Modafinil Augmentation Therapy in Unipolar and Bipolar Depression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Article Abstract

Objective: Current pharmacologic treatments for a depressive episode in unipolar major depressive disorder (MDD) and bipolar depression are limited by low rates of remission. Residual symptoms include a persistent low mood and neurovegetative symptoms such as fatigue. The objective of this study was to examine the efficacy and tolerability of augmentation of first-line therapies with the novel stimulant-like agent modafinil in MDD and bipolar depression.

Data Sources: MEDLINE/PubMed, PsycINFO, 1980-April 2013 were searched using the following terms: (modafinil or armodafinil) and (depressi* or depressed or major depressive disorder or major depression or unipolar or bipolar or dysthymi*). Inclusion criteria were as follows: randomized controlled trial (RCT) design, sample comprising adult patients (18-65 years) with unipolar or bipolar depression, diagnosis according to DSM-IV, ICD-10, or other well-recognized criteria, modafinil or armodafinil given as augmentation therapy in at least 1 arm of the trial, and publication in English in a peer-reviewed journal.

Study Selection: Double-blind, randomized, placebo-controlled clinical trials of adjunctive treatment with modafinil or armodafinil of standard treatment for depressive episodes in MDD and bipolar depression were selected.

Data Extraction: Two independent appraisers assessed the eligibility of the trials. A random-effects meta-analysis with DerSimonian-Laird method was used. Moderator effects were evaluated by meta-regression.

Results: Data from 6 RCTs, with a total of 910 patients with MDD or bipolar depression, consisting of 4 MDD RCTs (n = 568) and 2 bipolar depression RCTs (n = 342) were analyzed. The meta-analysis revealed significant effects of modafinil on improvements in overall depression scores (point estimate = −0.35; 95% CI, −0.61 to −0.10) and remission rates (odds ratio = 1.61; 95% CI, 1.04 to 2.49). The treatment effects were evident in both MDD and bipolar depression, with no difference between disorders. Modafinil showed a significant positive effect on fatigue symptoms (95% CI, −0.42 to −0.05). The adverse events were no different from placebo.

Conclusions: Modafinil is an effective augmentation strategy for acute depressive episodes, including for symptoms of fatigue, in both unipolar and bipolar disorders.

J Clin Psychiatry 2013;74(11):1101-1107

Submitted: May 1, 2013; accepted August 22, 2013 (doi:10.4088/JCP.13r08560).

Corresponding author: Cynthia H. Y. Fu, MD, PhD, School of Psychology, University of East London, Stratford Campus, Water Lane, London E15 4LZ UK (

Volume: 74

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