Evidence Grows for Value of Antipsychotics as Antidepressant Adjuncts

The FDA recently approved the use of aripiprazole (Abilify) in combination with antidepressant medication for the treatment of major depression in adults. Although a variety of agents have been used in efforts to augment the effect of antidepressants, this first approved adjunct is likely to increase this use of atypical antipsychotics. In November, coinciding with the FDA approval of this supplemental New Drug Application for aripiprazole, a randomized controlled trial in Annals of Internal Medicine demonstrated increased antidepressant effect from the addition of risperidone (Risperdal) to antidepressant monotherapy.¹

The FDA approval of aripiprazole as an adjunct to antidepressant medication was based on 2 double-blind, randomized placebo-controlled studies with a total of 743 patients whose depression had not responded adequately to an antidepressant, by history and in an 8-week prospective trial.² Placebo or aripiprazole was then added to the antidepres-sant regimen for 6 weeks. Aripiprazole dosage started at 5 mg daily and was adjusted in weekly increments of no more than 5 mg to a range of 2 to 20 mg daily. The maximum dosage of aripiprazole when used in combination with fluoxetine (Prozac) or paroxetine (Paxil) was capped at 15 mg daily in consideration of the ability of these anti- depressants to increase aripiprazole levels via their inhibitory effect on the hepatic cytochrome isoenzyme CYP450 2D6.

The primary measure of efficacy was mean change in the Montgomery-Asberg Depression Rating Scale (MADRS) score from the end of the 8-week antidepressant trial to the sixth week of treatment with the antidepressant combination. Response to treatment was established as a 50% or greater reduction in score, and remission was defined as a MADRS total score of 10 or less. According to an announcement by the aripiprazole manufacturer, Bristol-Myers Squibb, both studies showed that the active medication combination was superior to the antidepressant and placebo in reducing depressive symptom score.²

From pooled data of the 2 studies, the manufacturer indicated that addition of the antipsychotic for 6 weeks was not associated with "clinically important differences" in metabolic parameters or prolactin levels. There was, however, a median 5% increase from baseline triglyceride levels in those receiving aripiprazole and no change with the addition of placebo; weight gain of 7% or greater occurred in 5% of those taking aripiprazole compared with 1% with placebo. Discontinuation because of adverse events occurred in 6% of those taking the active combination compared with 2% with the placebo and antidepressant. The most common adverse events associated with the addition of aripiprazole were akathisia (25% vs 4% with placebo addition), restlessness (12% vs 2%), and insomnia (8% vs 2%).²

In the one study that was published, Robert Berman, MD, and colleagues at Bristol-Myers Squibb and Otsuka Pharmaceutical reported a MADRS score mean reduction of 8.8 with active combination and 5.8 with placebo in their cohort of 358 patients participating in the 6-week treatment phase.³ They note that the difference was statistically significant, and showed a treatment effect size of 0.39 favoring aripiprazole.³ Berman and colleagues found that 26% of those receiving the active combination met criteria for remission, compared with 15.7% taking placebo and antidepressant. The number needed-to-treat with the anti psychotic-antidepressant combination to have 1 patient respond sufficiently to meet criteria for remission was 10.

Berman and colleagues point out that these results, which leave a substantial number of depressed patients symptomatic, should be considered in the context of response rates in patients who have not previously responded to antidepressant medication. They note that in the STAR*D trial, almost two thirds of patients did not respond adequately to their first antidepressant trial, and rates of remission decreased substantially in patients who did not respond to a second antidepressant course.⁴

Although the addition of aripiprazole to an antidepressant improved outcome in some patients in these short-term trials, Berman and colleagues acknowledge, "it remains to be determined whether these improvements will translate into long-term improvements in remission rates in this difficult-to-treat population, and the long-term safety profile of aripiprazole in this population remains to be clarified."³

Additional add-on?

The recently published study with risperidone also involved a 6-week treatment period, in patients with depression characterized in the study title as "treatment-refractory," and more precisely and possibly more accurately in the methodology section as "suboptimally responsive to antidepressant therapy."¹ This population of 274 patients underwent a 4-week prospective trial to confirm the history of inadequate response to an antidepressant before 268 were randomized to the addition of either placebo or a risperidone regimen initiated at 0.25 mg daily and adjusted to between 1 and 2 mg daily. The primary measure of efficacy was a reduced score on the 17-item Hamilton Rating Scale for Depression (HRSD-17), with a 50% reduction indicating response and remission defined as a score of 7 or less.

Ramy Mahmoud, MD, of Ethicon, Inc, and coauthors at Ortho-McNeil Janssen and Hoffman-La Roche Medical Affairs reported statistically significantly higher rates of remis- sion with risperidone augmentation (24.5%) than with placebo (10.7%) at completion of the 6-week controlled treatment phase. Response rate with the risperidone-antidepressant combination was 46.2%, compared with 29.5% with placebo add-on. The calculated number needed-to-treat for remission was approximately 7. There was a reduction in HRSD-17 mean score from a baseline in both groups of approximately 24 to approximately 13.4 with the risperidone adjunct and 16.2 with placebo add-on.

Dropout rates of 19% with risperidone and 12% with placebo add-on left 226 patients at the completion of the 6-week treatment phase. Premature discontinuation because of adverse effects occurred in 5.8% of risperidone recipients and 2.3% of those receiving placebo. The authors described adverse events and rates, including motor effects, as similar in both groups, and noted that no patient required benztropine (Cogentin) for motor symptoms.¹

Mahmoud and colleagues indicated that although there was a "modest" mean numerical reduction in HRSD-17 score, the treatment effect could be considered clinically significant given the statistically significant differences in the number of patients achieving response and remission. In addition, they noted, there were statistically significant differences favoring risperidone over placebo add-on in improved scores on the clinician-rated Clinical Global Impression-Severity of Illness and the patient-rated Patient Global Improvement scale. According to the authors, the findings suggest "the potential for short-term (6 weeks) benefit of risperidone augmentation for poorly responsive major depressive disorder."¹

In a meta-analysis of randomized clinical trials of antipsychotic adjunctive treatment of antidepressant medication, George Papakostas, MD, of Massachusetts General Hospital, and his colleagues found support for this depression treatment strategy. They identified 10 clinical trials that they judged to have sufficiently rigorous design to address the question of efficacy for acute treatment, involving 1500 patients.⁵ Although the definition of remission varied between studies, each defined response as a 50% reduction in depressive symptom rating scale score.

Across these 10 randomized controlled trials, Papakostas and colleagues found that antipsychotic augmentation resulted in greater remission and response rates than adjunctive placebo treatment, with remission rates of 47.4% versus 22.3% and response rates of 57.2% versus 33.4%. There was no statistically significant difference between antipsychotic and placebo add-on groups in discontinuation rates resulting from inefficacy, but there was more than a 3-fold higher rate of discontinuation because of adverse reactions with the antipsychotic adjunct.

Although Papakostas and colleagues found support for use of the antipsychotic adjunct, they caution that they also found an associated side-effect burden. They also noted that there are no comparative data distinguishing among antipsychotics for adjunctive effects, or differentiating the efficacy of adding an antipsychotic from that of other augmentation strategies. The data from short-term trials need to be extended to long-term outcomes, they emphasized.

These concerns notwithstanding, Papakostas and colleagues encourage further study of this and other interventions to improve depression treatment outcomes. "In light of the challenge that treatment-resistant major depressive disorder poses to clinicians and patients alike," they declared, "there is urgent need to develop novel treatment strategies for resistant depression that are both safer and more effective than those currently employed."⁵

References:

References

1.

Mahmoud RA, Pandina GJ, Turkoz I, et al. Risperidone for treatment-refractory major depressive disorder.

Ann Intern Med.

2007;147:593-602.

2.

Bristol-Myers Squibb (BMS). US Food and Drug Administration approves Abilify (aripiprazole) as the first medication for add-on treatment of major depressive disorder (MDD). November 20, 2007. Available at:

http://newsroom.bms.com/index.php?s=press_releases&item=324

. Accessed December 20, 2007.

3.

Berman RM, Marcus RN, Swanink R, et al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind placebo-controlled study.

J Clin Pyschiatry.

2007;68:843-853.

4.

Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report.

Am J Psychiatry

.

2006;163:1905-1917.

5.

Papakostas GI, Shelton RC, Smith J, Fava M. Augmentation of antidepressants with atypical antipsychotic medications for treatment-resistant major depressive disorder: a meta-analysis.

J Clin Psychiatry.

2007;68:826-831.