Botulinum toxin has shown promising antidepressant effects, and might be helpful for several other indications
Botulinum toxin, a potent neurotoxic protein produced by the bacterium Clostridium botulinum, has been used as treatment for a variety of medical indications for more than 25 years (Box,1-12 page 10). Recently, researchers have been explor-ing the role of botulinum toxin in psychiatry, primarily as an adjunctive treatment for depression, but also for several other possible indications. Several studies, including randomized controlled trials (RCTs), have provided evidence that glabellar botulinum toxin injections may be a safe and effective treatment for depression. In this article, we provide an update on the latest clinical trials that evaluated botulinum toxin for depression, and also summarize the evidence regarding other potential clinical psychiatric applications of botulinum toxin.
Several RCTs suggest efficacy for depression
The use of botulinum toxin to treat depression is based on the facial feedback hypothesis, which was first proposed by Charles Darwin in 187213 and further elaborated by William James,14,15 who emphasized the importance of the sensation of bodily changes in emotion. Contrary to the popular belief that emotions trigger physiological changes in the body, James postulated that peripheral bodily changes secondary to stimuli perception would exert a sensory feedback, generating emotions. The manipulation of human facial expression with an expression that is associated with a particular emotion (eg, holding a pen with teeth, leading to risorius/zygomaticus muscles contraction and a smile simulation) was found to influ-ence participants’ affective responses in the presence of emotional stimuli (eg, rating cartoons as funnier), reinforcing the facial-feedback hypothesis.16,17 From a neurobiologic standpoint, facial botulinum toxin A (BTA) injections in rats were associated with increased serotonin and norepinephrine concentrations in the hypothalamus and striatum, respectively.18 Moreover, amygdala activity in response to angry vs happy faces, measured via func-tional magnetic resonance imaging (fMRI), was found to be attenuated after BTA appli-cations to muscles involved in angry facial expressions.
19,20 Both the neurotransmitters as well as the aforementioned brain regions have been implicated in the pathophysiol-ogy of depression.21,22 More than a century after Charles Darwin’s initial proposal, Wollmer et al23 conducted the first RCT exploring the effect of BTA as an adjunctive treatment to anti-depressants in 30 patients with depression. BTA or normal saline injections were given at 5 points in the glabellar region (Figure,24 page 11). Positive effects on mood were mea-sured at 7 points over 16 weeks using the 17-item version of the Hamilton Depression Rating Scale (HAM-D17; administered using the Structured Interview Guide for the Hamilton Depression Rating Scale with Atypical Depression Supplement [SIGH-ADS]); the Beck Depression Inventory (BDI) self-rating questionnaire; and the Clinical Global Impression Scale (CGI).
Changes in glabellar frown lines were tracked at each study visit using the 4-point Clinical Severity Score for Glabellar Frown Lines (CSS-GFL) and standardized photographs of the face with maximum frowning. Compared with those in the placebo group, participants in the BTA group had a higher response rate as measured by the HAM-D17 at 6 weeks after treatment (P = .02), especially female patients (P = .002). Response to BTA, defined as ≥50% reduction on the HAM-D17, occurred within 2 weeks, and lasted another 6 weeks before slightly wearing off. Assessment of the CSS-GFL showed a statistically significant change at 6 weeks (P < .001). This small study failed, however, to show significant remission rates (HAM-D17 ≤7) in the BTA group compared with placebo. In a second RCT involving 74 patients with depression, Finzi and Rosenthal25 observed statistically significant response and remission rates in participants who received BTA injections, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS). Participants were given either BTA or saline injections and assessed at 3 visits across 6 weeks using the MADRS, CGI, and Beck Depression Inventory-II (BDI-II). Photographs of participants’ facial expressions were assessed using frown scores to see whether changes in facial expression were associated with improve-ment of depression. This study was able to reproduce on a larger scale the results observed by Wollmer et al.23 It found a statistically significant increase in the rate of remission (MADRS ≤10) at 6 weeks following BTA injections (27%, P < .02), and that even patients who were not resistant to antidepressants could benefit from BTA. However, although there was an observable trend in improvement of frown scores associated with improved depression scores, the correlation between these 2 variables was not statistically significant. In a crossover RCT, Magid et al26 observed the response to BTA vs placebo saline injections in 30 patients with moder-ate to severe frown lines. The study lasted 24 weeks; participants switched treat-ments at Week 12. Mood improvement was assessed using the 21-item Hamilton Depression Rating Scale (HDRS-21), BDI, and Patient Health Questionnaire-9 (PHQ-9). Compared with patients who received placebo injections, those treated with BTA injections showed statistically sig-nificant response rates, but not remission rates. This study demonstrated continued improvement throughout the 24 weeks in participants who initially received BTA injections, despite having received pla-cebo for the last 12 weeks, by which time the cosmetic effects of the initial injection had worn off. This suggests that the anti-depressant effects of botulinum toxin may not depend entirely on its paralytic effects, but also on its impact on the neurotrans-mitters involved in the pathophysiology of depression.18 By demonstrating improve-ment in the placebo group once they were started on botulinum toxin, this study also was able to exclude the possibility that other variables may be responsible for the difference in the clinical course between the 2 groups. However, this study was limited by a small sample size, and it only included participants who had moderate to severe frown lines at baseline. Zamanian et al27 examined the therapeu-tic effects of BTA injections in 28 Iranian patients with major depressive disorder (MDD) diagnosed according to DSM-5 criteria. At 6 weeks, there were significant improvements in BDI scores in patients who received BTA vs those receiving pla-cebo. However, these changes were demon-strated at 6 weeks (not as early as 2 weeks), and patients didn’t achieve remission. A large-scale, multicenter U.S. phase II RCT investigated the safety, tolerability, and efficacy of a single administration of 2 different doses of BTA (30 units or 50 units) as monotherapy for the treatment of mod-erate to severe depression in 258 women.28 Effects on depression were measured at 3, 6, and 9 weeks using the MADRS. Participants who received the 30-unit injection showed statistically significant improvement at 3 weeks (-4.2, P = .005) and at 9 weeks (-3.6, P = .049). Although close, the primary end-point at 6 weeks was not statistically signifi-cant (-3.7, P = .053). Surprisingly, the 50-unit injection failed to produce any significant difference from placebo and thus no supe-riority from the 30-unit group; this finding calls into question the dose-response rela-tionship. Both doses were, however, well tolerated. Allergan is planning to move for-ward with BTA injections for depression in larger phase III trials.29 More recently, in a case series, Chugh et al30 examined the effect of BTA in 42 patients (55% men) with severe treat-ment-resistant depression. Participants were given BTA injections in the glabel-lar region as an adjunctive treatment to antidepressants and observed for at least 6 weeks. Depression severity was mea-sured using HAM-D17, MADRS, and BDI at baseline and at 3 weeks. Changes in glabellar frown lines also were assessed using the CSS-GFL. The authors reported statistically significant improvements in HAM-D17 (-9.0 ± 3.5, P < .001), MADRS (-12.7 ± 4.0, P < .001), and BDI (-12.5 ± 4.2, P < .001) scores at 3 weeks. BTA’s antide-pressant effects did not differ between male and female participants (R2 ≤ .042), demonstrating for the first time in the larg-est male sample to date that botulinum toxin’s effects are independent of gender. However, this study was limited by its lack of placebo control. A summary of the RCTs of BTA for treat-ing depression appears in Table 1.23,25-2
Benefits for other psychiatric indications
Borderline personality disorder. In a case series of 6 women, BTA injections in the gla-bellar region were reported to be particu-larly effective for the treatment of borderline personality disorder symptoms that were resistant to psychotherapy and pharma-cotherapy.31 Two to 6 weeks after a 29-unit injection, borderline personality disorder symptoms as measured by the Zanarini Rating Scale for Borderline Personality Disorder and/or the Borderline Symptom List were shown to significantly improve by 49% to 94% from baseline (P ≤ .05). These findings emphasize the promising therapeutic role of BTA on depressive symptoms concomitant with the emotional lability, impulsivity, and negative emotions that usually characterize his personality disorder.31,32 A small sample size and lack of a placebo comparator are limitations of this research.
Neuroleptic-induced sialorrhea. Botulinum toxin injections in the salivary glands have been investigated for treating clozapine-induced sialorrhea because they are thought to directly inhibit the release of acetylcho-line from salivary glands. One small RCT that used botulinum toxin B (BTB)33 and 1 case report that used BTA34 reported suc-cessful reduction in hypersalivation, with doses ranging from 150 to 500 units injected in each of the parotid and/or submandibu-lar glands bilaterally. Although the treat-ment was well tolerated and lasted up to 16 weeks, larger studies are needed to repli-cate these findings.33-35
Orofacial tardive dyskinesia. Several case reports of orofacial tardive dyskinesia, including lingual dyskinesia and lingual protrusion dystonia, have found improve-ments in hyperkinetic movements fol-lowing muscular BTA injections, such as in the genioglossus muscle in the case of tongue involvement.36-39 These cases were, however, described in the literature before the recent FDA approval of the vesicular monoamine transporter 2 inhibitors val-benazine and deutetrabenazine for the treatment of tardive dyskinesia.40,41 Studies examining botulinum tox-in’s application in areas of psychiatry other than depression are summarized in Table 2.31,33,36-38
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 over-all 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 antide-pressant effects were shown to be inde-pendent of frown line severity or patient satisfaction with cosmetic effects.45 The tri-als 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 mono-therapy improved equally to those who received it as an adjunctive treatment to antidepressants. Overall, on primary end-point 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 treat-ment 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 antide-pressant effect at 6 weeks with the 30-unit BTA injection, and also failed to prove a dose-effect relationship, as the 50-unit injec-tion 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 limi-tations 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 bot-ulinum 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 underestima-tion of the placebo effect relative to clini-cal 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 con-ducted in small samples, which limits their statistical power. Larger controlled trials will be needed to replicate the positive find-ings 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 reli-ably 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 popu-lation.
Perhaps there is a potential bias for females to be more attracted to these stud-ies 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 agita-tion item scores to separate the 15 partici-pants who received BTA into low-agitation (≤1 score on agitation item of the HAM-D scale) and high-agitation (≥2 score on agi-tation item of the HAM-D scale) groups. They found that the 9 participants who responded to BTA treatment had signifi-cantly 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 magni-tude 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 border-line personality disorder31 also shed light on the potential positive effect of BTA treat-ment 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 identify-ing optimal candidates for this innova-tive 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 interest-ing 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
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