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González-Rodríguez, A.;  Monreal, J.A.;  Seeman, M.V. The Effect of Menopause on Antipsychotic Response. Encyclopedia. Available online: https://encyclopedia.pub/entry/32086 (accessed on 23 June 2024).
González-Rodríguez A,  Monreal JA,  Seeman MV. The Effect of Menopause on Antipsychotic Response. Encyclopedia. Available at: https://encyclopedia.pub/entry/32086. Accessed June 23, 2024.
González-Rodríguez, Alexandre, José A. Monreal, Mary V. Seeman. "The Effect of Menopause on Antipsychotic Response" Encyclopedia, https://encyclopedia.pub/entry/32086 (accessed June 23, 2024).
González-Rodríguez, A.,  Monreal, J.A., & Seeman, M.V. (2022, October 31). The Effect of Menopause on Antipsychotic Response. In Encyclopedia. https://encyclopedia.pub/entry/32086
González-Rodríguez, Alexandre, et al. "The Effect of Menopause on Antipsychotic Response." Encyclopedia. Web. 31 October, 2022.
The Effect of Menopause on Antipsychotic Response
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Whenever estrogen levels decline, psychosis symptoms in women increase. At menopause, this can happen in two main ways: (a) the loss of estrogen (mainly estradiol) can directly affect central neurotransmission, leading to increase in schizophrenia-related symptoms, and (b) the loss of estrogen can decrease the synthesis of enzymes that metabolize antipsychotic drugs, thus weakening their efficacy.

antipsychotics drug metabolism menopause schizophrenia

1. Differences in Short and Long Outcomes in Women with Schizophrenia

The literature on short term treatment outcomes (under 10 years) that compare men and women with schizophrenia consistently point to female advantage. Compared to men, women are shown to have fewer and shorter hospitalizations plus a lower rate of suicide, homelessness, substance abuse, and forensic involvement [1].
Women’s family and social relationships are reported as superior to men’s [2][3], and women are generally found to exhibit a more robust response to treatment [4]. Importantly, however, long term outcomes (over 10 years) are similar in men and women [5]. Equally important are data that show women with schizophrenia, but not men, experiencing increases in symptom severity at midlife (over age 40) [6]. Increases in cognitive symptoms and functional decline over time are often attributed to age, but positive, negative, and affective symptoms also worsen. Two main potential explanations for increased symptoms in women post menopause are (a) estrogen loss directly affects neurotransmitters that mediate those symptoms and (b) estrogen loss moderates the efficiency of enzymes that metabolize antipsychotic drugs such that less of the drug arrives at target sites in the brain [7].

2. Why Estrogen Is Important

Three estrogens (estrone, 17β-estradiol (E2), and estriol) regulate many central nervous system functions [8] and operate through three estrogen receptor subtypes, Erα, Erβ and G-protein-coupled estrogen receptor 1 (GPER). The three ER subtypes are genetically distinct and mediate different estrogenic actions. ERα and Erβ, initiate both genomic and non-genomic traditional sexual and reproductive functions while GPER mediates neuroprotection and cognition [8].
Estrogens are synthesized from the parent molecule, cholesterol, with estradiol (E2) being the most potent of the three [9][10]. E2, mainly produced in ovarian oocytes, gradually decreases over the course of perimenopause [11]. Estrone (E1) is mainly synthesized in the adrenal glands and adipose tissue and continues to be available after menopause. Estriol (E3) is mainly produced during pregnancy. Estrogens originate in many body sites, including the brain.
At menopause (the cessation, in women, of menses due to the death of oocytes), many women experience cognitive problems because the decline in E2 is associated with a reduction in the volumes of both the hippocampus and the parietal cortex [11]. There are other effects of estrogen decline that can lead to a variety of symptoms at this time because E2, the estrogen that is lost at menopause, serves many functions. It insulates against the effects of injury, inflammation, ischemia and apoptosis; it activates signal transduction pathways and modulates intracellular homeostasis. It also promotes neuronal growth and activates other neuroreparative processes such as decreasing blood–brain barrier permeability, reducing oxidative stress, neuroinflammation and excitotoxicity, and promoting synaptic plasticity, axonal growth, neurogenesis, and remyelination [12].

3. The Perimenopause

There are two stages to the years leading up to menopause—the early menopausal transition when menstrual cycles remain mostly regular, and the late transition, where amenorrhea becomes more prolonged and lasts for at least 60 days until it stops altogether [13]. Perimenopause usually lasts from 7 to 14 years during which, in the early phase, estrogen levels may paradoxically increase [14]. This is because, in order to stimulate estrogen production, follicle-stimulating hormone (FSH) secretion rises in response to decreasing levels of oocyte estrogen secretion [15]. Most women are able to accommodate to estrogen level fluctuations during this period because of prior exposure to menstrual period fluxes, the 9-fold gradual rise of estrogen over the course of pregnancy [16] and the precipitous drop postpartum. This sharp, abrupt fall precipitates postpartum psychosis in approximately one woman in a thousand [17]. The drop at menopause is more gradual but no less significant and, in a substantial number of women with schizophrenia, is associated with an increase in the severity of psychotic symptoms [18][19][20].

4. Estrogen, Dopamine, and Schizophrenia

The menopausal risk of increased psychosis severity may be tied to the link between estradiol and brain dopamine [21][22], the neurotransmitter most closely implicated in the pathogenesis of schizophrenia [23]. Relatively little is known about sex differences in dopamine function but D2/D3 dopamine receptors, the neuronal membrane receptors to which most antipsychotic medications preferentially bind [24] do show some differences between men and women. The results of human positron emission tomography (PET) studies show that women have more D2 receptors than men in the frontal and temporal cortex and in the thalamus. In the striatum, D2 receptor density declines with age faster in men than in women. Animal studies also point to similar sex differences [25].
One research group studied sex differences in D2 receptor occupancy after administration of the antipsychotic drug, olanzapine, and demonstrated that women are able to achieve the same D2 receptor occupancy as men while taking a lesser daily oral dose [26]. Current thinking is that the dopamine transporter that returns dopamine to its presynaptic cell after secretion into the synaptic gap is key to the hyperdopaminergic state responsible for psychotic symptoms, and estradiol activity has been found at the transporter site [27]. It is thought that the lower the estrogen level in relevant parts of the brain, the more severe the psychosis [28]. The amount of antipsychotic medication that reaches the brain is determined by its level in the plasma, and that, in turn, is chiefly influenced by liver and gut enzymes that break down antipsychotic drugs.
Further suggestive evidence of the potential link between estrogen and dopamine transmission is the well-established fact that women first express the symptoms of schizophrenia at a later age than men [29][30]. Important also is the high incidence rate of schizophrenia in women with Turner’s syndrome [31][32]. Turner’s syndrome (one X chromosome wholly or partially missing) is a chromosomal abnormality characterized by reduced serum estrogen levels. Further evidence is that both male and female schizophrenia patients show reduced levels of plasma estrogen when compared to age and sex peers [33]. Another confirmatory finding is that early puberty in girls (but not in boys) is associated with relatively later onset of symptoms in young people who go on to develop schizophrenia [34][35][36]. It is also known that symptoms fluctuate over the menstrual cycle in women with schizophrenia, increasing in severity when estrogen levels are low [37][38]. At postpartum, when estrogen levels precipitously drop, women with schizophrenia often relapse [39]. An interesting epidemiological finding is that the relative male/female incidence of schizophrenia reverses after age 40 [40]. There is also evidence that estrogen-reducing drugs trigger acute psychosis [41]. Perhaps most convincingly, adding estrogen or selective estrogen receptor modulators (SERMS) to an antipsychotic regimen improves treatment efficacy [42].

5. Estrogen and Antipsychotic Efficacy

Duffy and Epperson concluded that estrogen levels influenced both the efficacy and the side effects of antipsychotic drugs after reviewing 12 human brain imaging studies that investigated sex differences in antipsychotic response [43]. None of the 12, however, were looking for a menopausal effect. It has been clinically noted that, after menopause, the dose of the antipsychotic medication often needs to be increased in women to maintain symptom stability. This is either because symptoms have become more severe or because the drugs function less well. The time duration since menopause has been shown to correlate negatively with antipsychotic response in postmenopausal women. The results of a 12-week prospective study of 64 postmenopausal women diagnosed with schizophrenia [7] used the duration of reproductive years (menarche to menopause) as an indirect measure of cumulative estrogen exposure. The antipsychotic response was defined as a reduction of at least 30% on the Positive and Negative Syndrome Scale. Antipsychotic adherence was assessed by plasma level monitoring at 4 weeks. Forty-two participants (66%) were found to be antipsychotic responders. Time since menopause was significantly and negatively associated with antipsychotic response, explaining almost 42% of the variance. This finding could be a consequence of a direct effect of estrogen loss on dopamine transmission and, thus, on psychotic symptoms, or, alternatively, a direct effect of estrogen loss on drug metabolism and, hence, on plasma levels of antipsychotics entering the brain.

6. Estrogen after Menopause

Estradiol levels continue to fluctuate to some degree after menopause. Estrone continues to be produced in the adrenal glands (until adrenopause) and in adipose tissue, and estrogens are synthesized in bone, vascular endothelium, aortic smooth muscle cells, and in numerous sites in the brain [44][45]. In women after menopause, estrone levels increase from premenopausal levels. Estradiol (E2) levels are the ones that drop [9][10].
Estradiol is synthesized in both neurons and glial cells and is classified as a neurosteroid. Neurosteroids directly modulate plasma membrane ion channels and regulate intracellular signaling and they exert powerful effects on the brain before and after menopause [46]. Of relevance to the effect of estrogen in schizophrenia is the distribution of estrogen receptors in the brain. They are most abundant in the subcortical structures that are involved in schizophrenia (the hippocampus, amygdala, thalamus, and nucleus accumbens) and within neurotransmitter pathways (dopaminergic, serotonergic, and glutamatergic), all of which are implicated in the pathogenesis of schizophrenia symptoms [47].

7. Symptom Exacerbation after Menopause Due to Stress

Above contents have not yet mentioned a potential explanation for worsening symptoms and the need for increased antipsychotic dosing in women with schizophrenia after menopause that is independent of estrogen loss. Menopause itself is a stressful time for women. The physiological symptoms of menopause (vasomotor, sleep, sexual, and cognitive) are distressing. There are further psychological and social pressures at this time (children leaving home, parents dying, marital, employment and economic constraints). The impact of fertility loss, the need to adapt to aging, and the onset of a variety of new medical conditions further augment the stress experienced by menopausal women [18]. The effect of stress is not altogether independent of estrogenic influence, however, since the hypothalamic-pituitary-adrenal stress axis (HPA-axis) responds, to some degree, to estrogen. This has been well shown in animal studies, but the results in human studies are more controversial. Men consistently show greater HPA reactivity than women when evaluated for achievement. Some studies have found greater reactivity in women when the stressor is social performance. Sex difference (and, by implication, estradiol level) appears to depend on the nature of the stress [48]. Important to note is that both antipsychotics and stress increase prolactin levels, which, in turn, decreases estrogen levels [5].

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