PRACTICAL THERAPEUTICS

Drugs 47 (5): 741-773. 1994 00 12-6667/94/0005-0741/$16.50/0 © Adis International Limited. All rights reserved.

Depot Antipsychotic Drugs Place in Therapy

John M. Davis, 1 Leor Metalon,2 Mark D. Watanabe3 and Lesley Blake1

1 Department of Psychiatry, University of Illinois, Chicago, Illinois, USA 2 School of Medicine, University of Illinois, Chicago, Illinois, USA 3 Department of Pharmacy Practice, University of Illinois, Chicago, Illinois, USA

Contents 741 742 742 743 743 7-13 744 745 746 746 747 747 747 754 754 754 754 755 755 755 757 761 762 763 764 767

Summary

Summary I. Methodological Considerations

1.1 Criteria for Relapse 1.2 Patient Noncompliance

2. Pharmacotherapeutic Considerations in Treating Schizophrenia 2.1 Antipsychotic Medication in Prevention of Relapse 2.2 General Properties of Depot Antipsychotics 2.3 Clinical Pharmacokinetics and Therapeutics

2.3.1 Bromperidol Decanoate 2.3.2 Clopenthixol Decanoate 2.3.3 Flupenthixol Decanoate 2.3.4 Fluphenazine Enanthate and Decanoate 2.3.5 Fluspirilene 2.3.6 Haloperidol Decanoate 2.3.7 Perphenazine Enanthate 2.3.8 Pipothiazine Palmitate and Undecylenate 2.3.9 Zuclopenthixol Decanoate

2.4 Depot Drug in Nonresponsive Patients 3. Current Treatment Issues

3.1 Progressive Nature of Relapse 3.2 Depot Versus Oral Medication 3.3 Targeted Treatment 3.4 Dosage Studies 3.5 Maintenance Medication and Psychosocial Treatment

4. Maintenance Implications and Future Research 5. Conclusions and Treatment Recommendations

The pharmacokinetics of depot antipsychotic medications are such that an intramuscular in­jection given at intervals of from 1 to 4 weeks will produce adequate plasma concentrations that are sufficient to prevent relapse over the dosage interval. Such medication is useful in patients who do not reliably take their oral medication. The pharmacokinetics and clinical actions of various depot formulations of antispychotic drugs have been extensively studied.

Unfortunately, patients who do not reliably take their oral medications are unlikely to volunteer

742 Drugs 47 (5) 1994

for controlled studies. This is because the same factors that influence a patient to not cooperate with the physician in taking the medication as prescribed will also interfere with their willingness to volunteer for research protocols. Thus, evidence from blinded controlled trials may not neces­sarily reflect the actual patient population at risk.

We feel that particularly important evidence of efficacy of depot vs oral medication comes from mirror-image studies. In these trials, the number of hospitalisations after initiation of depot medication is compared with that observed when the patient was solely taking oral medication. Studies of this type show that depot medication substantially reduces the rate of relapse.

There is considerable evidence about how long depot medications should be used. For many patients, depot medication to prevent relapse in schizophrenia should be used for the life of the patient. As the conventional antispychotic agents are replaced by a new generation of agents, the need for depot formulations will continue, and the knowledge gained about the current formula­tions should transfer to future generations of drugs.

This paper discusses the role of depot mainte­nance antipsychotic medication and the treatment of chronic relapse in schizophrenia. Depot medica­tion is generally administered by intramuscular in­jection, and its pharmacokinetics are such that a single injection will last, with adequate plasma concentrations, roughly 1 week to 1 month, de­pending on the formulation.

Because a great many patients have compliance problems and do not reliably take their oral medi­cation, the depot formulation provides a better way to administer medication, since all that is required is that the patient attend the clinic for the injection. The principal role of depot medication is to ensure patient compliance. The most common cause of noncompliance is forgetfulness; however, patients may have a variety of reasons for not taking their medication, including adverse effects and pes­simism about the likelihood of improvement (Tegeler & Lehmann 1981). To determine the sig­nificance of using depot medication as a means of ensuring compliance, the importance of continu­ous maintenance medication and its indications for use are examined.

1. Methodological Considerations 1.1 Criteria for Relapse

The great majority of investigators use different criteria or definitions of relapse, making direct comparisons between studies difficult, if not im­possible. Therefore, comparison of absolute re­lapse rates should be avoided. On the other hand, it is accurate to quantify and analyse the data of

each study compared with its control group, thus employing an internal control.

It is pertinent to discuss the ethical and practical problems of doing maintenance trials. The most disastrous outcome is the occurrence of relapse with violence, suicide or extremely psychotic behaviour that has a negative impact on the pa­tient's home or job. The next most serious conse­quence is hospitalisation. Somewhat less pro­found, but still unfortunate, is an increase in psychotic behaviour necessitating the removal of the patient from the study. These events are varied in nature and magnitude, and are essentially never quantified as an outcome of a clinical trial.

To a fair degree, aftercare now is able to prevent rehospitalisations and disruptive psychotic epi­sodes. In the past, the relapse rates were as high as 10 or 15% per month (Davis 1985). Now, with more adequate treatment, the rate is getting low enough that many investigators consider it too rare for statistical analysis. Since extreme psychotic behaviour, hospitalisations and major clinical re­lapses are clinically meaningful, however, we feel investigators should report these rates so we can pool the data. Then, through the use of meta-anal­ysis (Mantel & Haenszel 1959), we can calculate the relapse rate and hospitalisation rate over time for patients on antipsychotic medications.

Since it is undesirable to keep the patient in the placebo group to the point where he or she has had a full-blown relapse and is consequently exposed to its associated negative events, most experimen­tal designs try to limit this consequence by using

Depot Antipsychotic Drugs

other end-points to measure the effect of the drugs. These surrogate end-points can include minor pro­dromal nonspecific symptoms, minor exacerba­tions of psychotic symptoms, or major exacer­bations of psychotic symptoms that fall short of a full-blown relapse with hospitalisation.

There is a good correlation between the various levels of relapse, whether it be prodromes, minor symptom worsening, major symptom worsening or hospitalisation (Carpenter et al. 1990; Herz et al. 1990, 1991; Marder et al. 1987). Drug-placebo differences show up no matter which indices are taken. It is quite possible that frank hospitalisa­tions may not parallel in every respect the surro­gate end-points used because surrogate end-points are valid for statistical purposes, while hospital­isations may not be numerous enough to warrant statistical treatment.

1.2 Patient Noncompliance

Even in general medicine some patients have difficulty remembering to take their medication. In psychiatry, this trait is further complicated by the patient's mental illness. Many patients are not fully recovered and have some degree ofresidual posi­tive and negative symptoms that may interfere with compliance. Unfortunately, noncompliant patients are a difficult population in which to do research. The same factors that cause compliance problems in these patients often cause them to be uncooper­ative study participants or to not volunteer for re­search. In a sophisticated research laboratory where patients receive a large variety of experi­mental procedures (such as endocrine tests), only cooperative patients are studied.

We parenthetically note that, in general, only a minority of clinical decisions are based on results of controlled clinical trials. The great majority of decisions a physician makes in clinical practice is based on education, common sense, intuition and clinical experience. It is false to assume that every clinical decision can be based on a controlled clin­ical trial, since this information is often unavail­able. For example, ethical considerations make certain trials impossible or impractical.

743

2. Pharmacotherapeutic Considerations in Treating Schizophrenia 2.1 Antipsychotic Medication in Prevention of Relapse

Soon after antipsychotic drugs were discovered, many noncomparative, unblinded clinical studies and case histories established that most patients experienced relapse upon the withdrawal of phar­macotherapy. This clinical observation was sup­ported by 35 randomised, double-blind studies that reported the number of patients who relapsed on placebo versus maintenance medication (Davis 1975).

We initially summarised these data and updated them in figure 1 (Adelson & Epstein 1962; An­drews et al. 1976; Baro et al. 1970; Blackburn & Allen 1961; Caffey et al. 1964; Cheung 1981; Chien & Cole 1975; Clark et al. 1971, 1975; Dia­mond & Marks 1960; Ekland & Forsman 1990; Engelhardt et al. 1967; Freeman & Alson 1962; Garfield et al. 1966; Gross 1974; Gross & Reeves 1961; Hershon et al. 1972; Hirsch et al. 1973; Hogarty & Ulrich 1977; Kinross-Wright & Charalampoud 1965; Leff & Wing 1971; Levine et al. 1980; Melnyk et al. 1966; Morton 1968; Nishikawa et al. 1982; Prien & Cole 1968, 1969; Prien et al. 1969; Rassidakis et al. 1970; Rifkin et al. 1977; Ruskin & Nyman 1991; Schiele 1975; Shauver et al. 1959; Troshinsky et al. 1962; Whita­ker & Hoy 1963; Wistedt 1981).

Of the 3720 patients, 55% receiving placebo ex­perienced relapse, compared with only 21 % re­ceiving maintenance medication. Our own meta­analysis of the data found the difference highly significant (X2 = 483; df = 1; P < 10-107). In patients in full remission, antipsychotic medications have a prophylactic effect, and in those in partial remis­sion, these medications maintain the patients' cur­rent state. In the latter case, symptomatology worsened substantially with drug discontinuation. The relapse rate differs markedly from study to study, partly because patients studied for longer periods of time are more likely to have experienced relapse and also because the definition of relapse differs across studies.

744 Drugs 47 (5) 1994

Fig. 1. Meta-analysis of double-blind. controlled studies comparing antipsychotic drugs with placebo for the prevention of relapse in schizo­

phrenia (Chalmers & Lau 1993; Woolf 1955). Left: The odds ratio. with a 95% confidence interval. of antipsychotic drugs in preventing relapse

in comparison to placebo. An odds ratio of 1 (vertical line) indicates the drug is no different from placebo. An odds ratio less than 1 (left of the

line) means that there are fewer relapses in the drug-treated group than with placebo. A 95% confidence interval that does not pass through

an odds ratio of 1 indicates that drugs prevent relapse to a statistically significant extent. Most. but not all. of the individual studies find a

significant effect. The bottom line indicates the 95% confidence interval for combined results. Right: A cumulative odds ratio that antipsychotic

drugs prevent relapse better than placebo. Studies are arranged in chronological order. with the study done on the earliest date at the top and

the most recent study at the bottom. The vertical line indicates an odds ratio of 1. The first study was almost statistically significant. After the

second study. the cumulative odds ratio (of both the first and the second studies) was clearly statistically significant and did not cross the

vertical line. Note also that the confidence interval was markedly decreased. The cumulative probabilities that the studies showed a statistically

significant reduction in relapse are as follows: first 2 studies = 10-3; first 3 studies = 10-4; first 4 studies = 10-7; first 5 studies = 10-15. This

is illustrated graphically by the increasingly narrow width of the confidence interval. Note that the width of the confidence interval decreases

progressively as more studies are performed. but after the fifth study the probability is essentially vanishingly small. This figure demonstrates

that there is absolutely no doubt that antipsychotic drug maintenance treatment prevents relapse. (Adelson & Epstein 1962; Andrews et al.

1976; Baro et al. 1970; Blackbum & Allen 1961; Caffey et al. 1964; Cheung 1981; Chien & Cole 1975; Clark et al. 1971; Clark et al. 1975; Diamond & Marks 1960; Ekland & Forsman 1990; Engelhardt et al. 1967; Freeman & Alson 1962; Garfield et al. 1966; Gross 1974; Gross & Reeves 1961 ; Hershon etal. 1972; Hirsch etal. 1973; Hogarty & Ulrich 1977; Kinross-Wright & Charalampoud 1965; Leff & Wing 1971; Levine

et al. 1980; Melnyk et al. 1966; Morton 1968; Nishikawa et al. 1982; Prien & Cole 1968.1969; Prien et al . 1969; Rassidakis et al. 1970; Rifkin

et al. 1977; Ruskin & Nyman 1991; Schauver et al. 1959; Schiele 1975; Troshinsky et al. 1962; Whitaker & Hoy 1963; Wistedt 1981).

2.2 General Properties of Depot Antipsychotics

Due to noncompliance with the prescribed ther­apy, many schizophrenic patients experience re­lapses. To reduce the risk of relapse, long-acting depot medications have been developed. Chemi­cally, depot antipsychotics are formed from esteri­fication of the classical antipsychotic agent by a fatty acid. These esters are much more lipophilic than the corresponding classical antipsychotic agent and are injected in an oily solution.

Because these esters have a high oil/water par­tition ratio, they are only slowly released from the site of injection into the circulation. For example, in rat studies, 80 to 95% of the total radioactivity

in the administered radio labelled depot antipsy­chotic agent remained in the injected leg (Curry et at. 1978).

Once the ester gets into circulation, it is rela­tively rapidly split by esterases present in many tissues, including blood and brain, liberating the parent compound. Since absorption is generally slower than drug elimination, a purely mathemati­cal pharrnacokinetic analysis predicts that the time to reach steady-state would be a function of the absorption rate constant, while the concentration at steady-state is a function of the elimination rate constant. Essentially, this model translates into prolonged times to reach peak plasma antipsy­chotic concentrations of the given drug, as well as

Depot Antipsychotic Drugs

extended elimination half-lives, especially after multiple injections.

For example, 2 formulations that are currently available in the US are the decanoate esters of fluphenazine and haloperidol. The time to reach peak concentrations following a single injection averages 0.3 to 1.5 days for fluphenazine decano­ate and 3 to 9 days for haloperidol decanoate. After a regimen of multiple injections given over a pe­riod of months, the elimination half-life of fluphenazine decanoate approximates 14 days, whereas that of haloperidol decanoate may reach 21 days (Ereshefsky et al. 1984; Reyntiens et al. 1982).

The advantage of using these preparations in the noncompliant patient becomes evident. The clini­cian no longer has to assume that the patient is conscientiously adhering to a daily oral regimen in order to assess medication response. Instead, the patient only has to remember follow-up appoint­ments in a clinical setting after a predetermined number of weeks, at which time compliance with the medication is assured.

General recommendations for patients who are candidates for depot antipsychotic pharmacother­apy include that they first be stabilised On the oral form of the medication. This strategy allows proper determination of whether the drug is appropriate for the patient in terms of therapeutic efficacy and tolerability. It is also important to start with a known oral dosage that induces clinical improve­ment and to use empirical guidelines for the COn­version of oral administration to estimated, thera­peutically equivalent depot dosage. Because of wide interpatient variability with respect to the plasma concentrations achieved after injections of depot antipsychotics, no clear guidelines have yet been established for the requirement of oral sup­plementation before reaching pharmacokinetic steady-state with the depot formulation alone.

The effects of pathophysiological and demo­graphic variables On the pharmacokinetics of depot antipsychotics have not been adequately re­searched. Although most available antipsychotic medications inherently undergo significant hepatic

745

metabolism, dosage adjustment is probably minor in patients with mild to moderate liver disease ow­ing to the rather slow release of free drug from the depot site. Likewise, renal dysfUnction would not be expected to influence the clearance of depot an­tipsychotics any more than with orally adminis­tered agents, in which clearance is more depend6l1t on adequate hepatic function. Geriatric patients may require up to a 50% reduction of standard an­tipsychotic dosages (Viukari et al. 1982). Smok­ing, which has been demonstrated to increase the clearance of oral antipsychotics (Ereshefsky et al. 1985), has a similar effect after depot administra­tion, which may necessitate the use of slightly higher dosages in patients who smoke (Ereshefsky et al. 1985).

Similarly, very few controlled studies have pro­vided convincing support for therapeutic drug monitoring of plasma concentrations during depot antipsychotic pharmacotherapy. One report used measurements of drug plasma concentrations to justify the use of loading dose regimens to reduce the amount of time required to reach steady-state after initiation of depot injections (Ereshefsky et al. 1990).

In general, the use of depot antipsychotics is considered relatively safe, and the development of adverse effects is limited, with the exception of extrapyramidal system reactions. Neuroleptic ma­lignant syndrome does rarely occur (Addonizo & Susman 1991), however, and this syndrome may be difficult to manage in a patient receiving depot antipsychotics because of the extended elimination half-lives of the administered drugs.

We will not discuss adverse effects, but refer the reader to the reviews of Marder (1984), Glazer and Kane (1992) and Glazer (1984).

2.3 Clinical Pharmacokinetics and Therapeutics

Table I summarises clinical pharmacokinetic parameters for a sample of depot antipsychotics that are available worldwide. There are shorter-act­ing depot antipsychotics used in Europe, e.g. clopenthixol acetate and fluspirilene, that do not require that patients be stabilised before initiation.

746 Drugs 47 (5) 1994

Table I. Clinical pharmacokinetics of depot antipsychotic medications

Drug Ester Vehicle Dosage (mg)/interval tmax hI! (days) Reference (weeks) (days) single dose multiple dose

Fluphenazine Decanoate Sesame oil 12.5-100/2-5 0.3-1.5 6-9 14 Ereshefsky et al. (1984)

Fluphenazine Enanthate Sesame oil 12.5-100/1-4 2-3 3.5-4.0 NA

Haloperidol Decanoate Sesame oil 20-400/4 3-9 NA 21 Beresford & Ward (1987)

Clopenthixol Decanoate Low viscosity 5Cl-60011-4 4-7 NA 19 Jorgensen & Overo vegetable oil (1980)

Flupenthixol Decanoate Low viscosity 10-50/2-4 7 8 17 Reynolds (1993) or vegetable oil palmitate

Pipothiazine Palmitate Low viscosity 50-200/4 10 NA 14-21 Reynolds (1993) vegetable oil

Bromperidol Decanoate Sesame oil 40-300/4 3-9 NA 21 Parent et al. (1983)

Perphenazine Enanthate Sesame oil 25-200/2 2-3 NA 4-6 Larsson et al. (1984)

Fluspirllene Aqueous 2-6/1 2 7 NA Janssen et al. (1970) solution of microcrystals

Abbreviations: tmax = time to reach peak plasma concantration; tl~ = elimination half-life; NA = not available.

These are used primarily for the management of acute psychotic episodes and acute exacerbation of chronic psychotic disorders, as opposed to long term maintenance pharmacotherapy. Charac­teristic pharmacokinetics of various depot antipsy­chotics are elucidated below.

2.3.1 Bromperidol Decanoate Bromperidol is a butyrophenone with general

properties similar to those of haloperidol. The pharmacokinetic parameters determined for the decanoate ester are derived from a study of 9 hospitalised patients with chronic psychosis re­ceiving a mean dosage of bromperidol decanoate 150mg intramuscularly every 28 days for up to 1 year (see table II) [Parent et al. 1983]. Steady-state plasma bromperidol concentrations were achieved after 3 months and approached a value of 8 ~glL. The plasma elimination half-life was approxi­mately 3 weeks. For the most part, the pharmaco­kinetics of this drug are similar to those of haloper­idol decanoate. McLaren et al. (1992) compared bromperidol with fluphenazine decanoate and ob-

served 6 relapses on the former and none with the latter.

2.3.2 Clopenthixol Decanoate A thioxanthine derivative, the decanoate ester

of clopenthixol, was found to have an apparent elimination half-life of 19 days after a multiple in­jection study in humans (Jorgensen & Overo 1980). The usual dosage interval is 3 to 4 weeks (Baastrup et al. 1993; Jorgensen & Overo 1980). Plasma concentrations may range from 10 to 100 ~glL as a result of a variety of doses (e.g. 50 to 600mg of the drug) and dosage intervals. However, no direct correlation between blood concentrations and clinical response has yet been established (Jor­gensen & Overo 1980).

Patients treated with c1openthixol decanoate show significant improvement on Brief Psychiatric Rating Scale (BPRS) ratings, depression and social adaptation while suffering few autonomic or neu­rological adverse effects (Carney & Sheffield 1973; Gravem et al. 1978).

Depot Antipsychotic Drugs

2.3.3 Flupenthixol Decanoate This depot formulation is a thioxanthine deriv­

ative injected intramuscularly in an oil solution ev­ery 2 weeks (Jorgensen & Overo 1980; Nymark et al. 1973). In the same study that examined clo­penthixol decanoate, Jergensen and Overo (1980) determined the apparent elimination half-life of flupenthixol decanoate to be approximately 8 days after a single injection and 17 days after multiple injections of 25 to 300mg doses. As with clopenthixol, a relationship between blood concen­trations and clinical response has not yet been found (Moller-Nielsen et al. 1973).

Flupenthixol decanoate has been shown to im­prove mood and has shown fewer extrapyramidal adverse effects when compared with fluphenazine decanoate (Carney & Sheffield 1976). There are no significant therapeutic differences between flu­penthixol decanoate and pipothiazine undecyl­enate, but significantly fewer adverse effects occur with flupenthixol. Carney and Sheffield (1973) showed that, compared with fluphenazine decano­ate or enanthate, fewer patients were readmitted with fewer adverse effects on flupenthixol decano­ate.

2.3.4 Fluphenazine Enanthate and Decanoate The phenothiazine fluphenazine enanthate dif­

fers chemically from the decanoate in that the par­ent fluphenazine molecule has been esterified with enanthic acid, a 7 -carbon fatty acid, imparting dis­similar pharmacokinetics from the decanoate (Pol­lack et al. 1964). The elimination half-life of the enanthate after a single dose [0.91ml (3.6mg)] is only 3.5 to 4 days and the therapeutic action per­sists for only 1 to 3 weeks (Bucci et al. 1970; Caffey et al. 1964).

On the other hand, the mean apparent half-life of fluphenazine decanoate is about 14.3 days, which suggests that the time to reach steady-state plasma concentrations approximates 4 to 6 weeks. For this reason, more clinicians are likely to prefer the decanoate form, which can be administered less frequently after steady-state concentrations have been achieved (Marder et al. 1990).

747

Furthermore, our review of 5 well controlled studies comparing the 2 depot forms of fluphenaz­ine indicates that the decanoate form causes slightly fewer adverse effects than its enanthate counterpart (Bankier et al. 1968; Barsa & Saunders 1967; Haider 1968; Kurland et al. 1970; Revaris et al. 1965). Of note, smoking has been reported to increase fluphenazine decanoate clearance by a factor of 2.33 (Ereshefsky et al. 1985), thereby po­tentially affecting measured blood concentrations.

We have performed a small pharmacokinetic study measuring unchanged fluphenazine in plasma and noted high plasma concentrations fol­lowing the injection (Chang et al. 1985). After day 1, plasma concentrations were lower and reason­ably constant throughout the dosage interval. It has been noted that patients often have extrapyramidal symptoms (EPS) or adverse effects in the fIrst few days following the fIrst dose (Hogarty & Ulrich 1977).

2.3.5 Fluspirilene This drug is a diphenylbutylpiperidine deriva­

tive and differs from other depot medications in that it is not bound to a carrier to achieve delayed release. Other long-acting antipsychotic prepara­tions are esterifIed with a fatty acid to achieve their extended elimination half-life. However, fluspiri­lene is a hydrophobic compound that is directly administered intramuscularly as a micronised aqueous suspension, allowing only gradual ab­sorption of active drug from the injection site. In addition, injected fluspirilene is immediately ac­tive without the need for preliminary chemical con­version. Thus, unlike other depot antipsychotic agents, its absorption and action are regular and reproducible from one injection to the next.

After a single dose, the elimination half-life ap­pears to be about 7 days, with about 70% of the drug excreted in 27 days (Chouinard et al. 1986). This pharmacokinetic profile allows for once­weekly administration, which closely parallels the observed length of clinical effectiveness of fluspirilene (Svestka et al. 1971).

Fluspirilene has been shown to be very effective in improving both psychotic symptoms and social

Tabl

e II.

Effi

cacy

of v

ario

us d

epot

med

icat

ions

in th

e tre

atm

ent o

f sch

izop

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ia

--.l

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0

0

Ref

eren

ce

Stu

dy

No.

D

rug/

dose

(m

g)/ro

ute

Inte

rval

D

urat

ion

Out

com

e C

omm

ents

de

sign

pi

s

Ste

rkm

ans

et

NC

22

F

lusp

irile

ne 5

-11.

25 1

M

1wk

3m

os

Hig

hly

sign

ifica

nt im

prov

emen

t in

psyc

hotic

A

t opt

imum

dos

e, m

ost f

requ

ent A

Es

al.

(196

9)

sym

ptom

s vs

pre

viou

s ag

ents

, pr

imar

ily

wer

e fa

tigue

(4

pts)

and

EP

S (

5 pi

s);

All

halo

perid

ol

pis

mal

e

Bar

o e

tal.

NC

/DB

vs

38

Pen

flurid

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0-40

PO

1w

k 1

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In N

C p

hase

sta

tistic

ally

sig

nific

ant

NC

stu

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r 8 m

as c

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(197

0)

plac

ebo

impr

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n ps

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tic s

ympt

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vs

penf

lurid

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revi

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treat

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t, pr

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pts

penf

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s pla

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pis

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bet

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Cho

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prov

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75

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70%

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970)

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sco

res

16 fl

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al

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Fl

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twee

n gr

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, sig

nific

ant B

PR

S in

crea

ses,

flu

spiri

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pts

had

EP

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luph

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25-1

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M

but n

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its a

nd

All

pts

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ale

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nd o

n a

5-po

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eval

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Zwan

ikke

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53

Flu

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1-1

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s ef

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ive

as p

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D

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ased

EP

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s pr

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. (1

971)

tre

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PS

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ptom

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75%

of p

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al.

(197

2)

seve

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and

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PR

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10.

35 1

Mb

1wk

15

wks

F

lusp

irile

ne s

igni

fican

tly r

educ

ed m

enta

l N

o si

gnifi

cant

diff

eren

ce;

PIs

all f

emal

e,

Ver

eeck

en

Pen

flurid

ol 8

3.0

POb

1wk

dist

ortio

n. P

enflu

ridol

Sig

nific

antly

am

elio

rate

d pr

evio

usly

trea

ted

with

flus

piril

ene

(197

2)

affe

ctiv

e im

pove

rishm

ent a

nd h

allu

cina

tions

. S

igni

fican

tly g

reat

er im

prov

emen

t in

occu

patio

nal t

hera

py w

ith p

enflu

ridol

Ver

eeck

en e

t D

B

26

Flu

spiri

lene

10.

77 1

Mb

1wk

11 w

ks

Sta

tistic

ally

sig

nific

ant d

eter

iora

tion

in s

peec

h,

Pip

othi

azin

e gr

oup

had

sign

ifica

ntly

al

. (1

972)

m

ood,

faci

al e

xpre

ssio

n, g

ener

al in

form

atio

n m

ore

AE

s vs

flus

piril

ene

grou

p; A

ll pt

s tl

P

ipot

hiaz

ine

2w

ks

i:! un

decy

lena

te 1

03.8

1M

b w

ith p

ipot

hiaz

ine

unde

cyle

nate

vs

prev

ious

fe

mal

e, p

revi

ousl

y tre

ated

with

oa

'" flu

spiri

lene

trea

tmen

t flu

spiri

lene

""'- '-

l --.

. ~ .... \0

~

Ban

kier

et a

l. D

B

22

Flu

spiri

lene

6.7

1M

b 1w

k 4

mo

s N

o st

atis

tical

diff

eren

ce b

etw

een

grou

ps,

both

E

PS

sig

nific

antly

gre

ater

with

0

(197

3)

Trif

luop

eraz

ine

42.5

PC

b bi

d ha

d hi

ghly

sig

nific

ant i

mpr

ovem

ent o

ver

triflu

oper

azin

e vs

flusp

irile

ne

.g ~

prev

ious

trea

tmen

t >

B

akke

(19

73)

DB

INC

38

5 F

luph

enaz

ine

enan

that

e 2

wks

=

V

arie

s by

In

DB

com

paris

on,

adeq

uate

effe

cts

in ~75%

All

drug

s as

sess

ed in

non

com

para

tive

a.

'"0

2.5-

75 1

M

drug

, up

of

pts

with

acu

te p

sych

osis

rec

eivi

ng lo

w d

ose

stud

y fo

r S30

mos

, and

add

ition

'" '<

to

30

mos

flu

phen

azin

e en

anth

ate

and

perp

hena

zine

, pe

rphe

nazi

ne e

nant

hate

and

low

dos

e n

Per

phen

azin

e en

anth

ate

2 w

ks

::r

0 10

-300

1M

w

ith n

o re

laps

es,

no s

igni

fican

t diff

eren

ces

fluph

enaz

ine

enan

that

e al

so c

ompa

red

a.

n

Flu

phen

azin

e en

anth

ate

2w

ks

betw

een

grou

ps;

Bot

h flu

phen

azin

e D

B fo

r :1:

40 d

ays;

Hig

h do

se

~ 2O

Q-5

00IM

de

cano

ate

and

flusp

irile

ne w

ere

pote

nt

fluph

enaz

ine

enan

that

e us

ed fo

r gra

ve

(Jq

an

tipsy

chot

ic a

gent

s w

ith e

ffect

s si

mila

r to

acut

e ps

ycho

ses,

mai

nly

acut

e '"

Flup

hena

zine

dec

anoa

te

2-3

wks

flu

phen

azin

e en

anth

ate

and

perp

hena

zine

sc

hizo

phre

nia

and

man

ia, a

nd m

assi

ve,

2.5-

75 1

M

enan

that

e; A

utho

rs w

ere

'inse

cure

' abo

ut

chro

nic

schi

zoph

reni

c co

nditi

ons;

F

lusp

irile

ne 4

-20

1M

1wk

antip

sych

otic

effe

ct o

f flu

phen

azin

e F

luph

enaz

ine

enan

that

e an

d

Flu

pent

hixo

l dec

anoa

te

2-3w

ks

deca

noat

e; H

igh

dose

flup

hena

zine

ena

ntha

te

perp

hena

zine

ena

ntha

te s

how

ed A

Es

in

10-6

0 1M

ve

ry s

ucce

ssfu

l in

treat

ing

grav

e ac

ute

two-

third

s of

par

tiCip

ants

, w

ith a

sim

ilar

psyc

hose

s, b

ut li

ttle

effe

ct o

n ch

roni

c,

AE

pro

file

seen

in p

atie

nts

rece

ivin

g m

assi

ve p

sych

oses

flu

phen

azin

e de

cano

ate

and

flusp

irile

ne.

Flup

hena

zine

dec

anoa

te

caus

ed A

Es

at th

e do

ses

give

n

Cam

ey&

N

C

134

Flu

pent

hixo

l dec

anoa

te

3w

ks

28

mo

s S

tatis

tical

ly S

igni

fican

t im

prov

emen

t on

In c

ompa

rison

with

sep

arat

e st

udy

by

She

ffiel

d 30

-120

1M

m

odifi

ed W

ing'

s sc

ale.

8%

of p

ts w

ith s

ever

e C

arne

y &

She

ffiel

d (1

976)

on

(197

3)

depr

essi

on d

urin

g tre

atm

ent,

5 pt

s w

ith

flupe

nthi

xol d

ecan

oate

, E

PS

par

ticul

arly

pe

rsis

tent

ane

rgia

, 4

pts

with

tran

sien

t ane

rgia

ak

athi

sia,

rep

orte

d le

ss fr

eque

ntly

with

flu

pent

hixo

l dec

anoa

te (3

2%)

vs

fluph

enaz

ine

deca

noat

e (4

0"10

) and

ju

dged

less

sev

ere.

Psy

chot

ic r

elap

se

rate

sim

ilar

Cot

trel e

t al.

NC

40

F

lusp

irile

ne 4

-12

1M

1wk

2m

os

Impr

ovem

ent m

ore

nota

ble

in p

ts w

ith a

cute

A

t mea

n do

se o

f 5.4

mg

EP

S

(197

3)

vs c

hron

ic d

isea

se, e

spec

ially

in r

egar

d to

un

com

mon

, in

crea

sed

EP

S a

t 12

mg

illus

ions

(st

atis

tical

ly s

igni

fican

t)

Den

cker

et

DB

67

P

ipot

hiaz

ine

palm

itate

4

wks

1y

S

tatis

tical

ly s

igni

fican

t im

prov

emen

t in

BP

RS

N

o si

gnifi

cant

diff

eren

ce in

AE

s al

. (1

973)

25

-400

1M

w

ith fl

uphe

nazi

ne d

ecan

oate

afte

r 6 m

os

Flu

phen

azin

e de

cano

ate

4 w

ks

3.1-

50 1

M

Sin

gh (

1973

) N

C

40

Flu

spiri

lene

2-1

4 1M

1w

k 6-

24w

ks

Sta

tistic

ally

sig

nific

ant i

mpr

ovem

ent o

n K

atz

EP

S r

epor

ted

as m

inor

and

lim

ited

to

Adj

ustm

ent S

cale

and

BP

RS

th

e fir

st 4

8h a

fter i

njec

tion

cont

inue

d on

nex

t pag

e -.

.I ~

\0

Tabl

e II.

Co

ntd

-.

J U

l 0

Ref

eren

ce

Stu

dy

No.

D

rug

/do

se (

mg)

/rou

te

Inte

rval

D

urat

ion

Ou

tco

me

C

om

me

nts

de

sig

n

pts

Ast

rup

et

al.

DB

/NC

4

3

Flu

pent

hixo

l de

can

oa

te

2-4

wks

2

/6 m

os

No

sig

nific

ant

diff

eren

ces

betw

een

grou

ps.

AE

s si

gnifi

cant

ly m

ore

freq

uent

with

(1

974)

5

0-3

00

1M

B

oth

impr

oved

BP

RS

an

d C

GI

sign

ifica

ntly

in

pip

oth

iazi

ne

than

flu

pent

hixo

l; T

rial

Pip

othi

azin

e 2-

4 w

ks

DB

tria

l. In

ne

xt 6

mo

s o

f N

C tr

ial,

18

pts

we

re

bega

n w

ith 4

wk

inte

rval

bet

wee

n

un

de

cyle

na

te 2

5-3

00

1M

im

prov

ed,

14

unc

hang

ed,

11 w

ors

e

inje

ctio

ns,

but

inte

rval

dec

reas

ed t

o 2

wks

fo

r m

ost

pts

dur

ing

NC

tria

l

Cra

wfo

rd

DB

31

T

riflu

oper

azin

e N

R

10

mo

s

Tri

fluop

eraz

ine

with

dra

wa

l rat

e (4

8.9%

) an

d In

vest

igat

ors

note

d co

nsid

erab

le b

ias

in

(197

4)

PO

(d

ose

uns

peci

fied)

re

hosp

italis

atio

n ra

te (

26.6

%)

hig

he

r tha

n w

ith

dra

win

g th

e sa

mpl

e in

th

at t

he

tria

l

Flu

phen

azin

e d

eca

no

ate

N

R

fluph

enaz

ine

(14

.6%

an

d 0

%,

resp

ectiv

ely)

, g

rou

p h

ad a

be

tte

r pr

ogno

sis

than

the

1M (

do

se u

nspe

cifie

d)

thou

gh d

iffer

ence

no

t sig

nific

ant;

BP

RS

g

en

era

l pop

ulat

ion

scor

es s

igni

fican

tly h

igh

er f

or

fluph

enaz

ine

deca

noat

e vs

tri

fluop

eraz

ine

Got

tfri

es &

N

C

12

8

Flu

pent

hixo

l de

can

oa

te

2w

ks

2-6

y R

elap

se f

requ

ency

sig

nific

antly

low

er t

han

AE

s le

d to

dis

cont

inua

tion

in 5

% o

f pts

G

reen

(19

74)

20-6

0 1M

be

fore

tre

atm

ent,

rel

apse

rat

es w

ere

hig

her

in

pts

wh

o d

isco

ntin

ued

tre

atm

en

t

Roe

lofs

D

B v

s 15

P

enflu

rido

l 40

P()

b 1

wk

6m

os

Pen

fluri

dol-

trea

ted

gro

up

sig

nific

antly

be

tte

r A

ll pt

s tr

eate

d w

ith p

enflu

rido

l bef

ore

(197

4)

plac

ebo

than

pla

cebo

with

reg

ard

to w

ard

beh

avio

ur

tria

l, 8

pts

then

sw

itche

d to

pla

cebo

at

an

d d

i rec

t ps

ycho

tic e

ffec

ts

on

set

of t

rial;

Sig

nific

ant d

eter

iora

tion

in

faci

al e

xpre

ssio

n a

nd P

arki

nson

ism

in

pla

ceb

o g

rou

p

Tru

eman

&

NC

2

2

Flu

pent

hixo

l de

can

oa

te

3w

ks·

>1yb

S

ymp

tom

s sc

ore

on 5

-ite

m s

cale

de

cre

ase

d

AE

s le

ss fr

eque

nt/s

ever

e th

an w

ith

Val

entin

e 40

1Mb

from

99

with

pre

vio

us

tre

atm

en

t to

51

pre

vio

us

trea

tmen

t; 1

0 pt

s tr

eate

d fo

r

(197

4)

>1

y

Ca

rne

y &

C

O

418

Flu

phen

azin

e en

anth

ate

3w

ks

21-4

1 1

read

mis

sion

fo

r e

very

28

5 p

t-m

os o

n D

ose

s lis

ted

are

mo

de

dos

es;

Se

vere

She

ffiel

d 25

1M

mo

s flu

phen

azin

e d

eca

no

ate

vs

1 re

adm

issi

on/1

84

EP

S m

ost

co

mm

on

with

flu

phen

azin

e

(197

6)

Flu

phen

azin

e d

eca

no

ate

3

wks

pt-m

os o

n flu

phen

azin

e e

na

nth

ate

and

1/1

82

enan

that

e, l

east

co

mm

on

with

251M

fo

r flu

pent

hixo

l; le

ss p

atie

nt c

oope

ratio

n on

flu

pent

hixo

l de

cano

ate;

Inv

estig

ator

s

Flu

pent

hixo

l de

can

oa

te

3w

ks

flupe

nthi

xol d

eca

no

ate

vs

oth

er

drug

s su

gg

est

cur

rent

ma

inte

na

nce

do

se fo

r

30-4

0 1M

flu

pent

hixo

l d

eca

no

ate

as

wel

l

Ger

lach

et

al.

DB

56

P

enflu

rido

l 20

-15

0 P

O

1w

k 3

mo

s

Non

sign

ifica

nt tr

end

to g

rea

ter

impr

ovem

ent

App

roxi

mat

ely

the

sa

me

deg

ree

of A

Es

(197

5)

Flu

pent

hixo

l de

can

oa

te

2w

ks

with

pen

fluri

dol

vs f

lupe

nthi

xol

deca

noat

e; N

o

(aka

this

ia,

Par

kins

onis

m,

au

ton

om

ic

tl

20-1

50 1

M

sign

ifica

nt c

ha

ng

e in

con

ditio

n w

hen

pts

sym

pto

ms)

in b

oth

grou

ps

... ::::

abru

ptly

sw

itche

d fr

om p

enflu

rido

l to

~ '"

flupe

nthi

xol

de

can

oa

te a

nd

vic

e ve

rsa

-I:>

. '-

l ""' ~

.....

\0 '£.

Gui

dice

et a

l. C

O

88

Flu

phen

azin

e 5-

80 P

O

od

23

mo

s

Hig

hly

sign

ifica

nt in

crea

se in

cha

nce

of b

eing

L

ow

inci

denc

e o

f AE

rep

orte

d; A

ll pt

s 1:1

(1

975)

F

luph

enaz

ine

enan

that

e 15

d ho

spita

lised

with

flu

phen

azin

e vs

m

ale

.g sa.

12.5

-25

1M

fluph

enaz

ine

enan

that

e; S

mal

l and

>

no

nsig

nific

ant p

lace

bo e

ffec

t aS

SO

Cia

ted

with

::I

:::t

o pl

aceb

o in

ject

ion

tog

eth

er w

ith f

luph

enaz

ine

'0 '" '<

Cho

uina

rd &

D

B

33

Pe

nflu

rid

ol4

0-1

20

PO

1

wk

3w

ks

Pen

flurid

ol s

igni

fican

tly s

up

eri

or t

o

Sig

nific

antly

mor

e ch

lorp

rom

azin

e pt

s 0 t:

r

Ann

able

ch

lorp

rom

azin

e fo

r p

ts w

ith lo

w in

itial

BP

RS

w

ith d

row

sine

ss,

nons

igni

fican

t tre

nd t

o

0 C

hlor

prom

azin

e 3

00

-90

0

od

:::to

0 (1

976)

P

O

and

IMP

S s

core

s; c

hlor

prom

azin

e si

gnifi

cant

ly

gre

ate

r se

veri

ty o

f EP

S w

ith p

enflu

ridol

~ su

peri

or to

pen

flurid

ol f

or

pts

with

hig

h in

itial

(J

q

scor

es;

no s

igni

fican

t diff

eren

ce in

CG

I; P

is

'" re

ceiv

ing

eith

er d

rug

impr

oved

eno

ugh

for

disc

harg

e in

3 w

ks

Rifk

in e

tal.

C

O

73

Flu

phen

azin

e 5-

20 P

O

od

1y

Rel

apse

rat

e w

ithin

1 y

ea

r fo

r pla

cebo

pts

S

igni

fican

tly m

ore

dro

pout

s du

e to

(197

7)

Flu

phen

azin

e de

cano

ate

2 w

ks

(68%

) si

gnifi

cant

ly h

igh

er t

han

for

drug

se

vere

aki

nesi

a in

flup

hena

zine

5-20

1M

tr

eate

d pt

s (1

0%).

No

sign

ifica

nt d

iffer

ence

in

deca

noat

e gr

oup

(35%

) vs

oral

rela

pse

rate

s (7

%)

betw

een

the

2 d

rugs

flu

phen

azin

e

Dom

(19

78)

DB

21

C

lope

nthi

xol d

ecan

oate

3

-4w

ks

5m

os

Sta

tistic

ally

sig

nific

ant i

mpr

ovem

ent i

n B

PR

S,

Fe

w a

uton

omic

or

neur

olog

ical

AE

s

7 m

g/kg

1M

po

sitiv

e ef

fect

on

soci

al a

dapt

atio

n

Fal

loon

et a

l. D

B

41

Pim

ozid

e P

O (

dose

2

wks'

1y

Pis

on

pim

ozid

e ra

ted

Sig

nific

antly

hig

her t

han

(197

8)

unsp

ecifi

ed)

fluph

enaz

ine

deca

noat

e on

asp

ects

of

Flu

phen

azin

e de

cano

ate

2 w

ksc

soci

abili

ty,

leis

ure,

per

sona

l rel

atio

nshi

ps,

1M (

dose

uns

peci

fied)

ho

useh

old

task

s an

d ch

ild r

earin

g

Fra

ngos

et

DB

50

F

lusp

irile

ne 4

-20

1M

1w

k 4

mo

s

Sig

nific

antly

hig

he

r B

PR

S a

nd N

OS

IE w

ith

Flu

phen

azin

e as

soci

ated

with

al.

(197

8)

Flu

phen

azin

e de

cano

ate

2 w

ks

flusp

irile

ne v

s flu

phen

azin

e, n

onsi

gnifi

cant

si

gnifi

cant

ly m

ore

AE

s (E

PS

,

25-1

50 1

M

tren

d to

hig

her

CG

I fo

r flu

spiri

lene

P

arki

nson

ism

, tr

emor

) th

an f

lusp

irile

ne

Deb

erdt

et a

l. N

C

38

H

alop

erid

ol d

ecan

oate

4

wks

3-12

mo

s T

hera

peut

ic e

ffec

t of h

alop

erid

ol d

ecan

oate

H

alop

erid

ol d

ecan

oate

dos

es 2

0-fo

ld

(198

0)

30-3

00 1

M

sim

ilar t

o th

ose

of o

ral h

alop

erid

ol,

pts

coul

d g

rea

ter t

han

prev

ious

ora

l hal

oper

idol

read

ily b

e s

witc

hed

from

PO

to

1M

d

ose

s w

ere

opt

imal

vs

10-

or

30-f

old

Mol

can

et a

l. N

C

25

Flu

spiri

lene

6 1

M

1-2

wks

3

3w

ks

Glo

bal s

tate

mod

erat

ely

impr

oved

8

1%

of p

atie

nts

had

incr

ease

d in

tenS

ity

(198

0)

of A

Es

com

pare

d w

ith b

asel

ine

Pin

ard

&

NC

12

F

lusp

irile

ne 3

-40

1M

~1 d

ay

4m

os

Sta

tistic

ally

sig

nific

ant i

mpr

ovem

ent i

n B

PR

S

Pt s

ele

ctio

n b

ase

d o

n a

cute

Ro

sale

s an

d N

OS

IE

exa

cerb

atio

ns

of

schi

zoph

reni

a; E

PS

(19

80

) in

mo

st p

ts

Sch

oo

lere

t D

B

214

Flu

phen

azin

e 2.

5-60

PO

od

1

y 2

8%

of p

ts r

elap

sed

aft

er

1 y,

with

no

No

sign

ifica

nt b

etw

een-

grou

p di

ffer

ence

al.

(197

9)

Flu

phen

azin

e de

cano

ate

3 w

ks

diffe

renc

e be

twee

n gr

oups

; N

o di

ffere

nce

in

in p

ts t

erm

inat

ing

due

to A

Es;

Pis

sel

f-

12.5

-100

1M

af

fect

ive

sym

ptom

atol

ogy

or

soci

al a

djus

tmen

t ra

ting

as

havi

ng m

ore

sym

ptom

dis

tres

s

betw

een

grou

ps

rela

psed

ear

lier

with

flup

hena

zine

de

can

oa

te th

an w

ith fl

uphe

nazi

ne

-...l

cont

inue

d on

nex

t pag

e U

1

Tab

le I

I. C

ontd

-..

.J V

I t-.>

R

efer

ence

S

tudy

N

o.

Dru

g/do

se (

mg)

/rou

te

Inte

rval

D

urat

ion

Out

com

e C

om

me

nts

desi

gn

pts

LaP

ierr

e et

N

C

23

Flu

spiri

lene

2·2

0 1

M

1wk

18 m

os

Sta

tistic

ally

sig

nific

ant

impr

ovem

ent

in C

GI,

Mild

EP

S in

78%

of p

ts

al.

(198

1)

NO

SIE

and

BP

RS

, m

ost

pro

noun

ced

rega

rdin

g an

ergi

a an

d th

ough

t di

sord

er

McC

read

ie e

t D

B

28

Pim

ozid

e 10

·60

PO

1

wk

9m

os

No

sign

ifica

nt d

iffer

ence

in r

elap

se r

ate

or

Pim

ozid

e gr

oup

had

sign

ifica

nt in

crea

se

al.

(198

2)

Flu

phen

azin

e de

cano

ate

1wk

clin

ical

sta

te b

etw

een

grou

ps

in d

yski

nesi

a; 7

5% d

evel

oped

at

leas

t

2-25

1M

m

ild t

ardi

ve d

yski

nesi

a, b

ut n

o

sign

ifica

nt in

crea

se o

bser

ved

with

fluph

enaz

ine

deca

noat

e

Par

ent e

t al.

NC

15

B

rom

peri

dol d

ecan

oate

4

wks

6-12

mos

N

o si

gnifi

cant

diff

eren

ce in

CG

I fr

om t

hat

EP

S in

9 p

ts;

Red

uced

req

uire

men

t fo

r

(198

3)

40-3

00 1

M

durin

g pr

evio

us t

reat

men

t; no

nsig

nific

ant

anti-

Par

kins

on d

rugs

; A

ll pt

s m

ale

tren

d to

impr

ovem

ent i

n B

PR

S

Wis

ted

t&

DB

3

2

Flu

pent

hixo

l dec

anoa

te

3w

ks

2y

Non

sign

ifica

nt tr

end

to g

reat

er im

prov

emen

t N

o si

gnifi

cant

diff

eren

ce in

EP

S

Ran

ta (

1983

) 31

1Mb

in C

PR

S s

core

s fo

r sc

hizo

phre

nia

and

betw

een

grou

ps

Flu

phen

azin

e de

cano

ate

3w

ks

depr

essi

on f

or fl

upen

thix

ol;

Sig

nific

ant

271M

b di

ffer

ence

s in

fav

our

flupe

nthi

xol o

n si

ngle

item

s of

CP

RS

; B

oth

drug

s si

gnifi

cant

ly

impr

oved

CG

I an

d B

PR

S a

fter

12

wks

Wis

tedt

et a

l. D

B

51

Hal

oper

idol

dec

anoa

te

4w

ks

5m

os

CP

RS

and

clu

ster

obs

erva

tions

for

N

o si

gnifi

cant

diff

eren

ce in

AE

s;

(198

4)

50-3

00 1

M

depr

essi

on s

igni

fican

tly b

ett

er f

or h

alop

erid

ol;

Ant

i-Par

kins

on d

rugs

sig

nific

antly

Flu

phen

azin

e 12

.5-2

00

4w

ks

no d

iffer

ence

s in

CG

I in

crea

sed

for

fluph

enaz

ine

by

1M

we

ek

20

Jorg

ense

n et

N

C

20

Zuc

lope

nthi

xol

1-4w

ks

NR

S

igni

fican

t and

hig

h co

rrel

atio

n be

twee

n

al.

(198

5)

deca

noat

e 75

-400

1M

d

ose

and

ser

um c

once

ntra

tion;

Hig

h do

ses

and

seru

m c

once

ntra

tions

corr

elat

ed w

ith p

oore

st c

linic

al

stat

e

Kis

slin

g et

al.

DB

31

H

alop

erid

ol d

ecan

oate

4

wks

6m

os

No

sign

ifica

nt d

iffer

ence

in B

PR

S o

r IM

PS

M

inim

al A

Es

for

both

gro

ups,

but

(198

5)

801M

b be

twee

n gr

oups

; P

sych

otic

rel

apse

occ

urre

d p

ts u

sing

hal

oper

idol

req

uire

d

Flu

phen

azin

e de

cano

ate

2w

ks

in b

oth

grou

ps w

ithin

3 d

ays

aft

er

chan

ge to

si

gnifi

cant

ly le

ss (

half)

ant

i-

211M

b de

pot a

nd c

ould

no

t be

man

aged

by

Par

kins

on m

edic

atio

n; S

igni

fican

tly

incr

easi

ng d

epot

do

sag

e

mo

re fl

uphe

nazi

ne p

ts (

13 p

ts,

tl

z60

%)

drop

ped

out

vs h

alop

erid

ol p

ts

~ 00

(10

of 3

0 p

ts,

z33%

) du

e '"' -I:>..

toA

Es

'" ~ .... \Q

:-e.

Ebe

rhar

d &

D

B

32

Hal

oper

idol

dec

anoa

te

~wks

11 m

os

In fi

rst 2

4 w

ks, p

ts' c

ondi

tion

was

sta

ble;

aite

r D

B c

ross

over

, P

m r

ecei

ved

halo

perid

ol

0 H

ellb

om

25-3

00 1

M

cros

sove

r, C

GI a

nd C

PR

S s

igni

fican

tly

deca

noat

e or

flup

enth

ixol

dec

anoa

te fo

r .g

0

(198

6)

impr

oved

for

halo

perid

ol V

B fl

upen

thix

ol,

with

24

wks

, th

en s

witc

hed;

Dos

e in

terv

al

.... Fl

upen

thix

ol d

ecan

oate

~wks

>

120

1M

sym

ptom

s fu

rther

redu

cing

on

halo

perid

ol a

nd

varie

d in

firs

t 12

wks

, w

as fi

xed

at 4

::s .g.

in

crea

sing

on

flupe

nthi

xol

wee

ks;

No

sign

ifica

nt d

iffer

ence

in A

Es,

O

Il

gene

rally

mild

; 4-

wee

k in

terv

al

'<

n ::r

appr

opria

te fo

r ha

lope

ridol

, but

too

long

0 ::to

fo

r flu

pent

hixo

l 0

Rap

p(19

86)

DB

25

H

alop

erid

ol d

ecan

oate

4

wee

ks

11 m

os

No

sign

ifica

nt d

iffer

ence

in C

PR

S b

etw

een

No

sign

ifica

nt d

iffer

ence

in E

PS

~

200

1M

grou

ps;

Non

sign

ifica

nt tr

end

tow

ards

gre

ater

be

twee

n ha

lope

ridol

or p

erph

enaz

ine

0<1 OIl

Per

phen

azin

e en

anth

ate

2 w

ks

depr

essi

on w

ith p

erph

enaz

ine

33-2

00 1

M

Cho

uina

rd e

t D

B

72

Hal

oper

idol

dec

anoa

te

2-4w

ks

Bm

os

No

sign

ifica

nt d

iffer

ence

in C

GI o

r BP

RS

N

o si

gnifi

cant

diff

eren

ce in

EP

S

al.

(198

9)

15-9

00 1

M

betw

een

grou

ps.

Hig

her s

core

s fo

r lin

gual

and

be

twee

n gr

oups

Flu

phen

azin

e de

cano

ate

2-4

wks

ja

w m

ovem

ents

with

hal

oper

idol

2.5-

300

1M

You

ssef

C

O

62

Hal

oper

idol

dec

anoa

te

4w

ks

5y

Impr

oved

BP

RS

sco

res

for

both

trea

tmen

ts

Sig

nific

antly

few

er A

Es

with

hal

oper

idol

(1

989)

5Q

-300

IM

over

5 y

ears

; S

igni

fican

tly fe

wer

rela

pses

in

VB

oth

er tr

eatm

ent,

tard

ive

dysk

ines

ia in

Oth

er a

ntip

sych

otic

s 1M

V

ario

us

halo

perid

ol g

roup

9%

of p

ts re

ceiv

ing

halo

perid

ol V

B 3

5%

or P

O (

dose

s va

ried)

in

terv

als

on o

ther

age

nts

McL

aren

et

DB

47

B

rom

perid

ol d

ecan

oate

4

wks

1y

N

o si

gnifi

cant

diff

eren

ces

in p

ositi

ve a

nd

No

sign

ifica

nt d

iffer

ence

in E

PS

or

al.

(199

2)

25-4

00 1

M

nega

tive

sym

ptom

s or

dep

ress

ion

betw

een

wei

ght c

hang

e

Flu

phen

azin

e de

cano

ate

4 w

ks

grou

ps, b

ut s

igni

fican

t im

prov

emen

ts in

soc

ial

B.3-

3OO

1M

di

sabi

lity

on fl

uphe

nazi

ne;

6 pt

s re

laps

ed o

n br

ompe

ridol

VB

0 o

n flu

phen

azin

e (s

tatis

tical

ly

sign

ifica

nt)

Baa

stru

pet

CO

14

8 Z

uclo

pent

hixo

l ace

tate

3

days

6

days

N

o di

ffere

nce

in e

ffica

cy o

r rap

idity

of o

nset

Z

uclo

pent

hixo

l ace

tate

had

gre

ates

t al

. (1

993)

50

-200

IMe

betw

een

the

3 tre

atm

ents

in

itial

sed

atio

n, l

east

EP

S, f

ewes

t

Hal

oper

idol

5-1

0 IM

e P

oe

q6h

requ

ired

hosp

italis

atio

ns

Zuc

lope

nthi

xol1

0-20

IMe

q6h

Poe

a M

ean

inte

rval

. b

Mea

n do

se.

c In

itial

dos

e.

Abb

revi

atio

ns: A

Es = a

dver

se e

ffect

s; b

id =

twic

e da

ily; B

PR

S =

Brie

f Psy

chia

tric

Rat

ing

Sca

le; C

D =

clope

nthi

xol d

ecan

oate

; CG

I = Cli

nica

l Glo

bal I

mpr

essi

on; C

O =

com

para

tive;

C

PR

S =

Com

preh

ensi

ve P

sych

iatri

c R

atin

g S

cale

; D

B =

doub

le-b

lind;

EP

S =

extra

pyra

mid

al s

ympt

oms;

1M

= int

ram

uscu

lar;

IMP

S =

Inpat

ient

Mul

tidim

ensi

onal

Psy

chia

tric

Sca

le;

NC

= no

ncom

para

tive;

NO

SIE

= Nu

rses

' Obs

erva

tion

Sca

le fo

r In

-pat

ient

s E

valu

atio

n; N

R =

not r

epor

ted;

ad

= onc

e da

ily;

PO

= ora

l; qx

h or

q~ =

ever

y x

hour

s or

day

s.

-..l

UI

w

754

adaptation (Chouinard et al. 1971; Lapierre et al. 1981; Pinard & Rosales 1980; Singh 1973; Sterkmans et al. 1969; St-Laurent et al. 1972; Tan­ghe & Vereecken 1971; Zwanikken et al. 1971).

2.3.6 Haloperidol Decanoate The pharmacokinetic parameters associated

with this butyrophenone allow for monthly inter­vals between injections instead of weekly or biweekly injections (Roose 1981). Peak plasma concentrations are reached 3 to 9 days after intra­muscular injection (Beresford & Ward 1987).

The apparent elimination half-life of depot hal­operidol is 3 weeks (vs around 24 hours for oral haloperidol). The associated time to reach steady­state haloperidol concentrations is 2 to 3 months for depot (vs 7 days for oral). Thus, oral supple­mentation during initiation of depot therapy is clin­ically warranted (Zissis et al. 1982; Zuardi et al. 1983). There appears to be a strong linear correla­tion (r = 0.86) between a constant haloperidol decanoate dose of 100mg per month after 3 con­secutive monthly injections and measured plasma concentrations, which can range from 3 to 10 Jlg/L (Reyntijens et al. 1982).

Nair and coworkers (1986) have demonstrated the effectiveness of haloperidol decanoate in con­trolling psychotic symptoms in patients with chronic schizophrenia. They also showed that the incidence ofEPS and other adverse effects may not be increased by its use.

Studies have compared patients randomly as­signed to receive either fluphenazine decanoate or haloperidol decanoate (Chouinard et al. 1984, 1989; Kissling et al. 1985; Wistedt et al. 1984), finding that there may be more EPS or an increased requirement of anti-Parkinsonian medication in patients receiving fluphenazine. This must consid­ered in regard to patient compliance.

Reduced clearance of haloperidol decanoate has been reported in geriatric patients, which may ne­cessitate a dosage reduction (Viukari et al. 1982).

2.3.7 Perphenazine Enanthate The literature has reported pharmacokinetic pa­

rameters for perphenazine enanthate after multiple

Drugs 47 (5) 1994

but not single doses. The approximate elimination half-life of this agent at steady-state is only 2 to 4 days, which is similar to that of the enanthate ester of fluphenazine (Larsson et al. 1984). Comparison of this formulation with perphenazine decanoate, which is available in Scandinavia, shows that ad­ministration of the latter ester results in fewer fluc­tuations in the measured plasma concentrations of perphenazine (Knudsen et al. 1985).

2.3.8 Pipothiazine Palmitate and Undecylenate These depot compounds are members of the

phenothiazine family and are slowly absorbed from the site of intramuscular injection. Both com­pounds gradually release pipothiazine into circula­tion, making them appropriate for depot injections. The palmitate ester is administered at average in­tervals of 4 weeks, while the undecylenate ester is given at average intervals of 2 weeks (Reynolds 1993).

Girard found that peak plasma concentrations of the palmitate ester were reached in the second week after administration (Girard et al. 1984). The elimination half-life was not assessed. No direct relationship has been found between plasma con­centration or half-life and therapeutic effects (De Schepper et al. 1979).

2.3.9 Zuclopenthixol Decanoate This thioxanthine derivative is the cis isomer of

clopenthixol decanoate. Aaes-Jorgensen (1989) examined the pharmacokinetics of 3 different in­jectible zuclopenthixol preparations, of which only one, zuclopenthixol, has been formulated for main­tenance pharmacotherapy. After doses ranging from 50 to 800mg, peak serum concentrations were obtained 1 week after the zuclopenthixol inj~ction, with detectable amounts of drug persisting after 28 days. Significant correlations were found between dose and serum concentrations when measured on individual days. Elimination half-lives were not explicitly calculated, but a clinical effect lasting 2 to 4 weeks was reported.

Depot Antipsychotic Drugs

2.4 Depot Drug in Nonresponsive Patients

Antipsychotic medication is known to undergo extensive first-pass metabolism when adminis­tered orally. A substantial part of orally adminis­tered antipsychotic agents is metabolised by the liver. After the oral drug is swallowed, it is ab­sorbed through the gut wall and has its first pass through the liver, where a substantial part of the dose is metabolised before it reaches the systemic circulation.

In addition, antipsychotics may be metabolised in the gut wall. It is possible that some patients may have so extensive a first-pass effect that they, in essence, do not absorb the drug, resulting in plasma concentrations that are too low for therapeutic ef­ficacy. Clinically, we have seen that patients who were resistant to treatment with oral antipsychotic agents and had extremely low plasma drug concen­trations could successfully be treated with higher than normal depot doses.

Furthermore, the depot antipsychotic agent by­passes the liver when it is administered intramus­cularly. One empirical study has specifically exam­ined first-pass effect in relation to antipsychotic response (Adamson et al. 1973). The investigators selected long-stay schizophrenic patients. These patients would be expected to be nonresponders; otherwise, they would not have remained admitted for extended periods in the hospital.

From 97 patients given a test dose of oral and intramuscular chlorpromazine, 37 were selected who had very low oral plasma concentrations, sub­stantially lower than the corresponding intramus­cular concentrations. These patients were treated in a double-blind, randomised study. One group received oral chlorpromazine 150 to 300 mg/day. The others received fluphenazine decanoate 12.5mg on day 1 and 25mg on day 7. The patients were studied for 28 days. Those in the fluphenazine group had a significantly better response by day 28 than those receiving oral chlorpromazine.

The investigators interpreted the results as sup­porting the hypothesis that the depot drug avoid first-pass effects. We do not precisely know, how­ever, what an equivalent oral dose of chlorproma-

755

zine is in comparison to a depot fluphenazine dose. Therefore, a possible alternative interpretation would be that this study simply demonstrates a dose/response curve, in that the dose of depot flu­phenazine was equivalent to a higher dose of chlor­promazine. Nevertheless, it is an intriguing find­ing.

There remains a reasonable possibility that de­pot drug may be used as a means of bypassing the absorption state in patients who exhibit extensive first-pass metabolism of oral medication. Patients may metabolise antipsychotics in the gut and have a high first-pass effect and, thus, little drug may actually reach the systemic circulation after an orally administered dose. A depot preparation that shortcircuits this phase may be the preferred route of administration. As a practical matter, some pa­tients, even in inpatient settings, may 'cheek' their medication (hide it in their cheek and not swallow it, spitting it out later) and may not receive an ad­equate dose of medication. Whether this phenom­enon or excessive first-pass metabolism explains the failure to respond, there may be an indication to try depot medication in the nonresponding inpa­tient.

3. Current Treatment Issues 3.1 Progressive Nature of Relapse

It was once thought that patients should be maintained on medication for 6 months to 1 year. If they did not relapse in this length of time, they might be in a true remission and therefore not re­quire maintenance medication. In our judgment, it now appears that many schizophrenic patients need these medications for life.

Evidence for this view is provided by examin­ing the time frame of relapse. Linear plots of the number of patients relapsing versus time are mis­leading because the absolute number of patients relapsed per unit time decreases with time. A quan­titative examination should adjust for the number of not-yet-relapsed patients remaining in the trial. When we analysed clinical trials of long term pla­cebo or drug therapy (Davis 1975; Davis et al. 1980) we found that relapse occurred along an ex-

756

ponential function similar to that seen with the half-life of drugs in plasma.

This finding would indicate that relapse occurs at a constant rate for the first few years (Davis 1975). Beginning with a fixed number of patients in a study group, the number of patients relapsing will always be a constant percentage of the overall number of patients remaining in the study. As the study progresses, the actual number of patients re­lapsing will decrease due to the diminishing patient pool, but the rate (i.e. percentage) of relapse will remain constant.

We have plotted data from both comparative and noncomparative studies of relapse and found that an exponential model fits the data more accu­rately than a linear model (Davis 1975; Davis et al. 1980). Without drug treatment, the relapse rate was 15.7% per month (Caffey et al. 1964), 10.7% (Hogarty et al. 1974), and 8% per month (Prien et al. 1969). When we examined the kinetics of re­lapse in a large number of longitudinal studies, we found that patients relapsed progressively at an ap­proximately constant rate, at least for the first year or two after their medication was discontinued.

It is sometimes said that since 50% of patients relapse with drugs, those 50% who remain relapse­free therefore do not need medication. Most of the maintenance studies (in table I) lasted only 4 to 6 months and, at a rate of 10% per month, this yields a ",,50% relapse rate per year. Generalising from the longer 1- to 5-year studies, however, we would ex­pect that had the period been extended to 1 year, 75% would relapse. Had the studies been extended to 2 years, 87% would relapse. We do not know if the curve goes on to 100% relapses (Davis et al. 1980).

If the observation of constant relapse is true, then the great majority of patients will relapse without drug treatment if followed up for an ade­quate period of time. We believe this generalisation is reasonable if it is kept in mind that this applies to the type of patient being studied in these inves­tigations, i.e. patients in maintenance medication clinics. In some of the longer studies, the relapse rate may decrease somewhat after 18 months to 2

Drugs 47 (5) 1994

years (Capstick 1980; Johnson 1979; Johnson et al. 1983). Unfortunately, it is difficult to test for sta­tistical significance, since very few patients are left in anyone trial after several years.

Regardless of whether the relapse rate is con­stant for many years or if it decreases somewhat in later years, consideration of the kinetics of relapse demonstrates its progressive nature. It is crucial that clinicians appreciate this progressive nature. Given enough time, most patients will relapse in the absence of drug treatment. Therefore, it is im­portant to administer drug treatment to prevent the occurrence of relapse.

The second question that can be addressed re­garding the time course of relapse relates to the clinical fate of patients who have been successfully maintained on medication without relapse over the course of several years. If, while on medication, relapse is prevented for some time, have these pa­tients become less prone to relapse after discontin­uing medication or will the rate still be about 10% per month?

Several studies have been performed to assess this question. Levine et al. (1980) examined pa­tients stabilised on medication for 1 year and ran­domly assigned them to continue medication or re­ceive placebo. These researchers found that patients receiving placebo started to relapse at the expected relapse rate, while those on medication relapsed at almost half the placebo relapse rate. In a similar study, Hogarty and Ulrich (1976) found that when antipsychotics were withdrawn after 2 to 3 years of successful treatment, the initial relapse rates were similar to those for patients who had been taken off maintenance medications after only 2 months of therapy. The former group continued to relapse in an exponential manner, with a con­stant rate of 10% per month. Likewise, Cheung (1981) investigated 30 patients with schizophrenia who remained in full remission on medication for 3 to 5 years. They were then randomly assigned to receive benzodiazepines or antipsychotics. Eight of 13 patients relapsed on benzodiazepines vs 2 of 15 on antipsychotics.

Depot Antipsychotic Drugs

In patients stable on medication, Johnson (1979) performed a notable study investigating the relapse rate and symptom-free interval before and after discontinuing medication. In this study, pa­tients or physicians made the decision of discon­tinuing medication, and therefore it was not randomised. A case-controlled group of patients were chosen from the same population of patients by selecting the next patients on the clinic register who matched the experimental group for age, sex and duration of illness. The time that patients were free of symptoms and stable prior to entering the study was 12 to 24 months, 25 to 36 months, 37 to 48 months, respectively. A case-controlled group of patients was chosen by selecting the next pa­tients on the clinic register who matched the exper­imental group for age, sex and duration of illness. Thus, this is a case-controlled study with a 2 by 3 matched group design, i.e. patients who discon­tinued drugs vs those who maintained drugs by 3 levels of months stable on medication before en­trance into the study. The relapse rate at discontin­uation of medication was approximately the same in all 3 groups, namely, 80, 90 and 70%, respec­tively, at 18 months. The relapse rate for patients on control medication was 35, 15 and 19% at the 18-month follow-up period. Hence, regardless of the length of time patients were previously stable, those discontinuing medication relapsed at a rate of approximately 80% at 18 months, while patients continuing medication relapsed at a much lower rate (43%).

Data from the above 4 studies demonstrate that patients who have been stabilised for 1 year, for 2 to 3 years, or for 3 to 5 years all relapse at the same rate once they are switched to placebo. Thus, no evidence exists for a decrease in relapse rate re­lated to the number of years stable on medication.

Several other studies have specifically exam­ined whether it would be possible to identify pa­tients with chronic schizophrenia who can be suc­cessfully managed without medication. Morgan and Cheadle (1974) selected 74 of 475 patients as suitable candidates for management without the use of medication. Only 5 of these 74 remained

757

relapse-free after several years without mainte­nance medication. Relapse in the other 69 occurred on average 4.5 months after removal of the drugs.

In a related study, Capstick (1980) gradually discontinued drug therapy in patients who had been stable on depot medication for an average of 29 months (range 3 to 91 months). Although the antipsychotics were discontinued gradually, 80% of the patients relapsed. Like those examined by Morgan and Cheadle (1974), these patients were chosen for discontinuance, and yet the relapse rate was appreciable.

Johnson (1979) also studied the effects of dis­continuing depot antipsychotics in typical multiply relapsing outpatients with chronic schizophrenia whose medications were discontinued on the basis of doctor's orders. The doctors felt the disease to be in remission and thought it was reasonable to discontinue antipsychotic medication. Thus, it might be expected that the discontinuing group would have a better prognosis than the control group, who were felt to need continuous medica­tion. In fact, the relapse rate in the group that dis­continued antipsychotics was substantially higher than that of patients maintained on antipsychotic drugs. These findings clearly indicate that even se­lected, good-risk patients with chronic schizophre­nia are at a high risk of relapse if not maintained on drug therapy.

3.2 Depot Versus Oral Medication

When poor medication compliance becomes an issue during the course of maintenance antipsy­chotic therapy, the clinician may opt to use depot formulations to ensure that the patient receives an adequate pharmacotherapeutic trial. We note first that there is no inherent difference in clinical effi­cacy when compliance is assured between depot and oral medications. Other differences between oral and depot formulations are highlighted in table III.

Six double-blind studies of inpatients (Black­burn & Allen 1961; Diamond & Marks 1960; En­gelhardt et al. 1967; Gross & Reeves 1961; Itil & Heskiner 1970; Leff & Wing 1971) compared

758 Drugs 47 (5) 1994

Table III. Difference in clinical effects of oral and depot formulations

Study Duration of PIs on No. Ptson No. Difference Odds Confidence interval

treatment oral drug relapsed depot drug relapsed (oral- depot) rati08 low high (y) (%) (%) [%]

Crawford & Forrest 40wks 13 27(4) 14 0(0) 27 11.34 0.55 223.12

(1974)

Falloon et al. (1978) 1 21 24(5) 20 40(8) -16 0.49 0.13 1.79

Guidice et al. (1975) 1 57 90 (51) 25 44 (11) 46 9.98 3.24 30.75

Hogarty et al. (1979) 2 50 65(32) 55 40(24) 24 2.25 1.03 4.91

Rifkin et al. (1977) 28 11 (3) 23 9(3) 2 0.80 0.16 3.94

Schooler et al. 107 33(35) 107 24(26) 9 1.50 0.83 2.72

(1979)

a A test of whether depot drugs produce a decrease in replase rates compared with oral drug. An odds ratio of 1 indicated no difference, while ratios of 11 or 10 indicate a marked decrease in relapse rates.

fluphenazine enanthate or decanoate with oral an­tipsychotic. They found essentially equal efficacy between oral and depot routes of delivery. One study found the oral route to be slightly superior, another study found depot delivery to be slightly superior, and the other 4 found no difference. In an inpatient setting, however, compliance is less of a problem and is relatively well assured, even though an occasional patient can cheek a tablet and dispose of it later without swallowing it. These results are not pertinent to outpatients, in whom compliance is a problem.

When studies comparing the efficacy of depot vs oral medication are performed in an outpatient setting, particularly in a more typical public sector setting, a large difference between depot and oral drugs is shown (Denham & Adamson 1973; Devito et al. 1978; Freeman 1980; Gottfries & Green 1974; Marriot & Hiep 1976; Tegeler & Lehmann 1981). Several double-blind studies comparing re­lapse rates in outpatients treated with depot vs oral medication are illustrated in table IV.

For the purpose of a depot versus oral compar­ison, these studies are as well controlled as the high-technology studies (i.e. studies in which en­docrine, plasma and other sophisticated medical tests are regularly performed) because they have 2 critical ingredients: random assignment and blind evaluation. Such patients, who are already actively cooperating with the clinician by allowing blood

and urine samples to be taken and submitting to numerous other tests, are likely to take their med­ication.

The study of Guidice and coworkers (1975) is particularly important because the setting was a public sector clinic treating severely disturbed and frequently noncompliant schizophrenic patients. It used a double-blind, random-assignment design and, thus, was a methodologically valid study, but was performed in a population with a high propor­tion of noncompliant patients. Also noteworthy is that it was one of the first studies to use survival statistical methodology to quantify differences be­tween treatments in psychiatry.

Crawford and Forrest (1974) also performed a double-blind study of 40 weeks' duration on a more typical public sector population. They found depot medication superior to oral. Likewise, Hogarty et al. (1979) in a 2-year study found depot medication superior to oral. Several controlled studies spon­sored by the US National Institutes of Mental Health (NIMH) [Clark et al. 1975; Pinard & Rosales 1980; Schooler et al. 1979] with rigorous protocols found little difference between depot and oral delivery. However, these trials are more likely to have been examining compliant patients. We found that by combining the results of the control­led studies in table IV by meta-analysis demon­strates a highly significant reduction in relapse rate

Depot Antipsychotic Drugs

with depot medication (p = 0.0002, Mantel­Haenszel Test).

The utility of depot medication is further sup­ported by several studies using mirror-image con­trols. In a mirror-image study, patients are placed on depot medication for some period of time and the number of relapses are determined. This num­ber is compared with the number of relapses or days in hospital determined for an equal period of time prior to administering depot medication. Re­lapses to hospital or days in hospital are an objec­tive index of outcome.

Denham and Adamson (1973) performed such a mirror-image study. 103 schizophrenic patients were followed up an average of 24.8 months after initiation of depot antipsychotic medication, as well as being assessed for an equal period of time while previously on oral medication. Hospitalisa­tions were reduced from 8719 days to 1335, and the number of relapses from 191 to 50. Of the 50 relapses, 11 occurred when patients failed to attend a clinic for their injections. There were 5 admis­sions for adverse effects and 34 relapses despite depot medication. The investigators did not pro­vide enough data to allow a statistical assessment for the change of total days spent by patients in a hospital. Thus, we could not compute the time pa­tients spent in hospital as a result of relapse. How­ever, the decrease in number of relapses (including readmissions for adverse effects and for patients

759

not attending clinic for injections) was highly sta­tistically significant (p = 10-15).

Gottfries and Green (1974) performed a mirror­image study of flupenthixol decanoate, comparing treatment with this agent and patients' prior treat­ment. Though they only performed a cursory di­chotomous examination, they did publish their raw data in chart form, presenting the number of admis­sions and the number of days in hospital after pa­tients were treated with flupenthixol in comparison to those occurring an equal period of time before. Since data were available in the chart form, we performed 2 statistical analyses, 1 involving a paired t-test on the number of days in hospital be­fore depot treatment and 1 after depot treatment. On flupenthixol, the patients spent approximately one-quarter the number of days in hospital that they had spent before depot treatment, a highly sta­tistically significant result (t = 4.07; df = 35; P = 3 X 10-4). Compared by the Mann-Whitney test, these patients experienced a substantial reduction in the number of readmissions after depot therapy (Z = 4.0; p = 6 x 10-5).

Marriott and Hiep (1976) performed a mirror­image study of 131 patients, finding that, prior to depot treatment, the patients spent 12434 days in hospital. After antipsychotic drug treatment, pa­tients spent only 5619 days in hospital, a signifi­cant difference (p = 10-5) when we combine the results of male and female patients. Devito and his

Table IV. Mirror-image studies comparing number of hospital days with depot vs oral medication

Study No. of Duration No. of hospital days pValue patients (y) on oral medication on depot medication

Denham & Adamson (1973) 103 12-40 mos 8719 1335 10-15a

Devito et al. 1978 122 3329 314 10-2b

Freeman (1980) 143 12 19510 4376 10-25C

Gottfries & Green (1974) 36 2-6 12390 2940 1Q-4C

Marriott & Hiep (1976) 131 ~1 12434 5619 1Q-5c

Tegeler & Lehmann (1981) 78 5 19110 3276 10-5c

a Since these authors did not provide a p value or index of variance for number of hospital days, we calculated the p value from the difference in number of admissions.

b p Value as listed in reference.

c p Value calculated from graph or data provided in reference.

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coworkers (1978) also performed a mirror-image study examining the number of admissions in the depot group before the trial and comparing them with admissions afterwards. 57% of 61 patients had some admissions before the depot trial, but only 16 had admissions after the depot trial. Fur­thermore, the admissions were shorter, averaging 9.5 days after the trial, compared with 35.8 days before the trial.

In a mirror-image study performed by Freeman (1980), 143 patients spent 19510 days in hospital before treatment with depot medication, compared to 4376 days after depot medication. Freeman (1980) also presented a histogram in which pa­tients were stratified for a year of study, from 1966 to 1977. By extrapolating data from this figure we calculated that the net reduction in hospitalisation was highly significant (t = 13; p = 10-25). Although some inaccuracy may occur in the data as a result of the inexact nature of the charts, the trend is clearly shown.

It might be reasonably hypothesised that the re­duced rate of relapse was due to some time­dependent event during this time period (e.g. a gen­eral trend to hospitalise patients less often). The advantage of depot medication in comparison with oral medication is present in almost every year over this 12-year period, however, establishing that this phenomenon is primarily a depot versus oral phe­nomenon rather than a so-called secular trend.

Tegeler and Lehmann (1981) carried out a mirror-image study comparing time after a patient was switched to a long-acting depot antipsychotic vs the same time period while receiving classical, short-acting antipsychotics. Again, the use of a long-acting antipsychotic reduced the number of readmissions to about one-quarter of previous lev­els (t = 5.47; P = 10-6). When only the year before and immediately after use of long-acting medica­tions were compared for statistical analysis, the values were t = 17; P = 10-27 . Before using long­acting antipsychotics, the duration of hospital stay on average was 35 weeks. After switching to long­acting antipsychotics, the duration of hospitalisa­tion averaged only 6 weeks (t = 4.48; p = 10-5).

Drugs 47 (5) 1994

These 6 mirror-image studies comparing hospitalisation stays with depot vs oral medication are summarised in table IV. Almost all these studies failed to statistically analyse days in hospital or oral medication before or after days on depot med­ication. We performed these analyses, generally based on data available from charts given by these authors, and for all these studies, we found a sta­tistically significant decrease in the number of days hospitalised with the use of depot medication.

Johnson et al. (1983) examined 287 patients for almost 3 years after discharge from hospital. Pa­tients were allocated to 1 of 2 clinical follow-up teams depending on their place of residence. One team routinely prescribed depot injections, while the other prescribed oral medication. There was a marked difference in the relapse rate, in that 60% of the patients who received depot antipsychotics remained well throughout the follow-up period vs 40% of those who received oral medication. Of the patients who discontinued antipsychotics, only 20% remained well. Although not a randomised study, the referral process produced an dichotomy that provides evidence in support of depot therapy.

Devito et al. (1978) also reported a naturalis­tic/observational study that compared an outpa­tient setting where depot medication was pre­scribed with another where oral medication was used. Even though patients receiving depot medi­cation were sicker, with a higher percentage of pro­cess schizophrenic patients (i.e. those having symptoms from childhood with a gradual onset of illness) and a higher percentage of patients who never married, the number of readmissions was lower in this group. Of the oral group, 27 of 61 had readmissions compared with 15 of 61 in the depot group.

Youssef (1989) also performed a naturalistic study comparing 36 patients receiving haloperidol decanoate for up to 5 years with 28 patients receiv­ing other depot or oral antipsychotics, 11 of whom were receiving oral antipsychotics. The number of readmissions during the 5-year follow-up period was 0.6 ± 0.08 on haloperidol decanoate and 2.2 ± 0.24 in the comparison group. Since random as-

Depot Antipsychotic Drugs

signment and blind evaluation were not done, these findings must be viewed with caution.

The most important population in which to study depot vs oral medication is uncooperative, noncompliant patients. Yet, these patients are not readily available for research. This absence makes the case-controlled studies of Johnson, as well as mirror-image studies, especially pertinent, since it is practically impossible to do research on patients who are unlikely to volunteer for study. Certain patients would have to be randomly identified and targeted for a depot medication approach as extra treatment above and beyond what would normally be given. At the same time, the control population would not receive an active intervention. In addi­tion, considerable effort would be required to fol­low up both patient groups.

The same considerations would have to be ap­plied when evaluating the difference between de­pot formulations, such as a depot medication that lasts 1 month versus a depot medication lasting 1 week. One would expect no difference with pa­tients who are regular clinic attendees, while for patients who are not regular attendees, a formula­tion that lasts for a significantly long period of time might have considerable advantages.

3.3 Targeted Treatment

The principle behind depot medication is that it is superior to oral medication in noncompliant pa­tients. As mentioned above, however, these pa­tients do not typically volunteer for study. One method of gathering relevant data about whether continuous medication, as assured by depot admin­istration, is actually necessary is to deliberately in­terrupt continuous medication in a study control group and compare it with continuous administra­tion. In effect, this strategy is used with so-called targeted treatment studies, making it relevant here to review these investigations.

The premise of targeted treatment is as follows. Since patients with chronic schizophrenia often ex­perience nonspecific prodromal symptoms in the few days to a week preceding a relapse (Gaebel et al. 1993; Goldberg et al. 1977; Herz et al. 1991),

761

the clinician can medicate quickly in an attempt to abort the relapse. Further, if an impending relapse can accurately be predicted, then the clinician might effectively treat the patient by restricting or targeting medication to only those instances in which relapse is imminent, thereby eliminating the need for continuous medication.

To examine this premise, 5 controlled studies comparing targeted treatment with continuous maintenance medication have been performed (Carpenter et al. 1990; Gaebel et al. 1993; Herz et al. 1991; Jolley 1990; Schooler 1993). Jolley (1990) found that only 3 of 25 patients in a contin­uous-medication control group relapsed (2 requir­ing hospitalisation). Of 24 patients in the targeted treatment group, 12 relapsed and 8 required hospitalisation.

Herz and his coworkers (1991) found 15 of 50 targeted patients relapsed (with 12 rehospitalised), while only 8 of 51 in the continuous treatment group relapsed (with 8 hospitalised). Carpenter et al. (1990), in a randomised, controlled clinical trial found 53% of 57 targeted therapy patients relapsed (with hospitalisation), while only 36% of 59 con­tinuous-therapy patients relapsed with hospitalisa­tion.

Gaebel and coworkers (1993) found 159 of 364 patients completed their 2-year trial. 23% of the continuous medication group relapsed, contrasted with 63% of the crisis intervention group, who re­ceived medication only when relapse seemed im­minent, and 49% of the early intervention group, who received medication at the onset of predromal symptoms.

NIMH carried out a large collaborative study comparing targeted treatment with continuous and low dose treatment (Schooler 1993). The targeted group did substantially worse than the continuous group on all measures. The survival curve for tar­geted medication showed few patients did not re­lapse, whereas many patients were doing well without these indices of relapse on the standard medication, with low dose medication in between. Patients in the targeted group also required a sub­stantially greater amount of antipsychotic medica-

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tion overall compared with that needed in patients on standard dose depot medications. Examination of rehospitalisation rates indicates that the targeted group fared significantly worse than the other groups.

In summary, 5 well controlled studies of tar­geted vs continuous treatment show that episodic treatment is much less effective than continuous treatment. We performed a meta-analysis (Mantel­Haenszel test) that reveals that 25% of continu­ously medicated patients relapsed, in contrast to relapse in 50% in the targeted treatment groups (in one form or another, including crisis intervention). This result is highly statistically significant (p < 10-2°). Failure oftar:geted medication to be effec­tive is one of the greatest reasons why continuous depot medication, administered in a manner that avoid compliance problems, may be truly neces­sary in many patients.

3.4 Dosage Studies

There have been 4 dose-response studies of fluphenazine depot medication (Hogarty et al. 1988; Johnson et al. 1983; Kane et al. 1983; Marder et al. 1987). Generally, most groups used a stand­ard dose of fluphenazine decanoate 25mg intra­muscularly every 2 weeks, although some used dosage ranges, and compared either the standard dose or dose range with lower doses.

The lowest dose used was that by Kane and his coworkers (1983), who chose fluphenazine decanoate 1.25 to 5mg. In their study, only 3 of 64 patients in the standard dose group relapsed, while in the low dose (1.25 to 5mg) group, 26 of 62 pa­tients relapsed. Marder et al. (1987) used doses of fluphenazine decanoate 25mg in comparison to 5mg, although in this study, patients who showed very early signs of relapse could have their dosage doubled. We consider the 5 to 25mg dose to be their fixed starting dose. Of those on the starting dose of 25mg, 10 relapsed and 21 remained well. Of those on the lower dose of 5mg, 22 relapsed and 13 re­mained well. When the patients had early signs of relapse, their dose was doubled and the dose-

Drugs 47 (5) 1994

response relationship began to level out to no dif­ference.

Hogarty et al. (1988) employed doses of fluphenazine decanoate 25mg versus an average of 3.8mg and found that in the standard dose group, 6 of 25 patients relapsed, whereas in the low dose group, 9 of 30 patients relapsed. Though not statis­tically significant, relapses were more frequent in the low dose group, and had a larger sample size been used, the differences might be expected to reach statistical significance.

As alluded to in section 3.3, NIMH (Schooler 1993) performed a large, controlled clinical trial comparing targeted treatment, low dose mainte­nance treatment and full dose maintenance treat­ment. The study employed random assignment and was blinded with respect to medication. Patients could receive supplementary oral medication if they showed early signs of relapse, prodromal signs or other indications. This occurrence was not considered a drug failure per se nor a reason to drop a patient from the trial, since the investigators felt (and we share their opinion) that patients receiving depot medication should also receive oral medica­tion intermittently when they show prodromal symptoms of impending relapse.

As mentioned above, however, oral supplemen­tation is also a valuable indicator in evaluating the efficacy of a medication regimen and of supportive or intensive psychotherapy. If a patient requires continuous supplementation, then some aspect of the core depot medication or the psychotherapy support is failing. In this study (Schooler 1993), treatment was considered to have failed if patients required 140 days of oral supplementation. The 313 patients undergoing the trial were split almost evenly between the 2 dosage groups. A standard dose of fluphenazine decanoate 12.5 to 25mg every 2 weeks was administered, while the low dose group received 2.5 to 10mg. The results indicated that the low dose range was significantly less ef­fective than the standard range.

Thus, these 4 studies taken collectively clearly demonstrate that lower doses of fluphenazine decanoate are less effective than higher doses.

Depot Antipsychotic Drugs

Dosages of less than 2.Smg administered every 2 weeks appeared to be substantially less effective than the standard dose. Doses in the range of 2.S to lOmg were also somewhat less effective than those averaging 2Smg or greater. These findings roughly define the dose-response relationship for fluphen­azine decanoate. While some patients may be suc­cessfully maintained on doses in the range of 2.S to 10mg, many will require doses of 12.S to SOmg.

Johnson and coworkers (Johnson 1984; John­son et al. 1987) performed a dosage study using flupenthixol decanoate. On a standard dose (range 4 to 20mg), 4 of31 patients relapsed in 18 months. Of those who received half the usual dose (range 1.7 to 10mg), 12 of28 patients relapsed in this time period. We assume that the dose used in Johnson's half-dose group was equivalent to that used in the low dose groups of Hogarty et al. (1988) and Mar­der et al. (1987), but qualify this assertion, since there are no firm data for determining dose equiv­alence with confidence.

Aagrup-Andersson et al. (1974) performed what essentially was a dose-response study. These researchers identified a group of schizophrenic pa­tients, most of whom were stable on flupenthixol decanoate 40mg given every 2 weeks, although some patients received a slightly higher dose [3ml (60mg) every 2 weeks] and some a slightly lower dose [lml (20mg) every 2 weeks]. The patients were randomly assigned to 2 groups, 1 of which continued the full dose, while the other received placebo every other dosage interval. This research is similar, but not identical, to a dose-response study since it varies dosage interval as well as ab­solute dosage. Two of 29 patients from the full dose group relapsed, while 6 of 27 patients from the half-dose group relapsed.

Johnson and Wright (1990) provide a survey of dosages administered to schizophrenic outpatients in England by depot injection. They considered fluphenazine decanoate 2Smg every 2 weeks equal to flupenthixol decanoate 40mg every 2 weeks, which was considered equal to haloperidol decano­ate 100mg per month. In flupenthixol decanoate equivalents, we calculated from their data that

763

SOmg every 2 weeks was the average dosage, but the standard deviation was almost SOmg, with the range varying from 0 to 20mg every 3S or more days to over 100mg every 7 days (Johnson & Wright 1990).

Davis and coworkers (1993), in a multicentre collaborative study, compared the efficacy of hal­operidol decanoate 2S, SO, 100 and 200mg. They found that 2Smg per month differed significantly from the 3 higher doses, and defined the dosage range appropriate for haloperidol decanoate to be between SO and 200mg per month. In other words, the linear part of the dose-response curve for hal­operidol decanoate was roughly between SO and 200mg per month. The clinician should adjust the dose according to the patient's response within these approximate guidelines. Haloperidol decano­ate is available in a 100mg formulation, which is very useful, in that many patients need a dose of 100 to 200mg per month (McNeil Pharmaceutical 1993).

Hence, studies using the decanoate forms of flupenthixol and haloperidol are similar to the fluphenazine decanoate studies in that increased relapse rates are seen at the lower doses. The break point for the minimally effective dose would prob­ably be just slightly higher than the low dose ranges in the studies mentioned above. This find­ing would indicate that the clinician must balance several factors when choosing the proper therapy: (i) long term risk of tardive dyskinesia; (ii) the problem of dysphoric adverse effects; (iii) likeli­hood of a severe relapse; (iv) likelihood of suicide; and (v) the disruption caused by a minor relapse. It may be preferable to avoid more serious adverse effects at the cost of a few additional relapses if the relapses do not require hospitalisation or produce serious impairment in social functioning.

3.S Maintenance Medication and Psychosocial Treatment

Several studies have examined whether the pre­sence of psychosocial treatment has a beneficial effect above and beyond that produced by mainte­nance antipsychotics alone (Falloon et al. 1982;

764

Goldstein et al. 1978; Hogarty & Goldberg 1978; Hogarty et al. 1974, 1979, 1991; Leff et al. 1982, 1990; Muller et al. 1992; Tarrier et al. 1988). Since schizophrenic patients from families with high ex­pressed emotion (i.e. demanding, overcritical, with unrealistically high expectations of the patient) have higher relapse rates than those from families with low expressed emotion (Brown et al. 1972; Leff & Wing 1971; Vaughn & Leff 1976; Vaughn et al. 1984) it is plausible that psychosocial treat­ment may reduce the rate of relapse by reducing these stressors.

The effect of psychosocial treatment on relapse rates in schizophrenic patients taking antipsychotic medication is shown in table V. Of note, many of the earlier studies of family therapy were essen­tially done by strong supporters of psychosocial intervention in general or of family therapy specif­ically. Unfortunately, this enthusiasm introduces possible bias towards their treatment known as the Hawthorne effect (Benson 1984).

In addition, it is patently clear that those patients receiving family therapy are aware they are receiv­ing this therapy. No attempt at placebo psychother­apy was made. This should be a plausible interven­tion, with the nonspecific factors of therapy present, but with the specific factors of a given intervention absent. It is important to see if these family intervention techniques can be replicated under ordinary circumstances, such as in a collab­orative study where investigators are testing hypotheses originally formulated by others.

One such collaborative study is the large NIMH investigation (Schooler 1993) referred to in other sections of this paper. This study also examined the role of intensive group family therapy in the pre­vention of relapse. As well as being blinded with respect to medication, patients were also randomly assigned to receive either supportive family man­agement or intensive family treatment under con­trolled conditions. In addition, many patients had previous admissions and relapses, typical of the chronic relapsing schizophrenic patient treated by maintenance medication. All patients received some family intervention, but the intensity of ther-

Drugs 47 (5) 1994

apy given to the control group was modest com­pared with the concentrated psychotherapeutic ef­fort provided to the experimental group, who re­ceived weekly family therapy. Regrettably, family therapy showed no benefit over the control condi­tions. While we recognise the failure of this study to replicate the results of the studies shown in table V, we nonetheless encourage family interventions.

4. Maintenance Implications and Future Research

We feel that generalisations on treatment dura­tion should focus on the average schizophrenic pa­tient. If clinicians believe that schizophrenic pa­tients generally need lifelong maintenance medication, they will be more apt to prescribe med­ication in this fashion. On the other hand, if they consider schizophrenia a transitory phenomenon, equating a period of remission with permanent cure, they may be liable to stop the medication if the patient is doing well.

Ideally, we feel that relapsing schizophrenic pa­tients should be treated prophylactically with life­long medication after their first psychotic episode. However, we certainly do not advocate mainte­nance medication for a patient who will have only 1 psychotic episode and never suffer relapse. The problem in making this distinction is knowing at the first episode which patient is destined to have multiple relapsing schizophrenia and which may have just a single episode and never relapse, even in the absence of drug therapy.

This discrimination is an important area of re­search. The only predictive evidence we have is several studies showing that medication use in the past predicts relapse. In other words, patients who have been treated in the past with high doses of antipsychotics are more likely to relapse than those who have not (Carpenter et al. 1990; Hogarty et al. 1988).

Nevertheless, before antipsychotic drugs were discovered, a substantial body of literature indi­cated that process vs reactive symptoms predict the course of schizophrenia. A minority of first-epi­sode patients having just 1 psychotic episode with

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Table V. Relapses in patients treated with antipsychotic drugs with or without psychosocial rehabilitation

Study Comment Study duration No. of pts receiving drug alone No. of pts receiving drug and

psychosocial rehabilitation

well relapsed well relapsed

Falloon et al. (1982) 9mos 9 9 16 2

Goldstein et al. (1978)8 6wks 42 8 44 2

Hogarty et al. (1974)b 22mos 45 52 60 35

Hogarty et al. (1979) 2'1" 23 29 28 25

Hogarty et al. (1991)9 Compliant 2y 11 10 39 15

Noncompliant 2y 13 13

Leff et al. (1990) 2y 3 9 6 6d

Tarrier et al. (1988) High expressed 9mos 6 8 25 9b

emotion

Low expressed 9mos 7 2 7 2

emotion

a This is a 6-week follow-up after a brief hospitalisation. It is the results of treatment of the acute episode that is persisting into the

maintenance phase.

b The intensely treated groups had 3 relapses in 22 patients and the educational-only group had 6 relapses among 12 patients.

c Hogarty et al. (1979) also presents data for a 22-month period with 27 (without relapse) and 23 (with relapse) patients represented as

a period comparable with that in Hogarty et al. (1974).

d 4 relapses, 2 suicides.

e Hogarty et al. present data where information on the dose taken was available in 55 of 57 patients receiving active medication. Only 13 patients were noted to have taken their medication as prescribed; 18 did not take it at all; 12 had gross irregularities in the

dosage taken; and 12 had some irregularities.

excellent recovery have an illness referred to as 'reactive schizophrenia'. This concept was incor­porated into the Diagnostic Statistical Manual sys­tem as brief psychotic reaction, schizophreniform disease. Unfortunately, there is no research on maintenance medication in this indication. This form is associated with good premorbid function­ing and the acute onset of a florid illness without a prodrome and precipitated by marked environmen­tal stresses (Stephens & Astrup 1963).

In contrast, so-called 'process' schizophrenic patients have a premorbid personality charac­terised by asocial and eccentric tendencies from childhood, and have a very gradual onset of schizo­phrenia with many prodromal signs (Stephens & Astrup 1963). Although it is difficult to identify the exact age of onset, these patients tend to have rel­atively early onset schizophrenia and psychosis is not associated with acute environmental events.

Conceptually, therefore, those who have multi­ple relapsing schizophrenia should be treated after the first episode, but as has been shown, predictors of the relapsing variant of schizophrenia need fur­ther study. In determining the need for prophylactic antipsychotics, the outcome of the first episode might be a useful predictor in that some recover completely from the first episode, while others re­cover, but are still troubled by lingering symptoms. Perhaps in the future biochemical tests will be available to identify which patients need prophy­lactic medication from the outset.

In practice, it is nearly impossible to study schizophrenic patients for more than 5 years. Treat­ment recommendations must, thus, be made on the basis of available data. We feel that the 5-year limit the Consensus Panel on Neuroleptic Treatment (Kissling 1991 b) places on treatment misrepre­sents the problem. We know that the Consensus Panel was concerned about the lack of long term

766

data, but in certain ways it is appropriate to gener­alise from the existing data. Most importantly, we feel that the problem is that there may not be one recommendation that applies to all patients with schizophrenia or schizophrenic-like diseases. It would be better to identify which patients might be considered for lifetime maintenance treatment ver­sus which patients might need a relatively brief trial of antipsychotic medication (5 years or less). If the latter approach is taken, the answers are more readily apparent. In practice, schizophrenic pa­tients are seen regularly (e.g. every week or every month) by psychiatrists, so their condition is under continuous review. For example, patients are not placed on medication with the clear intention of their remaining on it for 5, 10 or 15 years. They are evaluated at every visit. However, we feel that the intent should be that many patients would receive medication for life.

It is our opinion that the Consensus Panel was wrong to recommend, on the basis of the fact that present studies are generally short term (i.e. a few years), that patients should not be placed on anti­psychotic medication for more than 5 years. As a practical matter, it is impossible to perform long term studies, but clinicians should, nevertheless, try to interpret their findings in a clear manner. An alternative and more precise way to view the data is to ask which schizophrenic patients need treat­ment for life and which do not, and to consider the problem of which subtype of patients an individual might belong to. In practice, patients are evaluated every time they come in to take their medication and the clinician can always change the prescrip­tion. Some patients probably will need treatment for life. Another type of patient may not need life­time medication; for example, a patient with a sin­gle psychotic reaction and an apparently complete recovery, who may have been stable for some years on medication.

Rather than think of a 5-year limitation on our data, we feel it is more useful to think of the prob­lem as a subtype problem. We already know that patients who have been stable for 1 to 5 years con­tinue to relapse if they are switched to placebo. It

Drugs 47 (5) 1994

is doubtful that extending this time period in a con­trolled study another 5 years is going to alter that. Although not systematically investigated, many of these patients have had multiple relapses in the past. More likely, a few patients may not need long term medication and we may be able to identify them by investigating subtypes of patients' re­sponses to treatment. To investigate this premise, we need a study that selects recovered schizophre­nic outpatients who have been stable on medication for several years with essentially no residual symp­toms and then switches them to placebo.

In addition, there are no data on patients who make a good recovery from their illness, return home with good functioning and no residual symp­toms and maintain this recovery on maintenance medication. We should focus our attention on this subgroup. When considering subtypes, we should remember that virtually no data exist regarding the prevention of schizoaffective disorder, a clearly re­current disease, which is treated with lithium, carbamazepine, valproic acid (sodium valproate) and/or antipsychotics.

Some argue that maintenance medication should not be started after the first episode. How­ever, this question has been investigated specific­ally by Crow and coworkers (1986), who found that many patients relapse when switched to pla­cebo after the first episode. In addition, they found that maintenance medication prevented relapse when given after the first episode, although statis­tically the relapse rate is higher in patients who have had multiple episodes.

Johnson (1979) also studied the relapse of first­episode schizophrenic patients who discontinued maintenance antipsychotics on doctor's orders. The relapse rate after the first episode was lower than the rate after multiple episodes, but there was an appreciable relapse rate (43%) at a maximum of 4 years follow-up. While it is common clinical sense to give maintenance medication to schizo­phrenic patients having multiple relapses, we re­ally need to know who should be started on main­tenance medication after the first episode. This knowledge can only come from studies that predict

Depot Antipsychotic Drugs

the variant of schizophrenia in which a psychotic episode occurs only once.

We point out that it would be desirable for in­vestigators who have carried out individual studies to pool data from their placebo-treated groups to see if they could reliably identify patients who do not relapse. Pooling mUltiple studies is necessary, since only a small minority of schizophrenic pa­tients do not require maintenance medication. Some information is already available, but not yet analysed.

5. Conclusions and Treatment Recommendations

The principal reason for administration of depot medication is to achieve continuous medication in the admittedly noncompliant patient. Another indi­cation for depot medication is frequent relapses in patients who do not report failing to take their med­ication.

We feel that when patients relapse frequently, it should be assumed that the relapse is due to non­compliance in the absence of hard evidence that compliance is assured. Of course, some patients cared for in transitional-care facilities ('halfway houses') may be reliably receiving medication, but they relapse frequently due to the severity of the disease.

While frequent relapse does not always mean noncompliance, it very often does. We have had the clinical experience of patients reporting that they are taking their medication, but whose plasma con­centrations indicate that they are not, although we have not performed a controlled study on this mat­ter. Nonetheless, if a self-proclaimed compliant pa­tient is relapsing, we believe the presumption should be that he or she is not, in fact, taking the medication as prescribed.

It has been shown that schizophrenic patients can have episodes of depression superimposed on the schizophrenia. Such depressed episodes are re­sponsive to treatment with antidepressant drugs and prophylaxis with maintenance antidepres­sants. The presence of depression is found most frequently in noncompliers than in compliers

767

(Johnson 1981; Pan & Tantam 1989). This latter finding has the obvious implication that the clini­cian should be alert to noncompliance in the schizophrenic patient with superimposed depres­sion or apathy.

When using depot medication, supplementation with oral medication for exacerbations, combined with psychosocial rehabilitation, may lower the re­lapse rate to one-fifth of the potential relapse rate. Thus, instead of having 10 to 15 relapses during a lifetime, a patient may have only 2 or 3. Many pa­tients, instead of being in the hospital every year or so, can now have long periods (5 to 10 years) without hospitalisation and with only very occa­sional relapses, allowing them to maintain a job and have a family.

Undoubtedly, not everyone will have as favour­able an outcome as this, but on the other hand, cli­nicians, particularly those who are hospital-based, are seeing a biased sample, because they are only seeing patients who do relapse. Those patients do­ing well in the community may be hospitalised only infrequently.

There is a philosophical point to be made re­garding whether recommendations should be ex­tended beyond areas where we have double-blind data. The question is: should patients be treated with medication for life or should they be consid­ered for discontinuation of treatment after a certain length oftime (e.g. 5 years of treatment)? For now, our recommendation is that patients predicted to relapse should be treated with lifelong mainte­nance medication.

Others would argue that this recommendation should apply only to a 5-year period because no one has done studies of a duration longer than 5 years. We disagree. In medicine, there will never be enough controlled studies to give us good data to make all possible clinical decisions. Therefore, rather than concluding that we cannot advocate treatment past 5 years because we have no data beyond this point, we need to make the best esti­mation at the present time using reasonable exten­sions from the available data. We agree with Kiss­ling (1991a), who in his very perceptive article

768

pointed out that the state of the art in relapse pre­vention is unsatisfactory, but a first step is to rec­ognise the need for medication for life.

The concept of lifelong treatment of relapsing schizophrenia should not be confused with the de­sire to know at first episode what type of psychosis a patient has. With reactive psychosis, prophylactic medication for life may not be necessary. Due to the hazards of long term adverse effects such as tardive dyskinesia, it is desirable to limit the use of antipsychotics. On the other hand, maintenance medication paradoxically may decrease the likeli­hood oftardive dyskinesia.

The vicious cycle created when patients are in­adequately treated with antipsychotic medication often causes patients to experience frequent re­lapses and break social ties. As a result, the course of schizophrenia deteriorates. We feel that inade­quate treatment with medication early in the illness may be related to more hospitalisations and higher dose treatment later on.

In fact, Johnson (1979; section 3.1) found that the experimental group that initially discontinued antipsychotics received a 20% greater cumulative antipsychotic dose than the continuous medication control group after 18 months. This was because 80% of patients in the experimental group experi­enced increased frequency and severity of relapses that ultimately required treatment with antipsy­chotics. Moreover, while a review of tardive dys­kinesia is outside the scope of this paper, some evi­dence exists that drug holidays may increase the incidence of tardive dyskinesia (Kane et al. 1992), although we hasten to add that this evidence is not definitive. Nonetheless, if clinicians overemphas­ise the minimisation of drug use, they may para­doxically exacerbate the problem with tardive dys­kinesia.

It is therefore desirable to prevent relapse using the lowest dose of medication necessary to achieve this. Patients who relapse on a certain dose should probably be tried on a higher dose. Since it may take years before relapse occurs, dosage adjust­ment is admittedly difficult. Furthermore, it takes 3 to 5 half-lives of a drug to establish a new steady-

Drugs 47 (5) 1994

state and increasing the dose of intramuscular med­ication would take much too long to be of immedi­ate benefit. Consequently, we recommend that pa­tients be maintained on an effective dose of maintenance medication, and when they show early signs of impending relapse, the clinician should quickly supplement the dosage with oral medication. Later, when their condition has stabilised, oral medication can be tapered and with­drawn.

We note parenthetically that it is impossible to do a controlled study on patients who fail to keep their appointments. Blinded studies require coop­erative patients who can give informed consent. We feel that there is a clear-cut advantage for drugs with longer dosage intervals, such as haloperidol decanoate in such patients. Given limited re­sources, a longer dosage interval puts fewer de­mands on the noncooperative patient to come to the clinic and, because of limited resources for home visits, fewer demands on the treating staff.

We would also like to emphasise that rehabili­tative treatment in comprehensive community services involves much more than maintenance medication. Moreover, although maintenance medication is a necessary precondition for compre­hensive rehabilitation, these services, if adequately funded and provided, allow patients to have rela­tively normal lives largely outside the hospital.

Cost-effectiveness studies show that outpatient treatment is only somewhat less effective in mon­etary terms than inpatient treatment. However, these comparisons are misleading in that the out­comes are substantially different in a qualitative sense (i.e. comparing apples with oranges). Outpa­tient rehabilitative programmes produce a much better quality of life than frequent hospitalisations, so that even though only a modest saving is realised, there is a substantial difference in the quality of life the patients experience. Kissling (1990), reviewing his own as well as Marder's and Gaebel's work, estimates that in Germany only about 50% of patients who need prolonged antipsy­chotic medication receive it.

Depot Antipsychotic Drugs

Since the problem with noncompliant patients is that they do not reliably take their oral medica­tion, intramuscular medication can be a substitute, but only if the patients come for their appoint­ments. Accordingly, home visits and telephone contact to follow up and reschedule missed ap­pointments may be tried.

There is a large body of data on how to prevent schizophrenic relapse. These data teach us much about the nature of the relapse process. Particularly pertinent here is that a large number of relapses occur because of patient noncompliance. As Kiss­ling (1990) pointed out, some of the failures to pre­vent relapse might well be characterised as 'physi­cian noncompliance' .

We feel that physicians should recognise the progressive nature of schizophrenic relapse and try to prevent relapse by the systematic application of maintenance medication. In particular, they should consider the administration of depot medication in patients who do not take their oral medication. Much of the work has been done with fluphenazine enanthate or flupenthixol, but the same principles apply to-any depot medication. The longer the dos­age interval and the fewer adverse effects, the bet­ter the formulation and the more readily a drug will be used.

We feel that the findings of this body of data generalise to relapse prevention in schizophrenia far beyond the specifics of the design of a particu­lar study. In summary, most patients with schizo­phrenia need medication for life and, where non­compliance is a problem, depot medication should be given.

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Correspondence and reprints: John M. Davis, MD, lliinois State Psychiatric Institute, Research Department, 1153 N. Lavergne, Chicago, IL 60651, USA.