Clinical Implications of Gender Differences in Schizophrenia

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SIGNIFICANCE FOR PRACTICING PSYCHIATRISTS

KEY POINTS

I did most of my psychiatric residency in the early 1960s on an all-women’s ward in New York City dedicated to research in schizophrenia. There were 30 beds and each patient stayed in the hospital for a long time, so I got to know the women well. I would describe them collectively as well-groomed, chatty, friendly, moody, and smart. It was consequently a shock when in 1975 in Toronto, Canada, I was put in charge of a schizophrenia outpatient clinic and discovered that the patients were mostly young men who were, by contrast to the women I had known, emotionally distant, apathetic, disheveled, and angry. Had my perception of people changed over the years, or, I wondered, does schizophrenia affect men and women differently?

Demographic differences

I wondered why there were so many more men than women in my new clinic. Part of the answer was because the incidence of schizophrenia is higher in men than in women, especially in young adulthood. Nevertheless, the prevalence appears to be similar, perhaps because more men than women with schizophrenia succumb to suicide and accidental death. The men in my clinic were mostly young adults, whereas the women in the clinic tended toward middle age. This forcibly brought home the point that men develop schizophrenia earlier in life than women by several years.

Functional differences

The relative dearth of women in the clinic was also attributable to the fact that the women were too busy to attend. They were working, socializing, having babies, and living full lives to which the men could only aspire to.

Symptom differences

The relatively few women who were eager to attend clinic activities felt outnumbered. As a result, I started a women-only therapy group. The members of this group were very friendly with each other; gossiping about clothes and diets. They went out for coffee after group together. In other words, they showed little flattening of affect, few negative symptoms, few evident cognitive defects, although they harbored many delusions and reported a variety of hallucinations.

Because the women’s group was going well, I invited the men to form their own group. By the end of a year of weekly group meetings, none of the eight men who had agreed to join knew the name of any other group member. They didn’t interact. All remarks in the group (mainly about sports, a little about cars) were addressed to me. There was evident poverty of speech, apathy, and many relatively blank facial expressions. There was also a manifest lack of grooming and basic hygiene in this group.

Outcomes over time

In 1985, I left the clinic to work at another hospital. I had learned that women with schizophrenia respond well to treatment. I had also noticed that they rarely had to be rehospitalized. Many of the women worked outside the home. Many stayed in committed intimate relationships and forged strong therapeutic alliances with their care providers. At the same time, I had unfortunately witnessed many male suicides; many men who abused alcohol and many who required extremely high dosages of antipsychotics. Most of the men did not work and continued to be dependent on aging parents.

Eight years later, I returned to the clinic, where I was in for an unexpected shock. The forlorn, listless men I had said goodbye to welcomed me back warmly and told me jokes! In some cases, their parents had died, so they now lived in group homes and were managing surprisingly well. They seemed content, even purposeful. They spent socially productive time in the hospital cafeteria, chatting and laughing with their buddies. On the other hand, the once high-achieving women had lost their jobs, were cycling in and out of the hospital, and were no longer responsive to their medications.

I am generalizing, of course, and there was much overlap between the men and the women, but the pattern was very clear. The men were doing better while the women were doing worse.

Explanations for sex differences in schizophrenia

One explanation for these observations about sex differences in this disease rests on the many and varied neuroprotective actions of estrogens.¹ The hypothesis is that female hormones delay the onset of schizophrenia, allowing women to finish their schooling and to acquire substantial interpersonal skills before illness puts a stop to further socialization. Estrogens help the antidopaminergic action of antipsychotics so that dosages can stay relatively low in women, preventing adverse effects and, thus, permitting steady employment and the development of personal relationships. At menopause, however, these advantages are lost.

Further evidence confirmatory of the estrogen hypothesis are premenstrual (low estrogen) exacerbation of psychotic symptoms in women, postpartum exacerbations, and the significant improvement brought about when estrogens or selective estrogen receptor modulators (SERMS) are added to the medication regimen.^2-5

The estrogen hypothesis is not wholly satisfactory, however. Ovaries are not functional in fetal life, so much of the estrogen found in human fetal brain comes from the testosterone derived from testes in boys. Thus, the brains of girl fetuses are exposed to relatively less estrogen. Because fetal life is when schizophrenia allegedly starts, why are male brains not more (rather than less) protected than female brains at the outset?

Perhaps the early female advantage lies not only in hormones but also in the double X chromosome, in sexually dimorphic microglia, in epigenetic effects on schizophrenia genes, on structural differences in male and female brains, and in gene – environment interactions.

Clinical implications

Prevention. Primary prevention rests in the hands of women and their clinicians. With knowledge and guidance, affected women can minimize the risk of schizophrenia in offspring by choosing male partners without a history of psychosis, who are younger than age 40 (but not too young either), and who live in their country of origin. They can time conception to avoid birth in late winter or early spring. Most importantly, they can be very assiduous in attending prenatal appointments, taking prescribed immunizations and vitamin/mineral supplements, paying attention to diet, avoiding alcohol and drugs of abuse, keeping antipsychotic doses low, managing their stress levels, avoiding infections whenever possible, and not tolerating any form of domestic abuse.

Clinicians need to ensure that pregnant women with schizophrenia are monitored frequently and have adequate incomes, safe housing, and sufficient social support. Children of both male and female parents with schizophrenia require careful monitoring and support throughout childhood and adolescence to prevent the development of psychosis or to catch and sidetrack psychotic symptoms, should they develop.

Finally, contraceptive guidance and genetic counseling are also important aspects of prevention.

Diagnosis. Diagnostic strategies differ in men and women. In men, it can be difficult to distinguish the beginning of schizophrenia from substance-induced psychosis. In women, because affect is preserved, schizophrenia is not easily distinguishable from affective psychosis. Also, in women, differential diagnoses such as anorexia-induced psychosis, steroid psychosis, thyroid disease-associated psychosis, and psychosis secondary to autoimmune disorder and its treatment need to be actively considered.

Treatment

Physical health. Maintenance of physical health is very important in schizophrenia because mortality rates are high.⁶ Psychiatrists need to ensure that their patients stay in regular contact with a general practitioner and that men and women are screened for disorders relevant to their sex (ie, cervical smears, breast examinations and mammograms, prostate and colon cancer screening), that they are adequately immunized against infectious agents, and regularly checked for the sequelae of chronic intake of antipsychotic medication (ie, obesity, diabetes, hypertension, osteoporosis, cardiovascular disease). Psychiatrists should advocate for their patients to ensure prompt and state-of-the-art care when they are ill.

Reproductive issues. Antipsychotics have sexual adverse effects that need to be asked about and addressed. Intimate relationships and contraceptive methods require attention. Women with schizophrenia usually have questions about changes in their menstrual periods and many experience premenstrual exacerbations of symptoms.² Because of antipsychotic adverse effects, some women may believe that they are pregnant when they are not, whereas women who want to be mothers may find it difficult to conceive. Some pregnant women may deny their pregnancy; others may seek abortions. Pregnant women should be seen often, their medication dosages adjusted carefully, and their domestic situation addressed with referrals not only to obstetrics but also to affordable housing, income support, and substance abuse programs as necessary. Family meetings usually become necessary at this time to garner as much support as possible for the mother-to-be.

The postpartum period is a time of risk for women with schizophrenia. Home visits are important, with monitoring required for both mother and baby. Parenting support is critical and help from a child welfare agency may be necessary. The question of breast-feeding needs to be addressed, with most guidelines recommending no breast feeding because of unresolved safety concerns about psychotropic medications. If a medication is taken immediately after breastfeeding and just before the infant’s longest sleep period, however, and the infant’s serum drug level is monitored, there are definite advantages to breastfeeding for both infant and mother. Consultation with a lactation expert is helpful. It is critical that mothers not stop their medications during this vulnerable time.

The menopausal transition is an important one for all women. Most women experience symptoms of menopause that need to be anticipated and effectively treated. The personal meaning of menopause needs to be explored with women who have schizophrenia. Unfortunately, psychotic symptoms may worsen during this time and antipsychotic dosages may have to be adjusted.

Safety. Safety issues are of utmost importance in the treatment of schizophrenia. Patients with severe mental illness need to be protected from their own sometimes very unhealthy lifestyles and from suicidal urges. A suicide in a treatment setting can lead to chain events in a vulnerable population. Treatment with antipsychotics can also pose risks in situations in which being fully alert matters (ie, driving, operating heavy machinery, looking after young children).

Women, more than men, must be protected from exploitation and violence inflicted by others, whether intimate others, co-patients on hospital wards, or strangers. Both men and women need protection from stigmatizing attitudes, in particular on the part of childcare workers (women), police, and the justice system (men) as well as medical professionals (men and women).

There are also understandable safety concerns about individuals with schizophrenia acting on dangerous delusional beliefs and command hallucinations, especially when inebriated. Family members are most at risk.

Medication dosage. Standard antipsychotic treatment frequently requires modification in women. Women respond to lower dosages and, because they are usually on many more different medications than men and have a more active immune system, they experience more adverse effects.^7,8 Dosages may need to be adjusted over the menstrual month, during pregnancy, the postpartum, and the menopausal transition. In older age, dosages should be kept low in both women and men.

Several other clinical interventions useful to individuals with schizophrenia, such as exercise programs, substance abuse programs, employment programs, and weight-loss programs also benefit from sex-specific modifications.

Conclusion

In an ideal world, each patient is treated individually because no two persons are identical, but that may be impossible for now. Differentiating between men and women is a first step.

Suggested Reading

• Escott-Price V, Smith DJ, Kendall K, et al. Polygenic risk for schizophrenia and season of birth within the UK. Psychol Med. 2018; Epub ahead of print.

• Hung YN, Yang SY, Kuo CJ, Lin SK. Diagnostic consistency and interchangeability of schizophrenic disorders and bipolar disorders: a 7-year follow-up study. Psychiatry Clin Neurosci. 2018;72:180-188.

• Lu Y, Pouget JG, Andreassen OA, et al. Genetic risk scores and family history as predictors of schizophrenia in Nordic registers. Psychol Med. 2018;48:1201-1208.

• Riecher-Rössler A, Butler S, Kulkarni J. Sex and gender differences in schizophrenic psychoses: a critical review. Arch Womens Ment Health. 2018; Epub ahead of print.

• Terres NM. Resources for psychiatric clinicians working with breastfeeding mothers. J Psychosoc Nurs Ment Health Serv. 2018;56:37-46.

Disclosures:

Dr Seeman is Professor Emerita, Department of Psychiatry, Institute of Medical Science, University of Toronto, Ontario, Canada. Dr Seeman reports no conflicts of interest concerning the subject matter of this article.

References:

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2. Seeman MV. Menstrual exacerbation of schizophrenia symptoms. Acta Psychiatr Scand. 2012;125:363-371.

3. Vigod SN, Rochon TG, Fung K, et al. Factors associated with postpartum psychiatric admission in a population-based cohort of women with schizophrenia. Acta Psychiatr Scand. 2016;134:305-313.

4. Kulkarni J, Gavrilidis E, Wang W, et al. Estradiol for treatment-resistant schizophrenia: a large-scale randomized-controlled trial in women of child-bearing age. Mol Psychiatry. 2015;20:695-702.

5. Zhu XM, Zheng W, Li XH, et al. Adjunctive raloxifene for postmenopausal women with schizophrenia: a meta-analysis of randomized, double-blind, placebo-controlled trials. Schizophr Res. 2018; Epub ahead of print.

6. Reininghaus U, Dutta R, Dazzan P, et al. Mortality in schizophrenia and other psychoses: a 10-year follow-up of the AESOP first-episode cohort. Schizophr Bull. 2015;41:664-673.

7. Zhu Y, Li C, Huhn M, et al. How well do patients with a first episode of schizophrenia respond to antipsychotics: a systematic review and meta-analysis. Eur Neuropsychopharmacol. 2017;27:835-844.

8. Seeman MV. Schizophrenia: women bear a disproportionate toll of antipsychotic side effects. J Am Psychiatr Nurses Assoc. 2010;16:21-29.