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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 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 ®   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 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 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