OBJECTIVES: Despite different pharmacological strategies in the management of depression, many patients experience inadequate response to treatment in clinical practice. A systematic review was carried out to perform a qualitative assessment of studies examining different antidepressant monotherapies in patients with major depressive disorder (MDD), and an inadequate response to prior selective-serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) therapy. METHODS: MEDLINE^®, Embase^®, Cochrane, CDSR, and PsychINFO^® databases, and clinical trial registries were searched from January 1980 to 27 March 2014. The review included trials in patients with MDD with inadequate response to SSRIs/SNRIs. Included studies underwent a two-stage screening process conducted by two independent reviewers, with discrepancies reconciled by a third independent reviewer. Data were extracted by a single reviewer with quality check performed by another, and multiple publications were linked. The quality of included studies was critically appraised based on recommendations from national guidelines. RESULTS: The database search retrieved 11 953 citations, of which 27 randomised controlled trials from 54 publications met the inclusion criteria. The switch interventions assessed included: SSRIs, SNRIs, and other non-SSRI/SNRI antidepressants such as monoamine oxidase inhibitors, tricyclic antidepressants, tetracyclic antidepressants, with a few studies comparing different antidepressants in switch therapy. The evidence varied in terms of: type of treatment, study duration (ranging from 2 weeks to 14 weeks), depression scale, sample size (<100 to >500 patients), prior therapy, and definition of inadequate response. Generally, the mean age of included patients was comparable (44 years to 48 years). Overall, few of the included studies were deemed to be of good quality. CONCLUSIONS: A comprehensive overview of switch studies assessing antidepressant monotherapies in prior SSRI/SNRI non-responding patients found an overall low strength of evidence for studies evaluating these monotherapies. Limited clinical data have been retrieved but give the possibility to perform further quantitative evaluations.