Schizophrenia

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The genetic risk of schizophrenia
1% in general population rises to 50% risk if one has an affected twin
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Possible environmental risks for scizophrenia?
Prenatal infection, malnutrition, cannabis exposure, urban living, stress in adolescence
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What is the dopamine hypothesis of schizophrenia?
Dopamine hyperactivity underlies positive symptoms
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Drug evidence for the dopamine hypothesis
Amphetamine, L-Dopa can cause psychotic symptoms. Effective antipsychotics block d2 receptors in the brain, and affinity for D2 receptors correlate with clinical potency of drug.
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Genetic evidence for the dopamine hypothesis
Associations in the dopaminergic system includng DRD2, DRD3, BDNF, COMT
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Post-mortem evidence for DA hypothesis
Increased number of D2 dopamine receptors in schizophrenic brain at post mortem
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Define typical and atypical antispychotics
Typical - developed pre-1980s, atypical - 1980s onwards
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Two typical antipsychotic drugs
Chlorpromazine and Haloperidol
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Mechanism of action of typical antipsychotics
act as agonists at D2 receptor.
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Bad things about the typical antipsychotics
Only the positive symptoms are tackled, and there is a lag in clinical relief, Side effects
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Side effects of typical antipsychotics
Sedation (H1 block), Hypotension (a-adrenoreceptor block), anticholinergic effects, And side effects due to widespread D2 blockade
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Side effects of D2R blockade
Mesolimbic - overactive in Sz. Tuberoinfundibular pathway - increase prolactin secretion leading to gynaecomastia. Nigrostriatal pathway = extrapyramidal side effects
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Examples of reversible extrapyramidal side effects
Dystonia, parkinson's like symptoms. 20% of patients
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An example of a possibly permanant side effect
Tardive dyskinesia, possibly due to dopamine overactivity, compensatory D2 upregulation
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Two Atypical anti psychotic drugs
Clozapine and Olanzapine
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What receptors do the atypical antipsychotics block
5-HT, DA-D4.
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What is the effect of blocking the D2 and D4 receptors
Combats positive symptoms, d4 is not found in nigrostriatal pathway so less extrapyramidal pathway
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How are negative symptoms addressed
5HT2-R Blockade may underlie this, more research is needed
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Side effects of atypical antipsychotics
Sedation, hypotension, anticholinergic effets as per typicals, weight gain and insulin resistance
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Another important side effect
Leucopenia or agranulocytosis, reversible fatal loss of neutrophils, basophils and eosinophils. Seen w clozapine. Rare idiosyncratic event seen in 1-2% of patients in first few weeks.
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Another mechanism proposed by drugs in development
Glutamate hypoactivity
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Genetic associates for glutaminergic involvement
GRIN1 - a NMDAR1 subunit. NRG1, neuregulin, controls expression of glutamate.
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Mice experiements for glutamate involvement
NMDA-R knockdown shows stereotyped beh that can be reversed with antipsychotics. Pencyclidine mimics positive and negative symptoms
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Possible environmental risks for scizophrenia?

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Prenatal infection, malnutrition, cannabis exposure, urban living, stress in adolescence

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What is the dopamine hypothesis of schizophrenia?

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Drug evidence for the dopamine hypothesis

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Genetic evidence for the dopamine hypothesis

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