SCHIZOPRENIA

Incidence of SCHIZOPHRENIA: World Health Organization (1992)

DEVELOPED COUNTRIES ROCHESTER, NY MOSCOW, RUSSIA AARHUS, DENMARK

DEVELOPING COUNTRIES AGRA, INDIA CALI, COLUMBIA IBADAN, NIGERIA

RESULTS: INCIDENCE OF SCHIZOPHRENIA IS SIMILAR ACROSS ALL CITIES

SOME STATISTICS:

1% OF U.S. POPULATION1 in 3 PSYCHIATRIC HOSPITAL BEDS$65 BILLION

DIRECT TREATMENT SOCIETAL COSTS

hospitals and institutionslaw enforcement and judicial system

FAMILY COSTS

TWO CATEGORIES OF SYMPTOMS:

POSITIVE SYMPTOMS THOUGHT DISORDERS DELUSIONS-BELIEFS CONTRARY TO FACTS

PERSECUTIONGRANDEURCONTROL BY OTHERSPARANOIA

HALLUCINATIONS Auditory most

common

NEGATIVE SYMPTOMS FLATTENED EMOTIONAL

RESPONSES POVERTY OF SPEECH LACK OF INITIATIVE SOCIAL WITHDRAWAL INABILITY TO

EXPERIENCE PLEASURE COGNITIVE

DYSFUNCTIONS

NEGATIVE SYMPTOMS

These symptoms are similar to those observed in people with FRONTAL LOBE DAMAGE.

NEUROLOGICAL DISORDERS Catatonia Abnormal visual pursuit Staring, no eye contact with others Altered blinking (too much or not at all) Poor pupillary reflex

EVIDENCE FOR A BIOLOGICAL BASIS FOR SCHIZOPHRENIA?

GENETIC DATAPHARMACOLOGICAL DATABRAIN IMAGING DATADEVELOPMENTAL DATA

WHAT IS THE EVIDENCE?

GENETICS

THE GENETICS OF SCHIZOPHRENIA

FAMILY STUDIES

TWIN STUDIES MONOZYGOTIC TWINS ~ identical twins DIZYGOTIC ~ fraternal twins

CONCORDANT both twins SCHZO.

DISCORDANT one twin SCHZO.

ADOPTION STUDIES

Kety (1994)

Denmark Adoptee Studies 1. 5.6% of the relatives of schizophenics were diagnosed with schizo. or latent schizo. 2. 0.9 % of the relatives of normal adoptees were diagnosed with these disorders 3. Schizo. More common in 1st degree relatives - Schizophrenia in 1st degree relatives = 12% - Schizophrenia in 2nd degree relatives = 2.2% 4. Biological relatives of schizophrenics show

no increased rate of other mental disorders

IMPORTANT POINTS TO REMEMBER FROM TWIN STUDIES:

SCHIZOPHRENIA has a genetic component.Genetics, however, is not the whole story.

Concordance rate far less than 100%.Genetics may predispose an individual to

developing SCHIZOPHRENIA.Environmental factors may interact with

genetics to increase susceptibility.Therefore, there must be “unexpressed,

dormant, schizophrenic genes”

PHARMACOLGICAL DATA: THE DOPAMINE HYPOTHESIS

Origins of antipsychotic drug development:Laborit ~ accidentally found that

antihistamines reduced anxiety in presurgical patients.

Charpentier ~ chlorpromazine “quieted hyperactive” mental patients & “activated withdrawn” mental patients.

Since the early drugs (e.g., chlorpromazine and reserpine) produced Parkinsonian effects, these drugs were believed to act on the dopamine system.

ADDITIONAL EVIDENCE FOR THE DOPAMINE HYPOTHESIS

Cocaine, amphetamine, L-Dopa

Positive Symptoms of Schizophrenia (blocked by antipsychotics)Suggestion: Antipsychotics = dopamine receptor

antagonists (neuroleptics)

SNYDER (1976,1978)

Examined the ability of antipsychotic (neuroleptic) drugs to bind to dopamine receptors.

Examined the relationship of a drug’s receptor binding affinity with its potency to reduce schizophrenic symptoms.

SNYDER (1976, 1978)

Extracted neostriatum from calf brains - neurons contain dopamine receptorsExposed neurons to radioactive dopamineWashed away unbound dopamineMeasured amount of radioactivity in the

neostriatum = measure of dopamine receptor binding

Measured the ability of various antipsychotics to block the binding of radioactive dopamine.

SNYDER (1976, 1978)

RESULTS:

Highly clinically effective antipsychotics had a high binding affinity for dopamine receptors.Less effective antipsychotics had a lower

affinity.One exception = Haloperidol - highly clinically effective for schizophrenia - low binding affinity to striatal dopamine receptors

The Haloperidol Puzzle

Striatal Neurons mostly D1 receptorsChlorpromazine binds to D1 and D2

receptorsHaloperidol binds preferentially to D2

receptorsChlorpromazine = Phenothiazines = D1,

D2Haloperidol = Butyrophenones = D2

selective

The Dopamine Receptors

D1D2aD2bD3D4 Clozapine binds to D4 receptors D5Clozapine = an atypical neuroleptic. No

Parkinsonian side effects. High binding to D4

Haloperidol binds best to D2 receptors

WHAT IS WRONG WITH THE DOPAMINERGIC SYNAPSE IN SCHIZOPHRENICS?

POSSIBILITIES: 1. Increased release of dopamine?

- More excitatory input to dopamine-containing neurons - Fewer or defective autoreceptors on dopamine neuron

2. Overabundance of dopamine receptors on post-synaptic neuron? - more response in postsynaptic neuron to dopamine receptor activation

Where are the dopaminergic abnormalities located?

The Neostriatum?Amygdala?Frontal cortex?Nucleus accumbens? - D4 receptors located here

The Nucleus Accumbens

Are reinforcement/reward and schizophrenia related? -If reinforcement mechanisms are active at inappropriate times, then inappropriate behaviors (e.g., delusional thoughts) may be reinforced.-Elation/euphoria reported to occur at onset

of schizophrenic episode.

BRAIN ABNORMALITIES AND SCHIZOPHRENIA

Since typical antipsychotics DO NOT alleviate negative symptoms associated with schizophrenia

and the negative symptoms are similar to those produced by frontal lobe damage

…Then, maybe frontal lobe dysfunction contributes to the negative symptoms of schizophrenia.

Weinberger (1980’s – present)

Studied discordant identical twins:SCHIZOPHRENIC twin showed

enlarged ventricles in 16 of 17 pairs.SCHIZOPHRENICS, in general, have

larger ventricular to brain ratios (i.e., larger ventricles, less brain).

Weinberger (1992)

Wisconsin Card Sorting Task (WCST)WCST activates the lateral prefrontal

lobe Patients with lateral prefrontal lobe damage

Deficient in WCSTIdentical twins: discordant for

SCHIZOPHRENIAPET scan during WCST

Weinberger, 1992 - WCST

Weinberger (1992)

RESULTS:SCHIZOPHRENIC twin impaired on task,

just like people with prefrontal lobe damage

SCHIZOPHRENIC twin shows hypoactivity in frontal lobe (decrease blood flow vs. unaffected twin)

Many SCHIZOPHRENICS are impaired on task and show frontal lobe hypoactivity

Wolkin et al. (1992)Correlated the NEGATIVE SYMPTOMS

with FRONTAL LOBE metabolism (e.g., activity) in SCHIZOPHRENIC patients.

RESULTS: The more severe the negative symptoms, the less the metabolism (activity)

However, NO GROSS STRUCTURAL ABNORMALITIES in SCHIZOPHRENICS!!!!!!

WHAT ARE THE CAUSES OF hypoFRONTALITY?

Abnormality in the development of frontal lobe?

Benes et al. (1986,1991)

Took a closer look at the cells in the FRONTAL CORTEX…

SCHIZOPHRENIC BRAINS vs NORMAL BRAINS:

Benes et al. (1991)

Abnormally LOW number of neurons in LAYERS I and II (outer layers) of the FRONTAL CORTEX.

Abnormally HIGH number of neurons in LAYER V (deep layers)of the FRONTAL CORTEX.

Suggest: Abnormalities NOT due to degeneration (since levels of glia cells normal) but due to DEVELOPMENTAL abnormalities.

WHAT DEVELOPMENTAL FACTOR(S) MAY CAUSE BRAIN ABNORMALITY?

A VIRUS?

GENETIC ABNORMALITY?

AN INTERACTION OF THE TWO?

Epidemiological Evidence for an Environment influence

Mednick (1988) - Helsinki, Finland -1957 ~ Asian Flu Epidemic (Virus) - Higher incidence of SCHIZOPHRENIA in fetuses carried during the epidemic vs. before epidemic - KEY POINT: Fetuses whose mothers developed the Flu during the 2nd trimester of pregnancy had highest incidence of schizophrenia as adults

WHAT HAPPENS DURING THE 2ND TRIMESTER OF PREGNANCY?

Marked development of the neocortexCortex develops inside out:Cells migrate to deep layers 1st.Cells of the outer layers must migrate

through deep layers).In the SCHIZOPHRENIC brain, cells

destined to be the outer layers of the cortex get STUCK and never make it there.

ADDITIONAL SUPPORT FOR DEVELOPMENTAL FACTORS…Brach et al. (1992)

“CHRONO MARKERS” OR “FOSSILS” OF 2ND TRIMESTER development: CORTEX AND FINGER TIP DERMAL CELL MIGRATION

Studied: MONOZYGOTIC TWINS

- NON-SCHIZOPHRENIC PAIRS (n=7) - SCHIZOPHRENIC DISCORDANT PAIRS

(n=23) Measured: INTRA-TWIN

DIFFERENCES IN FINGER TIP RIDGE PATTERNS

Brach et al. (1992)

RESULTS: - NON-SCHIZOPHRENIC TWINS ALL

HAVE SAME FINGER PRINTS (not a lot of differences). - TWINS DISCORDANT FOR

SCHIZOPHRENIA have different finger prints!

Brach et al. (1992)

CONCLUDE: - During the 2nd trimester of pregnancy,

something in the “environment” may have differentially affected one twin but not the other.

- Maybe it was a virus, but we still don’t have the answer…

IN SUMMARY:

SCHIZOPHRENIA IS A BIOLOGICAL DISEASE THAT MAY INVOLVE DISRUPTION OF MANY SYSTEMS FRONTAL CORTEX DOPAMINE SYSTEMS

GENETIC, ENVIRONMENTAL AND DEVELOPMENTAL FACTORS ARE IMPORTANT FOR THE GENISIS OF THE DISEASE

An Animal Model of Schizophrenia??

Phencyclidine (PCP) – “angel dust”Single ingestion transient schizo. symptomsChronic use long lasting schizo. symptoms - social withdrawal - flattened emotional responses - hallucinations - thought disorders - delusions, paranoia - Cognitive dysfunction, hypofrontality

Jentsch et al. (1997)

Effects of chronic PCP exposure in monkey - twice/day for 14 daysMeasured: - cognition dependent on normal frontal lobe

dopamine levels - frontal lobe dopamine utilizationTask – “Object Retrieval with a Detour” task -transparent box with one open side -open side oriented to the front, right or left of

monkey -box contains a treat -monkey retrieves treat from one orientation (front)

Jentsch et al. – cont.

- re-orient the box opening to left - monkey must redirect response without touching a

closed side to be successfulDesign: - give PCP or saline for two weeks, then stop

treatment - administer task from 7-28 days later Results: - PCP-treated monkeys showed perseveration when box is re-oriented. They keep making the original response

Jentsch et al. – cont.

Important Points: - Deficits identical to those seen in monkeys w/ frontal lesions or frontal dopamine depletion - Deficits similar to those seen in schizophrenics or humans with frontal lobe lesionsResults: Dopamine Assay - chronic PCP decreases dopamine utilization in the prefrontal cortex

Jentsch et al. – cont.Dopamine antagonists exacerbate cognitive dysfunction in schizo.Suggests: - a subset of schizo. symptoms may be due to dopamine hypoactivity in frontal lobesClozapine =atypical neuroleptic - improves performance of chronic PCP monkeys in object retrieval task -increases basal dopamine concentration in frontal cortex