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Department of Psychiatry, Hillside Hospital, Division of Long Island Jewish Medical Center, Glen Oaks, NY 11004, USA
b
Institute of Psychiatric Clinic, University of Trieste, Via S. Cilino 16, 34126 Trieste, Italy
c
Institute of Psychiatric Clinic, Via Liguria, 13, Cagliari, Italy
d
Psiquiatria, Alcale 152, 28028 Madrid, Spain
e
Dept. Pharmaceutical Sciences, University of Modena, Via Campi 183, 41100 Modena, Italy
f
Dept. of Biological Psychiatry, Innsbruck Univ. Clinics, Anichstrasse 35, A-6020 Innsbruck, Austria
g
Rheinische Landesklinik, Psychiatrische Klinik der Heinrich-Heine-Univ. Dusseldorf, Bergische Landestrasse 2, 4000 Dusseldorf, Germany
h
SCT Hans Hospital, Dept. 2, 4000 Roskilde, Denmark
i
Hopital
Paul Brousse, 12 Av. P.V. Couturier, 94804 Villejuif, France
j
Munchen, Ismaningerstrasse 22, 81675 Munchen, Germany
Dept of Psychiatry, Technische Universitat
k
Dept of Psychiatry, Institute of Mental Health Research, University of Ottawa, 1145 Carling, Ottawa, Ontario, Canada KIZ 7 K4
l
Department of Psychiatry, University Hospital, S-751 85 Uppsala, Sweden
m
Dept. of Psychiatry, University of Brussels, Erasme Hospital, 808 Rue de Lennik, 1070 Brussels, Belgium
n
Center of Neuropharmacology, Institute of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy
o
Urb. El Bosque E /Cycas 78 C, 11405 Jerez de la Frontera, Cadiz, Spain
p
Western Psychiatric Inst. and Clinic, 3811 O Hara St., Pittsburgh, PA 15213, USA
Received 1 December 1996; received in revised form 30 April 1997; accepted 16 May 1997
Abstract
These guidelines for depot antipsychotic treatment in schizophrenia were developed during a two-day consensus conference held on
July 29 and 30, 1995 in Siena, Italy.
Depot antipsychotic medications were developed in the 1960s as an attempt to improve the long-term treatment of schizophrenia (and
potentially other disorders benefiting from long-term antipsychotic medication). Depot drugs as distinguishable from shorter acting
intramuscularly administered agents can provide a therapeutic concentration of at least a seven day duration in one parenteral dose.
The prevention of relapse in schizophrenia remains an enormous public health challenge worldwide and improvements in this area can
have tremendous impact on morbidity, mortality and quality of life, as well as direct and indirect health care costs. Though there has been
debate as to what extent depot (long-acting injectable) antipsychotics are associated with significantly fewer relapses and rehospitalizations, in our view when all of the data from individual trials and metaanalyses are taken together, the findings are extremely compelling in
favor of depot drugs. However in many countries throughout the world fewer than 20% of individuals with schizophrenia receive these
medications.
The major advantage of depot antipsychotics over oral medication is facilitation of compliance in medication taking. Non-compliance is
very common among patients with schizophrenia and is a frequent cause of relapse. In terms of adverse effects, there are not convincing
data that depot drugs are associated with a significantly higher incidence of adverse effects than oral drugs. Therefore in our opinion any
patient for whom long-term antipsychotic treatment is indicated should be considered for depot drugs.
In choosing which drug the clinician should consider previous experience, personal patient preference, patients history of response
(both therapeutic and adverse effects) and pharmacokinetic properties.
In conclusion the use of depot antipsychotics has important advantages in facilitating relapse prevention. Certainly pharmacotherapy
*Corresponding author. Tel: 139 2 20488331; Fax: 139 2 29403673;
e-mail: brunello@imiucca.csi.unimi.it
0924-977X / 98 / $19.00 1998 Elsevier Science B.V. / ECNP. All rights reserved.
PII S0924-977X( 97 )00045-X
56
must be combined with other treatment modalities as needed, but the consistent administration of the former is often what enables the
latter. 1998 Elsevier Science B.V. / ECNP.
Keywords: Depot antipsychotics; Schizophrenia; Treatment; Relapse
1. Introduction
These guidelines were developed during a two-day
consensus conference held on July 29 and 30, 1995 in
Siena, Italy. The need for this effort was based on the
recognition that the prevention of relapse in schizophrenia
remains an enormous public health challenge world wide
and that improvements in this area can have tremendous
impact on morbidity, mortality and quality of life, as well
as direct and indirect health care costs. Despite overwhelming evidence that non-compliance in medicationtaking is a major contributing factor to unnecessarily high
relapse rates, there is still inadequate attention being paid
to strategies which can enhance medication acceptance and
adherence, ranging from better psychoeducation directed at
patients and families to the more extensive use of depot
antipsychotic administration. Estimates suggest that in
many countries throughout the world fewer than 20% of
individuals with schizophrenia receive long-acting injectable medication. It is hoped that the promulgation of clear
and concise guidelines for the use of depot drugs will help
to remedy one important aspect of this problem.
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Although non-compliance is very common among patients with schizophrenia, detection is often difficult. In
addition, though non-compliance is a frequent cause of
relapse, not all relapses are the consequence of noncompliance. Even full medication compliance, as insured
by the regular administration of depot neuroleptics is not a
guarantee of a relapse free state. As reviewed by Schooler
(1985), a series of studies that compared depot and oral
neuroleptic administration found relapse rates on depot
drugs that ranged between 8 and 40% during 10 to 24
months. These figures suggest that relapse cannot be taken
as a reliable marker for non-compliance because relapse
occurs in patients for whom compliance can be documented by depot medication administration. Depot neuroleptics do not completely prevent non-compliance. What
depot administration insures is that patients have received
medication and that non-compliance, defined as failure to
return for a scheduled injection, is immediately detected.
With oral medication, failure to take medication may not
be detected until some time after it has first occurred and
often not until the resulting relapse.
Another problem with the use of relapse to define
non-compliance is that even if schizophrenia patients are
non-compliant, relapse may not occur for some time after
medication has been discontinued. Hogarty et al. (1974)
reported a cumulative relapse rate of 80% on placebo over
24 months that is linearabout 3% a month. McEvoy et al.
(1984) documented the differences between relapsers who
are compliant with medication and those who are not.
Non-compliant relapsers have more classic psychotic
symptoms of schizophrenia and show a gradual onset of
symptoms as would be expected from data regarding
placebo relapse. Compliant patients show a more rapid
onset of symptoms and prominent affective symptoms.
Steingard et al. (1994) found that compliant patients who
relapsed improved during hospitalization regardless of
whether they received additional medication or not.
All of these factors relapse among compliant patients,
the variable time course of relapse among non-compliant
patients, the potential differences in the nature of relapse
for compliant and non-compliant patients and the fact that
response in compliant relapsers may not be a function of
medication changes makes the use of relapse as the sole
marker for non-compliance unwise although it is clearly
the outcome variable of greatest interest. The compliance
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2. Depot antipsychotics
What are depot drugs? So-called depot antipsychotic
medications were developed in the 1960s as an attempt to
improve the long-term treatment of schizophrenia (and
potentially other disorders benefiting from long-term antipsychotic medication). Depot drugs as distinguishable from
shorter acting intramuscularly administered agents can
provide a therapeutic concentration of at least a seven day
duration in one parenteral dose. The depot antipsychotics
are esters formed between the alcohol group of the drug
and a long chain of fatty acids (enantic, decanoic, palmitic,
and undecylenic acid), and this ester is dissolved in oil
(sesame oil or Viscoleo). Antipsychotics in themselves are
fat soluble, but the esterification increases this fat solubility a thousand fold, the longer the carbon chain, the
more solubility is increased.
The ester is released from the oil phase by slow
diffusion into the body water phase. The higher the fat
solubility, the slower the release. Upon release from the
oil, the ester is either immediately hydrolysed or distributed to other tissues and then hydrolysed. The goal is to
obtain a sufficiently constant delivery of the drug from the
depot, so that the serum level is kept as constant as
possible between injections.
The type of esters and oil vehicles of available depot
antipsychotics is seen in Table 1.
2.1. Pharmacokinetics
Table 1 (Barnes and Curson, 1994) provides a summary
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Table 1
Dosage and pharmacokinetic parameters of depot antipsychotic drugs
Preparation
Antipsychotic
group
Vehicle
Equivalent
doses a (mg)
Dose q2w
equivalent to
chlorpromazine
100 mg per day b
Test dose
Recommended
dose (mg)
Maximum
dose (mg)
t max
t ]1 c
Fluphenazine
decanoate d
Flupenthixol
decaonate e
Zuclopenthixol
decaonate
Pipothiazine
palmitate
Haloperidol
decaonate
Fluspirilene
Phenothiazine
(piperazine ring)
Thioxanthene
Sesame oil
25 q2w
10 mg
12.5100 q25w
824 h
14 d
Viscoleo
40 q2w
16 mg
12.5 (6.25 in
elderly)
20
20300 q24w
400 qlw
37 d
17 d
Thioxanthene
Viscoleo
200 q2w
80 mg
100
200400 q24w
600 qlw
47 d
19 d
Phenothiazine
(piperidine ring)
Butyrophenone
Coconut oil
50 q4w
20 mg
25
50100 q4w
200 q4w
1224 h
1516 d
Sesame oil
100 q4w
30 mg
50
5300 q4w
39 d
21 d
Phenybutylpiperidine
Aqueous
suspension
NA
NA
28 q1w
20 q1w
2472 h
over 72 h
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2.1.1. Advantages
Depot antipsychotics have several advantages over oral
medication, the major one being facilitation of compliance
Table 2
Controlled trials comparing different fixed doses of some depot antipsychotic drugs
Drug / Dose (mg)
FD 1.255
FD 2.510
FD 12.550
56%
24% Kane et al., 1983; Kane and Borenstein, 1985
14%
FD 510
FD 2550
22%
20% Marder et al., 1987; Marder, 1994
FLUD mean512
FLUD mean525
32%
10% Johnson et al., 1987
FD mean53.8
FD mean525
20%
14% Hogarty et al., 1988
HD
HD
HD
HD
60%
25% Kane, 1986
23%
15%
25
50
100
200
FD 2.510
FD 12.550
29%
20% Levine et al., 1980
FD5fluphenazine decanoate.
FLUD5flupenthixol decanoate.
HD5haloperidol decanoate.
2.1.2. Disadvantages
The potential disadvantages of depot drugs include
patient reluctance to accept injections or a sense of being
overly controlled. In addition, there is a fear on the part of
clinicians and sometimes patients that if adverse effects do
occur, they will be more difficult to manage because of the
inability to rapidly discontinue the medication.
Some clinicians and patients also continue to believe
that certain adverse effects may be more common with
depot drugs than with oral drugs. In the experience of the
panel, these disadvantages are exaggerated or insignificant.
If clinicians are patient in explaining the potential benefits
of depot drugs and can work with the patient to at least try
one or two injections (and if the injections are given
skillfully), the overwhelming majority of patients can
overcome any initial trepidation. The perceived loss of
control is more imagined than real and there are many
other areas of every day life where patients have ample
opportunity to become more autonomous without risking
psychotic relapse and its consequences.
In terms of adverse effects, there are not convincing data
that, when comparisons are made of equivalent dosages
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3. Conclusions
The prevention of relapse in psychotic illness and
particularly schizophrenia is an important public health
goal. The use of depot drugs has important advantages in
facilitating relapse prevention. Certainly pharmacotherapy
must be combined with other treatment modalities as
needed, but the consistent administration of the former is
often what enables the latter.
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