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 improvement 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 moderate to severe frown lines. The study lasted 24 weeks; participants switched treatments 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 significant 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 placebo for the last 12 weeks, by which time the cosmetic effects of the initial injection had worn off. This suggests that the antidepressant effects of botulinum toxin may not depend entirely on its paralytic effects, but also on its impact on the neurotransmitters involved in the pathophysiology of depression.18 By demonstrating improvement 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 therapeutic 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 placebo. However, these changes were demonstrated 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 moderate 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 endpoint at 6 weeks was not statistically significant (-3.7, P = .053). Surprisingly, the 50-unit injection failed to produce any significant difference from placebo and thus no superiority from the 30-unit group; this finding calls into question the dose-response relationship. Both doses were, however, well tolerated. Allergan is planning to move forward 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 treatment-resistant depression. Participants were given BTA injections in the glabellar region as an adjunctive treatment to antidepressants and observed for at least 6 weeks. Depression severity was measured 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 antidepressant effects did not differ between male and female participants (R2 ≤ .042), demonstrating for the first time in the largest 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 treating depression appears in Table 1.23,25-28
Continue to: Benefits for other psychiatric indications