Atypical Antipsychotic Augmentation for Treatment-Resistant Depression: A Systematic Review and Network Meta-Analysis

Abstract

Background: Previous meta-analyses of atypical antipsychotics for depression were limited by few trials with direct comparisons between two treatments. We performed a network meta-analysis, which integrates direct and indirect evidence from randomized controlled trials (RCTs), to investigate the comparative efficacy and tolerability of adjunctive atypical antipsychotics for treatment-resistant depression (TRD).

Methods: Systematic searches resulted in 18 RCTs (total n = 4422) of seven different types and different dosages of atypical antipsychotics and a placebo that were included in the review.

Results: All standard-dose atypical antipsychotics were significantly more efficacious than placebo in the efficacy (standardized mean differences [SMDs] ranged from -0.27 to -0.43). There were no significant differences between these drugs. Low-dose atypical antipsychotics were not significantly more efficacious than the placebo. In terms of tolerability, all standard-dose atypical antipsychotics, apart from risperidone, had significantly more side-effect discontinuations than placebo (odds ratios [ORs] ranged from 2.72 to 6.40). In terms of acceptability, only quetiapine (mean 250-350 mg daily) had significantly more all-cause discontinuation than placebo (OR = 1.89). In terms of quality of life/functioning, standard-dose risperidone and standard-dose aripiprazole were more beneficial than placebo (SMD = -0.38; SMD = -0.26, respectively), and standard-dose risperidone was superior to quetiapine (mean 250-350 mg daily).

Conclusions: All standard-dose atypical antipsychotics for the adjunctive treatment of TRD are efficacious in reducing depressive symptoms. Risperidone and aripiprazole also showed benefits in improving the quality of life of patients. Atypical antipsychotics should be prescribed with caution due to abundant evidence of side effects.

Keywords: Atypical antipsychotics; network meta-analysis; systematic review; treatment-resistant depression.

Figure 1.

Flowchart of study selection.

Figure 2.

Network plot of eligible comparisons for primary outcome. The width of the lines is proportional to the number of trials comparing every pair of treatments, and the size of every node is proportional to the number of randomized participants (sample size). ARI, aripiprazole; OFC, olanzapine/fluoxetine; PBO, placebo; QTP, quetiapine; RIS, risperidone.

Figure 3.

Network meta-analysis of primary efficacy and tolerability outcomes. Drugs are reported in order of efficacy ranking. Comparisons between treatments should be read from left-to-right, and the estimate is in the cell in common between the column-defining treatment and the row-defining treatment. To obtain standardized mean differences (SMDs) for comparisons in the opposite direction, negative values should be converted into positive values, and vice versa. For the primary efficacy, SMDs less than 0 favor the column-defining treatment. For the tolerability, odds ratios (ORs) higher than 1 favor the column-defining treatment. To obtain ORs for comparisons in the opposite direction, reciprocals should be taken. Significant results are in bold and underlined. CrI, credible intervals; L-ARI, low dose aripiprazole; L-OFC, low dose olanzapine/fluoxetine; PBO, placebo; S1-QTP, quetiapine (mean 250–400mg daily); S2-QTP, quetiapine (mean 150–250mg daily); S-ARI, standard dose aripiprazole; S-OFC, standard dose olanzapine/ fluoxetine; S-RIS, standard dose risperidone.

Figure 4.

Network meta-analysis of quality of life (QoL/functioning) and acceptability outcomes. Drugs are reported in order of efficacy ranking. Comparisons between treatments should be read from left-to-right, and the estimate is in the cell in common between the column-defining treatment and the row-defining treatment. For the QoL/functioning, standardized mean differences (SMDs) lower than 0 favor the column-defining treatment. To obtain SMDs for comparisons in the opposite direction, negative values should be converted into positive values, and vice versa. For the acceptability, odds ratios (ORs) higher than 1 favor the column-defining treatment. To obtain ORs for comparisons in the opposite direction, reciprocals should be taken. Significant results are in bold and underlined. CrI, credible interval; L-ARI, low dose aripiprazole; L-OFC, low dose olanzapine/fluoxetine; PBO, placebo; S1-QTP, quetiapine (mean 250–400mg daily); S2-QTP, quetiapine (mean 150–250mg daily); S-ARI, standard dose aripiprazole; S-OFC, standard dose olanzapine/ fluoxetine; S-RIS, standard dose risperidone.