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 accuphase? Is it used in rapid tranquilisation?
Accuphase (Zuclopenthixol Acetate) – Not technically RT and does not act “rapidly” (peak onset 24-36 hours).
Useful in severely agitated patients who have required multiple intramuscular injections. Almost like giving somebody a mini-depot
- Typical dose is 50-150mg IM*
- Dose can be repeated after 48-72 hours*
- Maximum cumulative dose is 400mg in 2 weeks*
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
How common is hyperprolactinaemia on antipsychotics? What are the symptoms?
34-42% men
59-75% women
Symptoms
- Often asymptomatic
- Women – Reduced libido, amenorrhoea, galactorrhoea, osteoporosis ?increased risk of breast cancer
- Men – Reduced libido, erectile dysfunction, gynaecomastia, galactorrhoea
How do you manage hyperprolactinaemia on antipsychotics?
Switch to a prolactin sparing agent, add in aripiprazole (partial dopamine agonist), dopamine agonists are generally avoided (e.g. carbergoline, bromocriptine)
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
What is the management of prolonged QTc on antipsychotics?
Switch to a more QTc sparing agent (not all APs are created equal!)
What is neuroleptic malignant syndrome?
An acute potentially life threatening complication of antipsychotic treatment
A disorder of thermoregulation and neuromotor control
How common is NMS? What are some risk factors for it?
Risk factors –
- High dose typicals,
- rapid dose changes,
- male gender,
- younger age
Seen in <1% of patients
What are the clincial features of NMS?
- Muscle rigidity
- Hyperthermia
- Hyporeflexia
- Diaphoresis (sweating)
- Autonomic dysregulation (e.g. tachycardia, hypotension)
- Altered consciousness
How do you diagnose NMS?
- Raised creatine kinase (CK)
- Leucocytosis
- Deranged liver function
- Deranged renal function (secondary to Rhabdomyolysis from raised CK)
How do you manage NMS?
- Stop causative antipsychotic
- Transfer to hospital/ITU
- Support care and fluids
- Benzodiazepines (relax muscles and manage agitation)
- Bromocriptine (dopamine agonist) and Dantrolene (muscle relaxant)
What are the 4 main abnormalities in EPSEs?
- Dystonia
- Tardive dyskinesia
- Akathisia
- Parkinsonism
What is the definition of EPSEs? What is the cause?
Refers to movement abnormalities mediated by movement pathways outside of the medullary pyramids i.e. the basal ganglia, cerebellum and motor cortex not the corticospinal tract
These abnormalities are mediated by dopamine blocked within the nigrostriatal dopamine pathway
When is Parkinson’s disease seen clinically in relation to dopamine neuron loss?
Clinical Parkinson’s disease seen when 80-90% of dopamine neurons are lost in the subtantia nigra pars compact due to Lewy Body formation
Drug induced Parkinsonism generally seen when 80% of dopamine neurons are blocked within the substantia nigra
What are the features of Parkinson’s disease?
Classic Parkinsonian symptom tetrad may be seen
Core features - Bradykinesia, rigidity, pill rolling tremor (4-6 Hz), postural instability
Additional features – Hypomimia, festinating gait with reduced arm swing
How do you distinguish between Parkinson’s disease and Parkinsonism caused by drugs?
Generally is bilateral, which is in contrast to Parkinson’s Disease which typically starts asymmetrically
Consider a dopamine transporter scan (DAT Scan, a from of SPECT imaging)
Generally develops after several weeks of treatment
How do you manage drug-induced Parkinsonism?
Switch medication, add in a regular antimuscarinic (e.g. procyclidine 5mg)
Define tardive dyskinesia. What are the risk factors?
An involuntary orofacial dyskinesia associated with long term antipsychotic use
Risk factors:
- Develops after months or years of treatment especially typical antipsychotics,
- high dose
- elderly age
What is the pathophysiology of tardive dyskinesia?
Chronic blockade of D2 receptors in the basal ganglia causes them to become “hypersensitive” (mechanism poorly understood)
How does tardive dyskinesia typically present?
Typically seen as continuous mouth and tongue movements, classic “lip smacking” presentation.
May also involve:
- eye closing,
- jaw clenching
- may affect the trunk/extremities
How do you manage tardive dyskinesia?
May be permanent even if medication is stopped.
Stop causative agent ASAP
If it persists, consider Tetrabenazine (25mg TDS)
What is dystonia? What are the types?
Involuntary muscle spasm/contractions
Can affect any part of the body. Specific names are given to certain forms
- Oculogyric crisis (eyes rolling upward)
- Torticollis (head and neck twisted to one side)
- Laryngeal dystonia (can compromise airway and be life threatening)
How does dystonia present? What are the risk factors?
Develops acutely, within hours of starting antipsychotics
Risk factors:
- Antipsychotic naïve
- young males,
- high dose typical antipsychotics
How do you manage dystonia?
Anticholingerics (e.g. procyclidine 5-10mg PO or IM)
What is akathisia? What is a risk with this long term?
A sense of internal restlessness. The patient feels compelled to constantly move, rock, fidget or pace around. Very unpleasant and associated with an increased risk of suicide
When does akathisia present?
Occurs within days to weeks of starting/increasing an antipsychotic
What are the risk factors for akathisia?
Typical antipsychotics, also commonly associated with aripiprazole/asenapine/lurasidone
How do you manage akathisia?
- Change medication,
- Diphenhydramine,
- Propranolol,
- low dose benzodiazepines
What are the complications of metabolic syndrome caused by antipsychotics?
May reduce overall life expectancy e.g. in schizophrenia overall life expectancy reduction by 15-20 years may be partially due to this
What is the pathophysiology of metabolic syndrome?
Some antipsychotics have the propensity to cause weight gain, dyslipidaemia and insulin insensitivity
Especially those that act of the H1 receptor e.g. clozapine, quetiapine and olanzapine
Effect on lipids and insulin appears not to be fully explained by weight gain alone
What is the management of metabolic syndrome from antipsychotics?
- Monitor weight, blood pressure, lipid profile and HbA1C
- Treat any complications on their merits (e.g. statins, anti-glycaemics, anti-hypertensives)
- Promote healthy eating and exercise
Why is clozapine still used despite the dangerous side effects?
The best drug to treat psychosis and used in treatment resistant illness. Has a bit of “magic” that other antipsychotics do not and is the gold standard
1/3rd with treatment resistant illness will respond very well to clozapine
The ONLY medication with an evidence base to treat negative symptoms
What is clozapine structurally similar to?
Similar to olanzapine, mirtazapine, quetiapine
All block H1 receptor and caus sedation and increased appetite
But clozapine is a very “dirty drug” pharmacologically (binds to >30 receptors). It binds extensively to a wide array of 5HT receptors in addition to dopamine receptors
List some side-effects of clozapine.
Sedation and appetite increase (with subsequent weight gain) +++
Clozapine specific:
- Hypersalivation
- Cardiomyopathy
- Tachycardia
- Hypotension
- Myocarditis
- Lowering of seizure threshold
- Prothrombotic (more so than other antipsychotics) leading to risk of DVT/PE
- Neutropenia/leucopenia/agranulocytosis
- Severe constipation
Why can’t you stop clozpine abruptly? What should you do if it is stopped?
High risk of rebound psychosis within 2 weeks if abruptly stopped
- Must be started at a low dose and titrated slowly due to the risk of cardiovascular instability
- Must be re-titrated if stopped for more than 48 hours
When is risk of agranulocytosis highest in clozapine?
First 18 weeks
What must be done when starting clozapine for a patient?
- Patients have to be registered with a national clozapine monitoring service (e.g. ZTAS, Clozaril, Denzapine)
- Patients require regular FBC monitoring due to the risk of neutropenia/ leucopenia/agranulocytosis (approximately 1% of patients)
- It is an idiosyncratic reaction (i.e. can occur at any time)
- Risk is highest in the first 18 weeks
How does monitoring for clozapine side effects work?
- Initially weekly, then fortnightly and monthly after 1 year of treatment:
- Patients given “Red, Amber or Green” result
- Green - Okay to continue
- Amber – Continue clozapine but FBC monitoring must be increased to twice weekly
- Red - Clozapine must be stopped immediately
Patients with Benign Ethnic Neutropenia (BEN) can be given a modified cell count range
