Antipsychotics Flashcards
What are the 5 symptom domains of schizophrenia?
- positive symptoms
- negative symptoms
- anxiety/depression
- aggressive symptoms
- cognitive symptoms
What are some examples of positive symptoms?
Delusions (paranoia)
Hallucinations (voices)
Thought disorder: thoughts controlled by external agency
Abnormal behaviours
*Lack of insight/self-awareness of abnormal behaviour
Which type of symptoms are more disturbing to patients and why?
Negative symptoms: something is missing
withdrawal from social contacts, flattening of emotional responses
When do negative symptoms occur?
Primary deficit of illness
Secondary to: depression, extrapyramidal symptoms, environmental deprivation, positive symptoms
What is cognitive dysfunction?
Impairment of selective attention
Impairment of working memory
Why is cognitive dysfunction a good predictor of treatment outcome?
Predicts level of social and vocational functioning more than positive symptoms
What are the causes of schizophrenia?
- Genetic: partially hereditary, candidate genes (DISC1, neuregulin-1, dysbindin-1, and catechol-O-methyltransferase(COMT))
- > not universal mutations of susceptibility genes - Environment: (during pregnancy) maternal viral infections or complications
- Neurodevelopmental disorder: enlarged ventricles, abnormalities in laminar organization of cortical cells
List the 4 dopamine pathways of the brain
- Nigrostriatal: substantial nigra to dorsal striatum
- Mesocortal: ventral tegmental area to prefrontal cortex
- Mesolimbic: VTA to limbic (emotional) brain
- Tuberoinfundibular: hypothalamus to anterior pituitary
Which dopamine pathways are most relevant to schizophrenia?
Mesocortal: reward & emotion
Mesolimbic: cognition & attention
Which 2 dopamine pathways are off-target for antipsychotics?
Nigrostriatal: voluntary movement/extrapyramidal motor system (EPS symptoms = parkinsonian)
Tuberoinfundibular: regulate prolactin secretion to activate milk production
How do the 3 theories of positive symptoms work?
Produce smx similar to acute schizophrenia: Dopamine agonist (amphetamine) Serotonin agonist (LSD 5-HT2) Glutamate antagonist (PCP, ketamine NMDA antagonist)
What is the main difference between typical and atypical antipsychotics?
Typical: EPS (extrapyramidal side effects in basal ganglia + nigrostriatal pathway) e.g. acute dystonia, tardive dyskinesia & akathisia
Atypical: less EPS
Why do EPS occur?
Acute dystonia: D2 antagonism in nigrostriatal pathway, reversible if drug stopped
Tardive dyskinesia & akathisia: upregulation or supersensitivity of dopamine receptors in nigrostriatal system, usually irreversible
Akathisia: correlates with duration on medication
List 4 typical antipsychotics
Haloperidol
Chlorpromazine
Fluphenazine
Trifluoroperazine
What are the ADRs associated with typical antipsychotics?
Antimuscarinic: dry mouth, constipation, blurred vision
1st gen antihistamine: sedation, weight gain
A-adrenergic receptor block: (vasodilation) postural hypotension, dizziness
Why is haloperidol the only frequently used typical antipsychotic now?
Less EPS
No antimuscarinic and sedative side effects due to single selective mechanism
List 4 atypical antipsychotics
Amisulpride
Aripiprazole
Clozapine/olanzapine
Risperidone
Which receptors do all atypical antipsychotics act on?
Antagonism of 5HT2 & D2 receptors
Why was olanzapine developed?
Clozapine had agranulocytosis (lack of granulocyte WBC) which was rare but could be fatal
-> Needed regular blood count monitoring
Olanzapine is related to clozapine but has no agranulocytosis adverse effect
Which atypical antipsychotics have the typical antipsychotic ADRs?
Clozapine & olanzapine: antimuscarinic & antihistamine (sedation)
Risperidone: (a1-adrenoceptor antagonism) postural hypotension & reflex tachycardia
Amisulpride has an atypical receptor affinity pattern for atypical antipsychotics because ___.
It has no serotonin affinity and no affinity for a-adrenoceptor, muscarinic or histamine antagonism.
It is a selective D2/D3 antagonist
How does amisulpride exert an effect on mammary glands and tissues?
Block dopamine receptors in anterior pituitary gland in tuberoinfundibular pathway -> increase prolactin secretion
Which drug causes gynaecomastia?
Amisulpride
Female: breast swelling, pain, lactation
Male: gynaecomastia
What is the mechanism of action of aripiprazole?
Partial agonist that displaces dopamine -> decrease effect of dopamine (antagonist effect)
What are some adverse effects that are only caused by 3 atypical antipsychotic drugs? Which drugs are these?
Olanzapine, clozapine, risperidone
Diabetes: may be irreversible -> 5-HT antagonism in hypothalamus or pancreatic beta cells
Weight gain: unexplained if caused by antihistamine or a-adrenoceptor & 5-HT receptor antagonism effect on hypothalamus
To which atypical antipsychotics do the following mechanisms of reduced EPS apply?
- Potent 5-HT2A receptor antagonism vs. weak D2 antagonism -> higher efficacy against negative symptoms (less effect on substantia nigra)
- High D3 > D2 antagonism: actions on the nucleus accumbens > striatum.
- High D4 > D2 antagonism: actions in the prefrontal cortex > striatum.
- High D2 > D1 antagonism: reduces impact of antagonism in the striatum.
- clozapine, olanzapine
- amisulpride
- clozapine
- amisulpride, risperidone
Why does D2 > D1 antagonism reduce impact of antagonism in the striatum?
Block postsynaptic D2 but also block D2 presynaptic feedback inhibition
- > partially mediate blockage effect
- > D2 is usually an autoreceptor -> inhibit dopamine release
- > block inhibition of dopamine release -> ameliorate deficit from blocking postsynaptic D2
There are additional benefits to atypical antipsychotics such as effectiveness against negative symptoms, improving cognitive dysfunction and mood stabilization. Which antipsychotic is does not ameliorate cognitive dysfunction?
a) Clozapine
b) Olanzapine
c) Risperidone
b) Olanzapine
In what situation should atypical antipsychotics be chosen?
Patients who start out with severe negative symptoms due to weak & incomplete effects on negative smx.
