High-dose antipsychotic therapy: does it have a role?

Case scenario

Aaron, a very large man in his mid-30s, presents a wad of prescriptions to your pharmacy assistant and asks to speak to you. He recently moved near your pharmacy, needs repeats of his medicines and has asked if he can leave his prescriptions with you. You notice Aaron is taking multiple psychotropic agents:

• olanzapine 20 mg at night
• aripiprazole 10 mg once daily
• desvenlafaxine 50 mg each morning
• perindopril 10 mg/amlodipine 10 mg each morning
• metformin 500 mg twice daily.

Both antipsychotics were prescribed by the psychiatrist on the same day, and Aaron has been taking both for several months. You decide to investigate this antipsychotic prescribing practice.

Introduction

Psychotropic polypharmacy is the co-prescribing of two or more psychotropics from the same or different class (e.g. antipsychotic polypharmacy or an antidepressant with an anxiolytic).^1,2

A high proportion of people prescribed antipsychotic polypharmacy are also taking high-dose antipsychotic therapy (HDAT). HDAT is increasingly used in the treatment of schizophrenia and other psychotic disorders.^2,3 In the past decade, this practice has been the subject of debate due to perceived unproven efficacy and increasing adverse effects; however, in recent times, HDAT has become more accepted.

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What is HDAT?

High-dose antipsychotic therapy is defined as either:⁴

• A total daily dose of a single antipsychotic which exceeds the upper limit stated in the product information with respect to age and indication, or

• A total daily dose of two or more antipsychotics which exceeds the upper limit stated in the product information with respect to age and indication using the percentage method (converting the dose of each drug into a percentage of the maximum recommended dose for each agent and adding these together). A total dose of more than 100% is a high dose.

The maximum doses published in manufacturers’ product information may not reflect recent professional guidance or new evidence.⁴ They are based on pharmacokinetic data from clinical trials that recruit healthy participants and are not inclusive of gender, age and ethnicity.^5,6 In general, the maximum doses of typical antipsychotics are doses approved for use but not recommended due to the risk of extrapyramidal adverse effects.⁵ Hospitals and local health services may also maintain local guidance and policies on the maximum dosing of certain psychotropic medicines.⁷ In the absence of specific Australian guidance on HDAT, and the limitations associated with manufacturers’ product information, it may be more appropriate to use the maximum doses for psychotic illness provided in the Therapeutic Guidelines to ascertain if a person is taking HDAT (see Table 1).⁸

What do the guidelines say? 

Professional practice guidelines regarding HDAT vary.¹⁰ The Royal College of Psychiatrists consensus states that ‘high-dose antipsychotic use should be the exception rather than the rule’.⁴ Recent guidance from the American Psychiatric Association notes the potential beneficial role of some antipsychotic combinations based on recent evidence; however, more research is needed to inform practice.¹¹

The Royal Australian and New Zealand College of Psychiatrists (RANZCP) recommends that higher doses of antipsychotics be used cautiously and monitored closely.⁶ Clozapine, as opposed to HDAT, should be considered whenever there is a poor response to antipsychotic monotherapy or significant side effects.⁶

The Therapeutic Guidelines state that antipsychotic dosing ‘above the recommended range is associated with increased adverse effects but rarely improves symptoms’. However, they note that higher doses of oral antipsychotics are often required to treat relapse, and they list the antipsychotic combinations to be used if a person is ‘clozapine-resistant’.⁸

What is the evidence for HDAT? 

There are two Cochrane reviews which examine the efficacy and adverse effects associated with HDAT and antipsychotic polypharmacy in schizophrenia.^25,26 Of 10 randomised controlled trials (RCTs) included in the first review, there were no clear differences between increasing or maintaining the antipsychotic dose for people with schizophrenia who did not respond to their initial antipsychotic.²⁵

In the second review, 62 studies were included, with half comparing clozapine monotherapy with clozapine combination therapy.²⁶ The reviewers found that most evidence for antipsychotic polypharmacy comes from short‐term trials, limiting the assessment of long‐term efficacy and safety. There was very low‐quality evidence that antipsychotic combinations improve clinical response, prevent relapses, or cause more serious adverse events than monotherapy.²⁶

Recent trials and reviews have provided additional data. A 2020 systematic review showed the mortality risk of antipsychotic polypharmacy in people with severe mental illness was comparable to that of monotherapy.²⁶ Another large Finnish study involving 62,000 schizophrenia patients examined rates of psychiatric rehospitalisation as a marker for relapse.²⁷ The researchers found that combining aripiprazole and clozapine was associated with the lowest risk of rehospitalisation. Overall, antipsychotic polypharmacy was linked with a 10% lower relative risk of rehospitalisation than monotherapy. On the back of these findings, the authors suggested that current guidelines should be more inclusive of antipsychotic polypharmacy.²⁷

How common is HDAT in practice? 

The practice of HDAT is under-researched but occurs commonly despite guideline advice.¹⁰ The use of single antipsychotics over maximum doses is relatively uncommon.^2,4,10 For most patients, HDAT is prescribed through antipsychotic polypharmacy, usually the combination of two oral atypical agents or the use of long-acting injectable antipsychotics with an oral agent.^12,13 A recent 2019 New Zealand study examined antipsychotic prescribing in 1,560 community mental health clients and found over 13% were taking HDAT.¹³ Nearly 80% of the high-dose prescribing was attributable to antipsychotic polypharmacy. A third of high-dose use involved oral olanzapine, followed by injectable preparations of paliperidone or olanzapine, which together accounted for a quarter of all HDAT.¹³

It is well established that antipsychotic use has increased worldwide over the last 20 years.^4,14

Australian use has increased 2.5-fold over this period, with a marked rise in atypical antipsychotic use.¹⁴ A 2016 systematic review found the Australian prevalence of antipsychotic polypharmacy ranged from 5% to 61%.¹⁴ Of studies assessing dosage, up to half of all those taking two or more antipsychotics received HDAT.¹⁴

A recent Australian study looked at psychotropic use in medication reviews of 318 community-based clients with severe mental illness and found that 18% were taking two or more antipsychotics, with a third receiving HDAT.² Use in NSW hospital psychiatric wards was higher where over half of those taking antipsychotics received HDAT.¹⁵ Australian combination antipsychotic prescribing has also increased over time, with prevalence rising from 5.7% to 7.3% from 2006 to 2015.¹⁶

Rationale for HDAT?

There are various reasons why high-dose antipsychotics are prescribed. The main reason is because many people with schizophrenia or another psychotic illness do not achieve a satisfactory response with their initial antipsychotic. Sometimes a higher dose, mostly achieved by adding a second antipsychotic, is used in these situations.^4,5,16

The RANZCP defines ‘treatment resistance’ in schizophrenia as ‘continued positive symptoms after trials of at least two different antipsychotics at moderate doses for a reasonable period (usually at least 6 weeks)’.⁶ Treatment resistance occurs in about a third of patients.^4,6

In general, the RANZCP and other guidelines endorse clozapine treatment and other treatment options, including long-acting injectable antipsychotics, before trying HDAT.^4,6,8,11

Other commonly reported rationales used to justify HDAT include^4,12,17:

• attempting to speed up or enhance therapeutic effect
• managing challenging symptoms such as aggression
• attenuating metabolic adverse effects
• believing higher doses will prevent relapse.

HDAT may also occur unintentionally when a prescriber makes small dose increases over time or adds a small dose of a different antipsychotic to existing treatment without realising the additive effects.⁴ Similarly, when an antipsychotic is prescribed ‘as needed’ to quickly calm a severely agitated patient who is already taking regular antipsychotics, it can result in doses above the recommended maximum.⁴ Many prescribers are reluctant to reduce doses when a patient has responded to antipsychotics for fear of future exacerbation, leading to extended durations of HDAT.^3,4

Pharmacological rationale for antipsychotic pharmacy 

Most antipsychotics exert their effect by inhibiting dopaminergic neurotransmission, with therapeutic effect more likely to occur when they block over 60% of D2 dopamine receptors.¹⁰ However, at 80% occupancy, the movement-associated adverse effects of antipsychotics occur.¹⁰ To maximise response and minimise adverse effects, D2 receptor occupancy needs to be between 65% and 80%.^4,17 From a pharmacological perspective, there are several reasons why HDAT might be justified. One of them is that sufficient drug may not reach optimum potency due to individual differences in pharmacokinetics.⁴ Studies of drug plasma levels reveal marked variation between individuals, with smoking, drug interactions and genetic variation in cytochrome P450 enzymes that metabolise these agents all contributing.^4,18 Inadequate response in the context of subtherapeutic serum drug concentrations and good adherence may indicate genetic polymorphism or drug interaction.¹⁸

Antipsychotics are mainly metabolised by cytochrome P450 enzyme subtypes: CYP1A2 (clozapine, olanzapine) CYP3A4 (aripiprazole, brexpiprazole, cariprazine, clozapine, lurasidone, paliperidone, quetiapine) and CYP2D6 (risperidone, aripiprazole, brexpiprazole, clozapine).^17,18

Smoking is an inducer of CYP1A2 and can lead to low serum levels of clozapine and olanzapine. Inhibition of CYP450 enzymes by other medicines (CYP1A2: fluvoxamine; CYP2D6: fluoxetine) may result in altered serum levels of antipsychotics metabolised through these pathways.^10,17 Finally, there is significant genetic variation in some CYP450 enzymes leading to individual variation in antipsychotic metabolism. Those with higher metabolic rates are likely to have lower drug plasma concentrations and potentially poorer efficacy.¹⁰ If the antipsychotic or interacting medicine cannot be changed, dose adjustment may be necessary.

Atypical antipsychotics differ from typical agents by blocking D2 dopamine receptors as well as serotonin receptors, predominantly the 5-HT2A subtype receptor.¹⁹ Antipsychotics can also have noradrenergic, cholinergic, and histaminergic blocking action.^8,17,19 Different agents vary in D2 receptor occupancy but also in their affinity for other receptors, which accounts for differences in efficacy but also in adverse effects.¹⁷ For example, olanzapine and quetiapine have strong muscarinic receptor affinities which can result in sedation and constipation, whereas newer antipsychotics (e.g. aripiprazole and lurasidone) have minimal affinity, thus fewer of these adverse effects. If the original antipsychotic is treating psychosis effectively but has problematic adverse effects, prescribers may try to minimise these by lowering their dose but then increase D2 receptor occupancy (and effect) by adding a different antipsychotic that has less effect on muscarinic or other receptors.¹⁹

For example, metabolic syndrome occurs commonly in those taking antipsychotics.²⁰ Three out of five criteria must be met for metabolic syndrome²¹:

• increased waist circumference
• hypertension
• reduced HDL
• elevated triglycerides, and/or
• fasting glucose.

Antipsychotics vary in their risk of metabolic syndrome. Clozapine and olanzapine are considered high risk, and aripiprazole, lurasidone and ziprasidone low risk.²² The mechanisms responsible for antipsychotic-related metabolic syndrome are theorised to include antagonism at 5-HT2C, histamine and muscarinic receptors. Although lifestyle interventions are recommended first-line, lower risk antipsychotics such as aripiprazole are sometimes added to facilitate dose reduction of antipsychotics (e.g. olanzapine) with a high risk for metabolic syndrome.²

Risks associated with HDAT

Most adverse effects of antipsychotics are dose related.^12,18 Adverse effects include QTc prolongation, sudden cardiac death as well as extra pyramidal symptoms (EPS), hyperprolactinemia, metabolic syndrome, postural hypotension and anticholinergic effects.^10,12,18 Some of these adverse effects can be monitored clinically, but others require blood tests and electrocardiograms.¹² Notably, the low incidence of EPS associated with atypical antipsychotic monotherapy does not persist when two atypical agents are combined.²³

Antipsychotic polypharmacy has been associated with other disadvantages, such as reduced adherence, increased risk of drug interactions, and more medicine errors due to treatment complexity. Patients also tend to receive additional medicines to address the adverse effects of antipsychotic polypharmacy, including anticholinergics.²⁴

What about clozapine

Due to limited high-quality evidence for HDAT and antipsychotic polypharmacy, alternative options for treatment should be considered first.^10,18 A clozapine trial remains first-line for treatment-resistant schizophrenia.^6,8 Clozapine is highly effective for those who do not respond to other antipsychotics; however, among eligible patients, the drug is often not prescribed (between 15% in the US and 54% in the UK) despite a strong evidence base.^6,10 Reluctance to use clozapine is probably due to its high rate of adverse effects (e.g. drowsiness, constipation, metabolic syndrome), higher risk of severe adverse effects and requirement for mandatory blood tests for agranulocytosis.^6,10 If clozapine cannot be used, the oral antipsychotic with the most evidence for effect is olanzapine, which is similar in structure and receptor pharmacology to clozapine.¹⁸

Although highly effective when used for patients with treatment-resistant schizophrenia, 40–60% of patients will have an incomplete response to clozapine monotherapy.²⁸ For these patients, clozapine in combination with a second antipsychotic currently has the most evidence for effect.^10,29 Notably, in the Finnish cohort study, six of the top 10 ranked treatments with lower rates of psychiatric rehospitalisation included clozapine in combination with another antipsychotic.²⁸ The most well-studied combination is clozapine and risperidone, although RCTs comparing this combination with clozapine monotherapy show mixed effectiveness.^10,29 Clozapine and aripiprazole co-prescribing has shown some promise ameliorating some of the adverse effects associated with clozapine, with evidence of improvement in body mass index (BMI) and cholesterol levels.^10,29

Deprescribing HDAT or antipsychotic polypharmacy

Most patients receive HDAT or antipsychotic polypharmacy during acute exacerbations. When the patient has responded to therapy or transitions to maintenance phase of treatment, many clinicians are reluctant to reduce doses or revert to monotherapy for fear of relapse.^3,6,8 Several studies have shown that switching from antipsychotic polypharmacy to monotherapy is successful, although a proportion of patients do not tolerate switching.²⁴

There is interim evidence that those taking clozapine or long-acting injectable combinations tolerate changing to monotherapy more than those taking two oral non-clozapine antipsychotics.²⁴

Recommended monitoring for HDAT 

If HDAT is prescribed: 

• The rationale should be well documented.¹⁸
• Ongoing appropriateness should be re-evaluated frequently and simplified if possible.^6,18
• Use should be considered a limited therapeutic trial for a maximum of 3 months unless benefit outweighs adverse effects.⁴
• Potential adverse effects should be monitored with physical examination, lipid levels, fasting glucose, prolactin level anticholinergic effects sought, and ECGs conducted before and during treatment.^4,18
• Screen for drug interactions whenever new medicines start.¹⁸

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Key points

• Antipsychotic monotherapy is effective for most patients. If two trials with antipsychotics have failed, clozapine should be trialled.
• If symptoms remain, potential causes such as non-adherence, illicit drug use, drug interactions or genetic polymorphisms should be identified and addressed before starting HDAT or using antipsychotic combinations.
• HDAT may be required to optimise treatment of psychotic disorders. In those who cannot take clozapine, HDAT olanzapine is the most evidence-based alternative.
• Combining aripiprazole with clozapine appears to reduce some adverse effects and prevent relapse; however, more research is needed to determine optimal antipsychotic polypharmacy and HDAT regimes.
• Patients on HDAT require periodical review for ongoing appropriateness and should be monitored closely for dose-related adverse effects. 

References

1. Govaerts J, Boeyckens J, Lammens A, et al. Defining polypharmacy: in search of a more comprehensive determination method applied in a tertiary psychiatric hospital. Ther Adv Psychopharmacol 2021;11:1–14.
2. Hu J, McMillan SS, Theodoros T, et al. Psychotropic medication use in people living with severe and persistent mental illness in the Australian community: a cross-sectional study. BMC Psychiatry 2022;22:705.
3. Lin SK. Antipsychotic Polypharmacy: A dirty little secret or a fashion? Int J Neuropsychopharmacol 2020;23(2):125–131.
4. Royal College of Psychiatrists. Report CR190: The risks and benefits of high dose antipsychotic medication. England: Royal College of Psychiatrists; 2014; January 2023 revision.
5. NHS Greater Glasgow & Clyde. Mental Health Service (MHS) 34 – High Dose Antipsychotic Monitoring Policy. 2021. At: https://mypsych.nhsggc.org.uk/medicines-companion/medicines-guidance-a-z/antipsychotics-high-dose-monitoring-policy-mhs-34/
6. Galletly C, Castle D, Dark F, et al. Royal Australian and New Zealand College of Psychiatrists (RANZCP) clinical practice guidelines for the management of schizophrenia and related disorders. 2016. At: ranzcp.org/files/resources/college_statements/clinician/cpg/schizophrenia-disorders-cpg.aspx
7. Government of Western Australia, Department of Health. Guidelines for Managing Specific High Risk Medications Relevant to the Organisation. 2012. At: health.wa.gov.au/~/media/Files/Corporate/Policy-Frameworks/Clinical-Governance-Safety-and-Quality/Policy/High-Risk-Medication-Policy/Supporting/Guidelines-for-Managing-Specific-High-Risk-Medications-Relevant-to-the-Organisation.pdf
8. Therapeutic Guidelines. 2021. Psychotropic. Principles of treating psychoses including schizophrenia. At: https://tgldcdp.tg.org.au/viewTopic?etgAccess=true&guidelinePage=Psychotropic&topicfile=principles-treating-psychoses
9. eMIMS cloud. 2023. Reagila full product information; [updated 2022 Sep 01]. At: emims.com.au/Australia/drug/info/Reagila/Reagila?type=full
10. Foster A, King J. Antipsychotic polypharmacy. Focus 2020;18:375–85.
11. American Psychiatric Association. The American Psychiatric Association Practice Guideline for the Treatment of Patients with Schizophrenia. 2020. At: https://psychiatryonline.org/doi/book/10.1176/appi.books.9780890424841.
12. Murphy P, Iles A, Sreedharan S. High-dose antipsychotics: Addressing patients’ resistance to physical health monitoring. BJPsych Advances 2015;21(2):88–97.
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22. DeJongh BM. Clinical pearls for the monitoring and treatment of antipsychotic induced metabolic syndrome. Ment Health Clin 2021;11(6):311–319.
23. Carnahan R, Lund B, Perry P, et al. Increased risk of extrapyramidal side effect treatment associated with atypical antipsychotic polytherapy. Acta Psychiatr Scand 2006;113: 135–141.
24. Samara MT, Klupp E, Helfer B, et al. Increasing antipsychotic dose for non-response in schizophrenia. Cochrane Database of Systematic Reviews 2018,5(5).
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29. Lähteenvuo M, Tiihonen J. Antipsychotic polypharmacy for the management of schizophrenia: evidence and recommendations. Drugs 2021;81(11):1273–84.

Our author

Associate professor Juanita Breen (she/her) PhD, MSc, BPharm, MPS, GradDipCommPracPharm has a varied background as a military, community, GP, academic and government pharmacist. She completed a PhD in 2011 on the roles for pharmacists in ensuring appropriate psychotropic use in residential aged care and presented her research at the Royal Commission into Aged Care Quality and Safety. She currently consults for the Aged Care Quality and Safety Commission, is an associate at the Wicking Dementia Centre at the University of Tasmania and occasionally performs medication reviews.

Our reviewer

Hun Liang Oon (he/him) BBiomedSc, MPharm, PgCertPsychTher, PgDipPsychPharm, MSHP