An Uplifting Experience: Can Botulinum Toxin Address Depressive Symptoms?

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CLINICAL REFLECTIONS

“An uplifting experience” is how a prominent Southern California aesthetic medicine specialist described to me the reaction from a notable number of his patients having botulinum toxin treatments during the coronavirus disease 2019 (COVID-19) pandemic. Multiple needle sticks in their face notwithstanding, these patients took particular relish in cocooning themselves (however briefly) in a sanctum sanctorum of self-indulgence, effectively sequestered from the barrage of unique stressors now understood to be associated with COVID-19.^1,2

This isolated anecdote may be simple serendipity or an example of a potential intervention. A recently published article might stimulate discussion about the potential of broadly effective management with neurotoxin injections.

Makunts and colleagues³ used the FDA Adverse Event Reporting System (FAERS) to analyze more than 40,000 botulinum toxin treatment reports across a variety of medical and cosmetic indications including hyperhidrosis, facial rhytides, migraine prophylaxis, spasticity, and spasms. They reported a significantly lower number of depression reports across all indications and injection sites compared with patients undergoing alternative treatments for the same conditions.

They also found a significantly lower incidence of depression-related adverse events (AE) with neurotoxin treatment compared with the control groups. For example, reporting odds ratios (ROR) of botulinum toxin’s depression AE frequencies were uniformly significantly lower compared with control, ranging from 0.12 (95% CI: 0.04, 0.33) to 0.60 (95% CI: 0.48, 0.74), irrespective of indication. The ROR analysis necessitates that depression risk associated with neurotoxin use has a reasonable underlying pharmacodynamic hypothesis. Therefore, these findings should be considered cautiously, as they may not reflect actual number of cases or frequencies in the general population as the FAERS system is voluntary and open to the public.

Although botulinum toxin does not have regulatory approval for the treatment of depression in the United States, this information should offer food for thought that there is a possibility that neurotoxin treatment may show promise in mitigating depressive symptoms. In fact, numerous reports corroborate the efficacy of botulinum toxin in attenuating symptoms related to major depressive disorder,^4-6 including several randomized placebo-controlled trials and observational studies.^7-13 Some believe that the muscles involved in facial expression, such as the corrugator muscles that elicit frowning, play a pivotal role in modulating the brain’s emotional circuitry and neural activity.14-17 Put simply, it is postulated that expressive behavior can alter emotional states, likely through afferent sensory modulation.¹⁵

Botulinum toxin injections have an excellent safety profile. Brin and colleagues¹⁸ reported no significant differences in the overall incidence of AEs, including serious AEs, in almost 2000 patients treated with botulinum toxin compared with patients treated with placebo injections based on the pooled results of 9 trials. Specifically, in trials of major depression, corrugator and procerus neurotoxin injections have noted that treatment-emergent AEs were localized to the treatment site and were temporary (headache and injection site irritation).^9,12 That said, it will remain critical to evaluate the comparative effectiveness of neurotoxin treatment versus established psychopharmacological options and psychotherapeutic strategies and determine if and where it might fit into the current treatment paradigm.

One of the barriers is training mental health professionals on how to perform freehand injections, particularly those that require dose accuracy at multiple injection sites as with neurotoxin injections. Even with extensive experience, injection dose accuracy is difficult to achieve. Kwolek and Block¹⁹ recently calculated that the average accuracy error associated with freehand injection of 40 consecutive 0.025 mL doses from a 1.0 cc syringe was approximately 10% for 2 highly-experienced injectors. Recognizing the urgency to achieve dose accuracy, several neurotoxin-dedicated devices have been developed and are undergoing clinical and regulatory evaluation.²⁰

In conclusion, preliminary evidence suggests botulinum toxin may have a positive impact on depressive symptoms. Additional research needs to be conducted to better determine the safety and efficacy of this treatment. If the data indicate this may be a worthwhile treatment option, administration barriers also will need to be addressed

Dr Blockis an independent clinical trialist and medical device consultant in San Francisco, CA. Website: www.drjonblock.com. The author reports no conflicts of interest concerning the subject matter of this article.

References

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2. Ettman CK, Abdalla SM, Cohen GH, et al. Prevalence of Depression Symptoms in US Adults Before and During the COVID-19 Pandemic. JAMA Netw Open. 2020;3(9):e2019686.

3. Makunts T, Wollmer MA, Abagyan R. Postmarketing safety surveillance data reveals antidepressant effects of botulinum toxin across various indications and injection sites. Sci Rep. 2020;10(1):12851.

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11. Magid M, Reichenberg JS, Poth PE, et al. Treatment of major depressive disorder using botulinum toxin A: a 24-week randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2014;75(8):837-844.

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13. Zamanian A, Ghanbari Jolfaei A, Mehran G, Azizian Z. Efficacy of Botox versus Placebo for Treatment of Patients with Major Depression. Iran J Public Health. 2017;46(7):982-984.

14. Franca K, Lotti T. Botulinum toxin for the treatment of depression. Dermatol Ther. 2017;30(2).

15. Hennenlotter A, Dresel C, Castrop F, et al. The link between facial feedback and neural activity within central circuitries of emotion--new insights from botulinum toxin-induced denervation of frown muscles. Cereb Cortex. 2009;19(3):537-542.

16. Kim MJ, Neta M, Davis FC, et al. Botulinum toxin-induced facial muscle paralysis affects amygdala responses to the perception of emotional expressions: preliminary findings from an A-B-A design. Biol Mood Anxiety Disord. 2014;4:11.

17. Lewis MB. The interactions between botulinum-toxin-based facial treatments and embodied emotions. Sci Rep. 2018;8(1):14720.

18. Brin MF, Boodhoo TI, Pogoda JM, et al. Safety and tolerability of onabotulinumtoxinA in the treatment of facial lines: a meta-analysis of individual patient data from global clinical registration studies in 1678 participants. J Am Acad Dermatol. 2009;61(6):961-970 e961-911.

19. Kwolek MS, Block JE. Maximizing botulinum toxin injections for cosmetic and therapeutic applications with a single use, disposable, exact dose injection assist device. Clin Cosmet Investig Dermatol. 2019;12:35-46.

20. Yoelin SG, Kwolek MS, Block JE. Commentary on Botulinum Toxin injections: a call for improved accuracy. J Clin Aesthet Dermatol. 2020;13(8).