In previously randomized controlled trials (RCTs) on the efficacy of antidepressants in restricted and repetitive behaviors (RRBs) in autism spectrum disorder (ASD), outcomes overwhelmingly showed no benefits of antidepressants studied in the larger multisite RCTs over placebo. However, the positive effect of antidepressants in the RRBs found in the small preliminary studies requires confirmation in larger trials. We aimed to systematically review the efficacy of antidepressants in the treatment of RRBs in ASD by including RCTs from the SCOPUS, PubMed, Embase, Cochrane Controlled Trials Register, Clinical Trials.gov, and other databases in January 2024. Analyzing data from 609 participants across nine RCTs showed no significant difference in the overall pooled mean-end score for RRBs between antidepressant- and placebo-treated groups [SMD (95% CI) of -0.25 (-0.53, 0.02), I2 = 54%, Tau2 = 0.10, prediction interval = -1.03, 0.53]. In small preliminary studies by one group, the clomipramine-treated group's pooled mean endpoint for obsessive-compulsive symptoms in ASD individuals showed a significantly better outcome than the desipramine-treated group, but in unconfirmed studies. Of the individual antidepressants investigated only clomipramine, and fluvoxamine illustrated some efficacy over placebo in small preliminary studies. These findings need confirmation in larger, multisite randomized controlled trials. There were no significant differences in the overall discontinuation rates or discontinuation due to adverse events between the antidepressant- and placebo-treated groups [RR (95% CI) of 1.30 (0.95, 1.78), I2 = 0%, and 1.33 (0.71, 2.47), I2=0%, respectively]. Common side effects included agitation, appetite disturbance, anorexia, gastrointestinal issues, and sleep disturbance, with no significant differences between the antidepressant and placebo groups. In conclusion, the results regarding the efficacy of antidepressants in the treatment of RRBs in ASD are inconsistent. Since previous evidence found a correlation between attention-deficit hyperactivity disorder (ADHD) symptoms including overactivity and impulsivity, and RRBs, further trials including the use of non-stimulants such as atomoxetine could be conducted.
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