How best to treat bipolar depression? CNS spectrum. March.2013

Bipolar patients spend considerably longer periods of time in depressive phase.The treatment of bipolar depression is one of the most difficult psychopharmacological challenges psychiatrists face.though the problem is severe and challenging, total number of well controlled studies  is relatively small.In USA only two medications are approved for bipolar depression : Fluoxetine  Olanzapine combination and Quetiapine.

Michael A. Cerullo, and Stephen M. Strakowski from the Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati report the results of the systematic review of the available evidence in bipolar depression ( BP 1 disorder only)

Quetiapine:  The five studies included ( total of 2539 participants) on quetiapine or placebo. All five studies found that quetiapine significantly reduced the symptoms.Dose of 300mg is effective and tolerated.There is no advantage with 600mg. Most common side effects reported included sedation, somnolence, dry mouth, and dizziness .Mean weight gain with 300mg Quetiapine was 1kg.

Olanzapine and olanzapine/fluoxetine : Two studies, both supported effectiveness of olanzapine alone or in combination with fluoxetine. Increased appetite, headache, dry mouth, sedation, and diarrhoea were common side effects . Weight gain was a problem. No increase in manic symptoms with SSRI combination.

Aripiprazole :  Two studies.  Neither found any significant effect of aripiprazole on the primary outcome measure (decrease of MADRS scores) at 8 weeks.  higher levels of akathisia, extrapyramidal symptoms, insomnia, nausea, and dry mouth in aripiprazole group compared to the placebo groups.

Ziprasidone :Two studies.No benefits.

Lamotrigine : Five studies with 1072 patients,  in all five studies, the primary outcome measure,  did not differ significantly from placebo,but pooled data showed increased response rate.The benefit was much  more in severe depression group.Headache, nausea, non serious rash, dry mouth, dizziness, and diarrhea were the most common side effects reported.

Divalproex: Three smaller studies with 97 participants. All showed benefit. Meta analysis also support increased response.The most commonly seen side effects were sedation, changes in appetite, myalgias/ weakness, dizziness, fatigue, and dry mouth

Lithium :  None met primary or secondary inclusion criteria.

Levetiracetam: One small study , no benefit.

Antidepressants:  Only one study  of antidepressant monotherapy that showed that Paroxetine did not differ compared to placebo in reducing the symptoms of depression.Four studies  identified using antidepressants as adjuncts to mood stabilizers or antipsychotics. Meta-analyses of these studies found that antidepressants were moderately effective in bipolar depression. However, a latter meta-analysis by Sidor and MacQueen (2011) found no significant treatment effect of antidepressants.These authors found  no evidence that antidepressants induced mania where as others have found high rates of switching.

Modafinil/armodafinil:  Two studies showing significant reduction in depressive symptoms. In these studies, modafinil was added to a mood stabilizer, while over half of the participants were also on an antidepressant. Headache, nausea, and insomnia were the most common side effects

Omega-3 fatty acids:  Two small studies.Findings in these studies were mixed.

Conclusions: Quetiapine has been studied in the greatest number of participants in five studies, which all showed significantly greater efficacy compared to placebo in reducing symptoms of depression .Lamotrigine also had five studies in bipolar depression, but all five were negative. However, the pooled data  showed significant efficacy among those with more severe depression. Two studies of Olanzapine and Olanzapine/Fluoxetine and three small studies of divalproex showed significant efficacy in treating bipolar depression. There is no head to head comparison data between quetiapine, lamotrigine, olanzapine, olanzapine/fluoxetine, and divalproex to make choices more clearer.

All the above data is on acute treatment. Step BD study  (Ghaemi et al 2010) showed that patients on both mood stabilisers and antidepressants can be weaned of their antidepressants with no difference in remission at 3 years. There is little evidence for benefit of antidepressants in bipolar depression. Novel approaches are needed to help our patients with bipolar depression.

Summary of the article:

systematic review of the evidence for the treatment of acute depression in bipolar I disorder.

Cerullo MA, Strakowski SM.CNS Spectr. 2013 Mar 18:1-10

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