Botulinum Toxin and Depression

We were skeptical when we saw the title: “Facing depression with botulinum toxin: A randomized controlled trial.” However, after reading that the researchers who published this recent paper in the Journal of Psychiatric Research had found a substantial antidepressant effect from injecting botulinum toxin into specific facial muscles of participants with depression, we became intrigued. Obviously, large-scale studies need to replicate this finding before it should be considered for general clinical use, but there are some interesting possible explanations for the results.

Botulinum toxin (the bacterial toxin that causes botulism in humans) paralyzes muscles by blocking release of the neurotransmitter acetylcholine, the chemical signal that drives muscle contraction. Plastic surgeons utilize botulinum toxin, perhaps better known as Botox, for various cosmetic procedures, including facial wrinkle “removal.” Although the treatment for wrinkles can last many months, eventually the effects of botulinum toxin wear off.

Many people who suffer from depression look depressed and have a sad facial expression. The specific muscles injected with botulinum toxin in this study are involved in the facial expressions we associate with emotions like sadness. Earlier research by a different research group demonstrated that feedback from these same muscles influences activity in brain regions involved with the regulation of emotions, including the amygdala. Is it possible that when a person looks sad, the associated activity of facial muscles influences brain circuitry that regulates depression? In the earlier research, paralyzing these muscles was shown to decrease nerve cell activity in the left amygdala and also diminish the left amygdala’s interactions with other brain areas involved in emotion.

In the current study, 30 research subjects received either botulinum toxin (15 subjects) or placebo (15 subjects). Sixty percent of subjects receiving active botulinum toxin showed a clinically meaningful decrease in depressive symptoms (versus 13% of those injected with a placebo), and 33 percent (versus 13 percent) responded so strongly that their depressions were considered to be in remission. Remarkably, this response followed only a single set of botulinum toxin injections. The antidepressant effect became noticeable about 2 weeks after treatment, and the magnitude of the antidepressant response increased throughout the 16 weeks of the study.

Naturally, most of the persons receiving botulinum injections were aware that they had received the active treatment and not placebo injections. This confounds the results because the participants were not truly “blind” to which treatment they received, and thus their expectations could have influenced the results. The participants wore surgical caps that covered their foreheads when they were evaluated for depressive symptoms by the researchers, and for the most part, the researchers remained unaware of which participants had received botulinum toxin. In fact, the researchers were not accurate in predicting whether individual participants were in the active or placebo group. Therefore, the study was at least single “blind” in the language of clinical trials.

We want to caution that these results are very preliminary and are based on a small sample of participants. Thus, they need to be reproduced in a larger and better controlled study. But why might injections with botulinum toxin work? One reason might involve the decreased feedback to the amygdala from the injected facial muscles. Also, when a person doesn’t look depressed (because of diminished frowning), perhaps they are treated differently by people who interact with them. In addition, when a depressed person looks in the mirror and sees a happier face, perhaps it helps him or her feel better.

If this approach turns out to be effective for a subset of patients with clinical depression, it would be another example of a rather unique way to influence brain function in order to help people with depression. However, we should be extremely cautious until much larger well-designed studies are performed. Too often, exciting preliminary findings turn out not to be reproducible, and placebo responses and non-replicated findings haunt psychiatric and depression literature. Psychiatry needs more effective and novel treatments. Pilot studies such as this one clearly represent innovative ways to think about treatment, but they require systematic, larger-scale replication before particular treatments can be recommended for clinical use.

This column was co-written by Eugene Rubin M.D., Ph.D. and Charles Zorumski, M.D.