Antipsychotics

Question 1

What are the 5 symptom domains of schizophrenia?

Answer 1

1. positive symptoms
2. negative symptoms
3. anxiety/depression
4. aggressive symptoms
5. cognitive symptoms

Question 2

What are some examples of positive symptoms?

Answer 2

Delusions (paranoia)
Hallucinations (voices)
Thought disorder: thoughts controlled by external agency
Abnormal behaviours
*Lack of insight/self-awareness of abnormal behaviour

Question 3

Which type of symptoms are more disturbing to patients and why?

Answer 3

Negative symptoms: something is missing

withdrawal from social contacts, flattening of emotional responses

Question 4

When do negative symptoms occur?

Answer 4

Primary deficit of illness

Secondary to: depression, extrapyramidal symptoms, environmental deprivation, positive symptoms

Question 5

What is cognitive dysfunction?

Answer 5

Impairment of selective attention

Impairment of working memory

Question 6

Why is cognitive dysfunction a good predictor of treatment outcome?

Answer 6

Predicts level of social and vocational functioning more than positive symptoms

Question 7

What are the causes of schizophrenia?

Answer 7

1. Genetic: partially hereditary, candidate genes (DISC1, neuregulin-1, dysbindin-1, and catechol-O-methyltransferase(COMT))
   - > not universal mutations of susceptibility genes
2. Environment: (during pregnancy) maternal viral infections or complications
3. Neurodevelopmental disorder: enlarged ventricles, abnormalities in laminar organization of cortical cells

Question 8

List the 4 dopamine pathways of the brain

Answer 8

1. Nigrostriatal: substantial nigra to dorsal striatum
2. Mesocortal: ventral tegmental area to prefrontal cortex
3. Mesolimbic: VTA to limbic (emotional) brain
4. Tuberoinfundibular: hypothalamus to anterior pituitary

Question 9

Which dopamine pathways are most relevant to schizophrenia?

Answer 9

Mesocortal: reward & emotion
Mesolimbic: cognition & attention

Question 10

Which 2 dopamine pathways are off-target for antipsychotics?

Answer 10

Nigrostriatal: voluntary movement/extrapyramidal motor system (EPS symptoms = parkinsonian)
Tuberoinfundibular: regulate prolactin secretion to activate milk production

Question 11

How do the 3 theories of positive symptoms work?

Answer 11

Produce smx similar to acute schizophrenia:
Dopamine agonist (amphetamine)
Serotonin agonist (LSD 5-HT2) 
Glutamate antagonist (PCP, ketamine NMDA antagonist)

Question 12

What is the main difference between typical and atypical antipsychotics?

Answer 12

Typical: EPS (extrapyramidal side effects in basal ganglia + nigrostriatal pathway) e.g. acute dystonia, tardive dyskinesia & akathisia
Atypical: less EPS

Question 13

Why do EPS occur?

Answer 13

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

Question 14

List 4 typical antipsychotics

Answer 14

Haloperidol
Chlorpromazine
Fluphenazine
Trifluoroperazine

Question 15

What are the ADRs associated with typical antipsychotics?

Answer 15

Antimuscarinic: dry mouth, constipation, blurred vision
1st gen antihistamine: sedation, weight gain
A-adrenergic receptor block: (vasodilation) postural hypotension, dizziness

Question 16

Why is haloperidol the only frequently used typical antipsychotic now?

Answer 16

Less EPS

No antimuscarinic and sedative side effects due to single selective mechanism

Question 17

List 4 atypical antipsychotics

Answer 17

Amisulpride
Aripiprazole
Clozapine/olanzapine
Risperidone

Question 18

Which receptors do all atypical antipsychotics act on?

Answer 18

Antagonism of 5HT2 & D2 receptors

Question 19

Why was olanzapine developed?

Answer 19

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

Question 20

Which atypical antipsychotics have the typical antipsychotic ADRs?

Answer 20

Clozapine & olanzapine: antimuscarinic & antihistamine (sedation)
Risperidone: (a1-adrenoceptor antagonism) postural hypotension & reflex tachycardia

Question 21

Amisulpride has an atypical receptor affinity pattern for atypical antipsychotics because ___.

Answer 21

It has no serotonin affinity and no affinity for a-adrenoceptor, muscarinic or histamine antagonism.
It is a selective D2/D3 antagonist

Question 22

How does amisulpride exert an effect on mammary glands and tissues?

Answer 22

Block dopamine receptors in anterior pituitary gland in tuberoinfundibular pathway -> increase prolactin secretion

Question 23

Which drug causes gynaecomastia?

Answer 23

Amisulpride
Female: breast swelling, pain, lactation
Male: gynaecomastia

Question 24

What is the mechanism of action of aripiprazole?

Answer 24

Partial agonist that displaces dopamine -> decrease effect of dopamine (antagonist effect)

Question 25

What are some adverse effects that are only caused by 3 atypical antipsychotic drugs? Which drugs are these?

Answer 25

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

Question 26

To which atypical antipsychotics do the following mechanisms of reduced EPS apply?

1. Potent 5-HT2A receptor antagonism vs. weak D2 antagonism -> higher efficacy against negative symptoms (less effect on substantia nigra)
2. High D3 > D2 antagonism: actions on the nucleus accumbens > striatum.
3. High D4 > D2 antagonism: actions in the prefrontal cortex > striatum.
4. High D2 > D1 antagonism: reduces impact of antagonism in the striatum.

Answer 26

1. clozapine, olanzapine
2. amisulpride
3. clozapine
4. amisulpride, risperidone

Question 27

Why does D2 > D1 antagonism reduce impact of antagonism in the striatum?

Answer 27

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

Question 28

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

Answer 28

b) Olanzapine

Question 29

In what situation should atypical antipsychotics be chosen?

Answer 29

Patients who start out with severe negative symptoms due to weak & incomplete effects on negative smx.