Among women with schizophrenia-spectrum disorders (SSD), previous studies have documented that lower estrogen levels are associated with more severe symptoms, and that women with schizophrenia may experience worsening symptoms during times when estrogen levels fall, for example during the postpartum period or during the premenstrual phase of the menstrual cycle.  Several recent studies have also shown that treatment with estrogen may have beneficial effects for women with schizophrenia and that raloxifene, a selective estrogen receptor modulator (SERM), may also have beneficial effects and may enhance the effectiveness of traditional antipsychotic medications.  

Relatively little is known about what happens to the clinical course of schizophrenia during the perimenopause and menopause, when estrogen levels fluctuate and then fall dramatically. Given the beneficial effects of estrogen, it has been hypothesized that perimenopausal women may be at increased risk for relapse and may experience a decrease in antipsychotic effectiveness. In a recent report, researchers from the University Medical Center Groningen in the Netherlands used Finnish health registers to follow the clinical course of women with SSD.

In this cohort, they identified 61,889 individuals (50% women) hospitalized at least once for either schizophrenia or schizoaffective disorder. Hospitalizations and medication usage for each participant were tracked over time. For their analysis, the researchers divided the cohort into five-year age groups (men and women separately), starting at ages 20 to 24 years, 25 to 29 years, and so on up until the age of 65 to 69 years.

Up until the age of about 45, rates of hospitalization for psychosis were similar between men and women in each age group. At around the age of 45, men and women diverge, with risk of hospitalization for women beginning to surpass risk of hospitalization in men. In the 45 to 49 age group, women have a 1.12-fold higher risk of hospitalization compared to men; this increases to a 1.22-fold increase in risk in the 65 to 69 age group. 

They also observed that women 45 and older who were taking standard doses of antipsychotic medication were also more likely to relapse than younger women or men of any age, with the most pronounced differences observed among women taking clozapine.

This study confirms what many of us have seen clinically, that the perimenopause is a time of vulnerability in women with histories of psychiatric illness. While most of our previous studies have focused on women with mood disorders, this study extends those observations to women with schizophrenia and schizoaffective disorder.  

While we should be vigilant and monitor perimenopausal and menopausal women for relapse, exactly how to manage breakthrough symptoms in women with SSD is less clear and deserves more research.  Because previous studies have documented that premenopausal women tend to respond to lower doses of antipsychotic medications, it seems reasonable to increase the dose of antipsychotic medication as women enter the menopause, if they are experiencing worsening symptoms. On the other hand, we also have data to indicate that older women are more vulnerable than men and younger women to the side effects of antipsychotic medications and may be more vulnerable to tardive dyskinesia. Although there may be data to support the use of estrogen-modulating agents in this population, there are concerns about the negative health consequences of extended estrogen replacement therapy and our ability to ensure adequate screening in individuals with severe mental illness.

Ruta Nonacs, MD PhD

Sommer IE, Brand BA, Gangadin S, et al. Women With Schizophrenia-Spectrum Disorders After Menopause: A Vulnerable Group for Relapse. Schizophr Bull. October 5, 2022. 

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