The Puzzle of Schizophrenia: Linking Neurochemistry , Cognition, and Symptoms

1. The Puzzle of Schizophrenia:Linking Neurochemistry, Cognition,and Symptoms Michael Kiang, MD, MS Dept. of Cognitive Science, UCSD

2. Schizophrenia • affects 1% worldwide • onset throughout lifespan, most commonly late adolescence or twenties • #7 cause of years lived with disability; #3 for 15-44 age group (WHO Global Burden of Illness Study)

3. Schizophrenia • "positive" symptoms (psychosis) • “negative” symptoms

4. Schizophrenia • "positive" symptoms (psychosis) • hallucinations • “negative” symptoms

5. Schizophrenia • "positive" symptoms (psychosis) • hallucinations • delusions • “negative” symptoms

6. types of delusions • persecutory: being harassed, cheated or persecuted • reference: events, objects, or others' behavior refers to oneself, or have a particular and unusual significance • grandiose: exaggerated conception of one's importance, power, or identity • guilt • control: one's actions or thoughts are being controlled by external forces; e.g. thought withdrawal/insertion/broadcasting/control • somatic (bodily)

7. “A dog lay in wait for me as he sat on the steps of a Catholic convent. He got up on his hind legs and looked at me seriously. He then saluted with his front paw as I approached him. Another man was a little way in front of me. I caught up to him hurriedly and asked if the dog had saluted him too. An astonished ‘no’ told me I had to deal with a revelation addressed to me.” Kurt Schneider, Klinische Psychopathologie (Clinical Psychopathology), 1931

8. Compton (2003): "Internet delusions." A 53-year-old woman, with a history of one hospitalization 1.5 years previously, presented to the hospital after calling the police due to increasing worries at home—“the control had gotten especially strong.” She described…that the Internet had been controlling her and her home for the past 3 years. For example, when she walked around in her home, if she bumped into furniture, she attributed this to the Internet controlling her. She believed that the Internet also controlled her appliances turning on and off, that it changed channels on the television, and that it caused her to burn herself on the iron or stove.

9. Other psychiatric symptoms included auditory hallucinations of voices whispering to her, passive suicidal thoughts, and vague worries that her grandson was in danger in some way. When asked about computers and the Internet, the patient denied having any familiarity with computers or having ever used computers in any capacity. When asked to describe what the Internet is, she commented that she assumes that it is “some big computer somewhere.”

10. Schizophrenia • "positive" symptoms (psychosis) • hallucinations • delusions • disorganized speech • disorganized behavior

11. Disorganized Speech in Schizophrenia • sequences of concepts appear unrelated • unusual wording • irrelevant responses  thought disorder

12. Schizophrenia • "positive" symptoms (psychosis) • delusions • hallucinations • disorganized speech • disorganized behavior • “negative” symptoms • flat affect • poverty of speech • apathy / social withdrawal / poor hygiene • cognitive deficits

13. Schizophrenia • diagnostic criteria (DSM-IV): A) 2 or more of the following, for at least 1 month: • delusions • hallucinations • disorganized speech • disorganized behavior • negative symptoms • only 1 required if delusions are bizarre; or hallucinations consist of a voice keeping up a running commentary on the person’s behavior or thoughts, or 2 or more voices conversing with each other

14. B) symptoms cause social/occupational dysfunction C) some sign of the disturbance has lasted at least 6 months D) not caused by a substance or a medical illness

16. Schizophrenia • genetic predisposition (e.g. twin studies) • unknown environmental contribution (prenatal, childhood, adult?)

17. Mortensen et al. (1999)

18. Mortensen et al. (1999)

19. Schizophrenia • no diagnostic findings on neuropathology / structural brain imaging • on average, smaller temporal lobe gray matter volume

20. Discovery of Antipsychotic Medication • Paris, 1952: surgeon Laborit tested chlorpromazine (known as antihistamine) for surgical shock • it calmed agitated patients, caused a "marked indifference" • Paris, 1953: psychiatrists Delay and Deniker found that it improved psychotic symptoms • Montreal, 1954: first use of antipsychotics in North America (Lehmann) • 1960s: deinstitutionalization

22. Danvers State Hospital, Danvers, MA In CA, from 1955 to 1980, institutionalized population declined from 37 000 to 2 500

23. Antipsychotic Medication: Problems • not fully effective at reducing symptoms in all patients

24. Antipsychotic Medication: Problems • not fully effective at reducing symptoms in all patients • frequently do not reduce negative symptoms as effectively as they do positive symptoms

26. Antipsychotic Medication: Problems • cause Parkinsonian side effects • slowing of movements (bradykinesia) • tremor • rigidity

27. Antipsychotic Medication: Mechanism • Seeman (1975): discovered dopamine receptor to which antipsychotics bind (block) • since then, all effective antipsychotic medications have been found to bind to this receptor (D2)

28. nigrostriatal mesocortical mesolimbic (nucleus accumbens)

29. Controls Patients D2-selective radio- labelled ligand Dopamine Dopamine D2 receptor dopamine level Abi-Dargham et al (2000)

30. Controls Patients D2-selective radio- labelled ligand Dopamine Dopamine D2 receptor dopamine level Abi-Dargham et al (2000)

31. Controls Patients D2-selective radio- labelled ligand Dopamine Dopamine D2 receptor dopamine level deplete dopamine Abi-Dargham et al (2000)

32. Dopaminergic overactivity ??? Pathophysiology of Schizophrenia Biochemical Cognitive Delusions, hallucinations, disorganization Phenomenological

33. Dopamine D2 receptors blocked ??? How Do Delusions Improve? Biochemical Cognitive Delusions improve Phenomenological

34. How Do Delusions Improve? • Although D2 blockade is rapid, improvement in delusions is gradual (usually over a period of weeks)

35. Pathophysiology of Delusions:A Hypothesis (Kapur, 2003) • In psychosis, increased dopamine activity causes abnormal salience of ordinary stimuli

36. nigrostriatal mesocortical mesolimbic (nucleus accumbens)

37. Pathophysiology of Delusions:A Hypothesis (Kapur, 2003) • In psychosis, increased dopamine activity causes abnormal salience of ordinary stimuli • Persistent abnormal salience leads to delusion formation, as an attempt to explain this abnormal sense of significance

38. Abnormal Salience “A dog lay in wait for me as he sat on the steps of a Catholic convent. He got up on his hind legs and looked at me seriously. He then saluted with his front paw as I approached him. Another man was a little way in front of me. I caught up to him hurriedly and asked if the dog had saluted him too. An astonished ‘no’ told me I had to deal with a revelation addressed to me.” Kurt Schneider, Klinische Psychopathologie (Clinical Psychopathology), 1931

39. Pathophysiology of Delusions:A Hypothesis (Kapur, 2003) • In psychosis, increased dopamine activity causes abnormal salience of ordinary stimuli • Persistent abnormal salience leads to delusion formation, as an attempt to explain this abnormal sense of significance • Antipsychotics decrease dopamine activity and reverse abnormal salience • An extended period free of abnormally salient stimuli allows delusion to gradually extinguish

40. More favorable toward CP After Pro-CP study After Anti-CP study Less favorable toward CP Lord et al. (1979)

41. Time Antipsychotic treatment initiated 6Abnormal salience of stimuli 6Preoccupation 6Negative Mood 6Action 6Conviction

42. Studying How Delusions Improve • Dimensions of Psychosis questionnaire • Based on detailed interview about a principal delusion, interviewer rates: • conviction • external perspective (insight) • cognitive preoccupation • emotional involvement • behavioural impact

43. Behavioural impact Emotional involvement Cognitive preoccupation Conviction External perspective Mizrahi, Kiang, Mamo et al. (2006)

44. Summary • symptoms tend to co-occur, but not all are present in each patient • interaction of genetic and environmental factors causes illness • brain studies suggest an abnormality of dopaminergic function • further research required on how this is related to symptoms, or whether it is the primary brain abnormality

46. Total Prison Mental Hospital Harcourt (2006)