Combined antipsychotics for 'difficult-to-manage' and forensic patients with schizophrenia: reasons for prescribing and perceived benefits

AIMS AND METHOD

We aimed to examine reasons for initiating and continuing theprescription of combined antipsychotics. A structured interviewwas carried out with the responsible medical officers for 40‘difficult-to-manage’ tertiary referral patientswith schizophrenia who were regularly treated with two or moreantipsychotics.

RESULTS

Lack of efficacy of monotherapy was the main reason for initiatingand continuing combined antipsychotics. Other reasons for continuingcombined antipsychotics included not wishing to change medicationas the patient was reasonably well, and safety considerations.Perceived benefits of combined antipsychotics included fewerpositive symptoms and less disturbed behaviour.

CLINICAL IMPLICATIONS

‘Difficult-to-manage’ and forensic treatment-resistantpatients with schizophrenia pose a particular therapeutic challenge.Use of combined antipsychotics, although not evidence-based,is perceived by some psychiatrists as beneficial when otheroptions have failed.

Introduction

TOP

Introduction

Use of combined antipsychotics is generally considered to reflectpoor prescribing practice and has been termed psychiatry’s‘dirty little secret’ (Stahl, 1999). Use is notrecommended in the Royal College of Psychiatrists’ ConsensusStatement (Thompson, 1994). National Institute for ClinicalExcellence guidance states that for schizophrenia, atypicaland conventional antipsychotics should not be prescribed concurrently (National Institute for Clinical Excellence, 2002a), and norshould combinations of any antipsychotics, except clozapineaugmentation when clozapine alone has proved insufficient (National Institute for Clinical Excellence, 2002b).There is a paucityof clinical trials to support the practice of prescribing antipsychoticcombinations, apart from clozapine augmentation with a moretightly bound D₂ receptor antagonist (Freudenreich & Goff, 2002).A further concern is the risks posed by combined antipsychotics:the possible association with torsade de pointes and sudden death, the likely increased incidence of side-effects and thepotential for adverse drug interactions (Taylor, 2002). Despitethis, use of combined antipsychotics is common and appearsto be increasing (Clark et al, 2002; Lelliott et al, 2002).

The aims of this study were to examine the reasons given bythe responsible medical officer (RMO) for initiating and continuingwith combined antipsychotics for ‘difficult-to-manage’patients with schizophrenia and those with a forensic historyin a tertiary referral centre. Where antipsychotic combinationswere considered beneficial, we sought to determine which aspectsof the patient’s mental state and behaviour the RMO ratedas improved.

Method

TOP

Method

St Andrew’s Hospital is a 500-bed charitable specialistpsychiatric hospital. The forensic and rehabilitation serviceis led by four consultant psychiatrists and comprises sevenwards, six of which are of low- or medium-security, for thetreatment of adult patients, many of whom exhibit challengingbehaviour. These patients are referred from prison or other psychiatric hospitals (including special hospitals) throughoutthe UK. Pharmacists examined the current prescription chartsof all inpatients of this service and identified those regularlyprescribed two or more antipsychotics. For patients prescribedcombined antipsychotics, the RMO was asked to provide an ICD-10clinical diagnosis (World Health Organization, 1992). Consentwas obtained from RMOs to take part in the study. For thosepatients diagnosed with schizophrenia and prescribed multipleantipsychotics, pharmacists interviewed the RMO using a structured questionnaire. Responsible medical officers were questionedabout the patient’s medication history, the reasons forinitiating and continuing with combined antipsychotics andwhether or not the patient had improved on combined antipsychoticscompared with monotherapy. Detailed medication histories, includingthe patients’ response to treatment, were prepared bypharmacists from the patients’ medical records to assistthe RMO. For each patient, the total antipsychotic dose wascalculated as a percentage as follows (Yorston & Pinney, 2000).Each regular prescribed dose was converted to a percentage of the British National Formulary (BNF; British Medical Association & Royal Pharmaceutical Society of Great Britain, 2002)recommended maximum dose for that drug, and then the percentageswere added. If the sum exceeded 100%, the patient was consideredto be receiving a high dose. Data collection complied withthe Data Protection Act 1998.

Results

TOP

Results

Of the 117 patients audited, 101 (86%) were regularly prescribed antipsychotics. Forty-one (35%) out of 117 patients were regularlyreceiving multiple antipsychotics. Forty of the 41 had a diagnosisof schizophrenia and these 40 formed the basis of this study.All four RMOs agreed to be interviewed.

Of the 40 patients, 35 (88%) were male and 5 (12.5%) were female.Their mean age was 37 years (range 23-56, s.d.=8.8). The meanlength of stay at St Andrew’s was 4.8 years (range 0.1-20.5,s.d.=4.5). Thirty-eight (95%) were detained under the MentalHealth Act 1983, 24 (60%) on Section 3 and 14 (35%) under PartIII of the Act. The mean length of detention under the Mental Health Act 1983 was 6.7 years (range 1-18, s.d.=4.1). Thirty-four(85%) patients were on locked wards.

Thirty-five (88%) patients were regularly prescribed two antipsychoticsand five were prescribed three (13%). Fourteen (35%) were prescribedoral atypical combinations, 13 (33%) oral atypicals with oralconventionals and 13 (33%) were prescribed a depot with anoral conventional and/or an oral atypical. The most commonlyprescribed antipsychotics were clozapine (18 cases; median daily dosage 550 mg, range 37.5-800 mg), olanzapine (14 cases, mediandaily dosage 20 mg, range 10-40 mg) and haloperidol (12 cases,median daily dosage 12.5 mg, range 5-50 mg). Twenty-four (60%)patients were prescribed high-dose antipsychotics, including5 (13%) who were prescribed an antipsychotic at above the BNFmaximum recommended dose.

For 36 (90%) patients, the RMO believed that the diagnosis was treatment-resistant schizophrenia (in most cases, documentationconfirmed the patient had received sequential trials of $>=$ 2 different antipsychotics for $>=$ 8 weekswithout improvement), 1 (3%) was not treatment-resistant andfor 3 (8%) a full medication history was not available. Thirty-two(80%) had been prescribed clozapine and 23 (58%) had receiveda trial of $>=$ 3 months of clozapine monotherapy.Ten of the 32 prescribed clozapine later refused to continuewith clozapine or the associated blood tests and another twostopped clozapine because of neutropenia.

The main reason given by the RMO for adding a second antipsychoticfell into one of seven categories, but there were also fivecases where the reason was unknown (see Table 1). The mostcommon reason was lack of efficacy of monotherapy. Reasons foradding a third antipsychotic were: to calm the patient at aparticular time of day (two cases), poor compliance with oralmedication (two cases), and lack of efficacy of existing combinedantipsychotics (one case). The RMO completed a checklist ofreasons for continuing with combined antipsychotics. More thanone reason could be given, and each reason could be rated asmajor or minor (Table 2). The main reasons were that a trialof monotherapy had given a poor outcome, and that the patientwas reasonably well and stable on the current medication. Concerns about further deterioration if the regimen were changed tomonotherapy, and about staff and patient safety, also featured.

View this table:
[in this window]
[in a new window]
Table 1. Main reason given by the responsible medical officer for adding a second antipsychotic (n=40)

View this table:
[in this window]
[in a new window]
Table 2. Reasons given by the responsible medical officer for continuing to prescribe combined antipsychotics (n=40)

For 29 patients, the RMO was able to compare mental state andbehaviour on combined antipsychotics with the most efficaciousmonotherapy previously prescribed. The patient was rated asbetter overall on combined antipsychotics than monotherapyin 26 cases (90%), no different in 1 case (3%) and better on monotherapy in 2 cases (7%). For the 26 cases where combinedantipsychotics were rated as superior, the RMO said the patienthad improved as follows: fewer positive symptoms (24 cases,92%), less disturbed behaviour (19; 73%), less aggression (15;58%), improved overall functioning (14; 54%), fewer side-effects(9; 35%) and fewer negative symptoms (8; 31%).

Discussion

TOP

Discussion

Use of combined antipsychotics was common in the populationsurveyed (35%). This group of patients poses a therapeuticchallenge. They are tertiary referrals who have required treatmentunder Section 3 (a minority had been referred from the courts)for several years in conditions of low- or medium-securitybecause of disturbed behaviour. For most patients, documentationconfirmed treatment-resistance (most had been tried on a large number of different antipsychotics) and 80% had been triedon clozapine (45% currently on clozapine and 35% no longeron clozapine, mainly because of intolerance or refusal). Lackof efficacy of monotherapy was the prime reason for prescribingantipsychotic combinations, as was reported by two studies of combined antipsychotics in out-patients (Taylor et al, 2002; Tapp et al, 2003). In our study, the RMOs reported that inmost cases combined antipsychotics had brought improvementsover monotherapy. In addition, some patients receiving clozapinewere thought to have benefited from the addition of a second antipsychotic, as this had enabled the dose of clozapine tobe reduced, leading to a reduction in side-effects (e.g. resolutionof secondary diabetes mellitus). This study cannot, and doesnot, purport to offer evidence for the efficacy of combinedantipsychotics. It is not a therapeutic trial, but a retrospectivesurvey of the RMO’s reasons and opinions. Although the RMOs reported combined antipsychotics to be beneficial, theyhad not carried out objective ratings to confirm this.

In this survey, 60% of patients prescribed combined antipsychoticsmet the study definition of high-dose treatment. Had we includedwhen required prescriptions in the calculation the proportionwould have been even higher. In only five instances was anindividual antipsychotic being prescribed at above its BNFmaximum recommended dosage. One danger of prescribing combined antipsychotics is that covert prescription of high dosagesmay occur without full staff or patient knowledge or withoutappropriate monitoring.

The problem facing clinicians is that there is virtually noevidence base for the efficacy of combined antipsychotics.Indeed, there is great difficulty in carrying out good studiesin this area. The patients in this study could not have beenincluded in a clinical trial - most are unable to give informed consent and many exhibit severely disturbed and assaultivebehaviour. Yet what does the clinician do when faced with suchseverely disturbed treatment-resistant patients? Is it ethicalto breach National Institute for Clinical Excellence guidanceand prescribe combined antipsychotics to patients who lackmental capacity?

Clearly, there are complex issues for the RMO and multi-disciplinaryteam to consider and it may be helpful to obtain a second opinion.The early use of clozapine is highly desirable, but may notbe possible for all patients. Where clozapine fails, a widerange of therapeutic approaches is needed (Williams et al, 2002). If all evidence-based treatments have been exploredwithout a satisfactory clinical response, it may be reasonableto carry out a time-limited therapeutic trial, preferably usingrating scales, of an antipsychotic combination. An alternativeapproach, similarly lacking an evidence base, would be to increasethe dose of a single antipsychotic into the high-dose range.However, the numbers of patients for whom these actions arejustifiable are likely to be small (Taylor, 2002).

Acknowledgments

We thank the consultants and pharmacists at St Andrew’sHospital for their assistance with data collection and ProfessorT. R. E. Barnes for his comments on the manuscript.

References

TOP