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SCHIZOPRENIA. Incidence of SCHIZOPHRENIA: World Health Organization (1992) zDEVELOPED COUNTRIES yROCHESTER, NY yMOSCOW, RUSSIA yAARHUS, DENMARK z DEVELOPING.

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Presentation on theme: "SCHIZOPRENIA. Incidence of SCHIZOPHRENIA: World Health Organization (1992) zDEVELOPED COUNTRIES yROCHESTER, NY yMOSCOW, RUSSIA yAARHUS, DENMARK z DEVELOPING."— Presentation transcript:

1 SCHIZOPRENIA

2 Incidence of SCHIZOPHRENIA: World Health Organization (1992) zDEVELOPED COUNTRIES yROCHESTER, NY yMOSCOW, RUSSIA yAARHUS, DENMARK z DEVELOPING COUNTRIES yAGRA, INDIA yCALI, COLUMBIA yIBADAN, NIGERIA RESULTS: INCIDENCE OF SCHIZOPHRENIA IS SIMILAR ACROSS ALL CITIES

3 SOME STATISTICS: z1% OF U.S. POPULATION z1 in 3 PSYCHIATRIC HOSPITAL BEDS z$65 BILLION yDIRECT TREATMENT ySOCIETAL COSTS xhospitals and institutions xlaw enforcement and judicial system yFAMILY COSTS

4 TWO CATEGORIES OF SYMPTOMS: zPOSITIVE SYMPTOMS yTHOUGHT DISORDERS yDELUSIONS-BELIEFS CONTRARY TO FACTS xPERSECUTION xGRANDEUR xCONTROL BY OTHERS xPARANOIA yHALLUCINATIONS Auditory most common z NEGATIVE SYMPTOMS yFLATTENED EMOTIONAL RESPONSES yPOVERTY OF SPEECH yLACK OF INITIATIVE ySOCIAL WITHDRAWAL yINABILITY TO EXPERIENCE PLEASURE yCOGNITIVE DYSFUNCTIONS

5 NEGATIVE SYMPTOMS zThese symptoms are similar to those observed in people with FRONTAL LOBE DAMAGE. zNEUROLOGICAL DISORDERS yCatatonia yAbnormal visual pursuit yStaring, no eye contact with others yAltered blinking (too much or not at all) yPoor pupillary reflex

6 EVIDENCE FOR A BIOLOGICAL BASIS FOR SCHIZOPHRENIA? zGENETIC DATA zPHARMACOLOGICAL DATA zBRAIN IMAGING DATA zDEVELOPMENTAL DATA

7 WHAT IS THE EVIDENCE? zGENETICS

8 THE GENETICS OF SCHIZOPHRENIA zFAMILY STUDIES zTWIN STUDIES yMONOZYGOTIC TWINS ~ identical twins yDIZYGOTIC ~ fraternal twins x CONCORDANT  both twins SCHZO. x DISCORDANT  one twin SCHZO. zADOPTION STUDIES

9 Kety (1994) zDenmark Adoptee Studies % of the relatives of schizophenics were diagnosed with schizo. or latent schizo % of the relatives of normal adoptees were diagnosed with these disorders 3. Schizo. More common in 1 st degree relatives - Schizophrenia in 1 st degree relatives = 12% - Schizophrenia in 2 nd degree relatives = 2.2% 4. Biological relatives of schizophrenics show no increased rate of other mental disorders

10 IMPORTANT POINTS TO REMEMBER FROM TWIN STUDIES: zSCHIZOPHRENIA has a genetic component. zGenetics, however, is not the whole story. Concordance rate far less than 100%. zGenetics may predispose an individual to developing SCHIZOPHRENIA. zEnvironmental factors may interact with genetics to increase susceptibility. zTherefore, there must be “unexpressed, dormant, schizophrenic genes”

11 PHARMACOLGICAL DATA: THE DOPAMINE HYPOTHESIS zOrigins of antipsychotic drug development: zLaborit ~ accidentally found that antihistamines reduced anxiety in presurgical patients. zCharpentier ~ chlorpromazine “quieted hyperactive” mental patients & “activated withdrawn” mental patients. zSince the early drugs (e.g., chlorpromazine and reserpine) produced Parkinsonian effects, these drugs were believed to act on the dopamine system.

12 ADDITIONAL EVIDENCE FOR THE DOPAMINE HYPOTHESIS Cocaine, amphetamine, L-Dopa Positive Symptoms of Schizophrenia (blocked by antipsychotics) Suggestion: Antipsychotics = dopamine receptor antagonists (neuroleptics)

13 SNYDER (1976,1978) zExamined the ability of antipsychotic (neuroleptic) drugs to bind to dopamine receptors. zExamined the relationship of a drug’s receptor binding affinity with its potency to reduce schizophrenic symptoms.

14 SNYDER (1976, 1978) zExtracted neostriatum from calf brains - neurons contain dopamine receptors zExposed neurons to radioactive dopamine zWashed away unbound dopamine zMeasured amount of radioactivity in the neostriatum = measure of dopamine receptor binding zMeasured the ability of various antipsychotics to block the binding of radioactive dopamine.

15 SNYDER (1976, 1978) zRESULTS:  Highly clinically effective antipsychotics had a high binding affinity for dopamine receptors.  Less effective antipsychotics had a lower affinity.  One exception = Haloperidol - highly clinically effective for schizophrenia - low binding affinity to striatal dopamine receptors

16 The Haloperidol Puzzle zStriatal Neurons mostly D1 receptors zChlorpromazine binds to D1 and D2 receptors zHaloperidol binds preferentially to D2 receptors zChlorpromazine = Phenothiazines = D1, D2 zHaloperidol = Butyrophenones = D2 selective

17 The Dopamine Receptors zD1 zD2a zD2b zD3  D4 Clozapine binds to D4 receptors zD5 Clozapine = an atypical neuroleptic. No Parkinsonian side effects. High binding to D4 Haloperidol binds best to D2 receptors

18 WHAT IS WRONG WITH THE DOPAMINERGIC SYNAPSE IN SCHIZOPHRENICS? zPOSSIBILITIES: 1. Increased release of dopamine? - More excitatory input to dopamine-containing neurons - Fewer or defective autoreceptors on dopamine neuron 2. Overabundance of dopamine receptors on post-synaptic neuron? - more response in postsynaptic neuron to dopamine receptor activation

19 Where are the dopaminergic abnormalities located? zThe Neostriatum? zAmygdala? zFrontal cortex? zNucleus accumbens? - D4 receptors located here

20 The Nucleus Accumbens zAre reinforcement/reward and schizophrenia related? -If reinforcement mechanisms are active at inappropriate times, then inappropriate behaviors (e.g., delusional thoughts) may be reinforced. z-Elation/euphoria reported to occur at onset of schizophrenic episode.

21 BRAIN ABNORMALITIES AND SCHIZOPHRENIA zSince typical antipsychotics DO NOT alleviate negative symptoms associated with schizophrenia zand the negative symptoms are similar to those produced by frontal lobe damage z…Then, maybe frontal lobe dysfunction contributes to the negative symptoms of schizophrenia.

22 Weinberger (1980’s – present) zStudied discordant identical twins: zSCHIZOPHRENIC twin showed enlarged ventricles in 16 of 17 pairs. zSCHIZOPHRENICS, in general, have larger ventricular to brain ratios (i.e., larger ventricles, less brain).

23 Weinberger (1992) zWisconsin Card Sorting Task (WCST) zWCST activates the lateral prefrontal lobe z Patients with lateral prefrontal lobe damage Deficient in WCST zIdentical twins: discordant for SCHIZOPHRENIA zPET scan during WCST

24 Weinberger, WCST

25 Weinberger (1992) RESULTS: zSCHIZOPHRENIC twin impaired on task, just like people with prefrontal lobe damage zSCHIZOPHRENIC twin shows hypoactivity in frontal lobe (decrease blood flow vs. unaffected twin) zMany SCHIZOPHRENICS are impaired on task and show frontal lobe hypoactivity

26 Wolkin et al. (1992) zCorrelated the NEGATIVE SYMPTOMS with FRONTAL LOBE metabolism (e.g., activity) in SCHIZOPHRENIC patients. zRESULTS: The more severe the negative symptoms, the less the metabolism (activity) zHowever, NO GROSS STRUCTURAL ABNORMALITIES in SCHIZOPHRENICS!!!!!!

27 WHAT ARE THE CAUSES OF hypoFRONTALITY? zAbnormality in the development of frontal lobe?

28 Benes et al. (1986,1991) Took a closer look at the cells in the FRONTAL CORTEX… SCHIZOPHRENIC BRAINS vs NORMAL BRAINS:

29 Benes et al. (1991) zAbnormally LOW number of neurons in LAYERS I and II (outer layers) of the FRONTAL CORTEX. zAbnormally HIGH number of neurons in LAYER V (deep layers)of the FRONTAL CORTEX. zSuggest: Abnormalities NOT due to degeneration (since levels of glia cells normal) but due to DEVELOPMENTAL abnormalities.

30 WHAT DEVELOPMENTAL FACTOR(S) MAY CAUSE BRAIN ABNORMALITY? zA VIRUS? zGENETIC ABNORMALITY? zAN INTERACTION OF THE TWO?

31 Epidemiological Evidence for an Environment influence zMednick (1988) - Helsinki, Finland ~ Asian Flu Epidemic (Virus) - Higher incidence of SCHIZOPHRENIA in fetuses carried during the epidemic vs. before epidemic - KEY POINT: Fetuses whose mothers developed the Flu during the 2 nd trimester of pregnancy had highest incidence of schizophrenia as adults

32 WHAT HAPPENS DURING THE 2 ND TRIMESTER OF PREGNANCY? zMarked development of the neocortex zCortex develops inside out: zCells migrate to deep layers 1 st. zCells of the outer layers must migrate through deep layers). zIn the SCHIZOPHRENIC brain, cells destined to be the outer layers of the cortex get STUCK and never make it there.

33 ADDITIONAL SUPPORT FOR DEVELOPMENTAL FACTORS… Brach et al. (1992) y“CHRONO MARKERS” OR “FOSSILS” OF 2 ND TRIMESTER development: CORTEX AND FINGER TIP DERMAL CELL MIGRATION yStudied: MONOZYGOTIC TWINS - NON-SCHIZOPHRENIC PAIRS (n=7) - SCHIZOPHRENIC DISCORDANT PAIRS (n=23) yMeasured: INTRA-TWIN DIFFERENCES IN FINGER TIP RIDGE PATTERNS

34 Brach et al. (1992) zRESULTS: - NON-SCHIZOPHRENIC TWINS ALL HAVE SAME FINGER PRINTS (not a lot of differences). - TWINS DISCORDANT FOR SCHIZOPHRENIA have different finger prints!

35 Brach et al. (1992) CONCLUDE: - During the 2 nd trimester of pregnancy, something in the “environment” may have differentially affected one twin but not the other. - Maybe it was a virus, but we still don’t have the answer…

36 IN SUMMARY: zSCHIZOPHRENIA IS A BIOLOGICAL DISEASE THAT MAY INVOLVE DISRUPTION OF MANY SYSTEMS yFRONTAL CORTEX yDOPAMINE SYSTEMS zGENETIC, ENVIRONMENTAL AND DEVELOPMENTAL FACTORS ARE IMPORTANT FOR THE GENISIS OF THE DISEASE

37 An Animal Model of Schizophrenia?? zPhencyclidine (PCP) – “angel dust” zSingle ingestion transient schizo. symptoms zChronic use long lasting schizo. symptoms - social withdrawal - flattened emotional responses - hallucinations - thought disorders - delusions, paranoia - Cognitive dysfunction, hypofrontality

38 Jentsch et al. (1997) zEffects of chronic PCP exposure in monkey - twice/day for 14 days zMeasured: - cognition dependent on normal frontal lobe dopamine levels - frontal lobe dopamine utilization zTask – “Object Retrieval with a Detour” task -transparent box with one open side -open side oriented to the front, right or left of monkey -box contains a treat -monkey retrieves treat from one orientation (front)

39 Jentsch et al. – cont. - re-orient the box opening to left - monkey must redirect response without touching a closed side to be successful zDesign: - give PCP or saline for two weeks, then stop treatment - administer task from 7-28 days later zResults: - PCP-treated monkeys showed perseveration when box is re-oriented. They keep making the original response

40 Jentsch et al. – cont. zImportant Points: - Deficits identical to those seen in monkeys w/ frontal lesions or frontal dopamine depletion - Deficits similar to those seen in schizophrenics or humans with frontal lobe lesions zResults: Dopamine Assay - chronic PCP decreases dopamine utilization in the prefrontal cortex

41 Jentsch et al. – cont. zDopamine antagonists exacerbate cognitive dysfunction in schizo. Suggests: - a subset of schizo. symptoms may be due to dopamine hypoactivity in frontal lobes Clozapine =atypical neuroleptic - improves performance of chronic PCP monkeys in object retrieval task -increases basal dopamine concentration in frontal cortex


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