Antipsychotics

Question 1

What are the general symptoms of schizophrenia?

Answer 1

• Periods of acute presentation with positive symptoms (abnormal behaviors added) are interspersed with periods during which the negative symptoms (normal behaviors subtracted) predominate.
• As the disease progresses, the negative symptoms become more dominant

Question 2

Positive symptoms of schizophrenia

Answer 2

• Delusions (often paranoia)
• Hallucinations (e.g. exhortatory voices)
• Thought disorder including feelings that thoughts are controlled by an outside agency.
• Abnormal behaviours (e.g. stereotypical or aggressive behaviors).

Question 3

Negative symptoms of schizophrenia

Answer 3

• Withdrawal from social contacts

- Flattening of emotional responses

Question 4

Possible cognitive dysfunction from schizophrenia

Answer 4

• Impairment of selective attention and working memory.
• Important because it predicts level of social vocational functioning.
• Persistent feature of the disease, not iatrogenic (caused by the physican or medication).

Question 5

Genetic factors that cause schizophrenia

Answer 5

• Incomplete hereditary tendency (50% risk in monozygotic twin of affected individual).
• Suspect chromosomal regions that prognosticate susceptibility to schizophrenia include:
  » DISC1, neuregulin-1, dysbindin-1 and catechol-O-methyl transferase (COMT).

Question 6

Environmental factors that cause schizophrenia

Answer 6

• Maternal viral infections during pregnancy

- Obstetric complications

Question 7

What causes schizophrenia in late adolescents / early adults?

Answer 7

Neurodevelopmental abnormality involving myelination of cortico-cortical pathways.
» Evidence of enlarged ventricles, abnormalities in laminar organization of cortical cells, pointing to a possible neurodevelopmental disorder.

Question 8

What are the different neurochemical theories?

Answer 8

1. Dopamine Theory
   - Amphetamine produces symptoms similar to acute schizophrenia.
   - Basis for pharmacotherapy: All antipsychotic drugs are D2 antagonists, with drugs that are stronger on D2 receptor antagonism resulting in higher clinical efficacy.
   - Dopamine increases in acute schizophrenia. This results in impaired emotion, cognition and attention span.
   - Dopamine Pathways of the Brain
   » Nigrostriatal: part of the extrapyramidal motor system
   » Mesolimbic: reward and emotion
   » Mesocortical: cognition and attention
   » Tuberoinfundibular: regulates prolactin secretion
2. 5-HT (Serotonin) Theory
   - LSD acts primarily as a 5-HT2 agonist, produces symptoms similar to acute schizophrenia.
   - Many of the newer atypical antipsychotics have 5-HT2 antagonism.
3. The Glutamate Theory
   - Drugs which block the NMDA receptor channel (e.g. phencyclidine (PCP) and ketamine) produce symptoms similar to acute schizophrenia.

Question 9

Names of typical antipsychotics

Answer 9

Chlorpromazine, Haloperidol

Question 10

Names of atypical antipsychotics

Answer 10

Amisulpride, clozapine, olanzapine and risperidone, aripiprazole

Question 11

Similarities between typical and atypical antipsychotics

Answer 11

Control positive symptoms of schizophrenia

Question 12

Differences between typical and atypical antipsychotics

Answer 12

Atypical antipsychotics produce less EPS than typical ones.

Question 13

What are examples of extrapyramidal side effects?

Answer 13

1. Acute dystonias
   - Parkinsonism-like syndrome (e.g. cogwheel rigidity and tremor at rest).
   - Caused by D2 antagonism in the nigrostriatal pathway.
2. Tardive dyskinesia and akathisia
   - Develop slowly (tardive) over months or years of treatment.
   - Repetitive and stereotyped involuntary movements of face, tongue and limbs (dyskinesia).
   - Involuntary movements and compulsion to act with restlessness, anxiety and agitation (akathisia).
   - Akathisia correlates directly with duration on medication, but not dyskinesia.
   - Caused by the upregulation or supersensitivity of dopamine receptors in the nigrostriatal system due to changes in dopamine pathways over time.

Question 14

Chlorpromazine side effects

Answer 14

1. M1 receptor: Dry mouth, constipation, blurred vision
2. H1 receptor: Sedation, weight gain
3. α1 receptor: postural hypotension, dizziness

Question 15

Characteristics of atypical antipsychotics

Answer 15

• Greater affinity at 5-HT2 receptors
• Greater affinity at D4 receptors
• Mixed antagonism at α-adrenoreceptors, H1 histamine receptors, muscarinic acetylcholine receptors and 5-HT2 receptors.
• Serotonin-dopamine antagonism (SDA) is the “core” of most atypical antipsychotics.

Question 16

Clozapine side effects

Answer 16

• M1 receptor: dry mouth, constipation, blurred vision
• H1 receptor: sedation, weight gain
• α1 receptor: postural hypotension, dizziness
• Clozapine-induced agranulocytosis
  » Clinical use of clozapine is limited by agranulocytosis.
  » Agranulocytosis develops in only approximately 1% of patients on clozapine but can be fatal.
  » Regular blood counts are required to ensure that patient does not develop agranulocytosis.
  »> Olanzapine: compound related to clozapine but without the adverse effect.

Question 17

Adverse effects of atypical antipsychotics

Answer 17

1. Dry mouth, constipation, blurred vision
2. Postural hypotension, reflex tachycardia
3. Sedation
4. New onset or exacerbation of diabetes
5. Drug-induced weight gain

Question 18

Which drugs are likely to cause dry mouth, constipation, blurred vision?

Answer 18

clozapine and olanzapine

anticholinergic side effects

Question 19

Which drugs are likely to cause postural hypotension, reflex tachycardia?

Answer 19

risperidone

α1-adrenoceptor antagonism

Question 20

Which drugs are likely to cause sedation?

Answer 20

clozapine and olanzapine

histamine H1 receptor antagonism

Question 21

Which drugs are likely to cause new onset or exacerbation of diabetes?

Answer 21

Olanzapine (most prone), clozapine
Risperidone (diabetes does not reverse when drug is stopped)
Antisulpride is an exception

Question 22

Which drugs are likely to cause weight gain?

Answer 22

clozapine, olanzapine, and risperidone

Question 23

What are the adverse effects of amisulpride?

Answer 23

• Few side-effects due to selectivity for D2/D3 receptor antagonism.
• Absence of α-adrenoreceptor block, antihistaminergic, and anticholinergic side-effects.
• Adverse effects on mammary glands and tissues:
  » Increased prolactin secretion due to the blockage of dopamine receptors in the anterior pituitary gland.
  » Breast swelling, pain and lactation.
  » Presents as gynecomastia in males.

Question 24

Which drugs have the strongest D1 receptor affinity?

Answer 24

clozapine, olanzapine

Question 25

Which drugs have the strongest D2 receptor affinity?

Answer 25

haloperidol, risperidone

Question 26

Which drugs have the strongest D3 receptor affinity?

Answer 26

amisulpride

Question 27

Which drugs have the strongest alpha adrenoreceptor affinity

Answer 27

risperidone

Question 28

Which drugs have the strongest H1 receptor affinity?

Answer 28

clozapine, olanzapine

Question 29

which drugs have the strongest muscarinic/cholinergic receptor affinity?

Answer 29

clozapine

Question 30

Receptor affinity of amisulpride

Answer 30

Amisulpride is a selective D2/D3 antagonist - may have 5-HT7 antagonism as well

Question 31

Why do atypical antipsychotics produce less EPS?

Answer 31

- Potent 5-HT2A receptor antagonism (clozapine, olanzapine) - High D3 to D2 antagonism ratio favors actions on the nucleus accumbens over the striatum (clozapine). - High D4 to D2 antagonism ratio favors actions in the prefrontal cortex over the striatum (clozapine). - High D2 to D1 antagonism ratio reduces impact of antagonism in the striatum (amisulpride, risperidone). >> Confer less complete blockade of dopaminergic function in the striatum as D2 antagonism will increase dopamine release

Question 32

Additional benefits of atypical antipsychotics

Answer 32

- Some are more effective against negative symptoms of schizophrenia than typical antipsychotics. >> Clozapine, olanzapine, risperidone - Some may ameliorate cognitive dysfunction >> Clozapine, risperidone - Some may be better at mood stabilization than typical antipsychotics. >> Clozapine, olanzapine, risperidone