Antipsychotics

Question 1

What is dopamine and how does it function in the CNS?

Answer 1

• Dopamine (DA) is a monoamine and a catecholamine.
• Acts principally as an inhibitory neurotransmitter.
• Highly concentrated in the basal ganglia and involved in motor control.
• Plays roles in behavioural effects via the reward pathway
• Involved in endocrine regulation.
• Receptors D1–D5 are all GPCRs.

Question 2

What is psychosis and how is it related to schizophrenia?

Answer 2

• Psychosis is a loss of touch with reality.
• Can occur in various mental illnesses including depression but schizophrenia is the most common psychotic disorder.
• Includes both positive (hallucinations) and negative symptoms (apathy).

Question 3

How does schizophrenia affect patients?

Answer 3

• Is often chronic, common in young people and leads to disability, reduced life expectancy, and high suicide risk.
• Despite pharmacological treatments, schizophrenia patients have a reduced life expectancy (20 years), in the top 10 for disease burden.
• Leads to suicide attempts in up to 30-50% of cases, about 5-10% of which are successful.

Question 4

What are some key schizophrenia statistics?

Answer 4

• Schizophrenia affects up to 1% of the population (i.e. ~600,000 people in the UK).
• Typical age of onset is 23-28 for men and 28-32 for women, often with an earlier phase of social isolation and withdrawal.
• ~65% of sufferers have one or more episodes with either no inter-episode impairment (~55%) or a constant level (10%).
• ~35% have multiple episodes with increasing levels of impairment.
• ~10% of sufferers commit suicide.

Question 5

What are the positive symptoms of schizophrenia?

Answer 5

• Hallucinations (usually auditory or visual).
• Delusions (e.g. persecution, control).
• Disorganised thought and speech.
• Impaired selective attention.

Question 6

What are the negative symptoms of schizophrenia?

Answer 6

• Apathy and anhedonia (inability to feel pleasure in normally pleasurable activities).
• Loss of empathy and blunted emotional response.
• Repetitive behaviours.
• Social withdrawal.
• Impaired motivation and attention.

Question 7

What is the genetic basis of schizophrenia?

Answer 7

• Schizophrenia has a strong genetic component - high heritability with familial clustering.
• Risk increases with genetic relatedness.
• 1% general risk, ~10% with close relative, ~50% in monozygotic twins, 1 in 8 in Non-identical twins.
• Likely polygenic with many genes involved — no single gene identified.
• Twin and adoption studies support the genetic component.

Question 8

How was the first antipsychotic drug discovered and what was it?

Answer 8

• Chlorpromazine was discovered accidentally in the 1950s.
• Used initially as a sedative and found to reduce hallucinations.
• Acts as a D2 dopamine receptor antagonist.
• Marked the beginning of pharmacological treatment for psychosis.

Question 9

What are dopamine receptor subtypes and how are they grouped?

Answer 9

• D1–D5 receptors grouped into two families:
• D1-like (D1, D5): stimulate adenylyl cyclase.
• D2-like (D2, D3, D4): inhibit adenylyl cyclase, activate K⁺ channels, inhibit Ca²⁺ channels.
• Most antipsychotics target D2-like receptors.

Question 10

What evidence supports the dopamine hypothesis of schizophrenia?

Answer 10

• Dopamine theory states that schizophrenic brains produce more dopamine than the brain of a normal individual.
• Supported by the fact that amphetamines (DA releasers) can induce psychotic symptoms.
• D2 agonists worsen symptoms.
• D2 antagonists treat positive symptoms.
• Further research shows abnormally high number of D2 receptors (or overactive D2 receptors), especially in the mesolimbic pathway.

Question 11

What defines typical (first-generation) antipsychotics?

Answer 11

• Older antipsychotics are primarily D2 antagonists.
• Effective against positive symptoms.
• High risk of extrapyramidal side effects.
• Examples: chlorpromazine, haloperidol.

Question 12

What extrapyramidal side effects are caused by typical antipsychotics?

Answer 12

• Acute dystonia (involuntary movements similar to parkinsons): rigidity, tremor, slowing of movement.
• Tardive dyskinesia (large involuntary, repetitive movements): occurs after long term treatment in 10-20% of patients.
• Caused by D2 receptor blockade in nigrostriatal pathway.
• May persist even after stopping treatment.

Question 13

How do atypical (second-generation) antipsychotics differ from typical ones?

Answer 13

• Lower risk of extrapyramidal side effects.
• Effective against both positive and negative symptoms.
• Broader receptor profile: block D2 and 5HT₂A receptors (possibly how they can also treat negative symptoms).
• Examples: Dibenzodiazepines (clozapine, risperidone)

Question 14

What makes clozapine a unique antipsychotic?

Answer 14

• Antagonist at D4>D3>D1>D2 and 5HT₂A/₂C.
• Effective for treatment-resistant schizophrenia.
• Associated with agranulocytosis (~1% risk), therefore requires regular blood monitoring.
• Very low extrapyramidal side effects risk.

Question 15

What are newer atypical antipsychotics and their features?

Answer 15

• Amisulpride: selective D2 (subunit) antagonist.
• Quetiapine: similar profile to clozapine but lower affinity.
• Lower extrapyramidal side effect risk.
• Still ~30% of patients show no response to treatment.

Question 16

What is D2 receptor subtype selectivity and why is it important?

Answer 16

• Most antipsychotics block D2, D3, and/or D4 subunits.
• Extrapyramidal side effects arise from D2 blockade in nigrostriatal pathway.
• Reduced side effects of newer drugs may be reduced by action on other receptors (e.g. mACh, 5HT₂) counteracting them.
• Clinical efficacy correlates with D2 binding affinity.

Question 17

How does PET imaging inform antipsychotic effectiveness?

Answer 17

• Shows D2 receptor occupancy in the brain.
• Therapeutic effect linked to ~80% D2 receptor occupancy.
• Differences seen between typical (e.g. haloperidol) and atypical (e.g. clozapine) drugs.

Question 18

What does clinical potency of antipsychotics depend on?

Answer 18

• Correlates with D2 receptor binding affinity.
• Higher potency drugs require lower doses.
• Weaker affinity drugs need higher therapeutic doses.
• PET scans show 80% D2 occupancy needed for therapeutic effect.
• Over 80–85% occupancy increases EPS risk.

Question 19

What are brain structure findings in schizophrenia?

Answer 19

• MRI reveals smaller cortical volumes and larger ventricles.
• Especially in medial temporal lobe and left hemisphere.
• Changes are mostly non-progressive → suggest developmental origin.

Question 20

What is the glutamate theory of schizophrenia?

Answer 20

• Based on psychosis from NMDA antagonists like PCP and ketamine.
• Reduced glutamate binding in post-mortem schizophrenic brains.
• Drugs targeting glutamate signalling have failed clinically so far.

Question 21

What is the serotonergic theory of schizophrenia?

Answer 21

• Some atypical antipsychotics block 5HT₂A receptors.
• LSD mimics serotonin and causes hallucinations via slow unbinding.
• Suggests serotonin and dopamine systems may act together in schizophrenia.
• Compatible with dopamine theory.

Question 22

What is the dopamine hypothesis of schizophrenia?

Answer 22

• Proposed that schizophrenia involves overactivity of dopaminergic signalling, particularly D2 receptors.
• Supported by the psychosis-inducing effects of amphetamines and D2 agonists.
• D2 antagonists are effective in treating positive symptoms.
• Imaging shows increased D2 receptor density in schizophrenic brains.

Question 23

How do D1 and D2 receptors relate to schizophrenia symptoms?

Answer 23

• Overactivity of D2 receptors in the mesolimbic pathway → positive symptoms.
• Reduced D1 receptor signalling in the mesocortical pathway → negative symptoms.
• D2 antagonists reduce positive symptoms but have limited effect on negative symptoms.

Question 24

What are atypical (second-generation) antipsychotics?

Answer 24

• Newer drugs with broader receptor profile.
• Block both D2 and 5HT₂A receptors.
• Fewer extrapyramidal side effects.
• More effective for negative symptoms.
• Examples: Clozapine, Risperidone, Quetiapine, Olanzapine, Aripiprazole.

Question 25

What are the risks and limitations of clozapine treatment?

Answer 25

* Agranulocytosis (loss of neutrophils) can be fatal if unmonitored. * Requires routine full blood counts. * Reserved as a last-resort drug. * Despite risks, highly effective for refractory cases.

Question 26

Why do atypical antipsychotics cause fewer extrapyramidal side effects?

Answer 26

* Lower affinity or rapid dissociation from D2 receptors in nigrostriatal pathway. * Additional antagonism at 5HT₂A, mACh may counteract motor side effects. * Selectivity reduces impact on motor control regions.

Question 27

What are the causes of treatment resistance in schizophrenia?

Answer 27

* ~30% of patients do not respond to current antipsychotics. * Exact reasons unknown — may involve receptor polymorphisms or non-dopaminergic pathology. * Ongoing research explores genetic and neurobiological causes.

Question 28

How do antipsychotics vary in receptor selectivity?

Answer 28

* Typical antipsychotics: D2 antagonists (less selective, more EPS). * Atypicals: D2 + 5HT₂A antagonists with broader action. * Clozapine acts on multiple receptors including D4, 5HT₂C, and mACh. * Selectivity influences side effect profile and efficacy.

Question 29

What are other common side effects of antipsychotics?

Answer 29

* Sedation (via H1 receptor blockade). * Weight gain and metabolic syndrome (especially with atypicals). * Anticholinergic effects (dry mouth, constipation). * Hyperprolactinemia (D2 block in tuberoinfundibular pathway). * QT prolongation and cardiac risk.

Question 30

What clinical considerations guide antipsychotic choice?

Answer 30

* Symptom profile: positive vs. negative symptoms. * Side effect tolerance: EPS, sedation, weight gain. * Past response or resistance to treatment. * Comorbidities and contraindications (e.g. cardiovascular risk). * Monitoring requirements (e.g. blood tests for clozapine).