Abstract
Psychotic illness presents somewhat differently in women and men, but much of our understanding of the mechanisms of causation and the routes of recovery is based on research that has been conducted, for the most part, in men [1]. This is why a review of psychosis as it applies to women is important. The last decade of research into the many facets of psychosis in women were reviewed for this paper by introducing the search terms: ‘women’ (or ‘sex’ or ‘gender’) AND ‘psychosis’ or ‘schizophrenia’, as well as ‘psychosis’ or ‘schizophrenia’ AND ‘menstruation’, or ‘conception’, or ‘pregnancy’, or ‘postpartum’, or ‘parenting’, or ‘menopause’, or ‘hormones’ or ‘aging,’ as well as ‘women (or ‘sex’ or ‘gender’) AND ‘brain’, or ‘neurodevelopment’ or ‘cognition’ or ‘antipsychotics’, or ‘treatment’, or ‘side effects’ or ‘suicide’ or ‘mortality’ into PubMed, PsycINFO and SOCINDEX.
Rates of psychosis may differ by gender, as do severity, onset and duration of illness, lifetime course of symptoms, response to treatment, impact on functioning and general quality of life. Added considerations for women with psychotic illness are the concomitant demands of reproduction and the challenges of child-rearing in socioeconomic straits with few supports, in addition to being under the constant threat of losing one's custodial rights.
Male/female differences in the expression of psychosis may, in part, be a result of differential levels and time courses of hormones. Estrogens, for instance, are known to exert a neuroprotective effect [2]. Estrogens have many actions in the CNS, among which is an important effect on mesolimbic and mesocortical dopamine neurons that modulate the expression of neuropsychiatric symptoms [3].
What is psychosis?
Psychosis refers to the presence of delusions (fixed beliefs that are firmly maintained despite contrary evidence) and hallucinations (sensory perceptions experienced in the absence of an external stimulus and occurring while the person is awake), both accompanied by cognitive distortions and emotional and/or behavioral impairments. In order to qualify for a diagnosis of psychosis, these experiences have to be serious enough to interfere with one's ability to distinguish the real from the unreal, and to undermine one's ability to meet the ordinary demands of life. To be considered as an illness, the manifestations of the condition have to be such as to distinguish the sufferer from his/her community of peers and to cause either subjective distress or distress to others. Psychosis can occur in response to a large number of brain insults, but is currently considered a disease in its own right in the American Diagnostic and Statistical Manual of Mental Disorders [101] when there is no evident direct precipitant and when the psychotic state lasts for at least 6 months.
The diagnosis of psychosis needs to be established by an experienced objective observer who uses standard and reliable criteria. Affected persons may be subjectively unaware that what they experience originates in their own minds; they may believe that the problem lies in others, not in themselves. No biological diagnostic marker exists. For most affected individuals, the symptoms come and go, probably in response to environmental stress [4,5]. They are not culture-specific, but occur throughout the world in a very similar form [6].
A variety of brain insults can contribute to psychosis. These insults include trauma, tumors, toxic substances (intoxication or abrupt withdrawal), starvation, sleep deprivation, sensory deprivation, acute psychological trauma, neurological disease, endocrine disorders, electrolyte disturbance, metabolic disorder, autoimmune disorder, vascular disorder or degenerative disorder. Some of these contributory factors occur more commonly in one gender than in the other. Besides schizophrenia, psychosis can take several forms (Diagnostic and Statistical Manual of Mental Disorders) (
These disorders differ from each other in terms of symptoms and the duration of symptoms. Precipitants and course of illness also differ. Because diagnostic systems change, the borders among these varieties of psychosis also change over time. Currently, a 6-month duration of psychotic symptoms is needed for an illness to qualify as schizophrenia and a deterioration of function is an added requirement [101].
Psychosis is not well understood. Studies from around the world consistently show that the public sees distorted images of psychotic illness in the media, images that emphasize dangerousness, criminality and unpredictability, and describe negative reactions to people with mental illness, including fear, rejection, derision, ridicule and discrimination [7]. The stigma of psychotic illness can become internalized, thereby reinforcing symptoms and impeding recovery [8].
Many triggers to psychosis appear to be relatively sex-specific, based on differential environmental exposures for men and women. Psychosis triggered by the use of diet pills is an example [7]. Another example is the starvation psychosis that can sometimes accompany anorexia nervosa [9]. Diet pills and anorexia are both more common in women because excess weight, at least in the western world, tends to be primarily a preoccupation of girls and women. Psychosis triggered by body-building steroids, on the other hand, is more common in men [10].
Autoimmune disease, for the most part more prevalent in women, can also be accompanied by symptoms of psychosis [11] and its treatment with high-dose corticosteroids is well known to induce psychosis at high doses [12]. Thyroid disease of all kinds is more prevalent in women than in men and both over- and underactivity of the thyroid gland can result in psychosis [13].
Risk factors for schizophrenia in men & women
The rest of this review will focus on schizophrenia, since this is the psychotic illness that most research addresses. The etiology of schizophrenia is complex and, thus far, little is known for certain. Schizophrenia behaves like a genetically transmitted disorder, but the putative genes responsible for this illness have not yet been discovered. Recently, one study found that girls were more likely to inherit schizophrenia from their fathers and boys from their mothers – an observation that is hard to explain on genetic grounds [14].
Forms of psychosis.
Brief reactive psychosis
Schizophreniform psychosis
Affective disorder with psychotic features
Schizoaffective psychosis
Delusional disorder
Organic psychosis
Girls appear to be more at risk than boys when schizophrenia is associated with viral infection during the mother's pregnancy [15], perhaps because male fetuses, generally more vulnerable than female fetuses to any environmental trauma [16], succumb to the infection and die in utero. Boys are more at risk than girls when schizophrenia is associated with obstetric complications at the time of childbirth [17]. On the other hand, the hormonal changes that accompany menstruation, labor and delivery, or the menopause, can help to precipitate schizophrenia in susceptible women [18].
In many studies, brain differences that distinguish schizophrenia subjects from controls have been found to be more pronounced in males [19,20], although the universality of this fact is debatable [21]. The pace of neurodevelopment is generally faster in girls than in boys [22], which is paradoxical since schizophrenia starts earlier in men. The earlier start proves to be a disadvantage for males.
Onset age of schizophrenia: men & women
The highest risk for the onset of schizophrenia symptoms in both women and men occurs in the period between late adolescence and early adulthood; relatively fewer individuals first develop psychotic symptoms before the age of 14 years or after the age of 35 years. One of the most replicated findings in schizophrenia research is that men get ill with schizophrenia, on average, 4–6 years earlier than women [23]. At the peak, the onset age of boys is advanced by 2 years on average. The rest of the difference is attributable to the second onset peak for women, which occurs in their forties [24].
When schizophrenia runs in families, however, there is no onset age difference between the genders [25]. It seems that whenever close observers are sensitized to the possibility of schizophrenia (by the presence of another ill family member), diagnosis in both sexes is arrived at early. Another possibility is that, in familial schizophrenia, onset age is inherited [26] and obliterates any triggering or protective factors that may originate in biologic sex.
Earlier onset age brings with it a characteristic clinical picture (flat affect and cognitive difficulties), the same picture that is usually thought to be distinctive of male schizophrenia [27]. In other words, the clinical traits that distinguish schizophrenia in men from that in women may be due to age at onset rather than to gender.
Although most women and men develop a first psychotic experience during the late adolescent/early adulthood peak risk period, second and third smaller peaks of incidence do occur in older age, mainly in women [24]. In 20% of women with schizophrenia, the illness begins after the fortieth year of life [24].
Schizophrenia prodrome differences: men & women
Prior to the expression of full-blown psychosis, young men show more negative symptoms, lower social functioning and they enjoy lower levels of social support than young women [28]. When they are first brought to assessment, men have more ‘typical’ symptoms of schizophrenia than women (flat affect, pronounced cognitive problems) and they are generally within the expected period of onset for schizophrenia (late adolescence or early adulthood), which should make diagnosis easier. Paradoxically, however, in most studies men show a longer duration of untreated psychosis (DUP) than women [29]. Studies from lower-income countries, however, report the opposite trend with females having a longer mean DUP than males [30]. DUP is probably culture-specific, with gender roles and traditions in some cultures leading to more rapid referral of males. This is an important issue because earlier diagnosis and treatment is associated with superior outcome, while a long DUP undermines self-confidence, friendships, family cohesion, as well as opportunities for academic and vocational achievement [31].
Male/female differences in the rate & expression of schizophrenia
While the lifetime prevalence of schizophrenia in most parts of the world is equal for men and women, the incidence is higher in men (1.4:1) [32]. The discrepancy may be attributable to the higher suicide rate in men with schizophrenia compared with women.
As already mentioned, men tend to have more negative and cognitive symptoms than women, whereas women have more affective symptoms. In the context of schizophrenia, women's episodes of psychosis tend to be briefer than those in men and the resolution of such episodes is more complete [33]. Comorbid substance abuse is more prevalent in men; twice as many males as females with schizophrenia qualify for a comorbid substance abuse diagnosis [34].
Although in the general population men are considered more aggressive than women and commit more crimes, the association of aggression with gender is less clear in psychiatric populations. Mental disorder appears to increase the criminal potential of females more than that of males so that, whereas the crime rate among males with schizophrenia is almost the same as that of the general male population, the crime rate among females with schizophrenia is two to four times higher than that of females with no mental disorder [35].
Women with schizophrenia are more likely to be employed than men and to retain their social support system after they fall ill [20]. They are more likely than men with schizophrenia to marry and bear children [20]. Their quality of life is superior to that of men with schizophrenia probably into the late thirties after which it declines and becomes indistinguishable from that of men [36]. All these schizophrenia sex differences are similar in China, suggesting that they are independent of culture [37].
Aging & mortality in schizophrenia
Among older schizophrenia patients, there is a preponderance of women [38]. Problems of aging, such as cognitive decline and chronic medical conditions, may be exacerbated by schizophrenia and the disorder is associated in both sexes with premature mortality. Hypertension, smoking, raised glucose, physical inactivity, obesity and dyslipidemia, and stress have been identified as global mortality risk factors [39]. The life pattern of patients with schizophrenia results in high levels of all these factors.
As a consequence, individuals with schizophrenia have a mortality risk that is two to three times that of the general population. Standard mortality ratios in a recent study from England were twice as high in schizophrenia as in the general population and higher in women than in men [40,41]. Cardiovascular death and death from cancer are the major culprits. Both cardiovascular and cancer deaths are facilitated by sedentary habits, substance use and smoking, but may also be attributable, in part, to antipsychotic medications that induce obesity and metabolic effects [42]. Although the likelihood of developing cancer among patients with schizophrenia is not greater than that of the general population, the cancer mortality rate among patients with schizophrenia is higher [43]. This suggests that patients either do not take preventive measures or do not present themselves for treatment or are not adequately treated when they do. It is known that following cardiac events individuals with schizophrenia experience a 47% lower rate of invasive coronary interventions relative to their peers [44]. In summary, the high mortality rate in schizophrenia is attributable to health needs being neglected because of limited social support, cognitive decline, low socioeconomic status [45] and perhaps treatment side effects and the stigma associated with severe mental illness.
Suicide in schizophrenia
The mortality rate in schizophrenia is additionally increased because of high rates of suicide. Relative to the general population, individuals with schizophrenia are 13-times more vulnerable to suicide. Almost half of all patients with schizophrenia attempt suicide and from 4 to 13%, depending on the study, die of suicide, with the mortality risk higher in men than in women [46]. Men are most at risk for suicide during the first decade after diagnosis [46]. In the population at large, the risk of suicide is considered to be three-times higher for men than women, so it is not surprising that men with schizophrenia take their lives more often than their female peers. The ratio of male/female suicide, however, is lower in schizophrenia than it is in the general population, meaning that women with schizophrenia are at greater risk of suicide (compared with women in general) than men with schizophrenia compared with their healthy male peers. Perhaps this is because there is a high prevalence of depressive symptoms among women with schizophrenia.
Special issues for women
Sexuality
It is not uncommon for men with schizophrenia to lose their sexual drive early in the course of illness and to abstain from sexual activity if their illness is severe, but this is generally not the case for women. Women with schizophrenia continue through their reproductive years to be interested in relationships with others and to have sexual partners [20]. Because such women often live in poverty, they may be tempted to exchange sex for money. Their relative difficulty in saying ‘no’ to unwanted advances and their social isolation may expose them to sexual victimization. Moreover, it has been observed that women with schizophrenia rarely use effective contraception. For all these reasons, they are at higher risk for both unwanted pregnancy and sexually transmitted disease [47].
Pregnancy & childbirth
Women with schizophrenia in the west have almost as many children as their well peers. Currently, approximately half of all women with schizophrenia become mothers [48]. This is a difficult area for clinicians if a decision has to be made about the advisability of childbearing. Assessment of decisional capacity becomes important in this context [49].
It is critical to carefully reassess treatment during pregnancy because pharmacologic agents used to treat psychotic symptoms may adversely affect the developing fetus. Although considered relatively safe, antipsychotics, like any drugs, are best avoided whenever possible between week 4 and week 10 postconception. Accurate estimates are difficult but it is generally thought that the older drugs increase the risk for congenital anomalies by approximately 4% over baseline [50]. There is still relatively little information on the newer antipsychotics. Because of differing metabolic pathways, the dose of some may need to be decreased and of others increased during pregnancy in order to maintain efficacy [51,52]. Prenatal care is important to maintain mother s health, ensure nutrition and vitamin intake, address potential issues such as obesity, smoking, or alcohol and drug use, and monitor stress and delusional symptoms. Delusional denial of pregnancy is sometimes present [53], which may necessitate safety precautions and liaison with child protection agencies.
In general, pregnancy is a period of relative well being for women with psychosis. Admission rates to hospital are relatively low during pregnancy, usually lower than during pre- or postpregnancy [54]. Women with psychosis are, however, vulnerable to relapse during the postpartum period and are, in addition, more likely than the general population to have babies born prematurely, thus necessitating a greater caretaking burden [54].
Antipsychotics, labor, delivery & the postpartum period
At delivery in a woman treated with antipsychotics during her pregnancy, drug concentrations are approximately the same in maternal serum and amniotic fluid. They are, however, twice as high in fetal serum. With respect to breast milk, the antipsychotic concentration is approximately three-times higher than that of maternal serum because breast milk is very high in lipids and antipsychotic drugs accumulate in adipose tissue [51].
The recommendations in the schizophrenia and pregnancy literature are that the antipsychotic dose be tapered, if clinically feasible, 2 weeks before anticipated delivery in order to prevent infant toxicity and withdrawal reactions. This, however, leaves the mother more vulnerable to postpartum psychosis so that the resumption of full antipsychotic doses is recommended immediately following childbirth. Breastfeeding is not precluded, but the literature recommends a thorough discussion about risks and benefits with the mother and her partner. In fact, with the postpartum period being such a vulnerable period, a larger than usual dose of antipsychotic drug is suggested for the first 6 weeks after delivery. Because it is difficult to leave the house during these 6 weeks (and in some cultures mothers are explicitly instructed not to [55]), home-based psychiatric services are recommended throughout this period, as is close liaison between mental health workers and child-protection workers.
Parenting
Childcare is a particularly difficult task for women prone to psychosis, and the rate of custody loss in this group is high. The children of mothers suffering from schizophrenia have an increased genetic risk for schizophrenia themselves; they may, perhaps because of this, be more difficult to raise than the average child. Both subtle neurologic deficits and developmental delays have been observed in these children [56]. Ensuring that the needs of these very vulnerable children are met becomes an important aspect of the comprehensive treatment of psychosis in women.
Many of the harms associated with being the child of a mother who suffers from psychosis appear to be mediated not by the illness itself but by associated risks such as single parenting, poverty, substance abuse, domestic violence, social isolation and/or substandard housing [56]. Intervention programs need to cut across agency divisions and provide wraparound care for the child, mother and family [57].
Menopause
Nearly 30% of individuals affected by mental illness (mood disorder as well as schizophrenia) report that menopause worsens their symptoms [58]. There is evidence that menopause in some women is accompanied by a variety of physical and psychosocial symptoms and that illnesses such as schizophrenia may be aggravated at this time, probably as a result of estrogen withdrawal [58]. This can be anticipated and prevented by the appropriate treatment.
How is psychosis treated?
Psychosis is treated primarily with antipsychotic medication, which acts by blocking dopamine 2 receptors on postsynaptic neurons. There are many antipsychotic drugs, all more or less equally effective, but with somewhat different side effects and requiring administration at different doses in order to assure efficacy. In order for antipsychotic action to take place, 60–80% of receptors need to be occupied [59]. Adjunctive treatments for psychosis are: ensuring safety, adequate sleep and adequate fluid intake and nutrition. Also important are emotional support, psychoeducation for the patient and family, family intervention, cognitive therapy, mobilization of support and ensuring quality of life (e.g., housing, income, medical treatment and occupation) [60]. Repetitive transcranial magnetic stimulation [61] or electroconvulsive therapy [62] may be appropriate for individual cases. An innovative and effective treatment of special importance to women is adjunctive estradiol or a selective estrogen receptor modulator [63,64].
Outcome of schizophrenia in men & women
During the first 10 years of illness, schizophrenia interrupts a woman's life less than it does a man's [65]. After their first episode, it is not uncommon to see women returning to work, dating, marrying and/or bearing children. This is rare for men. Women continue to maintain their friendships and their affiliations with family, and they usually adhere to their prescribed medication regimen. Men often do not. For all these reasons, being a woman is predictive of a superior outcome (especially with respect to rates of rehospitalization) up to 15 years after a first episode of schizophrenia [65]. After that time a woman's outcome advantage disappears. Later outcome for women and men, along most dimensions, becomes roughly similar [65].
Male/female differences in response to antipsychotic drugs
Women require lower doses of antipsychotic medication than men do to achieve symptom response [66], but they bear a higher side-effect burden. Men and women are differentially susceptible to side effects of antipsychotics, not only in terms of the incidence of specific side effects [67], but also in their differential ability to tolerate specific adverse outcomes [68]. For instance, the appearance and outward attractiveness of both men and women may suffer after long exposure to antipsychotic drugs (e.g., weight gain, greasy skin, acne, loss of hair, shuffling gait, tremor, loss of teeth, dyskinesias) but appearance is generally more important to women than to men [69]. Antipsychotic drugs sedate both men and women and this negatively affects scholastic ability as well as driving skills; women are further affected if they are mothers because of their special need to be alert to their babies' needs [70].
Women's vulnerability to adverse effects is due to sex-specific pharmacokinetics, which deliver higher concentrations of free drug to target sites, the enhancement of dopamine blockade by estrogen hormones, longer storage of antipsychotics because of the greater proportion of adipose tissue in women's bodies, higher prevalence of immune reactions in women, and higher risk of drug–drug interactions because of women's greater likelihood of suffering from and being treated for comorbid illnesses [71].
Prolongation of the QTc interval is an important risk for women, especially older women [72]. Hyperprolactinemia is a special problem for women, with subsequent amenorrhea, gynecomastia, galactorrhea and a potential heightened risk of osteoporosis and breast cancer [73]. Antipsychotic drugs induce several conditions of relevance to breast cancer: obesity, elevated prolactin levels and hyperglycemia. Women with schizophrenia as a group have relatively low parity, participate infrequently in mammography screening, are relatively less likely than other mothers to breast feed, show higher levels of social disadvantage, higher levels of smoking and alcohol consumption, and lower activity levels than other women [74]. Antipsychotic drugs, therefore, theoretically increase the risk of breast cancer in an already vulnerable population [74].
Services
Women have gender-based needs that require attention when planning mental health services [75,76]. Besides direct illness-related therapeutic services, both men and women suffering from psychosis require attention to income, housing, schooling, occupation, employment, crisis services, psychoeducation, family issues, general health, dual disorder and life skills training. The objective of all interventions is to integrate patients into their communities and to increase their autonomy [77]. In addition to this, women need services that address their safety, their reproductive integrity and the demands of childcare.
Women with schizophrenia are at significantly increased risk of violent victimization both inside and outside the home [78]. Many women with schizophrenia report experiences of domestic violence [79] and the lifetime prevalence of rape is said to be approximately 25% [80]. Certain women with severe mental illness, such as those who are homeless or those who are imprisoned, are at disproportionate risk for victimization [81]. The recommendation in the recent literature is that services for psychosis should be well informed about this important issue and be capable of ensuring the safety of their clients.
Reproductive needs demand special consideration and are at the forefront of mental health prevention in that addressing them lowers the risk of mental illness in offspring [82]. Mother–infant units in hospitals are examples of services designed with the needs of women in mind [83]. As more women with schizophrenia have children, there is an increasing need for services geared to mentally ill parents [84]. Parents with severe mental illness are usually women, many of whom are ill prepared for motherhood and require active and continuing support in their parental role.
Both genders require services where there is pharmacologic expertise that recognizes the effects of gender and gender–age interactions on the metabolism, tolerability and effectiveness of prescribed medications. Gender-sensitive services are a first step toward individual-specific personalized care.
Conclusion
The different ways in which men and women express psychosis are probably due to a variety of causes – sex steroids, sexually dimorphic genes and gender-specific exposure to environmental events. Genes, hormones and the environment interact to produce different end results. Now that researchers are examining male and female results separately and heeding the voices of women suffering from psychosis, important gender differences have been recognized. The next step is to provide effective treatment that takes gender into account.
Future perspective
Ten years from now it will be everyday knowledge that the physiology of males and females differs, and that men and women experience the same disease differently and often require different therapies. Treatment guidelines for psychosis will differentiate between the two sexes with respect to doses of medications, types of medications, staging of interventions and array of treatments offered. Pace of development and of aging and how these affect the male and the female brain will further individualize treatment and make it both safe and effective.
Executive summary
There is as yet no biological diagnostic marker for psychosis, which can be triggered by a variety of brain insults.
Many triggers to psychosis are sex-specific.
There are many examples of precipitants for schizophrenia differing in men and women.
Onset age for men is 4–6 years earlier than for women; when schizophrenia runs in the family, onset age for men and women is similar.
Earlier onset age is associated with flat affect and cognitive difficulties.
Approximately 20% of women are first diagnosed in their forties.
Prior to full-blown psychosis, young men show more negative symptoms, lower social functioning and lower levels of social support than young women.
Men generally have a longer duration of untreated psychosis than women but this may vary with culture.
The incidence of schizophrenia is higher in males: 1.4:1. The prevalence is equal.
Comorbid substance abuse is more prevalent in men.
Women are more likely to be employed, retain a social support system, marry and bear children.
Quality of life is superior in women until they are in their late thirties, after which time it is similar to that of men.
Sex differences in schizophrenia are independent of culture.
Mortality risk is two-to-three times higher than that of the general population.
Individuals with schizophrenia are 13-times more vulnerable to suicide than those in the general population.
Men with schizophrenia commit suicide more than women, but the rate is higher in women with schizophrenia relative to women without schizophrenia.
Women with schizophrenia rarely use effective contraception.
Treatment during pregnancy is a challenge with respect to medication; psychosis is exacerbated during the postpartum period.
Mothers with schizophrenia require intensive ongoing support.
Menopause exacerbates symptoms.
Outcome is initially better for women but evens out after menopause.
Women require lower doses of antipsychotic medication than men but have more side effects.
Women need services that address safety, reproduction and childcare.
Footnotes
Acknowledgements
The author acknowledges with gratitude the contributions to science made by the members of the Women's Clinic for Psychosis, Centre for Addiction and Mental Health, Toronto, ON, Canada.
The author is a medical director of Clera, a pharmaceutical start-up company. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.