8 Controversies in Bipolar Disorder Addressed

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


June 30, 2016

Controversy 3: Neuroleptics Long-term?

Should neuroleptics be used on a long-term basis as "mood stabilizers"?

Dr Ghaemi: My view is that these agents are mistakenly viewed as effective by themselves for long-term prophylaxis of BD. Some have US Food and Drug Administration indications to this effect, but those studies are "enriched"—meaning that patients are preselected to respond to the neuroleptic for an acute mood episode before the prophylaxis study begins. In the 1 year or so of the prophylaxis study, most relapses occur in the first 6 months or less; in my view, this indicates relapse into the same acute mood episode that was present before the study began, not prevention of a totally new mood episode.

So if you treat a patient for acute mania with a neuroleptic, and then you stop the neuroleptic after the patient improves a few months later, and then the patient gets manic again a few months later—is that a totally new episode, or is that the same manic episode that the patient just experienced? It would be more convincing if episodes of the opposite polarity were prevented: that is, if a depressive episode occurred in the placebo arm after stopping treatment for an acute manic episode. But available data find that such enriched studies don't prevent episodes of the opposite polarity.

In short, if you are known to like chocolate cake and are preselected to enter a study because you like chocolate cake, and no one else is allowed in the study, then if you are randomly assigned to eat chocolate vs vanilla cake, you'll still like chocolate cake. This doesn't prove that chocolate cake is inherently better than vanilla cake.

Dr Strakowski: Although I actually prefer vanilla cake (and lemon meringue pie even more), one could argue that the only truly established "mood stabilizer" is lithium, given the breadth of trials and its long history of use in European and other lithium clinics. In fact, in my own practice, lithium is my first drug of choice for all patients with BD.

That said, unfortunately, many patients cannot tolerate effective serum levels—and among those who do, a sizeable minority simply will not respond, so that alternatives are needed. Among these alternatives are anticonvulsants and antipsychotics, none of which has overwhelming evidence for long-term mood stabilization. Consequently, for individual patients, careful symptom monitoring during systematic trial and error to find which alternative is best tolerated and reduces the occurrence of affective episodes over longer periods is critical. I cannot overemphasize the importance of mood-charting over months, and even years, when making these decisions.

Among the antipsychotics, there is probably no role for long-term use of conventional (neuroleptic) antipsychotics, because studies suggest that at best they fail to prevent depression and at worse may precipitate depression (although studies are admittedly limited). Second-generation and later antipsychotics appear to be better choices but, to Dr Ghaemi's point, remain incompletely tested.


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