Objective:Augmentation strategies are commonly applied when an individual is unresponsive to antidepressant monotherapy. Lamotrigine is currently considered at best only as second line augmentation for treatment-resistant unipolar depression while its clinical efficacy and safety profiles remain inconclusive. We intended to assess the therapeutic effects and safety profiles of lamotrigine augmentation in patients with treatment-resistant unipolar depression by conducting a meta-analysis.Methods:MEDLINE, Embase, EBSCO, Cochrane, Web of Science, Scopus, Wanfang and Ariniti databases were searched. Coprimary outcomes, including changes in severity of depression and response rate, were measured in this study. Secondary outcomes were defined as the safety profile of the intervention, including reported discontinuation rate and adverse events.Results:Eight double-blinded randomized controlled trials with 677 patients overall were included. Significant improvements in Hamilton Rating Scale for Depression scores and response rates were shown in lamotrigine augmentation groups compared with control groups, of which the pooled result of six Chinese studies showed positive effects of Hamilton Rating Scale for Depression improvement while the pooled result of two non-Chinese studies was statistically non-significant. Patients with more severe illness and longer duration of illness were more effectively treated with lamotrigine augmentation. The magnitude of depression improvement after lamotrigine augmentation was higher in patients treated with selective serotonin reuptake inhibitors than those treated with serotonin-norepinephrine reuptake inhibitors. Lamotrigine augmentation is well-tolerated in terms of all-cause discontinuation rate and adverse events.Conclusions:Lamotrigine augmentation may serve as a possible choice for patients with treatment-resistant unipolar depression and further trials are warranted to clarify the optimal dosage of lamotrigine augmentation together with the treatment duration and safety over time.