Do We Frown Because We’re Depressed?

Michele Magid

Michele Magid, MD, University of Texas Southwestern

Guest Blogger and Botox and depression researcher, Michele Magid, MD, (University of Texas, Southwestern) shares her insight on the phenomenon Psychiatrists around the globe are pondering in this blog post, “Do We Frown Because We’re Depressed, Or Are We Depressed Because We Frown?

Smiling makes us feel better! In a TED talk, researcher Ron Gutman discussed the facts that people with bigger smiles tended to live longer lives, have happier marriages, and appear more competent to others.1  In addition, smiling can reduce stress levels by decreasing cortisol, and improve mood by increasing endorphins.1 Gutman’s talk received criticism as it was unclear whether the link between smiling and success was correlative or causative.2

According to evolutionary theorist Charles Darwin and philosopher/psychologist William James, the relationship is causative—we are happy because we smile, we are sorry because we cry, and we are angry because we clench our teeth, not the other way around.3,4 In other words, changes in facial expression create and enhance emotion and are not merely a consequence of that emotion.

If facial expression can influence emotional experience, then what would happen if depressed patients were no longer able to frown?

Three recent studies5–7 (with sample sizes of 30 to 85) set out to answer this question. Male and female participants with major depressive disorder were injected with botulinum toxin A (BTA) into the forehead region, causing a reduced ability to frown (ie, paralysis of the corrugator and procerus muscles, which control expressions of fear, anxiety, and anguish). In all 3 double-blind, placebo-controlled trials, BTA was associated with a statistically significant reduction in depressive symptoms compared with placebo. More interestingly, in our 24-week trial,7 the antidepressant effects of BTA continued even after the cosmetic effects had worn off.

Today Show interviews Dr. Eric Finzi 7/11/14

Today Show interviews Dr. Eric Finzi 7/11/14

If botulinum toxin in the frown muscles improves symptoms of depression, why?

Some may argue that looking aesthetically better leads to feeling better, but our study7 excluded those with concern about their frown lines. Others argue that the more pleasant and less depressed we look, the more inviting we are to others, leading to improved social interactions and, subsequently, improved mood. These arguments, however, do not explain why mood continues to improve even when the BTA is no longer cosmetically active.

A final argument is that BTA in the forehead alters peripheral feedback to the brain. A recent study8 showed that people who were given BTA in the frown muscles had reduced activity in the left amygdala on functional magnetic resonance imaging (fMRI) when mimicking angry facial expressions. In theory, paralysis of the forehead muscles reduces sensory information from the trigeminal tract to the brainstem, which then alters activity between the brainstem and left amygdala. These findings are important as hyperactivity in the left amygdala has been linked to anxiety, depression, posttraumatic stress disorder, and heightened fear responses.9 In one study,10 20 depressed patients exhibited exaggerated left amygdala activity when shown pictures of emotional faces, especially fearful faces. After antidepressant treatment, left amygdala hyperactivity returned to normal.

Botox for Depression, Research, Dr. Eric Finzi, Dr. Norman E. Rosenthal, Botox, DepressionIs botulinum toxin a viable treatment option for major depressive disorder?

Regardless of whether one subscribes to a more behavioral or biological mechanism of action, further trials are warranted to determine if BTA is indeed a viable therapeutic option for depression and if specific patient populations are more likely to respond (eg, a recent study11 showed that higher agitation scores are predictive of response). If larger trials can replicate the findings of the 3 small trials, BTA may become a novel treatment in the management of major depressive disorder.

Financial disclosure: Dr Magid received grant/research support from the Brain and Behavior Institute, Young Investigator Award, to fund this study. After completion and as a result of the study, Dr. Magid became a consultant for Allergan.

References

1. Gutman R. The hidden power of smiling. TED Talks. March 2011.http://www.ted.com/talks/ron_gutman_the_hidden_power_of_smiling.

2. Grohol J. Ron Gutman: smiling while confusing correlation with causation.http://psychcentral.com/blog/archives/2012/08/19/ron-gutman-smiling-while-confusing-correlation-with-causation/.

3. Darwin, C. The Expression of the Emotions in Man and Animals. London, England: John Murray; 1872.

4. James, William. The Principles of Psychology. New York, NY: Henry Holt & Co; 1890.

5. Wollmer MA, de Boer C, Kalak N, et al. Facing depression with botulinum toxin: a randomized controlled trial. J Psychiatr Res. 2012;46(5):574–581. PubMed

6. Finzi E, Rosenthal NE. Treatment of depression with onabotulinumtoxin A: a randomized, double-blind, placebo controlled trial [published online ahead of print December 16, 2013]. J Psychiatr Res. Abstract

7. Magid M, Reichenberg JS, Poth PE, et al. Treatment of major depressive disorder using botulinum toxin A: a 24-week randomized, double-blind, placebo-controlled study. J Clin Psychiatry [published online ahead of print May 13, 2014]. Abstract

8. Hennenlotter A, Dresel C, Castrop F, et al. 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):537–542. PubMed

9. Shin LM, Liberzon I. The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology. 2010;35(1):169–191. PubMed

10. Sheline YI, Barch DM, Donnelly JM, et al. Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study. Biol Psychiatry. 2001;50(9):651–658. PubMed

11. Wollmer MA, Kalak N, Jung S, et al. Agitation predicts response of depression to botulinum toxin treatment in a randomized controlled trial. Front Psychiatry. 2014;5:36. PubMed

Dr. Finzi To Present Research at World Congress of Psychiatry Meeting Sept. 18 in Madrid

Botulinum Toxin (aka Botox) to Treat Depression? 

3 Independent Studies Prove It’s Worth A Shot

Leading Researchers Including Dr. Eric Finzi, Dr. Alex Wollmer,  Dr. Kruger Tillmann and Dr. Michelle Magid To Present Data from Clinical Studies at the XVI World Congress of Psychiatry Meeting, on September 18, 2014 in Madrid, Spain

The authors of three independent double-blind, randomized, placebo controlled clinical trials will present “Botulinum Toxin, An Emerging Therapeutic for Depression” and their respective research study findings to mental health professionals at the XVI World Congress of Psychiatry (WCP2014) meeting in Madrid, Spain, on September 18th from 12:45-13:30 in Room 11 at the Madrid Congress and Convention Center

The WCP2014, organized by the World Psychiatric Association will take place September 14-18 in Madrid, and will focus on access, quality and humane care. Over ten thousand psychiatrists from all over the world are expected to be in attendance.

According to the World Health Organization, over 350 million people of all ages suffer from depression globally. As of 2012 in the United States, an estimated 16 million adults aged 18 or older had at least one major depressive episode in the past year. Unfortunately, most people never seek treatment. Left undiagnosed and untreated, depression can worsen, cause untold suffering, and may even result in suicide.

Oral antidepressants are designed to boost mood and relieve depression. However, one third of patients do not respond to oral medications. In addition, for some sufferers, side effects such as fatigue, nausea, insomnia, sedation and lack of sexual drive may be poorly tolerated. By contrast, botulinum toxin has few side effects in the doses used to treat depression.

Botulinum toxin is FDA approved to treat a wide variety of health issues including urinary incontinence, migraine headaches, cerebral palsy, excessive sweating, and cervical dystonia, among others. 

Botox for Depression, Eric Finzi MD, PhDIn the largest study to date on the effect of botulinum toxin on depression, researchers Eric Finzi, MD, PhD, and Norman E. Rosenthal, MD, found that 52% of subjects suffering from moderate to severe depression showed relief from depression after injection of botulinum toxin to the glabellar area between the eyes, compared with only 15% of those who received the saline placebo. The study, “Treatment of depression with onabotulinumtoxinA: A randomized, double-blind, placebo controlled trial” was published in Journal of Psychiatric Research, Volume 52 (May 2014). These findings help to confirm a novel concept for mental health – using facial expressions to influence thoughts and feelings. 

Dr. Eric Finzi, a dermasurgeon and artist in the Washington, DC, metropolitan area, made global headlines in 2006 when his pilot study was the first to report the inhibition of facial frowning with Botox injection could help depressed patients. In The Face of Emotion, How Botox Affects Our Mood and Relationships, published by Palgrave Macmillan in 2013, Finzi explains his groundbreaking research and study findings in narrative form, weaving personal stories and rich historical accounts to showcase how his theory came to light. Finzi’s thinking, which dates back to Charles Darwin and William James’s facial feedback theory, marshals together evidence from psychology, neuroscience, art, evolutionary biology, family and patients, to show that facial expressions are a central driving force of our emotions, and that there is an unlikely ally available to tame them: Botox.

Finzi explains, “Botulinum toxin’s inhibition of frowning gives us a novel tool to influence mood. We believe that the brain monitors the state of contraction of facial muscles, and this feedback to the brain is powerful. We look forward to presenting the results from the three clinical trials to the world psychiatric community.”

Stephen Colbert on Botox for Depression

Botox for Depression is No Joke

Satirist Stephen Colbert recently joked about the Botox for Depression study findings in this Comedy Central  The Colbert Report entitled Cheating Death: Depression Edition. Study co-author, Dr. Norman Rosenthal, explains the science behind the research findings in this video.

Dr. Norman Rosenthal’s written BLOG on the subject:

I have always gravitated to research approaches that are off the beaten track, such as the study of SAD and light therapy that I spearheaded at the National Institute of Mental Health (NIMH) over 30 years ago. At that time, seasonal affective disorder (SAD) had not yet been identified: we went on to name it and describe its typical symptoms.  Light therapy, as it’s used for SAD, was unknown.  My colleagues thought I had lost it. Yet now we recognize that millions of people the world over suffer from SAD and countless people have benefited from light therapy.

It was this same out-of-the-box instinct for a winner that went on alert when my colleague, Dr. Eric Finzi, a local dermatologist approached me with a novel idea for treating depression.  Some years before, after leaving the NIMH, I had opened up a private clinical research organization in the hope of doing innovative and creative studies. Although that was possible to some extent (for example, I was able to study the effects of Transcendental Meditation on bipolar disorder and post-traumatic stress disorder), the reality of the work revolved mostly around testing new drugs. So, I was always on the lookout for something really different and exciting.

Dr. Finzi had read the work of Charles Darwin and the famous psychologist William James, both of whom had suggested that cues from the body, including the face, had a powerful effect on human emotions.  Darwin called the frown muscles between the eyebrows “the grief muscles,” and suggested that they were not just a reflection of sorrow, but also fueled it. An extensive subsequent literature supported this “facial feedback hypothesis,” and numerous experiments showed that facial expressions affect the way we feel.

Finzi has described this history in a highly readable book, The Face of Emotion.  Now Finzi had an idea as to how these insights could be used to treat depression – by means of botulinum toxin (Botox), which is known to paralyze muscles.  How would it be, he wondered, if we paralyzed the frown muscles between the eyebrows in a double-blind study with saline as a control? An encouraging pilot study suggested it might work.  But this would now need to be tested in a controlled study. Would I be interested in conducting such a study in my research organization?  Well, I loved the idea! And that was the beginning of an enjoyable collaboration.

Another reason why Finzi’s idea appealed to me so much is that over a decade before he approached me, I had written a book about the science of emotion, called The Emotional Revolution.  In it I wrote:

Among the sensory nerves that influence our mood are those that pass directly through the skull and into the brain.  These are known as the cranial nerves.  Exposure to light stimulates one pair of these nerves, the optic nerves. Another pair, the olfactory nerves, transmits sensations of smell to the brain.  The fragrance of lemons lifts the mood of depressed patients with SAD.

It was highly plausible to me that frowning might send signals to the brain via different cranial nerves – the facial and trigeminal nerves.  But in this case, it seemed, the signals aggravated a person’s mood rather than relieving it.  So it made all the sense in the world to me that blocking these signals might reverse depression.

So Finzi and I embarked on a controlled study of Botox for depression in collaboration with a great team of psychiatrists and administrators at my research organization.  We entered 74 depressed people into a double blind, placebo controlled study and when we finally analyzed the data, the results were clear and strong. Botox beat placebo, significantly reducing depression levels, regardless of whether patients were already on antidepressants (to which they had not responded) or were untreated.

As a psychiatrist who has treated many people with depression, I am truly excited at this new treatment option. Although there are many available treatments for this very painful affliction, they are often only partially effective and have troublesome side-effects.  I am delighted that we now have a new treatment option which can be used safely

NBC Washington Features Botox for Depression Research

Dr. Eric Finzi and Sarah Bergman, a Botox for depression study patient, were interviewed by WRC-TV news anchor Barbara Harrison on Tuesday, April 1, 2014 about the latest study findings published in the Journal of Psychiatric Research in May 2014.

Dr. Eric Finzi on NBC Washington, WRC-TV mid-day with Barbara Harrison