Psychotic Disorders - Schizophrenia Flashcards
Name 3 psychotic disorders you know.
Schizophrenia
Bipolar disorder
Major depressive disorder
What are the main symptoms of psychosis ?
Delusions, hallucinations and ‘lack of insight’
How are SCZ symptoms classified ?
Name which symptoms according to their class.
Positive (Type 1) : - auditory hallucinations - delusions - thought disorder - thought broadcasting. Negative (Type 2) : - lack of drive - social withdrawal - motor disturbance (catatonia). Cognition impaired
What is the prevalence of SCZ ?
When does it usually arise ?
What percentage of affected individuals attempt suicide ?
- 1% prevalence
- Onset: late teens / early 20s
- 40% attempt suicide
What are the possible causes of SCZ ?
- “It’s genetic” (17% dizygotic twins, 48% monozygotics)
- “It’s viral”
- Developmental disorder?
- The pink spot theory (rubish)
What are the main NTs involved in SCZ ?
DA - Amphetamine
5-HT - LSD
Glutamate - PCP
What are the “D1-like” DA Rs ?
What about the “D2-like DA Rs ?
D1-like = D1 + D5 D2-like = D2, D3, D4
What evidence led to the “Dopamine Hypothesis” of SCZ ?
• Amphetamine
Drugs release dopamine and produce symptoms identical to positive symptoms of
schizophrenia – blocked by antipsychotics
• D2-like DA R agonists
Drugs like apomorphine and bromocriptine (used in PD) produce positive symptoms of schizophrenia.
• Reserpine (antihypertensive drug that depletes DA from synaptic vesicles)
• D2-like DA R antagonists
Reduce positive symptoms of schizophrenia and amphetamine-induced behavioural changes.
Is there direct biochemical evidence supporting the DA hypothesis of SCZ ?
No, or at least it is not as supportive. There is only indirect evidence of this hypothesis.
Which DA pathways are affected in SCZ ?
How does this correlate w/ +ve and -ve symptoms.
The mesocortical pathway (VTA to PFC) in hypoactive (“hypofrontality”) –> -ve symptoms
The mesolimbic pathway (VTA to NAcc) is hyperactive –> +ve symptoms
In a normal individual, what is the interaction between the mesocortical and mesolimbic pathways ?
It is though that, normally, the mesocortical pathway inhibits thee mesolimbic pathway.
What do we mean by typical anti-psychotics ?
Anti-psychotics that cause “typical” side effects :
- postural hypotension
- sedation
- anti-muscarinic effects (dry mouth, blurred vision, contipation etc.)
Give examples of typical anti-psychotics.
Phenothiazines
- Chlorpromazine (aliphatic) –> low D2affinity (1, H1 and mAch receptor antagonist)
- Thioridazine (piperidine) (strong mAch receptor antagonist)
- Trifluoperazine/Fluphenazine* (piperazine) –> higher affinity (*depot administration - esters of decanoate/ethanate)
Thioxanthines
- Flupenthixol
Butyrophenones
- Haloperidol –> highest D2 affinity
Does a typical anti-psychotic binding affinity have any influence on its effect ?
Correlation of typical antipsycholtic binding affinity with clinical effect.
What effects do typical antipsychotics have on the different DA pathway ?
Which of these are desriable Vs non-desirable ?
Mesocorticolimbic tracts –> Neuroleptics prevent hallucinations ==> good
Nigrostriatal system –> Neuroleptics induce movement disorders (EPS) ==> bad
Tuberoinfundibular system (hypothalamic) –> Neuroleptics cause hyperprolactinaemia ==> bad
What are the side effects of neuroleptics ?
Extrapyramidal Symptoms (EPS)
- Parkinsonian-like (akinesia, rigidity, tremor)
- Dystonia (head/neck/trunk muscle spasm – oculogyric crisis, glossospasm, torticollis)
- Tardive dyskinesia (involuntary face/tongue/limb movement)
- Akathesia (involuntary motor restlessness)
Hyperprolactinaemia (gynaecomastia/galactorrhea/pseudopregancy)
Sedation (H1 receptor block)
Autonomic effects
- Orthostatic hyptension (1-adrenoceptor block)
- Dry mouth, mydriasis/blurred vision/glaucoma, xerophthalmia, constipation, urinary hesitancy (mAch receptor block)
Aplastic anaemia (chlorpromazine) [Neuroleptic malignant syndrome]
How effective are typical antipsychotics at treating the +ve Vs -ve symptoms ?
DA receptor antagonists reduce positive symptoms
- nucleus accumbens
Typical neuroleptics do not reduce negative symptoms
- hypofrontality syndrome (prefrontal cortex)
What are the advantages of a drug such as clozapine ?
- High efficacy than previous neuroleptics with just 30% D2 occupancy
- Fewer EPS
- Positive AND negative symptoms addressed
- Drug-resistant psychosis
- Less tardive dyskinesia
Name dibenzazepine derivatives and benzisoxazole derivatives that are atypical neuroleptics.
DIBENZAZEPINE DERIVATIVES - Clozapine - Olanzapine - Quetiapine BENZISOXAZOLE DERIVATIVES - Risperidone - Paliperidone (primary active metabolite of risperidone) - Ziprasidone
What is the proportion of D2 Rs occupied by atypical neuroleptics ?
30%
What is the proportion of D1 Vs D2 Vs 5HT-2A Rs occupied by :
- chlorpromazine
- haloperidol
- atypicals
Chlorpromazine :
- medium D1, D2 and 5HT-2A occupancy
Haloperidol :
- no D1, Large D2, small 5HT-2A occupancy
Atypicals :
- small D1, small D2, medium 5HT-2A occupancy
What are the side effects of atypical neuroleptics ?
Hyperprolactinaemia (gynaecomastia/galactorrhea/pseudopregancy) Autonomic effects Orthostatic hyptension (1-adrenoceptor block) ECG prolongation (QT interval) Metabolic Effects Weight gain (esp olanzapine) Hypercholesterolaemia Type 2 diabetes Sialorrhoea (dribbling) Agranulocytosis (1%)/ leukopenia
How do 3rd generation antipsychotics work ?
D2 partial agonist (high affinity/low intrinsic activity)
5HT-1A partial agonist
5HT-2A weak antagonist
Name a 3rd generation anti-psychotic.
Aripiprazole.
What are the pros and cons of 3rd generation antipsychotics such as aripiprazole ?
Pros: - Few EPS – no difference from placebo - Little weight gain –Few CV (Q-T) abnormalities - Apparently safe in overdose Cons: - Hyperprolactinaemia - Hypercholesterolaemia - Akathisia - emerging as a problem
