Early Career Psychiatrists Meta-Analysis

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 stimulantlike 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, placebocontrolled 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 © Copyright 2013 Physicians Postgraduate Press, Inc. 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 ([email protected]). D is the leading cause of disability worldwide in terms of years lost due to illness.1 Among the key neurovegetative features of depression are fatigue, lack of energy, sleep disturbances, and loss of concentration.2–4 According to survey data, about three-quarters of patients experience fatigue or lack of energy and sleep disturbances.2–4 In addition to being primary features of depressive episodes, these symptoms may also occur as adverse side effects of antidepressants and mood stabilizers.5,6 Furthermore, they can also persist as residual symptoms despite adequate pharmacotherapy and clinical remission.7 Nonresponse and partial response to antidepressants remain problematic, with approximately one-third of depressed patients failing to achieve symptomatic remission.8 For example, hypersomnia has been reported as a residual depressive symptom in up to 15% of patients no longer meeting full criteria for major depressive disorder (MDD).9 In a recent study,10 25% of patients with bipolar disorder in an acute depressive episode reported hypersomnia during the interepisode. These residual symptoms are known to predict relapse of major affective episodes in both MDD11 and bipolar depression.12 One potential candidate for augmenting current firstline therapies for depression is the novel stimulant-like agent modafinil, which is US Food and Drug Administration (FDA)–approved for treating excessive sleepiness in narcolepsy, obstructive sleep apnea, and shift work sleep disorder.13 Modafinil is a racemic mixture of Rand S-enantiomers, while the isolated R-enantiomer, armodafinil, has a longer half-life and is also available with identical FDA approval.14 The exact mechanisms underlying the action of modafinil are complex and yet to be fully elucidated. It is known to directly bind to, and inhibit, both the dopamine transporter and norepinephrine transporter, thus elevating extracellular levels of dopamine and norepinephrine in a similar manner to conventional amphetamine-like psychostimulants.15 Modafinil, though, has a relatively localized rather than widespread brain activation, a diminished side effect profile, and a lower potential for abuse.15 Unlike those of conventional stimulants, the wake-promoting effects of modafinil have been largely attributed to increased hypothalamic histamine release, which has a central role in the regulation of arousal and circadian rhythms.16 Modafinil also raises orexinergic, serotonergic, and glutamatergic activity15 and decreases the release of γ-aminobutyric acid.17 These effects are thought to be secondary to the elevated catecholamine levels and increased activation of α-adrenergic, D1, and D2 receptors.15 The multimodal actions may be responsible for its diverse effects, in which orexinergic and histaminergic actions Modafinil Augmentation Therapy in Unipolar and Bipolar Depression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials Alexander J. Goss, BA, MSc; Muzaffer Kaser, MD, MPhil; Sergi G. Costafreda, MD, PhD; Barbara J. Sahakian, PhD; and Cynthia H. Y. Fu, MD, PhD