Botulinum to Relax Frown Lines Relieves Major Depression

Daniel M. Keller, PhD

March 13, 2012

March 13, 2012 (Prague, Czech Republic) — For patients with chronic major depression that does not sufficiently respond to other treatments, a single injection of botulinum neurotoxin into the glabellar muscle of the forehead to relieve frown lines appears to lead to strong and sustained improvement of the depression.

Tillmann Kruger, MD, Associate Professor in the Department of Psychiatry, Social Psychiatry and Psychotherapy at Hannover Medical School in Hannover, Germany, reported here at the 20th European Congress of Psychiatry that these findings support the concept that facial musculature not only expresses mood states but also affects mood.

Dr. Tillmann Kruger

He explained that frowning expresses negative emotions such as anger, fear, or sadness. A facial feedback hypothesis says that the frown itself reinforces negative emotions, with the implication that suppressing frowning will help to relieve the negative emotions.

"The theory is pretty old, and it says that many or most of the emotions we have develop somewhere in the brain, and some of them are expressed in your face, for example...and this is again received and sent back to the central nervous system by this proprioceptive feedback," he told Medscape Medical News. He said that in some cases of depression, there are signs of increased glabellar muscle activity.

Single Injection

To test the hypothesis, Dr. Kruger and colleague Axel Wollmer, MD, of the Psychiatric Hospital of the University of Basel in Switzerland, performed a randomized, double-blind, placebo-controlled trial using an injection of onabotulinumtoxinA (29 units for women, almost 40 units for men) or placebo into a total of 5 points in the procerus and corrugator muscles in the glabellar region of 30 patients with chronic major depression.

Patients were 25 to 65 years old; they had a moderate to severe glabellar frown line and were undergoing stable treatment with antidepressant medication. The primary endpoint was the Hamilton Depression Rating Scale (HAM-D17, an expert-rated instrument) score 6 weeks after treatment compared with baseline.

The investigators found that a single injection session led to diminished frown lines (P < .001) and to strong and sustained improvement in the depression in these patients who had not responded sufficiently to previous treatments.

At 2 weeks, patients showed an improvement of mood, with a -5 point change on the self-reported Beck Depression Inventory (BDI) scale. There was only a slight improvement of mood in the placebo-treated patients.

The botulinum-treated patients showed an almost 50% reduction in their HAM-D17 scores from 22 at baseline to about 12 at 6 weeks compared with only a 9% improvement in the HAM-D17 scores for the placebo group. The reductions in HAM-D17 scores were significant at all times points from 2 to 16 weeks (P < .001 at 16 weeks); similarly, the BDI score at 16 weeks was significantly improved compared with baseline (P < .01).

More than 80% of the botulinum group had at least a partial response vs only a 25% partial response in the placebo group. A full response, meaning at least a 50% reduction on the HAM-D17 scale, occurred in 60% of the botulinum group but in only 13% of the placebo group. A full remission at 6 weeks, being a HAM-D17 score of 7 or less, occurred in 33% of the botulinum group.

Dr. Kruger noted that typically among depressed patients, there is a fairly strong placebo effect, which he did not see in his patients. He explained the low rate and level of improvement in the placebo group as a result of the high proportion of participants with chronic depression and resistance to multiple previous therapies. Botulinum was later offered to patients in the placebo group. No patients dropped out of the study in either group.

Facial Feedback Theory

"Not all glabellar frown lines have to disappear to guarantee a good psychological effect," Dr. Kruger said, and full remissions have been observed in patients with residual frown lines.

"We think, regarding possible mechanisms, that the reduced proprioceptive feedback — the facial feedback theory — is the most important one. I think this is something that works 24 hours per day," he added.

There may also be some effect of social feedback in that friends and family may tell patients that they do not look so angry.

Dr. Kruger said that botulinum is able to travel in a retrograde direction via nerve fibers to the central nervous system, but given the small amount of drug used, he thought this mechanism would not explain the effects seen.

However, when asked whether a more appropriate control than placebo injections would be botulinum injections into a cranial muscle that did not affect frowning, he agreed that such a procedure would be a good control for a possible effect of botulinum not related to the relief of frown lines. Therefore, it is still possible that botulinum acted through a mechanism other than relief of frown lines.

Dr. Kruger said the study also showed that botulinum injections had excellent safety and tolerability. "It may be even economic because it's only a single injection [session], and it works for more than 16 weeks, as we have seen," he said, but the study needs to be validated in larger trials.

At present, botulinum is not indicated for treatment of depression. "But Botox has an indication to treat glabellar frown lines...and if someone has frown lines and has a depression and says, 'I want to have them away, these frown lines,' you can, of course, use it," Dr. Kruger noted.

Not Ready for Prime Time

Session moderator Frank Padberg, MD, Associate Professor and Director of the Brain Stimulation Laboratory in the Department of Psychiatry and Psychotherapy at Ludwig Maximilian University in Munich, Germany, commented to Medscape Medical News that the study was a pilot with a small sample size, "so you have to be, of course, cautious in interpreting the results, and it's of course difficult to have a good placebo control because the patients are aware that something changes or changes not," with botulinum or with placebo.

"So the placebo response in rather treatment-resistant patients was quite low, and that's often a problem in pilot studies" because of less than adequate blinding, so "a significant effect comes out due to a low placebo response rate," he said. "But the data were interesting, and the effect was quite robust of the injection leading to improvement over a period of 6 weeks...so the basic principle of treatment seemed to work in this group."

"The mechanisms of action are not clear," Dr. Padberg cautioned. "That is the main issue, but it is an interesting pilot work." In addition, patients in the study had to have frown lines, so it is a question of how many patients may be eligible for this sort of treatment. And he feels it is still too early to use this therapy outside of clinical trials.

The study was not commercially funded. Funding came from the private foundation Gottfried & Julia Bangerter-Rhyner-Stiftung in Bern, Switzerland. Dr. Kruger reported that he has been on speakers' bureaus for Pfizer, MSD, Servier, and Lundbeck. Dr. Padberg had no relation to the study and has disclosed no relevant financial relationships.

EPA 2012: 20th European Congress of Psychiatry. Abstract #O-29. Presented March 4, 2012.

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