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The Puzzle of Schizophrenia:Linking Neurochemistry, Cognition,and Symptoms
Michael Kiang, MD, MS
Dept. of Cognitive Science, UCSD
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)
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 aCatholic convent. He got up on his hind legs and lookedat me seriously. He then saluted with his front paw as Iapproached him. Another man was a little way in front of me. I caught up to him hurriedly and asked if the doghad saluted him too. An astonished ‘no’ told me I had todeal 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
sequences of concepts appear unrelated unusual wording irrelevant responses
thought disorder
Schizophrenia "positive" symptoms (psychosis)
– delusions– hallucinations– disorganized speech– disorganized behavior
“negative” symptoms– flat affect– poverty of speech– apathy / social withdrawal / poor hygiene– cognitive deficits
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
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 genetic predisposition (e.g. twin studies) unknown environmental contribution
(prenatal, childhood, adult?)
Schizophrenia no diagnostic findings on neuropathology /
structural brain imaging on average, smaller temporal lobe gray
matter volume
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
In CA, from 1955 to 1980, institutionalized population declined from 37 000 to 2 500
Danvers State Hospital, Danvers, MA
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
Antipsychotic Medication: Problems
cause Parkinsonian side effects– slowing of movements (bradykinesia)– tremor– rigidity
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)
dopamine level
PatientsControls
D2-selective radio-labelled ligand
Dopamine
DopamineD2 receptor
Abi-Dargham et al (2000)
dopamine level
PatientsControls
D2-selective radio-labelled ligand
Dopamine
DopamineD2 receptor
Abi-Dargham et al (2000)
deplete dopamine
dopamine level
PatientsControls
D2-selective radio-labelled ligand
Dopamine
DopamineD2 receptor
Abi-Dargham et al (2000)
Dopaminergic overactivity
???
Pathophysiology of Schizophrenia
Delusions, hallucinations, disorganization
Biochemical
Cognitive
Phenomenological
Dopamine D2 receptors blocked
???
How Do Delusions Improve?
Delusions improve
Biochemical
Cognitive
Phenomenological
How Do Delusions Improve?
Although D2 blockade is rapid, improvement in delusions is gradual (usually over a period of weeks)
In psychosis, increased dopamine activity causes abnormal salience of ordinary stimuli
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
Pathophysiology of Delusions:A Hypothesis (Kapur, 2003)
Abnormal Salience
“A dog lay in wait for me as he sat on the steps of aCatholic convent. He got up on his hind legs and lookedat me seriously. He then saluted with his front paw as Iapproached him. Another man was a little way in front of me. I caught up to him hurriedly and asked if the doghad saluted him too. An astonished ‘no’ told me I had todeal with a revelation addressed to me.”
Kurt Schneider, Klinische Psychopathologie(Clinical Psychopathology), 1931
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
Pathophysiology of Delusions:A Hypothesis (Kapur, 2003)
After Pro-CP study After Anti-CP study
Lord et al. (1979)
Belief Perseverance
-2.5
-2
-1.5
-1
-0.5
0
0.5
1
1.5
2
Ch
an
ge in
Att
itu
de
ProponentsOpponents
More favorabletoward CP
Less favorabletoward CP
Antipsychotic treatmentinitiated
Abnormal salienceof stimuli
Conviction
Preoccupation Negative Mood Action
Time
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
Behavioural impactEmotional involvementCognitive preoccupation
Conviction
External perspective
Mizrahi, Kiang, Mamo et al. (2006)
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
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