The Efficacy of Psychostimulants in Major Depressive Episodes: A Systematic Review and Meta-Analysis

J Clin Psychopharmacol. 2017 Aug;37(4):412-418. doi: 10.1097/JCP.0000000000000723.


Background: Psychostimulants are frequently prescribed off-label for adults with major depressive disorder or bipolar disorder. The frequent and increasing usage of stimulants in mood disorders warrants a careful appraisal of the efficacy of this class of agents. Herein, we aim to estimate the efficacy of psychostimulants in adults with unipolar or bipolar depression.

Methods: The PubMed/Medline database was searched from inception to January 16, 2016 for randomized, placebo-controlled clinical trials investigating the antidepressant efficacy of psychostimulants in the treatment of adults with unipolar or bipolar depression.

Results: Psychostimulants were associated with statistically significant improvement in depressive symptoms in major depressive disorder (odds ratio [OR], 1.41; 95% confidence interval [CI], 1.13-1.78; P = 0.003) and bipolar disorder (OR, 1.42; 95% CI, 1.13-1.78; P = 0.003). Efficacy outcomes differed across the psychostimulants evaluated as a function of response rates: ar/modafinil (OR, 1.47; 95% CI, 1.20-1.81; P = 0.0002); dextroamphetamine (OR, 7.11; 95% CI, 1.09-46.44; P = 0.04); lisdexamfetamine dimesylate (OR, 1.21; 95% CI, 0.94-1.56; P = ns); methylphenidate (OR, 1.49; 95% CI, 0.88-2.54; P = ns). Efficacy outcomes also differed between agents used as adjunctive therapy (OR, 1.39; 95% CI, 1.19-1.64) or monotherapy (OR, 2.25; 95% CI, 0.67-7.52).

Conclusions: Psychostimulants are insufficiently studied as adjunctive or monotherapy in adults with mood disorders. Most published studies have significant methodological limitations (eg, heterogeneous samples, dependent measures, type/dose of agent). In addition to improvements in methodological factors, a testable hypothesis is that psychostimulants may be more appropriately tested in select domains of psychopathology (eg, cognitive emotional processing), rather than as "broad-spectrum" antidepressants.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Benzhydryl Compounds / therapeutic use
  • Central Nervous System Stimulants / therapeutic use
  • Depressive Disorder, Major / diagnosis*
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / psychology
  • Dextroamphetamine / therapeutic use
  • Humans
  • Methylphenidate / therapeutic use
  • Modafinil
  • Psychotropic Drugs / therapeutic use*
  • Treatment Outcome


  • Benzhydryl Compounds
  • Central Nervous System Stimulants
  • Psychotropic Drugs
  • Methylphenidate
  • Modafinil
  • Dextroamphetamine