Study Notes on Schizophrenia Etiology and Neuroanatomy

Epigenetics and Schizophrenia

  • Researchers are exploring epigenetic factors affecting gene expression (Cromby, Chung, Papadopoulos, & Talbot, 2016).

    • Environmental conditions chemically modify DNA, influencing gene activity and consequently the development of cells, tissues, and organs.

    • MZ twins discordant for schizophrenia (one twin has it; the other does not) display differences in the molecular structure of their DNA.

      • Differences notably occur in genes that regulate dopamine systems (Petronis et al., 2003).

      • MZ twins concordant for schizophrenia exhibit fewer molecular DNA differences.

    • Potential causes for these epigenetic differences may involve stress (Howes, McCutcheon, Owen, & Murray, 2017).

    • Environmental factors impacting fetal development may elevate schizophrenia risk (Diwadkar, Bustamante, Rai, & Uddin, 2014).

Heritability of Schizophrenia

  • High heritability estimates from classical twin studies favor molecular genetics studies of schizophrenia.

    • The classical twin method depends on the equal environment assumption (EEA).

      • The assumption suggests identical and fraternal twins experience similar environments when raised together.

    • Evidence indicates identical twins share more similar childhood experiences critical to psychosis development, such as:

      • Bullying

      • Sexual abuse

      • Physical maltreatment

      • Emotional neglect and abuse

      • General trauma

    • Challenges the assumption that these similarities can be explained exclusively by gene-environment interactions.

    • Adoption studies exhibit methodological flaws and provide misleading evidence of genetic effects.

  • Molecular genetics studies yield minor findings that, with environmental data, support a stress-based sociopsychobiological model of schizophrenia etiology (Fosse Joseph & Jones, 2016).

Brain Abnormalities in Schizophrenia

  • Clinical and research observations indicate substantial neurological differences in individuals with schizophrenia.

    • Advances in brain imaging technology (PET, CAT, MRI) reveal deficits in brain structure and function.

      • Most theorists view schizophrenia as a neurodevelopmental disorder resulting from factors affecting brain development during pregnancy and early life.

    • A consistent finding is a significant reduction in gray matter specifically in:

      • Medial temporal

      • Superior temporal

      • Prefrontal cortex

    • Individuals at risk for schizophrenia due to familial history display abnormal prefrontal cortex activity (Lawrie, McIntosh, Hall, Owens, & Johnstone, 2008).

      • The prefrontal cortex is essential for language, emotional expression, planning, and action execution, linking all cortical regions and limbic system involved in emotion/cognition and basal ganglia for motor control.

    • Individuals with minimal or inactive prefrontal cortex frequently show cognitive, emotional, and social deficits typical in schizophrenia.

Genetic Risk and Familial Patterns

  • As genetic similarity with a person with schizophrenia decreases, the risk to develop schizophrenia also decreases:

    • First-degree relatives (50% genetic share) have approximately a 10% risk.

    • Second-degree relatives (25% genetic share) have around a 3% risk.

    • General population risk is less than 1%.

    • First-degree relatives with schizophrenia show a sixfold higher prevalence compared to the general population (Chou et al., 2017).

    • Second-degree relatives show a 2.4% increased risk of developing schizophrenia.

  • Genetic risks for schizophrenia are complex and multifaceted:

    • Risk estimates:

      • 27% for children of two affected parents.

      • 50% for monozygotic (MZ) twins with one affected sibling.

      • Adopted children with a biological parent with schizophrenia have a 6 to 10 times higher risk than the general population (Tifu et al., 2020).

  • Genetic susceptibility does not equate to inevitability:

    • 87% of children with one parent diagnosed with schizophrenia do not develop the disorder.

    • Family history elevates the risk of not only schizophrenia but also related conditions such as mood and delusional disorders.

    • Offspring of parents with severe mental illnesses (SMI) may develop various psychiatric disorders by early adulthood.

    • Family members of individuals with schizophrenia have increased bipolar disorder risk indicating shared genetic factors (Lichtenstein et al., 2009).

    • Studies in Sweden reveal that children of parents with schizophrenia are five times more likely to develop bipolar disorder.

Adoption Studies and Heritability

  • Adoptive situations complicate the understanding of schizophrenia heritability.

    • Children of parents with schizophrenia might be exposed to stressful home environments affecting their financial and psychological wellbeing, not solely genetics.

    • Kety et al. (1994) revealed that biological relatives of adoptees with schizophrenia were ten times more likely to have the disorder compared to biological relatives of non-psychotic adoptees.

    • Tienari studies (2003; Tienari et al., 2006) showed that about 10% of children from mothers with schizophrenia developed schizophrenia or other psychotic disorders compared to only 1% in children whose mothers did not have schizophrenia.

Evaluating Twin Studies

  • Heritability estimates from twin studies are often higher than data from the general population, typically ranging from 41% to 87%.

  • Meta-analysis of twelve European and North American studies indicates heritability could be as high as 81% with evidence of shared environmental influences.

    • Swedish studies yield a heritability estimate of 64.3%.

    • Taiwanese studies present an even lower estimate of 47.3%.

  • The differences in estimates reflect variations in research methods (Chou et al., 2017).

  • Comparative concordance rates:

    • MZ twins: 46%

    • Dizygotic twins: 14%.

  • The Genain quadruplets illustrate that while they shared genes and environment, schizophrenia's manifestation varied greatly among them (Mirsky et al., 2000).

Neuroanatomical Abnormalities and Schizophrenia

  • The prefrontal cortex experiences significant development from adolescence to early adulthood, implicating it in the emergence of schizophrenia (Galván & Tottenham, 2016).

  • Neuroimaging in adolescents with schizophrenia highlights structural changes across the cortex, especially the prefrontal area, pre-symptom onset (Sun et al., 2009).

  • The hippocampus also reveals consistent discrepancies in those with schizophrenia; it’s critical for long-term memory formation.

    • Schizophrenia patients often display abnormal activation during memory-related tasks (Barch, Csernansky, Conturo, & Snyder, 2002; Schacter, Chiao, & Mitchell, 2003).

    • Studies have shown both shape and volume abnormalities in the hippocampus (Knable, Barci, Webster, Meador-Woodruff, & Torrey, 2004; Lieberman et al., 2018).

    • Such abnormalities also appear in first-degree relatives of affected individuals (Seidman et al., 2002).

  • White matter reductions in the brains of schizophrenia patients affect working memory, and such deterioration is observable even prior to overt symptoms (Karlsgodt et al., 2008).

  • Structural changes such as expanded ventricles suggest significant brain tissue loss (Lawrie et al., 2008).

    • Enlarged ventricles correlate with social and emotional deficits pre-diagnosis, an indicator of severe symptoms and reduced medication responsiveness.

Causes of Neuroanatomical Abnormalities

  • Genetic and epigenetic factors are major contributors to neuroanatomical changes in schizophrenia (Howes et al., 2017).

  • Additional factors include:

    • Birth complications

    • Traumatic brain injuries

    • Viral infections

    • Nutritional deficiencies

    • Lack of cognitive stimulation (Barch & Sheffield, 2017; Howes & Murray, 2014).

  • Birth complications known to elevate schizophrenia risk include:

    • Emergency cesarean sections

    • Pregnancy bleeding

    • Preeclampsia

    • Gestational diabetes

    • Low birth weight.

Prenatal and Birth Complications

  • Research confirms that severe birth issues are more prevalent in schizophrenia patients compared to those without it (Cannon et al., 2003; Kotlicka-Antczak et al., 2017).

    • Neurodevelopmental damage can have long-lasting impacts, when symptoms are typically observed in young adulthood.

  • Longitudinal studies suggest individuals with a history of obstetric complications face a higher likelihood of developing schizophrenia (Mittal et al., 2009).

  • Studies linking perinatal hypoxia (oxygen deprivation during delivery) indicates its damaging effects on future schizophrenia risk, exhibiting tissue volume loss and increased ventricle size indicative of related brain issues.

Maternal Illness and Exposure Risks

  • Epidemic-related studies show increased odds of schizophrenia for babies whose mothers were infected with viral and bacterial diseases during pregnancy (Stilo & Murray, 2019).

    • Heavy research focus on maternal influenza exposure during pregnancy correlates with children's future schizophrenia risks (Kendler, 2020).

  • Infection during pregnancy (influenza, rubella, and various other pathogens) may disrupt fetal neurodevelopment potentially resulting in reassociated psychiatric risks.

  • The COVID-19 pandemic raises new concerns about maternal infections leading to increased neuropsychiatric conditions in exposed offspring.

  • Understandably, maternal immune activation (MIA) is linked to multiple psychiatric disorders.

The Gut Microbiome and Schizophrenia

  • Current theories examine the link between psychiatric illnesses and altered gut microbiota composition.

    • The gut microbiome plays a significant role in influencing brain function (Martinez, Leone, & Chang, 2017).

Neurotransmitter Involvement

  • Dopamine's critical role in schizophrenia is emphasized via the original dopamine theory.

    • This theory proposed symptoms arise predominantly from excess dopamine activity, particularly in key brain regions related to positive symptoms (hallucinations and delusions).

  • The diathesis-stress model suggests that stress can influence the hypothalamus-pituitary-adrenal (HPA) axis, hence affecting dopamine production (Stilo & Murray, 2019).

    • Stress may amplify vulnerability to schizophrenia through dopamine's release and subsequent system dysregulation.

  • Effectiveness of dopamine antagonists (antipsychotics) in mitigating symptoms further supports dopamine's involvement.

    • Increased dopamine activity in the mesolimbic pathway correlates with symptom severity (Howes et al., 2015).

  • More complex theories postulate variations in dopamine receptor function and distribution across brain regions as a more comprehensive account of schizophrenia symptoms, compelling a need to consider atypical antipsychotic medication which selectively block dopamine receptors in certain pathways.