• Bipolar disorder
• Schizophrenia

• Types
  • Depression
  • Anxiety
  • Bipolar disorder
• Heritability
  • proportion of variance in trait accounted for by genetic factors
  • Monozygotic: .69
  • Dizygotic: .13

• Formerly “manic depression” or “manic depressive disorder
• Alternating mood states
  • Mania or hypomania (milder form)
  • Depression
• Cycles 3-6 mos in length, but
  • Rapid cycling (weeks or days)
• Suicide risk 20-60x normal population, (Baldessarini, Pompili, and Tondo 2006)

• 1-3% prevalence, subthreshold affects another 2%
• Subtypes
  • Bipolar I: manic episodes, possible depressive ones
  • Bipolar II: no manic episodes but hypomania (disinhibition, irritability/agitation) + depression

• Psychosis (hallucinations or delusions)
• Anxiety, attention-deficit hyperactivity disorder (ADHD)
• Substance abuse

• Overlap between bipolar disorder and schizophrenia
• Genes for voltage-gated Ca++ channels
  • Regulate NT, hormone release
  • Gene expression, cell metabolism
• (Craddock and Sklar 2013)

• Mood stabilizers
  • Lithium (Li)
  • Valproate (Depakote)
• Anticonvulsants
  • GABA agonists
  • Usually to treat epilepsy
  • e.g. lamotrigine (Lamictal)
• Atypical antipsychotics

• Injections of manic patients' urine with lithium compound (chemical stabilizer) into guinea pig test animals
• Had calming effect
• John Cade discovered in 1948
• Earliest effective medications for treating mental illness

• Reduces mania, minimal effects on depressive states
• Preserves PFC, hip, amyg volume
• downregulates DA, glu; upregulates GABA
• modulates 5-HT, NE
• levels can be tested/monitored via blood test
• (Malhi et al. 2013)

• Psychotherapy
• Electroconvulsive Therapy (ECT)
• Sleep medications

• STEP-BD cohort (n=1469)
  • 58% achieved recovery
  • 49% had recurrences within 2 years
  • Residual depressive symptoms can persist
• (Geddes and Miklowitz 2013)

• Changes in mood, but ≠ depression
• Genetic + environmental risk
• Changes in emotion processing network activity, size of hippocampus
• Heterogeneous
• No simple link to a specific NT system

• 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
  • Coined term “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 receptor 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.

• 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 infancy (0-2 years) increased risk
• Increased risk associated with an allele of a cortisol-related gene

• 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
• One disorder or many?

• Emotion, happiness, and reward