Abstract and Introduction
Abstract
Background and Hypothesis: Throughout the life stages of women with schizophrenia-spectrum disorders (SSD), lower estrogen levels are associated with more severe disease course. At perimenopause in the mid-forties, estrogen levels decline to remain persistently low after menopause. This period is hypothesized to increase relapse risk and reduce antipsychotic effectiveness in preventing relapse.
Study Design: The cohort of persons with schizophrenia/schizoaffective disorder was identified from Finnish nationwide registers (N = 61 889) and stratified by sex and age <45 vs. ≥45 years. Hospitalizations for psychosis were defined per 5-year age group during the follow-up 1996–2017. Risk of psychosis hospitalization (Adjusted Hazard Ratio, aHR) was assessed using within-individual design, by comparing antipsychotic monotherapy use to nonuse periods in the same individuals for seven dose categories in defined daily doses (DDDs/day).
Results: Starting at age 45–50, women were consistently more often hospitalized for psychosis than their male peers. Women ≥45 had significantly higher aHRs than women <45 at antipsychotic monotherapy >0.6 DDDs/day, and than men at >1.1 DDDs/day. This female-specific age-dependent decrease in effectiveness was present for clozapine doses >0.6 DDDs/day, olanzapine doses >1.4 DDDs/day, and for specific doses of quetiapine (0.9–1.1 DDDs/day) and risperidone (0.6–0.9 DDDs/day).
Conclusions: While younger women have a lower risk of relapse and generally need a lower antipsychotic dose to prevent rehospitalization than men, antipsychotic effectiveness declines in women after the age of 45. Starting in mid-forties, older women with SSD should be regarded as a vulnerable group that deserve special attention.
Introduction
Every woman with a schizophrenia spectrum disorder (schizophrenia or schizoaffective disorder, SSD) will eventually face a period of lasting impact on their endogenous estrogen production: menopause. The onset of menopause is defined as the cessation of natural menstrual cycles for 12 months and on average occurs at the age of 49 world-wide, with European mean age at menopause of 50.5.[1] In the years preceding menopause (i.e. perimenopause), menstrual cycles become irregular with longer periods between menses and ovarian hormone production starts to decline.[2]
Throughout the life stages of women with SSD, an association between estrogen levels and disease severity is present. At the first psychotic episode, women tend to function better than men, a sex difference that has been attributed to estrogen's protective effects.[3] Ovarian hormones strongly impact brain and behavior of women, both in physiological and in pathological states. Estrogens support cognition and maintain high cognitive functioning under chronic stress.[4] They act as antioxidants, increase neuroplasticity, and facilitate neurotransmission.[5] As a result, women with natural menstrual cycles, on average have more severe psychotic symptoms and more admissions for psychosis during low estrogenic phases, which occurs preceding and during menses, compared to high estrogen periods surrounding ovulation.[6] During pregnancy, high estrogen states are associated with relatively mild symptom severity, while the sharp drop in sex hormone levels after delivery forms the prelude of more severe symptoms.[7] After menopause, estrogen levels remain low which is associated with a deterioration in the clinical course.[8] Therefore, women with SSD have sex-specific psychiatric needs, that differ according to their life stage.[9,10]
Estrogens also affect pharmacokinetics of antipsychotic medication.[11] They inhibit the liver enzyme cytochrome P-450 (CYP) 1A2, which metabolizes many antipsychotic drugs, especially olanzapine and clozapine. Lower activity of this enzyme leads to higher blood levels of these antipsychotics. A notable exception is quetiapine, which is mainly metabolized by an enzyme facilitated by estrogens, CYP3A4. Risperidone is metabolized by both CYP3A4 and CYP2D6, of which the latter is not dependent on estrogen levels. In addition, estrogens increase dopamine (D2) receptor sensitivity in the ventral tegmentum, which results in a higher D2 receptor occupancy of antipsychotics in women of fertile age, as compared to men, at equal plasma concentrations.[12]
After menopause, women with SSD lose these neuroprotective and pharmacokinetic and pharmacodynamic effects, as estrogen levels of postmenopausal women are no higher than those of men. While the process of aging causes a relative increase in plasma levels of antipsychotic medications in both sexes,[13] the steep drop in natural estrogen production causes important additional changes in the CYP-metabolism of women. Low estrogen levels lead to lower activity of the CYP3A4 enzyme, while it leaves the CYP1A2 enzyme more active. The result may be that after menopause, plasma concentrations of specific drugs change. Due to the absence of estrogens, olanzapine and clozapine are metabolized more rapidly while that of quetiapine is slowed down.[13] At the brain level, animal models of menopause show that dopamine receptor sensitivity declines in this life phase.[14] This would suggest lower effectiveness of antipsychotic medication, especially of clozapine and olanzapine in postmenopausal women as compared to premenopausal women, but also as compared to men of similar age. Although the postmenopausal era is recognized as a period of increasing symptom severity, reduced efficacy of antipsychotic drugs and increased need for care,[8,15] there is a remarkable paucity on quantitative data on this vulnerable period that all women with schizophrenia will experience.[8] We here provide detailed, quantitative data on life-stage dependent clinical changes occurring in women with SSD, using an intra-individual design to prevent confounding. The main aims of this study are:
To compare hospitalization rates for psychosis between women and men with SSD at different age groups.
To compare effectiveness of commonly used antipsychotic monotherapies in terms of dose-dependent psychosis hospitalization risk in men and women before and after the age of 45, as a proxy for menopausal status in women.[16]
Schizophr Bull. 2023;49(1):136-143. © 2023 Oxford University Press
