I’m not very good at précis but will do my best by cutting and pasting what I think are relevant bits apart from the obvious hormonal/reproductive ones .
Our group found that, on retrospective interview, the first sign of behavioral disturbance eventually leading to a diagnosis of schizophrenia occurred at approximately the same age in women and men, but that the pre-psychotic prodrome was almost twice as long for women[58]. The duration of untreated psychosis did not differ between the two sexes, but the interval between first behavioral sign and first treatment did - the lag was six years for men and nine years for women[58]. The corollary to this finding is that factors other than early diagnosis must determine prognosis because women’s outcome relative to men’s, despite a longer untreated interval, is generally superior, at least over the reproductive years[59,60]. Potential factors that favor women, besides estrogen levels, are premorbid functioning generally superior to that of premorbid men, more friendships, closer family relations, greater academic success, and a relative absence of substance abuse[61-63].
. Nevertheless, it is my clinical experience that women’s diagnoses frequently changes from depression to posttraumatic stress syndrome to eating disorder to schizophrenia to bipolar disorder (not necessarily in that order). This may be because it is more difficult to apply textbook schizophrenia criteria to women than to men. Women do not always exhibit the characteristic symptoms; they show few “negative” symptoms, few cognitive symptoms, and they rarely show flattened affect[64-66]. Prior to being diagnosed with a schizophrenia-related disorder, women with psychosis are often considered to be suffering from a mood disorder whereas, in men, a first tentative diagnosis is frequently alcohol or drug-induced psychosis[67]. Differential diagnoses sometimes missed in women include thyroid disease, autoimmune disorder, corticosteroid treatment, and anorexia-related starvation. All these conditions are much more prevalent in women than in men[68,69] and need to be ruled out before a diagnosis of schizophrenia is made.
In women of reproductive age, effective drug doses can usually be lower than doses recommended for men[71-75]. Women’s ability to respond at lower doses has been attributed to the effects of female hormones on the absorption and metabolism of AP drugs and also to women’s relatively increased blood flow to the brain, carrying with it more drug to cell receptor targets[76]. The presence of estrogen at the dopamine receptor site helps to slow the transmission of dopamine[77], an excess of which is thought responsible for psychotic symptoms.
In addition, because AP drugs are lipophilic and women’s reserves of adipose tissue are on average larger than men’s, women store these drugs in their bodies for comparatively longer periods. This means that psychotic relapse after drug discontinuation is not as rapid in women[78-80]. It also means that, in theory, the intervals between women’s intramuscular depot AP injections can be longer than those in men, but the sex-specific spacing of AP depot drugs has not yet been researched.
Another reason why AP drug doses can generally be lower in women than in men is because many women take more concomitant drugs than men do, notably antidepressants, mood stabilizers, analgesics, and contraceptives or hormone replacements, all of which can interact with and influence the blood level of AP medication[78,81].
Unfortunately, AP medications have many side effects[114] and on average, women suffer more negative effects than men[115,116]. Women may be more vulnerable than men to adverse drug reactions because the doses recommended when a drug goes on the market are calculated on the basis of a 70 kg man.
There are well-known gender differences in drug reactions. In a recent study of over a thousand patients with psychosis, twice as many women as men described their side effect burden as severe. In this study[117], the effects that women complained of (more than men) included: Concentration difficulties, sedation, blurred vision, nausea, constipation, dizziness on rising, heart palpitations, pruritus, photosensitivity, increased pigmentation, weight change, galactorrhoea and headache.
Women have unique risk factors for some adverse effects of APs, such as Torsade de Pointes[118], which is a form of ventricular tachycardia that occurs in patients whose QT interval is relatively long. The QT interval is a measure of the time between the start of the Q wave and the end of the T wave on the electrocardiogram; it is the time it takes for the heart to come back to normal after depolarization, which, on average, is longer in postpubertal women than it is in men. For this reason, two-thirds of Torsade de Pointes occur in women[118]. That being said, more men with schizophrenia than women die of heart disease. Much remains unknown about gender differences in cardiovascular function and cardiac response to therapeutic drugs.
In our study of clinic members with longstanding schizophrenia, more women than men were working outside the home[134], probably because “women’s” jobs were more plentiful at the time in our region. Job availability always depends on time, place, and economic conditions. When homeless, or living in room and board homes or with parents, the housewife role is not readily available to women with schizophrenia. Many prefer self-employment opportunities[135] and appreciate assistance in the form of supported employment, individual placement, and job buddies. They welcome opportunities to learn, to volunteer and to be of help to others. Like men, women need creative channels to enable self-expression as they seek ways to be meaningfully occupied.
The population at large does not always appreciate the fact that those who suffer from schizophrenia, and this is especially true for women, are more often victims than perpetrators of violence[138]. Different studies have used different definitions of both violence and of victimization, making these terms difficult to quantify across studies. Within a one-year period, it has been estimated that between 11% and 52% of persons with serious mental illness (SMI) exhibit violence at a 2-8 higher rate than that found in the general population[139]. The same study found rates of victimization in persons with SMI to be between 20% and 42%, 23 times that of the general population. Perpetration of violence and victimization are risk factors for each other and often overlap in the same person. Interestingly, Desmarais et al[139] reported higher rates of perpetration of violence among women with SMI than among men. They speculate that this is due to the fact that violence in this population most often occurs in the context of close relatives, and women with SMI are more likely than men to be living with family; consequently, they have more opportunity to vent their rage at domestic targets such as husbands and parents.
Women with schizophrenia are too often victims of sexual exploitation, domestic abuse, and random violence[106-108]. Risk factors are age, place of residence, and degree of psychopathology, in addition to personality and behavioral factors[140]. The factors that contribute to the perpetration of violence have been described by the same research team as substance abuse, young age, homelessness, unemployment, low educational attainment, low socioeconomic status, membership in an ethnic minority, past hospitalization for psychosis, past conviction for violent crime, personality factors, and residence in disorganized neighborhoods[140]. These are risk factors for both women and men, but they occur more frequently in men.
,54]. These theoretical examples suggest that effective prevention of schizophrenia may, in the future, be possible in a sex-specific manner[55,56], though this is not the case presently.
EARLY ACCURATE DIAGNOSIS
It is well-established that delay in seeking treatment once psychotic symptoms have emerged is associated with impaired treatment response and a relatively poor prognosis[57]. Our group found that, on retrospective interview, the first sign of behavioral disturbance eventually leading to a diagnosis of schizophrenia occurred at approximately the same age in women and men, but that the pre-psychotic prodrome was almost twice as long for women[58]. The duration of untreated psychosis did not differ between the two sexes, but the interval between first behavioral sign and first treatment did - the lag was six years for men and nine years for women[58]. The corollary to this finding is that factors other than early diagnosis must determine prognosis because women’s outcome relative to men’s, despite a longer untreated interval, is generally superior, at least over the reproductive years[59,60]. Potential factors that favor women, besides estrogen levels, are premorbid functioning generally superior to that of premorbid men, more friendships, closer family relations, greater academic success, and a relative absence of substance abuse[61-63].
As important as the speed of diagnosis is its accuracy. Diagnosis leads, at least in theory, to disease-specific treatment, although this is not always true in psychiatry where illness categories often overlap and the same treatments are used for different diagnostic entities. Nevertheless, it is my clinical experience that women’s diagnoses frequently changes from depression to posttraumatic stress syndrome to eating disorder to schizophrenia to bipolar disorder (not necessarily in that order). This may be because it is more difficult to apply textbook schizophrenia criteria to women than to men. Women do not always exhibit the characteristic symptoms; they show few “negative” symptoms, few cognitive symptoms, and they rarely show flattened affect[64-66]. Prior to being diagnosed with a schizophrenia-related disorder, women with psychosis are often considered to be suffering from a mood disorder whereas, in men, a first tentative diagnosis is frequently alcohol or drug-induced psychosis[67]. Differential diagnoses sometimes missed in women include thyroid disease, autoimmune disorder, corticosteroid treatment, and anorexia-related starvation. All these conditions are much more prevalent in women than in men[68,69] and need to be ruled out before a diagnosis of schizophrenia is made.
COMPLEXITY OF THE MENTAL HEALTH SYSTEM
The mental health system in most countries is very complex and leaves individuals who experience mental distress not knowing whether to turn to physicians or social workers or psychologists or spiritual counselors. Family doctors may or may not recognize symptoms of early psychosis and, even when they do, may not know where to refer their patients. Waiting lists for the various mental health professionals are often long. Visits may or may not be covered by available insurance. Navigation services that help patients identify financial, linguistic, cultural, logistical and educational barriers to mental health care and provide guidance to access are badly needed by both women and men[70]. The routes to care differ in the two sexes, obstetricians and midwives sometimes serving as intermediaries for women, and guidance counselors and police more often paving care routes for men.
EFFECTIVE TREATMENT
Treatment is known to be most effective when it is individualized to meet the specific needs of the person being treated. Gender, age, family situation, place of residence, state of health, and personal preferences all play a part in determining optimal intervention. One example is the decision-making process around drug dosing. In women of reproductive age, effective drug doses can usually be lower than doses recommended for men[71-75]. Women’s ability to respond at lower doses has been attributed to the effects of female hormones on the absorption and metabolism of AP drugs and also to women’s relatively increased blood flow to the brain, carrying with it more drug to cell receptor targets[76]. The presence of estrogen at the dopamine receptor site helps to slow the transmission of dopamine[77], an excess of which is thought responsible for psychotic symptoms.
In addition, because AP drugs are lipophilic and women’s reserves of adipose tissue are on average larger than men’s, women store these drugs in their bodies for comparatively longer periods. This means that psychotic relapse after drug discontinuation is not as rapid in women[78-80]. It also means that, in theory, the intervals between women’s intramuscular depot AP injections can be longer than those in men, but the sex-specific spacing of AP depot drugs has not yet been researched.
Another reason why AP drug doses can generally be lower in women than in men is because many women take more concomitant drugs than men do, notably antidepressants, mood stabilizers, analgesics, and contraceptives or hormone replacements, all of which can interact with and influence the blood level of AP medication[78,81].
An important aspect of pharmacotherapy for women is that levels of female hormones change over the course of a monthly cycle and also over reproductive phases such as pregnancy, lactation, and menopause. This affects the dosage requirement of AP medication, i.e ., there will be a need for higher doses during low estrogen phases[47-50,82,83]. Adjunctive estrogen or selective estrogen receptor modulators can make treatment more effective and can reduce AP doses and, thus, help to prevent side effects. This applies to both sexes, but is especially applicable to women[84-90].
Besides pharmacotherapy, other aspects of schizophrenia treatment need to be differentiated according to the patient’s gender, e.g ., substance abuse treatment, cancer screening (breast, prostate, cervix)[91-96], interventions for sexual dysfunction[97-99], contraceptive prescribing[12], treatment of comorbidities (osteoporosis and cardiovascular care for instance[100,101]), safeguards against domestic abuse and victimization[102-108], screening for proclivity to violence[109], provision of parenting support and child custody issues[110-112].
DRUG SIDE EFFECTS
Effective treatment means the removal of symptoms and improvement of function; ideally, it also means freedom from adverse side effects. Side effects cause distress, stop patients from regularly taking the medicines they need, and often cause serious harm to health, perhaps even contributing to the high mortality rate among individuals with schizophrenia[113]. Unfortunately, AP medications have many side effects[114] and on average, women suffer more negative effects than men[115,116]. Women may be more vulnerable than men to adverse drug reactions because the doses recommended when a drug goes on the market are calculated on the basis of a 70 kg man.
There are well-known gender differences in drug reactions. In a recent study of over a thousand patients with psychosis, twice as many women as men described their side effect burden as severe. In this study[117], the effects that women complained of (more than men) included: Concentration difficulties, sedation, blurred vision, nausea, constipation, dizziness on rising, heart palpitations, pruritus, photosensitivity, increased pigmentation, weight change, galactorrhoea and headache.
Women have unique risk factors for some adverse effects of APs, such as Torsade de Pointes[118], which is a form of ventricular tachycardia that occurs in patients whose QT interval is relatively long. The QT interval is a measure of the time between the start of the Q wave and the end of the T wave on the electrocardiogram; it is the time it takes for the heart to come back to normal after depolarization, which, on average, is longer in postpubertal women than it is in men. For this reason, two-thirds of Torsade de Pointes occur in women[118]. That being said, more men with schizophrenia than women die of heart disease. Much remains unknown about gender differences in cardiovascular function and cardiac response to therapeutic drugs.
The hypercoagulability state induced by APs raises the risk for venous thromboembolism, pulmonary embolism, and cerebrovascular accident. The use of oral contraceptives, as well as hormone replacement therapies, pregnancy, the immediate postpartum state, and obstetrical complications are all risk factors for these complications[119]. There are many such factors, however, including ethnicity[120]. Despite the many contributing factors, pregnant women on APs have been shown to be at significantly higher risk for venous thromboembolism than pregnant women in the general population[121,122].
With respect to the potential for AP to heighten the risk of breast cancer via weight gain and prolactinemia, the jury is still out[94] on this important concern. What is known, however, is that the cancer death rate of women with schizophrenia is high relative to women in the general population[95], although this cannot be attributed to AP drugs. Many side effects of APs, e.g ., weight gain, skin blemishes, and hair loss[123], negatively affect appearance (Table 1)[124]. Women are more sensitive to such effects than men are.
Table 1 Side effects of antipsychotics that negatively affect appearance[124].
APs also have negative reproductive effects. They can disrupt menstrual cycles[125], interfere with a woman’s ability to conceive[126], increase the risk for gestational diabetes[127], increase the risk of premature labor[127] and, by entering breast milk, can make breastfeeding a risk for infants of mothers with schizophrenia[128]. The secondary effect of hyperprolactinemia can lead to hirsutism, amenorrhea, galactorrhea, pseudocyesis[129], and osteoporosis[125].
In addition, older women may be more susceptible than older men to tardive dyskinesia (TD)[114]. It is known that TD prevalence is influenced not only by age and sex, but also by many confounding factors, such as individual genetics[130], the specific AP used, its dose, treatment duration, alcohol, tobacco, and marijuana usage, ethnicity, the precise definition of TD, the rating scale used to assess TD, the predominant symptoms (positive or negative) and the presence or absence of prior brain damage. Because estrogen modulates dopamine-mediated behaviors and protects against oxidative stress-induced cell damage caused by long-term exposure to AP medication, one hypothesis is that when all the confounding factors are controlled, TD prevalence is equal in women and men prior to menopause and becomes subsequently higher in women[131].
Because of sex differences in immunity, women are also more susceptible to the agranulocytosis inducible by clozapine[132]. In general, older individuals, men as well as women, are at relatively increased risk of adverse effects of all drugs[133].
VOCATIONAL AND AVOCATIONAL OPPORTUNITIES
Women with schizophrenia want meaning in their lives, as do men. Meaning comes in several forms: hope in the future, the belief that one is needed, interest in what one is doing, earning money, engaging in artistic endeavors, pursuing a goal. In our study of clinic members with longstanding schizophrenia, more women than men were working outside the home[134], probably because “women’s” jobs were more plentiful at the time in our region. Job availability always depends on time, place, and economic conditions. When homeless, or living in room and board homes or with parents, the housewife role is not readily available to women with schizophrenia. Many prefer self-employment opportunities[135] and appreciate assistance in the form of supported employment, individual placement, and job buddies. They welcome opportunities to learn, to volunteer and to be of help to others. Like men, women need creative channels to enable self-expression as they seek ways to be meaningfully occupied[136].
FREEDOM FROM STIGMA
Stigma (being devalued and discriminated against, with consequent loss of self-respect) is a significant problem in schizophrenia[137]. The diagnostic label of schizophrenia is itself frightening to many people, conjuring up fears of dangerousness, unprovoked and uncontrollable violence, irrationality, and incurability. The population at large does not always appreciate the fact that those who suffer from schizophrenia, and this is especially true for women, are more often victims than perpetrators of violence[138]. Different studies have used different definitions of both violence and of victimization, making these terms difficult to quantify across studies. Within a one-year period, it has been estimated that between 11% and 52% of persons with serious mental illness (SMI) exhibit violence at a 2-8 higher rate than that found in the general population[139]. The same study found rates of victimization in persons with SMI to be between 20% and 42%, 23 times that of the general population. Perpetration of violence and victimization are risk factors for each other and often overlap in the same person. Interestingly, Desmarais et al[139] reported higher rates of perpetration of violence among women with SMI than among men. They speculate that this is due to the fact that violence in this population most often occurs in the context of close relatives, and women with SMI are more likely than men to be living with family; consequently, they have more opportunity to vent their rage at domestic targets such as husbands and parents.
Women with schizophrenia are too often victims of sexual exploitation, domestic abuse, and random violence[106-108]. Risk factors are age, place of residence, and degree of psychopathology, in addition to personality and behavioral factors[140]. The factors that contribute to the perpetration of violence have been described by the same research team as substance abuse, young age, homelessness, unemployment, low educational attainment, low socioeconomic status, membership in an ethnic minority, past hospitalization for psychosis, past conviction for violent crime, personality factors, and residence in disorganized neighborhoods[140]. These are risk factors for both women and men, but they occur more frequently in men.
In general, schizophrenia is a heavily stigmatized illness, men perhaps suffering more than women because of the perception that they are prone to act out violently and indiscriminately. Women, however, suffer from a specific form of stigma - the frequent conviction of health workers that individuals with schizophrenia should not bear children, and, in the event of pregnancy, should seek abortion. Women with this illness are widely considered incapable of being good mothers, making prenatal care more problematic, as women fear disclosing that they are pregnant, afraid that their infants will be apprehended at birth[141,142]. Healthcare professionals may not be aware of their own discriminatory attitudes, often communicated inadvertently by words and gestures[143]. Finding effective ways of combating biased attitudes both in oneself and in others is a critical issue for all care providers treating patients with stigmatized illnesses.
RELIEF FROM THOUGHTS OF SELF-HARM AND SUICIDE
In the context of schizophrenia, triggers for male suicidal activity (ideation, attempts, and completed suicide) have been described as being: (1) psychotic symptoms and (2) the prospect of chronic disability, while triggers for suicidal activity in women have been mainly attributed to depression. Male suicides in this population decline with age, whereas this is not the case for women. In a longitudinal study, a 10.5% rate of suicide in the first two years after hospital discharge in men dropped to 0% twenty years later, while women’s rate of suicide (6%) was spread more evenly over the twenty years[144].