10.2 Etiology and Neurobiology of Schizophrenia

Schizophrenia's complex origins involve both genetic and environmental factors. Genes play a significant role, with heritability estimates of 60-80%. Environmental risks include prenatal complications, urban living, and cannabis use. These factors interact, shaping brain development and influencing schizophrenia risk.

Brain abnormalities in schizophrenia support the neurodevelopmental hypothesis. Structural changes like enlarged ventricles and reduced gray matter are present before symptoms appear. Functional abnormalities include altered activation patterns during cognitive tasks and abnormal connectivity between brain regions.

Genetic and Environmental Risk Factors

Risk factors for schizophrenia

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• Genetic factors
  • Heritability estimates range from 60-80% suggests a strong genetic component in the development of schizophrenia
  • Higher concordance rates in monozygotic twins (identical) compared to dizygotic twins (fraternal) indicates a greater role of shared genetic material in the risk of developing schizophrenia
  • Increased risk for first-degree relatives (parents, siblings, children) of individuals with schizophrenia compared to the general population
  • Multiple genes with small effects contribute to the risk of developing schizophrenia rather than a single gene with a large effect (polygenic inheritance)
• Environmental factors
  • Prenatal and perinatal complications
    • Maternal infections during pregnancy (influenza, rubella, toxoplasmosis) may increase the risk of schizophrenia in the offspring
    • Maternal malnutrition during pregnancy can affect fetal brain development and increase the risk of schizophrenia
    • Obstetric complications (hypoxia, low birth weight, prematurity) during delivery may lead to abnormal brain development and increased risk of schizophrenia
  • Urban living and social adversity such as poverty, social isolation, and discrimination may contribute to the development of schizophrenia
  • Cannabis use, particularly during adolescence when the brain is still developing, can increase the risk of developing schizophrenia
  • Childhood trauma and abuse (physical, sexual, emotional) may alter brain development and increase the risk of schizophrenia later in life
• Gene-environment interactions
  • Certain genetic variations may increase susceptibility to environmental risk factors, leading to a higher risk of developing schizophrenia when exposed to adverse environmental conditions
  • Environmental factors may modulate gene expression through epigenetic mechanisms (DNA methylation, histone modifications) without changing the underlying genetic code, influencing the development of schizophrenia

Neurodevelopmental Hypothesis and Brain Abnormalities

Neurodevelopmental hypothesis of schizophrenia

• Neurodevelopmental hypothesis proposes that schizophrenia is a result of abnormal brain development rather than a degenerative process
  • Disruptions in early brain development (prenatal, perinatal, childhood) lead to the emergence of symptoms later in life, typically during late adolescence or early adulthood
• Supporting evidence for the neurodevelopmental hypothesis
  • Presence of minor physical anomalies (abnormal facial features, dermatoglyphics) and neurological soft signs (subtle neurological abnormalities) in individuals with schizophrenia suggests early developmental disruptions
  • Delayed developmental milestones (motor, language, social) and cognitive deficits in childhood are more common in individuals who later develop schizophrenia
  • Increased prevalence of obstetric complications (low birth weight, preterm birth, hypoxia) in individuals who later develop schizophrenia suggests prenatal and perinatal risk factors
  • Structural brain abnormalities (enlarged ventricles, reduced gray matter volume) are present before the onset of symptoms, indicating abnormal brain development rather than a result of the disorder

Brain abnormalities in schizophrenia

• Structural brain abnormalities observed in individuals with schizophrenia
  • Enlarged lateral ventricles, particularly in the third and fourth ventricles, suggest a reduction in the surrounding brain tissue
  • Reduced volume of the hippocampus, amygdala, and superior temporal gyrus, which are involved in memory, emotion processing, and language, respectively
  • Decreased cortical thickness, particularly in the prefrontal and temporal regions, which are associated with cognitive functions and auditory processing
• Functional brain abnormalities observed in individuals with schizophrenia
  • Altered activation patterns during cognitive tasks
    • Reduced activation in the prefrontal cortex during working memory tasks (n-back, Wisconsin Card Sorting Test) suggests impaired executive functioning
    • Increased activation in the superior temporal gyrus during auditory hallucinations indicates abnormal processing of internal auditory stimuli
  • Abnormal functional connectivity between brain regions
    • Decreased connectivity between the prefrontal cortex and other brain areas (temporal lobe, striatum) may underlie cognitive deficits and disorganized thoughts
    • Increased connectivity within the default mode network (medial prefrontal cortex, posterior cingulate cortex) may be associated with internal preoccupation and difficulty distinguishing between internal and external stimuli

Neurotransmitter Systems in Schizophrenia

Neurotransmitters in schizophrenia pathophysiology

• Dopamine hypothesis of schizophrenia
  • Hyperactivity of dopamine in the mesolimbic pathway (ventral tegmental area to nucleus accumbens)
    • Associated with positive symptoms (hallucinations, delusions) due to excessive dopamine signaling in the limbic system
  • Hypoactivity of dopamine in the mesocortical pathway (ventral tegmental area to prefrontal cortex)
    • Associated with negative symptoms (anhedonia, avolition) and cognitive deficits due to insufficient dopamine signaling in the prefrontal cortex
  • Antipsychotic medications primarily target dopamine D2 receptors to reduce dopamine signaling and alleviate positive symptoms
• Glutamate hypothesis of schizophrenia
  • Hypofunction of the N-methyl-D-aspartate (NMDA) receptor, a type of glutamate receptor
    • May lead to excessive dopamine release in the mesolimbic pathway, contributing to positive symptoms
    • Associated with cognitive deficits and negative symptoms due to insufficient glutamatergic signaling in the prefrontal cortex
  • NMDA receptor antagonists (ketamine, phencyclidine) can induce schizophrenia-like symptoms (hallucinations, delusions, cognitive deficits) in healthy individuals, supporting the role of glutamate in schizophrenia
• Interaction between dopamine and glutamate systems in schizophrenia
  • Glutamatergic dysfunction may lead to dopaminergic abnormalities by altering the balance between excitatory and inhibitory neurotransmission
  • Dopaminergic modulation of glutamatergic neurotransmission in the prefrontal cortex may contribute to cognitive deficits and negative symptoms in schizophrenia