03-11-23 – Antipsychotics

Question 2

Learning outcomes

Answer 2

• To identify the proposed neurotransmitter pathways underpinning schizophrenia and psychosis
• To name examples of first- and -second generation antipsychotics
• To relate the principles of receptor specificities of the first- and second-generation antipsychotic agents to their therapeutic outcomes and side effects
• To discuss the rationale behind appropriate treatment selection and barriers to effective treatment

Question 3

What are 3 other names for antipsychotics?

What is a common property oaf antipsychotics?

What are they mainly used for?

What are 3 other conditions antipsychotics are used for?

Answer 3

• 3 other names for antipsychotics:
  1) Neuroleptics
  2) Antischizophrenic Drugs
  3) Major Tranquillisers
• Common property of antipsychotics is antagonising the actions of dopamine in the brain.
• Mainly used in the treatment of schizophrenia and other psychotic illnesses
• 3 other conditions antipsychotics are used for:
  1) Emesis
  2) Huntingdon’s disease
  3) Depression

Question 4

How common is schizophrenia?

What are 3 characteristics of schizophrenia presentation?

What are the 2 types of clinical features of dementia?

Answer 4

• Schizophrenia affects ~1% of the population
• 3 characteristics of schizophrenia presentation:
  1) Can occur from an early age
  2) Can be chronic and highly disabling
  3) Strongly hereditary
• 2 types of clinical features of dementia:

1) Positive Symptoms
* Delusions
* Hallucinations
* Thought disorders (a disturbance in how thoughts are organized and expressed)

2) Negative Symptoms
* Withdrawal from social contact
* Flattening of emotional responses

Question 5

Theories of Schizophrenia: Dopamine Theory.

Describe how dopamine content/synthesis is affected in schizophrenia.

What is there a strong correlation between regarding antipsychotics?

What drugs can produce similar symptoms to schizophrenia?

Answer 5

• Theories of Schizophrenia: Dopamine Theory
• ↑ dopamine content in restricted area of the temporal lobe of schizophrenics (amygdala)
• ↑ dopamine synthesis and release in the striatum of schizophrenics
• Strong correlation between clinical potency of antipsychotics and D2 blocking action
• Amphetamine produces symptoms almost indistinguishable from schizophrenia
• D2-receptor agonists produce similar symptoms in animals and exacerbate symptoms in humans

Question 6

Describe 4 pathways involved in dopamine pathways of the brain

Answer 6

• 4 areas pathways in dopamine pathways of the brain

1) Mesocortical and mesolimbic pathways
* Involved in mood

2) Nigrostriatal pathway
* Motor and refinement of motor movements

3) Tuberhypophyseal pathway
* Involved in endocrine system
* All of these pathways can become dysregulated in schizophrenia

Question 7

What is IC50 of a drug?

How is effectiveness of a drug linked to affinity for D2 receptors?

Answer 7

• IC50 of a drug is the concentration of a drug required to block 50% of receptors
• There is a positive correlation between effectiveness and affinity for D2 receptors
• With drugs that act as reversible D2 receptor antagonists, the lower the IC50, the lower the average clinical dose required
• This is due to the drug having a higher affinity for D2 receptors

Question 8

Theories of Schizophrenia: Glutamate Theory.

What is the NT for MDA receptors?

What symptoms can NMDA receptor antagonists produce?

How are glutamate levels and receptor densities affected in schizophrenic brains?

How was this similar in mice?

Answer 8

• Theories of Schizophrenia: Glutamate Theory
• The NT for NMDA receptors is glutamate
• NMDA receptor antagonists (e.g. phencyclidine and ketamine) produce psychotic symptoms
• ↓ glutamate and receptor density reported in postmortem schizophrenic brains
• Transgenic mice with ↓ NMDA receptor expression show stereotypic schizophrenic behaviours and ↓ social interactions – also respond to antipsychotics

Question 9

Theories of Schizophrenia: Glutamate Theory.

Describe 3 steps in how glutamate and dopamine can cause positive and negative symptoms seen in schizophrenia

Answer 9

• Theories of Schizophrenia: Glutamate Theory
• 3 steps in how glutamate and dopamine can cause positive and negative symptoms seen in schizophrenia:

1) Glutamate and dopamine exert excitatory and inhibitory effects respectively on GABAergic striatal neurones
* project to the thalamus and constitute a sensory ‘gate’

2) Too little glutamate or too much dopamine disables the ‘gate’ allowing uninhibited sensory input to reach the cortex

3) Excess dopamine could be responsible for the positive symptoms and reduced glutamate for the negative symptoms

Question 10

What are the 3 types of First Generation (FGAs) or ‘Classical’ Antipsychotics?

What is an example of each?

Answer 10

• 3 types of First Generation (FGAs) or ‘Classical’ Antipsychotics:

1) Phenothiazines
* Chlorpromazine

2) Butyrophenones
* Haloperidol

3) Thioxanthines
* Flupentixol
* Zuclopenthixol

Question 11

What are the 3 types of Second Generation (SGAs) or ‘Atypical‘ Antipsychotics?

What is an example of each?

What receptors do they work on?

Answer 11

• 3 types of Second Generation (SGAs) or ‘Atypical‘ Antipsychotics:

1) Benzamides
* Amisulpride (selective D2 and D3 receptor antagonist)

2) Dibenzodiazepines
* Clozapine and olanzapine (very unselective receptor blocking profile)
* Clozapine is one of the most important, as if a patient is resistant to other antipsychotics, they will end up on this

3) Others
* Risperidone, paliperidone (mixture of receptor types blocked)
* Quetiapine (a adrenoceptor blocker)
* Aripiprazole (Dopamine and 5-HT antagonist)

• Quetiapine and aripiprazole are associated with less side-effects
• Better outcomes with quetiapine

Question 12

What are 4 factors that typical and atypical antipsychotics differ in?

Answer 12

• 4 factors that typical and atypical antipsychotics differ in:

1) Receptor profile

2) Incidence of extrapyramidal side-effects
* (less in atypical group)

3) Efficacy in treatment-resistant group of patients
* Patients often end up on clozapine if they are resistant to other antipsychotics

4) Efficacy against negative symptoms
* Atypical tend to be better for negative symptoms
* Both are good for positive symptoms

Question 13

Describe the relative receptor affinity of antipsychotic drugs for the following receptors:
1) Cholinergic (muscarinic) receptors
2) Alpha-adrenergic receptor
3) Dopamine receptor
4) Serotonin receptor
5) H1 histamine receptors

Answer 13

Question 14

Relative receptor affinity of antipsychotic drugs (in picture)

Answer 14

Question 15

What are 3 behavioural side-effects of antipsychotics?

What are these effects distinct from?

Answer 15

• 3 behavioural side-effects of antipsychotics:

1) Apathy and reduced initiative

2) Display few emotions, drowsy
* Can be easily stirred from this

3) Aggressive tendencies inhibited

• Effects are distinct from those produced by hypnotics and anxiolytics

Question 16

What are 9 common side-effects of antipsychotics?

Answer 16

• 9 common side-effects of antipsychotics:
  1) Urinary retention
  2) Weight gain
  3) Seizure
  4) Sedation
  5) Extrapyramidal symptoms
  6) Postural hypotension (Alpha 1 receptors)
  7) Sexual dysfunction
  8) Arrhythmias and sudden cardiac death
  9) Dry mouth

Question 17

What are extrapyramidal symptoms?

What are the 2 types of extrapyramidal symptoms?

What are the 2 main types of extrapyramidal disturbances that occur in antipsychotics?

Answer 17

• Extrapyramidal signs include increased motor tone, changes in the amount and velocity of movement, and involuntary motor activity.
• They include two groups of signs and related disorders: hypokinetic (similar to Parkinson’s disease) and hyperkinetic (similar to Huntington’s disease).
• 2 main types of extrapyramidal disturbances that occur in antipsychotics:

1) Acute, reversible Parkinson-like symptoms (hypokinetic)
* Due to block of nigro-striatal dopamine receptors

2) Slowly developing tardive dyskinesia
* One of the most serious problems with antipsychotics

Question 18

What is tardive dyskinesia?

When can it appear?

What is it associated with the proliferation of?

What is the treatment?

What is tardive dyskinesia less common with?

Answer 18

• Tardive dyskinesia is involuntary movements of face and limbs
• It appears after months/years of treatment
• Associated with proliferation of dopamine receptors in the corpus striatum
• Treatment is generally unsuccessful, and can lead to symptoms being permanent
• Less common with newer antipsychotics

Question 19

What are 8 other types of unwanted side-effects from antipsychotics?

Answer 19

• 8 other types of unwanted side-effects from antipsychotics:

1) Anti-muscarinic actions
* Blurring of vision, dry mouth & eyes, constipation
* Can help attenuate (reduce) extrapyramidal actions

2) α-adrenoreceptor blocking actions
* Orthostatic hypotension

3) H1-receptor blocking actions
* Sedative and anti-emetic actions

4) Endocrine actions
* ↑ prolactin secretion by blocking D2 receptors in the pituitary

5) Neuroleptic malignant syndrome
* Fever, muscle rigidity, altered mental status, autonomic dysfunction
* Rare, but life threatening: Risk mostly upon initiation or change of dose

6) Jaundice
* Chlorpromazine was one of the most common causes of drug-induced liver disease in the 1960-70s

7) Diabetes

8) Leukopoenia and agranulocytosis
* Granulocytosis is a life-threatening condition that involves having severely low levels of white blood cells called neutrophils.
* Leukopenia is a condition where the body doesn’t have enough disease-fighting leukocytes in the blood
* Predominately clozapine, requires white cell monitoring (via CPMS – Clozaril (clozapine) patient monitoring service)

Question 20

What are 3 risks of Antipsychotic use in the elderly with dementia

Answer 20

• 3 risks of Antipsychotic use in the elderly with dementia:

1) Increased risk of stroke
* 3x compared to placebo with risperidone or olanzapine

2) Increased risk of mortality
* About 1-2% increase with newer antipsychotics, can’t be excluded with older treatments
* Increased risk if risperidone co-prescribed with furosemide (diuretic – common in elderly)

3) Risperidone is licensed for treatment of dementia related behavioural disturbances
* Only short-term for persistent aggression in moderate to sever Alzheimer’s where there is risk of harm

Question 21

Relative adverse effects of antipsychotics (in picture)

Answer 21

Question 22

Monitoring patients on antipsychotics (in picture)

Answer 22

Question 23

Describe the First Episode Schizophrenia flow chart (in picture)

Answer 23