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Psychotic Disorders (Psychosis (Schizophernia, Bipolar disorder, major…

- - - - auditory hallucinations
      - delusions
      - thought disorder
      - thought broadcasting
    - - lack of drive
      - social withdrawal
      - motor disturbance (catonia)
  - - - 17% dizygotic twins
      - 48% monozygotic twins
    - - disproved
  - - - receptors
        
        D1 family
        
        D1
        
        D5
        
        D2 family
        
        D2
        
        excessive stimulation in Psychosis
        
        D3
        
        D4
      - Dopamine hypothesis
        
        Drugs that release DA produce symptoms similar to positive symptoms of schizophrenia
        
        D2-like DA receptor agonists
        
        produce positive symptoms of Schizophrenia
        (e.g. apomorphine, bromocriptine - drugs used in Parkinsonism)
        
        only indirect evidence for this hypothesis
        
        Working Hypothesis
        
        Mesolimbic pathway hyperactivity
        
        positive symptoms
        
        Mesocortical pathway hypoactivity
        
        negative symptoms
        
        mesocortical pathway excites regions in prefrontal cortex, which are inhibitory interneurons that inhibit mesolimbic pathway
        
        Resperine (antihypertensive drug that depletes dopamine from synaptic vesicles) and D2-like DA receptor antagonists
        
        reduce positive symptoms of Schizophrenia and amphetamine-induced behavioural changes
      - Amphetamine can elicit psychosis-like symptoms
      - Dopaminergic pathways
        
        Ventral Tegmental Area
        
        Mesocortical pathway (attention)
        
        Mesolimbic pathway (reward)
        
        Striatum
        
        Nigro-Striatal pathway (motor)
        
        Arcuate Nucleus of the Hypothalamus
        
        Tubero-infundibular pathway (prolactin release)
    - - 5HT2 antagonist do not alleviate psychotic symptoms
      - 5HT 2A
        
        excitatory
      - 5HT 1A
        
        inhibitory
- - - - Chlorpromazine
        
        D2 low affinity receptor antagonist
        
        also A1, H1, and mACh receptor antagonist
      - Thioridazine
        
        strong mAChR antagonist
      - Trifluoperazine/Fluphenazine
        
        higher D2 affinity
      - Thioxanthimes
        
        e.g. Flupenthixol
      - Butyrophenones
        
        Haloperidol
        
        highest D2 affinity
      - Positive correlation with typical antipsychotic affinity to D2 receptors with clinical effect
      - effects on different DA systems
        
        mesocorticolimbic tracts
        
        prevent hallucinations
        
        Nigrostriatal system
        
        induce movement disorders (EPS)
        
        Tuberoinfundibular system (hypothalamus)
        
        cause hyperprolactinaemia
      - side effects
        
        Extrapyramidal Symptoms (EPS)
        
        Parkinson-like (tremor, akinesia, rigidity)
        
        Dystonia (head/neck/trunk muscle spasp
        
        Tardive dyskinesia (involuntary face/tongue/limb movement)
        
        Akathesia (involuntary motor restlessness)
        
        Hyperprolactineamia
        
        Sedation
        
        H1 receptor blcok
        
        Autonomic effects
        
        hypotension (A1-adrenoceptor block)
        
        Dry mouth, mydriasis, glaucoma, constipation (mAChR block)
        
        Aplastic anaemia
      - Positive vs negative symptoms
        
        reduce positive symptoms
        
        do not reduce negative symptoms
      - Phenothiazine
        
        causes sedation
      - mechanism of action
        
        block D2 receptors
  - - - Clozapine
        
        Pros
        
        Fewer EPS
        
        Positive and Negative symptoms addressed
        
        Drug-resistant psychosis
        
        less tardive dyskinesia
      - side effects
        
        Hyperprolactinaemia
        
        Autonomic effects
        
        orthostatic hypotension
        
        ECG prolongation (QT interval)
        
        Metabolic effects
        
        weight gain
        
        type 2 diabetes
        
        hypercholeterolaemia
        
        Sialorrhoea
        
        Agranulocytosis
      - mechanism of action
        
        block the inhibitory presynaptic 5HT2 receptors on the DA neurons in mesocortical pathway to increase the DA release
        
        low affinity for D1&D2 receptors
        
        reduce negative symptoms
      - Resperidone
  - - - mechanism of action
        
        5HTA agonist
        
        5HT2A antagonist
        
        D2 partial agonist
        (high affinnity, low intrinsic activity)
      - pros
        
        few EPS - no differece from placebo
        
        little weight gain
        
        few cardiovascular (Q-T) abnormalities
      - cons
        
        Hyperprolactineamia
        
        Hypercholeterolaemia
        
        Akathisia