THERAPY

Depot antipsychotics - an underutilised option?

-Rodger Hal/-

Although antipsychotics have been available since 1956, with depot preparations available since 1960, there are still great differences in the prescribing habits of psychiatrists. At the 'Schizophrenia: Exploring the Spectrum of Psychosis' 3rd International Conference [Vancouver, Canada; August 1994], several speakers felt that depot anti psychotics are underutilised. Research should focus not only on developing new compounds, but also on how to deliver the antipsychotic molecule in a way that is safe and reliable. said Dr J Jeffries of the University of Toronto, Canada.

Misunderstanding of pharmacokinetic data, prescribing fads, worries about adverse effects or problems with compliance can all lead to suboptimal therapy. In patients with schizophrenia, suboptimal therapy increases the likelihood of relapse and also the personal loss, societal disruption and monetary cost.

Depot preparations underuti&ed Drs Gary Remington and Martha Adams from

the Clarke Institute of Psychiatry, Toronto, Canada, feel that the investigation of depot anti psychotics has been neglected. even though they have been available for 30 years. Although depot preparations are equally effective without a higher incidence of adverse effects, they are underutilised.

Only about 5% of patients with schizophrenia in the US and about 40% of such patients in the UK are currently receiving depot preparations. At Dr Jeffries clinic in Canada, 46% are receiving depot antipsy­chotics.

Drs Remington and Adams outlined several advantages of depot anti psychotics including: • pharmacokinctic aspects - bioavailabiiity., uuration

of action, etc • diminished relapse rates • improved compliance; although compliance cannot

be ensured. recognition of the problem is made easier and it is simpler to distinguish between noncom­pliance and treatment resistance

• avoidance of problems associated with abuse or overdose of these drugs. However, depot preparations also have disadvan­

tages, including: • difficulties in dose titration • the present lack of atypical anti psychotics in this type

of formulation • slow elimination; this can be a problem when serious

adverse effects such as neuroleptic malignant syndrome arise.

Factors in using depot antipsychotics Dr W Glazer from the Yale School of Medicine,

Connecticut, US, said that physicians' criteria for selecting patients for depot antipsychotic therapy are vague and undeveloped. This theme was also endorsed by other presenters, and factors to consider in using depot anti psychotics were discussed. Is there a committed 'team' and an organised programme?

Medical, nursing and support staff, all need to be committed to the success of a Depot Clinic. Patients also need education, encouragement and support.

0156-2703I94I0954-OO131$01.rxP Adls IntIImatIonat Umlted 1994. All rights reserved

Simplification Using a depot preparation means that, on a day to

day basis. dosage regimes are much less complex and more convenient for the patient. Simplification also helps compliance. Compliance

Physicians tend to concentrate on the negative theme of noncompliance in selecting patients for depot therapy. Noncompliance is a weak indicator for selecting patients for depot therapy because it cannot be predicted or identified accurately, and it occurs frequently. Using depot preparations from the earliest stages of therapy can help prevent compliance problems occurring. Suitability for a self-injection programme

Some patients realise that their noncompliance is a problem, yet do not wish to keep returning to a clinic for injections. After an education course, suitable patients who have reasonably stable disease. can self-inject said Dr Jeffries. Patients attending his centre have been self-injecting successfully since 1980 and several dozen patients are now in this nrOPr:lm • 0-------

Acute or initial treatment Oral preparations are not appropriate for some

patients during an acute attack, and these patients should be started on depot preparations. Injections of short-acting anti psychotics can be used until effective blood levels are obtained from the depot.

Examples of depot preparations available The availability of depot anti psychotics varies

around the world. This is one of the reasons for the different rates of utilisation of depot injections in different countries.

US Canada Rest of world

~ [ProIixin N) ~ [Modecate" ) ~

HIIopeI idol IHaIdoI LAN) ~ [HaIdoIN] ~ ~ [PIportiIN]

Pipolhiazi 18 [PIportiI'" )

~ [FIuanxolN)

~01 [FIuanxoIN]

FIusP.!iIene [imapN)

FIusp!jIene [Imap'")

ZucIopenIhixoI (CIopixoIN )

~01 (CIopixoIN]

Perpherlazin! [Trilafon Dec '"I Oxyprotepine

13

THERAPY

D p t antip ch ti - confirmed

When patients first commence on depot preparations, oral preparations can be used for prophylaxis while the dose of the depot is titrated. Rejrrletorinas 10 I1wIIIINIIl

Refractoriness is an indicator for the initiation of depot treatment - depot antipsychotics are superior to oral antipsychotics in 'revolving-door' patients, e.g. those who frequently swing between remission and relapse. Depot therapy can be considered for a patient who in the past year has suffered continuous positive symptoms and been admitted for treatment 2-3 times. The development of atypical antipsychotics suitable for depot injection will hopefully benefit patients currently resistant to treatment. Ab., ... EJ1«tr

The assumption that adverse effects, particularly tardive dyskinesia and neuroleptic malignant syndrome, are more frequent or more serious with the depot route is not backed up by clinical data. Dr Jeffries said that, in his clinical experience, and in almost aU published studies, depot preparations were both more effective and caused fewer adverse effects than oral preparations.

Extrapyramidal symptoms can occur at different times with different dru£s, e.g. perhaps after 3-4 days with fluspirilene [Imap ], but after 7-10 days with fluphenazine [Modecate"']. Symptoms also vary in time to peak and in level of intensity with different drugs. The antiparkinsonian regimen can be tailored to the patient's pattern of adverse effects. In practice, induration, tracking or bruising are generally not problems with depot preparations. IndividuDl rights

Preoccupation with individual rights, particularly in North America, sometimes clouds the logic of clinical decision-making, according to Dr Glazer. In practice, reduction in autonomy is not an issue with patients, he says. Depot preparations have a useful role in treating remand patients and in other situations where it is important to be certain that the patient is receiving hislher medication.

Few dilratDLB bttween available preparatiom The view is generally held that all the

commercially available depot antipsychotics are equivalent with respect to clinical response. A review of double-blind studies comparing those depots commercially available in North America confirms this, according to Drs Remington and Adams.

One study presented at the conference also found little difference between 4 different depot preparations.

Dr G Saad of Amman, Jordan, presented the results of his retrospective comparative study of 4 depot antipsychotics used to treat 185 (122 male, 63 female) outpatients with acute or chronic schizophrenia in his own practice. Patients had to have been seen at least once in the 6 months before commencing treatment with the depot preparation, and treatment had to continue for at least 12 weeks. The age distribution and psychological profile of the 4 groups was similar.

Dr Saad found that the age or sex of the patient, or type of p~ychosis, were not important factors and that all 4 preparations were equally effective [see table]. Symptoms persisted for 20-33% of his patients. Dr Saad felt that the unavailability of newer 'atypical' agents was a problem for these patients.

Ccmedk ...... aIfeded by depot tberapy? Dr Jeffries reported that 57% of his patients receiving

oral preparations of antipsychotics were taking benzodiazepines, compared with 24% of those receiving depot injections. He was unsure of the reason for this, but possibly the patients on oral treatment were skipping some doses and feeling ·unwell'. In contrast, 64% of those receiving depot preparations were receiving antiparkinsonian medication, compared with only 37% of those treated with oral medications. It was suggested that this could have been a function of the small range and high potency of antipsychotics available as depot preparations, or those receiving depot preparations may have had more serious illness. The use of antidepressants and 'mood stabilisers' was similar in both groups.

Future deveIopmetds with depot preparations According to Dr Jeffries, possibilities for future

development include: • the formulation of depot products containing less

'toxic' antipsychotic drugs, e.g. atypical agents • mini-depot preparations that act for 3-7 days, and

which can be used as bridging therapy • longer acting depot preparations for stable, reliable

patients. • long-acting oral or implant preparations.

The frrst company to make a depot preparation of a suitable atypical antipsychotic widely available will usefully increase the therapeutic options for the treatment of schizophrenia. However, the first atypical drug to be developed as a depot injection will probably not be clozapine because of the occurrence of agranulocytosis with this drug.

I11III7 ...

Table: Comparative tudy of depot antipsychotic treatment of outpatients

Drug Mean Mean frequency Improvement (% of patients) Extrapyramidal adverse dose (mg) of administration

(weeks) effec1s (% of patients)

None Mild Moderate Good

Auphenazine 35 2.9 26 35 25 14 55 decanoate

Haloperidol 75 3.8 19 21 44 16 42 decanoate

Zuclopenthixol 311 3 20 30 37 13 52 decanoate

Aupenthixol 59 3.2 34 19 41 6 56 decanoate

108ep 111141NPHARMA-