Menopausal hormone therapy and the risk of new onset psychotic disorders: a Swedish register-based study

Introduction: Schizophrenia and other psychotic disorders show a typical incidence peak in early adulthood [1]. Among women, several studies have also demonstrated a second peak in the incidence of psychotic disorders in midlife, around the menopausal transition [2]. This midlife increase in incidence, which is not observed among men of a similar age, has been hypothesized to be related to declining ovarian hormone levels, particularly estradiol, during perimenopause [2]. A few studies suggest that menopausal hormone therapy may be associated with improved clinical outcomes among women with psychotic disorders [3]. However, evidence on this topic, particularly regarding first-onset psychosis during perimenopause, remains scarce.

Aim: We aim to estimate the effect of initiating systemic menopausal hormone therapy on the risk of incident psychotic disorders among women in Sweden.

Methods: We implemented a target trial emulation framework using nationwide Swedish register data from 2008 to 2024. Eligibility criteria were defined as follows: women aged 50–59 years with no history of psychotic disorders, no dispensed antipsychotic medication in the year before baseline, no prior use of systemic menopausal hormone therapy before baseline, no use of estrogen-containing contraceptives in the year before baseline, and no medical conditions requiring systemic estrogen treatment, such as prior oophorectomy or chromosomal anomalies requiring hormone therapy. Outcomes were defined as: incident diagnosis of any psychotic disorder, incident diagnosis of schizophrenia or schizoaffective disorder, and hospitalization due to any psychotic disorder. Confounders included age, educational level, annual income, civil status, region of residence, country of birth, and psychotropic medication use in the year before baseline. Potential confounding and informative censoring (i.e., deviating from assigned intervention) were addressed using inverse-probability weighting to estimate per-protocol effects. Participants were classified based on initiation versus non-initiation of systemic menopausal hormone therapy at baseline and were followed for up to three years.

Results: The study population included 438,995 participants, of whom 143,964 initiated systemic menopausal hormone therapy and 295,031 did not initiate treatment. The mean age was 53.74 years (standard deviation [SD] = 2.51) among those who initiated treatment and 53.90 years (SD = 2.88) among those who did not. Initiation of systemic menopausal hormone therapy was associated with a lower risk of developing any psychotic disorder during follow-up (incidence rate ratio [IRR] = 0.44, 95% confidence interval [CI] = 0.27 – 0.73). A similar association was observed for the more specific outcome of schizophrenia or schizoaffective disorder (IRR = 0.23, 95% CI = 0.05 – 0.97). Menopausal hormone therapy use was not statistically significantly associated with hospitalization due to psychotic disorders, although the point estimate was in the same direction as the diagnostic outcomes (IRR = 0.55, 95% CI = 0.27 – 1.12).

Conclusion: Our results indicate that menopausal hormone therapy use may protect against the onset of new psychotic disorders among women during the menopausal transition.

References

1. Jauhar, S., Johnstone, M., McKenna, P.J., 2022. Schizophrenia. Lancet. 399 (10323), 473-486.
2. Culbert, K.M., Thakkar, K.N., Klump, K.L., 2022. Risk for midlife psychosis in women: critical gaps and opportunities in exploring perimenopause and ovarian hormones as mechanisms of risk. Psychol. Med. 52 (9), 1612-1620.
3. 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. Am. J. Psychiatry. 181 (10), 893-900.