Gender Issues In Schizophrenia

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Gender Issues In Schizophrenia

• Dr. Ahmed Shoka
• Consultant Psychiatrist

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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

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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?

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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.

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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.

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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.

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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.

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OR

• It may be that men come to medical attention
  earlier than women because of the nature of their
  behaviour when they are psychotic.

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OR

• It may be that women with schizophrenia are
  initially misdiagnosed.

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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 canprimeneural networks and
  result in an unanticipated response later

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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.

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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.

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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.

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To Follow

• Left IPL is involved in visual perception and
  spatial relationships.
• Right IPL governs persons 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.

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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.

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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

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The Oestrogen Factor

• Oestrogens 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.

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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.

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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.

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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.

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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.

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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.

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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.Johns 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.

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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.

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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

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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 studyto 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.

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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.

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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.

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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
  infants longest sleep of the day
• Consult with paediatrician

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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 infants
  neurudevelopment

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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.

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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.

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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.

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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.

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Conclusion

• While schizophrenia is not a womans 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.

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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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• Thank you

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