Maintenance therapies in bipolar disorder: focus on randomized controlled trials.
OBJECTIVE
Lithium remains the cornerstone of maintenance therapy for bipolar disorder despite growing use of other agents, including divalproex, lamotrigine, carbamazepine and the atypical antipsychotics. Lithium has the largest body of data to support its continued use as a prophylactic agent; however, most of this data comes from early studies that did not use contemporary analytic methods. Alternatives to lithium are needed because of the relatively high rate of non-response to lithium monotherapy and the drug's frequent side-effects. This article reviews available data with an emphasis on double-blind, placebo-controlled studies that examine the efficacy of lithium and other putative mood stabilizers: carbamazepine, divalproex, lamotrigine and olanzapine.


METHODS
The authors reviewed key literature using Medline searches using key words: bipolar disorder, controlled trials, mood stabilizer, lithium, lomotrigine, divalproex, olanzapine, carbamazepine.


RESULTS
Lithium remains the gold standard for overall preventative efficacy in bipolar disorder, especially to decrease manic or hypomanic relapse. Of the mood stabilizers that have marked prophylactic antimanic properties, lithium appears to possess the greatest antidepressant effect. Divalproex may also prevent recurrent bipolar mood episodes but the relative lack of controlled maintenance studies makes this less certain. There now exists an extensive and well-designed research database supporting the use of lamotrigine in the acute and prophylactic management of bipolar I disorder. Lamotrigine offers a spectrum of clinical effectiveness that complements lithium, in that it appears to stabilize mood 'from below baseline' by preventing episodes of depression and has been shown to be effective in rapid-cycling bipolar II disorder. Carbamazepine may be a useful alternative to lithium, divalproex and lamotrigine, particularly for patients with a history of mood-incongruent delusions and other comorbidities, but controlled data is more equivocal and it may lose some of its prophylactic effect over time. Emerging data continue to support the growing use of atypical antipsychotics, particularly olanzapine.


CONCLUSIONS
Any monotherapy for use as a maintenance therapy of bipolar disorder appears to be inadequate for long-term use in the management of the majority of patients with bipolar disorder. Combination therapy has become the standard of care in the treatment of bipolar disorder and particularly in patients with treatment-refractory variants such as those with rapid-cycling. The emerging consensus is that patients on monotherapy, if followed for sufficiently long periods, will eventually require concomitant treatment to maintain a full remission. There exists a need for controlled trials that use random assignment to parallel arms including combination therapy followed by data analyses that include both relapse rate and survival techniques.
Muzina
David J
DJ
Bipolar Disorders Research Unit, Department of Psychiatry and Psychology, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA. muzinad@ccf.org
Calabrese
Joseph R
JR
D001714:Bipolar Disorder / Q000188:drug therapy*; D006801:Humans; D016032:Randomized Controlled Trials as Topic