ANNOTATION (J. Jewel Shim)

The Finding:  The authors undertook a pooled analysis of all the randomized controlled trials examining the use of botulinum toxin A (BTA) injected in the glabellar region for major depressive disorder (MDD). The rationale for use of this novel treatment for depression is based on the facial feedback hypothesis which posits that contraction of the facial muscles sends messages to areas of the brain that process emotion. The authors theorize that paralyzing the muscles involved in frowning interrupts a proprioceptive feedback loop from the face to the emotion centers in the brain and inhibits the ability to feel negative emotions. The sample included 3 trials totalling 59 subjects who received BTA and 75 placebo subjects. All 3 trials studied BTA as an adjunctive therapy to antidepressants. One trial also analyzed BTA as a monotherapy for MDD. Outcomes were measured using the Hamilton Depression Rating Scale (HAM-D) and the Montgomery Asberg Depression Rating Scale (MADRS) 6 weeks after administration of BTA. They also measured the severity of frown lines at baseline and at 6 weeks using the Clinical Severity Score for Glabellar Frown Lines (CSS-GFL). They found a response rate of 54.2% for the BTA group vs. 10.7% for placebo, and a remission rate of 30.5% for the BTA group vs. 6.7% for placebo. Response rates did not differ significantly between subjects who received BTA as an adjunctive therapy vs as monotherapy. Interestingly, higher baseline CSS-GFL scores were predictive of less improvement in depression though this relationship was not statistically significant. It was hypothesized that subjects with greater baseline CSS-GFL scores indicated a longer period of being depressed and could be a marker of treatment resistance.

Strengths and Weaknesses: This study pools the data from 3 individual controlled studies, and in this achieves greater statistical power and significance. However, the overall number of subjects was still quite small and the improvement in CSS-GFL scores did not correlate significantly with improvements in mood. A major weakness of the study highlighted by the authors was the difficulty to effectively blind the subjects to group allocation as the presence/absence of cosmetic changes would be clear to the participant. Thus, the comparatively low placebo response rates may reflect this and make the estimation of the true effect size difficult.

Relevance: This analysis calls attention to a very interesting novel approach to the treatment of depression that is generally well tolerated with few side effects. Further studies are definitely warranted to explore the effectiveness of this option for the treatment of depression.