Preventing Relapse in Schizophrenia: Focus on Women’s Mental Health

Schizophrenia affects women differently than men, as estrogen is considered neuroprotective in schizophrenia. While men have a single peak age of schizophrenia (21-25), women’s 2 peaks of onset are at age 25 to 30 years, and over age 45.¹ The drop in estrogen at menopause coincides with the second peak of schizophrenia diagnosis in women.

Women of reproductive age (and thus individuals who have higher estrogen levels than their male counterparts) generally require lower doses of antipsychotic medication than do men. This is thought to be related to estrogen’s effects on antipsychotic medication absorption and metabolism.² In turn, periods of women’s lives when they have lower estrogen levels find greater risk of exacerbation or relapse of psychosis.³ In the postpartum period, there can be rapid drops in estrogen levels and the risk of psychosis is particularly high.²

A recent nationwide Finnish study found that men were diagnosed with schizophrenia earlier than women. Women were hospitalized slightly more than men for schizophrenia in the first decade after diagnosis, but women were less often prescribed clozapine or long-acting injectable (LAI) antipsychotics.⁴ Psychiatrists and mental health clinicians should ensure that they consider clozapine and LAIs in women as they do in men. Further, it should be kept in mind that estrogen inhibits the metabolism of both clozapine and olanzapine, leading to increased plasma levels in women.³

This article will review the issues unique to women and psychosis across their lifecycle. In general, for women in particular, the risk of recurrent psychosis is elevated predictably in periods of relatively decreased estrogen. Thus, we focus on menstruation, contraception, pregnancy, postpartum, menopause, and aging. The Table describes these 5 times in life, characteristic issues in schizophrenia, and strategies.

Menstruation

Some studies have found that girls with earlier onset of menarche have later onset of schizophrenia, implying the importance of estrogen.² Hormonal fluctuations in menstruating women are cyclical. During points of the menstrual cycle when estrogen is lower (days just preceding and during menses), there may be an increase in psychotic symptoms. While some patients may benefit from an increased dose of antipsychotic medication, research is lacking.^2,3 This is not too dissimilar to the increased dosage of antidepressants in cases of depression with premenstrual dysphoric disorder.

When women are prescribed oral or injected contraceptives, their antipsychotic dosing may be affected. Oral contraceptives may impact the levels of some antipsychotics. While long-acting injected contraceptives may be especially effective among those with difficult adherence,⁵ some women may experience exacerbations if increased antipsychotic dosing is not considered.⁶

Older antipsychotic medications and risperidone may lead to hyperprolactinemia, and decreased risk of pregnancy. However, hyperprolactinemia can suppress estrogen, increasing risks.³

Pregnancy

Some studies have suggested that women with schizophrenia demonstrate relative psychiatric stability during pregnancy, particularly for those who continue antipsychotic treatment. The decreased rate of psychiatric admission during pregnancy compared with preconception (incidence rate ratio 0.5)⁷ is often cited. However, these findings should be interpreted with caution, as decreased rates may not reflect a true reduction in illness burden, but rather factors such as underreporting of symptoms, barriers to care, lack of inpatient antepartum units, or fear of child protective service involvement. Unfortunately, antipsychotic discontinuation in pregnancy due to patient or provider fear of in utero exposure risk is common, with recent cohort data demonstrating discontinuation rates as high as 60% to 70%, most frequently during the first trimester.⁸ In a South Korean nationwide registry study of women with schizophrenia, only 25% to 35% maintained continuous antipsychotic treatment throughout pregnancy, while the remainder experienced discontinuation or treatment gaps.⁹ Antipsychotic discontinuation is associated with a 60% (high) relapse risk in primary psychotic disorders when compared with those who continue treatment. A Danish and Swedish cohort study found relapse rates are highest for women who discontinued medications during pregnancy compared with those who discontinued medication as part of preconception planning (adjusted hazard risk of 1.6 vs 1.24).¹⁰ This difference may reflect selection bias, as women who choose to become pregnant and discontinue medication could have greater baseline stability and longer periods of clinical remission compared with their peers.

Psychiatrists caring for women of reproductive potential with schizophrenia should provide preconception counselling including regarding the disproportionately higher rates of unintended pregnancy in women with schizophrenia, risk of untreated illness in pregnancy, and potential fetal risks of in utero medication exposure.¹¹ Clinicians should emphasize the largely reassuring safety data for most antipsychotics and recommend against abruptly discontinuing medication treatment in the event of unintended pregnancy (unless warranted by medication selection such as augmentation with valproate).¹² Psychiatrists should emphasize that pregnancy is best planned during a period of sustained psychiatric stability and facilitate access to effective contraception until conception is desired.

Individuals with a history of frequent or recent illness are at particularly high risk of relapse if medications are discontinued; continuation of current pharmacotherapy is usually recommended upon desired conception or pregnancy discovery (presuming they are not a known significant teratogen). In contrast, for those with milder illness or prolonged stability, cautious medication simplification may be considered. Abrupt discontinuation of antipsychotic agents should be avoided. Similarly, switching from an effective antipsychotic medication to another agent, especially if pregnancy is discovered after the critical organogenesis window of the first trimester, is cautioned against, given the risk of additional fetal exposures and potential psychiatric destabilization when treating with an agent the patient has not previously used.

When weighing risk of illness vs treatment decisions, psychiatrists and mental health clinicians should consider that schizophrenia carries an independent increased risk of poorer obstetric and neonatal outcomes, and that psychotic symptoms are associated with delayed or decreased prenatal care.¹³ During pregnancy, increased psychiatric follow-up to ideally monthly is recommended to optimize psychiatric stability and facilitate collaborative obstetric planning. Physiologic changes during pregnancy are associated with decreasing serum concentrations of many antipsychotic agents as pregnancy progresses, including quetiapine, haloperidol, risperidone, and aripiprazole, which may further increase relapse risk if doses are not adjusted appropriately over the course of pregnancy.^14,15

Working together with the patient’s obstetrician during pregnancy is recommended, as is family psychoeducation with consent. Finally, recommendations have been made for involuntary treatment of psychosis in pregnancy, when needed.¹⁶

Postpartum

Women are at particularly high risk for schizophrenia relapse in the early postpartum period because of factors such as rapid hormonal changes, including declining protective estrogen levels, increased stress, and sleep deprivation.¹⁷ Recent relapse is an independent risk factor for relapse within the first 3 months postpartum, with 28% of women relapsing during this period (aOR 1.30-2.27).¹⁷ Relapse risk may be mitigated through medication continuation and close postpartum monitoring to facilitate early detection of emerging symptoms. The South Korean population-based study found that women with schizophrenia who continued antipsychotic treatment had a 56% lower risk of postpartum relapse compared with those who discontinued medication.⁹

Shared treatment planning should ideally include discussion of elevated postpartum relapse risk, psychoeducation for patients and families regarding warning signs of postpartum psychosis, review of medication safety during lactation (if desired), and contraception counselling given the increased risk of rapid recurrent pregnancy among women with schizophrenia.¹⁸ Elevated postpartum risk necessitates frequent follow-up visits to support ongoing safety assessments, particularly for mothers caring for newborns, including screening for thoughts of harming the infant or concerns about neglect, as well as monitoring for early signs of relapse such as insomnia, worsening paranoia, disorganized behavior, mood lability, confusion, or emerging delusional beliefs.¹⁹

Frequent follow-ups also allow for timely antipsychotic dose adjustments as pregnancy-related physiologic changes in drug metabolism and volume of distribution return toward baseline postpartum, which may lead to rapid increases in serum antipsychotic concentrations.¹⁵ Psychiatrists should additionally be mindful that nighttime sedation from antipsychotic medications may impair a mother’s ability to safely provide overnight infant care and respond to infant needs, particularly during periods of sleep deprivation.

For mothers desiring to breastfeed, important considerations include balancing the benefits of breastfeeding with maternal risks of sleep disruption and psychiatric relapse, evaluating the relative safety of the particular antipsychotic exposure through breast milk, monitoring infants for sedation or feeding difficulties in concert with the baby’s pediatrician, and supporting medication adherence. Most first- and second-generation antipsychotics are considered compatible with breastfeeding, whereas clozapine is regarded as contraindicated because of concerns regarding infant sedation, agranulocytosis, and toxicity.^20,21

Menopause

Menopause is defined as 12 consecutive months without menstruation. Menopause signals a profound decline in estrogen levels. Perimenopause can last up to 10 years, but averages 4 years.³

Lower estrogen levels are associated with worsened disease course of schizophrenia. Accordingly, women with schizophrenia may be at increased risk of symptom exacerbation during perimenopause and after menopause as estrogen levels decline. A Finnish national study found that, beginning at age 45, women were persistently hospitalized more often for psychosis than their male counterparts.²² Additionally, antipsychotic medication appears to have reduced effectiveness after age 45.²² Thus, psychiatrists should be particularly cognizant of the increased risk of psychosis as women with schizophrenia age. Women in the menopausal transition may require increased doses of antipsychotic medications.² However, consideration should also be given to the increased potential for adverse effects with higher doses.²³

Women with schizophrenia also commonly have knowledge deficits about menopause. Most felt stress about menopause or approaching menopause and felt that menopause negatively affected their emotional state.²⁴ They experienced considerable menopausal symptoms in vasomotor, physical, sexual, and psychosocial realms.²⁵ The top menopause symptoms reported were in the psychological realm and included feeling depressed, anxious, or tired; lacking energy; and memory problems.²⁴ Psychiatrists should consider the overlap of menopause and mental health symptoms among women with schizophrenia.²⁵ Antidepressant medication may also be indicated related to perimenopausal depression or anxiety, or vasomotor symptoms.

Aging

Subsequent to the menopause transition, estrogen levels remain low, unless women are treated with hormone-replacement therapy (HRT). Women may continue to require increased antipsychotic doses after menopause. As well, if HRT is used and then discontinued, psychiatrists should be aware of increased potential for psychotic relapse.

Similarly, if patients are prescribed anti-estrogen drugs (such as in the treatment of breast cancer), there is increased risk.² Thus, patients should be educated of this potential risk, and psychiatrists should collaborate with their patients’ medical teams.

Concluding Thoughts

Women are unique in their treatment needs, across the life stages, ranging from menstruation to old age. Of note, these areas within women’s mental health remain understudied.³ Generally, it is well to heed the wisdom of starting low and going slow, while monitoring for adverse effects. Psychiatrists should take careful histories of their female patients, and consider the impact of endogenous hormones, hormonal contraception, and HRT. Inquiring about symptoms cyclically in menstruation, about symptomatic changes in pregnancy and the postpartum, and about menopausal symptoms and experiences is critical for optimal care of this population.

Dr Hatters Friedman is the Phillip J. Resnick Professor of Forensic Psychiatry; professor of psychiatry, reproductive biology, and pediatrics; and adjunct professor of law at Case Western Reserve University in Cleveland, Ohio. She served as editor of the Group for the Advancement of Psychiatry volume Family Murder: Pathologies of Love and Hate, which won the Manfred S. Guttmacher Award.

Dr Mulvihill is an assistant professor of psychiatry at Case Western Reserve University in Cleveland, Ohio.

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