Atypical Antipsychotics in Bipolar Depression Circa 2007: Ready For Prime Time?

The use of antipsychotic medications in the treatment of bipolar disorder is hardly new.

The effectiveness of the original, first generation antipsychotic agents was obvious from the start. They reduced the excitement, agitation, psychosis and other symptoms of the manic syndrome. And this made sense. Drugs defined as neuroleptics should produce an acute calming action. Recent pharmaceutical developments and new research has complicated this early, simple state of affairs and forced a reevaluation of the role of this class of medications in the treatment of manic-depressive illness.

Starting with clozapine (Clozaril) in the late 1980’s and followed by a series of pharmacological cousins such as risperidone (Risperdal), ziprasidone (Geodon), quetiapine (Seroquel) and aripiprazole (Abilify), second generation of antipsychotic agents have shown effectiveness against an increased range of symptomatology. While both the old and new agents were equally active in treating the positive symptoms of schizophrenia (such as hallucinations, delusions and formal thought disorder), the new medications were found to be significantly superior in reducing the disabling negative or deficit symptoms of apathy, amotivation and blunted affect. In addition, the frequency of certain side-effects was dramatically lower with this second generation class. The distinct mechanism of action responsible for their enhanced therapeutic scope combined with this reduced side-effect profile resulted in our designation of them as atypical.

Starting with the recognition of their action on the negative/deficit (they are similar but not synonymous) syndrome of psychotic disorders, research has been exploring the boundaries of effectiveness of these second generation agents. Initial case reports described an enhancement of antidepressant action in treatment-resistant depression. This was followed by exploration of their potential as monotherapy for depression.

This trend has culminated in a handful of recent articles assessing the role of atypical agents in the acute treatment of bipolar depression. Of these, there are two recent studies examining the effectiveness of one particular drug, quetiapine, that were well-controlled and generated impressive findings. I’ll briefly review these studies, their findings and the implications they have for clinical practice. Before doing so, it will be worthwhile to mention several facts about bipolar depression that provide context for any new research in this area.

First, bipolar depression is common and disabling. Depressive symptoms far outweigh manic symptoms in the overall course of both Bipolar I and Bipolar II subtypes (BP II much more so than BPI).

Second, depressive symptoms often fail to respond to treatment with mood stabilizers alone. Residual problems with energy, amotivation, hypersomnia and cognitive impairment are all too common.

Third, there is significant scientific controversy about the role of antidepressants in the treatment of bipolar depression. The controversy involves questions of efficacy and questions of potential side-effects. A recent article by Sachs in the New England Journal of Medicine (2007) demonstrated no significant benefit in duration of or recovery from bipolar depression when antidepressants were added to mood stabilizers compared to mood stabilizer monotherapy. Other articles document increased recovery rates with antidepressants and increased rates of relapse when antidepressants are withdrawn.

Adding to this complexity, there is an even greater controversy about whether antidepressants aggravate the course of bipolar illness, either by precipitating mania/hypomanic or mixed episodes and/or inducing mood cycling. Here, too, camps exist within the psychiatric field with one highlighting the dangers of antidepressant use and the other emphasizing the frequent benefit of these drugs.

From this inventory, the qualities of an ideal agent for the acute treatment of bipolar depression begin to emerge. It would act quickly, within several days. It would have strong, phase-specific activity. It would not aggravate the overall course of illness and would not precipitate manic or hypomanic episodes. Its acute antidepressant action would be complemented by an ability to prevent future episodes of depression. And last, it would treat and prevent manic and hypomanic symptoms and episodes. A tall order.

The two recent studies on quetiapine should be evaluated against this backdrop.

Known as BOLDER I and II (for BipOLar DEpRession), the two studies employed identical designs using double blind, randomized assignment and placebo controls to ensure maximum objectivity. The first publication came out in 2005, the replication study appeared the following year. The sample cohort was large, over 500 patients per study, consisting of both Bipolar I and Bipolar II patients experiencing a current depressive episode. After a washout period to eliminate any prior psychoactive medication, patients were randomized to receive either placebo, 300 or 600 mg/day of quetiapine. Over the next 8 weeks, subject’s moods were assessed with standard rating instruments. The findings were dramatic and consistent between both studies.

A broad and rapid antidepressant response, that was significantly greater than that found with placebo, was evident from the first week onward. Whether measured by response (usually defined as a 50% reduction in preexisting depression score) or the more complete elimination of symptoms seen in a remission, both doses of quetiapine outperformed the inactive comparator. In the first report, the two drug doses yielded virtually identical results. In the second, the lower dose produced a non-significantly greater effect size (a measure of effectiveness) than the larger dose.

One last point. There was no exacerbation of disease course with quetiapine: no induction of mania, hypomania, or mixed episodes nor any worsening of cycle frequency compared to placebo.

So, where do these results leave us? Should quetiapine be considered a first line drug for the acute treatment of bipolar depression? My answer: it’s getting close. Perhaps even very close. This position reflects a significant change in my viewpoint. Several years ago, I would have scoffed at the idea that atypical antipsychotics might have specific, as opposed to a more general, tranquilizing effect on the depressive symptoms of bipolar conditions. Similar to most of my colleagues, I viewed the use of these medications as a somewhat messy, nonspecific, symptomatic treatment reserved for manic and mixed syndromes. As good science should, these studies force a reconsideration of practice patterns and clinical outlook. So, having my mind pried open, does quetiapine meet the criteria for the ideal drug in this condition? Some remaining questions and concerns follow.

First, questions about the study methodology. This was a drug-washout design in which patients with bipolar depression, not responsive to their current regimen of medication, were taken off all psychoactive medication over a one to four week period. They were then randomized to placebo or quetiapine. The ensuing treatment arms thus examined not just the treatment of bipolar depression but also the presence of potentially confounding discontinuation of prior mood stabilizing medication. What effect does this twist have on the outcome and interpretation of the studies? Not clear. How much of the noted improvement was related to amelioration of any discontinuation effects vs. resolution of the depressive syndrome per se? A study using a drug augmentation format could provide reinforcement for, and clarification of these initial results. Such a design would add quetiapine or placebo to the ongoing drug regimens of patients experiencing a bipolar depressive episode. Tohen and colleagues have conducted such studies examining the benefit of the atypical antipsychotic, olanzapine (Zyprexa), when used alone or in conjunction with fluoxetine (Prozac) in the treatment of bipolar depressions and found significantly improved outcomes with combination vs monotherapy.

Two other significant reservations exist. First, the BOLDER studies extended over an 8 week period. Hence, they have demonstrated acute antidepressant effectiveness of quetiapine only. Whether quetiapine will be shown active in longer term maintenance or prophylaxis/prevention formats is unknown.

Second, like other atypical antipsychotics, quetiapine has it’s share of side-effects ranging from acute sedative and cognitive reactions to more serious, longer term metabolic changes in weight, lipid and glucose regulation.

The above reservations notwithstanding, and taking into account the current status of bipolar depression and the available options for its treatment, the acute antidepressant potential of quetiapine is looking quite strong.