OPINION | DEPRESSION |

In 2003, Heckmann et al published data suggesting that

treatment of the glabellar region with botulinum toxin

could produce a change in facial expression from angry,

sad, and fearful to happy, and that this could impact on

emotional experience.

THE ‘BOTOX PARADOX’: IS IT EFFECTIVE FOR DEPRESSION?Patrick Treacy considers the conflicting evidence of botulinum toxin use as a therapy for depression, and proposes that it all comes down to where the toxin is injected

PATRICK TREACY is Medical Director of Ailesbury Clinics Ltd and Ailesbury Hair Clinics Ltd; Chairman of the Irish Association of Cosmetic Doctors and Irish Regional Representative of the British Association of Cosmetic Doctors; European Medical Advisor to Network Lipolysis and the UK’s largest cosmetic website Consulti,ng Rooms. He practices cosmetic medicine in his clinics in Dublin, Cork, London and the Middle East

email: ptreacy@gmail.com

A RECENT ARTICLE by Claire Coleman1, published in the UK’s Daily Mail newspaper, has led to much confusion

with regard to the role of BOTOX® in treating or causing depression. The article was based on a study led by Dr Michael Lewis of the School of Psychology, Cardiff, Wales, who followed 25 people who had received BOTOX treatment for facial lines and examined the idea of facial feedback — where the expressions we make with our faces affect how we feel — and found that many women who have the treatment for cosmetic purposes feel depressed because they are no longer able to smile properly.

Previous studies, however, have found that the treatment of frown lines left patients feeling less depressed. In 2006, Dr Eric Finzi and Dr Erika Wasserman reported in Dermatologic Surgery that treating clinically depressed patients with BOTOX on their frown lines actually reduced patients’ feelings of depression2. Depression affects over 120 million people globally, making it one of the leading causes of disability in the world. Although there are a number of effective treatments,

therapeutic response remains unsatisfactory and depression can develop into a chronic condition in a considerable proportion of patients. An economic treatment option that could provide long intervals between treatments, and that is safe, would be very important to doctors. So, what is the truth? Is there an actual physiological reason to explain the different results?

The ‘grief’ muscles The story begins in 1872, when Charles Darwin recognised that negative emotions, such as anger, fear, and sadness — all prevalent in depression — are associated with hyperactivity of the corrugator and procerus muscles in the glabellar region of the face. Darwin called them the ‘grief muscles’ and formulated a new theory, known as the ‘facial feedback hypothesis’, which implied a mutual interaction between emotions and facial muscle activity. He published his new theory in The Expression of the Emotions in Man and Animals, which concerns the genetically determined aspects of behaviour.

In this book, Darwin aimed to trace the animal origins of human characteristics, such as the tightening of the muscles around the

eyes in anger and efforts of memory. Darwin even sought out the opinions of eminent British psychiatrists in preparation of the book, which forms Darwin’s main contribution to psychology. His theory implied a mutual interaction between emotions and facial muscle activity. Research into this stayed there during the great upheavals of both World Wars, until the rising popularity of BOTOX made scientists review his facial hypothesis.

In 2003, Heckmann et al3

published data suggesting that treatment of the glabellar region with botulinum toxin could produce a change in facial expression from angry, sad, and fearful to happy, and that this could impact on emotional experience. Many therapists argue that patients who had been treated in the glabellar area reported an increase in emotional wellbeing and reduced levels of fear and sadness beyond what would be expected from the cosmetic benefit alone.

In 1992, Larsen et al4 provided evidence that voluntary contraction of facial muscles could channel emotions, which were conversely expressed by activation of these muscles. Hennenlotter et al5 went one stage further and showed that botulinum toxin treatment to the

prime-journal.com | June 2013

❚ 67

| DEPRESSION | OPINION

68

❚ June 2013 | prime-journal.com

OPINION | DEPRESSION |

glabellar area stopped the activation of limbic brain regions normally seen during voluntary contraction of the corrugator and procerus muscles. This indicated that feedback from the facial musculature in this region in some way modulated the processing of emotions. Many other researchers continued on this track, with Havas et al6 noting that the processing time for sentences with negative affective connotation was prolonged in women after botulinum toxin treatment to the glabellar, and Neal and Chartrand7 speculating that the treatment interfered with the ability to decode the facial expression of other people. This is where things remained, until recently, when some authors suggested that this capacity

to counteract negative emotions could be put to some clinical use during the treatment of depression.

Reducing symptoms of depressionA seminal article by Finzi and Wasserman2 postulated that botulinum toxin injected into the glabellar reduced the symptoms of depression. The authors provided data from an open case series of 10 female patients. The article contained a footnote from editor Alastair Carruthers, who stated that the report must be considered anecdotal as there were no appropriate methods of control used. In addition, there were other methodological weaknesses, including

limited follow-up, lack of randomisation, the absence of blind evaluation, and in particular, the small number of subjects included. Many felt that the methodology of evaluating depression should have been more rigorous.

At the time, I noted by letter that patients’ self-report of depressive symptoms by administration of the BDI-II (Beck Depression Inventory) introduced a significant bias. This is of more concern because of the potential for secondary cosmetic gain. While the BDI-II is an accepted method of evaluating an individual’s level of symptoms over time, self-report in isolation was not considered an acceptable method of diagnosing depression. It was concluded that in order to ensure that patients’ psychiatric symptoms are accurately classified, a thorough psychiatric interview must be conducted.

In 2012, the Psychiatric University Hospital of the University of Basel, Switzerland, and the Medical School Hanover, Germany, conducted a randomised, placebo-controlled, double-blind trial8. The authors hypothesised that facial psychomotor features associated with depression are not just epiphenomena, but integral components of the disorder, and may be targeted in its therapy. To explore whether attenuation of these features produces alleviation in the affective symptoms, they conducted a randomised controlled trial of botulinum toxin injection to the glabellar region as an adjunctive treatment of major depression. The study was investigator-initiated and carried out independently of any commercial entity.

Participants in the study were recruited from local psychiatric outpatient units and psychiatrists in private practice. In order to avoid attracting candidates who were primarily motivated by receiving this treatment for cosmetic reasons, botulinum toxin treatment was not explicitly mentioned. Exclusion criteria included psychotic symptoms, suicidal tendency, and clinical severity requiring immediate intervention. The same injection scheme was applied as that of the open case series2. At each study visit, participants were assessed using the Hamilton Depression Rating Scale with Atypical Depression Supplement (SIGH-ADS), the BDI self-rating questionnaire, and the Clinical Global Impressions (CGI) Scale. To conceal

Havas et al noted that the processing time for sentences with negative affective connotation was prolonged in women after botulinum toxin treatment to the glabellar.

References1. Coleman C. Is Maria’s story proof Botox can make you depressed? London, UK: Daily Mail, 2013. http://tinyurl.com/bv2y3kr (accessed 21 May 2013)

2. Finzi E, Wasserman E. Treatment of depression with botulinum toxin A: a case series. Dermatol Surg 2006; 32(5): 645–9

3. Heckmann M, Teichmann B, Schröder U, Sprengelmeyer R, Ceballos-Baumann AO. Pharmacologic denervation of frown muscles enhances baseline expression of happiness and decreases baseline expression of anger, sadness, and fear. J Am Acad Dermatol 2003; 49(2): 213–6

4. Larsen RJ, Kasimatis M, Frey K. Facilitating the furrowed brow: an unobtrusive test of the facial feedback hypothesis applied to unpleasant affect. Cognition Emotion 1992; 6: 321–38

5. Hennenlotter A, Dresel C,

Castrop F, Ceballos-Baumann AO, Wohlschläger AM, Haslinger B. The link between facial feedback and neural activity within central circuitries of emotion--new insights from botulinum toxin-induced denervation of frown muscles. Cereb Cortex 2009; 19(3):537–42

6. Havas DA, Glenberg AM, Gutowski KA, Lucarelli MJ, Davidson RJ. Cosmetic use of botulinum toxin-a affects processing of emotional language. Psychol Sci 2010; 21(7): 895–900

7. Neal DT, Chartrand TL. Embodied emotion perception: amplifying and dampening facial feedback modulates emotion perception accuracy. Soc Psychol Personal Sci 2011; doi: 10.1177/1948550611406138

8. Wollmer MA, de Boer C, Kalak N et al. Facing depression with botulinum toxin: a randomized controlled trial. J Psychiatr Res 2012; 46(5): 574–81

prime-journal.com | June 2013

❚ 69

| DEPRESSION | OPINION

cosmetic changes from psychometric raters, participants wore an opaque surgical cap, which covered the glabella and forehead during examinations.

The study concluded — for the first time — that a single botulinum treatment of the glabellar region with BOTOX could reduce the symptoms of major depression. This effect developed within a few weeks and persisted until the end of the 16-week follow-up period. The effect sizes in the study were large and the response and remission rates high. It is still unknown how botulinum toxin actually reduces depression and it is postulated that a number of mechanisms may be involved. As a result of the clinical data relating to botulinum toxin treatment on emotional perception, it is assumed that reduced proprioceptive feedback from the paralysed facial muscles is a relevant mechanism of mood improvement.

As the authors did not include patients who were cosmetically concerned about their frown lines, it is unreasonable to assume that an aesthetic benefit was the major cause of mood improvement. There is a small possibility of either placebo effect or central pharmacological botulinum toxin effects, including possible pharmacodynamics or pharmacokinetic interactions with concomitant antidepressant therapy.

The ‘Botox Paradox’So, who is correct? Does Botox reduce or augment depression? How can the findings of Dr Lewis be in complete contrast to those of other researchers? I believe that both are correct, and that the

answer to tise apparent medical paradox lies with the original theories of Darwin.

Dr Lewis and colleagues found that people treated for another muscle (around the crows’ feet) left patients feeling more depressed. This does not contravene Darwin’s original hypotheses; in fact it supports it. The muscles around the eye are related to happiness and smiling, and to restrict their movement must interfere with the facial feedback hypotheses in a converse way to those in the glabellar area. We can only assume that reduced proprioceptive feedback from these paralysed facial muscles is a relevant mechanism of mood deterioration, and this is why they may increase depression. Accordingly, happiness can make you smile and smiling can make you happy. It is obvious that the facial musculature not only expresses, but also regulates, mood states. Botulinum toxin injection interferes with the ‘facial feedback hypothesis’ originally postulated by Darwin. (Perhaps it was my sixth sense, but I never felt right about totally removing crow’s feet around a patient’s eyes.)

ConclusionsThere is growing evidence that botulinum toxin injection to the glabellar region may be an effective, safe, and sustainable intervention in the treatment of depression. The reason for this has not yet been fully evaluated, but we must consider the concept that the facial musculature not only expresses, but also regulates, mood states. Owing to the longer intervals between treatments, it

may also be an economic option, and the safety and tolerability record of botulinum toxin injections to the glabellar region is excellent.

However, further studies are required, including focus on muscles in the lower sections of the face. It is possible that treatment of the depressor angularis oris and the mentalis muscles, for example, may also have mood-elevating effects, and may enhance the clinical effect of the glabellar injection of botulinum toxin.

Modulation of mood states with botulinum toxin may also be effective in the treatment of other clinical conditions involving negative emotions, like anxiety disorders. There have also been recent studies investigating the possibility of botulinum toxin for bipolar disorder and post-traumatic stress disorder (PTSD).

It is paramount to remember that botulinum toxin to the glabellar region may be an effective, safe, and sustainable intervention in the treatment of depression. The reason for this has not yet been fully evaluated, but we must consider the concept as depression affects a huge number of people, making it one of the leading causes of disability worldwide.