Is there a role for the depot clinic in the modern management of schizophrenia?

The value of antipsychotic medication in preventing relapsein schizophrenia has been apparent since soon after its introduction (National Institute of Mental Health, Psychopharmacology Service Centre Study Group, 1964)but non-compliance remains a problem.Failure to take prescribed medication is a challenge in generalmedicine but presents special difficulties when treating mentalillness; residual symptoms of psychosis and impaired insightafter discharge increase the likelihood that a patient willstop taking antipsychotic medication, thereby contributingto higher relapse rates. The development of depot antipsychoticmedication that could be administered intramuscularly at intervalsof several weeks raised treatment and outcome expectationsfor patients who were felt to be at higher risk of non-compliance when in the community. The need for regular administration andmonitoring of patients receiving depot medication led to depotand maintenance medication clinics. Today, with increasingnumbers of patients who would previously have been receivingdepot medication now taking atypical oral antipsychotics, is there still a need for the depot clinic?

Development and pharmacology

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Development and pharmacology

Depot antipsychotic medication is produced by esterifying theclassical antipsychotic agent with a longchain fatty acid andinjecting it in an oily solution. The resulting esters havea high oil-to-water ratio and are slowly released from thedepot administration site into the circulation. Esterases arepresent in many tissues and once the ester has been releasedinto the circulation it is rapidly split by these enzymes,thereby making the parent compound available.

It is recommended that patients who are candidates for depotmedication should first be stabilised on the oral form of themedication. Plasma concentrations have been used to justifythe use of loading doses to achieve earlier steady states afterinitiation of depot treatment (Ershefsky et al, 1990) butthere is wide inter-patient variability in plasma concentrationafter depot administration. There is little convincing support from controlled studies for therapeutic drug monitoring of plasma concentration during treatments. Depot antipsychotic adverseeffects are related to the active antipsychotic agent and aretherefore comparable to oral agents. One significant difference,however, relates specifically to the long half-life associatedwith depot medication; an adverse event such as neurolepticmalignant syndrome, although rare (Addonizio & Susman, 1991),may be much more difficult to manage in a patient receivinga depot medication with an extended elimination time. The literaturereview by Gerlach (1995) does not support the view that depotantipsychotics are associated with a greater risk of major side-effects than the oral equivalent.

Concerns have been raised (particularly during the first 10years of use) about the ethics of depot use; critics have associatedadministering medication in this form with coercive or forcedtreatment. Certain patients may indeed have persistent feelingsof loss of control over their treatment, necessitating thechange to oral medication. Others may develop a more positiveoutlook if lowest effective dose strategies are used early in treatment, allowing symptom control and insight improvementto take place while minimising distressing side-effects. Thesubjective experience of side-effects to medication is a criticalfactor in the development of negative feelings towards antipsychoticmedication (Gerlach & Larsen, 1999). A systematic reviewof patient attitude to depot antipsychotic medication by Walburnet al (2001) indicates that patients on depot antipsychoticsprefer this route of administration. However, the authors acknowledgethat the evidence base for this finding is limited.

Differing approaches to these concerns may partly explain someof the wide variations in depot antipsychotic use between countries:it has been consistently lower in the US and France than insome northern European countries (UK, Sweden and Denmark) (Dencker & Axelsson, 1996),although this may also be related tothe relatively limited selection of typical depots (haloperidoland fluphenazine) available in the US.

Particular management difficulties are presented by patientswith a history of poor compliance who are sensitive to theextrapyramidal side-effects of conventional antipsychotics.This group would seem to be particularly suited to atypicaldepot preparations. There are, however, no clear indicationsat present as to when these new depots might become available(although more than one is expected to be launched within thenext 3 years). Their exact place in therapy will only becomeclear when information about cost, dose intervals and relativeefficacy are available.

Efficacy

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Efficacy

Early attempts at assessing the efficacy of depot antipsychoticsin preventing relapse in schizophrenia (mirror image studies)were criticised for methodological shortcomings. In the mirrorimage studies, patients receiving depot antipsychotics werefollowed up for a set period of time and the number and lengthof relapses were recorded. This result was compared to the number of relapses or days in hospital for an equal period of timebefore the depot medication was commenced. Six of these mirrorimage studies were examined by Davis et al (1994), who notedthat the studies had failed to statistically analyse days in hospital or oral medication before or after days on depot medication.When these analyses were carried out, a statistically significantdecrease in the number of hospitalised days was detected (see Table 1). For example, Denham and Adamson (1973) followed up 103 patients after they commenced depot antipsychotic medication.The mean duration of follow up was 24.8 months. The numberof days in hospital during this period was compared to an equalamount of time on oral medication before commencement of thedepot. The number of days in hospital was reduced from 8719to 1335, and the number of relapses from 191 to 50. Eleven ofthe 50 relapses occurred after a patient had failed to attendat a depot clinic.

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Table 1. Mirror image studies comparing number of hospital days on depot and oral medication

A major limitation of the mirror image design is that it isunclear how much of the detected benefit can be attributedto a pharmacological effect and how much may have been dueto spontaneous improvement independent of treatment or to extrasupport and supervision provided by the staff in the clinicwhere the depot medication was administered. Controlled comparisonsof oral and depot forms of antipsychotic medication have notshown a clear compliance benefit for depot forms (Rifkin etal, 1977; Schooler et al, 1980) but this has been linked tothe assumption that patients with schizophrenia who enrol inclinical trials may have higher compliance rates than the general population with schizophrenia (Kane & Kissling, 1991).

It must also be borne in mind when attempting to criticallyevaluate these studies or other work looking at depot medication,that the very nature of the patient group who may benefit mostfrom depot medication and depot clinics tends to contain uncooperative,poorly compliant patients. Research with such a group is fraughtwith difficulty but the patient sample studied must be representativeof those attending depot clinics. Once the limitations of the early studies are acknowledged, there is still valuable informationto be gleaned from them.

Compliance and indications for depot use

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Compliance and indications for...

Carpenter et al (1990) have examined the intervals at whichdepot antipsychotic medication should be administered to helpprevent relapse. The study attempted dose reduction throughlengthening the time between injections rather than a reductionof the dose per administration. He detected no differencesbetween patients with schizophrenia receiving 25 mg fluphenazineevery 2 weeks and those receiving the same dose every 6 weeks.The patients were, however, only followed up for 54 weeks, so delayed effects associated with an overall reduction in antipsychoticdose may have been missed. All participants attended at 2-weekintervals and those in the 6-week group received placebo attimes when their dose was not due, thereby ensuring that therewas little difference in the intensity of care delivered tothe two groups.

The use of depot medication requires compliance on the partof the patient, although attending for administration of medicationonce every 2 or 3 weeks may be preferable to taking medicationevery day or several times a day. In a review of medicationcompliance in schizophrenia, Falloon (1984) reported 80% compliance with depot medication and 60% with oral antipsychotics. Thisis comparable to compliance rates among other medical out-patients.Increasing the complexity of the regime has been shown to causedecreased compliance (Hulka et al, 1976). The seriousnessof the disorder (as perceived by the patient) is also linked to compliance and this has particular importance in the treatmentof schizophrenia. Appointments can best be seen as part ofan educative process using negotiation to develop and maintaincompliance.

In order to reduce non-compliance associated with non-attendanceat depot clinic, it is important to be able to identify thegroup of patients who are at risk of dropping out of clinicattendance. Heyscue et al (1998) looked at groups of patientsattending urban and rural out-patient clinics to have depot antipsychotic medication administered. Clinic attendance washigh in both groups, averaging 95%. This compliance rate ishigher than that reported in previous depot medication studiesand may be owing to reportedly thorough follow-up on missedappointments at both sites. The patient was understood to becompliant if the depot dose was administered within 4 days ofthe scheduled date. The only characteristic associated witha decreased compliance rate was a history of substance misuse.Substance misuse has previously been linked to poor compliancein other studies. Focusing on those with a history of substancemisuse and reacting quickly to early signs of their defaultingfrom treatment may be important in increasing overall compliancerates at the depot clinic.

Although switching to a depot medication has been used as anattempt to increase compliance, it is important to recognisethat there are other methods of helping to achieve this. Turnerand Vernon (1976) reported on using telephone prompting toboost attendance at the first out-patient appointment afterdischarge. Considerable success was reported in this study inincreasing the percentage of patients who attend a first appointmentthrough the use of telephone prompting. The advantages of assigningstaff to this prompting were stressed. A long waiting periodwas associated with non-attendance, as was chronic illnessand poverty. Burgoyne et al (1983), however, were unable to replicate these results and concluded that earlier apparentimprovement caused by telephone prompting may in fact havebeen related to socioeconomic factors (having a telephone).Better compliance with aftercare in general after admissionto a psychiatric unit is associated with an increased numberof previous hospitalisations, a longer stay and less denialof need for medication and other treatments.

Patients not meeting these criteria, especially those with ahistory of substance misuse, may be best served at dischargewith a referral to a depot medication clinic. Increasingly,however, patients are receiving oral atypical antipsychoticmedication as first-line treatment. Is there a case to be made for greater use of depot typical medication in patients at higherrisk of non-compliance or is the non-compliance associatedwith troublesome side-effects and cognitive deficits that mayrespond better to atypical medication?

Cost-benefit analysis

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Cost-benefit analysis

Using a decision tree analysis model Glazer and Ereshefsky (1996) have looked at treatment selection for ‘revolvingdoor’ patients with schizophrenia. In the analysis, theexample of a 29-year-old with schizophrenia, hospitalised for30 days after a relapse, is taken. Three pharmacological optionswere considered before discharge: typical oral drug, typicaldepot drug and atypical oral drug. Five sets of cost and outcome combinations were considered. The results suggested that switchingto the depot route in a patient with a history of relapsesand readmissions could reduce total direct treatment costsby US$650-2500/year compared with an atypical oral drug andby US$460-1150/year when compared with an oral typical drug.However, a sixth set of assumptions was also considered: inthis scenario a compliance rate of 80% was selected for theatypical oral drug (equal to depot) (in the five earlier scenariosthe compliance rate for the atypical oral agent had been setat 65% as against 55% for the typical oral agent). A 25% reductionin wholesale price of the atypical agent was also assumed.In this scenario, treatment with the atypical oral agent wouldcost US$700 less than with depot medication and US$1860 lessthan with a typical oral agent. There are, however, severallimitations associated with a model like this. Primarily, themodel rests on assumptions about a ‘typical patient’.Although different combinations of costs and outcome were factoredinto the model, it cannot of course represent the full rangeof variables associated with outcome. There are also some questionsas to whether findings from a cost—benefit analysis canbe generalised from one country to another, given the differencesbetween health care systems (including differences in the thresholdat which readmission is considered and differences in admissionduration rates). The cost—benefit outlined above of switchingto an oral typical drug is dependent on an assumed increase in compliance.

Running a depot clinic

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Running a depot clinic

With a better side-effect profile than traditional drugs andthe capacity to improve the cognitive deficits associated withschizophrenia it is reasonable to assume, however, that compliancerates will improve with atypical antipsychotics. It may bepossible to increase compliance rates still further if someof the lessons learned in depot clinics are applied to the administration of atypical oral medication. Delays to firstappointment after discharge should be administered. Effortsshould be made to limit frequent changes of staff at the clinicto allow relationships to be built up and to facilitate earlydetection of impending relapse. The development of an outreachservice with a clear response policy to non-attendance or other possible signs of deterioration should be attempted. Enquiriesand examination for medication side-effects should be conductedat each assessment and the use of structured scales such asthe Abnormal Involuntary Movement Scale (AIMS, Guy, 1976) shouldbe considered. It is important that appointment intervals shouldnot be solely dictated by medication administration. This isespecially important if longer dosage intervals are being used.Finally, prompt medical review should be available for thosepatients who are relapsing or expressing dissatisfaction withtheir treatment. Medical review should also be arranged forthose patients showing an inadequate response to treatment(including refractory negative symptoms, cognitive deficitsand poor quality of life).

Conclusions

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Conclusions

It is clear that some patients fare poorly on oral antipsychoticmedication and the future introduction of depot atypical antipsychoticswill be a significant addition to treatment options. At present,typical antipsychotic depots retain their place in the armamentariumbut increasing numbers of patients are being switched to oralantipsychotic agents. Important lessons have been learned throughthe use of depot clinics and there are several ways in whichthe service provided can be improved. The skills and experience associated with these clinics can be put to best use by incorporatingthem into maintenance medication clinics, thereby helping tomaintain compliance and reduce relapse rates for those takingoral atypical medication as well as those continuing to takedepot medication.

References

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