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Objectives: A substantial portion of the morbidity associated with rapid-cycling bipolar disorder (RCBD) stems from refractory depression. This study assessed the antidepressant effects of lamotrigine as compared with placebo when used as add-on therapy for rapid-cycling bipolar depression non-responsive to the combination of lithium plus divalproex., Methods: During Phase 1 of this trial, hypomanic, manic, mixed, and/or depressed outpatients (n = 133) aged 18-65 years with DSM-IV RCBD type I or II were initially treated with the open combination of lithium and divalproex for up to 16 weeks. During Phase 2, subjects who did not meet the criteria for stabilization (n = 49) (i.e., remained in or cycled into the depressed phase) were randomly assigned to double-blind, adjunctive lamotrigine (n = 23) or adjunctive placebo (n = 26). The primary endpoint was the mean change in depression symptom severity from the beginning of Phase 2 to the end of Phase 2 (week 12) on the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Data were analyzed by analysis of covariance with last observation carried forward and a mixed-models analysis., Results:   During Phase 1, a high rate of study discontinuations occurred due to intolerable side effects (13/133; 10%) and study non-adherence (22/133; 17%). Only 14% (19/133) stabilized on the open combination of lithium and divalproex. Among the 49 (37%) patients randomized to the double-blind adjunctive treatment phase, mean ± standard error change from baseline on the MADRS total score was -8.5 ± 1.7 points for lamotrigine and -9.1 ± 1.5 points for placebo (p = not significant; mixed-models analysis). No significant differences were observed in the rates of response, remission, or bimodal response between lamotrigine and placebo., Conclusions: The poor tolerability, lack of efficacy, and high rate of early discontinuation with the combination of lithium and divalproex suggests this regimen was ineffective for the majority of patients with RCBD. Among patients who did not stabilize on lithium and divalproex, the addition of lamotrigine was no more effective than placebo in reducing depression severity. The findings suggest an opportunity for several design modifications to enhance signal detection in future trials of RCBD. The main limitation is the small number of subjects randomized to double-blind treatment., (© 2012 John Wiley and Sons A/S.)

Objective: The present study examined the relationship between medical burden in bipolar disorder and several indicators of illness severity and outcome. It was hypothesized that illnesses of the endocrine/metabolic system would be associated with greater psychiatric symptom burden and would impact the response to treatment with lithium and valproate., Methods: Data were analyzed from two studies evaluating lithium and valproate for rapid-cycling presentations of bipolar I and II disorder. General medical comorbidity was assessed by the Cumulative Illness Rating Scale (CIRS). Descriptive statistics and logistic regression analyses were conducted to explore the relationships between medical burden, body mass index (BMI), substance use disorder status, and depressive symptom severity., Results: Of 225 patients enrolled, 41.8% had a recent substance use disorder, 50.7% were male, and 69.8% had bipolar I disorder. The mean age of the sample was 36.8 (SD = 10.8) years old. The mean number of comorbid medical disorders per patient was 2.5 (SD = 2.5), and the mean CIRS total score was 4.3 (SD = 3.1). A significant positive correlation was observed between baseline depression severity and the number of organ systems affected by medical illness (p = 0.04). Illnesses of the endocrine/metabolic system were inversely correlated with remission from depressive symptoms (p = 0.02), and obesity was specifically associated with poorer treatment outcome. For every 1-unit increase in BMI, the likelihood of response decreased by 7.5% [odds ratio (OR) = 0.93, 95% confidence interval (CI): 0.87- 0.99; p = 0.02] and the likelihood of remission decreased by 7.3% (OR = 0.93, 95% CI: 0.87-0.99; p = 0.03). The effect of comorbid substance use on the likelihood of response differed significantly according to baseline BMI. The presence of a comorbid substance use disorder resulted in lower odds of response, but only among patients with a BMI > or = 23 (p = 0.02)., Conclusion: Among patients with rapid-cycling bipolar disorder receiving lithium and valproate, endocrine/metabolic illnesses, including overweight and obesity, appear to be associated with greater depressive symptom severity and poorer treatment outcomes.

Objective: To study treatment-emergent mania/hypomania (TEM) associated with second-generation antidepressant monotherapy in patients with rapid cycling bipolar disorder (RCBD)., Methods: Data of patients with RCBD (n = 180) enrolled into two clinical trials were used to study the risk for TEM during second-generation antidepressant monotherapy. History of TEM was retrospectively determined at the initial assessment by asking patients whether they were exposed to second-generation antidepressants and if a hypomania/mania episode emerged during the first four weeks of treatment. Data were analyzed using t-test, chi-square, and logistic regression., Results: Of the 180 patients (bipolar I disorder, n = 128; bipolar II disorder, n = 52) with RCBD, 85% (n = 153) had at least one antidepressant treatment. Among these patients, 94.1% (144/153) had at least one antidepressant monotherapy treatment. Overall, 49.3% of patients had at least one TEM and 29.1% (116/399) of treatment trials were associated with TEM. In regression analysis, an inverse association between the number of mood episodes in the last 12 months and TEM was observed with an odds ratio of 0.9. However, gender, bipolar subtype, a lifetime history of comorbid anxiety disorder, substance use disorder, or psychosis, and age of mood disorder onset were not associated with TEM. For individual antidepressants, the rates of TEM varied from 42.1% for fluoxetine to 0% for fluvoxamine and mirtazapine. As a group, there was no difference between selective serotonin reuptake inhibitors and venlafaxine or bupropion in the incidence of TEM., Conclusions: Use of second-generation antidepressants as monotherapy in RCBD is accompanied by clinically relevant rates of TEM. Even in patients with RCBD, differential vulnerabilities to antidepressant TEM may exist.