Antidepressant effects of facial botulinum toxin a injections: Insights from randomized controlled trials

Depressive disorders cause significant global disability, yet oral antidepressants often have systemic side effects and delayed onset. This systematic review and meta-analysis evaluated the efficacy and safety of facial injections of Botulinum toxin A (BoNT/A) compared with placebo and the active antidepressant sertraline. We searched PubMed, Embase, Cochrane CENTRAL, Web of Science, and PsycINFO for randomized controlled trials (RCTs) from inception to December 2025. Eight RCTs comprising 636 participants were included. Facial BoNT/A injection was associated with a significant reduction in depressive symptoms compared with control conditions (SMD = -0.81; 95% CI, -1.23 to -0.38; p < 0.001). Subgroup analysis revealed that BoNT/A was superior to placebo (SMD = -1.04) and demonstrated efficacy comparable to sertraline (SMD = -0.23). Regarding injection strategies, while standard glabellar protocols demonstrated significant antidepressant efficacy, the high-dose pan-facial subgroup showed no statistically significant difference compared to controls. Anxiety scores did not differ significantly between groups. While overall adverse event rates were similar to controls (RR = 1.04), BoNT/A was associated with transient local reactions, avoiding the systemic side effects observed with sertraline. Facial BoNT/A injection represent an effective, safe treatment for depression. These findings provide valuable insights into a non-systemic therapeutic alternative, particularly for patients intolerant to oral antidepressants or those with polypharmacy burdens. PROSPERO REGISTRATION NUMBER: CRD420261277524.