Anti-psychotics in Schizophrenia Flashcards
Do first or second generation anti-psychotics have greater efficacy?
Both first and second generation anti-psychotics are used to treat the positive symptoms of Schizophrenia (hallucinations, delusions etc) and for this they have the same efficacy aside from Clozapine.
However second generation anti-psychotics have been shown to be have superior efficacy for negative symptoms of Schizophrenia and therefore you may choose these if negative symptoms predominate.
List some of the first generation anti-psychotics.
Chlorpromazine
Haloperidol
Flupentixol
Levomepromazine
List some of the second generation anti-psychotics.
Clozapine
Quetiapine
Aripiprazole
Risperidone
Olanzapine
What does choice of anti-psychotics depend upon?
Past history of response
Has the patient been sensitive to a particular adverse effect/or have they got risk factors
Co-morbidities
Concurrent medication which would pre-dispose a particular side effect and interactions
Dosing profiles
Is a depot formulation of the anti-psychotic available to switch to - other formulations - swallowing difficulties
Patient preference
Likely risk vs benefits
Anti-psychotic side effect profile
Cost
What are the depot (long acting) anti-psychotic formulations?
Involves the administration the anti-psychotic by injection intramuscularly and then is released in the blood over a number of weeks
Which depots need a test dose beforehand?
To make this clear all anti-psychotics before being given as depots must have a trial period in the oral formulation to determine efficacy and side effect profile, however:
First generation depots are oil based and require a test dose for sensitivity to the oil base/test for EPSEs
Second generation no test dose is required due to having an aqueous base and lower incidence of EPSEs.
What are the main side effects associated with the first generation anti-psychotics?
Extra-pyramidal dose dependent side effects which includes:
Akathisia
Dystonia
Tardive dyskinesia
Parkinsonism
In addition to other side effects:
Anticholinergic
Cardiac
Hyperprolactinaemia
Sexual dysfunction
What are the general advantages of using depots?
Can quickly identify non-adherence - Doctor can be informed immediately when a patient has missed a dose
Good for patients who struggle with adherence
Good for patients who don’t want to take tablets every day
Ensures the patient is always receiving a therapeutic effect from their medication regardless of their state of mind
More consistent plasma levels - less side effects
Remains 1-2 weeks after a missed dose
Avoids first pass metabolism
What are the general disadvantages of using depots?
Can be painful, uncomfortable, produce injection site reactions
Oral to long acting injections can be complicated
Stigma
Preparations require mixing/refrigeration
Dosing titration may be more difficult than with oral
ADRs persist for longer
Poor injection technique
What are some of the general principles of prescribing anti-psychotics?
Use the lowest effective dose as possible and any dose increases should not occur within 1-2 weeks to see a full therapeutic effect
Use a single anti-psychotic when possible due to the increased risk of adverse effects
Only use combinations when a single anti-psychotic is inadequate
Antipsychotics should not be prescribed as when necessary for sedative effect
Assess response using rating scales and document outcome in patients records
Reduce dose gradually to prevent withdrawal and symptom rebound
How is high dose anti-psychotic classified?
As single dose therapy above the BNF maximum or two or more antipsychotics prescribed concurrently that, when expressed as a percentage of their maximum daily dose total more than 100%.
This includes PRN use.
Does using two anti-psychotics equate to greater effectiveness?
No there is nothing to suggest anti-psychotic polypharmacy leads to greater effectiveness.
If high dose anti-psychotic therapy is used what needs to be monitored?
Target symptoms
Therapeutic response
Side effects with close physical monitoring
When is rapid tranquiliser used?
It is used to:
Reduce patient suffering
Reduce risk of harm by others
To do harm by prescribing safe regimens and monitoring physical health
It can only be used once verbal de-escalation has failed and oral medication has been refused.
Which medications can be used for rapid tranquilisation?
IM Lorazepam, or IM Haloperidol with IM Promethazine
What is the monitoring required for rapid tranquilisation?
Bp
Temperature
Respiratory rate
Consciousness
Should be done hourly or every 15 minutes if the BNF maximum was exceeded or additional concerns were raised.
How is treatment resistant psychosis defined?
Lack of satisfactory improvement despite use of at least two different anti-psychotic drugs including a SGA prescribed for at least 4-6 week trial period.
This affects 1/3 of patients using anti-psychotics.
Which anti-psychotic is licensed for treatment resistant psychosis?
Clozapine
Explain how extra-pyramidal side effects occur with first generation anti-psychotics.
First generation anti-psychotics have a much greater affinity for the D2 receptor in comparison to second generation anti-psychotics. It is believed that Schizophrenia occurs due to dopamine hyperactivity at D2 receptors within the mesolimbic system causing the positive symptoms (responsible for the reward pathway).
First generation anti-psychotics were designed as D2 receptor antagonists with a clinical effect seen once 80% of D2 receptors within this pathway are occupied. However D2 antagonists are not specific to this one dopamine pathway, they also bind to D2 receptors within the other three pathways.
D2 antagonism within the nigrostriatal pathway leads to depleted dopamine leads to the extrapyramidal side effects as seen in the symptomatic presentation of Parkinson’s disease such as akathisia, dystonia, tardive dyskinesia.
What are the signs of dystonias?
Uncontrolled muscle spasms of the head and neck
Patients may also experience pain and stiffness
Eye rolling
What are the risk factors for developing dystonia?
Occurs in 10% of patients those at a higher risk are:
Young men, those taking anti-psychotics for the first time, higher potency anti-psychotics
When are dystonia likely to occur?
Acutely within hours and even faster with IM
Tardive dystonia after months or years after taking the anti-psychotic
What is the appropriate management of dystonia?
Anticholinergics such as Procyclidine which can allow the patient to continue at the effective dose
Switching to a SGA
Reducing the dose of anti-psychotic
What are some of the signs and symptoms of Parkinsonism?
Tremours
Rigidity
Bradykinesia - reduced facial expression, slow body movements, inability to initiate movement, speaking with a flat monotone voice
Which patients are more likely to experience Parkinsonism and when does it occur?
Elderly females, those with pre-existing neurological damage
Days to weeks of initiation or following a dose increase
What is the appropriate management of anti-psychotic induced Parkinsonism?
Using anticholinergics (Procyclidine again)
Dose reduction
Switching to one with less EPSEs such as SGA
How does Akathisia present?
As an inner restlessness including pacing or a shaking leg
Which patients are more likely to experience Akathisia and when does it occur?
25% of those taking FGAs will experience it acutely and it is common when starting Aripiprazole.
Can occur within hours or days of starting the anti-psychotic/increasing the dose and can persist for months.
What is the appropriate management of akathisia?
Reducing the dose
Using an alternative - SGA
Short course of Benzodiazepines such as Lorazepam when starting the anti-psychotic
What are some of the signs and symptoms of tardive dyskinesia?
Lip smacking, blinking, upper body movements and choreiform hand movements (such as playing the piano).
Which patients are more likely to experience tardive dyskinesia and when does it occur?
Older age, affective illness, Schizophrenia, high doses of anti-psychotics, acute EPSEs in early treatment.
Can take months to years to develop
What is the appropriate treatment for tardive dyskinesias?
Stop all anticholinergics
Reduce dose or switch, Quetiapine and Clozapine are good
Explain how hyperprolactinaemia occurs with anti-psychotics (particularly first generation).
As mentioned previously anti-psychotics particularly first generation due to their higher affinity for D2 receptors, also antagonises D2 receptors within pathways other than the mesolimbic pathway. D2 antagonism within the tuberohypophyseal extends from the pituitary to the hypothalamus. Dopamine within this pathway inhibits the release of prolactin, a hormone responsible for lactation. Therefore by depleting dopamine levels within this pathway by the administration of anti-psychotics this then results in hyperprolactinaemia as the inhibitory neurotransmitter is reduced so prolactin secretion is increased.
What is the symptomatic presentation of hyperprolactinaemia?
Persistent elevation can cause suppression of the hypothalamic pituitary
- Sexual dysfunction
- Menstrual disturbances
- Breast growth and galactorrhoea (breasts leak milk)
- May include delusions of pregnancy
What are some of the longer term complications associated with hyperprolactinaemia?
Reduction in bone mineral density
Increased risk of breast cancer
What is the appropriate management for hyperprolactinaemia?
Reduction of dose
Switch to a prolactin sparing anti-psychotic
Adding a low dose Aripiprazole (has antagonist activity at 5-HT2A resulting in decreased prolactin secretion).
Explain the rationale for the development of the second generation anti-psychotics.
The second generation anti-psychotics were designed to reduce the extra-pyramidal and hyperprolactinaemia seen in the first generation anti-psychotics.
Second generation anti-psychotics antagonise 5-HT 2A receptors which cause an increase of dopamine at the striatum (nigrostriatal pathway) resulting in reduced extra-pyramidal side effects and counteracting the induced effects of D2 antagonism. Also 5-HT2A receptors inhibit the release of 5-HT, usually 5-HT increases prolactin secretion therefore by inhibiting this receptor this should reduce prolactin secretion and hence hopefully reduce hyperprolactinaemia and associated effects.
What are the main side effects associated with the second generation anti-psychotics?
Metabolic side effects (syndrome):
Weight gain
Hyperglycaemia
Hyperlipidaemia
In addition to other side effects:
Anticholinergic
Cardiac
Hyperprolactinaemia
Sexual dysfunction
What is some of the monitoring required for second generation anti-psychotics?
At baseline:
Waist circumference
Blood glucose (fasting)
Weight
HbA1c
Non-fasting blood lipids
Blood pressure
U&Es
This should be repeated at 12 weeks and then annually (every 3 months for the first year with Clozapine and Olanzapine).
Weights should be taken weekly for the first six weeks and then at 3 months, 12 months and then annually.
Which medications are most likely to cause sexual dysfunctions?
Risperidone and Haloperidol
Least likely with Aripiprazole and Quetiapine
What is the appropriate management of sexual dysfunctions?
Identify a cause before treating
Monitor prolactin levels
Consider the potential for spontaneous reduction
Adjust, omit of a single daily dose (measure trough levels)
3-6mg Aripiprazole
Sildenafil - specified circumstances
Consider urology referral if there appears to be an unidentified cause
Affinity to which receptors causes sedation?
Dopaminergic, histaminic or adrenergic receptors
Why can sedation be at times beneficial?
Can help to reduce agitation in psychosis
What is the appropriate management for sedation?
Risk reduction and management is central to management of sedation:
Review concurrent medications
Start at a low dose
Counsel patients on driving
Sedative effects are usually short term
Could trial a dose of reduction
Consider switching anti-psychotics
Consider prescribing at night or giving a bigger dose then
Avoid psychostimulants like modafinil (which also interacts with Clozapine)
What are the antihistaminic side effects?
Sedation
Dizziness
Blurred vision
Anxiety
Increased appetite leading to weight gain
GI - constipation, diarrhoea
Insomnia
Infrequent adverse effects:
Urinary retention
Palpitations
Hypotension
Headache
Hallucination
Psychosis
Erectile dysfunction
Which anti-psychotics have affinity to H1 and therefore have antihistaminic side effects?
Highest affinity:
Chlorpromazine
Clozapine
Levomepromazine
Olanzapine
Quetiapine
What are the anticholinergic side effects?
Cognitive impairment
Delirium
Hypothermia
Confusion
Dry mouth
Constipation
Blurred vision
Glaucoma
Urinary retention
Tachycardia
Which anti-psychotics have affinity to M1 and therefore have anticholinergic side effects?
Highest affinity:
Clozapine
Levomepromazine
Olanzapine
Quetiapine?
What is the most appropriate management of anticholinergic side effects associated with anti-psychotic use?
Identify patients with a pre-existing medical condition which may contraindicate their use to the anticholinergic side effects of anti-psychotics.
Review concurrent medications- minimalise anticholinergic burden
Start low, go slow
Trial a dose reduction
Switch
What are adrenergic alpha-1 antagonism mediated side effects?
Dizziness
Orthostatic/Postural hypotension
Reflex tachycardia
Why are patients with Schizophrenia at a 2-3x risk of death of CVD?
Smoking
Poor lifestyle - poor self-care, lack of exercise
Substance misuse
FGA/SGA
Which anti-psychotics have affinity to a1 and therefore have anti-adrenergic side effects?
Highest affinity:
Chlorpromazine
Clozapine
Haloperidol
Levomepromazine
Olanzapine
Paliperidone
Quetiapine
Risperidone
What are some of the more severe cardiac side effects?
This is associated with sudden cardiac death and include:
Ventricular tachycardia
Torsade des pointes
Delayed myocardial repolarisation
Myocarditis
Cardiomyopathy
What is the baseline cardiac monitoring for anti-psychotics?
At baseline:
Bp
Pulse
Possible ECG
This should be repeated at 12 weeks and then annually
What is the appropriate management for managing the cardiac side effects of anti-psychotics?
Ensure gradual titration as effects are seen more at the beginning and following rapid dose titrations
Consider a dose reduction
Co-prescribing medications to reduce heart rate
Reviewing if the patient is taking other medications which cause QT prolongation
Switch
If myocarditis is suspected STOP and refer to cardiology
What are some of the CVD risks associated with Clozapine?
Thromboembolism
Myocarditis - first 6-8 weeks
Cardiomyopathy - peaks at 9 months
What are the serotonin mediated side effects?
Weight gain (5-HT2c and 5-HT1) and increased appetite
Which receptors does Clozapine have affinity for?
Weak D2 receptor antagonist
Strong action at 5-HT2A
Anticholinergic
Antihistaminic
alpha-1 antagonist
What is the main side effect of Clozapine and how is it managed?
Risk of agranulocytosis or neutropenia
Patients have to have regular blood monitoring before starting treatment, weekly for first 18 weeks, fortnightly until a year and then monthly
Medication can only be supplied if bloods have been checked.
What are the different scales of Clozapine blood monitoring to manage against agranulocytosis and neutropenia?
Green:
WBC above or equal to 3500/mm3 and ANC above or equal to 2000/mm3
- Can be supplied
Amber:
WBC at 3500-3000/mm3 and ANC at 1500-2000/mm3
- Monitoring increased to twice weekly but can be supplied
Red:
WBC below 3000/mm3 and ANC below 1500/mm3
- STOP immediately and start daily bloods
How can agranulocytosis be avoided?
Gradually up-titrating the medication as agranulocytosis is associated with increased dosing.
What are some of the GI side effects associated with Clozapine?
Mainly Constipation but can also cause
Nausea and vomiting
Dyspepsia
These are due to anticholinergic, antihistaminic and antagonism of 5-HT receptors
What can exacerbate Clozapine induced constipation?
Other medications having similar effects
Dehydration
Immobility
What is the appropriate management for Clozapine induced constipation?
Dietary advice, fluid, fibres, exercise
Laxatives either stimulant, stool softeners or osmotic
Avoid
When and why does Clozapine induced hypersalivation occur?
Dose dependent hypersalivation occurs due M4 or alpha-2 antagonism with impaired swallowing reflex leading to dribbling/drooling but can also cause life threatening aspiration pneumonia.
Usually occurs at the beginning of treatment and may improve over time.
What is the appropriate management of aspiration pneumonia?
No licensed treatment
Dose reduction or switching may improve side effect however if the patient is already taking Clozapine - they may not work for their positive symptoms
Could use an antimuscarinic such as Hyoscine Hydrobromide but can then cause constipation
Chewing gum
Towel on pillow
What are some of the signs and symptoms of neuroleptic malignant syndrome?
Fever
Diaphoresis
Muscle rigidity
Alteration in mental state
Tachycardia
Tremor
Incontinence
Elevated creatine kinase, Leucocytosis, altered LFTs
What are the risk factors for neuroleptic malignant syndrome?
Male
Younger age
Dehydrated
Alcoholic
Hyperthyroidism
Parkinson’s
Psychomotor agitation
High potency FGAs
Recent rapid dose increases or reduction
Abrupt withdrawal
Antipsychotic polypharmacy
What is the appropriate management for neuroleptic malignant syndrome?
STOP anti-psychotics and monitor temperature, blood pressure and pulse
Consider use of benzodiazepines
Call an ambulance and transfer to hospital
What is the appropriate management following an episode of neuroleptic malignant syndrome?
Wait 5 days before restarting
Use a low dose and increase very slowly and this should be a medication that is structurally unrelated and with lower dopamine affinity such as Quetiapine, Clozapine, Aripiprazole
Avoid depots/LAIs
What are some of the pharmacodynamic interactions associated with anti-psychotics?
Anti-psychotic drugs can have an additive, synergistic or antagonistic effect, typically they interact with drugs also causing:
QT prolongation
Neutropenia/Agranulocytosis
Increased sedation
Increased anticholinergic side effects
Decreased blood pressure/increasing risk of falls
Increasing the risk of seizures
Increased weight gain/metabolic changes
What are some of the pharmacokinetic interactions associated with anti-psychotics?
CYP enzyme inducers and inhibitors that can alter the metabolism and therefore exposure of many anti-psychotics that are metabolised through this route.
What is the interaction between Clozapine and smoking?
Tobacco smoke causes CYP 1A2 induction, which is one of the enzymes responsible for metabolising Clozapine. Cigarette smoking reduces plasma levels of Clozapine therefore by up to 50%.
What is the appropriate management of Clozapine if the patient is also a smoker?
If the patient is consistently smoking this isn’t an issue however if they suddenly stop smoking for example get sectioned this can cause Clozapine levels to rise very quickly.
Take plasma levels a week before and then a week after stopping
Reduce dose gradual to 75% of the original
If the patient restarts smoking an upward dose titration can occur to the original dose over a week
What are some of the other anti-psychotics that can also experience a reduction in plasma levels with smoking?
Olanzapine
Haloperidol
Zuclopenthixol
Chlorpromazine
Fluphenazine
What is the interaction between Clozapine and caffeine?
It inhibits CYP 450 1A2 causing an increase in Clozapine levels of up to 60% and also affects Olanzapine.
What is the appropriate management of anti-psychotics and caffeine?
Not an issue if both remain the same however additional monitoring is required if caffeine intake changes - this includes not just coffee but also fizzy and energy drinks and chocolate.
When do discontinuation symptoms occur?
From 4 days to 1-2 weeks
What are some of the discontinuation symptoms associated with anti-psychotic use?
Nausea and vomiting
Seizures
Anxiety
Muscle pains
Insomnia
Dystonia
Risk of psychosis reoccurring
Anti-psychotics with significant anti-cholinergic effects may precipitate rebound
What are some of the prevention strategies to minimalize discontinuation symptoms?
Discontinue gradually and slowly
Educate on potential withdrawal
Most resolve spontaneously
Short term benzodiazepines may help with anxiety and insomnia for example
Anticholinergic drugs for cholinergic syndrome
Original anti-psychotics can be restarted if bad/slower tapering of dose
Cross taper when switching anti-psychotics
