Augmentation with aripiprazole.
A patient suffers with depression. He has experienced partial response with an antidepressant. At his next appointment, he asks about Abilify (aripiprazole), having seen an advertisement touting Abilify as augmentation of antidepressants.
Is aripiprazole an effective antidepressant augmentation strategy?
We first searched the Cochrane Database of Systematic Reviews (www.cochrane.org/reviews) to no avail. We then did a Medline search combining "aripiprazole" and "depression or depressive."
We found several case reports, retrospective chart studies, and open-label studies, but we will focus on the double-blind, placebo-controlled trials.
In one study, researchers conducted a multicenter, randomized, double-blind, placebo-controlled trial at 24 US. sites from June 2004 to April 2006 to examine the efficacy of adjunctive aripiprazole in major depressive disorder (J. Clin. Psychiatry 2007;68:843-53). Patients aged 18-65 years and who met DSM-IV-TR criteria for major depressive disorder that had lasted 8 weeks or more without adequate response, were included. Inadequate response was defined as a less than 50% reduction in depressive symptoms, as assessed by standardized methods, after having received one to three antidepressants for more than 6 weeks at adequate dosing. "Clinically significant current Axis II diagnoses of borderline, antisocial, paranoid, schizoid, schizotypal, or histrionic personality disorder" were excluded, the authors reported.
During the 8-week pre-aripiprazole phase, patients received adjunctive placebo and one of the following to reach a target dose by week 3: escitalopram 10 or 20 mg/day, fluoxetine 20 or 40 mg/day, paroxetine controlled-release 37.5 or 50 mg/day, sertraline 100 or 150 mg/day, or venlafaxine XR 150-225 mg/day. A total of 781 patients were enrolled in the pre-aripiprazole phase. Of those, 358 entered the 6-week aripiprazole phase: 176 received placebo and 182 received aripiprazole (mean dose 11.8 mg/day).
Efficacy was assessed using change in the Montgomery-Asberg Depression Rating Scale (MADRS). Response was defined as at least a 50% reduction in the MADRS total score, relative to the score just prior to entering the aripiprazole phase. Remission was defined as response plus a MADRS total score of 10 or less. At week 1, placebo patients experienced a 1.8% response rate, compared with 6.2% in aripiprazole patients. At 6 weeks, response rates in the two groups were 23.8% and 33.7%, respectively. Remission rates were also significantly different. At 3 weeks, placebo patients had a rate of 8.7%, compared with 18.8% in the aripiprazole patients; and at end point, the rates were 15.7% and 26.0%, respectively. The number needed to treat (NNT) for remission was 10. Of interest, the treatment difference in the last 2 weeks of the study favored aripiprazole over placebo in women only, and not in men, for whom placebo was favored.
In a second study, the researchers conducted a multicenter, randomized, double-blind, placebo-controlled trial at 36 U.S. sites from September 2004 to December 2006 also to examine the efficacy of adjunctive aripiprazole in major depressive disorder (J. Clin. Psychopharm. 2008;28:156-65). The inclusion criteria were the same as those in the previous study using the same standardized methods, and during the 8-week pre-aripiprazole phase, the patients received the same target dose of the same medications. Of 830 patients enrolled in the pre-aripiprazole phase, 647 entered the 6-week aripiprazole phase: 381 received placebo and 266 received aripiprazole (mean dose 11.0 mg/day). Efficacy was assessed using change in MADRS. At the end of the 6-week study, the response rates were 17.4% for the placebo group and 32.4% for the aripiprazole group; and remission rates were 15.2% and 25.4%, respectively. The number needed to treat for response was 7 and the number needed to treat for remission was 10. The researchers found no difference in response between men and women.
We located a third publication in which the authors pooled the data from the two aforementioned studies (J. Clin. Psychiatry 2008;69:1928-36).
We found two double-blind, placebo-controlled studies examining the efficacy of adjunctive aripiprazole in major depressive disorder. However, both studies were funded by Bristol-Myers Squibb Co., which manufactures aripiprazole (Abilify) and both were performed largely by the same group of researchers, some of whom are or were employees of the company or shareholders in it. Some of the same authors were also associated with the third study that reported on the pooled data.
There are a number of problems with these studies. First, what the authors defined as adequate dosing for adequate duration of pre-aripiprazole antidepressant treatment is questionable. Five weeks of fluoxetine 20 or 40 mg/day, sertraline 100 or 150 mg/day, or venlafaxine 150 or 225 mg/ day, hardly constitutes adequate dosing for adequate duration. Second, were the patients medication-adherent to the antidepressants? And, why did the treatment difference in the last 2 weeks of the first study favor aripiprazole over placebo in women and not in men? Is this treatment effect due to the greater prevalence of borderline personality disorder in women, and did aripiprazole actually treat symptoms of borderline personality disorder instead of depression? After all, what does the exclusion criteria of "clinically significant current Axis II diagnoses of borderline personality disorder" mean? Or was it simply due to greater mg/kg dosing in women? Finally, with an overall NNT of 10 for remission, the use of adjunctive aripiprazole for may be considered at the margins of being clinically worthwhile.
DR. LEARD-HANSSON is a forensic psychiatrist who practices in San Diego. DR. GUTTMACHER is chief of psychiatry at the Rochester (N. Y.) Psychiatric Center. They have no financial interest in any product or service discussed in this column. They can be reached at firstname.lastname@example.org.
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|Title Annotation:||EVIDENCE-BASED PSYCHIATRIC MEDICINE|
|Publication:||Clinical Psychiatry News|
|Article Type:||Clinical report|
|Date:||Jun 1, 2009|
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