Botulinum toxin for depression? An idea that’s raising some eyebrows

Although these improvements in depres­sion scores do not reach those seen with electroconvulsive therapy,^19,20 they are com­parable to placebo-controlled studies of antidepressants.^21,22

Doesn’t this technique work because people who look better, feel better?
Aesthetic improvement alone is unlikely to explain the entire story. A recent study showed that improvement in wrinkle score did not correlate with improvement in mood.²³ Furthermore, some patients in RCTs did not like the cosmetic effects of BTA but still reported feeling less depressed after treatment.¹⁰

How might it work?
Several theories about the mechanism of action have been proposed:
• The facial feedback hypothesis dates to Charles Darwin in 1872: Facial move­ments influence emotional states. Numerous studies have confirmed this. Strack et al²⁴ found that patients asked to smile while reading comics found them to be funnier. Ekman et al²⁵ found that imitating angry facial expressions made body temperature and heart rate rise. Dialectical behavioral therapy expert Marsha Linehan recognized the importance of modifying facial expres­sions (from grimacing to smiling) and pos­ture (from clenched fists to open hands) when feeling distressed, because it is hard to feel “willful” when your “mind is going one way and your body is going another.”²⁶ Accordingly, for a person who continuously “looks” depressed or distressed, reducing the anguished facial expression using botu­linum toxin might diminish the entwined negative emotions.

• A more pleasant facial expression improves social interactions, which leads to improvement in self-esteem and mood. Social biologists argue that (1) we are attracted to those who have more pleas­ant facial expressions and (2) we steer clear of those who appear angry or depressed (a negative facial expression, such as a growl­ing dog, is perceived as a threat). Therefore, anyone who looks depressed might have less rewarding interpersonal interactions, which can contribute to a poor mood.

On a similar note, mirror neurons are regions in the brain that are activated by witnessing another person’s emotional cues. When our mirror neurons light up, we can feel an observed experience, which is why we often feel nervous around anxious peo­ple, or cringe when we see others get hurt, or why we might prefer engaging with people who appear happier. It is possible that, after BTA injection, a person’s social connectiv­ity is improved because of a more positive reciprocal firing of mirror neurons.  

• BTA leads to direct and indirect neu­rochemical changes in the brain that can reduce depression. Functional MRI studies have shown that after glabellar BTA injec­tions, the amygdala was less responsive to negative stimuli.^27,28 For example, patients who were treated with BTA and then shown pictures of angry people had an attenuated amygdala response to the photos.

This is an important finding, especially for patients who have been traumatized. After a traumatic event, the amygdala “remem­bers” what happened, which is good, in some ways (it prevents us from getting into a similar dangerous situation), but bad in others (the traumatized amygdala may falsely perceive a non-threatening stimuli as threatening). A hypervigilant amygdala can lead to an out-of-proportion fear response, depression, and anxiety. Therefore, quell­ing an overactive amygdala with BTA could improve emotional dysregulation and posttraumatic disorders.

Many of our patients reported that, after BTA injection, “traumatic events didn’t feel as traumatizing,” as one said. The emotional pain and rumination that often follow a life stressor “does not overstay its welcome” and patients are able to “move on” more quickly.

It is unknown why the amygdala is qui­eted after BTA; researchers hypothesize that BTA suppresses facial feedback signals from the forehead branch of the trigeminal nerve to the brain. Another hypothesis is that BTA is directly transported by the trigeminal nerve into the brain and exerts central phar­macological effects on the amygdala.²⁹ This theory has only been studied in rat models.³⁰

When does it start working? How long does it last?
From what we know, BTA for depression could start working as early as 2 weeks and could last as long as 6 months. In one RCT, the earliest follow-up was 2 weeks,10 at which time the depressed patients had responded to botulinum toxin (P ≤ .05). In the other 2 controlled trials, the earliest follow-up was 3 weeks, at which time a more robust response was seen (P < .001). Aesthetically, BTA usually lasts 3 months. It is unclear how long the antidepressant effects last but, in the longest trial,3 depression symptoms contin­ued to improve at 6 months, after cosmetic effects had worn off.

These findings raise a series of questions:
   • Do mood effects outlast cosmetic effects? If so, why?
   • Does botulinum toxin start to work sooner than 2 weeks?
   • Will adherence improve if a patient has to be treated only every 6 months?