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

1
The Puzzle of SchizophreniaLinking
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 homethe control had
gotten especially strong. She describedthat
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 persons 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

15
(No Transcript)
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

21
(No Transcript)
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

25
(No Transcript)
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
Patients
Controls
dopamine level
Abi-Dargham et al (2000)
30
Patients
Controls
dopamine level
Abi-Dargham et al (2000)
31
Patients
Controls
dopamine level
deplete dopamine
Abi-Dargham et al (2000)
32
Pathophysiology of Schizophrenia
Biochemical
Cognitive
Delusions, hallucinations, disorganization
Phenomenological
33
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 DelusionsA Hypothesis
(Kapur, 2003)

• In psychosis, increased dopamine activity causes
  abnormal salience of ordinary stimuli

36
nigrostriatal
mesocortical
mesolimbic
(nucleus accumbens)
37
Pathophysiology of DelusionsA 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 DelusionsA 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

45
(No Transcript)
46
Total Prison Mental Hospital
Harcourt (2006)