Identifying repurposing opportunities using computational pharmacophenomics in major depressive disorder: a meta-analysis and systematic review of glabellar injection of Botulinum Toxin A

Major depressive disorder (MDD) is a Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V) recognized condition impacting hundreds of millions worldwide, with significant unmet need that may be addressed through drug repurposing. Botulinum Toxin A (BoNT/A) was identified as a potential treatment for MDD via a technique we are pioneering called computational pharmacophenomics, wherein machine learning models are used to identify novel or previously investigated drug repurposing opportunities. We conducted a meta-analysis and systematic literature review to investigate this potential drug repurposing opportunity further. Using PRISMA guidelines and Cochrane Handbook standards, we performed a systematic literature search, identifying 548 publications, of which six publications detailing seven randomized, placebo-controlled clinical trials met all predefined inclusion criteria. In a meta-analysis of these trials, BoNT/A demonstrates a moderate-to-large effect size ( d = -1.01, 95% CI [-1.81; -0.21]) in the ability to reduce clinical measures of depression, suggesting benefit in this patient population, though these data were subject to substantial heterogeneity and potential small studies biases (I 2 = 88.8%). The benefits of this intervention are also supported by other non-randomized interventional studies as well as mechanistic data in preclinical models. While this effect size may in part be influenced by small studies effects, displays heterogeneity, and substantial variability in placebo response, this treatment warrants further investigation and efforts to identify meaningful responder subpopulations. • Computational pharmacophenomics is a novel tool for rapidly identifying drug repurposing ideas • Botulinum toxin A (BoNT/A) was surfaced in this screen as a high-ranking treatment for depression • As many as 12 clinical studies were identified, with 7 randomized, placebo-controlled trials • A quantitative meta-analysis was performed, demonstrating a moderate-to-large effect size • BoNT/A for depression may warrant further study and use within psychiatric care pathways