Lamotrigine as add-on treatment to lithium and divalproex: lessons learned from a double-blind, placebo-controlled trial in rapid-cycling bipolar disorder.

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.

Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder.

Bipolar disorder (BD) is a serious mood disorder associated with circadian rhythm abnormalities. Risk for BD is genetically encoded and overlaps with systems that maintain circadian rhythms. Lithium is an effective mood stabilizer treatment for BD, but only a minority of patients fully respond to monotherapy. Presently, we hypothesized that lithium-responsive BD patients (Li-R) would show characteristic differences in chronotype and cellular circadian rhythms compared to lithium non-responders (Li-NR). Selecting patients from a prospective, multi-center, clinical trial of lithium monotherapy, we examined morning vs. evening preference (chronotype) as a dimension of circadian rhythm function in 193 Li-R and Li-NR BD patients. From a subset of 59 patient donors, we measured circadian rhythms in skin fibroblasts longitudinally over 5 days using a bioluminescent reporter (Per2-luc). We then estimated circadian rhythm parameters (amplitude, period, phase) and the pharmacological effects of lithium on rhythms in cells from Li-R and Li-NR donors. Compared to Li-NRs, Li-Rs showed a difference in chronotype, with higher levels of morningness. Evening chronotype was associated with increased mood symptoms at baseline, including depression, mania, and insomnia. Cells from Li-Rs were more likely to exhibit a short circadian period, a linear relationship between period and phase, and period shortening effects of lithium. Common genetic variation in the IP3 signaling pathway may account for some of the individual differences in the effects of lithium on cellular rhythms. We conclude that circadian rhythms may influence response to lithium in maintenance treatment of BD.

Use of insulin sensitizers for the treatment of major depressive disorder: a pilot study of pioglitazone for major depression accompanied by abdominal obesity.

OBJECTIVE: This study was conducted to examine the safety and efficacy of pioglitazone, a thiazolidinedione insulin sensitizer, in adult outpatients with major depressive disorder. METHOD: In a 12-week, open-label, flexible-dose study, 23 patients with major depressive disorder received pioglitazone monotherapy or adjunctive therapy initiated at 15 mg daily. Subjects were required to meet criteria for abdominal obesity (waist circumference>35 in. in women and >40 in. in men) or metabolic syndrome. The primary efficacy measure was the change from baseline to Week 12 on the Inventory of Depressive Symptomatology (IDS) total score. Partial responders (≥25% decrease in IDS total score) were eligible to participate in an optional extension phase for an additional three months. RESULTS: Pioglitazone decreased depression symptom severity from a total IDS score of 40.3±1.8 to 19.2±1.8 at Week 12 (p<.001). Among partial responders (≥25% decrease in IDS total score), an improvement in depressive symptoms was maintained during an additional 3-month extension phase (total duration=24 weeks) according to IDS total scores (p<.001). Patients experienced a reduction in insulin resistance from baseline to Week 12 according to the log homeostasis model assessment (-0.8±0.75; p<.001) and a significant reduction in inflammation as measured by log highly- sensitive C-reactive protein (-0.87±0.72; p<.001). During the current episode, the majority of participants (74%, n=17), had already failed at least one antidepressant trial. The most common side effects were headache and dizziness; no patient discontinued due to side effects. LIMITATIONS: These data are limited by a small sample size and an open-label study design with no placebo control. CONCLUSION: Although preliminary, pioglitazone appears to reduce depression severity and improve several markers of cardiometabolic risk, including insulin resistance and inflammation. Larger, placebo-controlled studies are indicated.