Antipsychotics

Question 1

What is schizophrenia?

When is the onset?

Answer 1

• chronic disease
• onset in late adolescence or early adulthood
• highly disabling to social and vocational functioning

Question 2

What are the symptoms of schizophrenia?

Answer 2

• positive (abnormal behaviours added)
• negative (normal behaviours subtracted)

Periods of acute presentation with positive symptoms are interspersed with periods during which the negative symptoms predominate.
As the disease progresses, negative symptoms become more dominant.

Question 3

What are the 5 symptom domains of schizophrenia?

Answer 3

• positive symptoms
• negative symptoms
• cognitive symptoms
• aggresive symptoms
• anxiety/depression

Question 4

What are the positive symptoms of schizophrenia?

Answer 4

• delusions
• hallucinations
• thought disorder
• abnormal behaviour

Positive symptoms bother others the most

Question 5

What are the negative symptoms of schizophrenia?

Answer 5

• withdrawal from social contacts
• flattening of emotional responses

For individuals with schizophrenia, negative symptoms often most distressing.
They are not self aware of their positive phases.

Question 6

What are some causes of the negative symptoms?

Answer 6

• primary deficit of the illness
• secondary to depression
• secondary to extrapyrimidal symptoms (EPS)
• secondary to environmental deprivation
• secondary to positive symptoms

Question 7

How is cognitive function impaired in schizophrenia?

Answer 7

• impairment of selective attention
• impairment of working memory

Cognitive impairment only recently recognised to be persistent core feature of the disease.

Question 8

Can schizophrenia be possibly due to neurodevelopmental disorder?

Answer 8

Yes. Onset in late adolescence or early adulthood is consistent with neurodevelopmental abnormality involving myelination of cortico-cortical pathways

Question 9

What are the neurochemical theories underlying schizophrenia?

Answer 9

Neurochemical theories primarily theories of the positive symptoms.

Dopamine theory (main theory): 
All antipsychotic drugs are D2 (dopamine) antagonists 

5-HT (serotonin) theory:
- many of the newer atypical antipsychotics have 5HT2 antagonism

Glutamate theory:
- possibly can use NMDA receptor agonists

Question 10

What are typical antipsychotics?

Examples of typical antipsychotics?

Answer 10

• control positive symptoms
• produce extrapyrimidal side effects (EPS)
• chlorpromazine was the first antipsychotic drug
• haloperidol remains one of the most widely used antipsychotic drugs

Question 11

What are some adverse effects of chlorpromazine?

Answer 11

D2 antagonism -> pharmaco effect
Alpha 1 adrenergic receptor antagonism -> postural hypotension and dizziness
H1 histamine receptor antagonism -> sedation and weight gain
M1 muscarinic receptor antagonism -> dry mouth, constipation and blurred vision.

Question 12

What are the adverse effects of haloperidol?

Answer 12

Has D2 antagonism (pharmaco action)

Alpha 1 antagonism -> postural hypotension

Question 13

What are extrapyrimidal side effects?

Answer 13

Acute dystonias
Tardive dyskinesia and akathisia
(Motor side effects due to actions of D2 antagonism on the extrapyrimidal motor pathways)

Question 14

What are some typical antipsychotics?

Answer 14

Chlorpromazine
Fluphenazine
Haloperidol
Trifluoperazine

Question 15

What are atypical antipsychotics?

Answer 15

Control positive symptoms

Produce less EPS

Question 16

What is the core of most atypical antipsychotics?

Answer 16

Serotonin (5HT2A) and dopamine (D2) antagonism

Question 17

What are the examples of atypical antipsychotics?

Answer 17

Clozapine, olanzapine and risperidone.

Question 18

What are the adverse effects of clozapine?

What is an important adverse effect of clozapine?

Answer 18

M1 receptor antagonism -> dry mouth constipation and blurred vision
H1 histamine receptor antagonism -> sedation and weight gain
Alpha 1 receptor antagonism -> postural hypotension and dizziness

Clozapine can also cause agranulocytosis (limits its use). Can be fatal, monitor patients with regular blood counts.

Question 19

What are the adverse effects of olanzapine?

Answer 19

M1 receptor antagonism -> dry mouth constipation and blurred vision
H1 histamine receptor antagonism -> sedation and weight gain
Alpha 1 receptor antagonism -> postural hypotension and dizziness

Question 20

What are the adverse effects of risperidone?

Answer 20

Postural hypotension, reflex tachycardia

Question 21

What is notable about amisulpride?

Answer 21

Amisulpride is a selective D2/D3 antagonist. No affinity for 5HT2 (serotonin)

Question 22

What are the adverse effects of amisulpride?

Answer 22

Few side effects due to selectivity for D2/D3 receptors.
Absence of alpha adrenergic block, antihistaminergic and anticholinergic side effects.

However, it can cause increased prolactin secretion due to block of dopamine receptors in the anterior pituitary gland -> breast swelling, pain and lactation in women and gynaecomastia in men

Question 23

What is a partial agonist used as antipsychotic?

Answer 23

Aripiprazole is not an antagonist, its a partial dopamine receptor agonist and acts as functional antagonist.

Question 24

What can atypical antipsychotics cause?

Answer 24

Atypical antipsychotics can induce hyperglycemia and diabetes. Effect is strong for clopazine, olanzapine and risperidone. Amisulpride may be an exception.

Diabetes may be irreversible (as with risperidone)

Mechanism is unknown.

Hence, FDA labelling on all atypical antipsychotics to warn of risk of diabetes.

Question 25

Weight gain of atypical antipsychotics?

Answer 25

Atypical antipsychotics can induce weight gain, especially clozapine, olanzapine and risperidone -> experimental use of olanzapine in treatment of anorexia.

Question 26

Why do atypical antipsychotics cause less EPS?

Answer 26

Potent 5HT2A (serotonin) receptor antagonism vs weak D2 (dopamine) antagonism -> lower EPS and higher efficacy against negative symptoms. (Clozapine and olanzapine)

Positive symptoms mostly mediated by dopamine and negative symptoms mostly mediated by serotonin.

High D3 to D2 antagonism ratio favours actions on nucleus accumbens over the striatum (Amisulpride)

High D4 to D2 antagonism ratio favours action in the prefrontal cortex over the striatum (Clozapine)

High D2 to D1 antagonism ratio reduces impact of antagonism in the striatum (Amisulpride, risperidone) bc antagonism of D2 at presynpase -> reduces negative feedback -> more dopamine in the synapse.

Question 27

What are some additional benefits of atypical antipsychotics?

Answer 27

• clozapine, olanzapine and risperidone are more effective against negative symptoms than typical antipsychotics (esp when there is severe negative symptoms)
• clozapine and risperidone can ameliorate cognitive dysfunction in schizophrenia better than typical antipsychotics
• clozapine, olanzapine and risperidone may be better at mood stabilization than typical antipsychotics

HOWEVER, effects of atypical antipsychotics on negative symptoms, cognition and stability of mood are weak, just better than typical antipsychotics.

Question 28

What are the outcomes of antipsychotic treatments?

Answer 28

There is still an unmet need for improved antipsychotic drugs.