Promising initial findings but multiple limitations
Although BTA injections have been explored as a potential treatment for several psychiatric conditions, the bulk of recent evidence is derived from studies in patients with depressive disorders. BTA injections in the glabellar regions have been shown in small RCTs to be well-tolerated with overall promising improvement of depressive symptoms, optimally 6 weeks after a single injection. Moreover, BTA has been shown to be safe and long-lasting, which would be convenient for patients and might improve adherence to therapy.42-44 BTA’s antidepressant effects were shown to be independent of frown line severity or patient satisfaction with cosmetic effects.45 The trials by Wollmer et al,23 Finzi and Rosenthal,25 and Magid et al26 mainly studied BTA as an adjunctive treatment to antidepressants in patients with ongoing unipolar depression. However, Finzi and Rosenthal25 included patients who were not medicated at the time of the study.
Pooled analysis of these 3 RCTs found that patients who received BTA monotherapy improved equally to those who received it as an adjunctive treatment to antidepressants. Overall, on primary endpoint measures, a response rate of 54.2% was obtained in the BTA group compared with 10.7% among patients who received placebo saline injections (odds ratio [OR] 11.1, 95% confidence interval [CI], 4.3 to 28.8, number needed to treat [NNT] = 2.3) and a remission rate of 30.5% with BTA compared with 6.7% with placebo (OR 7.3, 95 % CI, 2.4 to 22.5, NNT = 4.2).46 However, remission rates tend to be higher in the augmentation groups, and so further studies are needed to compare both treatment strategies.
Nevertheless, these positive findings have been recently challenged by the results of the largest U.S. multicenter phase II RCT,28 which failed to find a significant antidepressant effect at 6 weeks with the 30-unit BTA injection, and also failed to prove a dose-effect relationship, as the 50-unit injection wasn’t superior to the lower dose and didn’t significantly differ from placebo. One hypothesis to explain this discrepancy may be the difference in injection sites between the treatment and placebo groups.47 Future studies need to address the various limitations of earlier clinical trials that mainly yielded promising results with BTA.
A major concern is the high rate of unblinding of participants and researchers in BTA trials, as the cosmetic effects of botulinum toxin injections make them easy to distinguish from saline injections. Ninety percent of participants in the Wollmer et al study23 were able to correctly guess their group allocation, while 60% of evaluators guessed correctly. Finzi and Rozenthal25 reported 52% of participants in the BTA group, 46% in the placebo group, and 73% of evaluators correctly guessed their allocation. Magid et al26 reported 75% of participants were able to guess the order of intervention they received. The high unblinding rates in these trials remains a significant limitation. There is a concern that this may lead to an underestimation of the placebo effect relative to clinical improvement, thus causing inflation of outcome differences between groups. Although various methods have been tried to minimize evaluator unblinding, such as placing surgical caps on participants’ faces during visits to hide the glabellar region, better methods need to be implemented to prevent unblinding of both raters and participants.
Furthermore, except for the multicenter phase II trial, most studies have been conducted in small samples, which limits their statistical power. Larger controlled trials will be needed to replicate the positive findings obtained in smaller RCTs.
Another limitation is that the majority of the well-designed RCTs were conducted in populations that were predominantly female, which makes it difficult to reliably assess treatment efficacy in men. This may be because cosmetic treatment with botulinum toxin injection is more favorably received by women than by men. A recent comparison48 of the studies by Wollmer et al23 and Finzi and Rosenthal25 discussed an interesting observation. Wollmer et al did not explicitly mention botulinum toxin when recruiting for the study, while Finzi and Rosenthal did. While approximately a quarter of the participants in the Wollmer et al study were male, Finzi and Rosenthal attracted an almost entirely female population. Perhaps there is a potential bias for females to be more attracted to these studies due to the secondary gain of receiving a cosmetic procedure.
In an attempt to understand predictors of positive response to botulinum toxin in patients with depression, Wollmer et al49 conducted a follow-up study in which they reassessed the data obtained from their initial RCT using the HAM-D agitation item scores to separate the 15 participants who received BTA into low-agitation (≤1 score on agitation item of the HAM-D scale) and high-agitation (≥2 score on agitation item of the HAM-D scale) groups. They found that the 9 participants who responded to BTA treatment had significantly higher baseline agitation scores than participants who did not respond (1.56 ± 0.88 vs 0.33 ± 0.52, P = .01). All of the participants who presented with higher agitation levels experienced response, compared with 40% of those with lower agitation levels (P = .04), although there was no significant difference in magnitude of improvement (14.2 ± 1.92 vs 8.0 ± 9.37, P = .07). The study added additional support to the facial feedback hypothesis, as it links the improvement of depression to facial muscle activation targeted by the injections. It also introduced a potential predictor of response to botulinum toxin treatment, highlighting potential factors to consider when enrolling patients in future investigations.
The case series of patients with borderline personality disorder31 also shed light on the potential positive effect of BTA treatment for a particular subtype of patients with depression—those with comorbid emotional instability—to consider as a therapeutic target for the future. Hence, inclusion criteria for future trials might potentially include patient age, gender, existence/quantification of prominent frown lines at baseline, severity of MDD, duration of depression, and personality characteristics of enrolled participants.
In conclusion, BTA injections appear promising as a treatment for depression as well as for other psychiatric disorders. Future studies should focus on identifying optimal candidates for this innovative treatment modality. Furthermore, BTA dosing and administration strategies (monotherapy vs adjunctive treatment to antidepressants) need to be further explored. As retrograde axonal transport of botulinum toxin has been demonstrated in animal studies, it would be interesting to further examine its effects in the human CNS to enhance our knowledge of the pathophysiology of botulinum and its potential applications in psychiatry.50
Bottom Line
Botulinum toxin shows promising antidepressant effects and may have a role in the treatment of several other psychiatric disorders. More research is needed to address limitations of previous studies and to establish an adequate treatment regimen.
Related Resources
- Wollmer MA, Magid M, Kruger TH. Botulinum toxin treatment in depression. In: Bewley A, Taylor RE, Reichenberg JS, et al (eds). Practical psychodermatology. Oxford, UK: Wiley; 2014.
- Wollmer MA, Neumann I, Magid M. et al. Shrink that frown! Botulinum toxin therapy is lifting the face of psychiatry. G Ital Dermatol Venereol. 2018;153(4):540-548.
Drug Brand Names
Alprazolam • Xanax
Aripiprazole • Abilify
Biperiden • Akineton
Botulinum toxin A • Botox
Botulinum toxin B • Myobloc
Clozapine • Clozaril
Deutetrabenazine • Austedo
Flupentixol • Prolixin
Imipramine • Tofranil
Olanzapine • Zyprexa
Reserpine • Serpalan, Serpasil
Tetrabenazine • Xenazine
Valbenazine • Ingrezza
Ziprasidone • Geodon