CPD: Menopause and Botulinum Toxin

The menopause transition is a natural phase of women’s lives. Generally between the ages of 42 to 55, many women experience perimenopausal symptoms, which are described as a group of symptoms related to autonomic nervous dysfunction in women.¹ These symptoms are a consequence of pituitary hyper-function and ovarian function decline, with consequent fluctuation and/or decline in oestrogen levels. There are understood to be 34 known symptoms related to PMS, which include hot flushes, night sweats, depression and anxiety.² Literature presents evidence of women’s lived experience of shame relating to menopause symptoms, and pervasive, negative discourses regarding menopause and ageing.³ Loss of oestrogen activity may negatively impact mental wellbeing, including the experience of ageing.^4,5

Depression is a common psychiatric disorder but regardless of its prevalence and potential severity, clinical definitions for depressive disorders continue to be debated.⁶ DSM-IV has identified nine diagnostic criteria of depression, of which there needs to be five present over a defined length of time for diagnosis.⁷ It is understood that during perimenopause, women have an increased risk of developing depression with a higher severity rate than pre-menopause. Further, it is indicated that vasomotor symptoms are related to depressive symptoms during the menopausal transition.⁸

There is some evidence that recipients of botulinum toxin A (BoNT-A) facial cosmetic injections report increased emotional wellbeing beyond the cosmetic benefit.^9,10 Injecting the glabellar complex changes the facial expression from sadness or anger to happiness, which can lead to an improved emotional experience.¹¹ As such, we undertook a literature review to explore the potential use of botulinum toxin as a treatment for depression in menopausal women.

Methods

A search strategy was developed using MeSH and free text terms in the following databases: PubMed, CINAHL, DiscoverIT, FindIT and Google Scholar. Additionally, the reference lists of the identified screened publications were scrutinised. A search of electronic databases using key author names rather than key terms, in order to potentially identify additional research or other evidence published, was also undertaken.¹²

Keywords in the search strategy included: (botox* OR botulinum toxin* OR botulinum toxin type A* OR OnabotulinumtoxinA* OR botox injections*) AND (mood* OR low mood* OR depression* OR anxiety*) AND (menopause* OR perimenopause*) AND (treatment*). Initial exploration of the databases was conducted in January 2021, with a final search undertaken in May 2022. Results were limited to freely available publications dating from 2010 onwards, published in English language and duplicates excluded.

Discussion

Depression is a common illness worldwide, with more than 264 million people affected, and is associated with approximately 850,000 deaths by suicide each year. Indeed, across all countries, women have a lifetime risk of major depression roughly twice that of men. The perimenopausal phase of a woman’s life is a critical period for the potential to develop depression, which is characterised by anxiety, lack of energy and feelings of guilt, as well as somatic complaints such as headaches and muscle and joint pain.¹³ Depression during midlife is particularly worrisome, as the incidence of heart disease – a major killer of women – increases dramatically in the wake of the menopause, and is adversely affected by co-morbid depression, with increased mortality risk.¹⁴

Recently, there has been increasing interest in the glabellar use of BoNT-A as a novel intervention in the treatment of major depressive disorder (MDD). As discussed in Table 1, the first case series published in 2006 included a cohort of 10 female patients aged 18-65, diagnosed with MDD. Nine patients responded to treatment with onabotulinum to the glabellar complex, with eight going into remission for depression. One participant who displayed only a partial response had a diagnosis of bipolar disorder.¹⁵

It has been postulated that the mechanism of action of the glabellar injections of botulinum toxin (GBTx) targeting depression comprises: the attenuation of negative emotions through the relaxation of the frowning muscles, and the improvement of depressive symptoms following the reduction of negative emotional experiences.¹⁶

The first statement is about the facial feedback hypothesis, which proposes that a feedback mechanism from facial expressions has an impact on emotions, i.e. frowning can make a person feel angry, whereas smiling can make them feel happy.¹⁶ Indeed, in the 19th century, Charles Darwin and William James first predicted a link between our facial expression and emotions. According to them, facial expressions of sorrow or grief send signals to the emotional part of the brain, inducing or exacerbating feelings of distress.¹⁷

Facial expressions are thought to influence emotions through multiple pathways, categorised as the cognitive processing of emotional information, motivational behaviours and the autonomic nervous system activity.¹⁶ These pathways can be both complementary and/or overlapping¹⁶ depending on the stimulus, the circumstance and the involved feeling. In other words, according to the current facial feedback theory, the cognitive appraisal of a stimulus often initiates emotional reactions. At the same time, our facial expressions are highly influenced by cognitive appraisals.

The second proposed mode of action of GBTx suggests that mood improvement is the result of decreased negative emotional experiences. There is not enough evidence for such a prediction, though. In fact, reduction in negative emotional experiences represents only one aspect of a universe called depression. Depression, in a broader sense, can be secondary to exacerbated negative emotional reactions, attenuated positive emotional events, or, most likely, a combination of both.¹⁸ The age ranges for all the studies in the table below is 18-65; none of the studies identified if participants were perimenopausal. Table 1 presents the studies related to onobotulinum toxin and depression and omits those related to migraine and those addressing perimenopause and depression.

Table 1

Summary of findings

It is well known that depression can be severe and burdensome during the menopause transition.³¹ Extrapolation of the available findings and current knowledge demonstrates there is scope for further investigation of the impact of BoNT-A on mood during the menopause. For instance, as shown above, GBTx could be an alternative treatment for depressive patients who fail to properly respond to the standard antidepressant therapy, including perimenopausal women, who represent a large proportion of aesthetic patients. From a safety perspective, GBTx is very well tolerated with limited, short-lived adverse effects reported.³² However, until now, the effectiveness of GBTx for this purpose remains contestable, and it is not currently approved.

Current limitations

In Table 1, we can observe that the assessment of depression and its severity is highly heterogeneous across the revised trials, which reduces the overall comparability of results. Furthermore, the reviewed studies have used a variety of doses and sites of administration, making it even more difficult to compare or draw conclusions from the combined papers. 

Other limitations for the generalisability of the findings are related to gender due to females’ overrepresentation. Most of the RCTs also had small sample sizes – an average of 68 participants per study. Cole’s et al ²⁷ meta-analysis assessed seven clinical trials containing quantitative information for obtaining effect sizes. Their primary outcome was the comparison of depression scores between placebo and GBTx groups after six weeks from the baseline. They also investigated secondary outcomes referred to within-subject which was the comparison of depression severity, before and after treatment.

For both primary and secondary outcomes, a statistically significant reduction in depression scores was demonstrated six weeks after intervention. Nevertheless, a substantial asymmetry in the effect sizes distributions in both cases was noted, thus making the authors raise important concerns regarding the validity of the findings. The most relevant was the extraordinarily large effect size for the primary outcome, which was 2.65 times greater than the overall effect size of standardised antidepressant drugs. Additionally, almost 100% of the effect sizes came from researchers with conflicts of interest, i.e. sponsored by toxin manufacturers. 

Another limitation refers to the fact that in those clinical trials, it is somewhat difficult to blind investigators and patients to what they are injected with, since only BoNT-A treatment will have a notable effect on appearance, in contrast to the placebo. Finally, some evidence of publication bias has been uncovered in the meta-analysis.²⁷

The next steps

There are sufficient reasons for the pharmaceutical industry to invest large amounts of resources to test the impact of BoNT-A on mood in perimenopausal women. GBTx has a long safety record, requires treatment once every 12-16 weeks, is relatively inexpensive when compared with continuous medication and other therapeutic modalities and has a high rate of cosmetic efficacy and patient satisfaction.¹⁷ However, the methodological limitations and statistical concerns described above suggest it is premature to conclude in favour of GBTx as a first choice treatment for depression.

Continuing research

Research has turned its attention to novel approaches that are beginning to provide promising results in treating refractory depression.³² The initial hypothesis suggests there may be a causal link between perimenopausal women looking for cosmetic interventions, the disseminated use of BoNT-A in the aesthetics practice and an unintended consequence of improved mood. Conclusions point to several potential advantages of this treatment modality for depression, including safety, cost, compliance and efficacy.³³ 

However, for this specific indication, there is currently no approved treatment protocol for the use of BoNT-A. The reviewed studies have used a variety of doses and sites of administration, making it difficult to compare or draw conclusions from the combined papers. Additionally, there is disparity in the study’s run time, definition of pre-, peri- and post-menopausal age ranges and follow-up periods. Patient reported outcome, patient satisfaction and patient reported experience measures appear to have been omitted from all the studies. Understanding the interventions through the lens of the patient would add further quality and depth to research in this field.

Whilst BoNT-A can be considered an effective and safe treatment for patients with mild to moderate depressive symptoms, the findings are not valid for patients with severe symptoms or risk of suicide, nor for those with other psychiatric comorbidities. In such cases, a close follow-up with a psychiatrist is advised. Well-designed prospective clinical trials with larger samples and more objective assessment tools are necessary to confirm or refute the alluded benefits, and to establish recommendations and application protocols.

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