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Research Updates

Doris M. Hexsel, MD

Botulinum Toxin and Depression

Doris M. Hexsel, MD

Wednesday, December 16, 2015

Since the discovery for aesthetic use,1 botulinum toxin type A (BoNT-A) has become the most popular cosmetic procedure. Recently, other potential cosmetic and non-cosmetic indications for BoNT-A have been studied. Among these, major depressive disorder (MDD) is probably the one that is attracting the most attention in the scientific field.

Major depressive disorder directly influences mood and may cause functional impairment, worsening of quality of life and increased risk of mortality.2 The lifetime prevalence of MDD is high at 16.2%.3 Despite numerous drug trials in patients with MDD, up to a third of patients remain symptomatic after treatment with antidepressant drugs.4

Heckmann and colleagues reported that the treatment of glabellar lines with BoNT-A resulted in a happier facial appearance with less negative feelings, showing the influence of BoNT-A in the perception of mood.5 Other studies have also reported patients' positive feelings after aesthetic treatment with BoNT-A.6-8 The facial feedback hypothesis could support the positive effect of cosmetic treatments, such as BoNT-A, on people's emotions.9 Indeed, the results of a recent randomized controlled trial support the concept that facial musculature not only expresses but also regulates mood states.10

Although the treatment of depressive symptoms with BoNT-A injections has been suggested in the last decade,11 randomized controlled trials to assess the effects of BoNT-A injections in the glabella in patients with MDD are very recent (see Figure 1 for an example of a typical glabellar fold in an MDD patient).10,12-15 The results of those trials suggest that a single treatment of the glabella with BoNT-A can alleviate symptoms of depression in patients with MDD (see Table 1 for a summary of those trials).10,12-14

Image 1

Figure 1. A typical glabellar fold (between the eyebrows) in a patient with MDD. Photograph courtesy of Dr. Doris Hexsel.





Follow-up period

ONA dose

Primary endpoint

Wollmer MA, et al.10


  • Ongoing MDD
  • Stable dose of antidepressants
  • Aged 25-65 years

16 weeks

Women: 29 U

Men: 39 U

Change from baseline in HAM-D17 score at Week 6

Magid M, et al.12


  • Ongoing MDD
  • Aged 18-65 years

24 weeks; crossover at Week 12

Women: 29 U

Men: 39 U

Rate of HAM-D21 response (≥50% score reduction from baseline)

Finzi E, Rosenthal NE.13


  • Ongoing MDD
  • Aged 18-65 years

6 weeks

Women: 29 U

Men: 40 U

Response rate, defined by ≥50% decrease in MADRS score at Week 6

Hexsel D, et al.14


  • 25 subjects with MDD matched to 25 subjects without MDD
  • Aged 25-60 years

12 weeks

Women: 20 U + touch up: 10 to 20 U

Rate of BDI response

BDI=Beck Depression Inventory; HAM-D17=17-item Hamilton Depression Rating Scale; HAM-D21=21-item Hamilton Depression Rating Scale; MADRS=Montgomery-Åsberg Depression Rating Scale; MDD=major depressive disorder; ONA=onabotulinumtoxinA.

Wollmer and colleagues performed a randomized, double-blind, placebo-controlled trial in 30 patients aged from 25 to 65 years, who presented with ongoing MDD and were treated with a stable dose of antidepressants.10 Women were treated with 29 U of onabotulinumtoxinA (ONA), and men were treated with 39 U.10 Patients were assessed over a 16-week period. Patients who received active treatment with ONA had an improvement of almost one point on the Clinical Severity Score for Glabellar Frown Lines, while the severity of glabellar lines remained stable in the placebo group.10 Symptoms of depression were assessed with the Hamilton Depression Rating Scale and the Beck Depression Inventory (BDI). Patients in the active treatment group presented significant clinical improvement in symptoms of depression over time, while no significant difference was observed for the placebo group.10

Magid and colleagues performed a randomized, double-blind, placebo-controlled, crossover study in 30 patients with ongoing MDD, who were aged from 18 to 65 years.12 Initially, 11 patients received active treatment with ONA and 19 patients received placebo.12 After 12 weeks, 17 patients from the initial placebo group received ONA treatment for glabellar lines.12 As in the aforementioned trial by Wollmer and colleagues,10 women in this study were treated with 29 U of ONA and men were treated with 39 U.12 Patients were assessed up to 24 weeks. The investigators not only observed significant improvements in symptoms of depression with ONA versus placebo, but also reported that the improvements continued after the cosmetic effects disappeared.12

Finzi and colleagues performed a randomized, double-blind, placebo-controlled trial of ONA in which 74 patients aged from 18 to 65 years were enrolled.13 Patients had ongoing MDD and were followed up for 6 weeks after treatment.13 Forty-one patients concluded the study in the placebo group and 33 in the active treatment group.13 Women received 29 U of ONA and men received 40 U.13 The response and remission rates for the active treatment group were 52% and 27%, respectively, versus 15% and 7%, respectively, in the placebo group.

A study performed by our research team not only assessed the effects of BoNT-A in depression, but also correlated the improvement in symptoms of depression to patient self-esteem.14 Self-esteem and depressive symptoms in subjects with MDD and in healthy subjects were compared before and after injections of ONA in the glabellar area.14 The BDI scores decreased over time (until Week 12) in subjects with depression, whereas the scores for control subjects remained constant.14 Rosenberg Self-Esteem Scale (RSES) scores improved in depressed subjects up to Week 8 but remained stable from Week 8 until Week 12.14 Thus, besides supporting BoNT-A as a potential adjuvant treatment to improve depressive symptoms in patients with MDD, the results suggest that the improvement in depressive symptoms observed after ONA injections might not only be linked to enhancement of self-esteem. The correlation between BDI and RSES scores for depressed patients was significant up to Week 8, but no longer at Week 12.14 Thus, self-esteem scores alone could not explain the improvement in depressive symptoms.

Up to now, clinical trials have tested only the ONA commercial preparation of botulinum toxin in patients with MDD. It might be possible that other commercial preparations of botulinum toxin present similar effects in this indication. To confirm the potential application of other botulinum toxin types and preparations to improve the symptoms of MDD, randomized, double-blind, controlled studies are needed.

Other important questions regarding the treatment of MDD with BoNT-A have been raised. In a recent article, Kruger and Wollmer suggested that a gender effect may exist.16 However, no definite statements can be made because a considerably lower proportion of men participate in these studies. Kruger and Wollmer also speculate that other facial muscles involved in the expression of sadness, such as the mentalis muscle or the depressor anguli oris, may also be targeted with BoNT-A for the specific purpose of treating disorders associated with negative emotions.16

So far, all of the studies that tested the effects of BoNT-A in patients with MDD have presented strong evidence supporting the potential of this drug to improve depressive symptoms.10,12-15 Moreover, results suggest that the improvement in depression is not linked exclusively with the improvement in the aesthetic appearance12 or to self-esteem.14

Further studies are required to explore and identify the remaining open questions on this matter. Studies to assess the mechanisms of action of BoNT-A to improve depressive symptoms, the most appropriate treatment protocol, the effects of BoNT-A commercial preparations other than ONA, possible gender differences, and other possible target muscles should be performed to provide physicians and patients with complete and consistent data.



  1. Carruthers JD, Carruthers JA. Treatment of glabellar frown lines with C. botulinum-A exotoxin. J Dermatol Surg Oncol 1992;18:17-21.
  2. Katon WJ. Epidemiology and treatment of depression in patients with chronic medical illness. Dialogues Clin Neurosci 2011;13:7-23.
  3. Kessler RC, Berglund P, Demler O, et al. National Comorbidity Survey Replication. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003;289:3095-105.
  4. Gaynes BN, Warden D, Trivedi MH, et al. What did STAR*D teach us? Results from a large-scale, practical, clinical trial for patients with depression. Psychiatr Serv 2009;60:1439-45.
  5. Heckmann M, Teichmann B, Schröder U, et al. Pharmacologic denervation of frown muscles enhances baseline expression of happiness and decreases baseline expression of anger, sadness, and fear. J Am Acad Dermatol 2003;49:213-6.
  6. Dayan SH, Lieberman ED, Thakkar NN, et al. Botulinum toxin a can positively impact first impression. Dermatol Surg 2008;34(Suppl 1):S40-7.
  7. Sommer B, Zschocke I, Bergfeld D, et al. Satisfaction of patients after treatment with botulinum toxin for dynamic facial lines. Dermatol Surg 2003;29:456-60.
  8. Lewis MB, Bowler PJ. Botulinum toxin cosmetic therapy correlates with a more positive mood. Cosmet Dermatol 2009;8:24-6.
  9. Alam M, Barrett KC, Hodapp RM, Arndt KA. Botulinum toxin and the facial feedback hypothesis: can looking better make you feel happier? J Am Acad Dermatol 2008;58:1061-72.
  10. Wollmer MA, de Boer C, Kalak N, et al. Facing depression with botulinum toxin: a randomized controlled trial. J Psychiatr Res 2012;46:574-81.
  11. Finzi E, Wasserman E. Treatment of depression with botulinum toxin A: a case series. Dermatol Surg 2006;32:645-9; discussion 649-50.
  12. 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;75:837-44.
  13. Finzi E, Rosenthal NE. Treatment of depression with onabotulinumtoxinA: a randomized, double-blind, placebo controlled trial. J Psychiatr Res 2014;52:1-6.
  14. Hexsel D, Brum C, Siega C, et al. Evaluation of self-esteem and depression symptoms in depressed and nondepressed subjects treated with onabotulinumtoxinA for glabellar lines. Dermatol Surg 2013;39:1088-96.
  15. Han C, Park GY, Wang SM, et al. Can botulinum toxin improve mood in depressed patients? Expert Rev Neurother 2012;12:1049-51.
  16. Kruger TH, Wollmer MA. Depression - an emerging indication for botulinum toxin treatment. Toxicon 2015;107:154-7.