Antipsychotics Flashcards
What is schizophrenia?
When is the onset?
- chronic disease
- onset in late adolescence or early adulthood
- highly disabling to social and vocational functioning
What are the symptoms of schizophrenia?
- 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.
What are the 5 symptom domains of schizophrenia?
- positive symptoms
- negative symptoms
- cognitive symptoms
- aggresive symptoms
- anxiety/depression
What are the positive symptoms of schizophrenia?
- delusions
- hallucinations
- thought disorder
- abnormal behaviour
Positive symptoms bother others the most
What are the negative symptoms of schizophrenia?
- 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.
What are some causes of the negative symptoms?
- primary deficit of the illness
- secondary to depression
- secondary to extrapyrimidal symptoms (EPS)
- secondary to environmental deprivation
- secondary to positive symptoms
How is cognitive function impaired in schizophrenia?
- impairment of selective attention
- impairment of working memory
Cognitive impairment only recently recognised to be persistent core feature of the disease.
Can schizophrenia be possibly due to neurodevelopmental disorder?
Yes. Onset in late adolescence or early adulthood is consistent with neurodevelopmental abnormality involving myelination of cortico-cortical pathways
What are the neurochemical theories underlying schizophrenia?
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
What are typical antipsychotics?
Examples of typical antipsychotics?
- control positive symptoms
- produce extrapyrimidal side effects (EPS)
- chlorpromazine was the first antipsychotic drug
- haloperidol remains one of the most widely used antipsychotic drugs
What are some adverse effects of chlorpromazine?
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.
What are the adverse effects of haloperidol?
Has D2 antagonism (pharmaco action)
Alpha 1 antagonism -> postural hypotension
What are extrapyrimidal side effects?
Acute dystonias
Tardive dyskinesia and akathisia
(Motor side effects due to actions of D2 antagonism on the extrapyrimidal motor pathways)
What are some typical antipsychotics?
Chlorpromazine
Fluphenazine
Haloperidol
Trifluoperazine
What are atypical antipsychotics?
Control positive symptoms
Produce less EPS
What is the core of most atypical antipsychotics?
Serotonin (5HT2A) and dopamine (D2) antagonism
What are the examples of atypical antipsychotics?
Clozapine, olanzapine and risperidone.
What are the adverse effects of clozapine?
What is an important adverse effect of clozapine?
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.
What are the adverse effects of olanzapine?
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
What are the adverse effects of risperidone?
Postural hypotension, reflex tachycardia
What is notable about amisulpride?
Amisulpride is a selective D2/D3 antagonist. No affinity for 5HT2 (serotonin)
What are the adverse effects of amisulpride?
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
What is a partial agonist used as antipsychotic?
Aripiprazole is not an antagonist, its a partial dopamine receptor agonist and acts as functional antagonist.
What can atypical antipsychotics cause?
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.
Weight gain of atypical antipsychotics?
Atypical antipsychotics can induce weight gain, especially clozapine, olanzapine and risperidone -> experimental use of olanzapine in treatment of anorexia.
Why do atypical antipsychotics cause less EPS?
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.
What are some additional benefits of atypical antipsychotics?
- 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.
What are the outcomes of antipsychotic treatments?
There is still an unmet need for improved antipsychotic drugs.
