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 (Box1-12). Recently, researchers have been exploring 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 influence 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 functional magnetic resonance imaging (fMRI), was found to be attenuated after BTA applications to muscles involved in angry facial expressions.19,20 Both the neurotransmitters as well as the aforementioned brain regions have been implicated in the pathophysiology of depression.21,22Figure24). Positive effects on mood were measured 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.
Botulinum toxin is a potent neurotoxin from Clostridium botulinum. Its potential for therapeutic use was first noticed in 1817 by physician Justinus Kerner, who coined the term botulism.1 In 1897, bacteriologist Emile van Ermengem isolated the causative bacterium C. botulinum.2 It was later discovered that the toxin induces muscle paralysis by inhibiting acetylcholine release from presynaptic motor neurons at the neuromuscular junction3 and was then mainly investigated as a treatment for medical conditions involving excessive or abnormal muscular contraction.
In 1989, the FDA approved botulinum toxin A (BTA) for the treatment of strabismus, blepharospasm, and other facial nerve disorders. In 2000, both BTA and botulinum toxin B (BTB) were FDA-approved for the treatment of cervical dystonia, and BTA was approved for the cosmetic treatment of frown lines (glabellar, canthal, and forehead lines).4 Other approved clinical indications for BTA include urinary incontinence due to detrusor overactivity associated with a neurologic condition such as spinal cord injury or multiple sclerosis; prophylaxis of headaches in chronic migraine patients; treatment of both upper and lower limb spasticity; severe axillary hyperhidrosis inadequately managed by topical agents; and the reduction of the severity of abnormal head position and neck pain.5 Its anticholinergic effects have been also investigated for treatment of hyperhidrosis as well as sialorrhea caused by neurodegenerative disorders such as amyotrophic lateral sclerosis.6-8 Multiple studies have shown that botulinum toxin can alleviate spasms of the gastrointestinal tract, aiding patients with dysphagia and achalasia.9-11 There is also growing evidence supporting the use of botulinum toxin in the treatment of chronic pain, including non-migraine types of headaches such as tension headaches; myofascial syndrome; and neuropathic pain.12
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