What is the optimal dose of aripiprazole as augmentation for treatment-refractory depression? Researchers performed a systematic review and dose-effect meta-analysis.
“Mrs Norbert” is a 32-year-old Hispanic female with a history of recurrent major depressive disorder, with illness onset in her teens. She failed previous trials, with adequate dose and duration, of citalopram and sertraline (“felt worse”). She experienced some benefit with bupropion extended-released, titrated to 450 mg/day, although she has significant residual symptoms of depression. Subsequently, she failed a trial of adjunctive lithium due to tolerability concerns (nausea, diarrhea, and increased thirst). Her psychiatrist started adjunctive oral aripiprazole 10 mg daily. She reported improvements in depressed mood, irritability, energy, suicidal ideation, and overvalued ideas that people are generally against her in the first 2 weeks of treatment. The improvement was maintained after 4 weeks, and she requested to transition from oral to long-acting injectable aripiprazole.
Antidepressant non-response is common in major depressive disorder (MDD).1 Augmentation with atypical antipsychotics represents a viable strategy for treatment-refractory MDD.2,3 Among atypical antipsychotics, aripiprazole is an approved treatment in the United States, the United Kingdom, and Japan, with evidence of efficacy.4 However, the recommended dose of adjunctive aripiprazole in treatment guidelines varies widely (2 to 15 mg/day), which could impact on efficacy and tolerability.3
The Current Study
Furukawa and colleagues5 aimed to use dose-effect meta-analysis to inform on the optimal dose of adjunctive aripiprazole in patients with MDD and inadequate response to antidepressants. They included all assessor-masked trials of 2 or more doses of aripiprazole augmentation (versus continuation of antidepressant treatment) in adults with a primary diagnosis of non-psychotic MDD and inadequate response to at least 1 antidepressant trial.
Psychotherapy was permitted, but electroconvulsive therapy was exclusionary. They excluded trials with active comparators; quasi- and non-randomized trials; studies with a high risk of bias; trials with ≥20% of patients treated with tricyclic antidepressants; studies in patients with significant physical illness, alcohol, or substance use comorbidity; and trials in postpartum depression.
The authors systematically searched Cochrane, CENTRAL, PubMed, ClinicalTrials.gov, and the WHO’s International Clinical Trials Registry Platform for trials. They also hand-searched drug approval agencies in the United States, the European Union, the United Kingdom, Australia, and Japan. Lastly, they contacted the developer of aripiprazole, Otsuka Pharmaceutical Co, Ltd. The primary outcomes were efficacy (responder—defined as ≥50% reduction in depressive symptoms), tolerability (dropouts due to adverse effects), and acceptability (all-cause dropouts), measured as odds ratios.
Dose-effects relationships were analyzed using random effects models with restricted cubic splines with 3 knots, set at 3 mg (lowest expected effective dose), 1.5 mg, and 6 mg. Dose-effect curves of the primary analyses were used to estimate the 50% (ED50) and 95% (ED95) effective doses. The variance partition coefficient and funnel plots were used to evaluate heterogeneity and publication bias, respectively.
The authors identified 2678 records via databases and registries, and 14 through contact with Otsuka. Ten studies (7 published and 3 unpublished), comprising 2625 outpatient subjects, were identified for inclusion. These studies included 2 fixed-dose arms, 9 flexible-dose arms, and 10 placebo arms. The 3 unpublished studies were terminated early and only provided data for tolerability. The mean participant age was 42, and 55% were female. Median treatment duration was 6 weeks. The mean baseline Montgomery-Asberg Depression Rating Scale score was 26. There was no evidence of significant between-study heterogeneity.
The dose-efficacy curves showed an increase up to doses between 2 and 5 mg, then a non-increasing trend through doses up to 20 mg. The ED50 was 1.7 mg (OR=1.39, 95% CI 1.13-1.72), and the ED95 was 4.0 mg (OR=1.88, 95% CI 1.29-2.73). Tolerability also increased up to 5 mg, after which there was a non-increased trend. There was no significant difference in acceptability between aripiprazole and placebo at any dose. In the placebo arms, the average response rate was 23% and the all-cause dropout rate was 9%. Adjunctive aripiprazole at 4.0 mg had an estimate response rate of 36% and an all-cause dropout rate of 10%.
The authors performed the first dose-effect meta-analysis of aripiprazole augmentation in MDD. They concluded that aripiprazole may achieve most of its efficacy at the lower end of the dose range in patients with inadequate response to antidepressants, with limited evidence for efficacy above 10 mg. Study strengths included the identification of unpublished studies, modeling dose as a continuous variable, and consideration of efficacy, tolerability, and acceptability as outcomes. Limitations included the relatively small number of trials, especially in the lower end of the dose range, and risk of bias in the included trials.
The Bottom Line
Low-dose (2 to 5 mg) aripiprazole may maximize efficacy and tolerability in patients with inadequate response to antidepressants. However, dosing should be tailored to the individual patient.
Dr Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric TimesTM. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.
1. 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(11):1905-1917.
2. MacQueen G, Santaguida P, Keshavarz H, et al. Systematic review of clinical practice guidelines for failed antidepressant treatment response in major depressive disorder, dysthymia, and subthreshold depression in adults. Can J Psychiatry. 2017;62(1):11-23.
3. Taylor RW, Marwood L, Oprea E, et al. Pharmacological augmentation in unipolar depression: a guide to the guidelines. Int J Neuropsychopharmacol. 2020;23(9):587-625.
4. Luan S, Wan H, Zhang L, Zhao H. Efficacy, acceptability, and safety of adjunctive aripiprazole in treatment-resistant depression: a meta-analysis of randomized controlled trials. Neuropsychiatr Dis Treat. 2018;14:467-477.
5. Furukawa Y, Hamza T, Cipriani A, et al. Optimal dose of aripiprazole for augmentation therapy of antidepressant-refractory depression: preliminary findings based on a systematic review and dose-effect meta-analysis. Br J Psychiatry. 2022;221(2):440-447.