Women and Schizophrenia

Mary V. Seeman, MDCM, FRCPC, FACP

[Medscape Women's Health 5(2), 2000. © 2000 Medscape, Inc.]

Abstract

Several important questions emerge from the study of gender differences in schizophrenia: Why does schizophrenia begin later in women? Why is outcome superior in women, at least in the first 15 years after onset? What causes sex differences in symptoms? What can gender differences teach us about the etiology of schizophrenia? Do men and women require substantially different treatments? What interventions during pregnancy and after childbirth ensure optimal health for the children of mothers with schizophrenia? Although complete answers may not yet be forthcoming, it is important to define the questions and keep them in mind when delivering services to women suffering from this severe, persistent mental illness.

Introduction

Schizophrenia is a category of psychosis. Other disorders in this category are: brief reactive psychosis, schizophreniform psychosis, affective disorder with psychotic features, schizoaffective psychosis, delusional disorder, and organic psychosis. Type and duration of symptoms distinguish these disorders, as do the nature of precipitants and the life course of the illness. The actual demarcation of schizophrenia from the other psychotic disorders changes with changing diagnostic systems. This means that the question "Is schizophrenia more common in men than it is in women?" is very difficult to answer.

The longer the requisite duration of symptoms before a diagnosis of schizophrenia can be made, and the younger the age at first onset after which the diagnosis can no longer be made, the more women are excluded from this diagnostic category. The more the requirement of functional deterioration is needed to make the diagnosis, the fewer women will meet the full diagnostic criteria. The more categorically the presence of mood symptoms invalidates the diagnosis of schizophrenia, the fewer women will be diagnosed. This is because brief duration of symptoms, the presence of mood symptoms, lack of functional deterioration, and late onset are all more prevalent in women with schizophrenia-like illnesses than in men.[1-4]

Epidemiology

Definitions aside, it is difficult to compare male/female incidence rates of psychosis as determined by case registers, because in many parts of the world the 2 sexes have unequal access to care. Epidemiologic door-to-door surveys, on the other hand, may miss individuals who are in jail, on the street, or in hospitals. The epidemiology of schizophrenia is thus always in flux.

The highest risk for the onset of schizophrenia symptoms in both women and men occurs in the period from late adolescence to early adulthood; relatively fewer individuals develop this particular set of symptoms for the first time before age 14 or after age 35. Lifetime onset age differs significantly between men and women.[2] Men get ill with schizophrenia, on average, 4-6 years earlier than women.[3] This is one of the most replicated findings in schizophrenia research. Puzzlingly, however, in schizophrenia that runs in families, there appears to be no onset age difference between men and women if patients are ascertained through pedigree studies rather than through case registers or door-to-door surveys.[5] This suggests that when family members and physicians are more sensitized to the possibility of schizophrenia, they are more likely to make the diagnosis early, regardless of sex. An alternate explanation is that in such families, onset age is also inherited and obliterates any triggering or protective factors imposed by biologic sex.

Although most women and men develop a first psychosis during the late adolescent/early adulthood peak risk period, second and third smaller peaks of incidence occur in older age, but only in women.[4] There are 2 major unsolved questions about onset, schizophrenia, and gender: (1) Does adult-onset schizophrenia really begin 4-6 years later in women than in men, or is the delay only in hospital admission? (2) What accounts for late-onset schizophrenia, and why is it a disease almost exclusively of women?

Etiology

The etiology of schizophrenia is poorly understood. Familial forms are more common in women. More schizophrenia than expected is seen in the female offspring of mothers exposed to viral infection in the second trimester of pregnancy.[6] Why this should be the case for female and not male offspring is not clear. Obstetric complications have also been implicated as risk factors in schizophrenia. They occur more often in the mothers of male schizophrenics. The additional brain compromise that results from birth trauma may explain the earlier onset in men[7,8] and the greater initial severity of illness that occurs in men.

The pace of brain development is faster in women than in men. This may be an advantage in some illnesses and a disadvantage in others. Normal brain structural asymmetry is lost in schizophrenic men, but not in women. The significance of this is not clear. In the general population, women have a more bilateral distribution of cognitive functions than men. This may be an advantage if one side of the brain is specifically impaired in schizophrenia. High-resolution brain scanning has shown structural deficits in schizophrenia, particularly in frontal and temporal brain regions, but also throughout the gray matter of the brain. In many studies, brain differences found between schizophrenia subjects and controls are more pronounced in males.[9] After many years of illness, however, cognitive changes in attention, memory, and judgment are present to an equal extent in men and women, although olfactory deficits, which are markers of regional brain compromise, remain less prevalent in women with schizophrenia until menopause.[10,11]

Hormonal disparities presumably underlie gender brain dimorphism. Among other actions, women's hormones (estrogens) may compete with dopamine at dopamine receptors.[12] Whether they act as dopamine antagonists in the adult human brain is not clear, but it does seem as if women with schizophrenia are relatively protected from symptom severity during high estrogen times of the menstrual month[13] and perhaps also during pregnancy. Estrogens enhance the function of nerve growth factors[14] and may prevent accelerated neuronal cell death, a mechanism that has been considered potentially important in the induction of schizophrenia symptoms at the time of adolescence. A meaningful issue regarding schizophrenia causation and gender is: Do gender differences shed light on the etiology of schizophrenia?

Clinical Manifestations

The signs and symptoms of schizophrenia are not exactly the same in women as those seen in men.[15] The content of delusions, which in large part is culturally determined, is gender dimorphic. Delusions in women appear less bizarre, with more somatic and romantic preoccupations. Men are more concerned with political conspiracy and undercover activities and have more grandiose delusions of power, royalty, and divinity. Women experience delusions of being pregnant when, in reality, they are not -- or not being pregnant when, in reality, they are. Women have delusions of jealousy. These are so commonplace even in nonpsychotic individuals that they are easy for caregivers to empathize with. In general, women's delusions seem relatively understandable to clinicians; men's delusions appear more bizarre. Symptoms of apathy, flat affect, paucity of speech, and social isolation, with their consequent negative impact on relationships, are more often present in men.[16] Mood symptoms, especially depression, are more commonly seen in women.[15] The differences in symptoms make relationships with care providers stronger and longer lasting when the patient is a woman.

Women with schizophrenia use alcohol and drugs less often than their male counterparts, but the severity of the substance abuse disorder may not be very different.[17] Intriguing questions with respect to symptoms, gender, and schizophrenia are: (1) Is the prominence of specific symptoms wholly determined by environment? and (2) Do brain differences between the sexes help determine symptomatology?

Pharmacologic Treatment

Antidopaminergic agents that control hallucinations, delusions, and thought disorders were introduced in the early 1950s to treat schizophrenia. The antidopaminergic action caused parkinsonian side effects and increased prolactin levels. Increases in prolactin lowered estrogen levels, and many women became amenorrheic and infertile when in treatment. Newer antipsychotic drugs with fewer of these side effects have recently replaced the older ones. The newer products, because they do not increase prolactin levels to the same degree, are not thought to lower estrogen levels. (Because there is a theoretical link between low estrogen and subsequent osteoporosis and cardiovascular disease, this may be important, although there has never been direct evidence of an association of these illnesses with the older drugs.[18]) By the same token, the new drugs do not reduce fertility, so that unwanted pregnancies occur more often and may cause distress for women.[19] Tardive dyskinesia, a late side effect of the older drugs affecting elderly women in particular, is not thought to follow on long-term treatment with the newer drugs. One of these "atypical" drugs, clozapine, is currently being used for nonresponders to other medications. It carries a small risk of agranulocytosis, which seems to occur more often in women than in men.[20]

In general, women require lower doses of medication than men during both acute phases and maintenance phases of illness, at least until menopause.[19,21] Dose requirements may be a matter of the strength of adherence to prescribed regimens or may have to do with sexually dimorphic features, such as gastric absorption, lipid storage, and brain blood flow.[19] Effective dose is also influenced by the patient's concomitant use of such substances as nicotine, caffeine, alcohol, and nonsteroidal anti-inflammatory agents, to name a few.

The most troublesome side effect for women with the new drugs -- and one that interferes with treatment adherence[22] -- is weight gain. Increases in appetite and weight gain of 30 pounds or more can occur, which in turn leads to diminished self-esteem, especially in women, and increased health risks. Diabetes and cardiovascular incidents are more frequent among the overweight, and the disability from arthritis is more pronounced. An important clinical question is whether men and women with schizophrenia require different pharmacologic treatment regimens to maximize health and quality of life.

Course and Outcome of Illness

Premorbid functioning in patients who later develop schizophrenia has been shown to be superior in women in almost all studies that have addressed this issue.[23] Preschizophrenic women generally fare better than their male peers in social functioning, cognition, school achievement, and employment success.[24] As stated, women's initial episodes of acute psychosis occur chronologically later than those of men. As well, women recover faster. They stay in hospital for shorter periods and are discharged on a lower antipsychotic dose than their male peers.[24] In other words, schizophrenic illness, at least at the beginning, interrupts women's lives to a lesser degree than it does men's. After hospitalization, women return to employment more often than men do; they more often date, marry, and bear children; they develop and maintain larger and more intimate social support networks (this may be a dimension of better outcome; it is also a preexisting condition that determines better outcome); and they adhere better to their prescribed treatment regimen than men do.[24] Perhaps for all these reasons, female gender predicts superior outcome (especially with respect to rehospitalization rate) at 18 months and up to 15 years after a first episode of schizophrenia. After 15 years, the relative advantage for women seems to disappear. From that point on, outcome for women and men, along most dimensions, becomes roughly similar.[25]

More men than women with psychosis commit suicide.[26] This is especially true during the first decade after diagnosis. Because suicide is far more common among men than among women in the general population, this finding is not surprising. In fact, relative to the general population, the ratio of male/female suicide is lower in schizophrenia. Perhaps the greater severity and prevalence of depressive symptoms among women with schizophrenia help to explain this.

Mortality rates in schizophrenia are higher than those in the general population. This is largely accounted for by suicide.[27] These are some unanswered questions about schizophrenia, gender, and outcome:

  1. Do women fare better than men initially because they get ill later and, therefore, have more supports in place before illness hits?

  2. Do they fare better because they forge good relationships with caregivers and adhere to their treatment schedules much more assiduously than men?

  3. Do they get worse after 15 years of illness because they lose their social supports[28]?

  4. Is it that patients with better outcome are lost to research studies?

Sexuality

Whereas men with schizophrenia frequently lose their sexual drive early in the course of illness and are not likely to be sexually active if their illness is severe, this is generally not true for women. They continue to be interested in relationships and to engage in sexual intercourse. Because women with chronic psychosis are seldom employed or well off, their financial need may also lead to the exchange of sex for money. The relative passivity and isolation that accompany schizophrenia are fertile ground for sexual victimization. For these reasons, women with schizophrenia are at special risk not only for unwanted pregnancy but also for sexually transmitted disease. Counseling around these issues is essential.[29]

Pregnancy and Childbirth

The first trimester is a crucial time for making decisions about the advisability of maintaining pregnancy in a woman who suffers from a severe and chronic illness. It is also critical to reassess treatment at this time in case pharmacologic agents used to keep symptoms in check adversely affect the developing fetus. Although considered relatively safe, antipsychotics, like any drugs, are best avoided between week 4 and week 10 postconception. Although accurate estimates are difficult, the older drugs are thought to increase the risk for congenital anomalies by as much as 4% over baseline.[30] There is little information on the newer antipsychotics. Pregnancy, paradoxically, is not a particularly difficult period for women with psychosis. Admission rates during pregnancy are relatively low, either equal to or lower than during the prepregnancy period. The postpartum period, however, is a vulnerable one, and the stresses of subsequent child care may prove overwhelming for many women suffering from chronic psychotic illness.

Antipsychotics, Labor, Delivery, and the Postpartum Period

In a new mother being treated with antipsychotics, drug concentrations at delivery are similar in maternal serum and amniotic fluid but are twice as high in fetal serum. After delivery, the neuroleptic concentration in breast milk is about 3 times that of maternal serum, probably because of the high lipid content of breast milk. To prevent both infant toxicity and infant withdrawal reactions, it is important to taper neuroleptic dose 2 weeks before anticipated delivery. Because antipsychotic medication will need to be resumed immediately following childbirth to prevent postpartum psychosis, it is wisest to counsel against breast feeding. Also, because the postpartum period is such a vulnerable one, a larger than usual dose of antipsychotic drug may be required for the first 6 weeks to keep symptoms at bay.[30]

Decisions about appropriate pharmacotherapy at this time are very difficult to make and may have serious consequences. On one hand, it is important to prevent psychotic symptoms. On the other hand, it is equally important to not oversedate the mother, because she is in the process of bonding with her infant and learning new parenting skills. The mother is housebound during this period, and the prescribing psychiatrist may find it difficult to make home visits. Family supports may or may not be available. Frequently enough, the mother is single, alienated from her family of origin, and poor. Child-protection agencies are often involved, and although they are in a position to provide help and support to the mother and child, child-protection workers are usually perceived by mothers as a potential threat. Mothers are rightly concerned that their baby may be taken from them and, frequently enough, decide that it is better not to be perceived as requiring medication. Thus, at a time when they are most vulnerable to relapse, they are tempted to stop medication to prove to child-protection workers that they are illness-free. Close liaison between mental health workers and child-protection workers at this time is critical.

Child Care

Child care is a particularly difficult task for chronically and severely mentally ill women. The sedation that frequently accompanies effective psychopharmacologic treatment of psychosis is of particular significance for individuals caring for children. This is all the more important considering that these children are at increased genetic risk for the later development of psychosis themselves and may, therefore, be more difficult to raise than the average child. Subtle neurologic deficits and developmental delays may be present from infancy. Ensuring that the needs of these very vulnerable children are met is a most important task in the treatment of psychosis in women.

Summary

In summary, psychotic syndromes, especially those diagnostically categorized as schizophrenia, differ in their expression in women and men and also in requirements for treatment (see Table). There are several important unsolved questions pertaining to schizophrenia and gender:

  1. Why does schizophrenia begin later in women than in men?

  2. What can gender differences teach us about the causes of schizophrenia?

  3. What causes sex differences in symptoms?

  4. Why is outcome superior in women, at least in the first 15 years after onset?

  5. Do men and women require different treatments?

  6. What interventions during pregnancy and after childbirth ensure optimal health for the children of mothers with psychosis?

Table. Gender Differences in Schizophrenia

Variable

Women Men

Premorbid adjustment

Superior


Age at onset

Later


Obstetric complications in mother of schizophrenic


More

Symptoms

Mood symptoms, especially depression

Apathy, flat affect, paucity of speech, and social isolation

Outcome

Initially better


Familial risk

Greater


Brain structure impairment


More

Onset after age 45

More frequent


Response to antipsychotics

Lower doses needed


References

  1. Susser E, Wanderling J. Epidemiology of nonaffective acute remitting psychosis vs schizophrenia: sex and sociocultural setting. Arch Gen Psychiatry. 1994;51:294-301.
  2. Faraone SV, Chen WJ, Goldstein JM, et al. Gender differences in age at onset of schizophrenia. Br. J Psychiatry. 1994;164:625-629.
  3. Häfner H, Maurer K, Löffler W, et al. The epidemiology of early schizophrenia: Influence of age and gender on onset and early course. Br J Psychiatry. 1994;164:29-38.
  4. Castle DJ, Murray RM. The epidemiology of late-onset schizophrenia. Schizophrenia Bull. 1993;19:691-700.
  5. Alda M, Ahrens B, Lit W, et al. Age of onset in familial and sporadic schizophrenia. Acta Psychiatr Scand. 1996;93:447-450.
  6. Takei N, Sham P, O'Callaghan E, Murray GK, Glover G, Murray RM. Prenatal exposure to influenza and the development of schizophrenia: is the effect confined to females? Am J Psychiatry. 1994;151:117-119.
  7. Kirov G, Jones PB, Harvey I, Lewis SW, Toones BK, Rifkin L, et al. Do obstetric complications cause earlier age at onset in male than female schizophrenics? Schizophr Res. 1996;20:117-124.
  8. Verdoux H, Geddes JR, Takei N, et al. Obstetric complications and age at onset in schizophrenia: an international collaborative meta-analysis of individual patient data. Am J Psychiatry. 1997;154:1220-1227.
  9. Cowell PE, Kostianovsky DJ, Gur RC, et al. Sex differences in neuroanatomical and clinical correlations in schizophrenia. Am J Psychiatry. 1996;153:799-805.
  10. Kopala L, Clark C, Hurwitz T. Sex differences in olfactory function in schizophrenia. Am J Psychiatry. 1989;146:1320-1322.
  11. Szymanski S, Lieberman JA, Alvir JM, et al. Gender differences in onset of illness, treatment response, course, and biologic indexes in first-episode schizophrenic patients. Am J Psychiatry. 1995;152:698-703.
  12. Häfner H, Behrens S, De Vry J, et al. Oestradiol enhances the vulnerability threshold for schizophrenia in women by an early effect on dopaminergic neurotransmission. Eur Arch Psychiatry Clin Neurosci. 1991;241:65-68.
  13. Hallonquist J, Seeman MV, Lang M, et al. Variation in symptom severity over the menstrual cycle of schizophrenics. Biol Psychiatry. 1993;33:207-209.
  14. Toran-Allerand CD. Interactions of estrogens with growth factors in the developing central nervous system. In: Hochberg RB, Naftolin F (eds). The New Biology of Steroid Hormones. New York, NY: Raven Press; 1990.
  15. Goldstein JM, Link B. Gender and the expression of schizophrenia J Psychiatr Res. 1988;22:141-155.
  16. Fennig S, Putnam K, Bromet EJ, et al. Gender, premorbid characteristics and negative symptoms in schizophrenia. Acta Psychiatr Scand. 1995;92:173-177.
  17. Brunette M, Drake R. Gender differences in patients with schizophrenia and substance abuse. Compr Psychiatry. 1997;38:109-116.
  18. Hammer MB, Arana GW. Hyperprolactinaemia in antipsychotic-treated patients. CNS Drugs. 1998;10:209-222.
  19. Seeman MV. Neuroleptic prescription for men and women. Soc Pharmacol. 1989;3:219-236.
  20. Janicak PG, Davis JM, Preskorn SH, Ayd FJ. Treatment with antipsychotics. In: Principles and Practice of Pharmacotherapy 2nd edition. Baltimore, Md: Williams & Wilkins; 1997:205.
  21. Yonkers KA, Kando JC, Cole JO, et al. Gender differences in pharmacokinetics and pharmacodynamics of psychotropic medication. Am J Psychiatry. 1992;149:587-595.
  22. Wetterling T, Müsigbrodt HE. Weight gain: side effect of atypical neuroleptics? J Clin Psychopharmacol. 1999;19:316-321.
  23. Mueser K, Bellack A, Morrison R, et al. Social competence in schizophrenia: premorbid adjustment, social skill, and domains of functioning. J Psychiatr Res. 1990;24:51-63.
  24. Seeman MV. Current outcome in schizophrenia: women vs men. Acta Psychiatr Scand. 1986;73:609-617.
  25. Opjordsmoen S. Long-term clinical outcome of schizophrenia with special reference to gender differences. Acta Psychiatr Scand. 1991;83:307-313.
  26. Goldstein JM, Santangelo SL, Simpson JG, et al. Gender and mortality in schizophrenia: do women act like men? Psychol Med. 1993;23:941-948.
  27. Mortensen PB, Juel K. Mortality and causes of death in first admitted schizophrenic patients. Br J Psychiatry. 1993;163:183-189.
  28. Seeman MV. Narratives of twenty to thirty years of schizophrenia outcome. Psychiatry. 1998;61:249-261.
  29. Miller LJ. Sexuality, reproduction, and family planning in women with schizophrenia. Schizophr Bull. 1997;23:623-635.
  30. Cohen LJ, Heller VL, Rosenbaum JF. Treatment guidelines for psychotropic drug use in pregnancy. Psychosomatics. 1989;30:25-33.