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PREVALENCE

TANDOC ET AL, 2024

�

Point-Prevalence ranges between 2 and 10/1000 population	++�There are pockets of low and high prevalence	+�Impacted, in part, by diagnostic & treatment variations

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SOMMER ET AL, 2020

Age at diagnosis of schizophrenia-spectrum disorder.

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MALES VS FEMALES

Sommer et al, 2020

7142 women and 9006 men with schizophrenia/schizo-affective disorder in Finland
Men were diagnosed earlier (mean 34.4 [SD12.6] vs. 38.2 [SD 13.8])

Fig. 1: Last diagnosis preceding first hospitalisation for schizophrenia-spectrum disorder.

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DR MARY SEEMAN 2004 WHY ARE MALES STATISTICALLY MORE LIKELY TO BE DIAGNOSED EARLIER�

The onset of schizophrenia may be delayed in women

greater vulnerability of the male brain because of slower maturation
greater exposure to birth injury in males
a neuroprotective effect of female hormones
less lateralization of the female brain
and 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
it may be that women with schizophrenia are initially misdiagnosed

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SEX DIFFERENCES – HORMONES AND BRAIN DIFFERENCES

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LODHA AND KARIA, 2019 HORMONE DIFFERENCES

The onset of schizophrenia in males, often during adolescence, is also characterized by an increase in testosterone levels.

However, males expressing prodromal symptoms have been found to show decreased testosterone levels than healthy males.

Females with schizophrenia tend to experience less severe psychotic symptoms during periods of high estrogen release such as during pregnancy.

And symptom exacerbation during times of low estrogen such as during postpartum and menopause

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SALEHI ET AL, 2024 PREFRONTAL CORTEX AND TESTOSTERONE (FMRI)

The prefrontal cortex, a brain region involved in memory and cognitive processes, is implicated in schizophrenia and other psychiatric disorders

The degeneration of neurons connecting the prefrontal cortex to the cerebellum

Primary factor influencing the severity of negative symptoms in patients with schizophrenia?

Increased brain activity of this region in females with schizophrenia who exhibited less severe negative symptoms compared to males with a similar duration of illness.

Compensatory mechanism in prefrontal cortex of women with schizophrenia= resilience against severe negative symptoms?

Theory

A relationship between sex steroid hormones and cerebral function

Testosterone levels being increased in female schizophrenia patients relative to same-sex controls,

Male patients with schizophrenia show decreased overall testosterone levels compared to healthy male controls,

A positive correlation between increase in sex steroid hormone levels and cerebral activation may help to explain the increased prefrontal activity in women with schizophrenia

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LODHA AND KARIA, 2019 HORMONE TREATMENT

Low testosterone therapy (or testosterone replacement therapy [TRT]) initial side effects: euphoric sensation, higher confidence, and energy
But reported to wear off within 2 weeks.
Side effects: irritability, aggression, impulsivity, criticism toward others, self-centeredness, depression, and personality changes.
Thus, TRT not a promising intervention and
Needs greater research to understand longitudinal ramifications and possibilities with the treatment.

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OESTROGEN TREATMENT FOR FEMALES WITH SCHIZOPHRENIA

8-week, three-arm, double-blind, randomised-controlled trial.
180 female participants were aged between 18 and 45, with schizophrenia and ongoing symptoms of psychosis Positive and Negative Syndrome Scale (PANSS) score > 60 despite a stable dose of antipsychotic medication.
Depressive symptoms were assessed using Montgomery Asberg Depression Scale (MADRS) with a mean score of 73.77 at baseline.
Participants received transdermal oestradiol 200 μg or transdermal oestradiol 100 μg or an identical placebo patch.
Overall trend towards improvement of comorbid depressive symptoms in women with schizophrenia taking transdermal oestrogen 200 mcg compared with oestrogen 100 mcg or placebo.
The stronger ‘antidepressant’ effect of 200 mcg transdermal oestradiol was found at day 28 (p = 0.03).
Suggesting that adjunctive oestradiol treatment for depression may be a promising treatment for women with comorbid depression and schizophrenia. (Lascurain, 2019)

PANSS score of > 60 = moderately ill +

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ANDROCENTRISM IN RESEARCH AND TREATMENT

Treatment of women with psychosis is less evidence-based than that it is for men

Women are under-represented in clinical research trials (Professor Iris Sommer, University Medical Center Groningen, Groningen, Netherlands, 2022)

Differences in body composition and hormones can affect drug absorption, distribution, and metabolism

Women are likely to be overmedicated by default, Brand et al, 2021

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THE NEED FOR AN IDIOGRAPHIC APPROACH

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RESPONSES TO MEDICATION

Women tend to respond better to antipsychotic medication

Does it work better?
Are they more adherent to the medication regime?
Do they have better social support networks?
Is it hormonal differences?
Less heavy smoking than men? Or genotype dependent - lower plasma concentrate of antipsychotic with a non-2D6*10 homozygous genotype in smokers (Seeman, 2004)

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EFFECTS OF ANTIPSYCHOTICS ON WOMEN (BRAND ET AL, 2021)

Slower drug absorption, metabolism and excretion in women all lead to higher plasma levels

= increase risk of side effects

Women reach higher dopamine receptor occupancy compared to men at similar serum levels, since oestrogens increase dopamine sensitivity.

Current treatment guidelines are based on studies predominantly conducted in men

= women are likely to be overmedicated by default.

The risk of overmedicating generally increases when sex hormone levels are high (e.g. during ovulation and gestation
Higher doses may be required during low-hormonal phases (e.g. during menstruation and menopause)

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PATHOLOGY AND PATHOPHYSIOLOGY�TANDOC ET AL, 2024

Total brain volume is reduced with enlarged lateral and third ventricles	��+++�Present at illness onset, but may progress in subgroups	��++�To a milder degree, observed in unaffected family members	��+�Also observed in some individuals with other psychiatric disorders

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PLEIOTROPIC GENES - STAUFFER ET AL, 2023�

Human brain structure is heritable
Recent genome-wide association studies (GWAS) have confirmed
that human brain structure is heritable
typically measured by magnetic resonance imaging (MRI),
Large scale cohorts with both genetic and MRI data available
Is brain structural variation in the population is associated with genes that are also significantly associated with schizophrenia and other neuropsychiatric disorders?
Pleiotropic genes – structural brain changes + genetic inheritance of schizophrenia
However, no amount of evidence for pleiotropic association can resolve the causal relationship between the two genetically coupled phenotypes: do brain phenotypes cause schizophrenia or vice versa?

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PLEOTROPIC GENES FINDINGS

Significantly greater than expected intersection or overlap between the gene sets associated with regional brain phenotypes and the gene set associated with schizophrenia.
Approx 9% of the 586 genes significantly associated with schizophrenia were also significantly associated with normative variation in surface area of one or more cortical regions.

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EVIDENCE

Evidence for significant pleiotropic association with both schizophrenia and all three MRI metrics at all (Surface area, Cortical thickness) or almost all (Neurite Density Index) cortical areas, indicating that genetic risks for schizophrenia are also associated with widespread variations in regional Cortical anatomy.

NB: Neurite density index allow a quantifiable measurement of the packing density of axons or dendrites using MRI

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PARALIMBIC AREAS

genetic covariation with surface area was greatest in paralimbic areas of cortex previously been associated with polygenic risk for schizophrenia

NB: Polygenic – the risk of a specific condition based on the collective influence of many genetic variants

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THEORY

Neurodevelopmentally-enriched genes associated with schizophrenia also have an important role in development of anatomical inter-connectivity between cortical areas
Genetic variants associated with schizophrenia may cause atypical development of brain network hubs
Resulting in consequences for “higher order” cognitive processes that are often impaired in schizophrenia