You may have noticed a recent torrent of FDA approvals and clinical trials for atypical antipsychotics in every disorder under the sun–except psychosis. Is this simply an effort by the sponsoring companies to get us to prescribe more antipsychotics? Or are these drugs truly effective for non-psychotic disorders? What’s the quality of the evidence?
As the table below shows, all atypicals are approved for schizophrenia and bipolar mania. Seroquel (quetiapine) & Symbyax (olanzapine-fluoxetine) are the only ones approved for bipolar depression, while Abilify (aripiprazole) is the only one approved for adjunctive treatment of major depression. None are approved for monotherapy of major depression. Some small studies have supported off-label uses of these medications such as Abilify for treatment of borderline personality disorder, and risperidone for irritable aggression of PTSD. Let’s review the available evidence for some of the most common non-psychotic uses of the atypicals.
Seroquel for bipolar depression
As we reported in 2007, the BOLDER I & II clinical trials evaluated Seroquel for the treatment of bipolar I or II depression (Calabrese et al., Am J Psychiatry 2005;162:1351-1360; Thase et al., J Clin Psychopharm 2006;26:600- 609). Each study consisted of approximately 500 patients who met criteria for bipolar I or II disorder and suffered from a major depressive episode at the time of enrollment. Patients were randomized to one of three groups: Seroquel titrated to 300 mg QHS over 4 days, Seroquel titrated to 600 mg QHS over 7 days, or placebo. Both studies showed a statistically higher response to Seroquel (approximately 55%) as compared to placebo (37%), with no advantage of the 600 mg dose over the 300 mg dose.
However, several caveats must be noted. First, the data was strongest for depression in bipolar I disorder; one of the trials showed no separation from placebo for bipolar II depression. In addition, the BOLDER studies excluded anyone with substance use within 12 months, acute suicidality, current depression lasting longer than 12 months, other recently treated Axis I diagnoses, or current or previous failure of two full trials (six weeks) of antidepressants. The exclusion of any patients who have failed two prior trials of antidepressants seems particularly restrictive, because the diagnosis of bipolar depression is tricky and can be confused for depression with irritability. By the time you have clearly established a diagnosis of bipolar depression, it is likely that in most cases a patient would have already been through at least two trials of antidepressants – but all such patients were excluded from BOLDER.
Thus, the patients with “bipolar depression” in the BOLDER trials are unlikely to be seen in clinical practice, making it hard to conclude that Seroquel will actually be effective for the patients we see. Also, there are no head-to-head trials comparing Seroquel to mood stabilizers commonly used for bipolar depression, such as Lamictal (lamotrigine) or lithium.
Bottom Line: In patients with bipolar I depression, no significant comorbid disorders and a history of only one prior antidepressant trial, Seroquel (at 300 mg QHS) may be useful; the evidence for bipolar II depression less clear. Warn your patients about substantial weight gain and sedation.
Seroquel for anxiety symptoms
Two small randomized studies compared Seroquel vs. placebo augmentation of SSRIs in patients who had residual symptoms despite monotherapy. One study of 58 patients showed a benefit of Seroquel (mean dose, 182 mg/day) over placebo for both anxiety and depressive symptoms (McIntyre, et al., Depress Anxiety 2007; 24(7): 487-94). However, another study of 114 patients showed no benefit of Seroquel (25 mg-100 mg) as an adjunct to fluoxetine for either anxiety or depressive symptoms, although Seroquel was more helpful than placebo for insomnia (Garakani, et al., Int Clin Psychopharmacology 2008; 23(5):269-75). Thus, the data on Seroquel augmentation are mixed; higher doses may yield more benefit, but are likely to come with more side effects.
Seroquel for anxiety disorders
Several smaller randomized placebo-controlled studies have shown no evidence for use of Seroquel either alone or with an SSRI/SNRI for full-fledged anxiety disorders. Though these studies include only 15 to 70 subjects, each showed either no effect or a negative effect of Seroquel on social anxiety disorder, OCD, social phobia, or generalized anxiety disorder. Vaishnavi, et al., Prog Neuropsychopharmacol Biol Psychiatry 2007; 31(7): 1464-9; Simon, et al., Psychopharmacology 2008;197(4):675-81; Donahue, et al., J Anxiety Disord. 2008 Dec 24; Carey, et al., BMC Psychiatry 2005;5:5.
However, AstraZeneca has applied to the FDA for the Generalized Anxiety Disorder indication for Seroquel XR (an extended release form of Seroquel). According to the company’s website (http://www.astrazenecaus.com/search/?itemId=2782945), their application is based on the results of four placebo controlled trials evaluating three doses of Seroquel XR: 50 mg/day, 150 mg/day, and 300 mg/day. None of the data have been published, though some positive results were presented at the 2008 APA annual meeting. Whether these results will survive the FDA review process remains to be seen. Given Seroquel’s substantial metabolic side effects, we are skeptical that the psychiatric community will embrace it as a treatment for a condition for which there are safer alternative treatments.
Seroquel for insomnia
There are no large, well-designed studies of the Seroquel in the treatment of insomnia. Case reports indicate that dosages of 25-50 mg QHS can be helpful for insomnia of various etiologies. A double-blind placebo-controlled randomized cross-over study of 14 healthy men showed improved sleep architecture, overall sleep time, and sleep efficiency on Seroquel 25 mg-100 mg given one hour prior to bedtime (Cohrs, et al., Psychopharmacology 174:421-429). An open pilot study of 18 outpatients with primary insomnia showed similar benefits, and maintained them for the full six weeks studied (Wiegand et al., Psychopharmacology 2008;196(2):337-8). Interestingly, sleep latency was not shortened on Seroquel in either study; people slept better and longer, but didn’t fall asleep any faster with Seroquel, a finding that seems inconsistent with common clinical experience.
Abilify for depression augmentation
Two large multi-center randomized, double-blind, placebo-controlled trials showed Abilify (aripiprazole) to be an effective adjunct in major depression. (Berman RM et al., J Clin Psychiatry 2007;68(6):843-53; Marcus RN et al., J Clin Psychopharm 2008;28(2):156-165) Both studies began with eight weeks of antidepressant plus placebo; patients who did not respond to this treatment were then randomized to receive either Abilify or placebo for an additional six weeks. The average doses for the two studies were Abilify 11 mg and 11.8 mg daily. After six weeks of augmentation, the remission rates on Abilify were 25.4% and 26% (from the two studies), while the remission rates on placebo were 15.2% and 15.7%. This 10% difference was statistically significant, and the FDA granted approval for Abilify as an add-on treatment for depressed patients who have not responded to a standard antidepressant. However, the clinical significance of these findings was questioned in letters to the editor, one of which pointed that, in one of the studies, Abilify produced only a tiny 2.8 point improvement in the MADRS depression scale, and that Abilify did not outperform placebo on patient self-report depression measures in either study (Carroll BJ, J Clin Psychopharm 2009;29:91). In addition, Abilify caused akathisia in 25% of patients, a worrisome side effect for chronically depressed patients.
TCPR VERDICT: Seroquel: Probably useful for bipolar I depression and insomnia; anxiety use questionable. Abilify: Data for depression too weak to have deserved its FDA indication.