Injection of botulinum toxin (BoNT) into the glabellar region of the face is a novel therapeutic approach in the treatment of depression. This treatment method has several advantages, including few side effects and a long-lasting, depot-like effect. Here we review the clinical and experimental evidence for the antidepressant effect of BoNT injections as well as the theoretical background and possible mechanisms of action. Moreover, we provide practical instructions for the safe and effective application of BoNT in the treatment of depression. Finally, we describe the current status of the clinical development of BoNT as an antidepressant and give an outlook on its potential future role in the management of mental disorders.

Introduction: Botulinum toxin A (BTA) injection into the glabellar region is currently being studied as a treatment for major depressive disorder (MDD). Here we explore efficacy data of this novel approach in a pooled analysis. Methods: A literature search revealed 3 RCTs on this topic. Individual patient data and clinical end points shared by these 3 trials were pooled and analyzed as one study (n=134) using multiple regression models with random effects. Results: In the pooled sample, the BTA (n=59) and the placebo group (n=75) did not differ in the baseline variables. Efficacy outcomes revealed BTA superiority over placebo: Improvement in the Hamilton Depression Rating Scale or Montgomery-Asberg Depression Rating Scale 6 weeks after baseline was 45.7% for BTA vs. 14.6% for placebo (p<0.0001), corresponding to a BTA response rate of 54.2% (vs. 10.7%) and a BTA remission rate of 30.5% (vs. 6.7%). Discussion: Equalling the status of a meta-analysis, this study increases evidence that a single treatment of BTA into the glabellar region can reduce symptoms of MDD. Further studies are needed to better understand how BTA exerts its mood-lifting effect. ^* Equal contribution.

In a randomized, controlled trial (n=30) we showed that botulinum toxin injection to the glabellar region produces a marked improvement in the symptoms of major depression. We hypothesized that the mood-lifting effect was mediated by facial feedback mechanisms. Here we assessed if agitation, which may be associated with increased dynamic psychomotor activity of the facial musculature, can predict response to the treatment. To test this hypothesis we re-analyzed the data of the scales from our previous study on a single item basis and compared the baseline scores in the agitation item (item 9) of the Hamilton Depression Rating Scale (HAM-D) between responders (n=9) and participants who did not attain response (n=6) among the recipients of onabotulinumtoxinA (n=15). Results: Responders had significantly higher item 9 scores at baseline (1.56+0.88 vs. 0.33+0.52, t(13)=3.04, d=1.7, p=0.01), while no other single item of the HAM-D or the Beck Depression Inventory was associated with treatment response. The agitation score had an overall precision of 78% in predicting response in a receiver operating characteristic (ROC) analysis (area under the curve, AUC=0.87). These data provide a link between response to botulinum toxin treatment with a psychomotor manifestation of depression and thereby indirect support of the proposed facial feedback mechanism of action. Moreover, it suggests that patients with agitated depression may particularly benefit from botulinum toxin treatment.

Randomized controlled trials (RCTs) have shown an antidepressant effect of glabellar botulinum toxin (BoNT) injections. In the FDA Adverse Event Reporting System (FAERS) database, BoNT injection is associated with reduced incidence rates of depression across various non-psychiatric indications, which confirms the previous findings independently of specific expectations to an antidepressant effect of BoNT. The rationale of using BoNT to treat depression is to interrupt proprioceptive body feedback that may reinforce negative emotions. Negative emotions also occur in other mental disorders, suggesting a transdiagnostic therapeutic potential of BoNT in psychiatry. Here we report an analysis of the FAERS database, in which we found that, compared to alternative treatments, BoNT injections were associated with lower incidence of anxiety symptoms and related disorders. Among seven indications/injection sites, we found this protective effect of BoNT in cosmetic use/facial muscles, migraine/facial and head muscles, spasms and spasticity/upper and lower limbs, torticollis and neck pain/neck muscles, and sialorrhea/parotid and submandibular glands (reporting odds ratios 0.79–0.27). These findings are encouraging for possible future RCTs on the use of BoNT as a treatment for anxiety and related disorders.