1. Schizophrenia Lecture 23

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

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

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

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

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

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

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

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

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

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

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

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

14. 1 st Generation Neuroleptics n Relieve only positive symptoms n Chlorpromazine (Thorazine) l phenothiazines l primarily blocks D 1 & D 2 n Haloperidol (Haldol) l butyrophenones l primarily blocks D 2 n D 2 -R affinity and clinical potency ~

15. Patient Populations: Mental Institutions Thousands of patients 400 300 200 100 190019301960 1975 600 500 YEAR 1956

16. Strength of D2 binding Therapeutic effects Hi Lo Chlorpromazine Haloperidol Spiroperidol

17. 1 st Generation: Side Effects n Motor l Nigrostriatal pathway l Tardive Dyskinesia l Parkinson-like symptoms n Sedation l low compliance ~

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

19. 2 nd Generation Neuroleptics n Block DA and 5-HT receptors l Relieve positive & negative symptoms l Lower Parkinson’s-like side effects n Clozapine (Clozaril) l high risk agranulocytosis n Risperidone (Risperidal) l low risk of agranulocytosis ~

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