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Schizophrenia

Schizophrenia. Lecture 23. Mental Illness: Definition. Characteristically Controversial Deviations from normal Behavior Thought Processes Affect Harmful dysfunction Distress Impairment Magnitude & duration ~. Schizophrenia. Disordered thoughts & bizarre behavior

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Schizophrenia

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  1. Schizophrenia Lecture 23

  2. Mental Illness: Definition • Characteristically Controversial • Deviations from normal • Behavior • Thought Processes • Affect • Harmful dysfunction • Distress • Impairment • Magnitude & duration ~

  3. Schizophrenia • Disordered thoughts & bizarre behavior • 1 percent of population • equal among sexes • Progressive? • can only manage symptoms • Symptoms > 6 mo • 2 classes of symptoms • Positive • Negative ~

  4. Positive Symptoms • Thought disorders • incoherence • loose associations • Delusions • bizarre beliefs • persecution, grandeur • Hallucinations • sensory experiences • no external stimuli ~

  5. Negative Symptoms • Poverty of speech • little spontaneous speech • Poverty of emotion • Flattened, inappropriate affect • Social withdrawal • lack of personal hygiene ~

  6. Anatomical Indicators S • Increased ventricle size • 67% of cases • brain atrophy • HC • thalamus (Nancy Andresen, UI) • general atrophy Hippocampal Abnormalities • Atrophy •  Pyramidal cells • disorganized~ S N

  7. Physiological Indicators • Hypofrontality • less activation in frontal lobe • internal vs. external stimuli • Less frontal activation • Card sorting - complex rules • Hallucinations • auditory & visual ?

  8. Heritability • General Population 1% • One parent schiz. 17% • DZ twins 17% • MZ twins 50% • Strong genetic component • predisposition + stressor • Adoption Studies • risks more like biological parents • Evidence of gene(s) elusive ~

  9. Neurodevelopmental Hypothesis • Pre – neonatal environment • trauma  schizophrenia • Rh blood-type incompatibility • Season-of-birth effect •  incidence for winter births • viral infections • Cat virus • Toxoplasma gondii • Relatively weak correlations ~

  10. The Dopamine Hypothesis • Positive symptoms • too much DA activity • Not excessive DA levels • Maybe overabundance of receptors • 2 major DA systems • Mesolimbic • Nigrostriatal ~

  11. DA Tracts Substantia nigra • Nigrostriatal System • Mesolimbic System MFB VTA

  12. Limbic System Striatum Nucleus Accumbens NSB Mesolimbic pathway Major DA Pathways VTA SN

  13. DA Hypothesis: Evidence • Therapeutic Drugs • Neuroleptics (Antipsychotics) • DA antagonists • DA agonists • amphetamines, cocaine, etc. • induce symptoms

  14. 1st Generation Neuroleptics • Relieve only positive symptoms • Chlorpromazine (Thorazine) • phenothiazines • primarily blocks D1 & D2 • Haloperidol (Haldol) • butyrophenones • primarily blocks D2 • D2-R affinity and clinical potency ~

  15. Patient Populations: Mental Institutions 600 1956 500 400 Thousands of patients 300 200 100 1900 1930 1960 1975 YEAR

  16. 1st Generation: Side Effects • Motor • Nigrostriatal pathway • Tardive Dyskinesia • Parkinson-like symptoms • Sedation • low compliance ~

  17. DA Hypothesis: Problem • Physiologic effect? • Minutes • Therapeutic effect? • Weeks • Why the delay? • maybe homeostatic mechanisms • offset changes by drugs at first ~

  18. 2nd Generation Neuroleptics • Block DA and 5-HT receptors • Relieve positive & negative symptoms • Lower Parkinson’s-like side effects • Clozapine (Clozaril) • high risk agranulocytosis • Risperidone (Risperidal) • low risk of agranulocytosis ~

  19. Role of Glutamate • Prefrontal lobe • DA inhibits Glu release • NMDA-R •  NMDA-R  abnormal behavior in rats • PCP (phencylidine)  hallucinations • blocks NMDA-R • Glu treatment? • risk of excitotoxicity ~

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