Environmental Etiology of Schizophrenia

Estimated that approximately 65% of the risk of developing schizophrenia is attributed to genetic factors (including both unique and shared genetics).
This implies that around 35% of the risk is associated with environmental factors.

Latent characteristics: traits or qualities that require specific conditions or situations to manifest.
A true marker of latent vulnerability must possess a predictive value in indicating a heightened risk for future psychiatric disorders.
  - Latent Characteristics include:
    - Cognitive: e.g., reward processing
    - Emotion: e.g., fear responses
    - Environmental risk factors play a significant role in the manifestation of these latent characteristics.

The link between prenatal infection and subsequent schizophrenia is regarded as one of the most consistently replicated discoveries.
It is not restricted to a single pathogen; any pathogen leading to maternal immune activation (MIA) during pregnancy is relevant.
  - Common Pathway:
    - Maternal infection leads to an immune response (release of cytokines), which alters fetal brain development.
  - MIA disrupts:
    - Neuronal migration
    - Synaptic pruning
    - Development of the dopaminergic system
In animal models, immune activation alone may induce behavioral abnormalities, dopamine dysregulation, and cortical changes simulating schizophrenia manifestations.

Adversity during critical periods of brain development impacts developmental pathways:
  - Prolonged exposure to glucocorticoids is neurotoxic.
    - Chronic elevation of glucocorticoids reduces the number of neurons within the relevant pathways.
    - Disrupts efficiency of the negative feedback loop, resulting in an ineffective stress response.
High rates of psychiatric issues are observed in adults with a history of childhood trauma (CT), indicating CT as a potent risk factor for various health problems (as supported by the Kaiser-Permanente ACES Study).

Examines the relationship between childhood trauma and the psychosis spectrum in subjects including controls and schizophrenia patients.
Control group: N=261
Schizophrenia group: N=325

Conducted by Varese et al. (2012); gathered data from various studies:
  - Included 18 case-control studies (totaling 2048 psychotic patients and 1856 non-psychiatric controls).
  - Included 10 prospective and quasi-prospective studies (totaling 41,803 individuals).
  - Included 8 population-based cross-sectional studies (Total sample size = 535,546).
Estimated Population Attributable Risk (PAR) for childhood trauma at approximately 33% (Confidence Interval: 16%–47%).
Interpretation: Between 16% and 47% of individuals currently diagnosed with schizophrenia would not have the disorder had they not experienced trauma during childhood.
Emotional abuse is reported to have the most substantial impact in relation to psychosis.

Among the entire population of Denmark (over 3 million people), there are 204,505 individuals diagnosed with substance abuse and 21,305 diagnosed with schizophrenia.
Proportion of substance abusers diagnosed with schizophrenia is highlighted, along with the relationship between substance abuse and the onset of schizophrenia.

Cannabis-Psychosis Persistence Model:
  - Person A: Normal developmental expression of subthreshold psychotic experiences, mild and transient.
  - Person B: Similar expression but experiences longer persistence due to additional environmental exposure (cannabis use).
  - Person C: Prolonged persistence leading to transition to clinical psychotic disorder attributed to repeated cannabis use.
Relevant considerations:
  - Self-medication potential?
  - Cannabis comprises over 200 psychoactive compounds, thus termed a “dirty” drug.
  - Genetic risk factors for both cannabis abuse and schizophrenia may overlap.

A study on the total population of Sweden (over 4.4 million individuals) indicates a correlation between population density and the incidence of psychosis.

GxE interactions may present as environmental factors impacting DNA methylation, resulting in changes in gene expression through epimutations.
Epigenetics studies how behavior and environment can induce cellular changes affecting gene functionalities (altered gene expression and developmental changes).
Epigenetic modifications are reversible and do not alter the DNA sequence; however, they can modify how genes are interpreted by the body.
This topic raises connections to Lamarckian evolution, where acquired characteristics might be passed on.

Preconception Factors:
  - Famine
  - Exposure to viral infections
  - Pregnancy complications
  - Maternal depression
Developmental Exposures:
  - Trauma
  - Substance use
  - Urbanicity
  - Other factors.

It is unequivocally established that schizophrenia is a neurodevelopmental disorder resulting from an aberrant developmental trajectory.
While some knowledge exists concerning the affected cells and circuits, a comprehensive understanding may be decades away.
Causal factors are likely a combination of genetic, environmental, and their interaction.
It is crucial to acknowledge that psychotic disorders are heterogeneous, suggesting that the underlying causes are likely to be diverse as well, encompassing the Schizophrenias.