Transcript SCHIZOPHRENIA2001

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. 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
CONTROL 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
TWIN STUDIES
MONOZYGOTIC TWINS ~ identical twins
DIZYGOTIC ~ fraternal twins
 CONCORDANT
 DISCORDANT
ADOPTION STUDIES


both twins SCHZO.
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 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 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
Haloperidol binds best to D2 receptors
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 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 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?
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 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
- Cognitive dysfunction, hypofrontality
Jentsch et al. (1997)
Effects of chronic PCP exposure in monkey
- twice/day for 14 days
Measured:
- 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
Design:
- 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 lesions
Results: 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 lobes
Clozapine =atypical neuroleptic
- improves performance of chronic PCP
monkeys in object retrieval task
-increases basal dopamine concentration in frontal
cortex