strong>Abilify for Depression and Bipolar Disorder: A Meta-Analysis
Abilify (aripiprazole), which has long been FDA-approved for both schizophrenia and manic episodes of bipolar disorder, was recently approved for augmentation of antidepressants in patients with treatment-resistant depression. But there has been controversy about the degree of efficacy for mood disorders. A recent meta-analysis examined this issue by looking at all the available placebo-controlled trials of Abilify as adjunctive therapy for depression, as monotherapy for manic and mixed phases of bipolar disorder, and as monotherapy for bipolar depression (an indication for which it is not FDA approved). For adjunctive treatment of depression, Abilify yielded about a 10% advantage in remission rate, which was statistically significant. Across five studies examining the treatment of mixed or manic states, Abilify yielded an overall response rate that was significantly higher than placebo (about 50% vs. about 35%). Two trials found that Abilify was no better than placebo as monotherapy for bipolar depression. Abilify’s most bothersome side effect in these trials was akathisia. In the antidepressant augmentation trials, akathisia occurred in about 25% of depressed patients (average dose 11.5 mg of Abilify), compared to about 4% of patients on placebo; akathisia was reported in about 15% of patients taking an average dose of 25-30 mg of Abilify for manic or mixed states vs. about 4% on placebo (Arbaizar B et al., Gen Hosp Psychiatry 2000;31:478-483). The authors noted that two additional studies for mania and three trials for bipolar depression are marked as completed in a clinical trials registry but have not yet been published, suggesting the possibility of publication bias (the results of these studies have not been revealed by the companies sponsoring the trials). Further, one study with negative results for mania remains unpublished.
TCPR’s Take: The bottom line is that the published data suggest Abilify monotherapy is effective for mania or mixed states, but its effect as adjunctive treatment for unipolar depression is small and it is probably ineffective for bipolar depression.
Can an EEG Predict Antidepressant Response?
Clinical trials show which treatments work for “the average patient,” but we have little ability to predict which treatment will work best for any individual patient. QEEG (quantitative EEG) is a method in which a computer program reads EEG tracings and scores them along certain dimensions. A company called Aspect Medical Systems has been testing a proprietary QEEG system to see if it can predict antidepressant response. In one of the first studies to be published, 220 depressed patients underwent QEEG testing and then were given open-label Lexapro 10 mg/day. After one week of treatment, all patients were given another QEEG, and a number called the ATR (Antidepressant Treatment Response) index was calculated based on each EEG. Patients were then randomly assigned in a double blind fashion to one of three treatments: a) switch to Wellbutrin, b) add Wellbutrin to Lexapro, or c) continue Lexapro. Patients with ATRs above a certain threshold were 2.4 times as likely to respond to Lexapro as those with low ATRs. On the other hand, when patients with low ATR scores were assigned to Wellbutrin, they were 1.9 times as likely to respond to Wellbutrin as those low ATR patients who had remained on Lexapro. However, low ATR was not useful in predicting the response of patients to combination therapy (Leuchter AF et al., Psychiatry Res 2009;169:132-138).
TCPR’s Take: If future research validates the ATR score used in this study, then those patients who have high ATRs would be more appropriate for Lexapro treatment (and, by implication, possibly for any SSRI treatment while patients with low ATRs would be appropriate for Wellbutrin. But there are some caveats. The sample was relatively healthy, and any patient who had failed Lexapro or Wellbutrin in the current episode was excluded. The ATR threshold used to predict response was actually modified during the study and then tested on the second half of the patients enrolled. In order to be convincing, this same ATR threshold would have to be tested a priori in a different population of depressed patients. Finally, even if you were itching to start test-driving this system based on this study, you would be unable to obtain the special formula used to compute the ATR, because it is a trade secret of Aspect Medical Systems. We’ll have to wait for several more studies before the FDA will approve this diagnostic device. Meanwhile, brief surveys such as the Outcome Questionnaire-45 can also be used to predict treatment response (see October 2008 TCPR).
Antipsychotics: Small Benefits for Depression
Anecdotally, adding an atypical antipsychotic to an antidepressant is a common practice for achieving a response in patients who have failed several medication trials. Do the data support this use of atypical antipsychotics? A recent meta-analysis examined this topic, pooling the results of 16 randomized double-blind trials in which an atypical antipsychotic was compared to placebo in the adjunctive treatment of depression. Included were: five olanzapine trials (n=1000 participants), five quetiapine trials (n=1029), three aripiprazole trials (n=1065), and three risperidone trials (n=386). Participants had failed anywhere from one to four prior antidepressant trials. The overall response rate for adjunctive atypicals was 44% compared to 30% for adjunctive placebo, and the remission rate for adjunctive atypicals was 31% compared to 17% for adjunctive placebo. Both differences were statistically significant. The NNT (number needed to treat) was nine, meaning that nine additional patients would need to be treated with an atypical to generate a response or a remission that would not occur on adjunctive placebo. Discontinuation rates due to adverse events were 9% for atypicals versus 2% for placebo (Nelson JC et al., Am J Psychiatry 2009;166:980-991).
TCPR’s Take: These results are encouraging, and indicate that atypical antipsychotics are a viable adjunctive treatment option for treatment-resistant depression. Unfortunately, the meta-analysis reported only response and remission rates; average scores on rating scales were not provided, making it difficult to assess the exact level of difference between drug and placebo. While it seems clear that atypical antipsychotics provide a small boost as adjunctive antidepressants, typical side effects of these agents include weight gain, sedation, extrapyramidal symptoms, and akathisia, so we recommend a careful risk/benefit discussion with your patients before prescribing them as adjunctive medication for the treatment of depression.