Aripiprazole in combination with lamotrigine for the long-term treatment of patients with bipolar I disorder (manic or mixed): A randomized, multicenter, double-blind study (CN138-392)
Bristol-Myers Squibb, Plainsboro, NJ 0856-1616, USA. Bipolar Disorders
(Impact Factor: 4.97).
02/2012; 14(1):41-53. DOI: 10.1111/j.1399-5618.2011.00974.x
To evaluate the efficacy and safety of aripiprazole (ARI) plus lamotrigine (LTG) compared with placebo (PBO) plus LTG, for long-term treatment in bipolar I disorder patients with a recent manic/mixed episode.
After a 9-24 week stabilization phase receiving single-blind ARI (10-30 mg/day) plus open-label LTG (100 or 200 mg/day), patients maintaining stability (Young Mania Rating Scale/Montgomery-Åsberg Depression Rating Scale total scores ≤ 12) with ARI+LTG for eight consecutive weeks were randomized to continue on double-blind ARI + LTG or to receive PBO + LTG, after removing ARI from ARI + LTG treatment, and followed up for 52 weeks. The primary outcome measure was time from randomization to relapse into a manic/mixed episode.
A total of 787 patients entered the stabilization phase, and 351 were randomized to ARI + LTG (n = 178) or PBO + LTG (n = 173). ARI + LTG yielded a numerically longer time to manic/mixed relapse than PBO + LTG, but it was not statistically significant [hazard ratio (HR) = 0.55; 95% confidence interval (CI): 0.30-1.03; p = 0.058]. The estimated relapse rates at Week 52 were 11% for ARI + LTG and 23% for PBO + LTG, yielding a number needed-to-treat of nine (95% CI: 5-121). The three most common adverse events were akathisia [10.8%, 6.1% for ARI + LTG and PBO + LTG, respectively; number needed-to-harm (NNH) = 22], insomnia (7.4%, 11.5%), and anxiety (7.4%, 3.6%). Mean weight change was 0.43 kg and -1.81 kg, respectively (last observation carried forward, p = 0.001). Rates of ≥ 7% weight gain with ARI + LTG and PBO + LTG were 11.9% and 3.5%, respectively (NNH = 12).
ARI + LTG delayed the time to manic/mixed relapse but did not reach statistical significance. Safety and tolerability results revealed no unexpected adverse events for ARI combination with LTG.
Available from: Marc De Hert
- "In the lamotrigine study, 1169 patients were enrolled and 351 (178 aripiprazole þlamotrigine; 173 placebo þlamotrigine) were randomized (Table 1). The demographics of the randomized populations were similar between the two groups (Table 2) (Marcus et al., 2011; Carlson et al., 2012). At baseline 34% (n ¼113) of randomized patients in the lithium/valproate study were overweight (BMI 25–29.9) "
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ABSTRACT: BACKGROUND: Bipolar I disorder (BPD) patients are often overweight or obese, and likely to have metabolic syndrome. Several medications used to treat BPD are associated with increased body weight and/or worsening metabolic parameters. METHODS: Metabolic data were analyzed from two efficacy studies of aripiprazole plus the mood stabilizers, lithium/valproate (Study CN138-189), or lamotrigine (Study CN138-392), in the long-term treatment (52 weeks) of BPD. Changes in body weight, individual metabolic parameters, and incidence of metabolic syndrome were assessed. RESULTS: In the lithium/valproate study, modest increases in body weight were observed at Week 52 in both groups: 1.7±0.8kg in the lithium/valproate group, and 1.6±0.7kg in the adjunctive aripiprazole group; this difference was nonsignificant. In the lamotrigine study, decreases in body weight were observed at Week 52 with lamotrigine alone (-2.2±1.0kg), whereas a modest increase was observed when combined with aripiprazole (0.4±1.0kg). In both studies, rates of metabolic syndrome at 52 weeks did not increase from baseline with aripiprazole, and median changes from baseline in individual metabolic syndrome parameters were similar with both mood stabilizer monotherapy and the addition of aripiprazole as an adjunctive therapy. LIMITATIONS: This was a post-hoc analysis, and a low percentage of patients completed the lamotrigine study. CONCLUSIONS: Aripiprazole plus a mood stabilizer has minimal impact on metabolic changes in predominantly overweight/obese BPD patients over a 52-week period. In both studies, modest mean increases in weight with the addition of aripiprazole were not accompanied by increased rates of metabolic syndrome or changes in metabolic parameters.
Available from: Siegfried Kasper
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ABSTRACT: The current statement is a systematic review of the available data concerning the efficacy of medication treatment of bipolar disorder (BP). A systematic MEDLINE search was made concerning the treatment of BP (RCTs) with the names of treatment options as keywords. The search was updated on 10 March 2012. The literature suggests that lithium, first and second generation antipsychotics and valproate and carbamazepine are efficacious in the treatment of acute mania. Quetiapine and the olanzapine-fluoxetine combination are also efficacious for treating bipolar depression. Antidepressants should only be used in combination with an antimanic agent, because they can induce switching to mania/hypomania/mixed states/rapid cycling when utilized as monotherapy. Lithium, olanzapine, quetiapine and aripiprazole are efficacious during the maintenance phase. Lamotrigine is efficacious in the prevention of depression, and it remains to be clarified whether it is also efficacious for mania. There is some evidence on the efficacy of psychosocial interventions as an adjunctive treatment to medication. Electroconvulsive therapy is an option for refractory patients. In acute manic patients who are partial responders to lithium/valproate/carbamazepine, adding an antipsychotic is a reasonable choice. The combination with best data in acute bipolar depression is lithium plus lamotrigine. Patients stabilized on combination treatment might do worse if shifted to monotherapy during maintenance, and patients could benefit with add-on treatment with olanzapine, valproate, an antidepressant, or lamotrigine, depending on the index acute phase. A variety of treatment options for BP are available today, but still unmet needs are huge. Combination therapy may improve the treatment outcome but it also carries more side-effect burden. Further research is necessary as well as the development of better guidelines and algorithms for the step-by-step rational treatment.
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ABSTRACT: BACKGROUND: Abnormalities in circadian rhythms are prominent features of bipolar disorder. Disrupted circadian rhythms are associated with an increased risk of relapse in bipolar disorder. Normalizing the circadian rhythm pattern of bipolar patients may improve their sleep and lead to fewer mood exacerbations. This study evaluated adjunctive ramelteon for the treatment of insomnia and mood stability in euthymic bipolar patients. METHODS: Participants with euthymic bipolar disorder and sleep disturbances were randomized to receive adjunctive ramelteon or placebo in addition to their regular psychiatric medications for up to 24 weeks or until they experienced a relapse (defined as a depressed or manic event). RESULTS: 83 participants were randomized to receive ramelteon (n=42) or placebo (n=41). Forty participants relapsed (48.2%). Cox regression analyses indicated that participants who received ramelteon (odds ratio 0.48, p=.024) were less likely to relapse. Kaplan Meier curves also indicated longer median survival times in the ramelteon group (Mdn=188 days) versus the placebo group (Mdn=84 days) X2(1)=5.33, p=.02. There were no serious adverse events in this study. LIMITATIONS: This was a small study with only 83 participants. The one-week window of confirmed stability is shorter than time intervals used in other studies. CONCLUSIONS: The present study shows that ramelteon was effective in maintaining stability for individuals with bipolar disorder. Patients treated with ramelteon were approximately half as likely to relapse as patients treated with placebo throughout the 24-week treatment period.
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