schizophrenic out-patients. trial of fluphenazine ...

1 downloads 0 Views 1MB Size Report
SUMMARY. Fifty-seven patients with a diagnosis of schizophrenia were started on either fluphenazine decanoate or flupenthixol decanoate injections.
Depressive and extrapyramidal symptoms and clinical effects: a trial of fluphenazine versus flupenthixol in maintenance of schizophrenic out-patients. A Knights, M S Okasha, M A Salih and S R Hirsch BJP 1979, 135:515-523. Access the most recent version at doi: 10.1192/bjp.135.6.515

Reprints/ permissions You can respond to this article at Downloaded from

To obtain reprints or permission to reproduce material from this paper, please write to [email protected] http://bjp.rcpsych.org/cgi/eletter-submit/135/6/515 http://bjp.rcpsych.org/ on July 29, 2011 Published by The Royal College of Psychiatrists

To subscribe to The British Journal of Psychiatry go to: http://bjp.rcpsych.org/site/subscriptions/

Brit.J. Psychiat.(1979), 135,515-523

Depressive and Extrapyramidal Symptoms and Clinical Effects: A Trial of Fluphenazine versus Flupenthixol in Maintenance of Schizophrenic Out-patients By ANGELA

KNIGHTS,

M. S. OKASHA, MOHAMED and S. R. HIRSCH

AL! SALIH

SUMMARY Fifty-seven patients with a diagnosis of schizophrenia were started on either fluphenazine decanoate or flupenthixol decanoate injections in a double-blind trial just prior to discharge into the community. During the six month follow-up 30 per cent dropped out of the treatment. Of those observed for six months, 7 per cent relapsed, 54 per cent experienced depressive symptoms and 88 per cent extra pyramidal side-effects. Analysis of both clinical data and the ratings failed to discriminate between the two drugs. The

beneficial

effect of maintenance

drug

A recent double-blind

therapy in schizophrenia has been established in a number of trials; it has been shown by Hirsch ci al (1973) to prevent the recurrence of florid schizophrenic symptoms in patients with chronic or relapsing schizophrenia.

The depot

preparation

of fluphenazine

certain

canoate has been used for a number of years as maintenance treatment,yetitcausesundesirable side-effects in many patients. Extrapyramidal effects of varying degrees of severity were found in at least a third of cases reported by Johnson (1973). There are also reports byJohnson (1973) and Alarcon and Carney (1969) of depressive symptoms appearing or worsening during treat ment. These effects may cause patients to defect from treatment.

Flupenthixol,

a trifluomethylated

thioxan

be less sedative

and to produce

fewer extra

pyramidal side-effects than fluphenazine (True man and Valentine, 1974). There have even been reports of elevation of mood, cheerfulness and increase of energy in patients receiving flupenthixol injections (Carney and Sheffield, 1973) and in a few casesa manic reactionhas been reported (Hall and Coleman, 1972).

of low-dose

patients suffering depression, suggesting that flupenthixol has an antidepressant action in patients

(Young

ci al,

1976).

A comparative review of the literature (Okasha et al, 1978) regarding the relative

de

thene derivative, was introduced in 1963, and has been widely used in Europe. It is claimed to

comparison

oralflupenthixoland amitriptyline did not dis criminate between the two drugs for out

superiority of flupenthixol and fluphenazine has been inconclusive. Kelly and his co-workers

(1977) recently published a report of a double blind comparison of the two drugs in patients who had previously stabilised on depot in jections and were living in the community. Their results failed to confirm any advantage of one drug over the other, either on negative symptoms of schizophrenia or on social func tioning. Other comparisons between flupenthixol and fluphenazine decanoates have either combined treatment in the acute and maintenance stage (Johnson and Malik, 1975), have involved chronic in-patients (Haslam et al, 1975) or failed to incorporate a double-blind design. Ours is the first report to date involving a double blind comparison of maintenance treatment for

in-patients while they are receiving depot injections immediately prior to discharge into 515

516

TRIAL

OF FLUPHENAZINE

the community. We surveyed a different population of patients from chronic in-patients or those already discharged and maintained in the community. The trial examined the two treatments for :— (1) Their

efficacy

psychotic

as

maintenance

anti

medication.

(2) Their effect on mood, toms of depression. (3) The incidence and pyramidal side-effects.

especially severity

of

symp extra

a variety

of reasons

and

their clinicians to need maintenance therapy with neuroleptic drugs were included provided they had not received any depot injection for three months prior to inclusion in the trial. Patients were also excluded if (a) the diagnosis was

later

70 per

cent

of these

did so within the first six months of treatment (Johnson and Freeman, 1973). Johnson (1973) also reports that 60 per cent of extrapyramidal side-effects occur after three months of regular treatment. Six months was therefore chosen as the study period, since undesirable effects of the drugs were likely to appear during this time.

Methods Selection ofpatients All possibly schizophrenic patients admitted to a psychiatric unit in a London district general hospital were screened by the Syn drome Check List during the first year of the study. The Syndrome Check List is derived from 140 symptoms in the 9th edition of the Present State Examination (PSE) (Wing et al, 1974). The items are combined to form 38 syndromes and can be rated from the case notes for recent and past episodes. The first 25 syndromes can be fed into later stages of the Catego programme in order to reach a diagnostic classification. The criteria for diagnosis of nuclear schizo phrenia were based on first-rank symptoms of Schneider (Wing et a!, 1974). Later, patients were included from two other psychiatric units in London. All those who were considered by

changed

to affective

psychosis,

(b)

they

did not wish to receive injections, (c) they in tended to leave the area, and (d) the clinicians felt that the prognosis was too good or too poor to warrant this form of treatment. The Syndrome Check Lists were processed using

Treatment of out-patients provides a more exacting test of the effectiveness of the drugs than in-patient treatment because of the stresses often surrounding discharge from hospital and the greater relapse rate in those patients returning to critical or overprotective environ ments (Vaughn and Leff, 1976). In a survey of drug defaulters on long-acting medication about 20 per cent of patients discontinued treatment for

VERSUS FLUPENTHIXOL

the

Catego

programme,

and

in most

cases

the diagnosis was in agreement with clinical judgement. Of those 30 patients included in the study in the first year 87 per cent were diagnosed as

unequivocally

criteria

schizophrenic

by

the

Catego

(Wing et a!, 1974).

Instruments

1. The Present State Examination (PSE) was administered by a member of the research team, who was not involved in clinical de cisions, at the beginning and end of the trial or if the patient relapsed. 2. A Depressive Rating Scale (DRS) based on relevant items from the PSE was devised by the authors

and

was

completed

by

the

clinician

at

the beginning and end of the trial or, if any of the staff thought it necessary, during the trial. 3. Ratings on an extrapyramidal rating scale based on a scale used by Mindham et al (1972) were made at the beginning and end of the trial and also during the trial if the administration of antiparkinsonian

drugs

was

indicated.

The

rating scale includes a detailed physical exam ination and assessment of gait, tremor, rigidity, akathisia and dystonias, testing right and left arms and legs separately where relevant (scale available from authors). Treatment Oral medication prior to entry into the trial was restricted, where possible, to chlorproma zinc or trifluoperazine, and all oral neuroleptics were discontinued after the full dose of the trial drug had been administered. Each patient was started on either fiuphenazine or flupenthixol under double-blind conditions. Two injections were given on each occasion, one ampoule containing an inert substance, the other an

ANGELA

active

M. S. OKASHA,

form of one of the two drugs,

flupenthixol dose

KNIGHTS,

or 25 mg of fluphenazine.

(12.5

mg

of fluphenazine

MOHAMED

40 mg of

A test

or 20 mg

of

flupenthixol) was given after the intial evalu ation had been made, and all medication was reduced by half for one week and stopped com pletely

when

the

full dose

was

administered.

Most patients left hospital at this stage and continued to receive injections at three weekly intervals on an out-patient basis. The clinician was free to increase the dose of the drug pro viding the frequency of the injections remained

the same. In fact no patients warranted an increase in dose and several had the dose decreased, but only at the end of the trial after the final assessment. If the clinician felt the patient showed re currence of psychotic symptoms warranting a change in treatment and the patient was con sidered to have relapsed, all the evaluative tests were repeated and the patient was taken out of

517

AL! SALIH AND S. R. HIRSCH

the trial. If the clinician thought the patient was depressed and needed specific antidepressant therapy, the Depressive Rating Scale was re peated before treatment commenced. Similarly if antiparkinsonian drugs were required one of the research team assessed the patient immed iately before prescribing such drugs. The criteria for deterioration for each of the three areas under investigation were based on the clinician's opinion only. The research instruments were administered by an independent researcher. The end of the trial for each patient is defined

for this study as either completion treatment

of six months

or being taken out of the trial because

of a relapse as defined by a need to intervene clinically with other neuroleptic treatment. Results A comparison of the two treatment groups shows no important or significant differences for social and clinical variables.

[email protected] I Comparison of treatment groupsfor social and clinical variables. (Percentagefigures in brackets) Flupenthixol

Fluphenazine

n = 28

n = 29

Males

11(39)

12 (41)

Age 16—39

20(72) 8 (28)

21(72)

23 (82)

23 (80)

14(50)

18(62)

24(86)

15 (52)

40—65 Marital

8(28)

status

separated

and unmarried

Employment

unemployed

Living situation: with relative or companion alone hostel

1 (4) 2 (7) 2 (7)

no fixed abode or other Years since first admission for schizophrenia: 0-4 5 or more not known

Number of admissions for schizophrenia

0 2 or more not known

17 (61)

7(25) 4(14)

8(28) 4(14)

2 (7) 17(59) 10(34)

2 (7)

in past: 6(21) 7(25) 10(36) 5(18)

8 (28) 7 (24) 12(41)

2 (7)

518

TRIAL OF FLUPHENAZINE VERSUS FLUPENTHIXOL

Two patients in each treatment group relapsed (7 per cent). The readmission rate to the ward or day hospital during the trial was similar in both groups; eight patients (29 per cent) on flupenthixol and six patients (21 per cent) on fluphenazine were admitted for a variety of reasons which included relapse of schizophrenia, extrapyramidal side-effects, de pression and social factors. The drop-out rate in this study was high, an overall rate of about 30 per cent. Six patients (21 per cent) on fiupenthixol and eleven patients (38 per cent) on fiuphenazine dropped out of the study. The difference is not significant. It was not possible to follow up all the patients who dropped out. Of those who dropped out 80 per cent did so within the first three months. Some of the reasons are similar to those for exclusion from the trial, for example, moving away from the area or refusing injections. Others disliked the side-effects of the drugs. Eleven of the 17 patients

who

were

unwilling

to

continue

assessed at the time of leaving the study; had extrapyramidal side-effects.

were

they all

The clinical relapse rate was very low and the same in both groups. The PSE was analysed by a comparison

of the

treatments

over

time

on

the

basis of mean scores of six groups of symptoms based on the PSE syndromes. The symptom groups

used

for

the

analysis

were

derived

by

adding PSE scores from the individual ratings to make up the following six subscores derived from Catego syndromes :—

(b) SD-Simple depression (excluding rat ings in 3a above), ED-special features of depression, OD-other symptoms of de pression, IC-loss of interest and concen tration, NG-self neglect. 4.

Depressive delusions and hallucinations DD-Depressive ations.

delusions

and

hallucin

5. Anxiety and tension TE-Tension, Irritability, tion. 6.

GA-General WO-Worrying,

anxiety, IT AG-Agita

Slowneis and lack of energy SL-Slowness,

LE-Lack

of energy.

Because of the importance which has been attached to the tendency of one treatment or the other to affect the individual symptoms and syndromes such as depression and anergia, com parisons were made between the Catego defined syndromes at the final evaluation with and without an analysis of covariance. A comparison of the

mean

scores

showed

no difference

between

treatments

on the mean scores for schizophrenic

or general

psychotic

or end

of the

trial.

symptoms These

two

at the sets

beginning

of scores

were

derived from the subscores of Catego syndromes listed above. Similarly, there was no difference between treatments for specific schizophrenic or general psychotic symptoms, on the Wilcoxon matched pairs signed ranks test or the Mann Whitney U test.

1. Specific schizophrenic symptoms NS-Nuclear 2.

Depression

Syndrome.

Results are given the trial or relapsing,

General psychotic symptoms CS-Catatonic syndrome, NP-Non-specific psychosis, PE-Delusions of persecution, GR-Grandiose and religious delusions, SF-Sexual and fantastic delusions, OH Olfactory hallucinations, AH-Auditory hallucinations.

3.

Depression (a) Depressed mood pressed mood (sign).

(symptom),

de

of

the

trial

because

for 36 patients completing plus one who was taken out of

severe

extrapyramidal

side-effects. Syndrome groups described above relating to depression on the research doctor's PSE assessments at the outset and end of the trial were compared, using an analysis of covariance and showed no significant differences between the treatment groups. The Depressive Rating Scale (DRS) was devised for the clinician concerned with the patient to rate depression, and was based on relevant depres sion items in the PSE (scale available from

ANGELA

KNIGHTS,

M. S. OKASHA,

MOHAMED

authors). Scores for items which were strong diagnostic indicators of endogenous depression were weighted and a total score for each patient

treatments

but

patient

received

prescribed

having

antidepressants

depression

or increased

or

there

was

an

increase

of symp

toms over the trial period for both groups. No

was derived for each assessment. Conservative criteria of a change of at least seven points were required before a patient would be regarded as developed

519

ALl SALIH AND S. R. HIRSCH

ECT,

but

antidepressant

flupenthixol

27 per

and four patients

were

on fluphenazine).

Seven out of eight of the patients improved,

cent

drugs (six patients on prescribed

and of those who did

decreased severity of depression. The number of patients who received antidepressant medi cation was also noted for each treatment group. Because depression ratings were only made if depression became clinically evident during the trial and many patients dropped out early, there was not sufficient information available

not receive antidepressants six out of eight improved (the two patients in each group who were depressed at the time long-acting injections were started were not included). Thus there was a tendency for depressive symptoms to improve regardless of antidepressant drug treatment.

on drop-outs to include them in the analysis. Of the patients who completed the trial 43 per

Extrapyramidal

cent had an onset or increase of depression at some point after starting maintenance depot injections, but the incidence of depression did not differ between the two groups. The overall incidence of depression was 53 per cent for those on flupenthixol and 55 per cent for those on fluphenazine, including the two patients in each group who were noted to be depressed at the first assessment

but improved

during

the trial.

A change based on ratings made by the clinicians on the DRS at the time a change in depression was noted clinically was compared with ratings made by a clinician at the start of the trial; this showed no difference between

side-effects

The incidence of extrapyramidal side-effects is shown in Table III. Because extrapyramidal side-effects

dropping dropped

appeared

early or were a reason

out, information out was included

from patients in this analysis.

for

who Of

the 57 patients who started the trial 42 (74 per cent) developed extrapyramidal side-effects following the test dose, but an effect from previous oral medication cannot be excluded. During

the

extrapyramidal

trial

42

(74 per

cent)

exhibited

side-effects and they were not

necessarily those affected from the onset. Of the 40 patients who completed the six-months 22

(54 per cent) showed extrapyramidal

side-effects

T@usutII Depression during maintenance treatment of schizophreniafor patients who completed the trial (Percentagefigures in brackets) Flu

=l9**Fluphenazine npenthixol

n=l8SignificanceOnset trial5(26)5(28)NSWorsening of depression during of depression present at beinning of trial3 (16)3(17)NSTotal depression8(42)8(44)NSDecreaseofdepressionpresentatbeginningoftrial2 number with increased

(11)NSDepression change00Overall rated

at beginning

(Il)2 of trial but no

incidence of depression identified by clinicians10(53)10(55)NS

•¿@ For three patients no Depressive Rating Scale was completed at the end of the trial. Data from the PSE ratings for depression were analysed for these patients as described in the text.

520

TRIAL

OF FLUPHENAZINE

VERSUS FLUPENTHEXOL

TABLE

III

Extrapyramidal symptoms: comparison of treatment groups

(Percentagefigures in brackets) Flupenthixol n=28Fluphenazine

n=29Significance(a)Incidence ofextrapyramidal symptoms (76)NSduring following test dose20 trial NS(b)Use *Final assessment20

(71)22 (71) 14 (50)22

(76) 17 (59)NS

medicationfollowing of antiparkinsonian

(31)NSduring test dose11(39)9 (62)NSTotal trial12

(43)18

number who received medication23 *

Final

assessment

refers

to

either

six

month

follow-up,

at the six month assessment regardless of whether they had been treated with anti parkinsonian drugs. Seventeen patients dropped out, and of those 11 were assessed at drop-out and they all had extrapyramidal side-effects. One patient receiving fluphenazine had no ratings at either assessment. Table III shows that 50 (88 per cent) of the patients who entered the trial had antiparkin sonian medication at some stage in the trial period. Apart from two patients, antiparkin sonian medication was given to all patients who had a score on the extrapyramidal rating scale. Only one patient had to be withdrawn from the trial because of extrapyramidal side effects (which were worsening in spite of anti parkinsonian medication). Table III shows there was no significant difference between the two treatments in the prevalence of extrapyramidal side-effects after the test dose, during the trial and at six-month follow-up. There were no differences between treatments in the number of patients requiring antiparkinsonian medi cation following the test dose and during the trial. Although there were no differences between the treatment groups for prevalence of extra pyramidal side-effects or use of antiparkin sonian medication, a further analysis was carried out to determine whether there was any difference in the severity of extrapyramidal side-effects. These results are shown in Table

(82)27 time

of

drop

out

(93)NS or

relapse.

TABLE

IV

Severity of extrapyramidal side-effects (percentage figures in brackets)

EPSEFlup nenthixol = 28Flup 29TotalSevere10818(32)Moderate101626

nhenazine =

(46)Mild7411(19)

All between group comparisons not significant.

IV.

This

Table

was derived

by taking

the

highest rating on specific symptoms for each patient at any time during the trial: Severe symptoms —¿equivalent to maximum rating for one or more symptoms. Moderate symptoms —¿equivalent to any inter mediate rating in the absence of any maxi mum ratings. Mild symptoms —¿no rating of more than one on any symptom. All patients included had more than one symptom and only appeared once in the Table. It can be seen that there are no significant differences in severity of extrapyramidal side effects between the treatment groups. The extrapyramidal scales were also subjected

ANGELA

to an analysis each symptom

KNIGHTS,

M. S. OKASHA,

of covariance using subscores for of the extrapyramidal syndrome

including

gait, rigidity,

akathisia.

This suggests

tremor, there

dystonia

and

side-effects.

Depression

trend

Our finding of depression during

depot

should be considered reported phenazine was

first

elsewhere. decanoate made

maintenance

treatment

in the context of studies The suggestion caused severe

that flu depression

by Alarcon

and

their

by demonstrating

who supported

temporal

in 53 per cent of

relationship

claim

Carney

between

the

(1969),

a

adminis

among

patients

continuing

on

fluphenazine

injections and 17 per cent for those switched to placebo. Johnson (1973) identified a depressive mood swing requiring treatment in 15 per cent of patients on fluphenazine. He commented that he was unable to demonstrate an acceptable correlation between the rating score and clinical depression in overtly ill schizophrenic patients and concluded that the only objective measure ment that could be made for the incidence of depression was the decision to start anti depressive treatment. Since he could not demonstrate a temporal relationship between depression and the administration of the drug,

he concluded

that it would be wrong to assume

that there was any evidence that fluphenazine had any specific effect on mood that differed from the action of other phenothiazines. Carney and Sheffield (1973) detected depres sion in 15 per cent, (10 per cent severe, 5 per cent moderate) of a group of patients on flupenthixol decanoate; they stated that the incidence of depression, although no higher than that encountered in fluphenazine treated patients, was

disappointingly

high

for

a drug

used,

in

lower dosage, specifically for the treatment of neurotic depression. They found transient hypomania in 7 per cent of their patients and anergia in 7 per cent of patients. Johnson and

that it caused problems In the fluphenazine group

was towards

a lowering

of mood.

in the

These

results refer to acutely ill patients, not to those on maintenance treatment. The incidence of a depressive

syndrome

in

53

per

cent

of

our

patients

over six months is much higher than

reported

elsewhere.

The fact that 27 per cent of

the patients were prescribed the independent clinicians rating

tration of the drug and the onset of depression in one of their patients. They gave an overall incidence of depression of 8 per cent. Hirsch et al (1973) found a lower incidence of 3 per cent

a change

that was so marked in four patients who were already elated at the time the drug was first

administered management.

Discussion

patients

Malik (1.975) reported a significant elevation of mood with flupenthixol in six out of twenty patients after the first injection and in five out

of twenty after the second injection,

was no difference

between treatmentsin the nature of extra pyramidal

521

MOHAMED AL! SALIH AND S. R. HIRSCH

antidepressants suggests that

scale did not have a low threshold

in overrating

symptoms,

least six different

management idiosyncratic

or bias

and as there were at

psychiatrists

involved

this is unlikely prescribing

by our

in the

to be due

to

habits.

The role of long-acting antipsychotic drugs in the causation of depression in schizophrenic patients is far from clear. Martin and Townend (1974) observed that eight patients described as depressed had this manifestation reversed within 72 hours of prescribing antiparkinsonian medication. Certain symptoms of depression

may resemble those of parkinsonism and it may be difficult to separate the two syndromes. Our findings confirm incidence of depressive taking

antipsychotic

other reports of a high symptoms in patients medication

likely to be entirely symptoms

being

due

and

are

un

to extrapyramidal

misinterpreted

as depression,

as

half the depressed patients improved without medication. This leaves unanswered the question whether the symptoms were due to neuroleptic medication, were a reaction to the illness, or were present all the time but only became apparent in the absence of psychotic symptoms (Van Putten and May, 1978). Extrapyramidal

side-effects

It can be seen from Table III that the patients receiving fluphenazine showed a higher, but not significantly greater, incidence of extra pyramidal side-effects at the end of the trial or when dropping out of the trial. Johnson (1973) found extrapyramidal

side-effects

in 34 per cent

522

TRIAL

OF FLUPHENAZINE

of 140 patients on fluphenazine, a lower incidence than we observed. He considered this figure to he an underestimate, attributed to the fact that all his patients were receiving anti parkinsonian medication. Carney and Sheffield (1973) detected extrapyramidal side-effects in 28 per cent of patients on flupenthixol and commented that the routine prophylactic prescribing of antiparkinsonian drugs with flupenthixol decanoate would appear to be unjustified. Martin and Townend (1974) re ported only 30 per cent of patients on flu phenazine decanoate exhibiting extrapyramidal side-effects. Our findings are in agreement with Kennedy et al (1971), who found a prevalence of 88 per cent in patients taking trifluoperazine, which, like fluphenazine has a piperazine side chain. Their study involved regular detailed examin ation of each patient by two observers. We think our high figures are due, at least in part, to the fact that we stopped all antiparkinsonian medication with the first full dose of the depot injection and due to our detailed physical examinations and recording of extrapyramidal side-effects irrespective of severity. Our results also agree with those of Ching-Piao Chien et al (1974), who found one or more incidents of extrapyramidal side-effects with various degrees of intensity in all but one of 41 patients on fluphenazine (i.e. 98 per cent). This trial did not provide any evidence to support the claims that flupenthixol is less likely to cause extrapyramidal side-effects, or lowering of mood, slowness or lack of energy. Moreover, none of our patients appeared to

experience

the elevation

of mood described

by

other workers. The present study is one of the first attempts to compare, in the community setting the two decanoate depot preparations most widely used for maintenance treatment of schizophrenia. The drugs had a similar potency in preventing the remergence of schizophrenic symptoms. The method of observation revealed a higher incidence of depressive and extrapyramidal symptoms than other studies, but if our method was more sensitive in detecting symptoms it nevertheless did not reveal differences with

VERSUS

FLUPENTHIXOL

regard drugs.

to

these

symptoms

between

the

two

Acknowledgements We would like to thank Dr Peter Dally and all the consultants

and

staff

at Queen

Mary's

Hospital,

Roe

hampton, St Mary Abbot's Hospital, Kensington and at Charing Cross Hospital, Fulham, who co-operated enthusiastically in setting up and carrying out this trial.

We would also like to thank Dr A. A. Schiff of the pharmaceutical company, helped with the analysis ceutical

company,

E. R. Squibb and Co. Ltd. who of the data and the pharma

Lundbeck

Ltd.

who

also

helped

process the data and supplied the packaged drugs for the trial, Dr M. S. Simister, Mr Gerald Samuel and many others from Lundbeck who took part in discussions at all

stages. References ALARCON, R. DE & CARNEY, M. W. P. (1969) depressive mood changes intra-muscular fluphenazine

following injection.

Severe

slow release British Medical

Journal, iii, 564—7. CARNEY,

M.

W.

P.

& SHEFFIELD,

B. F.

(1973)

The

long

term maintenance treatment of schizophrenic out patients with depot flupenthixol. Current Medical

Researchand Opinion,1,423—6. CHING-PIAO CHIEN, DIMAscI0,

A. & COLE, J. 0.

(1974)

Antiparkinsonian agents and depot phenothiazines. American Journal of Psychiat ry, 131,86—90. HALL,

P.

& COLEMAN, J.

(1972)

treatment of schizophrenia. 120, 241—2.

Flupenthixol

in

the

British Journal of Psychiatry,

HA5LAsI, M. T., BROMHAM, B. M. & SCHIFF, A. A. (1975)

A comparative trial of fluphenazine decanoate and flupenthixol decanoate. Acta Psychiatrica Scandinavica, 51,92—100. HIRSCH, S. R., GAIND, R., ROHDE, P. D., STEVENS,B. C. & WING, J. K. (1973) chronic schizophrenic

fluphenazine:

Out-patient patients

double-blind

maintenance of with long-acting

placebo

trial.

British

MedicalJournal, i, 633—7. JOHNSON, D. A. W. (1973) The side-effects of fluphenazine decanoate. British Journal of Psychiatry, 123, 5 19—22.

& FREEMAN, H. (1973) Drug-defaulting by patients on long-acting phenothiazines. Psychological Medicine, 3,115—9. & MALIK, N. A. (1975) A double-blind comparison of

fluphenazine

decanoate

and

flupenthixol

de

canoate in the treatment of acute schizophrenia. Psychiatrica Scandinavica, 51, 257—67.

Acta

KELLY, H. B., FREEMANTLE, H. L., BANNING, B. & SCHIFF, A. A. (1977) Clinical and social comparison

of fluphenazine canoate

schizophrenia. 56—64. KENNEDY,

decanoate

in the community

P. F.,

de

therapy

of

International Pharmacopsychiatry, 12, HERSHON, H.

(1971) Extrapyramidal phenothiazine therapy.

118,509—18.

and flupenthixol maintenance

I.

& MCGUIRE,

R. J.

disorders after prolonged British Journal of Psychiatry,

ANGELA MARTIN,

I. C. A.

KNIGHTS,

& TowNE@n,

R.

M. S. OKASHA, A.

(1974)

MOHAMED

Implications

of sustained release phenothiazines: a study of fluphenazine decanoate. British Journal of Psychiatry, 124, 173—6. MINDHAM, R. I., GAn@n, R. & ANErFI, B. H. (1972) Comparison of orphenadrine and placebo on the control of phenothiazine-induced parkinsonism. Psychological Medicine, 2,406-13.

[email protected]@,M. S., HIRSCH,S. R., KNlosrrs, ANGELA& SALIN, M. Au (1978) Flupenthixol and fluphenazine decanoate—a comparative review. Psychiatric AnnaLs, 8,350—5. TRuI@@eAN, H. R. & VALENTINE, M. G. (1974) Flupen thixol decanoate in schizophrenia. British Journal of

Psychiatry,124, 58-9.

Angela Knights, W6 8RF,

AL!

SALIH

AND

S. R.

523

HIRSCH

VAN Pu'rrEN, T. & MAY, P. R. A. (1978) Akinetic depression in schizophrenia. Archives of General Psychiatiy,35, 1101—7. VAUGHN, C. E. & Lazy, J. P. (1976) The influence

of

family and social factors on the course of psychiatric illness. A comparisonof schizophrenic and depressed

neurotic patients. British Journal of Psychiatry,129, 125—37. WINO,

J.

K.,

CoOPF.R,

J.

E.

& SARToRIUS,

N.

(1974)

The Measurementand Classificationof PsychiatricSymp. toms.Cambridge University Press.

Yo@m@o,J. P. R., Huonzs, W. C. & Li@naa,M. H. (1976) A controlled comparison of fluphenazine ann triptyline

in depressed

out-patientL

British Medical

Journal, 1, 1116—8.

MB.,[email protected], Department of Psychiatty, Charing Cross Hospital, London

M. S. Okasha, M.D.,M.R.C.Psych., 12 Case Street, Norwich, Connecticut06360. Clinical Instructorin Psych iatry, Tale University School of Medicine,

Mohamed Au Salih, M.B..B.S.. M.R.c@P@ch., Consultant Psychiatrist, WhutecrofiHospital, Isle of Wig/it, Professor S. R. Hirsch, M.D.,M.Phil..M.R.C.P.,F.R.C.PIYCIL, Department of Psychiatry, Charing Cross Hospital, London W6 8RF

(Received 31 May 1978; revised 1 May 1979)