• Prevalence of mental illness
• Schizophrenia

• Lifetime prevalence ~ 1/100
• ~1/3 chronic & severe
• Onset post-puberty, early adulthood
• Pervasive disturbance in mood, thinking, movement, action, memory, perception

1. I think that I have felt that there are odd or unusual things going on that I can’t explain.
2. I think that I might be able to predict the future.
3. I may have felt that there could possibly be something interrupting or controlling my thoughts, feelings, or actions.

http://www.schizophrenia.com/sztest/primetest.pdf

1. I get confused at times whether something I experience or perceive may be real or may be just part of my imagination or dreams.
2. I have thought that it might be possible that other people can read my mind, or that I can read other’s minds.
3. I wonder if people may be planning to hurt me or even may be about to hurt me.

• Bleuler
  • Introduced “schizophrenia” or “split mind”
  • Not multiple personality disorder
• Kraeplin
  • Dementia Praecox and Paraphrenia (1919)
  • Emphasized developmental and hereditary origins

• “Additions” to behavior
• Disordered thought
• Delusions of grandeur, persecution
• Hallucinations (usually auditory)
• Bizarre behavior

• “Reductions” in behavior
• Poverty of speech
• Flat affect
• Social withdrawal
• Impaired executive function
• Anhedonia (loss of pleasure)
• Catatonia (reduced movement)

• Memory
• Attention
• Planning, decision-making
• Social cognition
• Movement

• Genetic disposition
• Brain abnormalities
• Developmental origins

• NOTCH4, TNF:
  • Part of major histocompatibility complex (MHC), cell membrane specializations involved in the immune system
• DRD2 (dopamine D2 receptor), KCNN3 (Ca+ activated K+ channel), GRM3 (metabotropic glutatmate receptor)

(Johnson et al. 2017)

• Related to ventricular enlargement?
• Early disturbance in brain development?

• Dentate gyrus (DG) in hippocampus critical for spatial coding, learning and memory, and emotion processing.
• DG dysfunction implicated in schizophrenia.
• Gene linked to schizophrenia, Transmembrane protein 108 (Tmem108) enriched in DG granule neurons
• Tmem108 expression increased during postnatal period critical for DG development.

• Tmem108-deficient neurons form fewer and smaller spines.
• Tmem108-deficient mice display schizophrenia-relevant behavioral deficits.

• DA (D2 receptor) antagonists (e.g. chlorpromazine)
  • improve positive symptoms
• Typical antipsychotics are DA D2 antagonists
• DA agonists
  • amphetamine, cocaine, L-DOPA
  • mimic or exacerbate symptoms

• New, atypical antipsychotics
  • (e.g. Clozapine) INCREASE DA in frontal cortex, affect 5-HT
• Mixed evidence for high DA metabolite levels in CSF

• Psychomimetic drugs induce schizophrenia-like states
  • Phencyclidine (PCP), ketamine
  • NMDA receptor antagonists
• Schizophrenia == underactivation of NMDA receptors?
  • NMDA receptor role in learning, plasticity
  • DG neurons in (Jiao et al. 2017) were glutamate-releasing.

• Wide-ranging disturbance of mood, thought, action, perception
• Broad changes in brain structure, function, chemistry, development
• Dopamine hypothesis giving way to glutamate hypothesis
• Genetic (polygenic = multiple genes) risk + environmental factors

• Urban vs. rural living
• Exposure to infection in utero, other birth complications

• Children (N=51,233) of parents who born during Nazi era (1922-1945)
• Emigrated before (indirect exposure) or after (direct exposure) to Nazi era
• Children exposed to direct stress of Nazi era in utero or postnatally
  • Did not differ in rates of schizophrenia, but
  • Had higher rehospitalization rates

• Danish cohort (n=1,141,447)
• Exposure to early life stress
  • in utero did not increase risk of schizophrenia, but
  • during 0-2 years increased risk
• Increased risk associated with an allele of a cortisol-related gene

• Emotion, happiness, and reward