Dosage of adjunctive aripiprazole for treatment-resistant depression


What is the optimal dose of aripiprazole as an add-on therapy for treatment-resistant depression? The researchers performed a systematic review and a dose-response meta-analysis.


“Ms. Norbert” is a 32-year-old Hispanic woman with a history of recurrent major depressive disorder, with onset illness in adolescence. She failed previous trials, with adequate dose and duration, of citalopram and sertraline (“felt worse”). She felt some benefit with sustained-release bupropion, titrated at 450 mg/day, although she had significant residual symptoms of depression. Subsequently, she failed a trial of supplemental lithium due to tolerance issues (nausea, diarrhea, and increased thirst). Her psychiatrist was started on oral supplemental aripiprazole 10 mg daily. She has reported improvements in depressed mood, irritability, energy, suicidal thoughts and overstated thoughts that people are generally against her within the first 2 weeks of treatment. The improvement was maintained after 4 weeks and she asked to switch from oral aripiprazole to long-acting injectable aripiprazole.

Unresponsiveness to antidepressants 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, United Kingdom, and Japan, with evidence of efficacy.4 However, the recommended dose of adjuvant aripiprazole in treatment guidelines varies considerably (2 to 15 mg/day), which could impact efficacy and safety.3

The current study

Furukawa and his colleagues5 aimed to use a dose-response meta-analysis to inform the optimal dose of adjuvant aripiprazole in patients with MDD and inadequate response to antidepressants. They included all evaluator-masked trials of 2 or more doses of aripiprazole escalation (vs. continuation of antidepressant treatment) in adults with a primary diagnosis of non-psychotic MDD and an inadequate response to at least 1 antidepressant trial.

Psychotherapy was allowed, but electroconvulsive therapy was exclusive. They excluded trials with active comparators; quasi-randomised and non-randomised trials; studies at high risk of bias; trials with ≥ 20% of patients treated with tricyclic antidepressants; studies in patients with significant physical illness, alcohol- or drug-related comorbidity; and trials on postpartum depression.

The authors systematically searched for trials in Cochrane, CENTRAL, PubMed, and the WHO International Clinical Trials Registry Platform. They also manually searched drug approval agencies in the United States, European Union, United Kingdom, Australia and Japan. Finally, they contacted the developer of aripiprazole, Otsuka Pharmaceutical Co, Ltd. ), measured as odds ratios.

Dose-effect relationships were analyzed using random-effects models with 3-node restricted cubic splines set at 3 mg (lowest expected effective dose), 1.5 mg, and 6 mg. Dose-response curves from the primary analyzes were used to estimate the 50% (ED50) and 95% (ED95) effective doses. The variance sharing coefficient and funnel plots were used to assess heterogeneity and publication bias, respectively.

The authors identified 2678 records through databases and registers, and 14 through contacts with Otsuka. Ten studies (7 published and 3 unpublished), including 2625 outpatients, 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 prematurely and only provided safety data. The average age of the participants was 42 years old and 55% were women. The median duration of treatment was 6 weeks. The mean initial Montgomery-Asberg Depression Rating Scale score was 26. There was no evidence of significant heterogeneity between studies.

The dose-efficacy curves showed an increase up to doses between 2 and 5 mg, then a non-increasing trend up to doses up to 20 mg. ED50 was 1.7 mg (OR=1.39, 95% CI 1.13-1.72) and ED95 was 4.0 mg (OR=1.88, 95% CI 1.29 -2.73). Tolerance 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 mean response rate was 23% and the all-cause dropout rate was 9%. Adjuvant aripiprazole 4.0 mg had an estimated response rate of 36% and an all-cause discontinuation rate of 10%.

Conclusions of the study

The authors performed the first dose-response 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 an inadequate response to antidepressants, with limited evidence of efficacy above 10 mg. Study strengths included identification of unpublished studies, modeling of dose as a continuous variable, and consideration of efficacy, tolerability, and acceptability as outcomes. Limitations included the relatively small number of trials, particularly at the lower end of the dose range, and the risk of bias in the included trials.

The essential

Low dose aripiprazole (2-5 mg) may maximize efficacy and tolerability in patients with an inadequate response to antidepressants. However, the dosage should be individualized for each 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 is chief of the schizophrenia section for Psychiatric timeMT. 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 more 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 antidepressant treatment response failure 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 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. Treat neuropsychiatric diseases. 2018;14:467-477.

5. Furukawa Y, Hamza T, Cipriani A, et al. Optimal dose of aripiprazole for the augmentation treatment of antidepressant-resistant depression: preliminary results based on a systematic review and dose-response meta-analysis. Br J Psychiatry. 2022;221(2):440-447.


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