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Objective: Bipolar disorder is highly comorbid with substance use disorders, and this comorbidity may be associated with a more severe course of illness, but the impact of comorbid substance abuse on recovery from major depressive episodes in these patients has not been adequately examined. The authors hypothesized that comorbid drug and alcohol use disorders would be associated with longer time to recovery in patients with bipolar disorder.Method: Subjects (N=3,750) with bipolar I or bipolar II disorder enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were followed prospectively for up to 2 years. Prospectively observed depressive episodes were identified for this analysis. Subjects with a past or current drug or alcohol use disorder were compared with those with no history of drug or alcohol use disorders on time to recovery from depression and time until switch to a manic, hypomanic, or mixed episode.Results: During follow up, 2,154 subjects developed a new-onset major depressive episode; of these, 457 subjects switched to a manic, hypomanic, or mixed episode prior to recovery. Past or current substance use disorder did not predict time to recovery from a depressive episode relative to no substance use comorbidity. However, those with current or past substance use disorder were more likely to experience switch from depression directly to a manic, hypomanic, or mixed state.Conclusions: Current or past substance use disorders were not associated with longer time to recovery from depression but may contribute to greater risk of switch into manic, mixed, or hypomanic states. The mechanism conferring this increased risk merits further study. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Clinicians have few evidence-based options for the management of treatment-resistant bipolar depression. This study represents the first randomized trial of competing options for treatment-resistant bipolar depression and assesses the effectiveness and safety of antidepressant augmentation with lamotrigine, inositol, and risperidone. METHOD: Participants (N=66) were patients with bipolar I or bipolar II disorder enrolled in the NIMH Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). All patients were in a current major depressive episode that was nonresponsive to a combination of adequate doses of established mood stabilizers plus at least one antidepressant. Patients were randomly assigned to open-label adjunctive treatment with lamotrigine, inositol, or risperidone for up to 16 weeks. The primary outcome measure was the rate of recovery, defined as no more than two symptoms meeting DSM-IV threshold criteria for a mood episode and no significant symptoms present for 8 weeks. RESULTS: No significant between-group differences were seen when any pair of treatments were compared on the primary outcome measure. However, the recovery rate with lamotrigine was 23.8%, whereas the recovery rates with inositol and risperidone were 17.4% and 4.6%, respectively. Patients receiving lamotrigine had lower depression ratings and Clinical Global Impression severity scores as well as greater Global Assessment of Functioning scores compared with those receiving inositol and risperidone. CONCLUSIONS: No differences were found in primary pairwise comparison analyses of open-label augmentation with lamotrigine, inositol, or risperidone. Post hoc secondary analyses suggest that lamotrigine may be superior to inositol and risperidone in improving treatment-resistant bipolar depression. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Little is known about clinical features associated with the risk of recurrence in patients with bipolar disorder receiving treatment according to contemporary practice guidelines. The authors looked for the features associated with risk of recurrence. METHOD: The authors examined prospective data from a cohort of patients with bipolar disorder participating in the multicenter Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study for up to 24 months. For those who were symptomatic at study entry but subsequently achieved recovery, time to recurrence of mania, hypomania, mixed state, or a depressive episode was examined with Cox regression. RESULTS: Of 1,469 participants symptomatic at study entry, 858 (58.4%) subsequently achieved recovery. During up to 2 years of follow-up, 416 (48.5%) of these individuals experienced recurrences, with more than twice as many developing depressive episodes (298, 34.7%) as those who developed manic, hypomanic, or mixed episodes (118, 13.8%). The time until 25% of the individuals experienced a depressive episode was 21.4 weeks and until 25% experienced a manic/hypomanic/mixed episode was 85.0 weeks. Residual depressive or manic symptoms at recovery and proportion of days depressed or anxious in the preceding year were significantly associated with shorter time to depressive recurrence. Residual manic symptoms at recovery and proportion of days of elevated mood in the preceding year were significantly associated with shorter time to manic, hypomanic, or mixed episode recurrence. CONCLUSIONS: Recurrence was frequent and associated with the presence of residual mood symptoms at initial recovery. Targeting residual symptoms in maintenance treatment may represent an opportunity to reduce risk of recurrence. [ABSTRACT FROM AUTHOR]

Objective: To review, firstly, published studies comparing classic antipsychotics, benzodiazepines, and/or combination of both; and secondly, available data on the use of atypical antipsychotic medications in controlling agitation and aggressive behaviour seen in psychiatric patients in emergency.Method: In the first review, studies comparing antipsychotics, benzodiazepines, and combination of both; and in the second review, efficacy trials of atypical antipsychotics that include an active and/or inactive comparator for the treatment of acute agitation were identified and reviewed. Data from clinical trials meeting the inclusion criteria were summarised by recording improvement rates, definition of improvement, and timing of defined improvement for individual studies.Results: In the first review, 11 trials were identified meeting the inclusion criteria, eight with a blind design. The total number of subjects was 701. These studies taken together suggest that combination treatment may be superior to the either agent alone with higher improvement rates and lower incidence of extrapyramidal side effects. In the review of atypical antipsychotic agents as acute antiagitation compounds, five studies were identified, three with a blind design. The total number of subjects was 711, of which 15% (104) was assigned to the placebo arm. This review found atypical antipsychotics to be as effective as the classic ones and more advantageous in many aspects.Conclusion: Atypical antipsychotics such as risperidone, ziprasidone, and olanzapine with or without benzodiazepines should be considered first in the treatment of acute agitation. If these agents are not available the combination of a classic antipsychotic and a benzodiazepine would be a reasonable alternative. An oral treatment should always be offered first for building up an alliance with the patient and suggesting an internal rather than external locus of control. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Bipolar spectrum disorders, which include bipolar I, bipolar II, and bipolar disorder not otherwise specified, frequently go unrecognized, undiagnosed, and untreated. This report describes the validation of a new brief self-report screening instrument for bipolar spectrum disorders called the Mood Disorder Questionnaire. METHOD: A total of 198 patients attending five outpatient clinics that primarily treat patients with mood disorders completed the Mood Disorder Questionnaire. A research professional, blind to the Mood Disorder Questionnaire results, conducted a telephone research diagnostic interview by means of the bipolar module of the Structured Clinical Interview for DSM-IV. RESULTS: A Mood Disorder Questionnaire screening score of 7 or more items yielded good sensitivity (0.73) and very good specificity (0.90). CONCLUSIONS: The Mood Disorder Questionnaire is a useful screening instrument for bipolar spectrum disorder in a psychiatric outpatient population. [ABSTRACT FROM AUTHOR]

Does adding a nurse-based intervention programme to usual care improve the effectiveness of treatment for bipolar disorder?METHODSCONCLUSIONSUsual care with a nurse-based intervention programme is more effective than usual care alone for treating bipolar disorder.Design: Randomised controlled trial. Allocation: Concealed.Blinding: Single blinded.Follow up period: Twelve months.Setting: Four health clinics in the USA; August 1999 to October 2000.Patients: 441 people treated for bipolar disorder type I or II (DSM-IV) in the previous 12 months. People were excluded if cognitive impairment prevented giving informed consent.Intervention: Usual care, or usual care plus a nurse-based intervention programme. The intervention programme consisted of an initial patient assessment and treatment planning session, followed by monthly telephone monitoring of mood symptoms and medication with the support of the treating mental healthcare team, together with a group psycho-educational programme.Outcomes: Psychiatric status ratings for mania and depression. Patient follow up: 44% completed the study.MAIN RESULTSUsual care with a nursed-based intervention programme reduced manic, but not depressive symptoms, compared with usual care alone, over 12 months (mania scores: p = 0.025; depressive scores: p = 0.82; actual values not stated). [ABSTRACT FROM AUTHOR]

Objective: To assess the efficacy of cariprazine, a dopamine D 3 -preferring D 3 /D 2 and serotonin 5-HT 1A receptor partial agonist, as adjunctive treatment for patients with major depressive disorder (MDD) and inadequate response to ongoing antidepressant therapy (ADT)., Methods: This randomized, double-blind, placebo-controlled study was conducted from November 2018 to September 2021. Adults with MDD per DSM-5 criteria were randomized (1:1:1) to cariprazine 1.5 mg/d or 3 mg/d plus ADT, or placebo plus ADT. The primary and secondary endpoints were change from baseline to week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) total score and Clinical Global Impressions-Severity of Illness (CGI-S) score, respectively., Results: A total of 249 placebo-, 250 cariprazine 1.5 mg/d-, and 251 cariprazine 3 mg/d-treated patients were included in the modified intent-to-treat population. At week 6, the least squares mean change in MADRS total score was -13.8 for cariprazine 1.5 mg/d, -14.8 for cariprazine 3 mg/d, and -13.4 for placebo; differences versus placebo were not statistically significant. Mean change from baseline in CGI-S scores at week 6 was not significant for cariprazine versus placebo, although a trend toward significance was observed for 3 mg/d ( P  = .0573 [not adjusted for multiplicity]). Common treatment-emergent adverse events (≥ 5% either cariprazine group and twice placebo) were akathisia and insomnia., Conclusions: There were no statistically significant differences for cariprazine 1.5 or 3 mg/d versus placebo on the primary or secondary outcomes. Cariprazine was generally well tolerated, and no new safety concerns were detected., Clinical Trials Registration: ClinicalTrials.gov identifier NCT03739203., (© Copyright 2023 Physicians Postgraduate Press, Inc.)

Objective: The purpose of this study was to investigate the efficacy of cariprazine, a dopamine D 3 -preferring D 3 /D 2 and serotonin 5-HT 1A receptor partial agonist, as adjunctive therapy for patients with major depressive disorder and nonresponse to at least one antidepressant monotherapy., Methods: In this double-blind placebo-controlled study, adults with major depressive disorder and inadequate response to antidepressants alone were randomized in a 1:1:1 ratio to placebo, cariprazine at 1.5 mg/day, or cariprazine at 3.0 mg/day. The primary outcome was change from baseline to week 6 in total score on the Montgomery-Åsberg Depression Rating Scale (MADRS). Least-squares mean differences were estimated in the modified intent-to-treat (mITT) population using a mixed-effects model for repeated measures with adjustment for multiple comparisons., Results: The mITT population comprised 751 patients (placebo: N=249; cariprazine 1.5 mg/day: N=250; cariprazine 3.0 mg/day: N=252). At week 6, the mean reduction from baseline in MADRS total score was significantly greater with cariprazine 1.5 mg/day than with placebo (-14.1 vs. -11.5) but not with cariprazine 3.0 mg/day (-13.1). Significant differences between the cariprazine 1.5 mg/day and placebo groups were also observed at weeks 2 and 4. Meeting the MADRS response criteria was significantly more likely among patients receiving cariprazine 1.5 mg/day than placebo (44.0% vs. 34.9%); remission rates were not significantly different among groups. Common treatment-emergent adverse events (≥5% in either cariprazine group and twice the placebo rate) were akathisia and nausea., Conclusions: Adjunctive cariprazine at 1.5 mg/day demonstrated efficacy in reducing depressive symptoms in adults with major depressive disorder and inadequate response to antidepressants alone. Cariprazine was generally well tolerated, with a safety profile that was consistent with previous findings.

Objective: In a phase 3 randomized double-blind placebo-controlled study, the authors investigated the efficacy and safety of 42 mg/day of lumateperone in patients with bipolar I or bipolar II disorder experiencing a major depressive episode., Methods: Patients 18-75 years old with a clinical diagnosis of bipolar I or bipolar II disorder and experiencing a major depressive episode were eligible for the study. Patients were randomized in a 1:1 ratio to receive 42 mg/day of lumateperone (N=188) or placebo (N=189), administered orally once daily in the evening for 6 weeks. The primary and key secondary efficacy endpoints were change from baseline to day 43 in score on the Montgomery-Åsberg Depression Rating Scale (MADRS) and total score on the Clinical Global Impressions Scale-Bipolar Version severity scale (CGI-BP-S), respectively. Safety assessments included treatment-emergent adverse events, laboratory parameters, vital signs, extrapyramidal symptoms, and suicidality., Results: At day 43, lumateperone treatment was associated with significantly greater improvement from baseline in MADRS score compared with placebo (least squares mean difference compared with placebo, -4.6 points; effect size=-0.56) and CGI-BP-S total score (least squares mean difference compared with placebo, -0.9; effect size=-0.46). Significant MADRS superiority for lumateperone over placebo was observed both in patients with bipolar I and bipolar II disorders. Somnolence and nausea were the only treatment-emergent adverse events that occurred with lumateperone at a clinically meaningful greater rate than placebo. The incidence of extrapyramidal symptom-related treatment-emergent adverse events was low and similar to that for placebo. Minimal changes were observed in weight, vital signs, or metabolic or endocrine assessments., Conclusions: Lumateperone at 42 mg/day significantly improved depression symptoms and was generally well tolerated in patients with major depressive episodes associated with both bipolar I and bipolar II disorders.

Objective: Cariprazine, a dopamine D 3 /D 2 and 5-HT 1A receptor partial agonist, was found to be effective in treating bipolar I depression in a previous phase 2 study. This phase 3 study further assessed the efficacy, safety, and tolerability of cariprazine in bipolar I depression., Methods: In a double-blind placebo-controlled study, adult participants (18-65 years old) who met DSM-5 criteria for bipolar I disorder and a current depressive episode were randomly assigned to receive placebo (N=158) or cariprazine at 1.5 mg/day (N=157) or 3.0 mg/day (N=165). The primary and secondary efficacy parameters were changes from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) score and Clinical Global Impressions severity (CGI-S) score, respectively. Least squares mean differences were estimated using a mixed model for repeated measures, and p values were adjusted for multiplicity., Results: Both dosages of cariprazine were significantly more effective than placebo in improving depressive symptoms (reducing MADRS total score); the least squares mean differences were -2.5 (95% CI=-4.6, -0.4) for cariprazine at 1.5 mg/day and -3.0 (95% CI=-5.1, -0.9) for cariprazine at 3.0 mg/day. Both cariprazine dosages were associated with lower CGI-S scores compared with placebo, but the differences did not reach statistical significance after adjustment for multiplicity (least squares mean difference, -0.2 [95% CI=-0.5, 0.0] for the 1.5 mg/day group and -0.3 [95% CI=-0.5, 0.0] for the 3.0 mg/day group). Common treatment-emergent adverse events (in at least 5% of participants in either cariprazine treatment group and twice the rate of the placebo group) were nausea, akathisia, dizziness, and sedation. Mean changes in weight and metabolic parameters were relatively small and comparable across groups., Conclusions: Cariprazine, at both 1.5 mg/day and 3.0 mg/day, was effective, generally well tolerated, and relatively safe in reducing depressive symptoms in adults with bipolar I depression.

Objective: To evaluate patient-reported determinants of treatment effectiveness and tolerability amongst persons with major depressive or bipolar disorders., Methods: The Depression and Bipolar Support Alliance (DBSA) conducted an online survey February 2016-April 2016 asking participants about which outcomes are most important in determining subjective treatment effectiveness and tolerability., Results: In total, 896 participants completed the survey [49.9% unipolar depression (n = 447) and 50.1% bipolar depression (n = 449)]. Survey respondents reported several previous medication trials with the minority (25% of depression and 29% of bipolar group) of respondents reporting that their current treatment plan was completely effective. When asked how they know that the treatment is working, for both groups, the highest rated response was, "I don't feel overly anxious, agitated or irritable." Weight gain was the adverse effect that most commonly led respondents to discontinue a medication. Lethargy, emotional blunting, shaking/trembling and anxiety were also identified as common treatment-emergent experiences leading to medication discontinuation in greater than one-third of respondents. The bipolar group more frequently identified several signs that suggested treatment was working (e.g., improved neurocognitive function, improved sleep), as well as more frequently reported several reasons to discontinue medications (e.g., weight gain, trembling)., Conclusion: Numerous factors emerged as important to patients when evaluating treatment effectiveness and tolerability. Some of these factors are inadequately assessed by current standard clinical trial outcome measures. Considering these important patient-centred outcomes in future clinical trials, treatment guidelines and direct patient care may serve to improve patient satisfaction, quality of life and the therapeutic alliance., (Copyright © 2018. Published by Elsevier B.V.)

Background: The majority of research in mood disorders has focused on pharmacologic, psychotherapeutic, and brain stimulation interventions. Conversely, the utility of less structured interventions, such as lifestyle modifications or wellness strategies, has remained understudied. The objective of the current study is to evaluate the frequency of use and perceived helpfulness of wellness strategies for bipolar and unipolar depression., Methods: The Depression and Bipolar Support Alliance (DBSA) conducted an online survey asking participants about the use and helpfulness of wellness strategies., Results: In total, 896 participants completed the survey (unipolar depression [n = 447] and bipolar depression [n = 449]). Wellness strategies were used by 62% and 59% of individuals with bipolar and unipolar depression, respectively. Listening to music, socializing, and adequate sleep were commonly reported wellness strategies. The majority of participants reported wellness strategies to be helpful. Use of wellness strategies was associated with greater overall perceived treatment effectiveness (P < .0001) and greater subjective helpfulness of medications (P = .039), psychotherapy (P < .0001), and peer support groups (P < .0001)., Conclusions: Wellness strategies were commonly used by the majority of respondents. These strategies were subjectively helpful for most respondents and were associated with greater overall treatment effectiveness and increased helpfulness of medications, psychotherapy, and peer support groups. As such, wellness strategies should be considered while developing a holistic treatment plan for depression. Further research is needed to evaluate the antidepressant effects of specific wellness strategies to better understand the role of these interventions in the management of depression.

Objective: To identify patient-reported factors that influence medication treatment decisions among individuals with bipolar and unipolar depression., Methods: The Depression and Bipolar Support Alliance (DBSA) conducted an online survey February 2016 to April 2016 asking participants about factors that influence treatment decisions (eg, starting and stopping specific medications)., Results: In total, 896 participants completed the survey (49.9% unipolar depression [n = 447] and 50.1% bipolar depression [n = 449]). The majority of respondents reported several previous medication trials. The most frequently reported factors impacting treatment decisions were side effects, doctor recommendations, cost, and how quickly the treatment will begin to work. The most common reason for changing treatments was ineffectiveness in the unipolar depression group and side effects in the bipolar depression group. Weight gain was the side effect that most commonly led respondents to discontinue a medication. When respondents currently using medications versus respondents not using medications were compared, doctor recommendations were more likely to be influential for those taking medications (P < .0001). Conversely, cost (P = .008) and impact on pregnancy/lactation (P = .045) were more likely to impact treatment decisions in participants not currently taking medications. Current medication use was associated with increased rates of perceived treatment effectiveness (P < .0001)., Conclusions: Side effects, doctor recommendations, cost, and rapidity of antidepressant effects were determined to be particularly important factors in making treatment decisions, with doctor recommendations being more influential for medication users and cost being more influential for participants not using medications. These findings highlight the importance of patient-centered factors in adjudicating treatment decisions., (© Copyright 2018 Physicians Postgraduate Press, Inc.)

Background: We evaluated the safety/tolerability of longer-term open-label treatment with cariprazine in patients who had responded to cariprazine for acute bipolar mania., Methods: In this multinational, multicenter study, open-label, flexible-dose, cariprazine 3-12mg/d was administered for up to 16 weeks to patients (18-65 years) with bipolar mania. Safety evaluations included adverse events (AEs), laboratory values, vital signs, and extrapyramidal symptom (EPS) scales. Symptom change was evaluated by Young Mania Rating Scale (YMRS) total score change from baseline using the last observation carried forward approach., Results: Of the 402 patients taking cariprazine, 33% completed the trial; the most frequent reasons for discontinuation were withdrawal of consent (20%), AEs (16%), and protocol violation (14%). Most common AEs leading to discontinuation were akathisia (4.7%) and depression (1.5%). Mean treatment duration was 57.7 days; mean cariprazine dose was 6.2mg/d. The incidence of serious AEs was 7.5% (most common: mania [2.2%], depression [1.2%]); 83.3% had treatment-emergent AEs, including akathisia (32.6%), headache (16.7%), constipation (10.7%), and nausea (10.4%). Mean body weight increased <1kg; 9.3% had ≥7% weight gain; 5.7% had sedation; 3% had somnolence. Mean changes in laboratory values, vital signs, ECGs, and ophthalmology parameters were not clinically significant. Mean YMRS total score decreased by -15.2 at week 16., Limitations: Uncontrolled, open-label design., Conclusions: Open-label cariprazine 3-12 (mean 6.2) mg/d for up to 16 weeks was generally well tolerated, with low (<10%) rates of sedation and ≥7% weight gain. Although akathisia occurred in 33%, it yielded discontinuation in <5%., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The impact of comorbid premenstrual dysphoric disorder (PMDD) in women with bipolar disorder (BD) is largely unknown., Aims: We compared illness characteristics and female-specific mental health problems between women with BD with and without PMDD., Materials & Methods: A total of 1 099 women with BD who participated in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were studied. Psychiatric diagnoses and illness characteristics were assessed using the Mini International Neuropsychiatric Interview. Female-specific mental health was assessed using a self-report questionnaire developed for STEP-BD. PMDD diagnosis was based on DSM-5 criteria., Results: Women with comorbid BD and PMDD had an earlier onset of bipolar illness (P < 0.001) and higher rates of rapid cycling (P = 0.039), and increased number of past-year hypo/manic (P = 0.003), and lifetime/past-year depressive episodes (P < 0.05). Comorbid PMDD was also associated with higher proportion of panic disorder, post-traumatic stress disorder, generalized anxiety disorder, bulimia nervosa, substance abuse, and adult attention deficit disorder (all P < 0.05). There was a closer gap between BD onset and age of menarche in women with comorbid PMDD (P = 0.003). Women with comorbid PMDD reported more severe mood symptoms during the perinatal period and while taking oral contraceptives (P < 0.001)., Discussion: The results from this study is consistent with research suggesting that sensitivity to endogenous hormones may impact the onset and the clinical course of BD., Conclusions: The comorbidity between PMDD and BD is associated with worse clinical outcomes and increased illness burden., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The optimal long-term management strategy for bipolar I disorder patients is not yet established. Evidence supports the rationale for circadian rhythm regulation to prevent mood episode relapse in bipolar patients. This study evaluated the efficacy and safety of a new sublingual formulation of the melatonin receptor agonist ramelteon (ramelteon SL) as adjunctive therapy in the maintenance treatment of bipolar I patients., Methods: In a double-blinded trial in the United States and Latin America, adult bipolar I disorder patients stable for ≥ 8 weeks before baseline and with a mood episode 8 weeks to 9 months before screening, were randomized to once-daily ramelteon SL 0.1mg (n = 164), 0.4mg (n = 160), or 0.8mg (n = 154), or placebo (n = 164), in addition to their existing treatment. The primary endpoint was time from randomization to relapse of symptoms. The prespecified futility criterion in a planned, unblinded, independent interim analysis was the failure of all ramelteon SL doses to achieve a conditional power ≥ 30% compared with placebo., Results: No significant differences between any dose of ramelteon SL and placebo were observed. The study was terminated after meeting the futility criteria. Ramelteon SL was well tolerated, with a safety profile consistent with that for oral ramelteon., Limitations: A low rate of relapse events precluded detection of any statistically significant difference between groups., Conclusions: The study failed to demonstrate the efficacy of ramelteon SL as adjunctive maintenance therapy for bipolar disorder. Interim analyses for futility in clinical studies are valuable in preventing unnecessary exposure of subjects to interventions., (Copyright © 2017. Published by Elsevier B.V.)

Background: The Bipolarity Index is a clinician-rated scale that rates cardinal features of the disorder across five domains: signs and symptoms, age of onset, course of illness, response to treatment, and family history. We tested the Index in routine clinical practice to identify the optimal cut-off for distinguishing bipolar from non-bipolar disorders., Method: Sequential patients in a private practice were rated with the Bipolarity Index (n=1903) at intake. Diagnoses were made with the MINI-6.0.0 International Neuropsychiatric Interview according to DSM-IV-TR criteria, except that cases of antidepressant-induced mania and hypomania were included in the bipolar group. A subset completed the self-rated Mood Disorder Questionnaire (MDQ) (n=1620) or Bipolar Spectrum Diagnostic Scale (BSDS) (n=1179). The primary analysis compared Bipolarity Index scores for bipolar vs. non-bipolar patients using receiver operator curves (ROC) to determine the optimal cut-off score. Secondary outcomes repeated this analysis with the MDQ, MDQ-7 (using only the symptomatic items of the MDQ) and BSDS., Results: At a cut-off of ≥50, the Bipolarity Index had a high sensitivity (0.91) and specificity (0.90). Optimal cut-offs for self-rated scales were: MDQ: ≥7 (sensitivity 0.74, specificity 0.71); MDQ-7: ≥6 (sensitivity 0.77, specificity 0.77); BSDS: ≥12 (sensitivity 0.71, specificity 0.77)., Limitations: The study utilized one rater at a single practice site; the rater was not blinded to the results of the MINI., Conclusion: The Bipolarity Index can enhance the clinical assessment of mood disorders and, at a score ≥50 has good sensitivity and specificity for identifying bipolar disorders., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: This Phase III, randomized, double-blind, placebo-controlled study investigated the efficacy and tolerability of flexibly-dosed cariprazine in patients with acute manic or mixed episodes associated with bipolar I disorder., Methods: Patients were randomized to 3 weeks of double-blind treatment with cariprazine 3-12mg/day (n=158) or placebo (n=154). The primary efficacy parameter was change from baseline to Week 3 in Young Mania Rating Scale (YMRS) total score. The secondary efficacy parameter was change from baseline to Week 3 in Clinical Global Impressions-Severity (CGI-S) score., Results: Mean change from baseline to Week 3 in YMRS total score was significantly greater for patients receiving cariprazine 3-12mg/day versus placebo (P=0.0004). Significant differences between groups in YMRS total score mean change were observed by Day 4 (first postbaseline assessment) and maintained throughout double-blind treatment (all assessments, P<0.01). Cariprazine also demonstrated statistically significant superiority over placebo on YMRS response (≥50% improvement: cariprazine, 58.9%; placebo, 44.1%; P=0.0097) and remission (YMRS total score≤12: cariprazine, 51.9%; placebo, 34.9%; P=0.0025) and mean change in CGI-S (P=0.0027) score and Positive and Negative Syndrome Scale (PANSS) (P=0.0035) total score. The most common cariprazine-related (≥10% and twice placebo) treatment emergent adverse events (TEAEs) were akathisia, extrapyramidal disorder, tremor, dyspepsia, and vomiting. Mean change from baseline in metabolic parameters were generally small and similar between groups., Limitations: Lack of active comparator arm; short duration of study., Conclusion: In this study, cariprazine 3-12mg/day was effective and generally well tolerated in the treatment of manic and mixed episodes associated with bipolar I disorder., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)

Only 3 medications are currently approved in the US for acute bipolar depression: 2 atypical antipsychotics and a combination atypical antipsychotic-selective serotonin reuptake inhibitor. Metabolic, neurologic, and hormonal adverse events are associated with all of the atypical antipsychotics approved for this indication. However, these agents differ in their propensity to cause weight gain or other side effects that significantly impact a patient's physical health and ability to function, and the selection of medication-which may also include a mood stabilizer-as well as other forms of treatment, will affect the outcome. It is important to design treatment based on individual needs. Evidence suggests that the collaborative care model, which incorporates individualized systematic treatment, may be more appropriate for the management of bipolar depression than the acute care model., (© Copyright 2015 Physicians Postgraduate Press, Inc.)

Once a molecule has been characterized as engaging an identified target at the appropriate location (affinity and potency), the next step involves designing experiments that will determine its pharmacodynamic activities both for efficacy (on target) and safety-tolerability (on/off target). Two expert presentations focused on looking back at completed programs and two concentrated on looking forward at ongoing programs. Specific discussions pertain to assessment of pharmacologic agonists (mGluR2/3, k-opiate, peroxisome proliferator-activated receptor gamma) and antagonists (orexin and cannabinoid) in disorders of cognition, mood, and anxiety. Advanced experimental study designs using genetics to guide a treatment trial in Alzheimer's disease and neural target-based approaches as the primary outcome measure in the National Institute of Mental Health-sponsored Fast-Fail Trials (FAST)-Mood and Anxiety Spectrum Disorders (MAS) initiative for depression showcases novel methodological approaches. Of interest, some of these initiatives were successful, while others were not, and two are currently ongoing. In conclusion, methodologies that were utilized and are currently employed to reach a successful clinical drug trial outcome are appreciated, and in case of failure, approaches to reviewing programs to enable learning that would be helpful to future programs are brought forth. This article is based on proceedings from the "Designing the Right Series of Experiments" session, which was held during the International Society for Clinical Trials Meeting (ISCTM) in Philadelphia, Pennsylvania, September 30 to October 2, 2013.

The majority of patients treated for bipolar disorder receive multiple psychotropic medications concurrently (polypharmacy), despite a lack of empirical evidence for any combination of three or more medications. Some patients benefit from the skillful management of a complex medication regimen, but iterative additions to a treatment regimen often do not lead to clinical improvement, are expensive, and can confound assessment of the underlying mood disorder. Given these potential problems of polypharmacy, this paper reviews the evidence supporting the use of multiple medications and seeks to identify patient personality traits that may put patients at a greater risk for ineffective complex chronic care. Patients with bipolar disorder (n = 89), ages 18 and older, were assessed on the Montgomery Asberg Depression Rating Scale (MADRS), Young Mania Rating Scale (YMRS), and the NEO Five Factor Inventory (NEO-FFI), and completed a treatment history questionnaire to report psychotropic medication use. We found that patients with lower scores on openness had significantly more current psychotropic medications than patients with higher scores on openness (3.7 ± 1.9 vs. 2.8 ± 1.8, p < 0.05). Patients with the highest lifetime medication use had significantly lower extraversion (21.8 ± 8.9 vs. 25.4 ± 7.6, p < 0.05) and lower conscientiousness (21.9 ± 8.2 vs. 27.9 ± 8.2, p < 0.01) than those reporting lower lifetime medication use. Low levels of openness, extraversion, and conscientiousness may be associated with increased psychotropic medication use. Investigating the role of individual differences, such as patient personality traits, in moderating effective polypharmacy warrants future research.

Objective: The risk-benefit profile of antidepressant medications in bipolar disorder is controversial. When conclusive evidence is lacking, expert consensus can guide treatment decisions. The International Society for Bipolar Disorders (ISBD) convened a task force to seek consensus recommendations on the use of antidepressants in bipolar disorders., Method: An expert task force iteratively developed consensus through serial consensus-based revisions using the Delphi method. Initial survey items were based on systematic review of the literature. Subsequent surveys included new or reworded items and items that needed to be rerated. This process resulted in the final ISBD Task Force clinical recommendations on antidepressant use in bipolar disorder., Results: There is striking incongruity between the wide use of and the weak evidence base for the efficacy and safety of antidepressant drugs in bipolar disorder. Few well-designed, long-term trials of prophylactic benefits have been conducted, and there is insufficient evidence for treatment benefits with antidepressants combined with mood stabilizers. A major concern is the risk for mood switch to hypomania, mania, and mixed states. Integrating the evidence and the experience of the task force members, a consensus was reached on 12 statements on the use of antidepressants in bipolar disorder., Conclusions: Because of limited data, the task force could not make broad statements endorsing antidepressant use but acknowledged that individual bipolar patients may benefit from antidepressants. Regarding safety, serotonin reuptake inhibitors and bupropion may have lower rates of manic switch than tricyclic and tetracyclic antidepressants and norepinephrine-serotonin reuptake inhibitors. The frequency and severity of antidepressant-associated mood elevations appear to be greater in bipolar I than bipolar II disorder. Hence, in bipolar I patients antidepressants should be prescribed only as an adjunct to mood-stabilizing medications.

Objectives: We sought to understand the association of specific aspects of care satisfaction, such as patients' perceived relationship with their psychiatrist and access to their psychiatrist and staff, and therapeutic alliance with participants' likelihood to adhere to their medication regimens among patients with bipolar disorder., Methods: We examined data from the multicenter Systematic Treatment Enhancement Program for Bipolar Disorder, an effectiveness study investigating the course and treatment of bipolar disorder. We expected that participants (n = 3037) with positive perceptions of their relationship with their psychiatrist and quality of psychopharmacologic care, as assessed by the Helping Alliance Questionnaire and Care Satisfaction Questionnaire, would be associated with better medication adherence. We utilized logistic regression models controlling for already established factors associated with poor adherence., Results: Patients' perceptions of collaboration, empathy, and accessibility were significantly associated with adherence to treatment in individuals with bipolar disorder completing at least 1 assessment. Patients' perceptions of their psychiatrists' experience, as well as of their degree of discussing medication risks and benefits, were not associated with medication adherence., Conclusions: Patients' perceived therapeutic alliance and treatment environment impact their adherence to pharmacotherapy recommendations. This study may enable psychopharmacologists' practices to be structured to maximize features associated with greater medication adherence.

Bipolar depression remains challenging for clinicians to assess and manage during routine office visits. When patients complete assessments before their office visits, clinicians are able to quickly review the results beforehand and spend more time engaging and assessing the patient. After completing the differential diagnosis, clinicians can focus on discussing treatment goals and expectations with patients, educate them about viable treatment options, and help them select a proven option that will best promote treatment adherence. Collaborating with patients and care partners enables patients to be active participants in the management process. Systematically using assessment tools provides clinicians with measurable data to gauge the effectiveness and tolerability for each treatment and then to guide the next treatment decisions. Patients with bipolar depression value individualized care and rely on the expertise of clinicians to help them achieve remission., (© Copyright 2013 Physicians Postgraduate Press, Inc.)

Objectives: High failure rates of randomized controlled trials (RCTs) are well recognized but poorly understood. We report exploratory analyses from an adjunctive ziprasidone double-blind RCT in adults with bipolar I disorder (reported in part 1 of this article). Data collected by computer interviews and by site-based raters were analyzed to examine the impact of eligibility criteria on signal detection., Method: Clinical assessments and a remote monitoring system, including a computer-administered Young Mania Rating Scale (YMRS(Comp)) were used to categorize subjects as eligible or ineligible on 3 key protocol-specified eligibility criteria. Data analyses compared treatment efficacy for eligible versus ineligible subgroups. All statistical analyses reported here are exploratory. Criteria were considered "impactful" if the difference between eligible and ineligible subjects on the YMRS change scores was ≥ 1 point., Results: 504 subjects had baseline and ≥ 1 post-randomization computer-administered assessments but only 180 (35.7%) met all 3 eligibility criteria based on computer assessments. There were no statistically significant differences between treatment groups in change from baseline YMRS score on the basis of site-based rater or computer assessments. All criteria tested improved signal detection except the entry criteria excluding subjects with ≥ 25% improvement from screen to baseline., Conclusions: On the basis of computer assessments, nearly two-thirds of randomized subjects did not meet at least 1 protocol-specified eligibility criterion. These results suggest enrollment of ineligible subjects is likely to contribute to failure of acute efficacy studies., Trial Registration: ClinicalTrials.gov identifier: NCT00312494., (© Copyright 2012 Physicians Postgraduate Press, Inc.)

Objective: To assess the efficacy and safety of adjunctive ziprasidone in subjects with acute mania treated with lithium or divalproex, with an inadequate response to the mood stabilizer., Method: The study enrolled subjects aged 18-65 years who had a primary DSM-IV diagnosis of bipolar I disorder, with the most recent episode manic or mixed, with or without rapid cycling, and a Young Mania Rating Scale (YMRS) score ≥ 18. Subjects were randomized under double-blind conditions to receive ziprasidone, 20 to 40 mg (n = 226) or 60 to 80 mg (n = 232), or placebo (n = 222) twice a day for 3 weeks in addition to their mood stabilizer. The primary efficacy variable was change in YMRS scores from baseline to 3 weeks. Secondary efficacy measures included the Montgomery-Asberg Depression Rating Scale, Positive and Negative Syndrome Scale, Clinical Global Impressions-Severity of Illness and -Improvement scales, and Global Assessment of Functioning. Computer-administered YMRS was included for quality control and to evaluate study performance. The study was conducted between April 2006 and December 2008., Results: Least-squares mean ± standard error changes in YMRS scores from baseline to week 3 were -10.2 ± 0.80 in the mood stabilizer + ziprasidone 60- to 80-mg group, -11.0 ± 0.80 in the mood stabilizer + ziprasidone 20- to 40-mg group, and -9.5 ± 0.80 in the mood stabilizer + placebo group. Mean treatment differences between adjunctive ziprasidone groups and placebo were not statistically significant on primary or secondary efficacy measures. Ziprasidone was well tolerated., Conclusions: Adjunctive ziprasidone treatment failed to separate from mood stabilizer (lithium or divalproex) treatment on primary and secondary end points., Trial Registration: ClinicalTrials.gov identifier: NCT00312494., (© Copyright 2012 Physicians Postgraduate Press, Inc.)

Sleep disturbance is a common feature during mood episodes in bipolar disorder. The aim of this study was to investigate the prevalence of such symptoms among euthymic bipolar patients, and their association with risk for mood episode recurrence. A cohort of bipolar I and II subjects participating in the Systematic Treatment Enhancement Program for Bipolar Disorder who were euthymic for at least 8 weeks were included in this analysis. Survival analysis was used to examine the association between sleep disturbance on the Montgomery-Asberg Depression Rating Scale (MADRS) and recurrence risk. A total of 73/483 bipolar I and II subjects reported at least mild sleep disturbance (MADRS sleep item ≥2) for the week prior to study entry. The presence of sleep problems was associated with a history of psychosis, number of previous suicide attempts, and anticonvulsant use. Sleep disturbance at study entry was significantly associated with risk for mood episode recurrence. Sleep disturbance is not uncommon between episodes for individuals with bipolar disorder and may be associated with a more severe course of illness. This suggests that sleep disturbance is an important prodromal symptom of bipolar disorder and should be considered a target for pharmacologic or psychosocial maintenance treatment.

The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was funded as part of a National Institute of Mental Health initiative to develop effectiveness information about treatments, illness course, and assessment strategies for severe mental disorders. STEP-BD studies were planned to be generalizable both to the research knowledge base for bipolar disorder and to clinical care of bipolar patients. Several novel methodologies were developed to aid in illness characterization, and were combined with existing scales on function, quality of life, illness burden, adherence, adverse effects, and temperament to yield a comprehensive data set. The methods integrated naturalistic treatment and randomized clinical trials, which a portion of STEP-BD participants participated. All investigators and other researchers in this multisite program were trained in a collaborative care model with the objective of retaining a high percentage of enrollees for several years. Articles from STEP-BD have yielded evidence on risk factors impacting outcomes, suicidality, functional status, recovery, relapse, and caretaker burden. The findings from these studies brought into question the widely practiced use of antidepressants in bipolar depression as well as substantiated the poorly responsive course of bipolar depression despite use of combination strategies. In particular, large studies on the characteristics and course of bipolar depression (the more pervasive pole of the illness), and the outcomes of treatments concluded that adjunctive psychosocial treatments but not adjunctive antidepressants yielded outcomes superior to those achieved with mood stabilizers alone. The majority of patients with bipolar depression concurrently had clinically significant manic symptoms. Anxiety, smoking, and early age of bipolar onset were each associated with increased illness burden. STEP-BD has established procedures that are relevant to future collaborative research programs aimed at the systematic study of the complex, intrinsically important elements of bipolar disorders., (© 2011 Blackwell Publishing Ltd.)

This analysis was conducted to compare the effects of adjunctive ziprasidone or placebo on metabolic parameters among patients receiving maintenance treatment with lithium or valproate. We also tested whether metabolic syndrome (MetS) and other risk factors were associated with baseline characteristics and treatment response. In the stabilization phase (Phase 1), 584 bipolar I disorder (DSM-IV) patients received 2.5-4 months of open label ziprasidone (80-160 mg/d) plus lithium or valproic acid (ZIP+MS). Patients who achieved at least 8 weeks of clinical stability were subsequently randomized into Phase 2 to 6-months of double-blind treatment with ZIP+MS (n=127) vs. placebo+MS (n=113). At baseline of Phase 1, MetS was found in 111 participants (23%). Participants with MetS (vs. non-MetS participants) were more likely to be aged 40 years or older, had significantly more severe manic symptoms, higher abdominal obesity, and higher BMI. Increase in abdominal obesity was associated with lower manic symptom improvement (p<0.05, as assessed by MRS change score) during Phase 1, while symptom improvement differed across racial groups. In the Phase 2 double-blind phase, the ZIP+MS group had similar weight and metabolic profiles compared to the placebo+MS group across visits. These results corroborate existing findings on ziprasidone which exhibits a neutral weight and metabolic profile in the treatment of schizophrenia and bipolar patients. Our findings suggest that MetS is highly prevalent in patients with bipolar disorder, may be associated with greater manic symptom severity, and may predict treatment outcomes., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Few studies have prospectively examined the relationships of sleep with symptoms and functioning in bipolar disorder., Methods: The present study examined concurrent and prospective associations between total sleep time (TST) and sleep variability (SV) with symptom severity and functioning in a cohort of DSM-IV bipolar patients (N = 468) participating in the National Institute of Mental Health Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), all of whom were recovered at study entry., Results: Concurrent associations at study entry indicated that shorter TST was associated with increased mania severity, and greater SV was associated with increased mania and depression severity. Mixed-effects regression modeling was used to examine prospective associations in the 196 patients for whom follow-up data were available. Consistent with findings at study entry, shorter TST was associated with increased mania severity, and greater SV was associated with increased mania and depression severity over 12 months., Discussion: These findings highlight the importance of disrupted sleep patterns in the course of bipolar illness., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: To assess efficacy and safety of adjunctive ziprasidone in subjects with bipolar depression treated with lithium, lamotrigine, or valproate., Method: 298 adult outpatients with bipolar I disorder (DSM-IV criteria) were randomized to receive ziprasidone, 20-80 mg twice a day, or placebo twice a day for 6 weeks plus their preexisting mood stabilizer. The primary efficacy variable was change in Montgomery-Asberg Depression Rating Scale (MADRS) total scores from baseline to 6 weeks. The key secondary efficacy endpoint was change from baseline to week 6 in Clinical Global Impressions-Severity (CGI-S) scores. Computer-administered assessments for diagnostic confidence were included for quality control and to evaluate study performance. The study was conducted between October 2007 and December 2008., Results: The mean ± SD daily dose of ziprasidone was 89.8 ± 29.1 mg. Least squares mean ± standard error changes from baseline to week 6 on MADRS total score for ziprasidone and placebo treatment groups were -13.2 ± 1.2 and -12.9 ± 1.1, respectively, with a 2-sided P value of .792. There was no significant difference on the key secondary variable (CGI-S). Adjunctive ziprasidone was well tolerated. Poor quality ratings at baseline were associated with a trend for better improvement on placebo than ziprasidone. Among 43 placebo-treated subjects with poor baseline quality ratings, 29 (67.4%) had baseline MADRS scores > 10 points higher on the computer-administered assessment than the MADRS administered by the site-based rater. The response favoring placebo over ziprasidone observed in this subgroup suggests that poor signal detection in some clinical trials can be a consequence of "subject inflation" as well as "rater inflation.", Conclusions: Adjunctive ziprasidone treatment failed to separate from mood stabilizer alone on primary and secondary endpoints. Possible contributions to this result include enrollment of a substantial number of subjects with low diagnostic confidence, low quality ratings on the MADRS, and overzealous reporting of symptoms by subjects., Trial Registration: clinical trials.gov Identifier: NCT00483548., (© Copyright 2011 Physicians Postgraduate Press, Inc.)

Over the past half century, substantial clinical trial data have accumulated to guide clinical management of bipolar disorder, and 13 medications have gained US Food and Drug Administration approval for the treatment of mania or bipolar depression or the maintenance treatment of bipolar disorder. While the number of studies has grown and many controversies related to pharmacologic treatment of bipolar disorder are not yet resolved, the task of transforming the accumulated evidence into useful guidance for clinical practice becomes more manageable and less error prone by limiting consideration to the highest quality studies. Therefore, this article emphasizes points of relative clarity by highlighting findings supported by double-blind, placebo-controlled clinical trials with samples of at least 100 subjects. A MEDLINE search was conducted and augmented by a manual search of bibliographies, textbooks, and abstracts from recent scientific meetings for randomized controlled trials published in English between 1950 and April 2010 with at least 100 subjects. Keywords used in the search included randomized controlled trial, mania, hypomania, depression, relapse prevention, placebo, antidepressant, switch, and maintenance treatment of bipolar disorder. A paradigm for implementing evidence-based treatment is offered along with consideration of patterns emerging across clinical trials., (© Copyright 2011 Physicians Postgraduate Press, Inc.)

Objective: The impact of hormonal fluctuation during the menstrual cycle on the course of bipolar disorder is poorly understood. The authors determined the course of illness and time to relapse of bipolar disorder in prospectively followed women with premenstrual exacerbation., Method: Participants were 293 premenopause-age women with bipolar disorder who were followed prospectively for 1 year as part of the Systematic Treatment Enhancement Program for Bipolar Disorder. Frequency of mood episodes was compared between 191 women with premenstrual exacerbation (65.2%) and 102 women without. Among 129 women who were in recovered status at baseline, time to relapse was compared between 66 women with premenstrual exacerbation (51.2%) and 63 without., Results: During follow-up, the group with premenstrual exacerbation had more episodes (primarily depressive) than did the group without, but they were not more likely to meet criteria for rapid cycling during this period. In contrast, they were more likely to report rapid cycling retrospectively. Women with premenstrual exacerbation had a shorter time to relapse and were at greater risk for relapse, but this association was not significant after adjustment for retrospectively reported rapid cycling. Women with premenstrual exacerbation had more depressive and mood elevation symptoms overall., Conclusions: Women with bipolar disorder and premenstrual exacerbation have a worse course of illness, a shorter time to relapse, and greater symptom severity, but they are not more likely to meet criteria for rapid cycling. Premenstrual exacerbation may be a clinical marker predicting a more symptomatic and relapse-prone phenotype in reproductive-age women with bipolar disorder.