5
8038 • Saturday 17 September 1977 CLINICAL TRIAL OF LIVE MEASLES VACCINE GIVEN ALONE AND LIVE VACCINE PRECEDED BY KILLED VACCINE Fourth report to the Medical Research Council by the Measles Sub-Committee of the Committee on Development of Vaccines and Immunisation Procedures* Summary Follow-up of 5000 children given a sin- gle dose of live attenuated measles vac- cine (Schwarz strain) when aged 10 months to 2 years shows a high level of protection in comparison with an unvaccinated group. This protection has been main- tained for 12 years. Measles in vaccinated children was less severe as well as less frequent throughout the period. There is no evidence from the follow-up so far that a further injection of vaccine is needed; this has been confirmed by measles hæmagglutination-inhibiting anti- body estimations in a sample of the children. Introduction IN the autumn of 1964 a trial of measles vaccines was begun under the auspices of the Medical Research Council Measles Vaccine Committee. The trial was planned to assess the protective action of measles vac- cine and followed a preliminary small study of antibody response and vaccine reactions. Three earlier reports of the protection trial have been published. The first2 gave details of the general plan of the trial and information on vaccine reactions and protection over the first six months. The second3 and third4 reports gave the results on protection for two years nine months and four years nine months respectively. The present report summar- ises the results on protection over the 12 years of the trial up to September, 1976. Methods General Plan The trial took place in 32 areas and children in the suscep- tible age-group of 10 months to 2 years took part. Two im- munisation procedures were investigated: (i) a single dose of killed vaccine followed 1 month later by live vaccine, and (ii) live vaccine alone. The killed vaccine was prepared by Pfizer *Members: Prof. Sir DAVID EVANS (chairman), Dr MAIRIN CLARKE, Prof. K. MCCARTHY, Dr T. M. POLLOCK, Prof. Sir CHARLES STUART- HARRIS, Dr I. SUTHERLAND, Dr G. SCHILD, Dr G. I. WATSON, Dr W. N. DUNNETT, and Dr CHRISTINE L. MILLER (secretary). Limited from the Enders-Edmonston B strain, and the live vaccine by Glaxo Laboratories Limited from the Schwarz strain. The children were randomly allocated by date of birth to one of the two vaccination groups or to an unvaccinated control group. When vaccination was complete there were approximately 10 500 in the killed/live vaccine group, 9500 in the live-vaccine group, and 16 000 in the control group. A further 10 500 either defaulted or were ineligible for vaccina- tion for various reasons; all these children were nevertheless included in the follow-up. Trial Population For the first 9 months of the trial vaccine protection was assessed from the attack-rates for all children who had com- pleted their vaccination in each of the two vaccinated groups, and those in the unvaccinated control group. In September, 1965, the total trial population was reduced by the withdrawal of five areas to take part in a community investigation.5 This decreased all groups to a similar extent, but the unvaccinated control and the defaulter/ineligible groups were then further reduced by vaccination offered to them according to an under- taking given on entry to the trial. About 7000 children were vaccinated under this arrangement; the follow-up of these vac- cinated children continued but no results are given in this report. Two further changes in the population were made from Sep- tember, 1969. By that time a number of children had been lost from the follow-up despite all efforts to trace them; more had been lost from the unvaccinated than from the vaccinated groups, probably for reasons given in the previous report.4 From October, 1969, therefore, only children still in contact were retained in the follow-up and thereafter children not heard of for 3 years were also excluded. This procedure further decreased the original unvaccinated controls, already reduced TABLE I-NUMBER OF CHILDREN AND PERCENTAGE CONTACTED DURING THE FOUR PERIODS OF THE TRIAL *From 1965 these figures are an annual average.

CLINICAL TRIAL OF LIVE MEASLES VACCINE GIVEN ALONE AND LIVE VACCINE PRECEDED BY KILLED VACCINE

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8038

• Saturday 17 September 1977

CLINICAL TRIAL OF LIVE MEASLES VACCINEGIVEN ALONE AND LIVE VACCINEPRECEDED BY KILLED VACCINE

Fourth report to the Medical Research Council bythe Measles Sub-Committee of the Committee on

Development of Vaccines and ImmunisationProcedures*

Summary Follow-up of 5000 children given a sin-gle dose of live attenuated measles vac-

cine (Schwarz strain) when aged 10 months to 2 yearsshows a high level of protection in comparison with anunvaccinated group. This protection has been main-tained for 12 years. Measles in vaccinated children wasless severe as well as less frequent throughout the period.There is no evidence from the follow-up so far that afurther injection of vaccine is needed; this has beenconfirmed by measles hæmagglutination-inhibiting anti-body estimations in a sample of the children.

Introduction

IN the autumn of 1964 a trial of measles vaccines was

begun under the auspices of the Medical ResearchCouncil Measles Vaccine Committee. The trial was

planned to assess the protective action of measles vac-cine and followed a preliminary small study of antibodyresponse and vaccine reactions. Three earlier reports ofthe protection trial have been published. The first2 gavedetails of the general plan of the trial and informationon vaccine reactions and protection over the first sixmonths. The second3 and third4 reports gave the resultson protection for two years nine months and four yearsnine months respectively. The present report summar-ises the results on protection over the 12 years of thetrial up to September, 1976.

Methods

General Plan

The trial took place in 32 areas and children in the suscep-tible age-group of 10 months to 2 years took part. Two im-munisation procedures were investigated: (i) a single dose ofkilled vaccine followed 1 month later by live vaccine, and (ii)live vaccine alone. The killed vaccine was prepared by Pfizer

*Members: Prof. Sir DAVID EVANS (chairman), Dr MAIRIN CLARKE,Prof. K. MCCARTHY, Dr T. M. POLLOCK, Prof. Sir CHARLES STUART-HARRIS, Dr I. SUTHERLAND, Dr G. SCHILD, Dr G. I. WATSON, DrW. N. DUNNETT, and Dr CHRISTINE L. MILLER (secretary).

Limited from the Enders-Edmonston B strain, and the livevaccine by Glaxo Laboratories Limited from the Schwarzstrain. The children were randomly allocated by date of birthto one of the two vaccination groups or to an unvaccinatedcontrol group. When vaccination was complete there wereapproximately 10 500 in the killed/live vaccine group, 9500 inthe live-vaccine group, and 16 000 in the control group. Afurther 10 500 either defaulted or were ineligible for vaccina-tion for various reasons; all these children were neverthelessincluded in the follow-up.

Trial PopulationFor the first 9 months of the trial vaccine protection was

assessed from the attack-rates for all children who had com-

pleted their vaccination in each of the two vaccinated groups,and those in the unvaccinated control group. In September,1965, the total trial population was reduced by the withdrawalof five areas to take part in a community investigation.5 Thisdecreased all groups to a similar extent, but the unvaccinatedcontrol and the defaulter/ineligible groups were then furtherreduced by vaccination offered to them according to an under-taking given on entry to the trial. About 7000 children werevaccinated under this arrangement; the follow-up of these vac-cinated children continued but no results are given in thisreport.Two further changes in the population were made from Sep-

tember, 1969. By that time a number of children had been lostfrom the follow-up despite all efforts to trace them; more hadbeen lost from the unvaccinated than from the vaccinated

groups, probably for reasons given in the previous report.4From October, 1969, therefore, only children still in contactwere retained in the follow-up and thereafter children notheard of for 3 years were also excluded. This procedure furtherdecreased the original unvaccinated controls, already reduced

TABLE I-NUMBER OF CHILDREN AND PERCENTAGE CONTACTED

DURING THE FOUR PERIODS OF THE TRIAL

*From 1965 these figures are an annual average.

572

Fig. I-Notifications of measles in quarterly periods October1964 to December 1976 and measles vaccinations 1968-76,England and Wales.

substantially both by cases of measles and by vaccination.Although no longer to be regarded as a randomly allocatedcontrol group, information on the attack-rate and the homeexposure to measles of unvaccinated children was still of value.

Consequently from October, 1969, children who had defaultedor had been ineligible for vaccination in 1964 (and were stillunvaccinated) were combined with the remainder of the orig-inal controls to form a single new unvaccinated group. Thiswas considered justifiable since, as shown in the previouspapers, attack-rates in the original unvaccinated control andthe defaulter/ineligible groups had been closely similar

throughout the trial. However, because of the amalgamationof these unvaccinated groups and the immunological changeswhich some of them underwent during the period (see table v)protection-rates are not given. The numbers in each group atsuccessive stages of the trial are shown in table i.

Background to the InvestigationSince the start of the trial in 1964 the children, then aged

between 10 months and 2 years, have passed through twomajor epidemics-in 1964/65 during the months immediatelyfollowing vaccination, and 2 years later in 1966/67 (fig. 1). In1968, after the introduction of measles vaccination as a

national policy, the expected outbreak failed to occur. Sincethen, with the exception of 1970 when there was a sharp riseto about 300 000, annual notifications in the country as awhole have not exceeded 150 000, a total similar to that in pre-vious inter-epidemic years. In 1976, by which time the trialchildren were aged between 12 and 14 years, there was afurther decrease to about 55 000-roughly half the lowesttotal in any previous year.

Follow-upFor the first 9 months of the investigation the follow-up was

carried out by health visitors who visited the families every 3months.2 From September, 1965, an annual postal inquiry wasmade from the Epidemiological Research Laboratory. The re-sponse is summarised in table I. For all cases of measles

reported by the parent the general practitioner was asked forconfirmation of the case, the degree of severity, and details ofcomplications and treatment. If the doctor stated that the casewas not measles, but for instance rubella, the parent was in-formed and the child remained in the trial. If measles wasconfirmed by the doctor (or if there was no doctor’s report) thechild was excluded from further follow-up. However, occa-sionally the parent reported "measles without a rash" in a trialchild after contact with measles in the home; these childrenwere retained in the follow-up. Children revaccinated in errorunder the national scheme were also followed up althoughexcluded from the results.

ResultsTable n shows the cases of measles reported by the

parent and confirmed by the doctor during the four per-iods of the trial. A smaller proportion of cases were seenand confirmed as measles in both vaccinated groups

TABLE !I——CASES OF MEASLES IN FOUR PERIODS ACCORDING TOVACCINE GROUP; REPORTED BY PARENT AND CONFIRMED BY

DOCTOR

* Including a few cases where the doctor was doubtful of diagnosis.

TABLE 111--CONFIRMED CASES OF MEASLES IN FOUR PERIODS ACCORDING TO VACCINE GROUP; DOCTOR’S ASSESSMENT OF SEVERITY

*Excluding those with no assessment of severity and those described as doubtful.

573

(and particularly in the live-vaccine group) than in theunvaccinated. The most likely explanation is that,because of the mildness of the illness in vaccinated

children, the doctor was not called so frequently to thesecases.

Table in shows the doctor’s assessment of the severityof cases of measles in the same periods. Throughout thetrial, when measles occurred in vaccinated children,more of the cases were mild than in unvaccinated chil-dren ; this difference was less striking in the third periodbut the number of cases in each group was by then ex-tremely small. Over the whole period few cases havebeen considered severe; even among the unvaccinatedthese were only 5% of the total and this has decreasedas the age of the trial children increased. Two deathsfrom measles have occurred, both in unvaccinatedchildren under 2 years of age in the first 6 months of thetrial. Since the last report,4 which covered the period upto October, 1969, complications reported by the doctorhave been few. There have been no convulsions or en-cephalitis and only 2 children, both unvaccinated, havebeen admitted to hospital (one with pneumonia and onewith abdominal pain and vomiting).

Unusual Cases ofmeaslesDoctors occasionally reported that cases of measles in

vaccinated children were unusual, either because of themildness of the symptoms or the nature of the rash. Upto 12 years after vaccination no particularly severe

forms of atypical measles, such as those seen in theU.S.A. after multiple doses of killed vaccine,6-8 havebeen reported in this trial.

Home ExposureParents were asked each year to report cases of

measles in other children in the home, and in 1973 and1974 doctors were asked for confirmation of these cases;this procedure confirmed that the parents’ informationcould be accepted. Fig. 2 shows the attack-rate in vac-cinated and unvaccinated children exposed to a case ofmeasles in the home over the four periods of the trial.The number of unvaccinated children in home contactwith measles has decreased sharply over the years but,

Fig. 2-Attack-rate in children exposed to measles in the home,in four periods, according to vaccine group.

despite this, the attack-rate in the unvaccinated in thishighly exposed group continues to be more than tentimes that in the vaccinated children. As mentionedabove, from time to time a parent reported that a vac-cinated child in contact with a sibling with measles had"measles without a rash". This usually consisted of aday or so of malaise, perhaps with sore eyes and runningnose, and sometimes a few spots; instead of progressingto measles the child then recovered completely. This wasreported more than twice as frequently in the killed/live-vaccine group as in the live-vaccine group (120 com-pared with 52) and was reported only once in an unvac-cinated child. In none of these children has clinicalmeasles subsequently developed.

Duration of ProtectionTable iv shows the attack-rate per 1000 of confirmed

cases of measles in the first 9 months and in successive12-month periods of the trial. For the reasons juststated, no, attempt has been made to estimate the per-centage protection from these rates. The attack-rate inthe two vaccinated groups was highest in the 9 monthsimmediately after vaccination-an epidemic period-but it is also possible that some reactions to vaccine dur-ing this period were notified as measles. From 1966

TABLE IV-ANNUAL INCIDENCE OF CONFIRMED CASES OF MEASLES (PER 1000) IN FIRST 9 MONTHS AND IN SUCCESSIVE 12-MONTHPERIODS (OCTOBER-SEPTEMBER) ACCORDING TO VACCINE GROUP

I 6- J I J I I I , I

’Expressed as annual incidence to assist comparison with subsequent periods.

TABLE V-H.I. ANTIBODY LEVELS AFTER 10 YEARS ACCORDING TO VACCINE GROUPI

*A titre of 16 is equivalent to 1 international unit.

574

onwards the attack-rate in the live-vaccine group de-clined. As was to be expected, the attack-rate in the un-vaccinated group was highest when notifications overthe whole country were high (fig. 1); the killed/live-vac-cine group also showed slightly increased attack-rates inthese years, but the live-vaccine group was unaffected.From this table there is no evidence of declining protec-tion over the 12 years.

Serological TestsSerological estimations made on a sample of children

at the outset of the trial showed that 92-96% hadhaemagglutination-inhibiting (H.I.) antibody after vac-cine.2 It was considered that antibody estimations onanother sample 10 years later would be of value despitethe lack of pre-vaccination or early post-vaccinationresults for these children.

Table v shows the number of children with H.I. anti-

body at each level according to vaccine group. 2 childrenin the killed/live-vaccine group and one in the live-vac-cine group had no detectable antibody, compared with12 in the unvaccinated. 92% in the killed/live-vaccinegroup and 95% in the live-vaccine group had H.i. anti-body levels of 16 or over. These results reinforce theclinical evidence of maintained protection.Of the 25 unvaccinated children with H.I. antibody of

16 or more, 9 were reported to have had contact withmeasles in the home. Of these, 3 had a slight rashshortly afterwards but in 2 (H.I. titres 128 and 16) thegeneral practitioner denied measles, and the third (H.I.titre 512) was not seen by a doctor; no symptoms werereported in the other 6 children in home contact withmeasles. 2 of the 16 other unvaccinated children weresaid to have had rubella but not measles. One had H.I.

antibody to measles of 1024 and to rubella of 128; theother had H.I. antibody to measles of 128 and none torubella. The remaining 14 children had had no homecontact with measles and no measles-like symptoms.Thus of 25 unvaccinated children with H.I. antibody of16 or more, 20 had no history which suggested measlesinfection; clearly, subclinical measles is more frequentthan is commonly supposed.Of the 12 unvaccinated children with no H.I. anti-

body, 3 were said to have had home contact with

measles; these 3 and 1 without contact have since had

measles, confirmed by their general practitioner. 3others have been vaccinated.

36 of the 71 children in the live-vaccine group and 20of the 47 in the killed/live vaccine group gave a historyof home contact with measles. The geometrical meantitres were 65 (4-1 units) and 58 (3-6 units) for thechildren in the live-vaccine and killed/live-vaccinegroups, respectively, who had a history of contact. Thiscompares with 52 (3-2 units) and 65 (4-1 units), respect-ively, in those without history of contact. There wasthus no evidence from the level of H.I. titre in this sam-ple that home contact with measles had resulted in ahigher H.i. antibody level.

DiscussionThe follow-up over a 12-year period of more than

5000 children given live attenuated measles vaccineshows that a high level of protection has been main-tained. This is particularly striking in children in con-tact with measles in the home where, despite the lowerincidence of measles in recent years, the difference in

attack-rates between vaccinated and unvaccinated hasnot changed. Protection from the killed/live-vaccineschedule, although less during the first years of the trial,was similar to that after live vaccine during the last 5years. There is thus no evidence of waning protection ineither vaccine group after 12 years.

Over the whole period, when measles occurred in vac-cinated children the cases tended to be milder and to

require less medical attention than those in the unvac-cinated. Severe atypical cases with pneumonitis and per-ipheral oedema, such as those reported 14 years afterkilled vaccine by Haas,7 have not been seen. However,killed vaccine was not used alone in the present trial andsuch cases should therefore be looked for also in childrenwho failed to attend for live vaccine having had killedvaccine, or who received more than one injection ofkilled vaccine in error. There were few of these children,and no severe atypical cases of measles have been re-ported among them during the 12 years. The killed/live-vaccine schedule has not been used in the U.K. since1968.

While the attack-rate of measles in unvaccinatedchildren in any year reflected the prevalence of measlesin the country at the time, the attack-rate in the live-vaccine group seems to have been unaffected. A possibleexplanation is that, in most children, protection fromvaccine was too complete to be affected by casual con-tacts even when these increased in number, and thatcases in the vaccinated continued to occur in the 4-8%of children who did not make antibody after vaccine.2The attack-rate in the live-vaccine group exposed tomeasles in the home, which remained at 4% despite thedecrease in the number exposed from 3000 to 400 overthe period (fig. 2), may be additional evidence of this.

It is still not possible to say to what extent the lastingprotection from vaccine is due to the presence in the

community of natural measles. Although the last epi-demic in the U.K. was in 1966/67, annual notificationsuntil 1976 exceeded 100 000. There has thus been con-

tinuing opportunity for the boosting of vaccine-inducedimmunity; circulating antibody is known to increaseafter exposure,9 and the cases of "measles without arash" reported by the parents in vaccinated childrenafter contact with measles may be clinical evidence ofthis. However, there was no evidence from the smallantibody study that home contact with measles resultedin higher H.i.-antibody titres in either of the vaccinationgroups. Nevertheless, 9 years after the introduction ofthe vaccine as a national policy, measles has by nomeans been eradicated. Thus any boosting effect fromnatural measles is likely to continue.The persistence of clinical protection is confirmed by

the serological findings after 10 years: only 1 child in thesample from the live-vaccine group had no detectableantibody and in 95% the titres were 16 or more. Similarresults were reported by Buynak in the U.S.A. after per-iods of 8 and 15 years of observation. 10 A booster injec-tion at this time is therefore not only unnecessary butalso unlikely to be effective. For example, Linneman,"and more recently Shasby12 and Yeager," have shownthat revaccination has a boosting effect only wheie theH.i.-antibody level is low. The boosting effect occurredmost frequently in children vaccinated under the age of12 months-particularly under 9 months, in those givenkilled vaccine only, and in those given immunoglobulin

575

with the vaccine. In the M.R.C. trial no children werevaccinated under the age of 10 months--only 6% of thetotal were under 12 months on entry-and no immuno-globulin was given. In view of the present findings, rou-tine revaccination, as recommended by Bass,14 seems notonly inappropriate but also undesirable.The presence in the community of children with no

history of measles or vaccination who may neverthelessbe immune is an interesting finding. It is possible that,as the incidence of measles decreases, a low infectingdose resulting in subclinical measles is more likely tooccur. Clearly not all the children remaining from theunvaccinated groups in the trial can still be consideredsusceptible, and this may be the explanation of the fall-ing attack-rate observed in the unvaccinated childrenexposed to measles in the home.Although measles has by no means been eliminated in

the U.K., the reduction from about 500 000 to 100 000annual notifications means that it is no longer an inevi-table disease of early childhood. Indeed 23 of the sampleof 37 unvaccinated children aged 10-12 years in thetrial had no detectable antibody although they had livedthrough two major epidemics. Children born since 1968have had even less chance of becoming infected, andthus those who escape vaccination may still be suscep-tible when they reach adolescence. The low rate ofmeasles vaccination over the past few years can only in-crease this likelihood. There have been several

reports15-17 from the U.S.A. of measles outbreaks in vac-cinated communities, but these outbreaks have beenattributed to the proportion of unvaccinated and im-properly vaccinated susceptibles still in the community.

In summary, the M.R.C. trial has shown convincinglythat protection against measles lasts up to 12 years aftervaccination. While this is encouraging, the implicationsof the low vaccination-rate must give rise to disquietregarding the future course of the disease in the U.K.

This study was made under the auspices of the Medical ResearchCouncil’s Measles Vaccine Committee (replaced in September, 1975,by the Measles Vaccine Sub-Committee of the M.R.C. Committee onDevelopment of Vaccines and Immunisation Procedures). Follow-up iscontinuing in the areas listed in the last report4with the exception ofBristol, Cardiff, Hull, Oxford, and Southampton, which withdrew in1966 to take part in a related study of mass vaccination againstmeasles. The trial was coordinated by Dr Christine Miller, CentralPublic Health Laboratory, Colindale Avenue, London NW9 5HT. Theresults were analysed by Dr Miller and Mrs A. Allchin. Dr Miller pre-pared the report and wishes to thank Prof. Sir David Evans, Dr Pol-lock, and Dr Sutherland for their comments. The Sub-Committee isgrateful to Mrs Allchin and the clerical staff of the EpidemiologicalResearch Laboratory for their work over the 12 years of the trial.

Requests for reprints should be addressed to Dr Miller.

REFERENCES

1. Medical Research Council. Br. med. J. 1965, i, 817.2. Medical Research Council. ibid. 1966, i, 441.3. Medical Research Council. ibid. 1968, ii, 449.4. Medical Research Council. Practitioner, 1971, 206, 458.5. Sutherland, I., Fayers, P. Br. med. J. 1971, i, 698.6. Fulginiti, V. A., Eller, J., Kempe, H.J.Am. med. Ass. 1967, 202, 1075.7. Haas, E. J., Wendt, V. E. ibid. 1976, 236, 1050.8. Morbid. Mortal. Wkly Rep. 1976, 25, no. 31.9. Krugman, S. J. Pediat. 1971, 78, 1.10. Buynak, E., Weibel, R., McLean, A., Hilleman, M. Proc. Soc. exp. Biol.

Med. 1976, 153, 441.11. Linneman, C. C. Am. J. Epidem. 1973, 97, 365.12. Shasby, D. M., Shape, T., Downs, H., Herrman, K., Polkowski, J. New

Engl. J. Med. 1977, 296, 585.13. Yeager, A., Davis, J., Ross, L., Harvey, B. J. Am. med. Ass. 1977, 237, 347.14. Bass, J. W., et al. ibid. 1976, 235, 31.15. Hinman, A. R. Am. J. Publ. Hlth, 1972, 62, 498.16. Conrad, J. L., Wallace, R., Witte, J. ibid. 1971, 61, 2304.17. Shreier, R. New Engl. J. Med. 1974, 290, 803.

PROPRANOLOL AS AN ADJUNCT TO THETREATMENT OF SCHIZOPHRENIA

NEIL J. YORKSTONSANIHA A. ZAKI

DAVID R. PITCHER

JOHN H. GRUZELIERDORIS HOLLANDER

HOWARD G. S. SERGEANT

Friern Hospital, Bethlem Royal and Maudsley Hospitals,Charing Cross Hospital Medical School, Royal Free Hospital,and University College Hospital Medical School, London

Summary Propranolol contributed usefully to thepractical management of patients with

chronic schizophrenia whose florid symptoms had notremitted with major tranquillisers. 14 patients who hadreceived an average equivalent of 954 mg per day ofchlorpromazine for 10 years were given, in addition,either propranolol or a placebo for 12 weeks. Both

groups had improved by the twelfth week, but the pro-pranolol group had improved significantly more.

, Introduction

FLORID schizophrenic symptoms remitted, at least

temporarily, in 28 out of 55 adults treated with pro-pranolol in uncontrolled studies at Friern Hospital.l-4The controlled study reported here was designed to com-pare the effects of adding either propranolol or a match-ing placebo to the treatment regimen of patients withchronic schizophrenia whose symptoms had not remittedwith conventional treatment.

Patients and Methods

Patients

14 patients who had each been diagnosed by two psychiat-rists as having chronic schizophrenia with -florid symptoms,and who could safely be given propranolol, were selected forthe trial. They were allotted at random to 2 groups--onegroup to receive propranolol, the other a placebo, for twelveweeks. The patients’ average age was 40 years (range 27-55years), the average age at onset of the illness was 30 years, andthe current episode, which was usually the first, had lasted anaverage of 9 years. The criteria of the Schizophrenic ResearchProjects were used to define the onset and duration of the ill-ness. The patients had been treated for a mean of ten yearswith major tranquillisers. The average modal dose, expressedas the chlorpromazine equivalent,6 was 954 mg per day; theaverage maximum dose was 1634 mg per day.To be included in the study a patient had to be rated as

"moderate" (at least) on 2 or more of the 10 "schizophrenia"scales of a modified’ Brief Psychiatric Rating Scale (B.P.R.S.).7At least one of these "moderate" ratings had to be on 1 of the3 "thought-disorder" scales-namely, conceptual disorganisa-tion, hallucinatory behaviour, or unusual thought content.The 7 "non-thought-disorder" schizophrenia scales were:

blunted affect, emotional withdrawal, suspiciousness, grandio-sity, mannerisms or posturing, hostility, and motor retarda-tion. The sum of these 10 "schizophrenia" scales gave the"total schizophrenia" score. There were also 9 "non-schizo-phrenia" scales: somatic concern, anxiety, feelings of guilt,tension, depressed mood, uncooperativeness, excitement, disor-ientation, and pressure of speech.

"First-rank" symptoms of schizophrenia* were looked forin a structured interview, and rated as "not present" if therewas any doubt. The mean number for the sample was 3-6 outof a possible 10.The diagnosis of schizophrenia was confirmed in all cases by

trained raters using the Present State Examination.9 The

Catego computer analysis9 subclassified 6 patients in the pro-