Lecture - Antipsychotics Flashcards
What is another name for antipsychotics?
Also known as neuroleptics as they were observed bring about a state of affective indifference and emotional blunting known as “neurolepsis”
Apart from psychosis, why else are antipsychotics used?
- Treatment of psychosis (e.g. schizophrenia, schizoaffective disorder, postpartum psychosis)
- Mood stabilisation in bipolar affective disorder
- Antidepressant augmentation in depression, anxiety, OCD
- Treatment of Gilles da la Tourette’s
What are the main symptom domains in psychosis?
- Positive symptoms – Hallucinations, delusions, thought disorder
- Negative symptoms – Alogia, apathy, avolition, asocialty, affective blunting
- Disorganisation symptoms – Bizarre, chaotic and agitated behaviour
What was the first antipsychotic?
Chlorpromazine was the first antipsychotic synthesised in 1951
Prior to this limited treatment e.g. ECT, psychotherapy, insulin coma, psychosurgery
What is the link between antihistamine and old antipsychotics?
Quite a lot of overlap in structure and function between the two
What is the dopamine theory of psychosis?
Release of dopamine from the mesolimbic pathway into the nucleus accumbens regulates motivation and facilitates reinforcement and reward.
In psychosis, excessive dopamine is thought to mediate the positive symptoms of psychosis (delusions and hallucinations)
Dopamine increasing drugs such as cocaine and amphetamine are observed to cause similar positive symptoms to those seen in schizophrenia (these are known as psychotomimetic drugs)
Misallocated dopamine rather than too much as actually dopamine deficiency in prefrontal cortex
The prefrontal cortex is considered to be key in the aetiology of the negative and cognitive symptoms of schizophrenia. Dopamine deficiency in the mesocortical circuit and ventromedial prefrontal cortex appear related to negative symptoms
Deficiency the dorsolateral prefrontal cortex appears key in cognitive symptoms
The orbitofrontal cortex and its connections to the amygdala appears linked with aggressive and impulsive symptoms
Which pathways regulate the following in psychosis:
- Positive symptoms
- Negative symptoms
- EPSE
- Hyperprolactinaemia
Four dopamine pathways exist in the brain
- Mesolimibic pathway (positive symptoms)
- Mesocortical (negative symptoms)
- Nigrostriatal (Extrapyramidal side effects)
- Tuberoinfundibular (hyperprolactinaemia)
Where are the connections of the mesolimbic pathway? How does this link to psychosis?
Connects dopaminergic cell bodies in the ventral tegmental area (VTA) of the midbrain to the ventral striatum of the basal ganglia (limbic region) in the forebrain
Excess dopamine mediates +ve symptoms of psychosis
What are the connections of the mesocortical pathway? What is its role in psychosis?
Connects dopaminergic cell bodies in the VTA to the prefrontal cortex. It is essential for the normal cognitive function and is thought to be involved in cognitive control, motivation and emotional response
Deficient dopamine mediates –ve symptoms of psychosis
What are the connections of the nigrostriatal pathway? What other conditions is it implicated in?
Projects from the dopaminergic cell bodies in the substantia nigra (midbrain) to axons terminating in the striatum/basal ganglia.
This pathway is part of the extrapyramidal nervous system and controls motor movements.
Deficiency of dopamine in this pathway causes extrapyramidal side effects (EPSEs).
Hyperactivity in this pathway underlies various hyperkinetic movement disorders such as chorea, dyskinesia and tics
What are the connections of the tuberoinfundibular pathway? What physiological change affects it?
This pathway projects from dopaminergic neurons in the hypothalamus to the anterior pituitary gland. Normally these dopaminergic neurons are active and work to inhibit the release of prolactin.
During the postpartum period these neurons become less active and prolactin levels rise, causing lactation for breastfeeding
How do you classify antipsychotics?
Broadly divided into older drugs and newer drugs
Typical antipsychotics aka First Generation Antipsychotics (FGAs)
- Chlorpromazine was the first typical to be synthesised
- Examples – Chlorpromazine, Haloperidol, Zuclopenthixol (Clopixol), Flupentixol (Depixol)
Atypical antipsychotics aka Second Generation Antipsychotics (SGAs)
- Clozapine was the first atypical to be synthesised
- Examples – Clozapine, Olanzapine, Quetiapine, Risperidone, Paliperidone, Aripiprazole, Lurasidone, Cariprazine
What is an antipsychotic by definition? How do newer ones differ?
A drug that treats psychosis by blocking D2 dopamine receptors within the mesolimbic dopamine pathway i.e. they are D2 receptor antagonists
Some modern atypicals work as partial agonists (e.g. aripiprazole, cariprazine, luradisone). A partial agonist essentially works as an antagonist in the presence of a full native agonist
What are the differences between typical and atypical antipsychotics?
Newer atypicals = lower risk of extrapyramidal side effects
Atypicals all act as antagonists at the 5HT-2A serotonin receptor. This has downstream effects that cause an increase in dopamine within the nigrostriatal dopamine pathway
i.e. main differences are atypical binding to 5HT-2A and having less EPSEs
Why do newer antipsychotic cause less EPSEs?
Blocking 5HT-2A can reduce antipsychotic receptor occupancy from 80% to 60% within the nigrostriatal pathway, therefore reducing the risk of EPSEs
What are “depots”? How are these given? What are some advantages and disadvantages?
Long acting injectible antipsychotics
Given IM rather than oral - beneficial when poor compliance BUT patients may not have insight and so unwilling to engage in treatment planning
Not all oral tablets are available as depots
A mixture of typical and atypicals are available as depot preparations
- Zuclopenthixol (Clopixol) – Given every 1-4 weeks
- Flupentixol (Depixol) Given every 1-4 weeks
- Haloperidol (Haldol) – Given every 4 weeks
- Olanzapine (Zyprexa) – Given every 2-4 weeks
- Paliperidone (risperidone metabolite) – Available as 4 weekly, 3 monthly (Trevicta) and soon to be 6 monthly (Hafyera)
- Aripiprazole (Abilify) – Given every 4 weeks
What % of dopamine receptors need to be blocked for clinical benefit?
60-80%
How do you start an antipsychotic?
Start at low doses to minimise side effects, especially in those who are antipsychotic naïve as they are at higher risk of experiencing extrapyramidal side effects
Doses are significantly lower in elderly populations
How long do antipsychotics take to work?
Sedative effects can occur rapidly, within minutes to hours
Begin exerting a clear antipsychotic effect after 1-2 weeks, maximum benefit generally seen within 6 weeks
When can you finally use clozapine?
If two antipsychotics have been given an adequate trial (6 weeks at a therapeutic dose including one atypical) then consider clozapine (i.e. treatment resistance pathway)
What is HDAT?
HDAT is defined as total antipsychotic dose (all APs, regular and PRN) being >100% of BNF maximum dose
May be needed in treatment resistant populations
What are the problems with HDAT?
Associated with an increased risk of;
- Cardiovascular side effects
- Metabolic syndrome
- Neuroleptic malignant syndrome
THEREFORE increased physical health monitoring required (blood, vitals, ECG)
What is an acute use for antipsychotics on the psychiatric ward?
Rapid tranquilisation
What antipsychotic drugs can be used for rapid tranquilisation? What form? When are these tried?
- They can be given PO or IM
- IM administration is termed “rapid tranquilisation” and is often undertaken with the use of restraint
- PRN antipsychotics count toward “total BNF Maximum” when determining HDAT
- Olanzapine and haloperidol are most commonly used - NOT first line
- Typically antipsychotics are 3rd line choices after benzodiazepines and promethazine have been tried
What cautions should be taken when antipsychotics are used in RT?
- Pre-treatment ECG needed with haloperidol due to risk of QTc prolongation
- IM olanzapine not to be given within 1 hr of IM lorazepam due to risk of respiratory depression
- No more than 3 days of IM olanzapine to be given in a row due to risk of post-injection syndrome
What is the definition of hyperprolactinaemia biochemically? Where is prolactin produced? What causes its release? How is it suppressed?
Defined as elevated serum prolactin
- >530 women mIU/L
- >424 men mIU/L
- Clinically significant if >1,000 mIU/L
Prolactin produced by the anterior pituitary gland - release stimulated by thyrotropin-releasing hormone (TRH) from hypothalamus
Physiological role is to stimulate lactation post partum
Release is supressed by dopamine as part of the tuberoinfundibular pathway
What is shown? How does this relate to antipsychotics?
QTc interval (corrected for heart rate hence the ‘c’) - should be <440ms in male, <470ms in females
QTc prolongation may be caused by antipsychotics
Why is prolonged QTc problematic?
QTc prolongation is a risk factor for developing cardiac arrhythmias
Specifically polymorphic ventricular tachycardia (Torsade de Pointes)
Risk increases significantly in QTc intervals >500ms
Apart from antipsychotics (as below) what can cause prolonged QTc?
Consider other risk factors
- Hypokalaemia
- Hypomagnesaemia
- Hypocalcaemia
- Liver disease, renal disease, hypothyroidism
- Other medication – Citalopram, venlafaxine, clarithromycin, fluconazole
