Perimenopause and risk of psychiatric disorders: a longitudinal, population-based study

THE PROBLEM
There are over 1.2 billion women over the age of 45 in the world, 29 million in the UK. About 70% of them develop neurological and psychiatric symptoms during perimenopause (the years around the final menstrual period). It has been suggested that perimenopause is also a high-risk period for the onset or exacerbation of psychiatric disorders, including major depression, schizophrenia and bipolar disorder. Research thus far has mainly focused on depressive symptoms. The very few studies that have investigated clinically significant major depression have found a 2-4 times greater risk of becoming unwell during perimenopause compared to the pre-menopause, even after controlling for other symptoms and predictors.
Professional bodies and institutions worldwide have highlighted the gender gap in mental health, including the knowledge gap on the effects of reproductive ageing. Little and inconsistent information is available on severe mental disorders and, more broadly, on the factors that may predispose women to become unwell during the transition to menopause. This lack of information is a major issue for women, their families and carers.
Some women who develop psychiatric disorders during perimenopause may not have any psychiatric history or may have been well for many years and not in contact with psychiatric services. Identifying these women and providing them with the necessary care is of vital importance.

THE RESEARCH
This research will address the current lack of information on the risk of severe mental illness related to perimenopause. It will systematically investigate a population of over 160,000 middle-aged UK women who have been followed up to the postmenopause using interviews and electronic health records from primary care and hospital admission. Data will be extracted and cleaned using standard procedures. We will calculate the risk of mental disorders at different time periods. We will test the hypothesis that the late perimenopause is a period of increased risk of mental disorders. As not all women are the same, we will seek to identify groups of women with similar risk profiles. We will also explore the effect of psycho-social, clinical and genetic factors on the risk of becoming unwell.
Women with lived experience have been involved in the design of this study and will be involved at all stages of research to provide input via an advisory group. They will also give talks at workshops and dissemination events.

BENEFITS
The findings of this study will help identify women at risk of developing mental illness in relation to the perimenopause. These women may benefit from closer monitoring and will be empowered to take steps to manage their own health to avoid relapse. Prompt recognition of early signs of illness will allow more rapid treatment, with the potential to save lives.
By providing evidence-based, easy-to-understand information to the public, the research may also contribute to raising awareness of the risks of mental illness during perimenopause. Moreover, it has the potential to give women themselves the tools to manage their illness more effectively and to contribute to the de-stigmatization of mental disorders associated to the perimenopause.
The results will also have the potential to improve the current approach to diagnosis, prevention and treatment of psychiatric disorders in middle-aged women by influencing guidelines and informing risk assessment tools.
The long-term goal is to improve personalised risk predictions and ultimately how we help women with perimenopause mental disorder, reducing the impact of episodes of illness in women at risk. Given the association between poor mental health in middle-age years and general health outcomes, our research also has the potential to contribute to improving the general health and wellbeing of women.

This study will be the first longitudinal, population-based, systematic investigation of the risk of psychiatric disorders associated with reproductive aging. It seeks to contribute addressing the gender gap in psychiatry highlighted by professional bodies and institutions worldwide.
First, we will seek to estimate the risk of psychiatric illness associated with reproductive aging and to test the hypothesis that, compared to the reproductive and late post-menopause stages, late perimenopause is a period of increased risk of psychiatric illness.
The primary analysis will include all women in UK Biobank who had their final menstrual period before 2010 (N=165,406). Linkage with pre-existing primary care and hospital electronical health records will provide longitudinal clinical information. The main outcome will be incident ICD-10 psychiatric diagnoses. Relative risks will be estimated using the period up to 10 years before the final menstrual period as a reference in survival analyses. Group-based trajectory modelling will identify groups of women with similar disease trajectories.
Second, we will evaluate the effect of possible predictors [reproductive (psychiatric) history, hormone replacement therapy, psycho-social factors, aggregated measures of genetic variation] on the risk of late perimenopause psychiatric episodes and on the group membership of disease trajectories. Replication efforts will exploit our in-house large clinical-genetic datasets.
To maximize the impact of our research, an advisory board of women with lived experience will be involved at all stages of research and will lead dissemination activities. Through our links with professional organizations, the results will have the potential to directly inform clinical practice. By providing evidence-based, easy-to-understand information to the public, this research may also contribute to the empowerment of women and to de-stigmatizing and raising awareness of perimenopause mental health.