Efficacy of off-label augmentation in unipolar depression: A systematic review of the evidence

Abstract

Treatment of unipolar depression with currently available antidepressants is still unsatisfactory. Augmentation with lithium or second generation antipsychotics is an established practice in non-responders to antidepressant monotherapy, but is also associated with a substantial non-response rate and with non-tolerance. Based on a systematic review of the literature, including meta-analyses, randomized controlled trials (RCTs), non-randomized comparative studies and case studies, off-label augmentation agents (administered in addition to an antidepressant, without FDA approval for treatment of MDD) were identified and evaluated regarding their efficacy using levels of evidence. The agents had to be added to an existing antidepressant regime with the aim of achieving an improved clinical response to an ongoing antidepressant treatment (augmentation) or an earlier onset of effect when starting antidepressant and augmentation agent simultaneously (acceleration). Five substances, modafinil, ketamine, pindolol, testosterone and estrogen (the latter two in hormone-deficient patients) were shown to be clinically effective in high evidence studies. For the six drugs dexamethasone, mecamylamine, riluzole, amantadine, pramipexole and yohimbine clear proof of efficacy was not possible due to low levels of evidence, small sample sizes or discordant results. For the two agents methylphenidate and memantine only studies with negative outcomes could be found. Overall, the quality of study designs was low and results were often contradictory. However, the use of pindolol, ketamine, modafinil, estrogen and testosterone might be an option for depressed patients who are not responding to antidepressant monotherapy or established augmentation strategies. Further high quality studies are necessary and warranted.

Keywords: Augmentation; Efficacy; Off-label; Systematic review; Unipolar depression.