Article by Dr. Paula Pifarré
More than 260 million people suffer from depression worldwide
Last week the Spanish Society of Aesthetic Medicine (SEME) published in its social networks a news item from the newspaper La Razón, which commented on the use of toxina botulínica (TBX) to alleviate symptoms associated with depressive disorders.
Recently, a Scientific Reports has been published in a high impact journal within the scientific community, the journal Nature. The article led by Stark and collaborators describes the modulation of neuronal activity against a facial emotion of the central nervous system by the application of botulinum toxin type A.
The group led by Eric Finzi first published in 2006 a clinical trial report describing the beneficial effect of TBX treatment on the glabella in patients with depressive disorders. In this study they treated 10 women who had previously been diagnosed with depressive disorders with 5 TBX injection sites. Regardless of whether or not they were taking any medication for depression, 8 weeks after treatment, 9 women no longer had symptoms to be diagnosed with depression.
In 2012 Wollmer et al. launched the first controlled clinical trial to see the impact of TBX treatment on depression. In it a group of 30 women and men were randomized to receive treatment with botulinum toxin or placebo following Finzi’s protocol. All patients in the study met the diagnosis of depression (medium to moderate) using 3 different clinical scales. In addition, these patients were receiving treatment with at least one drug to treat their condition. Men received 39 units of TBX, while women received 29 units, responding to anatomical differences in glabellar muscle mass. In this study, TBX treatment showed a significant improvement in symptoms to over 40% after two weeks, with the maximum at six weeks, and with an overall remission rate of 33%.
A second controlled clinical trial was conducted in 2014 by the same group of Finzi et al. It involved 74 women and men, who were randomized to receive TBX or placebo. Patients were not required to have antidepressant treatment but, those who were taking medication, had to keep it stable prior to the study. The results were similar, with TBX demonstrating symptom improvement in the majority of patients, total remission in 21% who were not on other treatment and 36% in combination with other therapy.
This complex study had a crossover design. Patients initially received either Toxin or Placebo, but were then switched between groups. This determined that regardless of when treatment was initiated, in both cases the depressive symptomatology was reduced after 6 weeks of receiving TBX. It was maintained for up to 24 weeks in those who received the toxin first.
A collaborative study among all the researchers concluded that the response rate to treatment with TBX was 54.2% compared to 10.7% with placebo. For its part, the total remission is 30.5% in TBX versus 6.7% for the placebo effect.
In 2017 Zamanian et al. conducted a new study with 28 patients injected in the glabella. At 6 weeks post-treatment, 40% of those injected with TBX had improvements versus 12% with placebo.
The largest clinical trial was conducted in 2020 by Brin and colleagues. They worked with 255 female patients, all with a score greater than 18 on the HAM-D scale. These patients were divided into 4 groups, and two doses of toxin and placebo (30 units and 50 units) were tested. Data were collected after 3, 6, 9 and 18 weeks. For the 30-unit doses, improvements were
For the 30-unit doses, improvements were observed after 6 weeks, as previously described. For those who received 50 units, the results were not greater. This was probably due to the high number of injections to which they were subjected, with a negative effect on the participants’ mood.
Although the effects were clear, the mechanism of action was unknown for the time being until the articles by Kruger (2022) and Stark (2023) both published as Scientific reports in the journal Nature.
It was already known that botulinum toxin was able to inhibit the release of acetylcholine (Ach) neurotransmitter responsible for muscle contraction in the neuromotor plate in the periphery. It was also known that Ach in the central nervous system is increased in people suffering from depression. This could have been one of the explanations why it works. While it is applied in the periphery, it could travel along the axons to the nervous system and there normalize Ach levels. However, all studies point to this being an indirect effect, rather than a direct effect on Ach levels in the brain.
Several hypotheses have been studied, the first of which was related to the cosmetic change produced by the toxin treatment. This change generated in people a higher level of self-satisfaction, thus raising self-esteem and triggering greater well-being. However, there is no temporal correlation between the aesthetic change and the improvement in depression symptomatology.
A second hypothesis is related to “social” improvement. By blocking the expression of negative facial emotions by the action of the toxin on the glabellar area, a more positive attitude is generated in the person’s environment. This is reflected in a more positive attitude towards the person, improving self-esteem and decreasing negative emotions.
People with depression show hyperactivity in the corrugator muscles responsible for expressing “negative” emotions. By paralyzing them, the negative proprioception from the face to the brain is inhibited, decreasing the negative reinforcement of negative emotions in people with depression.
The last hypothesis is known as the facial feedback hypothesis. This hypothesis was first described in 1988. It is based on the fact that expressed and felt emotions influence each other in a loop.
Already in the 19th century one of the pioneers in the interpretation of emotions and physiological descriptions of emotional processing, Williams James, said: “Avoid expressing a passion, and it will die”.
It is now accepted that contraction of facial musculature can modulate emotional experience. In Stark’s article, they focus mainly on studying the facial feedback hypothesis. To do this they treat the glabella muscle with TBX and measure the neural activity in the brain against images of happy or angry faces via MRI.
What they observed was that the impossibility of mimicking the emotion, due to the inhibition of the muscle, altered the processing of the emotion by a brain area called the amygdala. The amygdala is a fundamental part of the brain responsible for the modulation of emotions.
These results support the hypothesis that peripheral motor function is fundamental for the perception of an emotion and affects cognitive processes.
Figure 1- Image taken from Stark et al, 2023)
In the study they determine that the communication between the facial muscles of mimicry and the brain is bidirectional.
Thus, the activity of the corrugator muscles is sensed by the optic branch of the trigeminal nerve. It is in the midbrain that it establishes a relay station that projects axons to the Locus Coeruleus and the amygdala, and from there to the prefrontal cortex. Both structures are critical for the processing of emotions.
The amygdala is the area responsible for the balance between emotions. Its neuronal activity is increased when facial emotions of happiness and anger are perceived.
In Stark’s article they also describe the modulation of the neural activity of the fusiform gyrus. An area responsible for the processing of facial expressions and the face has been described there. In fact, patients with prosopagnesia (difficulty in distinguishing a familiar face) have a dysfunction of the fusiform gyrus. It is also related to differential activity for processing facial emotions of joy or anger and interacts with several areas of the brain, including the amygdala. During the study, they did not observe changes in the fusiform gyrus when treated with toxin during the processing of anger faces, but they did observe changes in the fusiform gyrus during the processing of joy faces. This provided evidence of its relationship with the emotion management system.
In the study by Kruger et al, they describe that dysfunction of the facial feedback loop could mitigate the sensation of negative emotions. This would in turn cause a decrease in amygdala activation in response to the emotional stimulus.
For these reasons, this treatment would not be restricted to depression, but could be extended to other disorders, such as borderline personality disorders with severe impairment of the ability to manage emotions.
In conclusion, the effect of toxin on depression appears to be multifactorial and involves the facial musculature, signaling through the trigeminal nerve, the amygdala and the fusiform gyrus in the central nervous system. The latter are associated with other areas of the brain, such as the locus coeruleus and the prefrontal cortex (Schulze 2021). Inhibition of the facial musculature of the glabella region prevents the formation of this feedback loop on brain structures that are fundamental for the processing of emotion.
Considering that more than 260 million people suffer from depression in the world, and that many patients do not respond to standard treatments, finding new therapeutic guidelines, of easy adherence and low cost, such as treatment with botulinum toxin is encouraging. However, more studies are needed to determine the timing, dosage and recurrence of botulinum toxin treatment in depressive disorders.
MASTERCLASS: Neuromodulatos
Bibliographic references
Stark, S., Stark, C., Wong, B., & Brin, M. F. (2023). Modulation of amygdala activity for emotional faces due to botulinum toxin type A injections that prevent frowning. Scientific reports, 13(1), 3333. https://doi.org/10.1038/s41598-023-29280-x
Kruger, T. H. C., Schulze, J., Bechinie, A., Neumann, I., Jung, S., Sperling, C., Engel, J., Müller, A., Kneer, J., Kahl, K. G., Karst, M., Herrmann, J., Fournier-Kaiser, L., Peters, L., Jürgensen, F., Nagel, M., Prager, W., Dulz, B., Wohlmuth, P., Heßelmann, V., Wollmer, M. A. (2022). Neuronal effects of glabellar botulinum toxin injections using a valenced inhibition task in borderline personality disorder. Scientific reports, 12(1), 14197. https://doi.org/10.1038/s41598-022-17509-0
Wollmer, M. A., Magid, M., Kruger, T. H. C., & Finzi, E. (2022). Treatment of Depression with Botulinum Toxin. Toxins, 14(6), 383. https://doi.org/10.3390/toxins14060383
Schulze, J., Neumann, I., Magid, M., Finzi, E., Sinke, C., Wollmer, M. A., & Krüger, T. H. C. (2021). Botulinum toxin for the management of depression: An updated review of the evidence and meta-analysis. Journal of psychiatric research, 135, 332–340. https://doi.org/10.1016/j.jpsychires.2021.01.016
Zamanian, A., Ghanbari Jolfaei, A., Mehran, G., & Azizian, Z. (2017). Efficacy of Botox versus Placebo for Treatment of Patients with Major Depression. Iranian journal of public health, 46(7), 982–984.
Magid, M., Reichenberg, J. S., Poth, P. E., Robertson, H. T., LaViolette, A. K., Kruger, T. H., & Wollmer, M. A. (2014). Treatment of major depressive disorder using botulinum toxin A: a 24-week randomized, double-blind, placebo-controlled study. The Journal of clinical psychiatry, 75(8), 837–844. https://doi.org/10.4088/JCP.13m08845
Wollmer, M. A., de Boer, C., Kalak, N., Beck, J., Götz, T., Schmidt, T., Hodzic, M., Bayer, U., Kollmann, T., Kollewe, K., Sönmez, D., Duntsch, K., Haug, M. D., Schedlowski, M., Hatzinger, M., Dressler, D., Brand, S., Holsboer-Trachsler, E., & Kruger, T. H. (2012). Facing depression with botulinum toxin: a randomized controlled trial. Journal of psychiatric research, 46(5), 574–581. https://doi.org/10.1016/j.jpsychires.2012.01.027
Finzi, E., & Wasserman, E. (2006). Treatment of depression with botulinum toxin A: a case series. Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.], 32(5), 645–650. https://doi.org/10.1111/j.1524-4725.2006.32136.x
