OnabotulinumtoxinA for the treatment of major depressive disorder: a phase 2 randomized, double-blind, placebo-controlled trial in adult females

Abstract

This 24-week double-blind placebo-controlled multicenter randomized phase 2 trial evaluated efficacy and safety of onabotulinumtoxinA (onabotA; BOTOX) vs. placebo for major depressive disorder (MDD) [NCT02116361]. Primary endpoint was the change in Montgomery-Åsberg Depression Rating Scale (MADRS); secondary endpoints were Clinical Global Impressions-Severity and 17-item Hamilton Depression Rating Scale at week 6. A total of 255 adult females were treated. OnabotA 30 U approached significance compared to placebo on MADRS (mixed-effect model repeated measures least-squares mean difference: −3.7; P = 0.053) and reached significance [least-squares mean differences: −3.6 to −4.2; P < 0.05 (two-sided)] at weeks 3 and 9. Secondary endpoints were also significant at several time points. At week 6, onabotA 50 U did not separate from placebo in any parameters. OnabotA was generally well-tolerated: the only treatment-emergent adverse events reported in ≥5% in either onabotA group, and more than matching placebo were headache, upper respiratory infection, and eyelid ptosis. OnabotA 30 U, administered in a standardized injection pattern in a single session, had a consistent efficacy signal across multiple depression symptom scales for 12 or more weeks. OnabotA 30 U/placebo MADRS differences of (observed ANCOVA) ≥4.0 points (up to week 15) and ≥2.0 points (weeks 18–24) agree with the 2-point change threshold considered clinically relevant in MDD. OnabotA is a local therapy and is not commonly associated with systemic effects of conventional antidepressants and may represent a novel treatment option for MDD.

Postmarketing safety surveillance data reveals antidepressant effects of botulinum toxin across various indications and injection sites

“…In the last decade, several randomized double-blind placebo-controlled clinical trials 11,[28][29][30] , case series 31 , and an open-label study 32 have demonstrated significant efficacy of BoNT injections into the glabellar region of the face in treating depression. These studies were followed by a larger, industry-sponsored Phase II trial with 258 participants however the results were mixed 12 . Although there was a decrease in depression rating scores and numeric superiority of BoNT over placebo, the results did not meet the primary endpoint criteria.…”

Efficacy and Safety of Botulinum Toxin vs. Placebo in Depression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

“…Twentythree articles were excluded; the reasons are presented in Figure 1. Finally, five RCTs met the inclusion criteria for this meta-analysis (13)(14)(15)(16)24).…”

“…We identified five eligible articles involving a total of 417 participants (189 patients in the BTX-A group, 228 patients in the placebo group), all of which were randomized, placebocontrolled trials published between 2012 and 2020. Notably, Brin et al (16) carried out a two-dose parallel groups study of low dosage (30 U) and high dosage (50 U) BTX-A. There were 389 females and 28 males, with a mean (SD) sample size of 70 (44.0) and a mean (SD) age of 46.4 (4.1).…”

“…All studies were blinded to participants, investigators, and outcome assessment (24). Only two articles were considered low risk of bias in terms of incomplete outcome data (13,16), while others were considered high risk of bias because the data regarding the differences in pre-and post-treatment means and SDs were not given directly. For other bias, we only rated one study as high risk of bias (24), but the risk of bias was unclear for four other studies.…”

“…Several subsequent trials reported similar results (14,15). However, a recent large study in 2019 showed that the effects of the high-dosage (50 U) BTX-A injections were similar to effects in the placebo group (16). Given the controversy among different studies, and the growing interest toward complementary and alternative medicine for depression, a systematic review and meta-analysis regarding the efficacy and safety of BTX-A on MDD is worth updating.…”