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Schizophrenia formulary guidance

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Contents

Adapted from National Institute for Health and Care Excellence (NICE) guidelines CCG 178 and CG 155 and NG 181.

1 Introduction

These guidelines are intended for routine use. However, there will be instances where they are not suitable for the patient you are managing, where more bespoke treatment will be necessary. In such instances the rationale for prescribing away from formulary must be recorded.

In the management of schizophrenia, antipsychotics may be used for the treatment of acute episodes, for relapse prevention and for emergency treatment of acute behavioural disturbance (rapid tranquilisation).

There is little evidence of any clinically significant differences in efficacy between antipsychotic drugs except for superior efficacy of clozapine when used for schizophrenia that has not responded adequately to other antipsychotic medication.

2 Prescribing and use of antipsychotics, key points

  • For people with newly diagnosed schizophrenia, acute exacerbation, or recurrence of schizophrenia, offer oral antipsychotic medication. Take into account the previous clinical response and side effects.
  • Valid consent should be sought.
  • For initial treatment with antipsychotic, choice of agent is determined by service user’s past medication history, current symptoms, co-occurring conditions, concurrent treatments and individual preferences. See table for suggested choices.
  • Discuss the condition and the benefits and side-effect profile of each drug with the service user and, or carer and provide written information.
  • Initiate treatment at the lower end of the licensed dose range and slowly titrate upwards within the recommended dose range. Antipsychotic-naive individuals may respond to doses of antipsychotics at the lower end of the recommended range.
  • Prescribe antipsychotics within the recommended dosage range as there is little evidence to support the use of higher dosage. High dose treatment is associated with a greater risk of side effects.
  • Carry out a trial of antipsychotic at the optimum dosage for 4 to 6 weeks. Oral antipsychotics are usually continued for at least 1 to 2 years after the person has recovered and remained stable, to reduce risk of relapse.
  • Consider depot or long-acting injectable antipsychotic medication for maintenance treatment of people with schizophrenia who would prefer such treatment after an acute episode or where necessary to avoid covert non-adherence.
  • Wherever possible, long-acting injectable antipsychotic treatment without prior stabilisation on oral treatment should not be used in treatment-naive or in acutely disturbed service users.
  • Do not initiate regular combined antipsychotic medication, except for short periods (for example, when changing medication) because this results in prescribing higher than necessary total dosage and increases the risk of side effects (see specific guidance on high dose).
  • Routine use of PRN antipsychotics is not supported, such prescriptions must be regularly reviewed, each week or as appropriate.
  • Do not use loading doses or intermittent dose maintenance strategies routinely.
  • For people with coexisting substance misuse, consider the level and type of substance misuse, potential interactions, and increased risk of side effects.
  • If withdrawing antipsychotic medication, undertake gradually and monitor regularly for signs and symptoms of relapse. After withdrawal from antipsychotic medication, continue monitoring for signs and symptoms of relapse for at least 2 years.
  • Patients who have failed to respond to two or more agents (ideally one of which should have been a second-generation agent), unless due to side effects, should be considered as treatment resistant and should be considered for Clozapine. For further information on treatment resistance see guidance further on.
  • If a patient is subject to consent to treatment rules, then ensure prescribing is in line with T2 and T3, CT011 and CTO12 and if not take suitable steps to update these, using a Sn62 if necessary.
  • Offer cognitive behavioural therapy (CBT) to all people with schizophrenia. This can be started either during the acute phase or later.

3 Side-effects and interactions

Antipsychotics can be divided into older first-generation (FGAs, conventional or typical) and newer second-generation (SGAs or atypical) antipsychotics.

All are associated with a high incidence and broad range of side effects including:

  • nausea, dry mouth, constipation, headache, lethargy, sedation, postural hypotension, weight gain
  • extrapyramidal side effects (EPSE) such as acute dystonia, akathisia, parkinsonism, and tardive dyskinesia
  • raised prolactin leading to menstrual abnormalities, sexual dysfunction, reduced bone density and osteoporosis
  • antimuscarinic effects such as blurring of vision, increased intra-ocular pressure, dry mouth and eyes, constipation and urinary retention can occur
  • metabolic effects (including hyperglycaemia and raised blood lipids)
  • blood disorders
  • neuroleptic malignant syndrome
  • seizures
  • QT-interval prolongation and tachyarrhythmia

The profile and clinical significance of side effects varies among drugs and individuals. SGAs have a lower but dose dependent risk of EPSE. However, they cause other side effects, such as weight gain hyperlipidaemia, hypertension, impaired glucose tolerance which can increase cardiovascular risk. See table 5 for comparisons.

Older adults are particularly prone to the side effects of antipsychotics. The balance of risks and benefit should be carefully considered before prescribing.

Important drug interactions can occur between antipsychotics and drugs that increase sedation (for example, alcohol, benzodiazepines), increase the risk of arrhythmias associated with QT-interval prolongation, increase hypotension risk, increase seizure risk and increase the risk of neuroleptic malignant syndrome (NMS). Antipsychotics inhibit the effect of dopamine agonists used for Parkinson’s disease. See table 4 for more details on interactions.

4 Warning

  • There is a clear increased risk of stroke and a small increased risk of death associated with use of both typical and atypical antipsychotics in older adults with dementia and in any person with pre-existing risk factors for stroke.
  • The possibility of cerebrovascular events should be considered carefully before treating people with a history of stroke or transient ischaemic attack, risk factors for cerebrovascular disease.
  • Antipsychotic use may be associated with an increased risk of venous thromboembolism (VTE). All possible risk factors should be identified before and during treatment, and preventative measures taken.
  • Seizures are a recognised dose-related side effect of antipsychotics, especially clozapine.
  • Neuroleptic malignant syndrome (NMS), a rare but life-threatening adverse effect, can occur with any antipsychotic and requires immediate discontinuation of antipsychotic. Symptoms include hyperthermia, muscle rigidity, autonomic instability, and fluctuating consciousness. NMS is a medical emergency and requires immediate management.
  • QT interval prolongation is a widely reported side effect of antipsychotics and considered to be a class effect. It increases the risk serious arrhythmia.
  • Antipsychotic drugs can cause sedation, poor concentration, and extrapyramidal symptoms, all of which can impair driving. Careful assessment is therefore needed to determine whether adverse effects of medication will impair driving.
  • Routine monitoring is a mandatory pre-requisite to clozapine use because of the risk of neutropenia and agranulocytosis. Ongoing monitoring must be maintained.
  • Smoking induces the metabolism of psychotropic medication (particularly olanzapine and clozapine). Dose adjustments may be necessary on smoking cessation.

5 Monitoring

Baseline physical health checks should be carried out including:

  • weight or body mass index
  • blood pressure
  • pulse
  • urea and electrolytes and renal function
  • liver function tests
  • full blood counts
  • glucose
  • lipids
  • where appropriate prolactin
  • ask about smoking status, alcohol, and substance misuse
  • an electrocardiogram (ECG) at baseline and after dose changes, if specified in product licence or if there is an identified risk, following taking a cardiac history, all inpatients should receive and ECG

Routine physical health screening of people prescribed antipsychotic drugs in the long term is required, within three months of initiation by secondary care and then annually thereafter in primary care. Results of all monitoring should be documented in the clinical records and communicated to the patient’s general practitioner (GP)

The following must be monitored and recorded throughout treatment (especially during titration and at least once a year): efficacy, side effects of treatment, adherence, and physical health.

People taking clozapine require registration with a clozapine monitoring service and frequent monitoring of full blood counts. See table 3 for monitoring schedule.

6 Switching antipsychotics

There are different options available, the one most clinically suitable should be chosen. If cross tapering be aware of the risk of high dose prescribing, and cumulative and synergistic side effects. Check specific in the summary of product characteristics (SPC) (opens in new window).

6.1 Oral to oral

  • Stop the first agent then introduce and titrate the new agent.
  • Start the new agent then gradually lower the old agent, whilst increasing the new.
  • Lower the dose of the existing agent before introducing the new agent and titrating upwards.

6.2 Oral to depot, long acting injectable (LAI)

  • Give a test dose of the depot then after the depot has started to become established gradually reduce and stop the oral agent.

6.3 Depot, long acting injectable (LAI) to oral

  • Omit the depot and start the new agent, and gradually titrate upwards, be aware of the half-life of the depot.
  • Start the oral medication the week prior to the last dose of the depot, and slowly titrate upwards.
  • Risperidone, ask for advice from pharmacy or a senior colleague if unsure, due its unique release characteristics.
  • notes difference between Risperdal Consta and Okedi.

6.4 Depot, long acting injectable (LAI) to depot (LAI)

  • Consider a test dose, then switch from one agent to the next.

7 Treatment resistant schizophrenia

Defined as an inadequate response to treatment despite the sequential use of adequate doses of at least two different antipsychotic drugs including at least one second-generation antipsychotic prescribed for an adequate duration.

  • Check adherence to treatment, dose and duration of treatment.
  • Clozapine has evidence of superior efficacy in people whose symptoms have not responded to other measures and should be considered first line for treatment resistance.
  • In cases of poor response to clozapine alone, augmentation with another antipsychotic may be beneficial. An adequate trial of clozapine augmentation may be up to 8 to 10 weeks. Choose a drug that does not compound the common side effects of clozapine.
  • Use of high-dose antipsychotic medication and combinations of antipsychotics is common, but there is little evidence of any significant benefit and side effects are greater. Routine use is not recommended.
  • Consider augmentation of antipsychotics with other drugs like lithium, carbamazepine, sodium valproate, lamotrigine, antidepressants and benzodiazepine.

See table 3 for additional details.

8 High dose antipsychotic prescribing

Current evidence does not justify the routine use of high-dose antipsychotic medication in general adult mental health services, either with a single agent or combined antipsychotics.

Calculating the level of antipsychotic dose.
The Consensus Working Group recommends the following definition for high dose: a total daily dose of a single antipsychotic which exceeds the upper limit stated in the British National Formulary or a total daily dose of two or more antipsychotics which exceeds the BNF maximum using the percentage method, including PRN medication.

Example, Olanzapine 15mg plus Aripiprazole 20mg:

  • ((15/20) x 100) + ((20/30) x100) = ~ 142%

Note, recommendations adapted from CR 138 (RCPSYCH 2006).

8.1 Considering prescribing high dose

Use of high dose of antipsychotics should only be considered in individual cases.

  • As a carefully monitored therapeutic trial and where evidence-based strategies have failed.
  • Involve an individual risk–benefit assessment by a fully trained psychiatrist (consultant only).
  • In consultation with the wider clinical team and the patient and a patient advocate, if available, and if the patient wishes their presence.
  • Taking full account of possible contraindications and drug interactions to high dose, for the drug(s) in the patient.

8.2 Having decided to prescribe high dose

Having decided explicitly to prescribe high dose of antipsychotics.

  • The decision should be documented in the case notes to include as a minimum:
    • risks and benefits of the strategy
    • define the length of trial, not less than 6 weeks but not more than 3 months
    • expected outcome and schedule for monitoring
  • Conduct baseline ECG to exclude cardiac contraindications, including long QT syndromes. This must be repeated after a few days and then ideally every 1 to 3 months in the early stages of high-dose treatment (the frequency being determined as clinically indicated).
  • Baseline U and E’s, repeated after a week are required as abnormal electrolyte levels can predispose patients to ECG abnormalities.
  • The use of PRN medication should be kept under regular review. Staff administering PRN should be aware of its potential to raise the total daily dose of antipsychotic above the high-dose threshold.

8.3 When used in the context or rapid tranquillisation

  • If high-dose antipsychotic treatment has been used, it is particularly important that the routine monitoring of a sedated patient is carried out, with particular attention to regular checks of pulse, blood pressure, respiration, temperature, and hydration, in line with the rapid tranquillisation policy.
  • ECGs should be carried out frequently during dose escalation, if and when possible, if unable due to patient factors this should be documented, and a risk benefit assessment carried out.
  • During acute violence or emergency tranquillisation avoid parenteral antipsychotics, if possible, but if used, ECG monitoring or regular ECGs should be performed, but see above.

8.4 Patients subject to consent to treat rules (Mental Health Act)

In line with CQC guidance high dose prescribing must be explicitly acknowledged on the form, with a cumulative maximum dose of antipsychotic stated.

These guidance notes must be read in conjunction with other trust guidance on medicines, and along with NICE guidance, including guidance on the use of ECG’s.

9 Special populations

9.1 BPSD in elderly

Good practice for prescribing any drug, including antipsychotics, for severe agitation and psychosis in dementia:

  • review vascular risk factors
  • explain the possible positive and negative effects of the medication
  • document risk assessment, capacity issues (best interests) and discussions with relatives or carers
  • identify (quantify) target symptom(s)
  • choose effective drug dose, low doses initially
  • choose timeframe (1 month), discontinue if no clear benefit
  • If good response, the prescriber should review (and document) the need for continued treatment every 6 to 12 weeks according to clinical need
  • avoid polypharmacy

The national strategy for dementia advises this should only be done by specialist services.

As part of the patients care plan relapse symptoms should be discussed with the patient, and what to do if this happens.

9.2 Child and adolescent mental health services

The National Institute for Health and Care Excellence (NICE) recommend for schizophrenia that Risperidone be considered first line and that aripiprazole (licensed from age 15) be considered second line.

NICE CG 155 states that antipsychotic medication should not be used for:

  • for psychotic symptoms or mental state changes that are not sufficient for a diagnosis of psychosis or schizophrenia
  • with the aim of decreasing the risk of developing psychosis

9.3 Learning disability key points

  • Since people with learning disability (LD)are more susceptible to side effects, detection of which is harder than in the general population, typical antipsychotics may be better tolerated.
  • Valid consent can be an issue in LD where in people lacking the ability to consent, this treatment is given in best interest of the patient under section 5 of Mental Capacity Act, or this decision is taken by the lasting power of attorney holder).
  • Patient information should be in LD easy read information forms.
  • Patients with LD are likely to be more sensitive to side effects, so a slower titration and final dose may be required.
  • They may require a longer period of treatment to assess proper response.
  • Risk of interactions may be higher in people with LD on polypharmacy, especially those on anti-epileptic medication.
  • People with LD with comorbid conditions and, or polypharmacy may require more frequent monitoring.
  • For more specific guidance on challenging behaviour refer to the current Frith and stopping over medication of people with a learning disability and autistic people (STOMP) guidelines.

10 Communication with primary care

Different areas of the trust have slightly different shared care arrangements with GPs, however in principle, with the GP’s agreement once the patient is on a stable dose then primary care can take over prescribing under shared care. Good communication is key, and clear lines of responsibility must be agreed between primary and secondary care (in Doncaster, a pro forma is in place to support this arrangement).

10.1 Stable patients

In line with new treatment models and NICE guidance there will be instances that it is reasonable to consider handing patients back to primary care. This would only be considered in patients who were stable, and well maintained, and no longer required secondary care input, and the GP agreed.

Information to be handed over to primary care:

  • specific information on the actual treatment (treatment plan)
  • results of recent tests and any actions planned from them
  • recommended monitoring
  • relapse signature
  • advice on stopping treatment if appropriate
  • how and when to re-refer back

If the patient has been transferred or discharged to primary care re-referral should be considered if:

  • relapse
  • nonadherence to medication
  • intolerable side effects of medication
  • co-morbid substance misuse
  • complicating co morbid illness
  • risk to self or others

11 Further information

Full guidance on prescribing and use, including information on possible side effects and interactions of antipsychotics available in the BNF or manufacturer summaries of product characteristics (SPCs).

Information on managing side effects can be found on the Medicines and Healthcare products Regulatory Agency (opens in new window).

12 References

13 Appendices

13.1 Table 1 Pharmacological treatments for schizophrenia

13.1.1 Table 1A First line general note

Drug or group Relative costs Notes
Appropriate antipsychotic (see first and second generation antipsychotic below) See individual antipsychotics NICE states that there is little evidence of any clinically significant differences in efficacy between antipsychotic drugs (except for clozapine for schizophrenia that has not responded adequately to other antipsychotic medication).

Choice of antipsychotic is determined by service user’s past medication history, current symptoms, co-occurring conditions, concurrent treatments, side effects and importantly, individual preferences.

13.1.2 Oral, first tier first-generation antipsychotic (FGA)

Oral, first tier FGA Relative costs Notes
Haloperidol £ High risk of extrapyramidal side effects, also useful for agitation, aggression, impulsive behaviour.
Sulpiride (liquid) £ (££) Increased agitation reported at high dosage, care in mania and hypomania.

Extrapyramidal side effects and hyperprolactinaemia common, beneficial in apathy and withdrawal.

Perphenazine ££ Also used as an adjunct in anxiety, agitation and violent or dangerously impulsive behaviour.
Zuclopenthixol £ Sedative drug, risk of extrapyramidal side effects, useful when switching between oral to depot.

13.1.3 Oral, first tier second-generation antipsychotic (SGA)

Oral, first tier SGA Relative costs Notes
Risperidone £ Increases prolactin, dose-dependent extrapyramidal side effects hypotension, tachycardia, weight gain, hyperglycaemia can occur.
Olanzapine £ Weight gain and metabolic side effects are common, low EPS, smoking induces metabolism of olanzapine, so stopping smoking can increase levels, possibly causing increased adverse effects.
Quetiapine (not MR) £ Low extrapyramidal side effects.
Quetiapine XL ££ XL preparation may be considered where twice daily difficult or not tolerated, prescribe as Biquelle.
Aripiprazole £ Consider in patients with either metabolic or cardiac history.
Lurasidone ££ Consider in patients who are at risk of significant weight gain, metabolic disorders or cardiac history.

13.1.4 Long lasting injections (LAI)

Long acting injections Relative costs Notes
Haloperidol decanoate ££ Longer-acting, suitable for monthly administration, higher incidence of extrapyramidal effects, risk of QT prolongation and ventricular arrhythmias may be increased with high doses or parenteral use.
Flupentixol decanoate ££ Not recommended for excitable or agitated people.
Zuclopenthixol decanoate ££ Less likely to cause sedation, hypotension or antimuscarinic effects but high risk of EPSE.

13.1.5 Table 1B Second line options

13.1.5.1 Oral, second tier first-generation antipsychotic (FGA)
Oral, second tier FGA Relative costs Notes, discuss benefits, side
effects and consider previous response
Chlorpromazine £ Highest incidence of sedation, potent anticholinergic effects, hypotension, can cause skin photosensitivity, advise using sunscreen if necessary.
Trifluoperazine ££ High liability for extrapyramidal side effects, supply problems.
Benperidol £££ Licenced for control of deviant antisocial sexual behaviour only. Caution, ECG necessary.
Flupentixol £ Not recommended if excitable or agitated.
Promazine £ Adjunctive treatment of psychomotor agitation and agitation/restlessness in the elderly.
Levomepromazine ££ Alternative to chlorpromazine especially when it is desirable to reduce psychomotor activity.
Pericyazine (syrup) ££ (£££) Also used as an adjunct in anxiety, agitation and violent or dangerously impulsive behaviour.
Amisulpride (liquid) ££ (£££) Marked prolactin elevation.
13.1.5.2 Antipsychotics requiring prior approval
Antipsychotics requiring
prior approval
Relative cost Consultant initiation only by
written request to chief pharmacist
Cariprazine £££ Not yet approved by RDASH for use.
Risperidone LAI £££ Risperdal Consta, Complex pharmacokinetics, 3 week lag time to release of drug, oral supplementation required, risk of prolactin elevation, increase risk of EPSE at higher doses Okedi Monthly (28 days) injection, biphasic release characteristics. It should be initiated 24 hours after the last oral dose of risperidone.
Paliperidone ££££ Not currently approved for general use.
Paliperidone palmitate long-acting injectable (LAI) ££££ For patients unable to tolerate side effects associated with FGA’s.
Aripiprazole LAI For patients unable to tolerate side effects associated with FGA’s.
Olanzapine embonate LAI £££ Not currently recommended for general use due to post injection syndrome, Olanzapine can cause significant weight gain, hyperglycaemia, sedation and injection-related side effects.

13.1.6 Table 1C Short acting injectable antipsychotics

Short acting injectable
antipsychotics
Relative costs Notes
Haloperidol £ Indicated for rapid tranquillisation, in line with the policy, and for when patients are refusing oral, and under section.
Aripiprazole ££ Indicated for rapid tranquillisation who are intolerant of haloperidol in line with the policy, and for when patients are refusing oral, and under section.
Olanzapine ££ No longer available as a licensed product in the UK, only available as a named patient drug.

13.2 Table 2 Managing treatment resistant schizophrenia

13.2.1 First line

First line Relative costs Notes
Clozapine ££ Offer clozapine where there is inadequate response to treatment despite the sequential use of adequate doses of at least two different antipsychotic drugs including at least one second-generation antipsychotic prescribed for an adequate duration or where there are unacceptable side effects from other medication.

  • Registration with a clozapine monitoring service (ZTAS) and routine blood monitoring are pre-requisites for clozapine use because of the risk of neutropenia and agranulocytosis.
  • Prescribers and pharmacy must ensure that effective ongoing monitoring is maintained.

Before starting clozapine:

  • check adherence to antipsychotic medication
  • ensure an adequate dose of antipsychotic has been prescribed and for an optimal duration
  • check that an adequate trial of two antipsychotics has been tried or history of intolerance
  • if not, consider switching to an alternative antipsychotic agent
  • consider other causes of non-response, such as co-morbid substance misuse
  • review engagement with and consider use of psychological treatments
  • Carry out baseline tests and register with monitoring service

During treatment, monitor bloods and side effects, especially weight gain and metabolic effects.

Prompt adjustment of clozapine dose is required when smoking stops.

13.2.2 Second line

Second line Relative costs Notes
Clozapine augmentation ££ to £££
  • Consider psychological treatments before adding a second antipsychotic to clozapine.
  • If unresponsive to clozapine alone, consider adding a second antipsychotic after checking adherence and optimising dose (including measuring plasma levels).
  • Caution, combined antipsychotics may imply higher than necessary total dosage and an increased risk of side effects.
  • An adequate trial of such an augmentation may need to be up to 8 to 10 weeks.
  • Monitor and review benefits of combination therapy regularly.
Clozapine and another SGA ££ to £££
  • Choose a drug that does not compound the common side effects of clozapine.
  • Amisulpride or sulpiride may be tried for predominantly negative symptoms.
  • Use lower doses, regularly monitor side effects and physical health.
  • Aripiprazole, especially if weight is problematic.
Clozapine and other agent ££ to £££ Limited evidence, augmentation with mood stabilisers (valproate and lamotrigine), anti-depressants (SSRIs, mirtazapine) and benzodiazepines may be tried, if clinically indicated
Combinations of antipsychotics (non-clozapine) £ to £££
  • There is little supportive evidence for superior efficacy but increased risk of side effects.
  • Combination use should be reserved to short periods during switching from one antipsychotic to another.
  • Only use combinations of antipsychotics where there are no obvious problems with use and as for an adequate therapeutic trial. Discontinue if no benefits are apparent.
  • Document reasons for use fully and monitor treatment outcome regularly.
  • Aripiprazole may reduce prolactin when used in combination with antipsychotics that raise prolactin.
  • Review continued use of combinations regularly and discontinue if no clinical benefits.

13.3 Table 3 Monitoring schedule for patients on antipsychotics

Clozapine,
clozapine monitoring
covered separately
Baseline At one
month
At three
months
At 6
months
At 12 months
then annually
(general information 1)
Blood pressure (legend 2 and 8) NICE guidance NICE guidance
Pulse (legend 2 and 8) NICE guidance NICE guidance
Bodyweight or BMI (legend 3) NICE guidance NICE guidance NICE guidance NICE guidance
HbA1c (legend 4) NICE guidance Olanzapine (legend 4) NICE guidance NICE guidance
Blood lipids NICE guidance NICE guidance NICE guidance
Renal function (U&E, eGFR) NICE guidance NICE guidance
Full blood count (FBC) NICE guidance NICE guidance
Liver function test (LFT) NICE guidance NICE guidance
TFT (Quetiapine only) Maudsley guidance Maudsley guidance
Prolactin (legend 5) NICE guidance NICE guidance NICE guidance
Creatine phosphokinase (CPK) (legend 6) Maudsley guidance
Electrocardiogram (ECG) NICE guidance NICE guidance
Side-effects (GASS or like) (legend 2) NICE guidance NICE guidance
Adherence to medication (legend 2) NICE guidance
Overall physical health (legend 2) NICE guidance NICE guidance
Smoking status NICE guidance NICE guidance
Alcohol or drug status NICE guidance NICE guidance
Movement disorders (legend 2 and 7) NICE guidance NICE guidance
Physical activity (legend 7) NICE guidance NICE guidance
Nutritional status (legend 7) NICE guidance NICE guidance

13.3.1 Legend

  1. Diagnosis discussed with patient and appropriate information sheet given as necessary.
  2. The choice of antipsychotic considered appropriate for the patient, has been discussed with the patient and or advocate. This includes advanced plans or directives if available and likely side effects of the specific drugs (see formulary).
  3. Written information regarding specific antipsychotic(s) given to patient or carer (opens in new window).
  4. Baseline physical health checks are carried out, recorded and discussed with the patient or carer to specifically include taking cardiac, smoking and alcohol histories.
  5. Review date to assess efficacy and tolerability made in the diary, and patients treatment plan.
  6. This guidance is based on results being within normal limits. Tests may need to be repeated more often due to individual clinical indicators.
  7. Additional detail is available in the trust formulary and individual drug summary of product characteristics (SPCs).

Monitoring (not necessarily prescribing). The secondary care team should maintain responsibility for monitoring service users’ physical health and the effects of antipsychotic medication for at least the first 12 months or until the person’s condition has stabilised, whichever is longer. Thereafter, the responsibility for this monitoring may be transferred to primary care under shared care arrangements.

13.3.2 Use of electrocardiogram (ECG) in monitoring for antipsychotics

Electrocardiogram (ECG) mandatory for haloperidol, pimozide and sertindole. Not required for:

  • antipsychotics with no or low to moderate effect on QT interval
  • where there are no other risks for arrhythmia
13.3.2.1 Inpatients
  • at baseline for all patients on admission
  • at dose change and when reaching target dose
  • prior to discharge if there has been a change in treatment
13.3.2.2 Community patients
  • patients with a personal history of cardiovascular disease
  • where there is an identified cardiac risk factors.
  • where specified in the drug’s summary of product characteristics
  • if ECG indicated, repeat at dose change and ideally annually

13.3.3 Table 3b, children and adolescents (from NICE CG155)

Baseline for all patients (Secondary care responsibility up to and including first six months) Weekly for first 6 weeks (Secondary care responsibility up to and including first six months) 3 months (Secondary care responsibility up to and including first six months) Monitor every 6 months thereafter (primary care responsibility) Monitor regularly throughout treatment and especially during titration (primary and secondary care)
  • Weight (legend 1) (plotted on a growth chart).
  • Height (legend 1) (plotted on a growth chart).
  • Waist and hip circumference (plotted on a percentile chart).
  • Pulse.
  • Blood pressure (plotted on a percentile chart).
  • Fasting blood glucose.
  • HbA1c.
  • Blood lipid profile.
  • Prolactin level.
  • Movement disorders (epse, akathisia, dystonia, and tardive dyskinesia).
  • Nutritional status and levels of daily activity.
  • Side effects the child or young person is most or least willing to tolerate.
  • ECG (legend 3).
Weight (legend 1) (plotted on a growth chart).
  • Weight (legend 1) (plotted on a growth chart).
  • Pulse.
  • Blood pressure (plotted on a percentile chart).
  • Fasting blood glucose.
  • HbA1c.
  • Blood lipid profile.
  • Prolactin level.
  • Weight (legend 1) (plotted on a growth chart).
  • Height (legend 1) (plotted on a growth chart).
  • Waist and hip circumference (plotted on a percentile chart).
  • Pulse.
  • Blood pressure (plotted on a percentile chart).
  • Fasting blood glucose.
  • HbA1c.
  • Blood lipid profile.
  • Prolactin level.
  • Movement disorders (epse, akathisia, dystonia, and tardive dyskinesia) (legend 2).
  • Nutritional status and levels of daily activity.
  • Efficacy.
  • Side effects.
  • Adherence.
13.3.3.1 Legend

Should be read in conjunction with the current BNF, BNFC and SPC.

  1. Calculate and document BMI (percentile).
  2. Even if no baseline assessment (and at each clinic appointment if more frequent).
  3. If specified in the SPC for adults and children, a physical examination has identified a specific cardiovascular risk (such as diagnosis of high blood pressure); there is a personal history of cardiovascular disease, there is a family history of cardiovascular disease such as sudden cardiac death or prolonged QT interval; or the child or young person is being admitted as an inpatient.

13.4 Table 4 Common interactions and problems with antipsychotics

See British National Formulary for more details.

Potential additive
side effects
Most problematic
antipsychotic(s)
Drug or class combined
with antipsychotic
QT prolongation
  • Haloperidol
  • Pimozide
  • High-dose antipsychotic prescribing
  • Escitalopram
  • Citalopram
  • High-dose methadone
  • Erythromycin
  • Clarithromycin
  • Co-trimoxamole
  • Mefloquine
  • Sotalol
  • Amiodarone
  • Ciclosporin
  • Hydroxyzine
  • Tamoxifen
Increased risk of neutropenia and agranulocytosis
  • Clozapine
  • Carbamazepine
  • Carbimazole
  • Chloramphenicol
  • Cyctotoxics long-acting depot
  • Antipsychotics
  • Penioncillamine
  • Phenylbutazone
  • Sulphonamides, for example, co-trimoxamole
Increased sedation
  • Chlorpromazine
  • Clozapine
  • Olanzapine
  • Quetiapine
  • Pericyazine
  • Zuclopenthixol
  • Alcoho
  • Antihistamines
  • Benzodiazepines
  • Mirtazapine
  • Opioid analgesics
  • Trazodone tricyclic antidepressants
Increased risk of anticholinergic side-effects, for example constipation, urinary retention, blurred vision and confusion
  • Chlorpromazine
  • Clozapine
  • Pimozide
  • Trifluoperazine
  • Zuclopenthixol
Anticholinergic drugs

  • Procyclidine
  • Hyoscine
  • Tricyclic antidepressants
  • Tolterodine
  • Oxybutnin
Decreased blood pressure or falls
  • Chlorpromazine
  • Clozapine
  • Pericyazine
  • Pimozide
  • Risperidone
  • Aripiprazole
  • ACE inhibitors
  • Alcohol
  • Anti-hypertensives tricyclic antidepressants
Increased risk of seizures
  • Chlorpromazine
  • Clozapine
  • Most phenothiazines
  • Sudden benzodiazepine withdrawal
  • Tricyclic antidepressants
Increased weight gain and metabolic changes
  • Chlorpromazine
  • Clozapine
  • Olanzapine
  • Perphenazine
  • Lithium
  • Mirtazapine
  • Other antipsychotics
  • Tricyclics
  • Valproate

13.5 Table 5 Relative side-effect profiles of antipsychotics

13.5.1 First-generation antipsychotic (FGA) oral agents

Drug Extrapyramidal Anticholinergic Cardiac Hypotension Sedation Weight Glucose Lipids Prolactin Seizures
Chlorpromazine ++ +++ ++ +++ +++ +++ +++ +++ +++
Flupenthixol ++ ++ + +/- + + ++ +
Haloperidol +++ +/- ++ +/- + + +++ +
Levomepromazine ++ +++ ++ +++ +++ +++ +++ +++ ++
Promazine + ++ ++ ++ +++ +++ +++ ++
Sulpiride + + + +/- +
Trifluoperazine +++ +/- ++ + +
Zuclopenthixol +++ ++ + + ++ ++ +

13.5.2 First-generation antipsychotic (FGA) depot

Drug Extrapyramidal Anticholinergic Cardiac Hypotension Sedation Weight Glucose Lipids Prolactin Seizures
Haloperidol +++ + ++ + + + +++ +
Fluphenazine +++ ++ ++ + ++ + +++
Flupenthixol ++ ++ + +/- + ++ +
Zuclopenthixol +++ ++ + + +++ ++ +

13.5.3 Second-generation antipsychotic (SGA) oral agents

Drug Extrapyramidal Anticholinergic Cardiac Hypotension Sedation Weight Glucose Lipids Prolactin Seizures
Amisulpride + +/- + +/- + + ++
Aripiprazole + +/- + +/- +++
Clozapine +++ +++ +++ +++ ++ ++ +/- +
Lurasidone +
Olanzapine + ++ +++ +++ ++ + +
Paliperidone +/- ++
Quetiapine + ++ ++ ++ ++ ++ +/-
Risperidone ++ ++ ++ ++ ++ ++ ++

13.5.4 Second-generation antipsychotic (SGA) depots

Drug Extrapyramidal Anticholinergic Cardiac Hypotension Sedation Weight Glucose Lipids Prolactin Seizures
Olanzapine + + +++ + +
Paliperidone + +/- + + + ++ ++
Risperidone + +/- + + + ++ ++ +
Aripiprazole + +/- + + +++

13.6 Guidance on missed doses of depots and long-acting injections

If a depot or long-acting injection (LAI) is missed for any reason, please follow the below guidance.

  • In all cases the prescriber must be informed if it is being administered outside the original prescription.

13.6.1 Flupentixol decanoate (Depixol), Haloperidol (Haldol), Zuclopenthixol (Clopixol)

  • For weekly depot injections, a dose can be given a day or two days late without significant effect on plasma levels. If more than two days late, please contact pharmacy.
  • For two weekly depot injections, a missed dose can be given up to a week late then continue every 2 weeks thereafter. Please contact pharmacy if longer than 7 days.
  • For three weekly depot injections, a missed dose can be given up to a week late then continue every 3 weeks thereafter. Please contact pharmacy if longer than 7 days.
  • For four weekly depot injections, a missed dose can be given up to a week late then continue every 4 weeks thereafter. Please contact pharmacy if longer than 7 days.

13.6.2 Aripiprazole (Abilify maintena), Paliperidone (Xeplion and Trevicta), Risperidone (Risperdal Consta) and Aripiprazole LAI (Abilify Maintena)

Aripiprazole is given as a monthly injection, and it can be given no sooner than 26 days after the previous injection.

13.6.2.1 Missed second or third dose and time since last injection
  • Greater than 4 weeks but less than 5 weeks, administer the LAI as soon as possible then resume monthly injection schedule.
  • Greater than 5 weeks, concomitant oral Ariprazole should be restarted for 14 days with next administered injection and then resume monthly injection schedule.
13.6.2.2 Missed fourth dose or subsequent dose missed (for example, at steady state) and time since last injection
  • Greater than 4 weeks but less than 6 weeks, administer the LAI as soon as possible then resume monthly injection schedule.
  • Greater than 6 weeks, concomitant oral Ariprazole should be restarted for 14 days with next administered injection and then resume monthly injection schedule.

If a dose is missed less than 4 weeks, give LAI as soon as possible then resume monthly injection schedule.

13.6.3 Paliperidone 1 monthly LAI (Xeplion)

13.6.3.1 Missed second initiation dose (100mg) and time since last injection
  • Less than 4 weeks, 100mg should be injected into the deltoid muscle as soon as possible. A third paliperidone injection of 75mg (deltoid or gluteal) should be administered 5 weeks after the first injection (regardless of the timing of the second injection). The normal monthly cycle of injections in either deltoid or gluteal muscle of 50mg to 150mg based on individual patient tolerability and efficacy should be followed thereafter.
  • Greater than 4 but less than 7 weeks:
    • day 1, 100mg deltoid injection as soon as possible
    • day 8, 100mg deltoid injection
    • day 36, resume the normal monthly cycle of injections (deltoid or gluteal) based on individual patient tolerability and efficacy
  • Greater than 7 weeks:
    • day 1, 150mg deltoid injection as soon as possible
    • day 8, 100mg deltoid injection
    • day 36, resume the normal monthly cycle of injections (deltoid or gluteal) based on individual patient tolerability and efficacy
13.6.3.2 Monthly maintenance dose and time since last injection
  • Less than 6 weeks, administer depot as soon as possible.
  • Greater than 4 but less than 6 months:
    • 50mg to 100mg.
    • day 1, deltoid injection at same dose patient was previously stabilised on as soon as possible
    • day 8, another deltoid injection (same dose)
    • day 36, resume the normal monthly cycle of injections (deltoid or gluteal) based on individual patient tolerability and efficacy
  • Greater than 6 months:
    • day 1, 150mg deltoid injection as soon as possible
    • day 8, 100mg deltoid injection
    • day 36, resume the normal monthly cycle of injections (deltoid or gluteal) based on individual patient tolerability and efficacy

Note, to avoid a missed monthly dose, patients may be given the injection up to 7 days before or after the monthly time point.

13.6.4 Paliperidone 3 monthly LAI (Trevicta) missed doses

If schedules dose is missed and the time since last injection is:

  • greater than 3 and half months and up to 4 months, the injection should be administered as soon as possible and then resume the 3 monthly injection schedule
  • 4 months to 9 months:
    • administer 1 monthly paliperidone palmitate injectable, two doses one week apart (into deltoid muscle) for day 1 and day 8 using doses as detailed below
    • then administer Trevicta (into deltoid or gluteal muscle), one month after day 8 using the dose as detailed below
    • recommended re-initiation regimen after missing 4 months to 9 months of Trevicta:
      Last dose was Day 1 Day 8 1 Month after day 8
      175mg 50mg 50mg 175mg
      263mg 75mg 75mg 263mg
      350mg 100mg 100mg 350mg
      525mg 100mg 100mg 525mg
  • greater than 9 months, re-initiate treatment with 1 monthly paliperidone palmitate injectable as described in the prescribing information for that product. Trevicta can then be resumed after the patient has been adequately treated with 1 monthly paliperidone palmitate injectable preferably for four months or more

13.6.5 Risperidone LAI (Risperidone Consta)

Time since last injection What happens to risperidone
plasma levels?
Plan
2 to 6 weeks. Therapeutic risperidone plasma levels remain. Administer LAI as soon as possible and consider supplementation with oral risperidone if indicated.
Greater 6 weeks but less than 7 weeks. Risperidone plasma level starts to decrease and may become subtherapeutic after a further 1 to 3 weeks. Administer LAI as usual but monitor mental state closely and consider supplementation with oral risperidone if indicated.
Greater than 8 to 9 weeks. All risperidone will have been eliminated from the body. Administer LAI as soon as possible and give oral risperidone for at least 3 weeks until plasma level is therapeutic.

13.6.6 Licensed injection sites for depot antipsychotics

Name of antipsychotic depot Available injection site
Flupentixol Deep intramuscular (IM) injection into gluteal or lateral thigh.
Haloperidol Deep IM injection into gluteal muscle.
Zuclopentixol Deep IM injection into gluteal or lateral thigh.
Fluphenazine (discontinued in the UK) Deep IM injection into gluteal muscle.
Pipothiazine (discontinued in the UK) Deep IM injection into gluteal or lateral thigh.
Aripiprazole Deep IM injection into gluteal or deltoid muscle.
Olanzapine Deep IM injection into gluteal muscle.
Paliperidone Deep IM injection into gluteal or deltoid muscle (First two loading doses must be deltoid).
Risperdal Consta Deep IM injection into gluteal or deltoid muscle.

If you wish to use any other site, apart from the licensed site, the medication would then become off label therefore pharmacy services must be contacted on 03000 211308 or rdash.pharmacy@nhs.net.

13.7 Guidelines for the management of QTc prolongation in adults prescribed antipsychotics

13.7.1 When to do an ECG

  • History of CVD, family history of CVD.
  • Where clinical examination reveals irregular pulse.
  • If patient taking certain medicines which are known to cause ECG abnormalities, for example erythromycin, fluconazole, tricyclic anti-depressants, methadone, domperidone, anti-arrhythmics.
  • See British National Formulary or Credible Meds (opens in new window) for further information).
  • The patient is on high dose antipsychotic therapy (HDAT).
  • The patient has factors which may predispose to arrhythmias including:
    • electrolyte abnormalities such as hypokalaemia, hypocalcaemia and hypomagnesaemia
    • systemic disease such as liver disease, renal disease and hypothrodism

13.7.2 Notes for consideration

  • Stress and anxiety can affect an electrocardiogram (ECG) and it may be necessary to manage the patient’s anxiety and repeat the ECG.
  • Electrolyte imbalances may need correcting.
  • Consider the risks associated with switching antipsychotics,
  • Patients should be warned to avoid other QTc prolonging medications (prescribed or over the counter types),

13.7.3 For specialist cardiology advice contact your local on call cardiologist

It is recommended that you have the following information prior to seeking advice.

  1. What medications have been prescribed for the patient’s mental health condition?
  2. What other medications is the patient taking (comprehensive list)?
  3. Has the patient experienced any faintness, near collapse or collapse episodes?
  4. Is the patient known to have any cardiac history or conditions?
  5. What was the patient’s heart rate and QTc (rate corrected QT-interval from the automatic report at the top of the tracing) before starting therapy?
  6. What is the patient’s latest heart rate and QTc measurement?
  7. Biochemistry results (within last two weeks): sodium, potassium, urea, creatinine, eGFR (positive magnesium level if potassium is less than 3.5mm/l), FBC results.
  8. Do you have alternative medication options open to you if the current regime needs to be changed because of excessive prolongation in the QT interval?

The cardiologist will need to have a copy of the relevant ECG(s) for the discussion.

13.7.4 Interpretation of QTc in relation to antipsychotic use

  1. Baseline ECG should be done for all patients commencing antipsychotic medication.
  2. Normal QTc, women are less than 470ms and men are less than 440ms. No action required. Repeat ECG at least annually if clinically indicated.
  3. QTc abnormal less than 500ms. Consider:
    1. consider decreasing the dose of drug or switching to an alternative drug with less risk of QTc prolongation (Aripiprazole)
    2. repeat ECG (ensure time elapsed for clearance of offending drug or dose):
      1. if abnormal refer to cardiologist
      2. if normal, repeat at least annually if clinically indicated
  4. QTc abnormal greater than 500ms:
    1. stop suspected causative drug
    2. syncope and pre-syncope equals emergency and need for ECG monitoring (cardiac arrest monitoring)
  5.  Urgent referral to cardiologist.

13.7.5 References

  • The Maudsley prescribing guidelines 2015.
  • Summary of product characteristics (opens in new window).
  • National Institute for Health and Care Excellence guidelines CG178, Psychosis and schizophrenia in adults, March 2024.
  • Lester UK adaptation positive cardiometabolic health resource 2016.
  • Psychotropic drug directory 2016.
  • Tees, Esk and Wear Valley NHS Foundation Trust, Northumberland Tyne and Wear NHS foundation Trust, Cumbria Partnership NHS Foundation Trust and Northern England Clinical Networks.

13.7.6 Effect of antipsychotics on QTc

No effect
(at therapeutic doses)
Low Medium High
  • Zuclopenthixol
  • Lurasidon.
  • Clozapine
  • Flupentixol
  • Olanzapine
  • Prochlorperazine
  • Risperidone
  • Sulpiride
  • Paliperidone
  • Fluphenazine
  • Asenapine Aripiprazole (note, yellow card reports to torsade de pointes and QT prolongation)
  • Chlorpromazine
  • Quetiapine
  • Amisulpride
  • High dose of antipsychotic therapy (HDAT)
  • Haloperidol
  • Pimozide

Page last reviewed: October 24, 2024
Next review due: October 24, 2025

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