Benzodiazepines in schizophrenia. Is there a trend towards long-term prescribing?

AIMS AND METHOD

We sought to determine the prevalence of long-term benzodiazepine prescribing in patients with schizophrenia occupying psychiatric rehabilitation beds. A cross-sectional survey was conductedin 11 National Health Service trusts.

RESULTS

Almost 10% of patients occupying rehabilitation beds had a diagnosisof schizophrenia and received long-term benzodiazepines incombination with one or more antipsychotics.

CLINICAL IMPLICATIONS

Our results are consistent with those of other authors and showthat benzodiazepines are frequently used in the long-term inpatients with schizophrenia despite a lack of open acknowledgementof this practice and a paucity of objective data to supportits efficacy.

Introduction

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Introduction

With a move away from using the sedative side-effects of antipsychotic drugs to control acute behavioural disturbance in the settingof mental illness, the use of benzodiazepines in this contexthas increased as they sedate effectively with minimal riskof side-effects. The Royal College of Psychiatrists consensusstatement on the use of high dose antipsychotics (Thompson, 1994)clearly states that benzodiazepines alone or in combinationwith standard doses of antipsychotics are the drugs of choicewhen rapid tranquillisation is required. The principle beingapplied here is ‘when sedation is required, use a sedative’.A problem then arises because of the time lag between the administrationof antipsychotic drugs and therapeutic effect (Keck et al,1989). For some patients this can be several weeks and additionalsedation is often required during this time. It is at thispoint that the use of benzodiazepines to control behaviouraldisturbance parallels their use to control anxiety symptoms.When does acute disturbance become chronic disturbance and isthe use of benzodiazepines in the longer term ever justified?It is our informal impression that the use of benzodiazepinesin the medium- or long-term in patients with a schizophrenicillness that is difficult to treat is increasing locally andwe sought to survey this in a larger patient sample.

Method

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Method

Pharmacists belonging to the South East Thames Psychiatric Pharmacists Network (a branch of the UK Psychiatric Pharmacy Group) wereasked to identify all patients cared for by their trust who:

occupied a psychiatric rehabilitation bed on the 9 November1998;
had a diagnosis of schizophrenia;
had been receivinga benzodiazepine for more than six weeks.

Patients prescribed as required (p.r.n.) benzodiazepines wereincluded only if doses were administered at least three timesweekly.

Prescription records and clinical notes were then used to obtainthe following demographic and clinical information for eachpatient: age, gender; age at onset of illness; and doses androutes of administration of all prescribed psychotropic drugs.The total number of beds surveyed by each pharmacist was recorded.

Results

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Results

Data were received from 11 trusts, covering a total of 315 rehabilitation beds. Participating trusts are listed in the Acknowledgements.

Twenty-nine patients with a diagnosis of schizophrenia who hadreceived a benzodiazepine for more than six weeks were identified,representing 9.2% of patients occupying these beds. Twenty-one(6.6%) received regular and eight (2.5%) p.r.n. benzodiazepines.The mean age of the patients was 40.7 years (range 21-68) andthe mean age of illness onset 21.4 years (range 11-34).

The most commonly prescribed benzodiazepine was lorazepam (n=17), followed by diazepam (n=7), clonazepam (n=4) and temazepam (n=1). The mean daily dose of lorazepam was 2.9 mg (range 1-6mg), diazepam 10.4 mg (2-20 mg) and clonazepam 1.7 mg (1-4mg).

All 29 patients were prescribed at least one regular antipsychoticwith 12 receiving two or more. Eight patients received clozapine(three in combination with other antipsychotics), 15 otheratypical antipsychotics (two in combination), 15 oral typicalantipsychotics (four in combination) and four depot preparations(all in combination). By using the maximum British NationalFormulary (BNF, 1999) dose as 100% and adding percentages forthose patients prescribed more than one antipsychotic, thetotal prescribed dose of antipsychotic ranged from 33-216%(mean 92%) per patient. Eight patients were prescribed morethan 100% of the BNF recommended dose.

Fifteen patients were prescribed other psychotropic medication,nine of whom received a mood stabiliser and six an antidepressant.

Discussion

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Discussion

Almost one in 10 patients occupying rehabilitation beds hada diagnosis of schizophrenia and received benzodiazepines inthe medium- or long-term. Possible reasons for this include:inadequate response to antipsychotics alone; an ‘antipsychoticsparing effect’ of the benzodiazepine; poor review ofthe drug regime after a period of acute disturbance; misuseby patients; and, in the case of p.r.n. medication, inappropriateuse by staff.

Inadequate response to antipsychotics
It is generally accepted that 30% of patients with schizophreniarespond poorly if at all to conventional antipsychotics anda third of this group respond poorly to clozapine (Kane, 1992).The patients in our sample occupied a long-term hospital bed,and there was a high prevalence of antipsychotic polypharmacy,use of antipsychotics in total doses of over 100% of the BNFmaximum and co-prescription of other psychotropic drugs, indicatingthat their illness was not easy to control. Alternative strategiesare clearly required for these patients.

Benzodiazepines are prescribed in schizophrenia for a varietyof reasons including: as hypnotics; to alleviate the side-effectsof neuroleptics such as akathisia and tardive dyskinesia; totreat comorbid anxiety considered unrelated to the primarydiagnosis and to treat core psychotic symptoms including negativesymptoms (Lingjaerde, 1991). They possess some pharmacologicaleffects that may, theoretically, be beneficial in patientswith psychotic illness. Benzodiazepines facilitate ${gamma}$ -aminobutyricacid (GABA) transmission and GABA inhibits some dopamine pathways.It has been postulated that the resultant effect is similarto that achieved by neuroleptics, but via a different route(Easton & Janicak, 1991). Benzodiazepines block stressactivation in the meso-prefronto-cortical tracts, a pathwaywhich has few dopamine receptors. Wolkowitz et al (1992) postulatethat this is the mechanism for augmentation of antipsychoticresponse in those individuals with schizophrenia who are sensitiveto stress.

There are many reports of benzodiazepines usefully augmentingantipsychotic response when given in standard doses, althoughnegative reports also exist. Wolkowitz & Pickar (1991) reviewed the literature in this area and concluded that 30-50%of patients respond favourably to the combination, althoughonly a few in a very striking way. Those with more severe psychosis,motor disturbance or anxiety symptoms may respond preferentiallyand improvement may be seen across the whole range of psychoticsymptoms including hallucinations, delusions, thought disorder and negative symptoms. Some patients were noted to respond within24 hours. Virtually all the literature describes only the acutephase of treatment, with follow-up data beyond eight weeksrarely available. One exception to this is the study by Wolkowitzet al (1992), where five of seven patients who initially respondedto alprazolam augmentation, showed sustained improvement after37 months.

There is a suggestion that the tribenzodiazepines (estazolam,alprazolam and the closely related clonazepam) may be superiorto the other benzodiazepines in augmenting neuroleptic response (Wolkowitz & Pickar, 1991). Some authors, however, recommendedavoiding these high potency benzodiazepines and state a preferencefor diazepam or chlordiazepoxide stating that their longerhalf-lives are likely to lead to less risk of withdrawal psychosissecondary to non-adherence (Christison et al, 1991). Thisis speculative rather than proven. The issue of ‘whichbenzodiazepine’ is particularly important as diazepamand lorazepam are the benzodiazepines most frequently usedfor rapid tranquillisation (Pilowsky et al, 1992) and therefore,by default, the most likely to be prescribed on a chronic basis.This is confirmed by our findings.

Antipsychotic sparing effect
Pecknold (1993), surveyed 149 out-patients diagnosed as sufferingfrom schizophrenia and found that 41% received both antipsychoticsand benzodiazepines on a chronic basis. Those patients receivingcombined antipsychotics and benzodiazepines received a loweroverall dose of antipsychotic than the group receiving antipsychotics alone. This may be due to an antipsychotic sparing effect ofthe benzodiazepine or simply to the fact that the cohort receivingbenzodiazepines were less ill. We did not survey antipsychoticdoses in those patients with schizophrenia who did not receivebenzodiazepines and so cannot confirm this finding.

Diazepam has been shown to be superior to placebo and as effectiveas fluphenazine in aborting prodromal symptoms of relapse inpatients with schizophrenia who were otherwise medication free (Carpenter et al, 1999). That is, an antipsychotic sparingeffect has been demonstrated in these circumstances. It iswell recognised that ongoing antipsychotic medication doesnot guarantee that the patient will be relapse free and itis possible, although not proven, that benzodiazepines may havea similar protective effect in patients receiving antipsychoticswho begin to decompensate, thus sparing them from exposureto increased doses of antipsychotics.

There are reports of both tolerance developing to the antipsychoticeffect of benzodiazepines, and rebound psychosis on withdrawal (Wolkowitz et al, 1992) where for some patients more severesymptoms than those that were initially present before benzodiazepineswere prescribed become apparent. This could be interpretedby prescribers as a benzodiazepine withdrawal reaction or,alternatively, as benzodiazepines having a true antipsychotic effect which when removed precipitates relapse.

Poor review of the drug regime
This may be in the form of failing to discontinue benzodiazepinesafter a period of acute disturbance, or failing to use a moreeffective antipsychotic (i.e. clozapine) where it is indicated.Most of the respondents reported a small number of patientswho fulfilled our criteria and there was not a striking differencein prevalence rates between trusts. It seems unlikely that a similar proportion of patients in each trust would have theirprescription review neglected in the same way. Our data doesnot allow further discussion of this point.

Misuse by patients
Dependence is potentially a major problem when benzodiazepinesare used to treat anxiety spectrum disorders and although someauthors express the opinion that such problems are less likelyin patients with schizophrenia (Wolkowitz & Pickar, 1991),a survey by Hawley et al (1994) which identified 6% (10 timesthe prevalence rate for schizophrenia) of hospital benzodiazepine-dependenceclinic attendees as suffering from schizophrenia would notsupport this view. Benzodiazepines should always be used with caution in those with a history of drug or alcohol misuse.

Inappropriate use by staff
Over a quarter of patients who were receiving benzodiazepineshad p.r.n. prescriptions which were administered at least threetimes a week. It is possible that staff resorted to medicationtoo easily and that using de-escalation techniques such astalking down, one to one attention or ‘time-out’may have reduced the need for p.r.n. Again, our data does notallow further discussion of this point.

Implications

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Implications

The results of this survey are in line with those of Pecknold (1993) and Hawley et al (1994) and show that a substantialproportion of patients with schizophrenia receive benzodiazepines in the long-term. It is time to openly acknowledge this practiceand gather objective data to evaluate its efficacy and risks.

Acknowledgments

We thank the following pharmacy departments for providing datafor the study: Bethlem & Maudsley NHS Trust, Horizon NHSTrust, Hounslow & Spellthorne NHS Trust, Lambeth NHS Trust,Lewisham & Guy's NHS Trust, Mid-Essex NHS Trust, OxleasNHS Trust, South Downs NHS Trust, St Clements NHS Trust, WestHertfordshire Community Trust, West Middlesex NHS Trust.

References

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