HRT Reduces Psychosis Relapse Risk in Middle-Aged Women

Schizophrenia spectrum disorders (SSD), which encompass schizophrenia and schizoaffective disorders, exhibit notable differences between men and women in various aspects. These include the age at which individuals receive a diagnosis, incidence rates of the disorders, clinical manifestations, and responses to treatment (Ochoa et al., 2012). Research indicates a concerning trend referred to as a “female-specific and time-dependent deterioration” (Brand et al., 2024, pg. 893). Specifically, women over the age of 45 are prone to experience higher incidence rates and more frequent psychotic relapses compared to their male counterparts of the same age, as well as younger women diagnosed with SSD (Sommer et al., 2023).

The observed differences in outcomes between sexes may be attributed to the oestrogen protection hypothesis (review, Sharpe, 2003). The transition into menopause, typically occurring between the ages of 45 and 55, is characterized by fluctuating and ultimately declining levels of oestrogen (Burger et al., 2007). Following the last menstrual period, oestrogen levels stabilize at a low state (Harlow et al., 2012). Oestrogen is known for its neuroprotective properties, modulating neurotransmitter systems crucial to the neurobiology of schizophrenia (Ross et al., 2006). As menopause progresses, women may experience increased vulnerability to psychosis and other psychiatric symptoms (Marwick, 2024) due to diminished hormonal influence over essential neurotransmitter systems.

This decline in oestrogen levels could significantly exacerbate symptoms associated with schizophrenia spectrum disorders. Consequently, there is growing interest in exploring how menopause hormone treatment (MHT) could potentially alleviate psychotic relapses. Evidence suggests that higher doses of antipsychotic medications have not successfully prevented symptomatic deterioration in women over 45 (Sommer et al., 2023). MHT, also known as Hormone Replacement Treatment (HRT), employs synthetic progestogen and/or oestrogen to ease menopausal symptoms such as hot flushes. Although studies have yielded mixed results regarding the efficacy of MHT on SSD in menopausal women, a systematic evaluation within a real-world context has been lacking—until now. The recent study by Brand et al., (2024) investigated the real-world effectiveness of MHT in reducing psychotic relapses among menopausal women diagnosed with SSD.

Study Design and Methodology for MHT Effectiveness

This cohort study meticulously identified women (biological sex) diagnosed with SSD who were hospitalized in Finland from January 1972 to December 2014. Data was sourced from a comprehensive hospital discharge register. The cohort was specifically narrowed down to women who began MHT between the ages of 40 and 62 from 1995 to 2017, with exposure to MHT determined via the prescription register, ensuring a targeted analysis of treatment outcomes.

Follow-up for this study extended from the initiation of MHT up until 2017 or until the patient’s death, whichever occurred first. Psychosis relapse was evaluated based on two key metrics:

• Hospitalization resulting from psychosis (primary outcome)
• Hospitalization due to any psychiatric reason (secondary outcome)

Outcomes were documented in the hospital discharge register. Women who modified their MHT prescriptions were included multiple times in the follow-up, allowing for a comprehensive analysis of each prescription’s impact separately.

Rigorous Statistical Analysis of MHT Effects

The statistical analyses conducted compared periods of MHT usage against periods of non-use. During these intervals, both primary and secondary outcomes were examined using stratified Cox models, categorized by age groups: 40-49, 50-55, and 56-62. Each patient served as their own control whenever changes occurred in their MHT regimen alongside any hospitalization event. Hazard ratios were then calculated to assess the risk of relapse associated with MHT usage for each outcome.

Key Findings on MHT and Psychosis Relapse

Demographics of the Study Cohort

An initial cohort comprising 30,785 women was identified and subsequently narrowed down to 3,488 women actively using MHT. The length of follow-up varied from three to fifteen years, influenced by the timing of MHT initiation and the point at which patients exited the study. Notably, women with shorter follow-up durations were either recruited towards the latter part of the study or commenced a new regimen of MHT.

From the final cohort, it was found that 52.70% had at least one hospitalization due to psychosis, while 63.20% experienced at least one hospitalization stemming from psychiatric reasons. Remarkably, 70.90% of the women remained on MHT for over a year, and 54.50% had only a single period of MHT utilization.

Importantly, 95.50% of the cohort reported experiencing at least one period of non-use, facilitating a within-subject comparison to assess the impact of MHT on hospitalization outcomes effectively.

Impact of MHT on Psychosis Relapse Risk

Overall, the utilization of MHT was correlated with a 16% reduction in relapse risk, particularly pronounced in women aged 40-55. Conversely, women who commenced MHT between the ages of 56-62 did not demonstrate a reduced risk of relapse.

When evaluating the effectiveness of various MHT formulations, findings revealed that both oestrogen-only treatments and those combining oestrogen with progestogen yielded similar benefits, reducing relapse risk by 14 to 21%. However, the method of administration proved crucial; transdermal delivery did not significantly mitigate relapse risk, whereas oral administration reduced the risk by 13-18% across both oestrogen-only and oestrogen-progestogen combinations.

Moreover, differences in the effectiveness of various oestrogenic and progestogenic compounds were noted, with certain combinations leading to a 15 to 25% lower risk of relapse. For instance, oestradiol-only and combinations of oestrogen with levonorgestrel, MPA, and norethisterone showed promise, while oestriol-only or oestrogen with dydrogesterone did not significantly affect relapse risk.

Reduction of Psychiatric Hospitalization Risk with MHT

The study also revealed that the risk of hospitalization due to psychiatric reasons decreased with MHT use. Furthermore, the trends observed across different age groups, MHT formulations, and methods of administration aligned closely with the primary outcome findings, reinforcing the potential benefits of MHT in managing psychiatric conditions.

Significant Insights and Conclusions on MHT’s Role

In a cohort comprising 3,488 women diagnosed with SSD at menopausal age, the findings linked MHT to a significant 16% reduction in relapse risk. This protective effect was particularly pronounced among women who initiated MHT between the ages of 40-55, underscoring the importance of timely intervention during menopause. Similar trends were observed regarding the reduction of hospitalization risk for psychiatric conditions. The effectiveness of MHT in minimizing risks was influenced by both the method of administration and specific formulations utilized. These findings stress the necessity of customizing MHT regimens to meet individual patient profiles, thereby maximizing the benefits for relapse prevention in women living with SSD.

Evaluating Strengths and Limitations in MHT Research

The research conducted by Brand et al. (2024) opens a promising pathway for treating SSD through MHT, echoing earlier findings regarding the relationship between SSD symptoms and MHT intervention (Lindamer et al., 2001). The outcomes highlight the potential to decrease hospitalizations due to psychosis and other psychiatric reasons, which are critically significant in clinical practice. While the consistency in findings across various MHT formulations bolsters the study’s conclusions, the variations between oral and transdermal administration raise essential questions about adherence to treatment regimens.

The observational nature of the data enhances its applicability to real-world scenarios. The reliance on objective measures of relapse, such as hospitalizations, provides invaluable insights into severe SSD cases. However, the authors acknowledge that such measures may be less relevant for milder cases of SSD, where symptom exacerbation could manifest through functional impairments or non-hospitalized psychotic episodes. Future research should aim to explore the effects of MHT on SSD using objective scales that can also capture everyday instances of symptom worsening.

One of the study’s strengths lies in its longitudinal design, allowing participants to act as their own controls over time. This approach effectively accounts for time-dependent factors, such as baseline illness severity and age. Antipsychotic treatments were carefully controlled to isolate the specific relationship between MHT and psychosis relapse. However, significant confounding factors—including ethnicity, family history of psychosis, and lifestyle choices—were not reported or controlled for, which can profoundly influence SSD diagnosis, progression, and treatment outcomes. The lack of ethnicity data limits the generalizability of these findings across diverse populations, which may exhibit varying SSD presentations and treatment access.

Another methodological consideration is that menopause was defined solely by age rather than by menstrual cycle information, which is typically utilized to characterize menopause stages (Harlow et al., 2012). This approach may obscure the precise phase of menopause, as different stages—like perimenopause—can present more pronounced symptoms that could exacerbate SSD. Improved characterization of menopause in this cohort would benefit the understanding of timing and the effects of MHT initiation on relapse prevention.

Practical Implications for Women’s Mental Health

This study underscores the critical need to prioritize women’s health through the establishment of effective systems, services, and support specifically tailored for women at risk of psychosis relapse, particularly those with a history of hospitalizations. Implementing tailored interventions, including improved access to MHT for this vulnerable demographic, could significantly reduce relapse risks while enhancing overall mental health outcomes. Despite lingering negative perceptions surrounding MHT, often focused on safety concerns, the authors highlight that a carefully managed, individualized dosage—considering factors such as age—can render MHT a highly beneficial treatment for women.

While this research demonstrates the influence of MHT on objective measures of relapse, it does not address subjective patient-reported outcomes, including individual perceptions of well-being, symptom management, or daily functioning. Incorporating patient-reported outcomes in future studies would facilitate a more comprehensive understanding of MHT’s impact, ensuring that interventions not only improve clinical markers but also significantly enhance patients’ lived experiences.

Moreover, while the focus is primarily on the clinical implications for women with diagnosed conditions, the findings also prompt important inquiries regarding the effects of menopause on mental health in women without prior psychiatric histories, in line with the oestrogen hypothesis. By raising awareness, healthcare providers can assist women in comprehending the connection between menopause and mental health, thereby enabling earlier intervention and support for those at risk of developing psychosis or other mental health issues during this transitional phase.

Further investigation is essential to ensure the safety and compatibility of MHT when combined with prescribed antipsychotic medications. This research will yield more definitive conclusions regarding treatment efficacy in women over 45, particularly where the effectiveness of antipsychotic medications tends to plateau (Sommer et al., 2023). Additionally, exploring the neural mechanisms that underlie the relationship between SSD and sex steroid hormones is crucial. This knowledge will facilitate the development of more effective, targeted therapies for women at risk of relapse during menopause, ultimately leading to improved mental health outcomes.

Disclosure of Conflicts of Interest

No conflict of interest to declare.

Essential References and Links

Primary Research Article

Brand, B. A., Sommer, I. E., Gangadin, S. S., Tanskanen, A., Tiihonen, J., & Taipale, H. (2024). Real-world effectiveness of menopausal hormone therapy in preventing relapse in women with schizophrenia or schizoaffective disorder. American Journal of Psychiatry, 181(10), 893-900. DOI: 10.1176/appi.ajp.20230850

Additional References

Burger, H. G., Hale, G. E., Robertson, D. M., & Dennerstein, L. (2007). A review of hormonal changes during the menopausal transition: focus on findings from the Melbourne Women’s Midlife Health Project. Human reproduction update, 13(6), 559-565.

Harlow, S. D., Gass, M., Hall, J. E., Lobo, R., Maki, P., Rebar, R. W., … & STRAW+ 10 Collaborative Group. (2012). Executive summary of the Stages of Reproductive Aging Workshop+ 10: addressing the unfinished agenda of staging reproductive aging. The Journal of Clinical Endocrinology & Metabolism, 97(4), 1159-1168.

Lindamer, L. A., Buse, D. C., Lohr, J. B., & Jeste, D. V. (2001). Hormone replacement therapy in postmenopausal women with schizophrenia: positive effect on negative symptoms?. Biological psychiatry, 49(1), 47-51.

Marwick K. The influence of the menopause in first onset of mental illness. The Mental Elf, 3 Oct 2024.

Ochoa, S., Usall, J., Cobo, J., Labad, X., & Kulkarni, J. (2012). Gender differences in schizophrenia and first‐episode psychosis: A comprehensive literature review. Schizophrenia research and treatment, 2012(1), 916198.

Ross, C. A., Margolis, R. L., Reading, S. A., Pletnikov, M., & Coyle, J. T. (2006). Neurobiology of schizophrenia. Neuron, 52(1), 139-153.

Sharpe, R. M. (2003). The ‘oestrogen hypothesis’–where do we stand now? 1. International journal of andrology, 26(1), 2-15.

Sommer, I. E., Brand, B. A., Gangadin, S., Tanskanen, A., Tiihonen, J., & Taipale, H. (2023). Women with schizophrenia-spectrum disorders after menopause: a vulnerable group for relapse. Schizophrenia Bulletin, 49(1), 136-143.

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