8 Controversies in Bipolar Disorder Addressed

Nassir Ghaemi, MD, MPH; Stephen M. Strakowski, MD


June 30, 2016

Editor's Note:
Medscape recently asked Stephen M. Strakowski, MD, inaugural chair of psychiatry at Dell Medical School, University of Texas, Austin, and Nassir Ghaemi, MD, MPH, a professor in the Department of Psychiatry at Tufts Medical Center in Boston, Massachusetts, to identify and address clinical controversies in the diagnosis and care of bipolar disorder (BD). What follows are their comments.

Controversy 1: Use of Antidepressants in BD

Should antidepressants be used in BD? If so, at what doses and in which patients?

Nassir Ghaemi, MD, MPH: My view is that antidepressants shouldn't be used in the vast majority of patients with BD, for the simple reason that they've been proven ineffective.

Experts like to argue the ins and outs of the various randomized clinical trials, and they will point out all the possible ways in which they can be interpreted to eke out a tiny bit of support for using antidepressants. But in fact, the majority of trials consistently show no benefit, or very little benefit, of antidepressants in treating the acute depressive episodes in BD. The same has been shown in prevention.

Again, I emphasize randomized trials, because in my experience, many clinicians who support the use of antidepressants in BD often cite a nonrandomized cohort here and there, as if the more valid randomized literature didn't exist. Besides the basic scientific point that our most valid studies find that the drugs don't work better than placebo, other randomized trials have found that they can worsen the illness, both by causing acute mania and by causing rapid cycling.

The acute mania issue is again debated by experts, because many studies don't differentiate from placebo—but others do. There are differences based on the agent used and dosing, but the fact that some agents can cause acute mania is reasonably proven.

The more important issue, in my view, is that replicated randomized trials have found that these agents can cause or worsen rapid-cycling. Thus, in some people, they are mood destabilizers that worsen the illness and counteract any potential benefits from mood stabilizers.

In sum, antidepressants in BD are ineffective at best, and harmful at worst, and thus best avoided in general.

Dr Strakowski: In general, I am in agreement with Dr Ghaemi. Like him, I do not believe there is strong evidence for the value of antidepressants in treating bipolar I disorder in particular, and probably in bipolar II disorder as well (although some studies suggest that selective serotonin reuptake inhibitors [SSRIs] might be useful in the latter). The STEP-BD study,[1] coupled with other recent work, was fairly convincing that modern antidepressants are neither particularly effective, but nor do they commonly precipitate mania.

There is also no strong literature supporting the efficacy of older antidepressants in this diagnosis; moreover, much of the literature suggesting that antidepressants induce mania arose primarily with tricyclic antidepressants (TCAs). However, whether TCAs and monoamine oxidase inhibitors (MAOIs) truly precipitate mania remains unclear; some studies, such as the NIMH Collaborative Depression Study,[2] found that depression in and of itself increases the risk for mania in BD, which virtually completely confounds antidepressant effects.

SSRIs may play a role in helping to manage co-occurring anxiety disorders in patients with BD, but the literature here remains modest. Consequently, in my own practice and most guidelines, there is still enough uncertainty that antidepressants are not completely removed from treatment pathways, but are perhaps third- or fourth-line therapy. In my own practice, instead I tend to lean on maximizing mood stabilizers, considering atypical antipsychotics, and incorporating cognitive-behavioral and other evidence-based therapies before considering antidepressants.

Dr Ghaemi: In terms of which agents are of the most concern regarding mania, clearly the older TCAs and MAOIs are associated with mania more so than the newer SRIs. The rates in observational trials tend to be about 25%-50% for the older agents, and about 10%-30% for SRIs. Among the latter, paroxetine has been studied the most and shown to be low risk in terms of acute mania. The same has been shown for bupropion, mainly at lower doses. Risk for acute mania with antidepressants also is inherently lower in type II than type I illness, with the above rates being cut in half or lower.

Dr Strakowski: Again, newer antidepressants, particularly in the presence of adequate mood stabilizers, appear to induce mania at rates no greater than placebo. The potential risks of TCAs and MAOIs, although not completely defined, coupled with their distasteful and risky side-effect profiles, suggest a truly limited role of these drugs in the treatment of individuals with BD.


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