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.

Fig. 1

Change from baseline in MADRS total score for (a) mLOCF^a MMRM^b clinic visits centered around week 6 for 30 U, and observed data ANCOVA, modified intent-to-treat for (b) 30 U treatments and (c) 50 U treatments. ^amLOCF was used to impute missing values for follow-up visits. ^bThe MMRM model used for combined dose cohort included treatment (BOTOX vs. placebo), visit (weeks 3, 6, and 9), treatment-by-visit interaction, dose cohort (30U vs. 50U), and investigator center as fixed effects; baseline clinic MADRS total score, duration of illness, and number of previous depression episodes as covariates; and patient was included as a random effect. The same model with dose cohort excluded was used for each dose cohort. Within each dose cohort, sites with fewer than 10 patients were combined into one pseudo-site. The ‘observed data' (without imputation for missing values) and P-values were obtained from an ANCOVA on the response variable. The model used within each dose cohort included treatment (onabotA vs. placebo) and investigator center as fixed effects, with baseline clinic MADRS total score, duration of illness, and number of previous depression episodes as covariates, each included as continuous rather than categorical variables. Within each dose cohort, sites with fewer than 10 patients were combined into one pseudo-site. ANCOVA, analysis of covariance; MADRS, Montgomery-Åsberg Depression Rating Scale; LS, least squares, mLOCF, modified last observation carried forward; MMRM, mixed-model repeated measures; U, units; mITT, modified intent-to-treat.

Fig. 2

Change from baseline in CGI-S score (observed data, ANCOVA, mITT population) for (a) 30 U and (b) 50 U treatments. The data used are ‘observed data' (without imputation for missing values) and P-values were obtained from an ANCOVA on the response variable. The model used within each dose cohort included treatment (onabotA vs. placebo) and investigator center as fixed effects, with baseline clinic CGI-S total score, duration of illness, and number of previous depression episodes as covariates, each included as continuous rather than categorical variables. Within each dose cohort, sites with fewer than 10 patients were combined into one pseudo-site. ANCOVA, analysis of covariance; CGI-S, clinical global impressions-severity; LS, least squares; mITT, modified intent-to-treat; U, unit.

Fig. 3

Change from baseline in HAMD-17 score (observed data, ANCOVA, mITT population) for (a) 30 U, (b) 50 U treatments. The data used are ‘observed data' (without imputation for missing values) and P-values were obtained from an ANCOVA on the response variable. The model used within each dose cohort included treatment (onabotA vs. placebo) and investigator center as fixed effects, with baseline clinic HAMD-17 total score, duration of illness, and number of previous depression episodes as covariates, each included as continuous rather than categorical variables. Within each dose cohort, sites with fewer than 10 patients were combined into one pseudo-site. ANCOVA, analysis of covariance; HAMD-17, 17-item Hamilton Depression Rating Scale; LS, least squares; mITT, modified intent-to-treat; U, units.