Treatment of depression with onabotulinumtoxinA: A randomized, double-blind, placebo controlled trial
Introduction
Major depressive disorder (MDD) is common, costly, and disabling (Greden, 2001, Nierenberg and DeCecco, 2001, Ustün et al., 2004). The World Health Organization has concluded that MDD is the greatest cause of disease burden in North America (Mathers and Loncar, 2006). The large scale Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study indicated that up to a third of depressed patients may not reach remission despite multiple drug trials. In addition, troubling side effects, such as decreased libido, anorgasmia, insomnia and nausea, are often reported with current antidepressants, and they are a major reason why patients discontinue treatment and subsequently relapse (Pollack and Rosenbaum, 1987, Remick et al., 1989, Baldessarini and Marsh, 1990, Clayton et al., 2006). Thus, there is a need for the development of new effective and better-tolerated treatments for depression.
Charles Darwin (1872) and William James (1890) proposed a novel theory of emotion: that the facial expressions feed information back to the brain, thereby influencing emotions positively or negatively. Multiple experimenters have subsequently confirmed aspects of this so-called “facial feedback hypothesis” (Strack et al., 1988, Adelmann and Zajonc, 1989, Larsen et al., 1992). For example, voluntary contraction of facial muscles into a smile or a frown can induce feelings of happiness or sadness respectively (Soussignan, 2002, Lewis, 2012), influence the emotional appraisal of events (Flack, 2006, Neal and Chartrand, 2011), and cause specific changes in the autonomic nervous system (Ekman et al., 1983).
Facial expressions of negative emotions such as fear, sadness and anger, all involve contraction of the corrugator muscles (Ekman, 2007). Multiple lines of evidence specifically implicate the corrugator muscles in depression. Thus, corrugator activity is greater and fails to decrease normally with happy imagery in depressed subjects (Schwartz et al., 1976). Normal subjects who viewed unhappy imagery had an increase in both depressed mood and corrugator activity, two variables that are highly correlated (Teasdale and Bancroft, 1977). Facial electromyography has been shown to be a predictor of treatment outcome in depression (Carney et al., 1981, Greden et al., 1985). Nevertheless, these correlations do not demonstrate a causal role for corrugator muscles in depression, which has not been researched until recently.
Botulinum toxin injection of muscles reversibly blocks acetylcholine release from neuronal axons into the synapse, inhibiting neuromuscular transmission (Burgen et al., 1949). OnabotululinumtoxinA (OBA) is one distinct subtype of botulinum toxin, and was the first botulinum toxin subtype to be FDA approved for the treatment of frown lines. OBA is now one of several botulinum toxins that are commercially available. Injection of OBA into the corrugator and procerus muscles (between the eyebrows) reversibly inhibits frowning for about three months (Carruthers and Carruthers, 1992) and provides a method for specifically and reversibly inhibiting frown facial expressions. Medical indications now outnumber cosmetic ones for the use of OBA. If the facial feedback hypothesis is correct and, specifically, if corrugator muscle activity is capable of propagating or enhancing sad or depressed feelings, we hypothesize that OBA injections into these muscles should have antidepressant properties.
In an open study of OBA injected into the frown muscles of ten depressed patients, Finzi and Wasserman, 2006, reported that eight out of ten went into remission after one treatment with OBA. Their study was limited, however, by its small sample size, lack of controls, and lack of blinding. Wollmer et al., 2012, in a small (N = 30) randomized, placebo controlled trial of OBA in depressed patients found a statistically significant (60%) response rate in OBA-treated subjects versus 13% in controls, but remission rates were not significantly different. They confined their study to patients who had both observable frowns and treatment-resistant depression. To evaluate the general therapeutic efficacy of OBA as a treatment for major depression, we have conducted a larger study with a broader clinical spectrum of patients. As in the study of Wollmer et al., we used a randomized double-blind design in which subjects received either OBA or placebo injections into the corrugator and procerus muscles as a treatment for major depressive disorder (MDD).
Section snippets
Patients
Subjects were recruited from advertisements placed in the local newspapers in the Washington, DC metropolitan area; from the Internet; and from local physicians. The study protocol and advertisements were approved by the Institutional Review Board, Quorum Review Seattle, Washington. Advertisements stated that we were recruiting depressed people for a double blind randomized clinical trial of OBA for depression. No mention was made as to any expected efficacy. Male or female outpatients aged
Statistical analysis
All subjects who met inclusion criteria and had at least one visit value in addition to a screening value were entered into the analysis. Chi square statistics and Fisher exact tests were used to assess response rates, and differences in response rates were assessed with the non-parametric Mann–Whitney U test. Descriptive statistics were obtained and tests for the statistical assumptions of normality and homogeneity of variance were made. These statistical assumptions were satisfied.
The time
Patients
121 subjects were screened. 36 subjects were excluded as they did not meet inclusion/exclusion criterion. The 85 subjects who met DSM-IV criteria for MDD were randomized, 41 subjects were randomized to receive OBA and 44 to receive placebo. Eleven patients were excluded: 8 patients in the OBA group; 3 for withdrawal of consent, 1 for protocol violation (starting a new antidepressant), 4 were lost to follow-up; and 3 in the placebo group; 2 for protocol violations (starting new antidepressants),
Discussion
The present study supports earlier research suggesting that OBA injected into the corrugator and procerus muscles can have antidepressant effects in people with major depressive disorder (Finzi and Wasserman, 2006, Wollmer et al., 2012, Finzi, 2013). The present study takes these findings further in a few ways: First, it is the largest controlled study to date; second, we found a significant increase in remissions following OBA vs. placebo; third, the patient population was not selected for
Funding
Research support has been provided solely by the Chevy Chase Cosmetic Center.
Conflict of interest
Eric Finzi has been awarded a patent for the treatment of depression with botulinum toxin. The Chevy Chase Cosmetic Center, which provided funding for this study, is solely owned by Eric Finzi. Norman Rosenthal has no conflicts of interest to disclose.
Acknowledgments
We are grateful to Joshua Z. Rosenthal,MD, Khursheed K. Khine,MD, Catherine T Tuggle, Allison Wagner,PA and Ronald Katz,MD for their work in collecting data for this study.We are most grateful to John J. Bartko,PhD and Eduardo Romano,PhD for performing statistical analysis.
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