antipsychotics in clinical practice: guidelines for safe and effective use

human psychopharmacology

Hum Psychopharmacol Clin Exp 2002; 17: 75–82.

Published online 11 February 2002 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hup.373

REVIEW

Antipsychotics in clinical practice: Guidelines for safeand effective use

Stephen Curran1*, Linda Harris2, Andrew Macdonald3, Colin Pollock4, Gerry Roney5

and David Silkstone6

1University of Huddersfield, Queensgate; Consultant in Old Age Psychiatry, Wakefield and Pontefract Community HealthNHS Trust, Fieldhead Hospital, Wakefield, UK

2National Service Framework for Mental Health—Primary Care Standards (Chair),Homestead Clinic, Wakefield

3Wakefield and Pontefract Community Health NHS Trust, Fieldhead Hospital, Wakefield4Wakefield Health Authority, Wakefield5Wakefield and Pontefract Community Health NHS Trust, Fieldhead Hospital, Wakefield6Pinderfields Hospital, Wakefield

Antipsychotic drugs have made a significant contribution to the treatment of schizophrenia but the older drugs in particularhave significant side-effects. The newer atypical drugs are effective for the treatment of both positive and negative symptomsand they also have significantly fewer serious side-effects. However, these drugs are considerably more expensive that theolder drugs and this has generated intense debate about their cost effectiveness. There is now good evidence that when allfactors are taken into consideration the atypical drugs are both cost effective and improve the quality of life of patients withschizophrenia. Despite the importance of these drugs there is widespread variation in their use and a national consensus onthis important issue is long overdue. Copyright # 2002 John Wiley & Sons, Ltd.

key words— antipsychotics; mental disorder; guidelines

INTRODUCTION

Although psychotropic substances have been avail-able for a considerable period of time the use of syn-thetic drugs in psychiatry is a relatively recentphenomenon. Phenobarbital was introduced in 1912(King, 1995), lithium in 1949 (Cade, 1949), chlorpro-mazine in 1952 (King, 1995), imipramine in 1958(Kuhn, 1958), diazepam in 1962 (Cooper, 1995) andclozapine in 1990 followed by risperidone in 1992.The efficacy of most of these drug classes has not sig-nificantly improved over the past 50 years or so. Theprincipal developments in psychopharmacology havefocused on developing drugs with improved side-

effect profiles, better tolerability and improved safety.However, the newer drugs are more expensive and thishas led to a growing debate about their cost effective-ness and the quality of life for patients because ofreduced side-effects. The greater emphasis on evi-dence based practice should ultimately result in betterand more consistent high quality care for patients.

TERMINOLOGY

A number of different terms are used to describe thesedrugs. The term antipsychotic is widely used (Laderand Herrington, 1990). However, these drugs are oftenused in patients without psychotic symptoms, espe-cially in those with severe agitation and behaviouraldisturbance. Shortly after the introduction of antipsy-chotic drugs the most widely used term was majortranquillizer but this is now seldom used. The term

Copyright # 2002 John Wiley & Sons, Ltd. Accepted 26 November 2001

* Correspondence to: Professor S. Curran, Wakefield and PontefractCommunity Health NHS Trust, Fieldhead Hospital, OuchthorpeLane, Wakefield WF1 3SP, UK. E-mail: [email protected]

antischizophrenic has also been used (especially in theUSA) but since these drugs are used in a much greaterrange of patients the term has never become popular inthe UK. The term neuroleptic (meaning ‘to grasp theneuron’) has been more widely used especially in theUK. However, the term antipsychotic is now widelyused and is probably the preferred term.

CLASSIFICATION

Antipsychotic drugs can be classified in a number ofdifferent ways and there is no universally agreed clas-sification and all have some limitations. They can beclassified according to their principal actions, e.g.sedative and non-sedative, or according to how longthey have been available, e.g. old and new. Otherclassifications include classical and novel, typicaland atypical, selective and broad spectrum and onthe basis of their chemical structures (Table 1).Another method is based on potency. Drugs thatproduce the same maximal effect are said to haveequal efficacy, but an agent that produces the max-imum effect at a lower dose is said to have a higherpotency (Hindmarch and Currie, 1995). Drugs withlow potency include chlorpromazine, thioridazine,sulpiride and clozapine whereas those with highpotency include haloperidol, trifluoperazine and risp-eridone. In clinical practice, clinicians often use avariety of classifications.

Selective antagonists

Sulpiride and remoxipride are selective D2 antagonistsand interestingly neither causes significant extrapyra-

midal side-effects (EPSEs). However, sulpiride has atendency to cause galactorrhoea and remoxiprideakathisia. The main role for sulpiride is in mainte-nance therapy in schizophrenia.

Broad spectrum antagonists

The prototype in this group is clozapine (Buchananand McKenna, 2000). It was first introduced intoEurope in 1975 but did not get a licence in the UKbecause of neutropenia. Kane et al. (1988) showedthat it was effective for treatment-resistant cases ofschizophrenia. It was granted a limited licence inthe UK in 1990. Multiple receptor antagonism mayhave some benefits. High muscarinic antagonismcould account for the lower incidence of EPSEs in thisgroup. Since 5-HT has been implicated in the aetiol-ogy of schizophrenia since the 1960s, 5-HT2 antagon-ism might also be a beneficial effect. Drugs withmixed D2/5-HT2 receptor antagonists have beendeveloped (e.g. risperidone) (Fleischhacker andMarder, 2000). Olanzapine displays high affinity for5-HT2, H1, �1, D1 and D2 receptors (Moore et al.,1993). Negative symptoms are thought to be morelikely to improve with D1 receptor blockade in theprefrontal cortex.

USE OF ANTIPSYCHOTIC DRUGSIN CLINICAL PRACTICE

Psychotic symptoms (hallucinations and delusions)occur in a range of clinical syndromes (e.g. schizo-phrenia and related disorders, paranoid disorders,acute and chronic organic disorders and affective dis-orders) and antipsychotics are commonly used tomanage these disorders. These drugs are also widelyused in patients with marked agitation and beha-vioural disturbance. Most of the research on antipsy-chotics has been conducted in young schizophrenicsand related disorders but there is also a significantbody of evidence for their use in other conditionsand in older people (Buchanan and McKenna, 2000;Buckley and Naber, 2000; Defilippi and Crismon,2000).

THE ‘IDEAL’ ANTIPSYCHOTIC

The ‘ideal’ antipsychotic would have a number ofcharacteristics and these are summarized in Table 2.Not surprisingly, no such drug exists although therehave been considerable improvements over the past30 or so years.

Table 1. Chemical classification of antipsychotics

Class Non-proprietary name

PhenothiazinesAliphatic ChlorpromazinePiperidine ThioridazinePiperazine Trifluoperazine, Fluphenazine

Thioxanthines Flupenthixol, ZuclopenthixolButyrophenones Haloperidol, DroperidolDiphenylbutylpiperidines PimozideSubstituted benzamides Sulpiride, RemoxiprideDibenzodiazepine ClozapineThienobenzodiazepine OlanzapineDibenzoxazepine LoxapineBenzisoxazole RisperidoneDibenzothiazepine QuetiapinePhenylindol derivative SertindoleDibenzothzolylpiperazine ZiprasidoneDibenzothiepine derivative Zotepine

(Moore et al., 1993; Buckley and Naber, 2000; Potkin and Cooper,2000).

76 s. curran et al.

Copyright # 2002 John Wiley & Sons, Ltd. Hum Psychopharmacol Clin Exp 2002; 17: 75–82.

CLASSICAL ANTIPSYCHOTICS

Classical antipsychotic drugs have had a profoundimpact on the treatment of schizophrenia and relateddisorders and until relatively recently have been themainstay of treatment. For example there is good evi-dence for the clinical effectiveness of chlorpromazinein schizophrenia. Thornley et al. (1997) in a review of144 studies, found that chlorpromazine significantlyreduced the relapse rate in schizophrenia, improvedpositive symptoms and functioning. However, it wasassociated with significant side-effects includingsedation, acute-movement disorders, parkinsonism,weight gain and seizures. Prescribing practices havealtered over time and low doses (with fewer side-effects) are now considered as effective as high doses.The principal difference between the classical andatypical antipsychotic drugs relates to their side-effectprofile and particularly the propensity of classicalantipsychotics to cause tardive dyskinesia (Tysonet al., 1999). Side-effects are usually dose relatedbut with careful monitoring can be easily detected(Chaplin et al., 1999). However, classical antipsycho-tics have an important role to play in a number of clin-ical situations, e.g. in patients requiring intramuscularmedication (Schultz and McGorry, 2000).

ATYPICAL ANTIPSYCHOTICS

There is good evidence that atypical antipsychoticsare at least as effective as classical antipsychoticsbut are associated with significantly fewer seriousside-effects (Beasely, 1996; Bondolfi et al., 1996;Tollefson et al., 1997; Taylor, 1997; Thomas andLewis, 1998; King, 1998; Fleischhacker, 1999;Hawkins et al., 1999; Brown et al., 1999; Vermaet al., 2001). Although atypical antipsychotics ingeneral have fewer side-effects, particularly EPSEs,they may be associated with a number of importantside-effects, e.g. neutropenia and gastrointestinal

obstruction with clozapine (CSM, 1999). There isnow a large body of information available on atypicalsand the reader is referred to other publications for adetailed discussion of neuropharmacological mechan-isms (Kerwin and Owen, 1999), behavioural pharma-cology (Moore, 1999), a critical analysis of side-effects (Barnes and McPhillips, 1999) and the effectof atypicals on cognition (Sharma, 1999). It is alsorelatively easy to switch to an atypical from a classicalantipsychotic (Amery and Marder, 1998). Althoughthe data are limited, there are several studies support-ing the use of atypical antipsychotics in older peoplewith schizophrenia including clozapine, risperidone,olanzapine, quetiapine and ziprasidone (Sajatovicet al., 2000). There is also a growing body of evidencethat atypical antipsychotics can be cost effective treat-ments (Glazer and Johnstone, 1997; Foster and Goa,1999; Almond and O’Donnell, 2000) and improvethe quality of life for patients with schizophrenia(Hamilton et al., 1998; Revicki et al., 1999).

Because of the importance of antipsychotics, thereis a need to develop national guidelines. We decidedto undertake a review of published guidelines, exam-ine a range of guidelines produced by other NHSTrusts in the UK and undertake a cross-sectionalsurvey of antipsychotic drug use in Wakefield, UK.

AUDIT PROJECTS

Two audits of antipsychotic drug use for schizophre-nia were undertaken at the Maudsley and BethlemHospitals in January 1998 and February 1999 (Tayloret al., 2000). Prior to the second audit a treatment pro-tocol for antipsychotic drug use in schizophrenia wasintroduced. In total, 2894 patients were included inboth audits. In the first audit 56.1% were taking clas-sical antipsychotics and 16.6% atypicals. After theintroduction of the treatment protocol, the figure forclassical antipsychotics fell to 45.7% whilst the figurefor atypicals increased to 25.5%.

PRESCRIBING GUIDELINES

There have also been a number of other prescribingguidelines including The Bethlem and MaudsleyNHS Trust Prescribing Guidelines (Taylor et al.,1999) and those produced by the American Psychia-tric Association (APA, 1997). In addition the NHSCentre for Reviews and Dissemination (1999) has alsoconsidered this issue. Unfortunately, the guidelinesare not entirely consistent. The Maudsley Guidelinesrecommend that atypicals can be used as first line(assuming no problems with funding), the APA

Table 2. The ‘ideal’ antipsychotic

� Clinically effective� Rapid onset of action� No tolerance� No side-effects� No withdrawal syndrome� No interactions with other drugs� Safe in overdose� Free� Range of formulations available� Ease of administration

antipsychotics in clinical practice 77


Guidelines suggest that classical or atypical antipsy-chotics can be used as a first line treatment for schizo-phrenia. The NHS Centre for Reviews andDissemination sits on the fence and suggests longerterm-studies are needed. National guidelines fromNICE are still awaited.

GUIDELINES PRODUCED BY NHS TRUSTS

A number of NHS Trusts have also produced ‘guide-lines’ in relation to the pharmacological treatment ofschizophrenia and related disorders. A random sampleof 25 NHS Trusts were identified and informationcollected about the availability of local ‘guidelines’.Sixteen Trusts replied and of these four did not pro-vide the requested information. Information on theremaining 12 Trusts is summarized in Table 3. Thereis enormous variation in the ‘guidelines’ and in manyit is not clear what the relationship is with primarycare. In some, it is clearly stated that the initiationof atypicals should be by the consultant psychiatrist.

USE OF ANTIPSYCHOTIC MEDICATIONIN WAKEFIELD

The adult population in Wakefield is approximately350 000. In 1999 there were a number of anecdotalreports received by Wakefield Health Authority(UK) that GPs had concerns about variations andinconsistencies in the prescribing practices of antipsy-chotics amongst Consultants in Adult Mental Healthin the Wakefield District. There were also concernsabout the position of clinical responsibility in relationto the initiation of treatment with atypical antipsycho-tics. In addition, cost pressures within the Districtresulted in a cash-limited drug budget and this rein-

forced the need for both Wakefield Health Authority,Primary Care and the Community Trust (Wakefieldand Pontefract Community Health NHS Trust) toidentify cost-benefits of different drugs based on evi-dence-based practice. Wakefield Health Authority waskeen to develop agreed Clinical Guidelines for the useof atypical antipsychotics in Wakefield in collabora-tion with the Community Trust, the Acute Trust,Primary Care Groups and the District PharmacyService to create a clearer and consistent approachto a new therapeutic area across the local community.It was felt that a cross-sectional survey of the currentuse of atypical antipsychotics in Wakefield would be auseful starting point prior to developing practiceguidelines.

METHODOLOGY

This study was a cross-sectional survey of atypicalantipsychotic use in patients with mental illnessaged 18–64 in the Wakefield District. Patientsincluded in the study were all being cared for by thesix Community Mental Health Teams working withinthe Wakefield and Pontefract Community HealthNHS Trust. Information was collected on all patientsin April 1999 and the project was completed inSeptember 1999. A pro forma was developed withsupport from the QED Department, Wakefield andPontefract Community Health NHS Trust and inform-ation was collected from patient records. The sameindividual undertook all the data collection anddiagnoses were based on ICD-10 criteria (WorldHealth Organization, 1992). In addition, financialinformation relating to atypical antipsychotics wascollected for the three financial years 96/97, 97/98and 98/99.

Table 3. Use of atypical antipsychotics by NHS Trusts

NHS Trust Atypical antipsychotics Atypical antipsychoticsavailable for first line available for secondtreatment of schizophrenia line treatment of schizophrenia

Bay Community NHS Trust No guidelines No guidelinesCH Sheffield NHS Trust YesDoncaster and South Humber HC NHS Trust No guidelines No guidelinesLeeds CMH NHS Trust (draft) YesNorfolk MHC NHS Trust No No (3rd line only)Northumberland MH NHS Trust YesNorth East Essex MH NHS Trust No guidelines No guidelinesRochdale HC NHS Trust No guidelines No guidelinesSouthern Derbyshire MH NHS Trust No Yes (only risperidone, olanzapine

and clozapine)Tees and North East Yorkshire NHS Trust No YesWest Kent Health Authority YesWorcestershire CHC NHS Trust Yes

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RESULTS

The total number of patients included in the study was469 with each of the six Community Mental HealthTeams (CMHTs) represented (Table 4). All age groupsin the range 18–64 years were represented (Table 5).

At the time of the study 33 patients (7%) were in-patients and 439 (93%) were being cared for in thecommunity. Although most of these patients hadscheduled outpatient appointments (358, 76%) only36 (8%) attended on a regular basis and in 75 (16%)no details were available regarding their outpatientappointments. In addition, the range of expected diag-noses were represented (Table 6) but diagnosis was

not recorded in 34 patients (7%) and some patientshad more than one diagnosis.

Information about the clinical responsibility forissuing the prescription of psychiatric medicationwas also collected (Table 7). Data were missing onfour patients. Consultants prescribed approximatelytwo-thirds of prescriptions and GPs one-third but in5% it was unknown who the prescribing agent was.In addition, information was collected on the durationof treatment. In 340 (72.5%) medication had beengiven for 3 months or longer. In total, 289 patientswere taking antipsychotics (69%) of the original sam-ple of 469 but data were missing in a further 50patients. A wide range of other drugs was takenincluding antidepressants, benzodiazepines, anticon-vulsants and medicines for physical illness. 50patients (12%) were taking three or more drugs, pre-dominantly psychotropic drugs.

The four atypicals used included clozapine, olanza-pine, risperidone and amisulpride. Of the patients tak-ing antipsychotics, 89% (257) were taking classicalantipsychotics and 21.5% (62) atypical antipsycho-tics. Approximately 11% of patients were taking bothatypical and classical antipsychotics. A �2 analysisundertaken to compare the use of the four atypicalsand classical antipsychotics with diagnosis revealedno significant differences (schizophrenia �2¼ 19.8,p< 0.47; manic depression �2¼ 1.4, p< 0.85; anxiety�2¼ 7.0, p< 0.53; depression �2¼ 15.4, p< 0.49).In addition, there were no significant differencesbetween the five consultant teams and use of aty-picals versus classical antipsychotic drugs (�2¼ 2.5,p< 0.64).

Table 4. Breakdown by CMHTs

CMHT Number Total reportedof cases cases (%)

Wakefield Central 88 19Horbury 65 14Crofton 47 10Pontefract 107 22.5South Kirkby 107 22.5Airedale 55 12

Total 469 100

Table 5. Breakdown by age group

Age group Number Patients in each(years) of cases group (%)

18–19 2 0.520–24 23 525–29 42 930–34 65 1435–39 69 1540–44 56 1245–49 52 1150–54 62 13.555–59 47 1060 to 64 46 10

Total 464a 100

aNo information available on 5 patients.

Table 6. Breakdown by diagnosis

Diagnostic category Responses Total cases(435) (%)

Schizophrenia 212 49Bipolar affective disorder 48 11Anxiety disorder 40 9Depression 113 26Other 53 12Total responses 466

Table 7. Breakdown by prescribing agent

Prescribing agent Responses Total cases(465) (%)

Consultant 298 64GP 157 34Other 19 4Not known 22 5

Table 8. Cost of prescribing atypical antipsychotics (in £)

Drug 96/97 97/98 98/99

Risperidone 46 949 44 234 39 379Clozapine 37 013 43 533 70 448Olanzapine 17 641 52 549 64 648Sertindole 830 1643 3211Quetiapine 0 889 9299Amisulpride 0 637 16 801

£102 433 £143 485 £203 787



DRUG COSTS

The cost of prescribing atypical antipsychotics inWakefield was calculated for the financial years96/97, 97/98 and 98/99 based on the cost of drugsduring the respective financial years and broken downfor the individual drugs (Table 8).

CONCLUSIONS

Antipsychotics have made a significant contribution tothe care of people with mental illness over the past 50years or so. There is good evidence that classical andatypical antipsychotics are effective in the treatmentof positive symptoms (delusions and hallucinations)and atypicals may also have some advantages forthe treatment of negative symptoms in patients withschizophrenia. Antipsychotics are also widely usedto treat other conditions including affective psy-choses, severe agitation and dementia but there is lessevidence for the use of antipsychotics in these disor-ders and further research is needed.

Classical and atypical antipsychotics differ signifi-cantly in terms of their side-effect profiles. In particu-lar, classical antipsychotics are associated with agreater range and severity of side-effects includingextrapyramidal symptoms, sedation, anticholinergicside-effects and postural hypotension compared withatypical drugs. They are also more dangerous in over-dose. However, many of these side-effects are doserelated.

In this study, both classical and atypical antipsycho-tics were commonly used. It was often not clearwhy a particular antipsychotic was prescribed. Gooddocumentation, communication between health careprofessionals and the provision of good quality infor-mation for patients are basic but integral to the pre-scribing process. In particular, it should be agreed atthe beginning who will initiate the drug and who willbe responsible for future prescriptions. In addition,patients commenced on treatment should not be lostto follow-up and every effort should be made to iden-tify those patients that have failed to attend for outpa-tient clinic review. The greater availability of ITsystems should make this easier to achieve.

There is no consistent advice available for the use ofatypical antipsychotics and there is also considerablevariability in the guidelines produced by NHS Trustsin the UK. There is a need for a clear set of national/international guidelines that are evidence based, takeaccount of financial considerations and are simple andeasy to use in clinical practice. A suggested frame-work is summarized in Appendix 1. This has been

agreed locally in Wakefield (UK) through a collabora-tive project involving the Community and AcuteTrusts, The Health Authority and the Primary CareGroups. It has also provided a useful framework forother therapy areas.

ACKNOWLEDGEMENTS

The authors would like to thank Karen Holland fromthe QED Department, Wakefield and PontefractCommunity Health NHS Trust for help with thecross-sectional survey of atypical antipsychotics inWakefield and the statistical analysis and the NHSTrusts that sent copies of their atypical antipsychoticdrug guidelines.

APPENDIX 1. USE OF ANTIPSYCHOTICSIN CLINICAL PRACTICE

* Where possible antipsychotics should be avoided.* Before patients are commenced on antipsychotics

they should have an appropriate assessment includ-ing psychiatric history, mental state examination,physical examination and appropriate investiga-tions. The nature of this assessment will depend onthe individual clinical circumstances. The clinicianmust be satisfied that the use of an antipsychoticwill be well tolerated, safe and appropriate to theclinical condition.

* The indications for prescribing an antipsychoticshould be clearly stated, e.g. schizophrenia, psy-chotic depression etc., and recorded in the patientrecord.

* Non-pharmacological treatments should be con-sidered before commencing antipsychotic drugs.

* If possible, the patient should be observed for aperiod (e.g. for 24–48 h) without an antipsychoticdrug. Patients often improve and either smallerdoses can be given or an antipsychotic might not beneeded.

* If an antipsychotic drug is used, start with a smalldose and increase gradually over a few weeks. Theantipsychotic effect often takes a couple of weeksto develop and there is therefore little benefit ingiving high doses initially.

* After commencing treatment the clinical responseand side-effects should be carefully monitored andrecorded.

* Patients should be given adequate informationabout the drug.

* In most situations, use only one antipsychotic andprescribe within BNF limits.

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* After starting treatment there should be adequatecommunication about this in writing to all thehealthcare professionals involved with the care ofthe patient.

* It should be clear who is initiating the prescription,how much medication has been given and who willcontinue to prescribe and monitor. This should beagreed before treatment is commenced and docu-mented and usually before the patient is dischargedfrom hospital.

* Patients commenced on antipsychotics should bereviewed on a regular basis and this should includegood documentation and written communicationwith other health care professionals. Patients whofail to attend clinics or other settings should befollowed-up to clarify the reasons for this.

* The choice of antipsychotic will depend on anumber of factors including pharmacological con-siderations, previous response to treatment, pre-vious side-effects, concomitant medication andmedical conditions, compliance and the ability toswallow tablets. This decision should be left to theclinician after a review of all the clinical evidenceand communicated to other health care profes-sionals involved with the care of the patient.

* Classical antipsychotics should be used as first linetreatments. The initial dose should be small andgradually increased to minimize side-effects and toenable tolerance to develop.

* Clinical efficacy and or tolerability should becarefully monitored and documented.

* If a patient has failed to respond to a classicalantipsychotic despite an adequate dose for a reason-able period of time and/or if the patient hasdeveloped unacceptable side-effects, this shouldbe changed to an atypical antipsychotic. Based onthe available evidence suitable atypicals wouldinclude amisulpride, olanzapine, quetiapine risper-idone and zotepine.

* Atypical antipsychotics should only be initiated byConsultant teams working in Mental Health after acareful review of all the clinical evidence. Theteam should take responsibility for prescribing theatypical antipsychotic until the patient’s conditionhas been stabilized.

* The patient’s General Practitioner should then takeresponsibility for prescribing the atypical antipsy-chotic in the context of Shared Care.

* Clozapine should be available for the managementof treatment resistant schizophrenia/psychosis afterregistration with the Clozaril Patient MonitoringService.

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antipsychotics in clinical practice: guidelines for safe and effective use

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