Menopause an Independent Risk Factor for Schizophrenia Relapse?

Menopause appears to be an independent risk factor for relapse in women with schizophrenia spectrum disorders (SSDs), new research suggests.

Investigators studied a cohort of close to 62,000 people with SSDs, stratifying individuals by sex and age, and found that starting between the ages of 45 and 50 years — when the menopausal transition is underway — women were more frequently hospitalized for psychosis compared with men and women younger than 45 years.

In addition, the protective effect of antipsychotic medication was highest in women younger than 45 years and lowest in women aged 45 years or older, even at higher doses.

“Women with schizophrenia who are older than 45 are a vulnerable group for relapse, and higher doses of antipsychotics are not the answer,” lead author Iris Sommer, MD, PhD, professor, Department of Neuroscience, University Medical Center of Groningen, the Netherlands, told Medscape Medical News.

The study was published online October 4 in Schizophrenia Bulletin.

Vulnerable Period

There is an association between estrogen levels and disease severity throughout the life stages of women with SSDs, with lower estrogen levels associated with psychosis, for example, during low estrogenic phases of the menstrual cycle, the investigators note.

“After menopause, estrogen levels remain low, which is associated with a deterioration in the clinical course; therefore, women with SSD have sex-specific psychiatric needs that differ according to their life stage,” they add.

“Estrogens inhibit an important liver enzyme (cytochrome P-450 [CYP1A2]), which leads to higher blood levels of several antipsychotics like olanzapine and clozapine,” said Sommer. In addition, estrogens make the stomach less acidic, “leading to easier resorption of medication.”

As a clinician, Sommer said that she has “often witnessed a worsening of symptoms [of psychosis] after menopause.” As a researcher, she “knew that estrogens can have ameliorating effects on brain health, especially in schizophrenia.”

She and her colleagues were motivated to research the issue because there is a “remarkable paucity” of quantitative data on “vulnerable period that all women with schizophrenia will experience.”

Detailed, Quantitative Data

The researchers sought to provide “detailed, quantitative data on life-stage dependent clinical changes occurring in women with SSD, using an intra-individual design to prevent confounding.”

They drew on data from a nationwide, register-based cohort study of all hospitalized patients with SSD between 1972 and 2014 in Finland (n = 61,889), with follow-up from January 1, 1996 to December 31, 2017.

People were stratified according to age (younger than 45 years and 45 years or older), with same person contributing person-time to both age groups. The cohort was also subdivided into 5-year age groups, starting at age 20 years and ending at age 69 years.

The primary outcome measure was relapse (ie, inpatient hospitalization because of psychosis).

The researchers focused specifically on monotherapies, excluding time periods when two or more antipsychotics were used concomitantly. They also looked at antipsychotic nonuse periods.

Antipsychotic monotherapies were categorized into defined daily doses per day (DDDs/d):

  • < 0.4

  • 0.4 to 0.6

  • 0.6 to 0.9

  • 0.9 to < 1.1

  • 1.1 to < 1.4

  • 1.4 to < 1.6

  • ≥ 1.6

The researchers restricted the main analyses to the four most frequently used oral antipsychotic monotherapies: clozapine, olanzapine, quetiapine, and risperidone.

The Turning Tide

The cohort consisted of more men than women (31,104 vs 30,785, respectively), with a mean (SD) age of 49.8 (16.6) years in women vs 43.6 (14.8) in men.

Among both sexes, olanzapine was the most prescribed antipsychotic (roughly one quarter of patients). In women, the next most common antipsychotic was risperidone, followed by quetiapine and clozapine, whereas in men, the second most common antipsychotic was clozapine, followed by risperidone and quetiapine.

When the researchers compared men and women younger than 45 years, there were “few consistent differences” in proportions hospitalized for psychosis.

Starting at age 45 years and continuing through the oldest age group (65-69 years), higher proportions of women were hospitalized for psychosis compared with their male peers (all Ps < .00001).

Age group (years)

Men (%)

Women (%)

















Women had 45 or more significantly higher risk for relapse associated with standard dose use compared with the other groups:

Age group (years)


aHR (95% CI)

< 45


0.44 (0.41-0.47)

< 45


0.46 (0.43-0.49)

≥ 45


0.52 (0.49-0.53)

≥ 45


0.48 (0.44-0.51)

aHR = adjusted hazard ratio

When the researchers compared men and women older and younger than 45 years, women younger than 45 years showed lower adjusted hazard ratios (aHRs) at doses between of 0.6-0.9 DDDs/d, whereas for doses > 1.1 DDDs/d, women aged 45 years or older showed “remarkably higher” aHRs compared with women younger than 45 years and men aged 45 years or older, with a difference that increased with increasing dose.

In women, the efficacy of the antipsychotics was decreased at these DDDs/d:


Dose (DDDs/d)


> 0.6


> 1.4






“We…showed that antipsychotic monotherapy is most effective in preventing relapse in women below 45, as compared to women above that age, and also as compared to men of all ages,” the authors summarize. But after age 45 years, “the tide seems to turn for women,” compared with younger women and with men of the same age group.

One of several study limitations was the use of age as an estimation of menopausal status, they note.

Don’t Just Raise the Dose

Commenting for Medscape Medical News, Mary Seeman, MD, professor emerita, Department of Psychiatry, University of Toronto, noted the study corroborates her group’s findings regarding the effect of menopause on antipsychotic response.

“When the efficacy of previously effective antipsychotic doses wanes at menopause, raising the dose is not the treatment of choice because it increases the risk of weight gain, cardiovascular, and cerebrovascular events,” said Seeman, who was not involved with the current research.

“Changing to an antipsychotic that is less affected by estrogen loss may work better,” she continued, noting that amisulpride and aripiprazole “work well post menopause.”

Additional interventions may include changing to a depot or skin-patch antipsychotic that “obviates first-pass metabolism,” adding hormone replacement or a selective estrogen receptor modulator or including phytoestrogens (bioidenticals) in the diet.

The study yields research recommendations, including comparing the effectiveness of different antipsychotics in postmenopausal women with SSDs, recruiting pre- and postmenopausal women in trials of antipsychotic drugs, and stratifying by hormonal status when analyzing results of antipsychotic trials,” Seeman said.

This work was supported by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital and the Academy of Finland . The Dutch Medical Research Association supported Sommer. Sommer declares no relevant financial relationships. The other authors’ disclosures are listed on the original paper. Seeman declares no relevant financial relationships.

Schizophrenia Bull. Published online October 4, 2022. Full text

Batya Swift Yasgur MA, LSW is a freelance writer with a counseling practice in Teaneck, NJ. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).

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