Botulinum Toxin Linked to Antidepressant Effects

Jeff Craven

August 12, 2020

A study using safety surveillance data of botulinum toxin found significant associations between its use and antidepressant effects, across several indications and different injection sites, according to the study's authors.

Their results show that the antidepressant effect of botulinum toxin "administered for various indications goes beyond the control of the intended disease states and does not depend on the location of the injection," according to Tigran Makunts, PharmD, of the Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of California, San Diego, and coauthors.

Previous high-quality studies have found botulinum toxin treatment has been associated with antidepressant effects when administered to the glabellar region of the face, they noted. The study was published in Scientific Reports.

The researchers evaluated adverse events reported to the Food and Drug Administration's current adverse event reporting system (FAERS) between September 2012 and December 2019, and the FDA's previous adverse event reporting system between January 2004 and August 2012. Overall, they analyzed 174,243 reports, which were divided into eight treatment-related groups based on the indication for botulinum toxin: Cosmetic use (20,684 patients), migraine (4,180 patients), spasms and spasticity not involving facial muscles (2,335 patients), neurological and urinary bladder disorders (915 patients), torticollis (1,360 patients), hyperhidrosis (601 patients), blepharospasm (487 patients), and sialorrhea (157 patients). Each group was matched to controls from the FAERS database, who had different treatments for the same indications. (Reports in which patients were on an antidepressant or where depression was listed as an indication were not included).

In nearly all treatment groups, reports of depression and depression-related adverse events were significantly lower among those who received botulinum toxin, compared with controls: For those who received botulinum toxin injections in facial muscles for cosmetic uses, the reporting odds ratio was 0.46 (95% confidence interval, 0.27-0.78). Significant effects were also seen in the following groups: those who received injections into facial and head muscles for migraine (ROR, 0.60; 95% CI, 0.48-0.74), injections into the upper and lower limbs for spasms and spasticity (ROR, 0.28; 95% CI, 0.18-0.42), injections into neck muscles for torticollis and neck pain (ROR, 0.30; 95% CI, 0.20-0.44), injections into eyelid muscles for blepharospasm (ROR, 0.13; 95% CI, 0.05-0.39), and injections into the axilla and palm for hyperhidrosis (ROR, 0.12; 95% CI, 0.04-0.33).

There were no cases of depression or depression-related adverse event reports among those treated with botulinum toxin for sialorrhea with injections into the parotid and submandibular glands, and there were decreased reports of depression among those who received detrusor muscle injections for neurological and urinary bladder disorders, but the results in both groups were not statistically significant, according to the researchers.

In an interview, Ruben Abagyan, PhD, study coauthor and professor at Skaggs School of Pharmacy and Pharmaceutical Sciences, said the study's finding go "beyond breaking a positive feedback loop between depression and the ‘frown' wrinkles in the glabellar region of the forehead." The data showing efficacy with botulinum toxin injected in other areas of the body can help clinicians "expand their search for the most effective injection location and dose beyond the facial injections to improve the depression-related therapeutic outcomes."

Another takeaway from the study, he noted, is that botulinum toxin can have effects beyond the local effect seen near an injection site. Administering botulinum toxin for spasms and spasticity, excessive sweating, migraine, urinary bladder disorders, blepharospasm, or excessive salivation/drooling could result in reduced depression and improved systemic neurological effects.

"Severe depression remains a very difficult condition to treat. The existing drugs have dangerous side effects, the onset of the therapeutic action is delayed by at least a month, and the adherence to the medication is suboptimal. Therefore, finding new ways to treat depression is critical," Dr. Abagyan said. "Botulinum toxin opens up a new physiological mechanism to be tried to reduce depression."

Michelle Magid, MD, MBA, of the department of psychiatry at the University of Texas at Austin, said in an interview that, although the study was retrospective, "physicians can feel confident that botulinum toxin treatment will not cause depression; it may very well lead to improved mood in some of their patients." Dr. Magid was not an author of this study, but has studied botulinum toxin as a possible treatment of depression.

"Previous studies have shown that botulinum toxin injected into the forehead region can improve symptoms of depression. The studies were small and confined to treating the glabellar region only," she added. "This is a large retrospective study showing that botulinum toxin injected into other regions, such as the neck, underarms, bladder, hands, arms, and legs, can also have an antidepressant effect."

Dr. Magid agreed that the use of botulinum toxin as an antidepressant should be investigated further, and could be a tool for patients who do not respond well to traditional antidepressant medications.

In their paper, the authors offered several plausible mechanisms for the antidepressant effects of botulinum toxin, including transneuronal transport to the parts of the central nervous system that regulate mood and emotion, systemic distribution, distributed muscle stress memory, and efficacy in the primary indication treatment. Although the mechanism of action is not well understood, Dr. Magid noted it could be the removal of somatic symptoms that contribute to an improvement in mood.

"It is possible that alleviating the psychological distress associated with neck spasms, excessive sweating [and so on] can be causing the antidepressive effects," she said. "However, it is also possible that depression is actualized by a series of somatic symptoms – body aches, insomnia, sweating, for example. By removing somatic symptoms, one may also remove the correlating mood dysregulation."

The study "certainly raises a lot of questions," particularly about the "apparent multiple mechanisms of action of BoNT that we don't understand yet," Mark Rubin, MD, a cosmetic dermatologist who practices in Beverly Hills, Calif., said in an interview. "I believe it lends great deal of credence to the use of [botulinum toxin] for depression and certainly validates the need for more robust clinical trials for that indication," he added.

"I think what we all as clinicians need to take away from this paper is that there is a great deal we don't understand about the global pharmacologic effects of [botulinum toxin] and equally important, that there are apparently other pharmacologic pathways we need to explore in the treatment of depression," said Dr. Rubin, of the department of dermatology at the University of California, San Diego, who was not an investigator in the study.

One author reported being a consultant for Allergan. Dr. Makunts and the other author report no relevant conflicts of interest; Dr. Magid reported being a consultant for Allergan and a speaker for Ipsen. Dr. Rubin had no related disclosures.

SOURCE: Makunts T et al. Sci Rep. 2020 Jul 30;10(1):12851. doi: 10.1038/s41598-020-69773-7.

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