Efficacy and Tolerability of Combination Treatments for Major Depression: Antidepressants plus Second-Generation Antipsychotics vs. Esketamine vs. Lithium

Abstract

Background: Successful treatment of major depressive disorder (MDD) can be challenging, and failures ("treatment-resistant depression" [TRD]) are frequent. Steps to address TRD include increasing antidepressant dose, combining antidepressants, adding adjunctive agents, or using nonpharmacological treatments. Their relative efficacy and tolerability remain inadequately tested. In particular, the value and safety of increasingly employed second-generation antipsychotics (SGAs) and new esketamine, compared to lithium as antidepressant adjuncts remain unclear.

Methods: We reviewed randomized, placebo-controlled trials and used random-effects meta-analysis to compare odds ratio (OR) versus placebo, as well as numbers-needed-to-treat (NNT) and to-harm (NNH), for adding SGAs, esketamine, or lithium to antidepressants for major depressive episodes.

Results: Analyses involved 49 drug-placebo pairs. By NNT, SGAs were more effective than placebo (NNT = 11 [CI: 9-15]); esketamine (7 [5-10]) and lithium (5 [4-10]) were even more effective. Individually, aripiprazole, olanzapine+fluoxetine, risperidone, and ziprasidone all were more effective (all NNT < 10) than quetiapine (NNT = 13), brexpiprazole (16), or cariprazine (16), with overlapping NNT CIs. Risk of adverse effects, as NNH for most-frequently reported effects, among SGAs versus placebo was 5 [4-6] overall, and highest with quetiapine (NNH = 3), lowest with brexpiprazole (19), 5 (4-6) for esketamine, and 9 (5-106) with lithium. The risk/benefit ratio (NNH/NNT) was 1.80 (1.25-10.60) for lithium and much less favorable for esketamine (0.71 [0.60-0.80]) or SGAs (0.45 [0.17-0.77]).

Conclusions: Several modern antipsychotics and esketamine appeared to be useful adjuncts to antidepressants for acute major depressive episodes, but lithium was somewhat more effective and better tolerated.

Limitations: Most trials of adding lithium involved older, mainly tricyclic, antidepressants, and the dosing of adjunctive treatments were not optimized.

Keywords: Antidepressants; antipsychotics; combination; depression; efficacy; esketamine; lithium.

Figure 1.

Forest plots of random-effects meta-analyses for clinical trials testing the efficacy of supplementing antidepressants with active agents or placebo for major depression: (a) second-generation antipsychotics (SGAs, 28 trials), (b) intranasal esketamine (7 trials), or (c) lithium carbonate (13 trials). SGAs tested were: APZ, aripiprazole; BRX, brexpiprazole; CAR, cariprazine; OFC, olanzapine+fluoxetine combination; QTP, quetiapine; RSP, risperidone; ZPS, ziprasidone. Adding all three types of active treatments were much more effective than adding placebo: (a) SGAs: pooled OR = 1.59 [CI: 1.44–1.75]; z-score = 9.16, p < 0.0001; (b) esketamine: pooled OR = 1.85 [1.45–2.35]; z-score = 4.98, p < 0.0001; Lithium: pooled OR = 2.12 [1.46–3.09]; z = 3.92, p < 0.0001. Heterogeneity ratings (I²) all were <1.0%.

Figure A1.

Flow-chart of selection of reports for inclusion in study, based on PRISMA recommendations (http://www.prisma-statement.org/PRISMAStatement/PRISMAStatement) to yield 39 reports (with 43 trials) included for analysis.