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

J Psychopharmacol. 2021 Aug;35(8):890-900. doi: 10.1177/02698811211013579. Epub 2021 Jul 9.


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.

Publication types

  • Comparative Study
  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Antidepressive Agents / administration & dosage*
  • Antidepressive Agents / adverse effects
  • Antipsychotic Agents / administration & dosage*
  • Antipsychotic Agents / adverse effects
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / physiopathology
  • Depressive Disorder, Treatment-Resistant / drug therapy
  • Depressive Disorder, Treatment-Resistant / physiopathology
  • Dose-Response Relationship, Drug
  • Drug Therapy, Combination
  • Humans
  • Ketamine / administration & dosage
  • Ketamine / adverse effects
  • Lithium Compounds / administration & dosage
  • Lithium Compounds / adverse effects
  • Randomized Controlled Trials as Topic


  • Antidepressive Agents
  • Antipsychotic Agents
  • Lithium Compounds
  • Esketamine
  • Ketamine