Major depressive disorder (MDD) is one of the most common mental health conditions in the world, affecting hundreds of millions of people. Despite several approved treatment options, many patients do not experience adequate relief, either due to limited effectiveness or because side effects and comorbidities restrict their use. A new Every Cure-led publication in Psychiatry Research Communications may offer hope for these patients. Using our AI platform and disease agnostic approach to drug repurposing, we identified botulinum toxin type A (BoNT/A), best known as Botox, as a promising repurposing candidate for MDD. After extensive review by our team and independent Scientific Advisory Council, it was selected as an Every Cure Repurposing Program (see full portfolio here) for advancement. In this publication, we evaluated this repurposing opportunity through a rigorous systematic review and meta-analysis of existing clinical trials and identified opportunities for further research in this space.

An Unmet Need in Depression Treatment

MDD remains a significant challenge in modern medicine. While treatments like selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and others are effective for many patients, a substantial portion don’t respond, experience side effects that limit long-term use, or have co-morbidities that limit treatment options. Finding additional treatment options, particularly those that are already approved and have well-established safety profiles, is required to meet this unmet need. 

Discovery through Computational Pharmacophenomics 

Every Cure is pioneering a novel approach to discover new uses for existing medications called computational pharmacophenomics to systematically evaluate the potential of all existing drugs across all diseases. Using this method, we generate scores for tens of millions of possible drug–disease pairs. Each pair is assigned a “treat score” between 0 and 1, where higher scores indicate a greater likelihood that the drug could be a biologically valid treatment for that condition. These scores help Every Cure prioritize hypotheses for further study, providing a relative ranking rather than a definitive prediction of effectiveness.

The top scoring repurposing opportunities are reviewed by our team of medical experts, who consider additional factors such as unmet medical need, existing evidence, and safety. To identify the most promising novel opportunities for major depressive disorder (MDD), we applied a series of filters, removing drugs already approved or commonly used for depression, as well as broad drug classes like antipsychotics and anticonvulsants. Through this process, Botox was the top novel candidate once established or expected treatments for MDD were removed (ranked 33rd out of nearly 2,000 approved drugs evaluated for MDD before filtering), further supporting its potential as a repurposed treatment.

What Is Botox, and Why Might It Work for Depression?

While it’s most widely known as a cosmetic treatment for wrinkles, Botox injection has a growing list of approved medical uses, including chronic migraine, overactive bladder, and cervical dystonia (a painful neurological disorder). When injected into the glabellar region of the face, the area between the eyebrows, it temporarily relaxes the muscles in the region.

Early laboratory research suggests Botox may have direct effects on brain chemistry. In animal studies, Botox has been shown to boost levels of serotonin and other molecules linked to mood, and to increase the density of connections between brain cells in regions associated with memory and emotional regulation. While these findings are promising, they have not been confirmed in humans. 

To better understand the existing evidence, we conducted a systematic review and meta-analysis of studies evaluating Botox as a treatment for depression.

What the Clinical Evidence Shows

We reviewed existing clinical research to better understand Botox’s potential as a treatment for MDD. Our team searched across major medical databases and identified 12 clinical trials studying glabellar Botox injections in patients with depression.

Of these, 7 studies met strict criteria for deeper analysis. These were high-quality trials that compared Botox to a placebo injection, focused on patients without other major health conditions, and measured outcomes using standard depression scales. In total, these studies involved 505 unique patients, including 362 females.

When results from these 7 trials were combined, Botox showed a moderate-to-large effect size in the reduction of clinical depression scores compared to placebo. Additional studies, not included in the analysis, also showed encouraging results. Some found Botox performed similarly to standard antidepressants, while others suggested it may help patients who have not responded to other treatments or work in patients with comorbidities limiting the use of SSRIs. Across all studies, Botox was generally well tolerated, with no serious side effects reported.

Important Caveats and the Path Forward

While Botox shows promise as a potential treatment for MDD, there are important limitations to consider. Many of the studies were relatively small, and because Botox has visible cosmetic effects, it can be difficult to fully “blind” participants and researchers to who received the treatment. In several trials, a high proportion of participants were able to correctly identify their treatment group, which may introduce bias. There was also variation across studies in design and measurement, and the possibility of publication bias, where positive studies are more likely to be published than negative ones. Notably, the largest included trial did not show a significant difference between Botox and placebo in one dosing group, though this study also had a substantial placebo response.

From Data to Real-World Impact

This publication reflects Every Cure’s approach: using computational pharmacophenomics to identify promising treatment opportunities, then evaluating those signals against the best available clinical evidence to ultimately reach patients. 

Botox has an established safety record, is widely available, and has been associated with reductions in depressive symptoms across multiple independent clinical trials. While these findings are encouraging, they are intended to highlight a promising opportunity for further study rather than serve as a treatment recommendation. Additional large, well-controlled trials could help confirm effectiveness and better understand which patients may benefit.

A Collaborative Effort

This work reflects the dedication of the Every Cure team, who is committed to saving and improving lives by repurposing drugs. We are grateful to everyone who contributed to this publication, including those at Coronado Research, and to the patients who participated in the clinical trials that made this meta-analysis possible.

Read the full paper: https://www.sciencedirect.com/science/article/pii/S2772598726000164