Transcript The Puzzle of Schizophrenia: Linking Neurochemistry

The Puzzle of Schizophrenia:
Linking Neurochemistry, Cognition,
and Symptoms
Michael Kiang, MD, MS
Dept. of Cognitive Science, UCSD
Schizophrenia
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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)
Schizophrenia

"positive" symptoms (psychosis)
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“negative” symptoms
Schizophrenia
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"positive" symptoms (psychosis)
– hallucinations
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“negative” symptoms
Schizophrenia
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"positive" symptoms (psychosis)
– hallucinations
– delusions
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“negative” symptoms
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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)
“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
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.
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.”
Schizophrenia

"positive" symptoms (psychosis)
– hallucinations
– delusions
– disorganized speech
– disorganized behavior
Disorganized Speech in Schizophrenia
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sequences of concepts appear unrelated
unusual wording
irrelevant responses
 thought disorder
Schizophrenia
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"positive" symptoms (psychosis)
– delusions
– hallucinations
– disorganized speech
– disorganized behavior
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“negative” symptoms
– flat affect
– poverty of speech
– apathy / social withdrawal / poor hygiene
– cognitive deficits
Schizophrenia
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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
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
Schizophrenia
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genetic predisposition (e.g. twin studies)
unknown environmental contribution
(prenatal, childhood, adult?)
Mortensen et al. (1999)
Mortensen et al. (1999)
Schizophrenia
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no diagnostic findings on neuropathology /
structural brain imaging
on average, smaller temporal lobe gray
matter volume
Discovery of Antipsychotic Medication
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Paris, 1952: surgeon Laborit tested
chlorpromazine (known as antihistamine) for
surgical shock
– it calmed agitated patients, caused a "marked
indifference"
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Paris, 1953: psychiatrists Delay and Deniker
found that it improved psychotic symptoms
Montreal, 1954: first use of antipsychotics in
North America (Lehmann)
1960s: deinstitutionalization
Danvers State Hospital, Danvers, MA
In CA, from 1955 to 1980, institutionalized population
declined from 37 000 to 2 500
Antipsychotic Medication: Problems
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not fully effective at reducing symptoms in all
patients
Antipsychotic Medication: Problems
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not fully effective at reducing symptoms in all
patients
frequently do not reduce negative symptoms
as effectively as they do positive symptoms
Antipsychotic Medication: Problems
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cause Parkinsonian side effects
– slowing of movements (bradykinesia)
– tremor
– rigidity
Antipsychotic Medication: Mechanism
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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)
nigrostriatal
mesocortical
mesolimbic
(nucleus accumbens)
Controls
Patients
dopamine level
D2-selective radiolabelled ligand
Dopamine
Dopamine
D2 receptor
Abi-Dargham et al (2000)
Controls
Patients
dopamine level
D2-selective radiolabelled ligand
Dopamine
Dopamine
D2 receptor
Abi-Dargham et al (2000)
Controls
Patients
dopamine level
deplete dopamine
D2-selective radiolabelled ligand
Dopamine
Dopamine
D2 receptor
Abi-Dargham et al (2000)
Pathophysiology of Schizophrenia
Biochemical
Cognitive
Phenomenological
Dopaminergic
overactivity
???
Delusions,
hallucinations,
disorganization
How Do Delusions Improve?
Biochemical
Cognitive
Phenomenological
Dopamine D2
receptors blocked
???
Delusions improve
How Do Delusions Improve?
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Although D2 blockade is rapid,
improvement in delusions is gradual
(usually over a period of weeks)
Pathophysiology of Delusions:
A Hypothesis (Kapur, 2003)
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In psychosis, increased dopamine activity causes
abnormal salience of ordinary stimuli
nigrostriatal
mesocortical
mesolimbic
(nucleus accumbens)
Pathophysiology of Delusions:
A Hypothesis (Kapur, 2003)
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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
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
Pathophysiology of Delusions:
A Hypothesis (Kapur, 2003)
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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
Belief Perseverance
More favorable
toward CP
2
Change in Attitude
1.5
1
0.5
0
Proponents
Opponents
-0.5
-1
-1.5
-2
-2.5
Less favorable
toward CP
After Pro-CP study
After Anti-CP study
Lord et al. (1979)
Time
Antipsychotic treatment
initiated
6Abnormal salience
of stimuli
6Preoccupation
6Negative Mood
6Conviction
6Action
Studying How Delusions Improve
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Dimensions of Psychosis questionnaire
Based on detailed interview about a principal
delusion, interviewer rates:
– conviction
– external perspective (insight)
– cognitive preoccupation
– emotional involvement
– behavioural impact
Behavioural impact
Emotional involvement
Cognitive preoccupation
Conviction
External perspective
Mizrahi, Kiang, Mamo et al. (2006)
Summary
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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
Total Prison
Mental Hospital
Harcourt (2006)