1. Chapter 16 Schizophrenia http://www.npr.org/programs/atc/features/2002/aug/schizophrenia/

2. 18.2 Treatment of the mentally ill

3. Schizophrenia – A serious mental disorder characterized by disordered thoughts, delusions, hallucinations, and mood disturbance.

4. Schizophrenia Positive Symptoms –Delusions –Hallucinations –Disorganized behavior Negative Symptoms –Social withdrawal –Mood disturbance –Reduced motivation John Nash © Najlah Feanny/CORBIS

5. Schizophrenia –Positive symptoms –Dopamine hypothesis: Overactivity of dopamine in mesolimbic pathway (VTA to nucleus accumbens and amygdala)

6. Schizophrenia –How are positive symptoms related to dopamine? –Hypothesis: Mesolimbic system important for reinforcement of behavior We all have irrational thoughts, but usually brush them aside But if mesolimbic system was active when the thought occurred, we might take it more seriously, leading to delusions

7. –Hypothesis cont.: Confirming piece of evidence: schizophrenics often report euphoria at onset of positive symptoms Disordered thinking? –System so active that it does not discriminate between thoughts, making it hard to follow a logical sequence Terrifying element of delusions? –Strong dopaminergic projection to amygdala

8. Dopamine Hypothesis Evidence for excessive dopamine

9. Dopamine agonists (cocaine, amphetamine, PCP) produce symptoms of psychosis. Dopamine antagonists reduce psychotic behavior. Patients may have abnormalities involving dopamine autoreceptors. Schizophrenia Positive Symptoms

10. Schizophrenia –Positive Symptoms –Chlorpromazine: A “typical neuroleptic” A dopamine receptor blocker for D 2 receptors –Clozapine: An “atypical neuroleptic” An antipsychotic drug that blocks D 4 receptors in the nucleus accumbens

11. Tardive dyskinesia involves tremors and involuntary movements. Supersensitivity: increased sensitivity of neurotransmitter receptors (D 2 ) to dopamine Due to side effects, about 50% now use atypical neuroleptics like clozapine. Courtesy David Healy, Academy for the Study of the Psychoanalytic Arts Schizophrenia Side Effects of Typical Antipsychotics

12. Schizophrenia Side Effects of Typical Antipsychotics

13. Dopamine Hypothesis Evidence for increase in D 3 receptors

14. Failure of Prepulse Inhibition in Schizophrenia

15. Restoring Prepulse Inhibition in Schizophrenia

16. Problems With a Excessive Dopamine Hypothesis 25% of patients do not respond to dopamine antagonists. Atypical antipsychotic medications (clozapine) act primarily on neurotransmitters other than dopamine. Drugs change dopamine activity immediately, but patient may not improve for weeks. PCP produces symptoms similar to schizophrenia by blocking the NMDA glutamate receptor.

17. Schizophrenia –Negative symptoms –Brain damage: Many of the negative symptoms are also seen in people with frontal lobe damage

18. Lifetime risks of developing schizophrenia

19. Search for Brain Abnormalities Evidence for changes in ventricular size Courtesy D.R. Weinberger, NIMH, St. Elizabeth’s Hospital, Washington, D.C.

20. Disorganization of cells in the hippocampus

21. Search for Brain Abnormalities Loss of gray matter with age

22. Search for Brain Abnormalities Loss of gray matter with age Cause of delay of onset??

23. Lower frontal lobe activity may account for the negative symptoms of schizophrenia. During rest (top) and an effortful cognitive test (bottom), patients with schizophrenia show less frontal lobe activity. Courtesy Dr. Karen F. Berman, Clinical Brain Disorders Branch, NIMH, NIH Hypofrontality in schizophrenia

24. Hypofrontality in schizophrenia Wisconsin Card Sorting Task

25. Possible Causes of the Brain Abnormalities –Seasonal effect –Latitude effect –Maternal exposure to viruses –Nutritional deficiency Hunger Winter study –Thiamine deficiency –Vitamin D deficiency (latitude effect?) –Father’s age –Rh Incompatibility

26. How are positive & negative symptoms related? VTA Prefrontal Cortex NA Dopamine Hypoactivity (too little DA) GABA neurons Dopamine hyperactivity (too much DA)

27. 18.17 Schematic representation of the neurodevelopmental model of schizophrenia

28. 18.16 A modified representation of the vulnerability–stress model