Major depressive disorder (MDD) is a well-known illness that affects 1 out of 6 adults each year.1 Although pharmacologic and nonpharmacologic therapies exist, MDD remains unremitting in about 15% and recurrent in about 35% of patients on these treatments.2 For patients with incessant MDD, adjunct therapies may be necessary – botulinum toxin is growing as one such possibility.

Other therapeutic alternatives per the American Psychiatric Association consist of somatic therapies, psychotherapy, and complementary therapies such as acupuncture; however, most of these treatments are viewed as time-consuming as they require multiple sessions.2 In an attempt to identify additional options, botulinum toxin A has been studied for its potential use in MDD.

Botulinum toxin A has historically been manufactured for cosmetic benefits (see Table I); however, evidence indicates that it may have a place in therapy adjunctively to standard MDD treatment. The hypothesized mechanism is that injection of botulinum toxin A into the corrugator and procerus muscles within the glabellar region exhibit an effect on facial feedback.  By blocking the release of acetylcholine from the neuronal axons into the synapse within these facial muscles, frowning is inhibited. Studies have found an association between frowning and depression, thus leading researchers to believe that botulinum toxin A may reduce MDD symptoms.3

TABLE I: MANUFACTURED BOTULINUM TOXIN TYPE A IN THE UNITED STATES AS OF 2020.

Generic Name Trade Name Studied for MDD Treatment?
abobotulinum toxin A Dysport No
incobotulinum toxin A Xeomin No
onabotulinum toxin A Botox/ Botox Cosmetic Yes
prabotulinum toxin A Jeuveau No

Botulinum Toxin A for MDD: The Data to Date

Meta-analysis in mid-aged women

A 2016 meta-analysis evaluated three randomized controlled trials (RCTs) with the primary outcome of mean change in primary depression scores between botulinum toxin A and placebo arms at six weeks post-injection. The compiled population consisted of 134 patients on antidepressants from four countries with 89.6% being female around 50 years old. In the intervention arm, males and females were given a single dose of 39-40 and 29 units, respectively, of botulinum toxin A in the glabellar region.

Response was identified as ≥50% reduction in the primary depression score. Remission was determined to be a score of ≤10 using the Montgomery-Asberg Depression Rating Scale (MADRS) and ≤7 using the Hamilton Depression Rating Scale (HAM-D). 3 Both the MADRS and HAM-D are validated depression scoring tools per the American Psychiatric Association (APA) MDD Treatment Guidelines.2

The results indicated a statistically significant difference in mean change in primary depression scores from baseline to 6 weeks in those that received botulinum toxin A vs placebo: -9.8 mean change in depression scores with a 95% CI of -12.9 to -6.7. Additionally, the remission rate was 4.6 times higher in the botulinum toxin arm versus placebo with a 95% CI of 1.6 to 13.1. A pooled number needed to treat (NNT) was calculated to be 2.3 for response rates, meaning three patients would need to be treated with a single dose of botulinum toxin A in the glabellar region for one patient to see a ≥50% reduction in their primary depression score after 6 weeks post-injection. A NNT of 4.9 was also calculated for remission rates, meaning five patients would need to be treated with a single dose of botulinum toxin A in the glabellar region to have one patient see a reduction of ≤10 using the MADRS and ≤7 using the HAM-D six weeks post-injection. Of note, the most common side effects reported in the botulinum toxin A group were headache and mild injection site pain.3

The limitations of this meta-analysis were small sample size, wide CI of remission rates, risk of publication bias with only three studies included, majority of participants were female, one RCT was unblinded, short duration, and re-dosing of botulinum toxin A after six weeks was not measured. Some strengths that aid in generalizability, however, were inclusion and exclusion criteria, population, recognized depression screening tools, botulinum dosing, follow up, and was conducted in four countries. Overall, the results indicate that injection of botulinum toxin A into the glabellar region may have clinical benefit as a safe, adjunct treatment for patients with MDD on antidepressants, particularly women around age 50 with MDD.

Onabotulinum toxin A as a monotherapy

A Phase 2, double-blind, parallel-group study was conducted at 32 US sites and compared 30 and 50 units of onabotulinum toxin A divided into six or eight glabellar injections, respectively, during one session versus equivalent units of placebo. The study population was 255 females around 43- to 44-years-old. Subjects had to have MDD, not be on antidepressants at the start or during the study, and be in an active depressive episode for ≥4 weeks at the start of the trial. The primary outcome was mean change in MADRS from baseline to 6 weeks post-injection for each treatment group (30 units and 50 units) compared to separate placebo arms (30 and 50 units).4

There was no statistical difference in mean change of MADRS with either 30 or 50 units compared to placebo at 6 weeks post-injection: -11.6 with 30-unit vs -7.9 with 30-unit placebo and -11.6 with 50-unit vs -12.9 with 50-unit placebo. There was a statistically significant difference in mean change of MADRS at Weeks 3 and 9 in the 30-unit arm: -7.8 with 30-unit vs -3.6 with placebo and -13.7 with 30-unit vs -10 with placebo, respectively. Onabotulinum toxin A had noted adverse events: headache in ≥10% of patients in the 30 and 50 unit arms, eyelid ptosis, and sinusitis in ≥5% of patients in the 30 unit arm, and upper respiratory tract infections occurring in ≥5% of patients in the 50 unit arm.4

The limitations of this study were the inclusion of only females and strictness of the exclusion criteria, specifically the inability to be on antidepressants. Some strengths were its design, multicenter, double-blinded, placebo-controlled, 24-week follow-up, and attempt to study different onabotulinum toxin A doses, 30 and 50 units. This study was further hindered in the generalizability of its results and did not show statistical or clinical significance in change of the mean MADRS from baseline. However, the study may support that onabotulinum toxin A should not be used as monotherapy, but rather in conjunction with antidepressants for MDD to produce an optimal effect.

Treatment-Resistant MDD

A case series from 2018 included 19 women and 23 men from New Delhi and Mumbai with MDD and treatment-resistant MDD. The participants had to be on antidepressants for at least 6 weeks and then received a single treatment of 29 units for women and 39 units for men of onabotulinum toxin A at five glabellar region sites.

The primary outcome was mean change in the HAM-D, MADRS, and Beck Depression Inventory (BDI) from baseline to three weeks post-injection.5 After 3 weeks, mean depression scores decreased by −9 ± 3.5 on the HAM-D, -12.7 ± 4 on the MADRS, and -12.5 ± 4.2, on the BDI. Approximately 53% of patients had ≥25% reduction in their depression scale scores after 3 weeks post-injection.5

 The major limitations were small sample size, inability to blind, randomize, or power, short follow up period, failure to report adverse event profiles, and being conducted outside the US. Some strengths were the inclusion of men and similarities in baseline characteristics. This case series did indicate an association between botulinum toxin A as an effective adjunct to antidepressants for men and women with treatment-resistant MDD.

More on treatment-resistant depression on our Psycom consumer site.

Professional Takeaways

Based on the evidence, botulinum toxin A given as a single treatment in the glabellar region may be efficacious when used adjunctively to pharmacotherapy for those with major depressive disorder. Botulinum toxin A has primarily been studied in middle-aged females and lacks sufficient data for use in males. With limited side effects and potential for improved adherence compared to other daily therapy options, botulinum toxin A may serve as a beneficial adjunct for female patients with MDD. More RCTs are necessary, however, to determine an optimal dose and frequency.

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Last Updated: Dec 15, 2020