlier age at onset; higher rate of elevated first/most recent episode, lifetime hospitalizations, and involuntary commitments; lower Global Assessment of Functioning score; and more current antipsychotic use. BDI and II patients had similar duration of illness, psychiatric family history, lifetime number of suicide attempts, current subthreshold symptoms, history of stressful life events, and overall psychiatric/medical comorbidity. CONCLUSION: BDII compared with BDI patients had more favorable sociodemographic features, but a mixture of specific unfavorable illness characteristics, confirming that BDII is not just a milder form of BD and requires further investigation in the field.

The Prevalence and Diagnostic Validity of Short-Duration Hypomanic Episodes and Major Depressive Episodes.

Current diagnostic criteria for a hypomanic episode, as outlined in both the fourth and fifth editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV and DSM-5), require a minimum duration of four consecutive days of symptoms of mood elevation. The 4-day criterion for duration of hypomania has been challenged as arbitrary and lacking empirical support, with many arguing that shorter-duration hypomanic episodes are highly prevalent and that those experiencing these episodes are clinically more similar to patients with bipolar disorder than to those with unipolar major depressive disorder. We review the current evidence regarding the prevalence, diagnostic validity, and longitudinal illness correlates of shorter-duration hypomanic episodes and summarize the arguments for and against broadening the diagnostic criteria for hypomania to include shorter-duration variants. Accumulating findings suggest that patients with major depressive episodes and shorter-duration hypomanic episodes represent a complex clinical phenotype, perhaps best conceptualized as being on the continuum between those with unipolar depressive episodes alone and those with DSM-5-defined bipolar II disorder. Further investigation is warranted, ideally involving large prospective, controlled studies, to elucidate the diagnostic and treatment implications of depression with shorter-duration hypomanic episodes.

COGNITION-CHILDHOOD MALTREATMENT INTERACTIONS IN THE PREDICTION OF ANTIDEPRESSANT OUTCOMES IN MAJOR DEPRESSIVE DISORDER PATIENTS: RESULTS FROM THE iSPOT-D TRIAL.

BACKGROUND: Childhood maltreatment (CM) history has been associated with poor treatment response in major depressive disorder (MDD), but the mechanisms underlying this relationship remain opaque. Dysfunction in the neural circuits for executive cognition is a putative neurobiological consequence of CM that may contribute importantly to adverse clinical outcomes. We used behavioral and neuroimaging measures of executive functioning to assess their contribution to the relationship between CM and antidepressant response in MDD patients. METHODS: Ninety eight medication-free MDD outpatients participating in the International Study to Predict Optimized Treatment in Depression were assessed at baseline on behavioral neurocognitive measures and functional magnetic resonance imaging during tasks probing working memory (continuous performance task, CPT) and inhibition (Go/No-go). Seventy seven patients completed 8 weeks of antidepressant treatment. Baseline behavioral and neuroimaging measures were assessed in relation to CM (history of childhood physical, sexual, and/or emotional abuse) and posttreatment depression outcomes. RESULTS: Patients with maltreatment exhibited decreased modulation of right dorsolateral prefrontal cortex (DLPFC) activity during working memory updating on the CPT, and a corresponding impairment in CPT behavioral performance outside the scanner. No between-group differences were found for imaging or behavior on the Go/No-go test of inhibition. Greater DLPFC activity during CPT significantly predicted posttreatment symptom improvement in patients without maltreatment, whereas the relationship between DLPFC activity and symptom change was nonsignificant, and in the opposite direction, in patients with maltreatment. CONCLUSIONS: The effect of CM on prefrontal circuitry involved in executive function is a potential predictor of antidepressant outcomes.

Enhanced ziprasidone combination therapy effectiveness in obese compared to nonobese patients with bipolar disorder.

OBJECTIVE: To assess longer-term ziprasidone effectiveness in obese and non-obese patients with bipolar disorder (BD). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Expanding bipolar outreach during college.

OBJECTIVES: To assess feasibility and clinical significance of tracking mania and depression in community college students before and after early identification and intervention. METHODS: From Affective Illness to Recovery: STudent Access to Rapid Treatment (FAIRSTART) is an early intervention program to provide diagnostic therapeutic consultation, short-term care, and community ongoing care referral for 18-28 year-old outpatient community college students (mean age 22.9±4.0 years) experiencing manic symptoms. Over three years, 54 FAIRSTART participants (70% with DSM-IV bipolar I/II/not otherwise specified disorder, BDI/II/NOS) were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation (ADE) and followed (range: one-time consult to 4.3±3.6 visits over 3-6 month follow-up) with the STEP-BD Clinical Monitoring Form. RESULTS: 38/54 patients (70%) had BDI/II/NOS, 11 unipolar depression (20%), 1 psychosis spectrum disorder (2%), 2 dysthymia/persistent depressive disorder (4%), and 2 incomplete intake with mood disorder diagnosis undetermined (4%). Average illness duration was 9.1±5.3 years. Among the 38 BD I/II/NOS patients, depression (SUM-D, t(30)=6.5; p<0.001) and mania (SUM-M, t(30)=4.7; p<0.001) scores improved significantly from baseline to last visit, with 17 (44.7%) reporting recovery by time transitioned from FAIRSTART to community care (after 4.3±3.6 visits). CONCLUSIONS: Short-term, early intervention in community college students with mood symptoms appeared feasible and yielded significant improvements in depression and mania scores. However, additional studies, with longer-term follow-ups, larger sample sizes, and comparison to current care standards, are needed to determine this early intervention program's impact on trajectory of mania symptoms in transitional age young adult populations.

Antipsychotic use in Northern Italian inter-episode bipolar disorder patients: considering both second- and first-generation agents.

Evidence supports increasing antipsychotic use in bipolar disorder, especially second-generation antipsychotics. However, data regarding first-generation antipsychotic contemporary use are limited. We studied 380 Northern Italian bipolar disorder inter-episode patients, grouped according to current antipsychotic use, stratified by bipolar subtype (BDI vs. BDII). Furthermore, we compared first-generation antipsychotic users vs. non-users. In our sample (n = 357), 81.8% were taking antipsychotics (74% second-generation antipsychotics, 24.1% first-generation antipsychotics), with antipsychotic use in BDI significantly more prevalent than in BDII (85.2% vs. 72.0%). Overall, antipsychotic users vs. non-users had higher rates of hypo/manic last episode, lifetime psychiatric hospitalization, psychosis, and current psychotropic use, but lower rates of anxiety disorder main comorbidity and current antidepressant use. First-generation antipsychotic use rates (30.3% in BDI vs. 6.5% in BDII) were associated with more frequently being unpartnered, having elevated first/last episodes, higher lifetime hospitalization, involuntary commitment, psychosis, and psychosocial rehabilitation rates, and more current psychotropic use, but lower Global Assessment Functioning scores and less current antidepressant use. Bipolar disorder patients had robust antipsychotic (second-generation antipsychotic > first-generation antipsychotic) use, consistently with previous reports. FGAs were still prescribed for a substantial group of patients, likely suffering from severe bipolar disorder. Prescriptions need to be monitored to assess their appropriateness and adherence to evidence-based recommendations.

Differential core pharmacotherapy in bipolar I versus bipolar II disorder and European versus American patients not in a syndromal episode.

Assess bipolar disorder subtype and treatment location effects on bipolar disorder core pharmacotherapy. Outpatients not in a syndromal episode referred to the University of Milan and Stanford University Bipolar Disorder Clinics were assessed with SCID for the fourth Edition of the Diagnostic and Statistical Manual of Mood Disorders, and the Systematic Treatment Enhancement Program for Bipolar Disorder Affective Disorders Evaluation, respectively. Prevalence and clinical correlates of antidepressant, antipsychotic, and mood stabilizer use, in aggregate and individually, were compared in bipolar I (BDI) versus II (BDII) patients in Milan/Stanford and in Milan versus Stanford patients, stratified by subtype. Milan/Stanford pooled BDI versus BDII patients significantly more often took antipsychotic (69.8 versus 44.8%), mood stabilizers (68.6 versus 57.7%), and valproate (40.1 versus 17.5%), and less often took antidepressants (23.1 versus 55.6%) and lamotrigine (9.9 versus 25.2%). Milan versus Stanford patients (stratified by bipolar disorder subtype) significantly more often took antipsychotic (BDI and BDII), antidepressants (BDII), and valproate (BDII), and less often took lamotrigine (BDI). Research regarding bipolar disorder core pharmacotherapy relationships with bipolar subtype and treatment location is warranted to enhance clinical management.

Antidepressants have complex associations with longitudinal depressive burden in bipolar disorder.

AIMS: Antidepressants are common in bipolar disorder (BD), but controversial due to questionable efficacy/tolerability. We assessed baseline antidepressant use/depression associations in BD. METHODS: 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. RESULTS: 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. LIMITATIONS: Tertiary BD clinic referral sample receiving open naturalistic expert treatment. Analyses without/with Bonferroni correction. CONCLUSIONS: Additional research is required to assess the complex associations between baseline antidepressant use and longitudinal depressive burden in BD.

Efficacy of Adjunctive Infliximab vs Placebo in the Treatment of Adults With Bipolar I/II Depression: A Randomized Clinical Trial.

Importance: To our knowledge, no study has previously evaluated whether individuals with bipolar depression enriched a priori on the basis of biochemical and/or phenotypic immuno-inflammatory activation would differentially respond to an anti-inflammatory agent for the treatment of depressive symptoms. Objective: To assess the antidepressant efficacy of adjunctive infliximab, a monoclonal antibody targeting tumor necrosis factor, in adults with bipolar I and bipolar II depression and inflammatory conditions. Design, Setting, and Participants: This 12-week, randomized, double-blind, placebo-controlled, parallel-group trial of 60 participants was conducted at 2 outpatient tertiary care sites in Canada and the United States. Eligible adults (aged 18-65 years) met DSM-5-defined criteria for bipolar I or bipolar II depression and exhibited pretreatment biochemical and/or phenotypic evidence of inflammatory activation. Participants were enrolled between October 1, 2015, and April 30, 2018. Data analysis was performed from May 1 through July 31, 2018, using modified intent-to-treat analysis. Interventions: Patients were randomized to receive 3 intravenous infusions of infliximab therapy or placebo at baseline and at weeks 2 and 6 of the 12-week study. Main Outcomes and Measures: The primary efficacy outcome was baseline-to-end point (ie, week-12) change in Montgomery-Asberg Depression Rating Scale (MADRS) total score. History of childhood maltreatment, as assessed by the Childhood Trauma Questionnaire, was used for exploratory analyses as 1 of several secondary outcomes. Results: A total of 60 participants were randomized to infliximab (n = 29 [48%]; mean [SD] age, 45.0 [11.7] years; 20 of 28 female [71%]) or to placebo (n = 31 [52%]; mean [SD] age, 46.8 [10.2] years; 26 of 30 female [87%]) across study sites. Overall baseline-to-end point change in MADRS total score was observed across treatment × time interaction (χ2 = 10.33; P = .04); reduction in symptom severity was not significant at week 12 (relative risk, 1.09; 95% CI, 0.80-1.50; df = 1; P = .60). As part of a secondary analysis, a significant treatment × time × childhood maltreatment interaction was observed in which infliximab-treated individuals with childhood history of physical abuse exhibited greater reductions in MADRS total score (χ2 = 12.20; P = .02) and higher response rates (≥50% reduction in MADRS total score) (χ2 = 4.05; P = .04). Conclusions and Relevance: Infliximab did not significantly reduce depressive symptoms compared with placebo in adults with bipolar depression. Results from secondary analyses identified a subpopulation (ie, those reporting physical and/or sexual abuse) that exhibited a significant reduction in depressive symptoms with infliximab treatment compared with placebo. Trial Registration: ClinicalTrials.gov identifier: NCT02363738.

Subjective versus objective evening chronotypes in bipolar disorder.

BACKGROUND: Disturbed sleep timing is common in bipolar disorder (BD). However, most research is based upon self-reports. We examined relationships between subjective versus objective assessments of sleep timing in BD patients versus controls. METHODS: We studied 61 individuals with bipolar I or II disorder and 61 healthy controls. Structured clinical interviews assessed psychiatric diagnoses, and clinician-administered scales assessed current mood symptom severity. For subjective chronotype, we used the Composite Scale of Morningness (CSM) questionnaire, using original and modified (1, ¾, ⅔, and ½ SD below mean CSM score) thresholds to define evening chronotype. Objective chronotype was calculated as the percentage of nights (50%, 66.7%, 75%, or 90% of all nights) with sleep interval midpoints at or before (non-evening chronotype) vs. after (evening chronotype) 04:15:00 (4:15:00a.m.), based on 25-50 days of continuous actigraph data. RESULTS: BD participants and controls differed significantly with respect to CSM mean scores and CSM evening chronotypes using modified, but not original, thresholds. Groups also differed significantly with respect to chronotype based on sleep interval midpoint means, and based on the threshold of 75% of sleep intervals with midpoints after 04:15:00. Subjective and objective chronotypes correlated significantly with one another. Twenty-one consecutive intervals were needed to yield an evening chronotype classification match of ≥ 95% with that made using the 75% of sleep intervals threshold. LIMITATIONS: Limited sample size/generalizability. CONCLUSIONS: Subjective and objective chronotype measurements were correlated with one another in participants with BD. Using population-specific thresholds, participants with BD had a later chronotype than controls.

Daytime midpoint as a digital biomarker for chronotype in bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is associated with later sleep and daily activity (evening rather than morning chronotype). Objective chronotype identification (e.g., based on actigraphs/smartphones) has potential utility, but to date, chronotype has mostly been assessed by questionnaires. Given the ubiquity of accelerometer-based devices (e.g. actigraphs/smartphones) worn/used during daytime and tendency to recharge rather than wear at night, we assessed chronotype using daytime (rather than sleep) interval midpoints. METHODS: Sixty-one participants with BD type I (BD-I) or II (BD-II) and 61 healthy controls completed 25-50 days of continuous actigraphy. The Composite Scale of Morningness (CSM) was completed by a subset of this group. Daytime activity midpoint was calculated for each daytime interval, excluding naps. Evening chronotype was defined as having a daytime interval midpoint at or after 16:15:00 (4:15:00 PM). RESULTS: BD versus controls had delayed daytime midpoint (mean ±â€¯standard deviation) (16:49:07 ±â€¯01:26:19 versus 16:12:51 ±â€¯01:02:14, p < 0.01), and greater midpoint variability (73.3 ±â€¯33.9 min versus 58.1 ±â€¯18.3 min, p < 0.01). Stratifying by gender and age, females and adolescents with BD had delayed and more variable daytime midpoints versus controls. Adults with BD had greater midpoint variability than controls. Within-person mean and standard deviations of daytime midpoints were highly correlated with sleep midpoints (r = 0.99, p < 0.01 and r = 0.86, p < 0.01, respectively). Daytime midpoint mean was also significantly correlated with the CSM (r = -0.56, p < 0.01). LIMITATIONS: Small sample size; analyses not fully accounting for daytime napping. CONCLUSIONS: Wrist actigraphy for determination of daytime midpoints is a potential tool to identify objective chronotype. Exploration of the use of consumer devices (wearables/smartphones) is needed.

Episode accumulation associated with hastened recurrence and delayed recovery in bipolar disorder.

AIMS: Assess episode accumulation (≥ 10 prior mood episodes) associations with demographic/baseline clinical characteristics and mood episode recurrence/recovery in bipolar disorder (BD). METHODS: 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). RESULTS: 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. LIMITATIONS: American tertiary BD clinic referral sample. CONCLUSION: 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.

Differential prevalence and demographic and clinical correlates of antidepressant use in American bipolar I versus bipolar II disorder patients.

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.

Abnormal sleep duration associated with hastened depressive recurrence in bipolar disorder.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. LIMITATIONS: Self-reported sleep duration. Limited generalizability beyond our predominately white, female, educated, insured American BD specialty clinic sample. CONCLUSIONS: 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.

Lifetime eating disorder comorbidity associated with delayed depressive recovery in bipolar disorder.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. LIMITATIONS: 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. CONCLUSIONS: Further studies are warranted to explore the degree to which EDs impact longitudinal depressive illness burden in BD.

Lifetime anxiety disorder and current anxiety symptoms associated with hastened depressive recurrence in bipolar disorder.

AIMS: To assess differential relationships between lifetime anxiety disorder/current anxiety symptoms and longitudinal depressive severity in bipolar disorder (BD). METHODS: 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. RESULTS: 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. LIMITATIONS: American tertiary BD clinic referral sample, open naturalistic treatment. CONCLUSIONS: 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.

American tertiary clinic-referred bipolar II disorder versus bipolar I disorder associated with hastened depressive recurrence.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.