Prevalence of multiple antipsychotic use and associated adverse effects in Australians with mental illness

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1 Prevalence of multiple antipsychotic use and associated adverse effects in Australians with mental illness This is the peer reviewed author accepted manuscript (post print) version of a published work that appeared in final form in: Westaway, Kerrie, Sluggett, Janet K, Alderman, Christopher, Procter, Nicholas & Roughead, Elizabeth 0 'Prevalence of multiple antipsychotic use and associated adverse effects in Australians with mental illness' International journal of evidence-based healthcare, vol., no., pp. 0- This un-copyedited output may not exactly replicate the final published authoritative version for which the publisher owns copyright. It is not the copy of record. This output may be used for noncommercial purposes. The final definitive published version (version of record) is available at: Persistent link to the Research Outputs Repository record: General Rights: Copyright and moral rights for the publications made accessible in the Research Outputs Repository are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognize and abide by the legal requirements associated with these rights. Users may download and print one copy for the purpose of private study or research. You may not further distribute the material or use it for any profit-making activity or commercial gain You may freely distribute the persistent link identifying the publication in the Research Outputs Repository If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

2 The Library Educating Professionals, Creating and Applying Knowledge, Engaging our Communities This is the accepted manuscript (post print) version of a published work that appeared in final form in International Journal of Evidence-Based Healthcare, published online May 0, pp. -, copyright 0 The Joanna Briggs Institute. This version has been peer reviewed, but may lack the final formatting of the published version. This article is copyright and may be used for non-commercial purposes. The final published version is available at:

3 Manuscript (All Manuscript Text Pages in MS Word format, including References and Figure Legends) No Author Contact Prevalence of multiple antipsychotic use and associated adverse effects in Australians with Introduction mental illness Treatment with medications is one of the most commonly used and effective therapeutic interventions for people with serious mental illness. Antipsychotic medications are critical in the pharmacological management of severe psychotic disorders. Although antipsychotics are at least partially effective in reducing core symptoms of psychoses, they have serious adverse effects. When more than one antipsychotic medication is used concurrently, or when the dose employed is at or above the upper limit of evidence based on clinical trials, the burden of side effects often causes considerable distress., Side effects can become so troubling, that some people do not adhere to the prescribed treatment regimen., In some cases, people do benefit from treatment to an extent that continues to motivate them to continue use, but nevertheless are affected by serious morbidity, and in some cases, premature mortality. - A literature review of controlled randomized trials and non-controlled studies showed that in almost all cases, concurrent use of multiple antipsychotics does not reliably produce greater benefit than that achievable with the use of a carefully selected single agent. Current Australian and, 0, international guidelines recommend the use of a single antipsychotic in most cases. Circumstances in which more than one antipsychotic at a time may be required include when a person is transitioning from one antipsychotic to another, or for cases where severe psychotic symptoms have not responded to treatment with clozapine alone., Clozapine is indicated for people with treatment-resistant psychotic symptoms including schizophrenia. That is, people who have been unresponsive to, or are unable to tolerate other antipsychotics despite an adequate dosage for a reasonable duration of time. However, situations where multiple agents might be 0, employed should generally be regarded as the exception rather than the rule.

4 DDD/000/day Use of more than one antipsychotic at a time is associated with a range of problems including an overall higher dose than is recommended, as well as the potential to cause increased frequency, range and severity of side effects., 0 Sedation, dizziness, postural hypotension, sexual dysfunction and extrapyramidal and anticholinergic effects are common dose related adverse effects which can be more prevalent in the context of antipsychotic polypharmacy. -, Adverse effects that more commonly develop over an extended period of time include significant weight gain, metabolic syndrome, parkinsonism (tremors and rigidity) and tardive dyskinesia (involuntary movements particularly affecting the face, mouth or tongue).,, The concurrent use of multiple antipsychotics is also associated with higher drug acquisition costs and may lead to higher overall treatment costs,, 0 higher hospitalisation rates and longer stays with increased morbidity and mortality. The use of antipsychotics, in particular atypical antipsychotics has increased significantly worldwide. 0, In Australia, overall antipsychotic use has increased two and half-fold over the last twenty years (Figure ). While there has been a decrease in the use of the older typical or first generation antipsychotics, there has been a significant increase in the use of the newer atypical or second generation antipsychotics. This increase is of considerable concern in both Australia and overseas. 0 0 Atypical antipsychotics Typical antipsychotics Antipsychotic use

5 0 0 0 Figure : Use of antipsychotic medicines in Australia from 0 to 0, The use of concurrent multiple antipsychotic medications have become increasingly common, despite a lack of evidence to support the practice and the likelihood of an increased severity and frequency of adverse effects. Although much is known about medication-related problems in the general hospital and community settings in Australia, - much less is known about the use of medications and medication-related adverse events in the mental health setting in Australia. Hence, this review aimed to determine the prevalence of multiple antipsychotic use in the Australian mental health setting, and the burden of side effects associated with multiple antipsychotic use. We also provide a summary of strategies that have been shown to reduce concurrent multiple antipsychotic use and explore potential opportunities for prevention in the future. Methods This work is a small part of a larger national review of medication safety in mental health in Australia, which was conducted for the Australian Commission on Safety and Quality in Health Care. The use of multiple antipsychotics, associated adverse effects and interventions shown to successfully reduce antipsychotic polypharmacy only are discussed here. We synthesised the Australian literature on multiple antipsychotic use reviewing quantitative studies published between January 000 and February 0. We did not find any Australian randomized controlled trials of interventions to reduce multiple antipsychotics in mental health patients. Hence, international controlled trials and systematic reviews of interventions undertaken to reduce multiple antipsychotic use in mental health settings were reviewed. We excluded data from conference abstracts and presentations that were not published. Selected qualitative studies were included to provide further detail as needed. Search strategies used included English language; conducted in the community, hospital or ambulatory care settings; and measured at least one patient outcome e.g. medicine-related hospitals admissions; adverse events; mortality; decreased quality of life; symptoms; surrogate health endpoints; medication knowledge or changes in the

6 0 0 0 quality of medicine use. Papers which meet these criteria describing strategies to reduce rates of medication adverse events, such as clinical pharmacist services, computerised decision support measures, and multifaceted approaches were eligible for inclusion. We included pre- and postintervention studies without control, randomised controlled trial or non-randomised controlled trial designs. The literature was sourced from Medline, Embase, Cinahl, Informit, PsychInfo, International Pharmaceutical Abstracts and Joanna Briggs Institute databases. The database search was supplemented with searches of relevant websites, including The Australian Commission on Quality and Safety in Health Care, NPS MedicineWise, Change Champions and the Cochrane Library database. The research was approved by the University of South Australia Human Research Ethics Committee and conforms to the provisions of the Declaration of Helsinki. Results Prevalence of multiple antipsychotic use We located Australian studies that provided estimates of the prevalence of concurrent multiple antipsychotic use (Figure ). The studies all involved a review of patient medical records, but they rarely specified the parameters used to establish how multiple antipsychotic therapy was defined, or the proportion of people receiving dual oral therapy compared to those receiving treatment with depot injections and concurrent oral therapy. Studies were located in the in-patient setting, forensic unit, and the community as well as amongst adults, children, people on community treatment orders (a legal order for a set period of time by which a mental health patient must accept medication while living in the community) 0 and people with an intellectual disability. In-patient stays: Studies assessing dual antipsychotic use during in-patient stays reported that between % and 0% of patients received dual antipsychotics. - Some of the studies are now ten or more years old and the higher rate comes from one study of only patients. There have also

7 0 0 0 been studies of the extent of prescription of dual antipsychotics at discharge. A Queensland study conducted across acute mental health inpatient services of patients with schizophrenia reported between % and % of patients on average were discharged on dual antipsychotics while another Western Australian retrospective audit of inpatients with schizophrenia spectrum disorders reported % were prescribed dual antipsychotics at discharge. The proportion of therapy that was dual oral therapy compared with depot injections and oral therapy was not reported. Children: One study retrospectively examined antipsychotic use among inpatients from a child and adolescent mental health service in Brisbane, Australia. Of the inpatients treated with an antipsychotic, two (%) received an atypical antipsychotic in combination with a typical antipsychotic. Patients who were switching between antipsychotics were not classified as receiving dual therapy. Within a forensic unit: In a New South Wales study involving 0 patients, % of patients were reported to be on dual antipsychotic therapy, % on an oral atypical or second generation agent in combination with a typical or first generation depot drug, and 0% receiving a first generation typical drug by both the oral and depot routes. Reasons given for use of an oral atypical agent plus a depot were specified as treatment resistance, history of non-compliance and to assist transfer to a lower security unit. Another study of patients admitted to a forensic hospital in New South Wales, Australia reported that % of antipsychotic users were being prescribed more than one antipsychotic. Patients with community treatment orders: A retrospective cross-sectional study in NSW examined dual antipsychotic use in participants randomly selected from people on community treatment orders, finding four in ten were on dual antipsychotics, where dual use consisted of oral use with injectable preparations. 0 Three in ten were treated with two or more different antipsychotics. High doses were also common with at least 0% being prescribed doses above the maximum recommended dose. 0 Of the consumers who had their community treatment orders

8 Dean 00 Botvinik 0 Plever 00 Plever 00 John 0 Bains 00 Martin 00 Tiller 00 Restifo 0 McGilvray 00 Doan 0 Callaly 000 Bains 00 Lowe 00 Gisev 00 Gisev 0 Waterreus 0 Vecchio 0 Pai renewed, % were maintained on two or more different antipsychotics and % remained on dosages above the maximum recommended dose. 0 Patients in the community: One study, undertaken in a regional community health service in Victoria, included data from people prescribed antipsychotic medication. This research found that the prevalence of dual antipsychotic use was % (% on conventional plus atypical oral therapy; % on conventional depot injection plus an atypical oral therapy and % on two oral atypical agents). The study was undertaken in which is prior to the large increase in antipsychotic use in Australia. All the other studies (n=) located were undertaken among people who were treatment resistant or required intensive case management or who were using clozapine., In these populations, the prevalence of dual antipsychotic use ranged from 0% among those with treatment resistant psychosis to % among clozapine users.,, The high impact psychosis survey found % of patients reported taking two atypical antipsychotics concurrently. Use of three antipsychotic agents, concurrently was reported at between % and % among people using clozapine. % 0 Hospital inpatients (children) Hospital inpatients (adults) Hospital discharge (all patients) Hospital discharge (schizophrenia patients) Forensic unit Geriatric psychiatry units Intellectual Disability clients on antipsychotics Community (all patients) Community (Intensive management) Clozapine users

9 0 0 0 Figure : Prevalence of multiple antipsychotic use in Australia by study setting or user group. Two Australian studies assessed antipsychotic doses among people receiving treatment via a community mental health service., In a Sydney, NSW study of people who received a Home Medicines Review, % took one or more antipsychotic medication at a dose exceeding the recommended maximum dose. This figure rose to % when the additive effect of taking multiple antipsychotics was considered. Twenty-two of the people taking multiple antipsychotics exceeded the maximum dose; in one case the dosage was seven times the maximum recommended dose. A second study of patients found % had an antipsychotic dose higher than that recommended. Adverse effects associated with multiple use Increased frequency and range of side effects: Multiple antipsychotic use is associated with an increased likelihood of the frequency and range of adverse effects. National Australian survey data showed that of the consumers taking two or more antipsychotics concurrently, 0% (verses 0% taking one antipsychotic) experienced at least one side effect. The number of side effects experienced was also greater among people taking multiple antipsychotics (Figure ).

10 Figure : Self-reported side effects from use of one antipsychotic compared to more than one. Increased severity of side effects: Australian studies show one-third of adults with a psychotic illness prescribed antipsychotic medications live with moderate to severe impairment due to medicationrelated side effects (Figure ). The studies did not clarify whether consumers taking more than one antipsychotic medication concurrently experienced more impairment than those taking only a single antipsychotic. However, almost a third of people were taking more than one antipsychotic in the 00 survey. % Any medicationrelated side effects Any impairment due to medication-related side effects Moderate-severe impairment due to side effects People using an atypical antipsychotic (n=) People using a typical antipsychotic (n=) People using both atypical and typical antipsychotics (n=) Public specialised mental health services - survey (n=) (%) Public specialised mental health services 00 survey (n=) (%)

11 0 0 0 Figure : Prevalence of medication-related side effects among adults with psychosis. Premature mortality from metabolic syndrome amongst people with severe mental illness is of significant concern. Metabolic syndrome is the collective term given to the adverse metabolic impact including weight gain, abdominal obesity, hyperglycaemia/diabetes, hypertension and dyslipidaemia that are associated with the cardiovascular events frequently observed amongst chronic users of antipsychotic medications. Australian studies indicate that one half to two thirds of people with severe mental illness taking multiple antipsychotics concurrently have manifestations of metabolic,, syndrome. One Australian study conducted in the Hunter New England Area, NSW, found the prevalence of metabolic syndrome in adult men and women with a serious mental illness taking more than one antipsychotic concurrently was considerably higher than in than those taking a single antipsychotic medication (Figure ) One atypical only Clozapine only Figure : Prevalence of metabolic syndrome in people taking multiple antipsychotics compared to one. Interventions that have shown to reduce multiple antipsychotic use One typical only One typical and one atypical We did not locate any Australian randomised controlled studies that assessed strategies to reduce multiple antipsychotic use, but a systematic review of interventions to reduce multiple antipsychotic use included three trials (one randomised and two open-label) where patients were switched from More than one atypical % with metabolic syndrome

12 dual therapy to monotherapy was identified. In the randomised controlled trial (n= outpatients), a joint decision between the doctor and consumer was made about which antipsychotic to cease. Overall, % of consumers were successfully switched to monotherapy, with better weight control in the monotherapy group, and no difference in psychiatric symptom changes or in hospitalisations, however, there were more participants who dropped out of the study in the monotherapy arm. In one open-label trial involving difficult to treat patients, (%) were successfully converted to monotherapy. In the other open-label trial involving patients, % were successfully converted to monotherapy. In this latter trial, % improved while on monotherapy, while % remained stable. The systematic review also identified studies that aimed to reduce antipsychotic polypharmacy by targeting interventions to physicians. Three of the studies were randomized controlled trials, all of which included multiple strategies as part of the intervention. One of these trials, which is further described below, resulted in a significant decrease in antipsychotic polypharmacy, however, the other two failed to show effect. In addition to the randomised controlled trials there were three single arm trials that assessed simple or modest educational programs, including the dissemination of pamphlets and videos or a treatment algorithm. In addition, there were eight single arm trials that assessed multiple component educational interventions. While effect sizes varied, the single arm trials all reported some effect, however, in some the outcome was all psychotropic medicines, not solely antipsychotic polypharmacy. The studies did not report outcomes for patients. The randomised controlled trial that demonstrated an effective intervention assessed an educational intervention for reducing antipsychotic polypharmacy targeting physicians and was undertaken in the United Kingdom. The multi-faceted intervention included: a minute academic-detailing session by a specially trained clinical psychiatric pharmacist,

13 0 0 0 a workbook for nurses and doctors containing educational materials and specific cognitive techniques to challenge antipsychotic polypharmacy and a range of alternative treatments a booster pamphlet sent eight weeks after distribution of the workbook a medication chart reminder system where pharmacists applied stickers to medication charts when patients were prescribed more than one antipsychotic and removed when antipsychotic polypharmacy was no longer prescribed and a guideline on antipsychotic prescribing. The study found that after delivering a multi-faceted intervention aimed at doctors and nurses, the odds of being prescribed multiple antipsychotics on mental health wards compared with a single intervention consisting of a guideline, was reduced by % (OR 0., %CI , p=0.0). No follow up beyond the month rotation period was conducted, so the extent of change sustained over time was not assessed. One single arm, quality improvement study involving a pharmacy led programme that was conducted over a six year period in a large inner city London hospital demonstrated that it was possible to reduce high rates of multiple antipsychotic use and high dose prescribing, and to embed these changes into routine clinical practice. Following a baseline survey early in 00 indicating that over half of the inpatients were prescribed a high dose or a combination of antipsychotics, a variety of targeted and precise strategies to improve practices were implemented. Data showed that over two-thirds of the antipsychotics prescribed were as required to control patients with acutely disturbed behaviour which continued throughout the admission, despite many patients achieving symptom control with regular antipsychotic medications. A commonly cited reason reported for prescribing multiple antipsychotics was a poor response to monotherapy. The routine prescribing of as required antipsychotics was discouraged and all as required antipsychotic prescriptions were to be reviewed at least weekly. Clinicians prescribing as required antipsychotics were reminded to individualise and specify dose and frequency, have a single route of administration only and to

14 0 0 0 document the precise reason for prescribing the drug. Pharmacists and doctors reviewed all inpatient prescriptions for high doses and multiple antipsychotic use and introduced alternative treatment options where possible. Follow up data were collected in 00 and 00 respectively, followed by implementation of further specific quality improvement strategies. Pharmacists set a target to reduce rates of high dose and multiple antipsychotic use to less than 0% by the end of 00. Final data collection occurred in 0. Results indicated a significant reduction in the rate of high dose prescriptions (% versus 0%, p 0.000) and multiple antipsychotic use (% versus %, p 0.000) by the end of the program. Rates of high dose prescribing (0% versus %, p 0.000) and multiple antipsychotic use (% versus %, p 0.000) were found to be significantly lower in the study hospital than in the rest of the country at the end of the program. The study did not report antipsychotic drug-related adverse effects experienced by participants in the study before or after implementation of strategies. Discussion Australian evidence suggests that up to approximately % of people with severe mental illness are treated with multiple antipsychotics, and on average 0% are treated with multiple antipsychotics. This is consistent with global estimates that around 0% of adults and 0% of children and adolescence with a severe mental illness are treated with multiple antipsychotics., A recent systematic review of studies from North America, Asia, Europe and Oceania collectively involving,, adults (of whom % had a diagnosis of schizophrenia) found that 0% of people received two or more antipsychotics concurrently. Multiple antipsychotic use was shown to occur most often in people with severe mental illness. On average 0.% of people were prescribed three or more different antipsychotics concurrently. Very few of these studies reported the number, type or impact of adverse effects experienced by people receiving multiple antipsychotics.

15 0 0 0 Multiple antipsychotic use has been reported among children and adolescents with mental illness. A systematic review of studies, from the United States, two from Europe and one from Australia, collectively involving,0 children and adolescents with a mental illness, found 0% received two or more antipsychotic medicines concurrently. One of the dangers of taking multiple antipsychotics is the potential for higher than recommended doses. Common dose related adverse effects of antipsychotics include extrapyramidal side effects, hyperprolactinaemia leading to prolactin-related adverse effects including amenorrhoea, gynaecomastia or galactorrhoea, prolonged QT interval, excessive sedation and anticholinergic effects., Randomized controlled trials and non-controlled trials indicate there is no benefit from the concurrent use of multiple antipsychotic use in people with a mental illness in the majority of cases. Australian and international guidelines recommend one antipsychotic at a time for almost all cases., 0, International evidence suggests up to half of people on concurrent multiple antipsychotics may be able to be successfully converted to monotherapy and remain well managed or improve. - Given the evidence supports transition from dual therapy to monotherapy can be achieved for the majority of people without worsening the symptoms of their mental illness, strategies to support trialling transition from dual therapy to monotherapy in routine practice are required. Complex multi-faceted educational strategies targeting clinicians and direct patient trials have been shown to be effective in changing behaviour and embedding practice into daily routine, while simple strategies appear not to be effective. Interdisciplinary cooperation involving medical clinicians, pharmacists and nurses in support of the person with mental illness holds great promise as a means to enhance and optimise the quality of care delivered and to minimise the impact of medication-related harm in a vulnerable group of people. Few studies that address multiple antipsychotic use report the impact or burden of people s experiences or outcomes., Engagement with people with a mental illness and their carers in discussions around which antipsychotic to cease and how, the impact of side

16 0 0 0 effects on the individual person and their quality of life is necessary to succeed in reducing multiple antipsychotic use. Conclusion Antipsychotic polypharmacy is common in patients with severe mental illness although there is little evidence to support the practice. Use of multiple antipsychotics concurrently exacerbates the side effect burden of patients causing significant morbidity and even premature mortality in some cases. Metabolic syndrome, a common long term adverse effect of antipsychotic medication, is a serious risk factor for premature and severe cardiovascular disease and stroke. Research suggests it is possible to effectively reduce therapy in the majority of people without worsening the symptoms of their mental illness. This review highlights the need for clinicians to discuss treatment options and associated side effects with their patients prior to commencing therapy and to consider strategies to reduce polypharmacy in those already taking multiple antipsychotic medications.

17 Title Page Include Author Information Title Page Title: Prevalence of multiple antipsychotic use and associated adverse effects in Australians with mental illness Authors: Dr Kerrie Westaway, Dr Janet K Sluggett, A/Professor Christopher Alderman, Professor Nicholas Procter, Professor Elizabeth Roughead Quality Use of Medicines and Pharmacy Research Centre, Sansom Institute for Health Research, University of South Australia, GPO Box, Adelaide, South Australia, Australia 0 Pharmacy Practice, Quality Use of Medicines and Pharmacy Research Centre, University of South Australia, Director of Teaching, Training and Research, South Australia Mental Health Nursing, University of South Australia, City East Campus, Centenary Building, North Terrace, Adelaide, South Australia 00 address for authors: Kerrie Westaway: Kerrie.westaway@unisa.edu.au Janet K Sluggett: Janet.Sluggett@unisa.edu.au Christopher Alderman: Chris.Alderman@sa.gov.au Nicholas Procter: Nicholas.Procter@unisa.edu.au Elizabeth Roughead: Libby.Roughead@unisa.edu.au Corresponding author: Kerrie Westaway Quality Use of Medicines and Pharmacy Research Centre, Sansom Institute for Health Research, University of South Australia, GPO Box, Adelaide, South Australia, Australia 0 Telephone: + Fax: Kerrie.westaway@unisa.edu.au Abstract word count: words Main body word count:, words

18 Figures: Acknowledgements: This work is part of a national review of Medication Safety in Mental Health in Australia funded by The Australian Commission on Safety and Quality in Health Care. Conflict of Interests: None declared Sources of funding: The Australian Commission on Safety and Quality in Health Care

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