Estrogens in schizophrenia: progress, current challenges and opportunities

Abstract

Purpose of review Schizophrenia is a heterogeneous psychiatric disorder with a different, but not necessarily milder clinical presentation in women as compared to men. These sex differences have largely been attributed to the protective role of estrogens. This article reviews the current state of estrogen research in schizophrenia. Recent findings Estrogens regulate important pathophysiological pathways in schizophrenia, including dopamine activity, mitochondrial function, and the stress system. Estrogen deficiency is common in both sexes and is associated with increases in psychotic symptoms. Hyperprolactinemia causes secondary estrogen deficiency and can be a reaction to stress, or secondary to prolactin-raising antipsychotics. Therefore, prolactin-sparing antipsychotics should be preferred especially in premenopausal women, who are more prone to hyperprolactinemia. Premenopausal women furthermore require lower doses of antipsychotics than men, since estrogens raise the availability and efficacy of antipsychotics. Summary The past years have established the importance of estrogens in the pathophysiology of schizophrenia and have shown its relevance to clinical practice through its influence on antipsychotic drug efficacy. Future research should focus on the neurobiological and clinical effect of contraceptives in premenopausal women with schizophrenia. Furthermore, the potential of estrogen-like augmentation with raloxifene and phytoestrogens in schizophrenia should be established in the coming years.

Antipsychotic medication for women with schizophrenia spectrum disorders

“…Consequently, they are more than twice as likely to develop antipsychotic-induced hyperprolactinaemia compared to postmenopausal women and men (González-Rodríguez et al, 2020;Kinon, Gilmore, Liu, & Halbreich, 2003). Moreover, prolactin secretion suppresses the production of sex hormones and induces oestrogen deficiency, which is already more frequent in female SSD patients compared to healthy females before menopausal age (Brand et al, 2021;Gogos et al, 2015;Lindamer et al, 2000;Riecher-Rössler, 2005) 2008) and reduced bone mineral density is present in 32% of women treated with prolactin-raising antipsychotics for >10 years (Meaney et al, 2004). Prolactin-sparing antipsychotics (e.g.…”

“…Consequently, they are more than twice as likely to develop antipsychotic-induced hyperprolactinaemia compared to postmenopausal women and men (González-Rodríguez et al, 2020; Kinon, Gilmore, Liu, & Halbreich, 2003). Moreover, prolactin secretion suppresses the production of sex hormones and induces oestrogen deficiency, which is already more frequent in female SSD patients compared to healthy females before menopausal age (Brand et al, 2021; Gogos et al, 2015; Lindamer et al, 2000; Riecher-Rössler, 2005). Oestrogen deficiency can lead to polycystic ovarian syndrome, infertility, osteoporosis, sexual dysfunction and an increased risk of breast cancer (De Hert, Detraux, & Peuskens, 2014; Haring et al, 2014; Pottegård, Lash, Cronin-Fenton, Ahern, & Damkier, 2018; Yum, Kim, & Hwang, 2014).…”

“…Side-effects of antipsychotic drugs that could be particularly relevant to younger female patients include weight gain, as obesity largely decreases self-esteem in women (Connors & Casey, 2006; Lieberman, Tybur, & Latner, 2012) and hyperprolactinaemia, which reduces oestrogen levels. These low oestrogen levels not only increase the risk for somatic complications but also potentially have also a negative impact on psychotic symptoms (Brand et al, 2021). Aripiprazole and lurasidone may, therefore, be drugs of first choice in this phase and options of second choice are olanzapine, quetiapine and clozapine (Table 2).…”

“…sex differences), such as body composition and hormonal transitions affect the drug pharmacokinetics, determined by the absorption, distribution, metabolism and excretion, and drug pharmacodynamics which involves receptor binding, receptor sensitivity and the receptor binding profile of a drug (Iversen et al, 2018; Lange et al, 2017; Zucker & Prendergast, 2020). The female sex hormones in general, and oestrogens in particular play a major role in these sex differences (Brand, de Boer, & Sommer, 2021; González-Rodríguez & Seeman, 2019). However, current guidelines on the prescription of antipsychotics do not take these differences in account (Keepers et al, 2020; Ventriglio et al, 2020).…”

Breast cancer in schizophrenia could be interleukin-33-mediated

“…The clinical presentation of schizophrenia differs in men and women and could be partly attributed to the neuroprotective properties of estrogens[ 73 ]. Modulation of dopamine 2 receptor occupancy of antipsychotics can also be associated with estrogens[ 74 ].…”