High dose antipsychotic therapy

Definition

The Consensus statement on high-dose antipsychotic medication (Royal College of Psychiatry Council Report CR190, November 2014) defines high-dose antipsychotic therapy (HDAT) use as:

A total daily dose of a single antipsychotic which exceeds the upper limit stated in the summary of product characteristics (SPC) or BNF with respect to the age of the patient and the indication being treated.

or

A total daily dose of two or more antipsychotics which exceeds the summary of product characteristics (SPC) or BNF maximum using the percentage method.

HDAT use should be the exception rather than the rule.

The evidence from randomised controlled trials (RCTs) to support the use of combined antipsychotics in schizophrenia remains scarce and there is little convincing evidence that antipsychotics higher than the maximum licensed dose are more effective than standard dosage for treatment-resistant schizophrenia. In addition, the evidence for combining non-clozapine antipsychotics is generally weak.

Key points

1. The responsibility to prescribe HDAT lies with the consultant psychiatrist responsible for the patient’s care.

2. The decision to prescribe HDAT should be discussed with the multidisciplinary team (including a clinical pharmacist). Where this is not possible, consider obtaining an informal second opinion from a local psychiatrist to support the use of HDAT.

3. Reason clearly documented within the patient’s clinical notes.

4. Ensure valid consent obtained and documented. Advice to support obtaining consent can be found at Choice and Medication website.

5. Where appropriate ensure that the statutory treatment plan on a T2B or T3B certificate or section 47 are in place.

6. A local register of patients prescribed HDAT to ensure that the recommended monitoring is undertaken. All patients must have a warning added to their EMIS record.

7. The use of HDAT in an emergency situation should be authorised by senior psychiatrist.

8. HDAT should be reduced to conventional dosing if no significant improvement is observed at review.

9. Ensure good communication at points of transition.

Risk factors

Risk factors and potential drug interactions must be considered prior to prescribing HDAT and at each review.

Risk factor	Rationale for potential risk of QT prolongation
Cardiac history	Particularly myocardial infarction, arrhythmias, bradycardia, abnormal ECG, long QT syndrome, heart failure Consider family history
Hepatic impairment	Potential impact on hepatic metabolism and clearance of antipsychotics QT prolongation is increased in alcoholic liver disease
Renal impairment	Potentially decreases clearance of renally excreted antipsychotics May increase risk of electrolyte disturbance
Alcoholism	Increased risk of hepatic impairment
Smoking	Increased risk of ischaemic heart disease Impact on hepatic metabolism of some antipsychotics
Substance misuse	Due to risk of QT prolongation with certain substances
Old age	Elderly more susceptible to QT changes
Extremes of weight	Impact of obesity on CV risk and hepatic function Very low BMI increases risk of electrolyte abnormalities and dehydration
Female gender	Women have longer QT intervals
Extreme physical exertion	e.g. individuals subject to restraint

Drug interactions

Drug interactions	Rationale for potential risk of QT prolongation
Medications known to prolong QT interval including anti-arrhythmics	A list of medications known to prolong the QT interval can be found at https://www.crediblemeds.org (an American website which categorises medications based on their risk)
Pharmacokinetic interactions	Medications that increase antipsychotic plasma levels. (NB smoking can decrease plasma levels of some antipsychotics, especially clozapine, therefore, smoking cessation will increase plasma levels and may require dose reduction)
Medications known to cause electrolyte disturbance e.g. diuretics	Electrolyte abnormalities e.g. hypokalaemia, hypocalcaemia, hypomagnesaemia can increase the risk of QT prolongation

Monitoring

At initiation of HDAT, a plan for ongoing monitoring must be agreed and completed by medical staff for the individual patient including;

• frequency of monitoring *

• responsibilities for monitoring and checking results

• regular review of progress

High Dose Antipsychotic Monitoring & Frequency*
Monitoring	Baseline	Ongoing
ECG	Yes If a prolonged QT interval is recorded at baseline (QTc > 450msec in men and > 460msec in women), review treatment. Consider cardiology assessment. If it is decided to continue treatment. Record reasons for doing so in patient’s case notes.	• When steady state serum levels have been reached after each dose increment (consult a clinical pharmacist for advice on appropriate timescales) • Then every 6-12 months *
U&Es	Yes	• Every 6 months *
LFTs	Yes	• Every 6 months *
Lipids Blood glucose and/or HbA1c (for high dose therapies with increased risk of metabolic disturbance)	Yes	• Every 6 months *
Standard observations (bp, pulse, temperature)	Yes	• At least every 6 months* • Following dose escalation, monitor for any deterioration in physical health.
Review of progress and ongoing need for HDAT		• Every 3 months
Symptom rating scales e.g. CGI	Yes	• At 6 weeks • At 3 months • Then at least annually *
Side rating scales e.g. GASS or LUNSERS	Yes	• At 6 weeks • At 3 months • Then at least annually *

If a patient refuses to consent to HDAT monitoring, then this should be clearly documented within their clinical notes. Ongoing refusal to engage with monitoring must prompt review and consideration of cessation of high dose antipsychotic therapy.

^* It is recommended that increased monitoring is undertaken when using higher risk therapy e.g. haloperidol, diuretics, concurrent medications known to cause QT prolongation or those with other risk factors.

With the exception of clozapine, plasma level monitoring is not routinely carried out for antipsychotics. In patients exhibiting signs of adverse effects/toxicity or where other risk factors are present, plasma level monitor of antipsychotics could be considered where assays and reference ranges are available.

Management of problems- QTc

Management of QTc prolongation in high dose antipsychotic therapy ¹
QTc Interval*	Males	Females	Recommendations
Normal	<450ms	<460ms	No action unless abnormal T-wave morphology ²
Borderline prolonged	>450 ms but <500ms	>460ms but <500ms	Consider dose reduction and/or switching to a drug of lower effect on QTc Repeat ECG
Prolonged	>500ms	>500ms	Immediate review and cessation of high dose therapy Switch to drug of lower effect on QTc Repeat ECG
A change in baseline QTc of >20ms should raise concern and should be assessed in conjunction with the overall QTc interval.

* The QT interval varies with heart rate. A number of formulas are used to correct the QT interval for heart rate. Once corrected, it is expressed as the QTc interval, which is reported on the ECG printout. The QTc is commonly normalised to a heart rate of 60bpm and may be inaccurate in patients with faster or slower heart rates.

¹NHS GG&C Medicines Update. QTc interval- summary. August 2023

²Taylor D, Paton C, Kapur S. The Maudsley Prescribing Guidelines in Psychiatry. Wiley Blackwell. 14th edition

Management of other adverse effects

Management of electrolyte disturbance in high dose antipsychotic therapy

Electrolyte disturbance

Reference range

Actions

Hypokalaemia

Hypomagnesaemia

Hypocalcaemia

K < 3.5mmol/l

Mg < 0.7mmol/l

Adjusted Ca < 2.1mmol/l

Low K and Mg in particular can increase the risk of QTc prolongation.

Consider the risk of electrolyte disturbance in the event of diarrhoea/vomiting or if diuretic therapy commenced.

Address electrolyte disturbance, repeat U&Es and ECG

Management of adverse effects in high dose antipsychotic therapy (Weigh up any perceived benefits of high dose treatment vs adverse effects)
Adverse effects	Action
Extrapyramidal side effects (EPSE)	Consider decreasing antipsychotics to conventional dosing
Metabolic side effects	Where high dose treatment or combination is associated with an increased risk of metabolic adverse effects, consider a change to treatment or manage metabolic changes appropriately

Off-licence use of medication

The use of HDAT is an off-license use of medication, further information can be found here.

Roles and responsibilites

For information on the roles and responsibilities of staff in HDAT see full guideline

Maximum doses of antipsychotics

In defining what constitutes HDAT for patients receiving more than one antipsychotic, use the percentage method for calculating high dose status. When expressed as a percentage of their respective recommended maximum dose and added together, a cumulative dose of greater than 100% is considered ‘high dose’.

For example:

clozapine 700mg and amisulpride 400mg daily.
Sum %= 78% + 33% = 111% (>100%, therefore high dose)

Use of ‘as required’ (or ‘prn’) antipsychotic medication should also be taken into account.

Antipsychotic	Maximum licensed adult dose (mg/day) 100% BNF maximum
Amisulpride	1200
Asenapine***	20
Aripiprazole oral/IM	30
Cariprazine	6
Chlorpromazine	1000
Clozapine	900
Flupentixol	18
Haloperidol oral/ IM *	20
Lurasidone	148
Olanzapine oral/IM	20
Paliperidone***	12
Pericyazine	300
Perphenazine	24
Pimozide**	20
Prochlorperazine	100
Promazine	800
Quetiapine	750 (Mania 800)
Risperidone	16
Sulpiride	2400
Trifluoperazine	50 (suggested by POMH****)
Zuclopenthixol	150

Depots/ Long-acting injections	Maximum licensed adult dose (mg/ time interval) 100% BNF maximum
Aripiprazole LAI	400 /month
Flupentixol decanoate	400 /week
Haloperidol decanoate	75 /week
Olanzapine embonate***	300 /fortnight
Paliperidone LAI (Xepilon)	150 /month
Paliperidone 3/12 LAI (Trevicta)***	525 /3 months
Risperidone LAI (Consta)	50 /fortnight
Zuclopenthixol decanoate	600 /week

* The use of haloperidol is contraindicated in combination with drugs that prolong the QTc interval and therefore, where possible the use of haloperidol in combination with other antipsychotics should be avoided. Haloperidol and QTc interval prolongation

** Subject to annual ECG irrespective of dosage.

*** Non formulary preparations within NHS GG&C MHS

**** Prescribing Observatory for Mental Health. POMH. Ready reckoner version 7. October 2017