Safety and Efficacy of Adjunctive Second-Generation Antidepressant Therapy With A Mood Stabiliser or an Atypical Antipsychotic in Acute Bipolar Depression: Randomised Systematic Review and Meta-Analysis of A Placebo-Controlled Trials.

(Reprinted with permission from Lancet Psychiatry 2016; 3: 1138-46).

Bipolar I and II Disorders; A Systematic Review and Meta-Analysis on Differences in Comorbid Obsessive-Compulsive Disorder.

CONTEXT: More than half of the bipolar disorder (BD) cases have an additional diagnosis; one of the most difficult to manage is obsessive-compulsive disorder (OCD). Although some authors recently investigated the co-occurrence of anxiety and BD, the topic remains insufficiently studied. The current study aimed to investigate differences in comorbid OCD between BD-I and BD-II. EVIDENCE ACQUISITION: A systematic review and meta-analysis was conducted on the prevalence and predictors of comorbid BD-I/BD-II and OCD. Relevant papers published until June 30, 2015 were identified searching the electronic databases MEDLINE, Embase, PsycINFO and the Cochrane Library. RESULTS: Fourteen articles met the inclusion criteria. The pooled prevalence of BD-I in OCD was 3.9% (95% confidence interval (CI), 2.4 to 6.4, I2 = 83%, Q = 56) while that of BD-II in OCD was 13.5% (95% CI, 9.3 to 19.3, I2 = 89%, Q = 91). The pooled prevalence of OCD in BD-I was 21.7 (95% CI, 4.8 to 60.3, I2 = 84%, Q = 95). With regard to OCD-BD predictors, mean age and rate of males did not predict the prevalence of BD-I (ß = 0.0731, 95% CI, -0.1097 to 0.256, z = 0.78; ß = 0.035, 95% CI, -0.2356 to 0.1656, z = 0.34) and BD-II (ß = 0.0577, 95% CI, -0.1942 to 0.0788, z = 0.83; ß = -0.0317, 95% CI, -0.1483 to 0.085, z = 0.53) in OCD. The mean age explained some of the observed heterogeneity (R2 = 0.13; R2 = 0.08). CONCLUSIONS: This first systematic review and meta-analysis of the prevalence and predictors of comorbid BD-I/BD-II and OCD suggests that BD-OCD comorbidity is a common condition in psychiatry. However, the available evidence does not allow to assess whether BD-I or BD-II are more common in patients with OCD.

Bipolar disorder in the digital age: new tools for the same illness.

"Nothing is more difficult than to ascertain the length of time that a maniacal patient can exist without sleep."-Dr. Sutherland (Br J Psychiatry 7(37):1-19, 1861). Dr. Sutherland's patient was suffering from an acute manic episode, which today is called bipolar illness. 150 years later, we continue to struggle with the same challenges in ascertaining accurate symptoms from patients. In era of new digital tools, the quantified self-movement, and precision medicine, we can ask the question: Can we advance understanding and treatment for bipolar illness beyond asking the same questions as in 1861?

Publication bias and the pharmaceutical industry: the case of lamotrigine in bipolar disorder.

Publication bias, especially the lack of publication of negative treatment studies, is known to be a major problem in the medical literature. In particular, it appears that the pharmaceutical industry is not routinely making data from negative studies available through the published scientific literature. In this paper, we review the case of studies with lamotrigine in bipolar disorder, describing evidence of lack of efficacy in multiple mood states outside of the primary area of efficacy (prophylaxis of mood episodes). In particular, the drug has very limited, if any, efficacy in acute bipolar depression and rapid-cycling bipolar disorder, areas in which practicing clinicians, as well as some academic leaders, have supported its use. The negative unpublished data now made available on lamotrigine provide an important context for clinical practice and research, and also raise important scientific and public policy concerns about having access to studies showing inefficacy with psychotropic medications.

Effectiveness of quetiapine in rapid cycling bipolar disorder: a preliminary study.

OBJECTIVE: The authors examined long-term effectiveness and study retention during open-label quetiapine treatment for rapid cycling bipolar disorder. METHODS: An open-label, nonrandomized trial was conducted in 41 patients with rapid-cycling bipolar disorder (type I=33, type II=7, NOS=1) who received flexibly dosed quetiapine monotherapy (n=19) or add-on therapy (n=22) for up to one year. Linear growth curves were calculated to assess longitudinal changes in depression and mania. RESULTS: Linear growth curves demonstrated highly significant reductions in manic (p<.0001) and depressive (p<.0001) symptoms. Effect sizes were large against manic symptoms (add-on therapy: Cohen's d=0.66; monotherapy: Cohen's d=0.75) but small-to-moderate against depression (monotherapy: d=0.29; add-on therapy: d=0.40). Most patients (68%) prematurely terminated the protocol (mean duration: 18.0+/-16.9 weeks, mean dose: 195.6+/-196.1 mg/day), most often because of the need for additional psychotropic treatments. LIMITATIONS: The study protocol involved an open label design with no placebo or active comparator group. The sample size provided adequate statistical power to detect large but not medium or small within-group effects. Premature dropout during the first six months precluded inferences about longer-term treatment outcome. CONCLUSIONS: These observational findings provisionally suggest some benefit with quetiapine for both manic and depressive symptoms in rapid cycling bipolar disorder, at dosages somewhat lower than previously described either for mania or bipolar depression. The relatively high dropout rate underscores the complexity of rapid cycling bipolar disorder and likely necessity for pharmacotherapy adjustments over time.

Adjunctive risperidone, olanzapine and quetiapine for the treatment of hospitalized patients with bipolar I disorder: a retrospective study.

This study evaluated the overall effectiveness and tolerability of atypical antipsychotics (risperidone vs. olanzapine vs. quetiapine) used in the treatment of bipolar inpatients. After screening 463 patients, the medical records of 158 inpatients with bipolar I disorder, who were given olanzapine, risperidone or quetiapine as adjuncts to mood stabilizers for at least 1 month and not administered with any other antipsychotics, were examined. Details of the tolerability and effectiveness were reviewed according to the treatment records during their hospital stay. The results showed equivalent effectiveness based on the Clinical Global Impression (CGI) and Global Assessment Functioning (GAF) score between the three atypical antipsychotics. The frequency of the extrapyramidal symptom-related side effects were higher in the risperidone-treated group than in the olanzapine and quetiapine-treated group. This suggests that risperidone, olanzapine and quetiapine have a comparable effectiveness in inpatients with bipolar I disorder in a naturalistic setting. However, there were some differences in tolerability between these results as reported from previous Western studies.

Benefits and limitations of antidepressants and traditional mood stabilizers for treatment of bipolar depression.

OBJECTIVE: The aim of this paper was to review the rationales, risks, and benefits for using standard antidepressants versus mood stabilizing agents and/or atypical antipsychotics to treat bipolar depression. METHOD: A selective literature review was conducted using key terms and by reference known to the authors. Bibliographies of articles and book chapters were further scrutinized for relevant literature. RESULTS: The strengths and limitations of current studies are described and critically reviewed in order to present optimal strategies for effective pharmacotherapy. Clinical factors that can mitigate or confound simple bivariate relationships between antidepressant use and outcome have seldom been examined using multivariate statistical techniques. For many of the key questions there is a paucity of informative literature and randomized clinical trials are of limited value in addressing some of the issues. CONCLUSIONS: Clinicians and investigators should be aware of the methodological shortcomings of existing studies. Decisions about the relative merits versus contraindications for antidepressant use should be made via more individualized, case-by-case profiling rather than by rigid prescribing practices.

Rapid titration versus conventional titration of quetiapine in the treatment of bipolar mania: a preliminary trial.

The present trial was designed as a pilot study to re-examine how fast the dose of quetiapine in combination with mood stabilizers can be titrated upward in acutely ill patients with bipolar mania. Patients were assigned to either a rapid titration group (RTG) or a conventional titration group (CTG). Quetiapine was administered twice daily in a 3-day period in the RTG (200 mg/day on day 1; 400 mg/day on day 2; and 600 mg/day on day 3) and in a 5-day period in the CTG (50 mg/day on day 1; 100 mg/day on day 2; 200 mg/day on day 3; 300 mg/day on day 4; and 400 mg/day on day 5). The Young Mania Rating Scale (YMRS) and Clinical Global Impression-Severity (CGI-S) scores were assessed at days 1 (baseline), 3, 5, 7, 14 and 21. The Barnes Akathisia Rating Scale and Simpson-Angus Rating Scale (SARS) were assessed at days 1, 2, 3, 4, 5, 6, 7, 14 and 21. RTG and CTG showed significant improvement on the scores of YMRS and CGI-S during the study without group differences. Both treatments were well tolerated without clinically significant differences in tolerability measures. Treatment was not limited by adverse events in the two groups. This study demonstrates the potential benefit and tolerability of rapid titration of quetiapine in the treatment of acutely ill bipolar disorder. This preliminary study proposes that rapid titration of quetipaine in combination with a mood stabilizer for the treatment of bipolar mania is effective and tolerable in comparison with conventional titration. A controlled study with a larger cohort should be performed.

Patient-based utilities for bipolar disorder-related health states.

BACKGROUND: Bipolar disorder is a psychiatric disorder which impacts patient functioning and well-being. With increasing interest in cost-effectiveness of treatments, it is necessary to provide estimates of patient's perspectives on treatment outcomes. This study estimated health state utilities for hypothetical bipolar-related health states and patient's current health from bipolar I patients. METHODS: Clinicians completed Young Mania Rating Scale, Montgomery-Asberg Depression Rating Scale, and Global Assessment Score. Patients completed structured standard gamble (SG) utility assessment interviews, and the other patient-based measures. Interviews obtained utilities for hypothetical bipolar-related health states describing symptom severity, functioning and well-being, and treatment-related side effects. RESULTS: Ninety-six patients were recruited from psychiatry outpatient practices. Mean utilities for inpatient states ranged from 0.12 to 0.33; outpatient mania states ranged from 0.29 to 0.64; outpatient stable states ranged from 0.53 to 0.85. Mean utility for current health was 0.80 (S.D.=0.22). Patients preferred monotherapy compared with combination therapy health states. Ordinary least squares regression indicated weight gain was associated with a 0.066 decrease in health state utilities (P=0.013). LIMITATIONS: Study sample consisted of selected stable and educated patients and small sample sizes may limit generalizability for some utilities. CONCLUSIONS: Bipolar disorder patients are capable of participating in utility assessment and providing ratings for hypothetical health states associated with different mood stabilizer treatments.

Sensitivity and specificity of a new bipolar spectrum diagnostic scale.

OBJECTIVE: To assess the sensitivity and specificity of a self-report questionnaire for bipolar disorder, the Bipolar Spectrum Diagnostic Scale (BSDS). METHODS: The BSDS was administered to 68 consecutive patients with bipolar illness and 27 consecutive patients with unipolar major depressive disorder. Created by Ronald Pies, it consists of a descriptive story that captures subtle features of bipolar illness, to which patients may assent on a sentence-by-sentence basis. BSDS scores were compared to clinicians' DSM-IV-based diagnoses. RESULTS: Sensitivity of the BSDS was 0.76, approximately equal in bipolar I and II/NOS subjects (0.75 and 0.79, respectively). The BSDS identified 85% of unipolar-depressed patients as not having bipolar spectrum illness. A shift in the threshold of the BSDS resulted in a large increase in specificity (from 0.85 to 0.93), without a significant loss of sensitivity. CONCLUSIONS: The BSDS was highly sensitive and specific for bipolar spectrum illness, especially with the amended threshold for positive diagnosis.