the puzzle of schizophrenia: linking neurochemistry, cognition, and symptoms michael kiang, md, ms...

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)

Schizophrenia "positive" symptoms (psychosis)

“negative” symptoms


– hallucinations



– hallucinations– delusions


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.”


– hallucinations– delusions– disorganized speech– disorganized behavior

Disorganized Speech in Schizophrenia

sequences of concepts appear unrelated unusual wording irrelevant responses

thought disorder


– 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?)

Mortensen et al. (1999)

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


not fully effective at reducing symptoms in all patients

frequently do not reduce negative symptoms as effectively as they do positive symptoms


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)

mesolimbic

nigrostriatal

mesocortical

(nucleus accumbens)

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)

mesolimbic

nigrostriatal

mesocortical

(nucleus accumbens)


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 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


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


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

Total Prison Mental Hospital

Harcourt (2006)

the puzzle of schizophrenia: linking neurochemistry, cognition, and symptoms michael kiang, md, ms...

Documents

twenties n

disorder slide

ucsd slide

worldwide n onset

psychiatric symptoms

internet delusions

puzzle of schizophrenia

symptoms michael kiang