Gender Issues In Schizophrenia Dr. Ahmed Shoka Consultant Psychiatrist
Introduction • Gender issues have long been of interest to both schizophrenia researchers and clinicians given the differences in the neurobiology, epidemiology, treatment responses and social context of the illness in women and men. • Antipsychotic prescription guidelines do not differ between male and female patients,yet human studies have shown that the pharmaco- dynamics of drugs differ between the two sexes
Introduction • Women bodies,on average ,contain 25% more adipose tissue than those of men and most antipsychotics are lipophilic • Are optimal maintenance regimens of antipsychotics the same for women and men? • To minimise the resulting side effects,should there be longer intervals between doses in women than men?
Some Gender Differences • Rates of side effects to most drugs are reported to be higher in women than men. • Women undergo menstrual cycles, and many take contraceptive pills .What is known about interactions between hormones and antipsychotics?. Should dose regimens in women be altered during menstrual cycle, pregnancy, postpartum period and the menopause.
Another Important Factor • Women in treatment for schizophrenia,more so than men,take a variety of adjunct drugs in addition to antipsychotics. In other words,there are more opportunities for drug interaction, culminating in the possibility of lowered or raised antipsychotic serum levels. • Antipsychotics are frequently prescribed for untoward behaviour(e.g.,aggression), reported higher prescribed doses in men may be due to this and not to response factors.
Sex Differences That Affect Drug Response In Schizophrenia • Diagnosis is delayed in women • Deficit symptoms are more prevalent in men • Therapeutic alliance is stronger in women • Men smoke more and use more substances of abuse • Women have more comorbid problems (mood problems,sleep disturbances,pain conditions, allergies.endocrine disturbances,eating disorders).They require more concomitant medications.
Making The diagnosis in Women and Men • Diagnosis of schizophrenia is usually made between ages of 15 and 25.During those 10 years, schizophrenia is diagnosed in 12 men to every 10 women.This may be because the onset of schizophrenia is delayed in women. • Greater exposure to birth injuries in males. • Neuroprotective effect of female hormones. • Less laterlisation of the female brain. • Greater exposure of males to head trauma.
OR It may be that men come to medical attention earlier than women because of the nature of their behaviour when they are psychotic.
OR It may be that women with schizophrenia are initially misdiagnosed.
OR A schizophrenic illness initially diagnosed as depression or a bipolar disorder (i.e.,in women) means that antidepressants and mood stabilisers have preceded treatment with antipsychotics. Such prior treatment can”prime”neural networks and result in an unanticipated response later
Course Of Schizophrenia in Women And Men • Women experience less severe symptoms, fewer hospitalistions, shorter admissions, more post-hospitalisation employment, less trouble with the law and more intimate relationship than men. • Response to antipsychotic drug treatment is more robust in women than men. • Schizophrenia mortality from unnatural factors ( suicide, accident, homicide) is significantly higher in men than in women.
Schizophrenia In Men Symptoms appear years before they do in women (ages 15-20 compared to ages 20-25 for women). Men have more subtle neurological abnormalities. They have more deficit symptoms such as the lack of will and directed energy. They have difficulty planning, completing things or making decisions.
Why Schizophrenia Hits Men Harder? • Recent imaging studies in a Johns Hopkins lab suggest that the way schizophrenia shapes the brains of men and women may underline these gender differences. • Godfrey Pearlson focused on a part of the cerebral cortex called the inferior parietal lobule (IPL). • IPL is a sort of neural crossroads where pathways from many different brain structures converge. Each brain hemisphere contains an IPL.
To Follow…… • Left IPL is involved in visual perception and spatial relationships. • Right IPL governs person’s understanding of where each body part is in relation to another. • Men have a larger IPL than women and their left IPL is larger than their right in contrast to women. • Schizophrenic men have a reversed asymmetry in the IPL, compared to healthy men.
To Follow…… • The overall size of the IPL of schizophrenic men is 16 % smaller than in healthy men. • Women with schizophrenia do not show significant difference in IPL size. • There is probably something in the whole circuit of which the IPL is the part that gets miswired in schizophrenia.
Antipsychotic Treatment Response And Serum Levels In Men And Women • Genetics, age,height,weigh,lean-fat ratio, diet, exercise, cocurrent disease, smoking and alcohol ,and the administration of cocomitant drugs all contribute to antipsychotic drug response as does end-organ sensitivity. • Men and women show differences in all these variables , either as a result of the action of sex-specific hormones or of divergent gender roles. • Women have higher antipsychotic plasma levels than men after receiving the same dose of drug
The Oestrogen Factor • Oestrogen’s effects are often cited as a possible biological modulator influencing the time of onset, course, and response to treatment in women with schizophrenia. • The decline in oestrogen levels that occurs at menopause has been suggested as a factor contributing to late-onset schizophrenia in women and higher neuroleptic doses in psychotic women in their forties than in younger women.
Menstrual Cycle • It has been postulated that hormonal fluctuations within phases of the menstrual cycle may influence pharmacokinetics and pharmaco-dynamics of drugs.Menstrual cycle changes do occur in renal,cardiovascular,haematological and immune sysytems and could also theoretically affect protein binding and the volume of distribution of a particular compound. • Disrupted menstrual cycles and amenorrhoea associated with schizophrenia are noted before the introduction of neuroleptics.
Menstrual Cycle • As antipsychotic drugs can also cause abnormal menses and amenorrhoea, it is sometimes unclear whether the disturbance is due to the disease ,the drugs, or both. • It is possible that women with schizophrenia , given their brain disease, will be especially vulnerable to drug-induced dysregulation of their hypothalamic-pituitary-ovarian axis. • All traditional antipsychotic drugs via their prolactin-elevating properties may induce reproductive and sexual side effects.
Fertility and Schizophrenia • The fertility of men and women with schizophrenia has been found to be reduced compared to their unaffected siblings with males showing greater reduction in reproductive fitness than females. • Causes include: illness itself, drugs used to treat it, societal factors such as institutionalisation and stigmatisation of people with severe mental illness.
The Evidence In a prospective drug-naïve population, antipsychotic response was shown to be superior in women and in chronically ill population,men were found to require twice as high a dose as women for effective maintenance. But studies comparing men and women are few.
The Evidence One study found no effect of menstrual cycle on cytochrome enzymes 2D6,3A or 1A2 suggesting that antipsychotic levels should be impervious to menstrual phase.
Drug Interactions • Women are more likely than men to be taking antidepressants,mood stabilisers,analgesics, and contraceptives or hormone replacements, and these agents can interact with antipsychotics especially those processed mainly by the CYP2D6 enzyme sybsystem. • Long-term administration of St.John’s wort resulted in a significant and selective induction of CYP3A activity in the intestinal wall-i.e., it potentially reduced the efficacy of ziprasidone and quetiapine.
Drug Interactions • SSRIs were significantly associated with 4-6 fold higher concentrations of risperidone. • Oral contraceptives inhibit the enzyme CYP1A2 • Ziprasidone,co-administered with ethinyl estradiol and levonorgestrel ,did not lead to a loss of contraceptive efficacy nor increase the risk of adverse events • Smoking induces CYP1A2, the main metabolising enzyme for olanzapine. This enzyme seems to be less active in women than men.
Volume Of Distribution • The volume of distribution of lipophilic drugs , such as antipsychotics, is greater in women than men; blood volume is smaller, but lipid compartments are larger.In women , the proportion of adipose tissue ranges from 33-48% in contrast with 18-36% in men, this prolongs the half-life of antipsychotics in the body,leading to accumulation over time, a phenomenon that becomes important when administering depot injections.After a steady state is achieved,dose intervals for women should be longer than for men
Treatment Side Effects • The incidence and severity of antipsychotic side effects are heavily dependent on a serum level. • Acute dystonia, long thought to be more prevalent among men, has been shown, in a first-episode,fixed-dose,10 week study;to occur at equivalent doses, more often in women. • TD still frequently cited as most common in elderly women, has been shown by a cohort study to be more risk factor for elderly men, although its severity may be relatively greater in women in their later years.
Treatment Side Effects • Antipsychotic side effects may hold different significance for men and women.On the whole , men are most disturbed by the effects that interfere with performance, especially sexual. • Women are more distressed by effects that detract from their appearance like obesity. • The results of several trials confirm that women are more susceptible to drug-induced hyperprolactiaemia than men.
Pregnancy And Schizophrenia • Denial of pregnancy is associated with a diagnosis of chronic schizophrenia. • Despite clinicians’ perception that women with schizophrenia improve during pregnancy, for many of these women pregnancy is a very stressful time with worsening of mental status especially in younger women with unwanted pregnancies. • A woman with delusions or psychotic denial is less likely to detect signs of labour and impending delivery.
Prescribing IN Pregnancy • Consider non drug options • Avoid drugs if possible during weeks 6-10 • Use antipsychotics about which most is known during pregnancy • Keep doses low before delivery • Increase dose postpartum • Have patient take medications just before infant’s longest sleep of the day • Consult with paediatrician
Concerns During Pregnancy • Altered pharmacokinetics across the 3 trimesters • Fear of teratogenesis • Need to safeguard the smooth progress of labour and delivery • Need to prevent withdrawal effects in the neonate • Concerns about subtle effects on the infant’s neurudevelopment
FDA Use-In-Pregnancy Ratings • Category A: Controlled studies show no risk to the foetus. • Category B: No evidence of risk in humans ; either animal findings show risk, but human findings do not. • Category C: Risk cannot be ruled out; human studies are lacking. Potential benefits outweigh risks. • Category D: Positive evidence of risk, data show risk to the foetus. Nevertheless, potential benefit may outweigh tisks. • Category X: Contraindicated in pregnancy; studies in humans or animals or postmarketing reports have shown foetal risk that clearly outweigh any possible benefit.
The Evidence • A recent study of over 2000 births to mothers diagnosed with schizophrenia found significantly increased risks for stillbirth, infant death, preterm delivery, low birth weight and small size for gestational age. • Another study of over 2000 children of women with schizophrenia found that these infants had an increased risk of postneonatal death largely explained by an increase in sudden infant death syndrome. • Olanzapine appears relatively safe.
Lactation • A drug that is safe for use during pregnancy may not be safe for the nursing infant. • Exposure to antipsychotics in breast milk markedly differs from exposure to antipsychotics by the foetus during pregnancy. • For any drug in breast milk, infants should be exposed to less than 10% of the dose per weight that would be prescribed to them directly. • The literature suggests that infant serum concentrations of antipsychotics are largely unpredictable.
Antipsychotics In Postpartum Period • Prolactin-sparing antipsychotic may be useful, e.g., olanzapine and quetiapine. • Clozapine use is restricted because of the haematological risk. • The risk of relapse of schizophrenia during this time is also significant like the mood disorders.
Conclusion • While schizophrenia is not a “woman’s disease”, women with schizophrenia may benefit from gender-focused management including strategies such as education and counseling about contraception and sexuality, support for parenting and integrated medical and psychiatric care specific to the stage of the reproductive cycle.
Conclusion • Sex differences in response to and side effects from medication and the modifying effects of hormones are evolving areas of study that may advance care for both men and women with schizophrenia. • The role of prolactin-sparing antipsychotics in treatment needs to be better understood.
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