The safety and efficacy of zotepine in thetreatment of schizophrenia: Results of aone-year naturalistic clinical trial

K PALMGREN1, A WIGHTON2,

CW REYNOLDS2, A BUTLER2,

JA TWEED2, J RANIWALLA2,

CP WELCH2 AND JR BRATTY2

1Ekasen Sjukhus, 10600 Ekenas, Finland; and

2Knoll Pharmaceuticals, Nottingham,

NG1 7AR, UK.

Correspondence Address

Dr K. Palmgren, Ekasen Sjukhus, 10600

Ekenas, Finland.

Tel: +358 19 224 3200 or +358 19 2241

Fax: +358 19 246 2319 or +358 19 224 3990

E-mail: kaj.palmgren@vns.ushp.fi

Received 11 October 1999; revised 10 April2000; accepted for publication 17 April2000

INTRODUCTION AND METHOD: The safety and efficacy of zotepine,75 ± 450 mg/day, were evaluated in an open multicentre one-year study inpatients suffering from acute exacerbation of schizophrenia; totalexposure amounted to 152.78 years.

RESULTS: Mean BPRS total score was reduced from 51.7 at baseline to40.8 at end-point (P <0.05). Similar significant reductions at all studytime-points were recorded for BPRS total and subscores, CGI severity andimprovement , BAS total scores and SANS total and global scores.Significant improvement s in EPMS and AIMS were recorded from week 12to end-point. Clinically significant improvements in acute symptoms,detected early in the study, were maintained to end-point.

CONCLUSION: Zotepine was well tolerated: weight gain, reduced serumuric acid, raised liver enzymes and increased heart rate were associatedwith chronic zotepine treatment. Seven patients experienced seizures

during the study, although concomitant medications and a knownhistorical predisposition to seizure are factors likely to have contributed to

these events. The improvement s in negative symptoms and low propensityto cause further extrapyramidal side-effects support the importance ofzotepine in maintenance treatment. (Int J Psych Clin Pract 2000; 4: 299 ±306)

Keywordsschizophrenia zotepinemaintenance long-termefficacy

INTRODUCTION

S chizophrenia is a devastating, chronic disease whichexcludes many individuals from participation in

society. Many patients require long-term, often highlyintensive, treatment and care. The personal burden of thisdisease is not only the impaired quality of life for theaffected individual , but also, very often, rests on thenetwork of family and friends who provide care andsupport for patients with schizophreni a.

A US epidemiological study estimated the one-yearprevalence of schizophren ic disorders in the adult popula-tion to be 1.1%.1 The medical resources and the healthcarecosts associated with treating schizophreni a are, however,proportionately much higher than this figure wouldsuggest. Schizophrenia was, for example, reported as the

third largest cause of National Health Service inpatientexpenditure in England for 1992-3, at 5.4%.2 Furthermore,the costs associated with treating long-stay inpatients withschizophren ic disorders in England have been estimated tobe four times the cost of specialist support at home.3

Compliance with treatment can be intermittent,especially for patients in the community. Poor compliancemay lead to relapse and hospital readmission . Relapse ratesin non-compliant patients with schizophren ia are reportedto be three times as high as those for treatment-compliantpatients.4 In addition, conventional antipsychotic drugtreatments, with pharmacology largely based on selectivedopamine D2-receptor blockade, have well-documentedlimitations. Their efficacy in treating negative symptoms islimited5 and their adverse-even t profile contributes sig-nificantly to poor compliance, with reported non-compli-

International Journal of Psychiatry in Clinical Practice 2000 Volume 4 Pages 299 ± 306 299Ó 2000 Martin Dunitz Ltd

Int J

Psy

ch C

lin P

ract

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Nyu

Med

ical

Cen

ter

on 1

2/07

/14

For

pers

onal

use

onl

y.

ance rates approaching 50%.6 In particular, the distressingextrapyramida l side-effect s (EPS) frequently associatedwith conventional antipsychotic drugs are a key determi-nant in decreasing patient compliance.7

All of these factors make schizophren ia difficult tomanage, especially in the long term. They highlight acompelling clinical need for more broadly effective, bettertolerated treatments for the long-term management of thedisease. New treatments with low potential to induce EPS,which can improve not only positive symptoms, but alsonegative symptoms, and maintain these improvements inthe long term, will be valuable in aiding the reintegration ofpatients back into the community.

Zotepine is a dibenzothiepine tricyclic antipsychoticagent currently licensed for the treatment of schizophren ia inGermany and Austria (Nipolept), Japan (Lodopin) and theUnited Kingdom (ZoleptilÒ ). Zotepine has a pharmacologi -cal profile which differs from that of typical first-generat ionantipsychotic drugs. Animal studies have characterisedzotepine’s receptor antagonism at different dopaminereceptor sites. Zotepine shows high affinity for dopaminereceptors, both D1-like (D1, D5) and D2-like (D2, D3, D4), andhigh affinity for certain serotonin sub-types, including5HT2A, 5HT2C , 5HT6, 5HT7.

8 ,9 The predominant affinityfor 5HT2A receptors and weaker D2 receptor affinity isthought toprovide efficacyagainstbothpositive and negativesymptoms, with reduced propensity to induce EPS.10

Zotepine also inhibits noradrenaline re-uptake11 and hasbeen shown to be effective in animal models of depression.12

In short-term double-blind comparative studies, zote-pine was at least as effective as haloperidol or chlorpro-mazine in controlling positive symptoms and itdemonstrated superior efficacy in managing negativesymptoms. The incidence of EPS in these acute studieswas also significantl y lower with zotepine treatment thanwith either haloperidol or chlorpromazine.13,14

In a double-blind comparison with haloperidol , intreatment-resis tant patients with chronic schizophreni a andprevailingl y negative symptoms, zotepine demonstratedsuperior efficacy in all rating scales, with fewer side-effect sthan haloperidol .15 Zotepine has also demonstrated efficacyin a placebo-controlled study in patients with chronicschizophreni a and a history of relapse. Significantly fewerrelapses were reported in the zotepine group, with the riskof relapse after 6 months’ treatment assessed at 8.7% and52.8% for the zotepine and placebo groups respectivel y(data available from Knoll Pharmaceuticals).

Theaimof thisstudywastoexaminethesafetyandefficacyof long-term zotepine treatment in patients with schizo-phrenia in a one-year open multiple-dose multicentre trial.

EXPERIMENTAL PROCEDURES

Before starting this study, written ethical approval wasobtained at each centre. The study was conducted inaccordance with the Declaration of Helsinki. All patients

gave written informed consent to participate in the studyand, in the opinion of the investigator , were able to complyfully with the study requirement s.

DIAGNOSIS: INCLUSION AND EXCLUSIONCRITERIA

Patients eligible for recruitment were either inpatients oroutpatients, aged between 18 and 65 years, of either sex,presenting with an acute first episode of schizophren ia oran acute exacerbation of subchronic or chronic schizo-phrenia. Diagnosis was based on the DSM-III-R criteria,17

with patients having a minimum score of 4 (at leastmoderately ill), according to the Clinical Global Impres-sions (CGI) severity scale.

The major exclusion criteria for patients admitted to thestudy were: a known hypersensiti vity to neuroleptic drugs; ahistory of drug or alcohol abuse, or considered at risk ofsuicide; any other significan t psychiatri c illness, epilepsy,Parkinson’ s disease, dementia or any other significan tneurologica l illness ; a history of cardiovascul ar or ECGabnormality, recent myocardial infarction, blood dycrasia orrenal and hepatic failure. Severe hypertension or hypoten-sion, prostatic hypertrophy, urine retention, narrow angleglaucoma and chronic respiratory disease or asthma werealso grounds for exclusion. Pregnant and lactating womenand those at risk of becoming pregnant were excluded. Inaddition, women with a history of breast neoplasm,prolactin-dependent tumours, significant menstrual irregu-larity or hyperprolact inaemia were also excluded.

STUDY DESIGN, TREATMENT AND ASSESSMENTS

This was an open-design, multicentre study conducted in29 centres in five European countries (UK, Ireland,Norway, Finland and France); treatment lasted 52 weeks.Patients received zotepine orally at doses of 75 mg,150 mg, 300 mg, and 450 mg/day, as three divided dailydoses. Dosage commenced at 75 mg/day and could then betitrated up or down by one dose level at a time, by theinvestigator , to individuali ze efficacy and minimize side-effects. Dose titrations were not enforced within fixed time-scale intervals and no restriction was placed on concomi-tant therapies, including other antipsychotic drugs andanti-parkinsonian medication.

Assessment s of symptoms during the study wereconducted using the Brief Psychiatric Rating Scale(BPRS),18 the Scale for Assessment of Negative Symptoms(SANS),19 and the Clinical Global Impression score(CGI).20 EPS were assessed using the Abnormal Involun-tary Movement Scale (AIMS),21 the Simpson and Angusextrapyramidal rating scale (EPMS),22 and the BarnesAkathisia Scale (BAS).23

In order to ensure consistency between investigators inthe use of the psychiatric rating scales (BPRS, CGI, SANS,AIMS, EPMS and BAS), the investigators and co-investiga -tors who conducted these assessment s attended a training

300 K Palmgren et al

Int J

Psy

ch C

lin P

ract

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Nyu

Med

ical

Cen

ter

on 1

2/07

/14

For

pers

onal

use

onl

y.

session run by a panel of psychiatrist s. Having viewedvideotaped interviews with patients, investigators ratedthese patients using the study scales. These scores werethen reviewed and approved by a panel of psychiatrist sbefore any patients were recruited at individual sites.

After baseline assessment, efficacy and EPS assessment swere conducted at weeks 2, 4, 12, 26 and 52. In addition, afurther assessment using the CGI global improvementscale,20 was made at these visits. Blood and urine sampleswere also taken and vital signs recorded.

STATISTICAL ANALYSIS

The study was planned for a minimum of 240 patients.Analyses were performed on an intent-to-treat population(all patients provided at least one post-baseline assessment )using the last observation carried forward. Changes frombaseline in BPRS, CGI and SANS rating scale assessmentswere assessed using the two-tailed paired t-test withsignificance determined by reference to the 5% level.Associated 95% confidence intervals (CI) were alsocalculated. Ninety-five percent Cls for the change frombaseline in EPMS, AIMS and BAS assessment s werecalculated using the nonparametri c Hodges-Lehmann meth-odology21. The statistical significance of these changes wasdetermined with reference to the 95% confidence intervals.

The number of patients reporting adverse events wasrecorded by dose, time of onset, body system according tothe COSTART classification system, severity (as mild,moderate or severe) and the relationship to the testmedication (as none, unlikely, possible , probable ordefinite).

RESULTS

A total of 255 patients entered the study; of these, 253received study medication and 115 completed the study.Summary baseline demographic characteristic s for thesepatients are presented in Table 1.

EFFICACY ANALYSES

The mean BPRS total score was reduced from 51.7 atbaseline to 40.8 at end-point . There were statisticallysignifican t differences between baseline and the BPRS totalscores at all time-points in the study (p <0.05). Afterreceiving zotepine treatment for 2 weeks, a mean reductionof 6.3 in BPRS total score was achieved. At weeks 4, 12, 26and 52 the mean changes from baseline were Ð 9.6, Ð 10.5,Ð 11.3, and Ð 10.9 respectively . Improvements recorded atweek 4 were therefore maintained to end-point and in somecases, further reductions in mean BPRS scores wererecorded. Figure 1 illustrates the mean changes frombaseline in BPRS total score during the course of the study.

Summary data based on mean BPRS total scores andend-point changes for all zotepine modal doses are

presented in Table 2 for the subset of patients (n=139)who provided a final assessment (i.e. continued beyondweek 26). The improved scores observed at all modal dosesare considered to be clinically significant . The majority ofpatients showed a sustained improvement with zotepinetreatment at 75 or 150 mg/day over the duration of thestudy. Improvements attributable to the highest modal dosewere, however, smaller in magnitude than those achievedwith lower doses. The most likely explanation for this is the

Table 1

Baseline patient demographics

Baseline characteristics; n=253

Mean

(SD)

Range of

distribution

Male : female

Caucasian : black : oriental ratio

Age, years

Duration of schizophrenia,

years

Bodyweight, kg

Inpatients : outpatients ratio

BPRS total score

CGI severity score

185 : 68

250 : 1 : 2

38.2 (10.8)

12.1 (9.0)

77.1 (15.7)

151 : 102

51.7 (11.8)

4.8 (0.8)

±

±

18 ± 65

0.5 - 40

46 ± 129

±

25 ± 93

4 ± 7

Figure 1

Mean change from baseline in BPRS total score

Table 2

Mean BPRS total scores at baseline and end-point, and mean changes

at end-point by modal dose for those patients providing a final

assessment (continuing beyond week 26)

Mean BPRS Modal daily dose of zotepine, mg (n)

total scores 75 (35) 150 (60) 300 (33) 450 (11)

Baseline ± week 0

Mean changes at

end-point

48.8Ð 15.9

53.3Ð 16.7

54.8Ð 14.8

53.1Ð 10.5

Zotepine in schizophrenia 301

Int J

Psy

ch C

lin P

ract

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Nyu

Med

ical

Cen

ter

on 1

2/07

/14

For

pers

onal

use

onl

y.

open titration design of the study, which resulted in thepatients who were most treatment-resis tant and mostdifficult to manage being found in the highest dose group.

Analysis of BPRS subscores showed that the meanchanges from baseline for activation, anergia, anxiety/depression, hostile/suspiciousness, thought disturbance,positive and negative items were all statistically significantl ydifferent at all time-points during the study (P <0.05).

There were statistically significan t improvements be-tween baseline values and all subsequent time-points in thestudy for CGI Severity (Figure 2), SANS total score (Figure3), and SANS global score. Patients also showed a meanreduction in CGI improvement score over time during thestudy. At the end, 64% of patients (159/248) showedimprovement on this parameter (Figure 4).

SAFETY ANALYSES

Overall patient exposure to zotepine in the study amountedto 152.78 years. One hundred patients completed a

minimum of 358 days treatment. The most frequentlyprescribed (modal) dose in the study was 150 mg/day.

Concomitant medicationThis was a naturalistic study, and therefore concomitantmedication was allowed to reflect the normal prescribingprocedure for antipsychotic medications. A total of 308medications were discontinued by 152 patients beforeentering the study: 206 of these medications were anti-psychotics and 19 were antiparkinson medication. Onehundred and seventy-three patients reported 205 ongoingand 448 new antipsychotic medications during the study; 26different antipsychotics were reported as concomitantmedication during the study, the most common beingchlorpromazine (152 reports), clozapine (71 reports),haloperidol (69 reports), thioridazine (59 reports) andmethotrimeprazine (56 reports); 80 patients did not receiveany concomitant antipsychotic medication during the study.Sixty-five patients reported ongoing, and 33 patientsreported new, antiparkinson medication during the study.

Figure 2

Mean change from baseline in CGI severity score

Figure 3

Mean change from baseline in SANS total score

Figure 4

End-point CGI improvement scores

302 K Palmgren et al

Int J

Psy

ch C

lin P

ract

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Nyu

Med

ical

Cen

ter

on 1

2/07

/14

For

pers

onal

use

onl

y.

EPS assessmentsThe median changes from baseline values to all study time-points for EPMS score, AIMS score and BAS total score aresummarised in Table 3. Improvements in EPMS and AIMSwere statistically significan t (P <0.05) from week 12,followed by maintenance of the improvement to the endof the study. Mean changes in BAS scores, compared withbaseline, were significan t after 2 weeks treatment withzotepine, and these improvement s were also maintained tothe end of the study.

Adverse eventsA total of 826 adverse events were reported by 220 patients;50 of these patients experienced serious adverse events andfive patients died during the study. In total, 138 patientswithdrew from the study. The reasons for withdrawal aresummarized in Table 4. Of the 44 patients who withdrewfor other reasons, the majority either withdrew theirconsent or failed to comply with the study procedures ordosing regimen.

Of the five deaths reported during the study, twooccurred while these patients were receiving zotepine150 mg day; one death was a suicide and the other was dueto ventricular arrhythmia. Any relationship to studymedication was recorded as unlikely in both cases. Of thethree deaths which occurred after zotepine treatment hadbeen stopped, two were suicides and the third was fromadenocarcinoma of the rectum. Relationship to studymedication was recorded as none for these deaths.

Fifty patients experienced serious adverse eventsrequiring hospitalization; of these, 21 were related toschizophreni a and six to anxiety or depression. Sevenpatients experienced one or more seizures, including onegrand mal seizure.

The most frequently reported adverse events (reportedby at least 5% of patients) are summarised in Table 5.Weight gain was the most frequently reported adverseevent (70 occasions by 70 patients). Patients’ mean weighthad increased by 4.3 kg at the end of the study, from itsmean baseline value. Most weight gain appeared to occur inthe first 12 weeks of treatment. Somnolence (46 occasionsby 38 patients) and laboratory test abnormalities (35occasions by 31 patients) were the second and third mostfrequently reported adverse events.

Of the 31 patients (12%) with reported abnormallaboratory assessments , a decrease in serum uric acid wasthe most common (20 patients). Raised liver enzymeswere the second most frequently reported abnormality,with increases in ALT, gamma GT and AST reported in16, 14 and 12 patients respectivel y. These observationsare consistent with earlier studies and the known

Table 3

Median changes from baseline for EPMS, AIMS and BAS tolerance scores

Change from baseline

Assessment Baseline score Week 2 Week 4 Week 12 Week 26 Week 52

EPMS

AIMS

BAS total score

3.5

4.0

0

Ð 0.5Ð 0.5Ð 0.6*

Ð 0.5Ð 0.5Ð 0.6*

Ð 0.5*Ð 0.1*Ð 0.6*

Ð 1.0*Ð 1.0*Ð 0.7*

Ð 1.0*Ð 1.5*Ð 0.7*

*Statistically significant at the 5% level (95% confidence intervals for EPMS and AIMS data were calculated using nonparametric Hodges-Lehmann

methodology and statistical significance determined from these confidence intervals).

Table 4

Reasons for withdrawal

Reason for withdrawal No. of patients

Adverse event(s)

Lack of efficacy

Lost to follow-up

Protocol violation

Death

Other

60

18

9

5

2

44

Total 138

Table 5

Most frequently reported adverse events

% patients

reported

Number of

reports

Weight increase

Somnolence

Asthenia

Lab. test abnormal

Constipation

Dry mouth

Anxiety

Insomnia

Depression

Akathisia

Gamma Glutamyl

Transpeptidase (GGT)

increase

Bronchitis

27.7

15.0

12.6

12.2

9.5

9.5

7.9

7.1

7.1

6.3

5.5

5.1

70

46

34

35

26

25

28

20

19

17

14

14

Zotepine in schizophrenia 303

Int J

Psy

ch C

lin P

ract

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Nyu

Med

ical

Cen

ter

on 1

2/07

/14

For

pers

onal

use

onl

y.

pharmacology of zotepine. Chronic administration ofzotepine is not associated with any significan t clinicall yworrying laboratory abnormalitie s necessitating routinemonitoring.

Thirteen patients (5%) experienced adverse eventsthat could be related to extrapyramida l effects (akathisia,salivation increase, extrapyramida l syndrome, tremor,dysarthria ) appearing for the first time during the study.Seven of these patients were also receiving a range ofantipsychotic medications that could have producedthese effects, either alone or in combination withzotepine.

In order to study any changes in the adverse eventprofile with chronic dosing of zotepine, the mostcommonly reported adverse events were analysed by theiroccurrence and persistence throughout the study. In thefirst 6 months of the study, the most frequently reportedadverse event which started and then resolved wassomnolence (32 patients). In the second 6 months,somnolence continued to affect only seven patients whohad experienced it in the first 6 months. In general, adverseevents were reported most frequently in the first 6 months;dry mouth, depression and insomnia were the mostpersistent and continued to affect patients in the second6 months. Anxiety was the most common adverse eventwhich started in the second 6 months of the study,affecting seven patients.

Vital signsBlood pressure changes were unremarkable. A small butsignifican t increase in mean heart rate of 3.6 beats/minfrom baseline to end-point was associated with zotepinetreatment (P <0.05). Fourteen patients with normal ECGat baseline were identified as abnormal at end-point. Therewere no reports of torsades de pointes and the mostcommon ECG abnormality was sinus tachycardia, whichmay be reflected in the increased mean heart rate observedin the study population.

DISCUSSION

The primary aim of this study was to assess the efficacyand safety of zotepine when prescribed chronicall y topatients with schizophren ia. Although this was not acontrolled study, zotepine accumulated over 150 years ofpatient exposure, in a clinical setting which realisticallymirrored the day-to-day treatment environment faced bymany psychiatrist s and their patients with schizophreni a.Co-prescripti on of additional antipsychotic drugs andother concomitant medication is representative of currentprescribing practice for patients with schizophreni a;however, the absence of a control group, the flexibletitration of zotepine dosages and the presence of co-prescribed medication prevented identification of aminimum effective maintenance dose for zotepine in thisstudy.

EFFICACY

Short-term, broad-spectrum efficacy in the treatment ofschizophren ia has been demonstrated with zotepine.25 ± 27

Results presented in this study demonstrate thatstatistically and clinicall y significan t efficacy effects,assessed by BPRS total and subscores , CGI severity andimprovement and SANS total and global scores, wereapparent after 2 weeks’ treatment with zotepine.Furthermore, these acute improvemen ts were maintained,and in some cases further improvements were evident,with the continued administration of zotepine. Theextent of the longer term efficacy demonstrated byzotepine in this study, where mean reductions in BPRSand SANS total scores between baseline and end-pointwere 20%, is somewhat less than that seen in previousshort-term trials.13,15 The dose of zotepine most fre-quently prescribed in this study was 150 mg; however, ahigh proportion of patients (22.9%) received therelatively low dose of 75 mg per day throughout thestudy (upward titration was discretionary and notenforced), compared with previous studies in which thezotepine dosage range was 150 ± 300 mg/day. Lowerdosage of zotepine in some patients may therefore havebeen a factor influencing the outcome of this study.Control of negative symptoms was maintained in thelonger term at a level comparable to that seen in short-term studies.

TOLERABILITY

Chronic zotepine treatment was generally well tolerated.A reduction in EPMS scores was seen over time,reaching significance (P <0.05) at week 12. Thirteenpatients (5%) experienced extrapyramida l effects for thefirst time in this study. A reduction in EPMS has beendemonstrated with zotepine in the short term;13 resultsfrom this study suggest this improvement is maintainedby zotepine in the longer term. Chronic treatment withzotepine was associated with an improvement inabnormal involuntary movement over time as assessedby AIMS scores. This reached significanc e (P <0.05) atweek 12 and was maintained to the end. Mean changesin BAS scores, compared with baseline, were significantafter 2 weeks’ treatment with zotepine. The propensit yto induce or aggravate extrapyramidal side effects withchronic zotepine treatment therefore appears to be low.This may be explained by the more balanced receptor-binding profile of zotepine compared with typicalantipsychotic drugs. Zotepine has high affinity for5HT6 and 5HT7 receptors, and pharmacolog ical activityat these sites has been suggested as a possible reasonfor reducing the incidence of EPMS.8 Zotepine’sinhibition of noradrenaline re-uptake and affinity for5HT receptors may also have contributed to theobserved improvement in BPRS subscores for depressionand anxiety.

304 K Palmgren et al

Int J

Psy

ch C

lin P

ract

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Nyu

Med

ical

Cen

ter

on 1

2/07

/14

For

pers

onal

use

onl

y.

The number of withdrawals reported is not unexpectedfor a one-year study with an antipsychotic drug, reflectingthe typically unstable nature of patients with symptoms ofschizophreni a. Patients’ compliance with chronic zotepinetreatment was good, with only 12 patients (4.7%)withdrawn for failure to comply with the study dosingregimen.

The nature and incidence of adverse events in thisstudy are not dissimilar to those observed in shorterterm zotepine studies. However, the incidence of seizureunderlines the need for additional vigilance whenzotepine is prescribed at high dosage ( > 300 mg day),particularly in patients with a history of seizure or whenconcomitant antipsychotic medication is being consid-ered. An increase in zotepine dosage was positivelycorrelated with increased use of concomitant antipsycho-tics in this study. The convulsion rate in controlledzotepine clinical studies using the recommended doserange of 150 ±300 mg day is 0.51% (data available fromKnoll Pharmaceuticals). This compares favourably withthat for other antipsychotic drugs.

A number of adverse events reported in the first 6months of the study, in particular somnolence , werereported less frequently in the second 6 months. Thereduction may be a result of habituation to the sedativeeffect of zotepine (alone or in combination with otherdrugs).

In common with other antipsychotic drugs, changes inliver enzymes were reported with zotepine in this study.The reasons for these changes are unclear; however, thereis no evidence of chronic liver disease in the zotepinedatabase, or from clinical experience in Japan and Germanyinvolving an estimated 2 200 000 patient exposures up tothe end of 1997 (data available from Knoll Pharmaceu-ticals). The most commonly reported laboratory abnorm-ality, decreased serum uric acid, has been reportedpreviously,13 and is consistent with the known uricosuri cpharmacology of the drug.

CONCLUSIONS

Zotepine is an effective antipsychotic agent. Statisticallyand clinically significan t efficacy with regard to bothnegative and positive symptoms was demonstrated from2 weeks and maintained to the end of the study.Overall, chronic zotepine therapy in the range of 75 ±450 mg/day was well tolerated. Improvements in EPMS,AIMS and BAS parameters were apparent at 2 weeksand maintained to the end. The results obtained in thisstudy are consistent with the licensed clinical experiencewith zotepine in Austria, Germany and Japan andindicate that more widespread use of zotepine will bebeneficial in the long-term management of schizophre-nia.

ACKNOWLEDGEMENTS

The authors would like to acknowledge the work of theother investigators involved in this trial: Prof UG Ahlfors,Hesperia Sairaala, Helsinki, Finland; Dr SA Ali, CommunityMental Health Centre, Beverley, UK; Dr D Bourgeois, CHSMontfavet, Montfavet, France; Dr S Colgan, Hope Hospital,Salford, UK; Dr G Clerc, Service de Psychiatrie Adulte,Pontorson, France; Dr P Dick, Royal Dundee Liff Hospital,Dundee, UK; Dr JAG D’Souza, Victoria Hospital, Blackpool,UK; Dr C Gaussares , CH Charles Perrens, Bordeaux,France; Dr JO Haug, Ostfold Sentralsykehus, Fredrikstad,Norway; Dr D Healy, North Wales Hospital, Denbigh, UK;Prof SR Hirsch, Charing Cross Hospital, London, UK; DrDV James, Horton Hospital, Epsom, UK; Dr P Kirwan,Regional Hospital, Limerick, Ireland; Dr J Lynch, St Luke’sPsychiatric Unit, Clonmel, Ireland; Dr J Morrison, St Luke’sPsychiatric Unit, Clonmel, Ireland; Dr AM Mortimer,Ealing Hospital, Southall, UK; Dr JM Mullin, De La PoleHospital, Hull, UK; Dr TH Notland, Blakstad Hospital,Asker, Norway; Dr D Nugent, Gransha Hospital, London-derry, Northern Ireland; Dr SS Palia, Princess of WalesHospital, Bridgend, UK; Dr V Raitasuo, Kellokoski Sairaala,Kellokoski , Finland; Dr P Rogue, Centre HospitalierSpeÂcialiseÂ, Hoerdt, France; Dr SK Sharma, HartwoodHospital, Shotts, UK; Dr VK Sharma, Fazakerley Hospital,Liverpool, UK; Dr DP Srinivasan, Garlands Hospital,Carlisle, UK; Dr AK Suri, Fazakerley Hospital, Liverpool,UK; Dr M O’Sullivan, West Cork, Ireland; Dr J Tiihonen,Niuvanniemi Sairaala, Kuopio, Finland; Prof M Webb, StJames’ Hospital, Dublin, Ireland.

KEY POINTS

· Zotepine is a new antipsychotic with high affinityfor dopamine and serotonin receptors; it alsoinhibits noradrenaline re-uptake

· Zotepine is effective in controlling positive andnegative symptoms in acute episodes ofschizophreni a

· Short-term improvements in symptoms duringacute episodes are maintained with longer termtreatment with zotepine

· Chronic administration of zotepine to patientswith schizophrenia is associated with a lowpropensity to induce extrapyramidal side-effect s

· Chronic zotepine treatment is generally welltolerated, so that zotepine could be a valuablemaintenance therapy in the management ofpatients with schizophren ia.

Zotepine in schizophrenia 305

Int J

Psy

ch C

lin P

ract

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Nyu

Med

ical

Cen

ter

on 1

2/07

/14

For

pers

onal

use

onl

y.

REFERENCES

1. Regier DA, Narrow WE, Rae DS et al (1993) The de facto USMental and Addictive Disorders System: epidemiologic catch-ment area prospective 1-year prevalence rates of disorders andservices. Arch Gen Psychiatry 50: 85 ± 94.

2. National Health Service Executive (1996) Burdens of diseasediscussion paper. National Health Service Executive, Leeds.

3. Knapp M, Kavanagh S (1997) Economic outcomes and costs inthe treatment of schizophrenia. Clin Therapeutics 19: 128 ± 38.

4. Weiden PJ, Olfson M (1995) Cost of relapse in schizophrenia.Schizophrenia Bull 21: 419 ± 29.

5. Tollefson GD, Beasley CM, Tran PV et al (1997) Olanzapineversus haloperidol in the treatment of schizophrenia andschizoaffective and schizophreniform disorders: results of aninternational collaborative trial. Am J Psychiatry 154: 457 ±65.

6. Kane JM (1987) Treatment of schizophrenia. Schizophr Bull 13:133 ± 56.

7. Hummer M, Fleischhacker WW (1996) Compliance andoutcome in patients treated with antipsychotics: the impact ofextrapyramidal symptoms. CNS Drugs 5 (suppl 1): 13 ±20.

8. Needham PL, Atkinson J, Skill MJ, Heal DJ (1996) Zotepine:Preclinical tests predict antipsychotic efficacy and an atypicalprofile. Psychopharmacol Bull 31: 123 ± 8.

9. Roth BL, Craigo SC, Choudray MS et al (1994) Binding oftypical and atypical antipsychotic agents to 5-hydroxytrypta-mine-6 and 5-hydroxytryptamine-7 receptors. J Pharmacol ExpTher 268: 1403 ±9.

10. Leysen JE, Janssen PMF, Schotte A et al (1993) Interaction ofantipsychotic drugs with neurotransmitter sites in vitro and invivo in relation to pharmacological and clinical effects: Role of5HT2 receptors. Psychopharmacology 112: S40 ± S54.

11. Leysen JE, Janssen PMF, Heylen L et al (1998) Receptorinteractions of new antipsychotics: relation to pharmacody-namics and clinical effects. Int J Psychiatr Clin Pract 2 (suppl 2):S3±S17.

12. Rowley HL, Kilpatrick IC, Needham PL, Heal DJ (1998)Elevation of extracellular cortical noradrenaline may contributeto the antidepressant activity of zotepine: an in vivo micro-dialysis study in freely-moving rats. Neuropharmacol 37: 937 ±44.

13. Petit M, Raniwalla J, Tweed J et al (1996) A comparison of anatypical and typical antipsychotic, zotepine versus haloperidolin patients with acute exacerbation of schizophrenia: a parallel-group double-blind trial. Psychopharmacol Bull 32: 81 ± 7.

14. Cooper SJ (1996) Abstract presented at 20th CollegiumInternationale Neuropsychopharmacologicum (CINP), Mel-bourne, Australia, June 23 ±27.

15. Barnas C, StuppaÈck C, Miller C et al (1992) Zotepine in thetreatment of schizophrenic patients with prevailingly negativesymptoms. A double-blind trial vs. haloperidol. Int ClinPsychopharmacol 7: 23 ± 7.

16. Cooper SJ, Butler A, Tweed J, Welch C, Raniwalla J. (2000)Zoterpine in the Prevention of Recurrence: A randomised,double blind placebo-controlled study for chronic schizophre-nia. Psychopharmacology 150: 237 ±43.

17. American Psychiatric Association (1987) Diagnostic andStatistical Manual of Mental Disorders (3rd edn) (DSM-III-R).APA, Washington, DC.

18. Overall JE, Gorham DH (1988) Introduction ±The BriefPsychiatric Rating Scale (BPRS): recent developments inascertainment and scaling. Psychopharmacol Bull 24: 97 ± 9.

19. Andreasen NC (1989) The scale for the assessment of negativesymptoms (SANS): conceptual and theoretical foundation. Br JPsychiatry 155 (Suppl. 7): 49 ± 58.

20. Guy W (1976) ECDEU Assessment Manual for Psychopharma-cology, revised. DHEW Pub. No. (ADM) 76 338. pp. 218 ±22.Rockville, MD: National Institute of Mental Health.

21. Guy W, ECDEU Assessment Manual for Psychopharmacology.Rev. Ed. DHEW Pub. No. (ADM) 76338 Rockville, MD:National Institute of Mental Health, pp. 534± 7.

22. Simpson GM, Angus JSW (1970) A rating scale for extrapyr-amidal side effects. Acta Psychiatr Scand 45 (suppl 212): 11 ±19.

23. Barnes TRE (1989) A rating scale for drug-induced akathisia. BrJ Psychiatry 154: 672 ± 76.

24. Hollander M, Wolfe DA (1973) Nonparametric statisticalmethods (pp. 33 ± 8). New York: Wiley.

25. Fleischhacker W, Barnas C, StuppaÈck CH et al (1989) Zotepinevs haloperidol in paranoid schizophrenia. Psychopharmacol Bull25: 97 ± 100.

26. Dieterle DM, MuÈ ller-Spahn F, Ackenheil M (1991) Efficacy andtolerance of zotepine in a double-blind comparison withperazine in schizophrenics. Fortschr Neurol Psychiatr 59 (suppl.1): 18 ± 22.

27. MuÈ ller-Spahn F, Dieterle DM, Ackenheil M (1991) Clinicalefficacy of zotepine in the treatment of schizophrenic negativesystems. Fortschr Neurol Psychiatr 59 (suppl. 1): 30 ± 5.

306 K Palmgren et al

Int J

Psy

ch C

lin P

ract

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Nyu

Med

ical

Cen

ter

on 1

2/07

/14

For

pers

onal

use

onl

y.