SCHIZOPRENIA
Incidence of SCHIZOPHRENIA: World Health Organization (1992)
DEVELOPED COUNTRIES
ROCHESTER, NY
MOSCOW, RUSSIA
AARHUS, DENMARK
DEVELOPING COUNTRIES
AGRA, INDIA
CALI, COLUMBIA
IBADAN, NIGERIA
SOME STATISTICS:
1% OF U.S. POPULATION
1 in 3 PSYCHIATRIC HOSPITAL BEDS
$65 BILLION
DIRECT TREATMENT
SOCIETAL COSTS
hospitals and institutions
law enforcement and judicial system
FAMILY COSTS
TWO CATEGORIES OF SYMPTOMS:
POSITIVE SYMPTOMS
THOUGHT DISORDERS
DELUSIONS-BELIEFS
CONTRARY TO FACTS
PERSECUTION
GRANDEUR
CONTROLL BY OTHERS
PARANOIA
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 DATA
PHARMACOLOGICAL DATA
BRAIN IMAGING DATA
DEVELOPMENTAL DATA
WHAT IS THE EVIDENCE?
GENETICS
THE GENETICS OF SCHIZOPHRENIA
FAMILY STUDIES
MONOZYGOTIC TWINS ~ identical twins
DIZYGOTIC ~ fraternal twins
- CONCORDANT ®
both twins SCHZO.
- DISCORDANT ®
one twin SCHZO.
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 in 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Charpentier ~ chlorpromazine "quieted hyperactive" mental patients & "activated withdrawn" mental patients.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 receptors
- Exposed neurons to radioactive dopamine
- Washed away unbound dopamine
- Measured 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 receptors
Chlorpromazine binds to D1 and D2 receptors
Haloperidol binds preferentially to D2 receptors
Chlorpromazine = Phenothiazines = D1, D2
Haloperidol = Butyrophenones = D2 selective
The Dopamine Receptors
D1
D2a
D2b
D3
D4 Clozapine binds to D4 receptors
D5
Clozapine = an atypical neuroleptic. No Parkinsonian side effects. High binding to D4
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?
- 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 DAMAGE 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 WCST
- Identical twins: discordant for SCHIZOPHRENIA
- PET 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?
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 developing during
2nd Trimester had HIGHEST incidence
of schizophrenia as adults
WHAT HAPPENS DURING THE 2ND TRIMESTER OF PREGNANCY?
Marked development of the neocortex
Cortex 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. symptoms
Chronic use long lasting schizo. Symptoms
- social withdrawal
- flattened emotional responses
- hallucinations
- thought disorders
- delusions, paranoia
- PCP Frontal lobe damage, hypofrontality in humans
Jentsch et al. (1997)
Effects of chronic PCP exposure in monkey
- twice/day for 14 days
- cognition dependent on normal frontal lobe dopamine levels
- frontal lobe dopamine utilization
- Task – "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 successful
- give PCP or saline for two weeks, then stop treatment
- administer task from 7-28 days later
- 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 lesions
- 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 lobes
Clozapine =atypical neuroleptic
- improves performance of chronic PCP
monkeys in object retrieval task
-increases basal dopamine concentration in frontal
cortex