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`
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`.\Cl'-\ l'hYCl ll.-\'l‘Rl(:.\
`S( Nl)lN.\\'lC.\
`[55‘ IM/flf-GWIX
`
`Risperidone versus perphenazine in the
`treatment of chronic schizophrenic patients
`with acute exacerbations
`
`Hoyberg OJ. Fcnsbo C. Remvig J, Lingjamle O. Sloth-Nielsen M,
`Salvcsen l. Risperidone versus pcrphenazine in the treatment of chronic
`schizophrenic patients with acute cxaccrbations.
`Aeta Psychiatr Scand 1993: 88: 395—402. © .Vlunksgaard I993.
`
`Risperidone (RIS), a new neuroleptie with 5-HT2- and dopamine D2
`receptor-blocking properties. was compared with pcrphcnazinc (PER) in a
`double-blind. multiccntrc. parallel-group study in [07 chronic
`schizophrenics with acute exacerbation. RIS 5—15 mg or PER l6—48 mg
`daily was given for 3 weeks. Psychopathology was assessed with the Positive
`and Negative Syndrome Scale (PAN SS) and Clinical Global impression.
`Seventy-eight patients completed the trial; there was an equal number of
`dropouts on both drugs. The mean daily dose at endpoint was 8.5 mg
`RlS and 28 mg PER. The reduction in total PANSS score to endpoint did
`not difi'er significantly. although there was a tendency in favour of RIS.
`The number of patients with predominantly negative symptoms who showed
`at least 20?0 reduction in total PANSS score was significantly larger in
`the RIS group. Furthermore, the number of patients showing at least 20'3”
`reduction in Brief Psychiatric Rating Scale (BPRS) score (BPRS being a
`subscalc of PANSS) was significantly larger in the RIS group. The hostility
`. cluster of BPRS improved more on RIS than on PER in the endpoint
`; analysis. We overall prevalence of side effects was fairly similar in the two
`groups.
`
`0. J. Hayborg ’. C. Fensboz, J. Remviga,
`o. Lingjairde‘, M. Sloth-Nielsens,
`I. Salvesen‘
`‘ Central Hospital. Department of Psychiatry.
`Aalesund, Norway. 2 Psychiatric Hospital.
`Aalborg. ‘1 Glostrup Hospital, Copenhagen.
`Denmark. ‘ Gaustad Hospital. Oslo. Norway.
`5 Janssen Pharma, Denmark. 3 Janssen Pharma.
`Oslo, Norway
`
`Key words: nsper-done: perphonazina: serotonin
`antagonism: sd'iizoohrenia: negative
`symptom; antipsydiotie drug
`Irene Salvesen, Medical Department. Jansen
`Pharma, Postboks 143 Holmlia. M1203 Oslo,
`Norway
`Accepted for pubieation July 17, 1993
`
`Neuroleptics are today regarded as a cornerstone in
`the treatment of schizophrenia. However. conven-
`tional neuroleptics are mainly effective against posi-
`tive symptoms, and it is often difficult to avoid ex-
`trapyramidal symptoms when giving effective dosage.
`There is thus a need to develop new neuroleptics that
`are more effective against the negative symptoms of
`schizophrenia, as well as inducing a lower frequency
`of extrapyramidal symptoms in therapeutic doses.
`It is believed that the antischizophrenic effect of
`neuroleptics is mainly due to their blocking of
`dopamine Dz-receptors, and one way to search for
`better neurolepties is to develop compounds that are
`more selective against these receptors or perhaps
`against a subgroup of Dz-receptors. These com-
`pounds inelude sulpiride, remoxipride and raclo-
`pride. HOWever, interference with other receptors in
`the brain may also be of therapeutic value in schizo-
`phrenia, and perhaps especially with regard to nega-
`tive symptoms. This is indicated by the remarkable
`antischizophrenic efi'ect of clozapine, which has a
`modest affinity for Dz-receptors. but a rather high
`
`affinity to. for example. serotonin 5-HT2-receptors.
`However. the relatively high frequency of agranulo-
`cytosis limits the use of elozapine.
`Rispendone is a benzisoxazole derivative with
`relatively strong blocking effect on both dopamine
`B; receptors and 5-HT; receptors (1, 2). Risperi-
`done binds also to 1,, a: and ii, receptors. It is a
`potent LSD antagonist, whereas it is practically de-
`void of anticholinergic effect. Animal experiments
`have indicated its low potency in inducing extrapy-
`ramidal symptoms (3. 4). and all things considered,
`risperidone thus seems to be a promising drug for
`use in schizophrenia. Early clinical trials suggest that
`RIS is effective on both positive and negative symp-
`toms of schizophrenia (5,6). Subsequent double-
`blind studies comparing it with haloperidol have
`confirmed these results (7, 8).
`In the present trial, we have compared therapeu-
`tic ef’ficacy and side effects of risperidone with that
`of another potent neuroleptic, perphenazine,
`in
`chronic schizophrenic patients suffering front an
`acute exacerbation.
`
`395
`
`1
`
`Exhibit 2052
`Slayback v. Sumitomo
`|PR2020—01053
`
`Exhibit 2052
`Slayback v. Sumitomo
`IPR2020-01053
`
`

`

`Hoyberg et al.
`
`Material and methods
`
`This was a multicentre double-blind parallel group
`study that was carried out in 18 centres in Denmark
`and Norway (see participants in Acknowledge-
`ments). The study was approved by the relevant
`ethics committees and was performed in accordance
`with the Declaration of Helsinki Il.
`
`Inclusion criteria
`
`Patients were eligible for this study if they met the
`following criteria:
`0 age between 18 and 65;
`O diagnosis according to DSM-lll-R of chronic
`schizophrenic disorder with acute exacerbation
`(295.14/‘295.24,/295.34;’295.94); and
`0 informed consent from the patients (or their rela-
`tives or legal guardians).
`
`Exclusion criteria
`
`The following patients were excluded:
`- patients with mental disorders other than chronic
`schizophrenic disorder;
`0 patients with clinically significant organic disor-
`dcrs:
`0 patients with clinically relevant abnormalities in
`laboratory tests before the start of the trial;
`0 patients with a history of alcohol or drug abuse as
`defined in DSM-lll-R within the 12-month period
`preceding the study;
`0 patients who had received oral neuroleptic treat-
`ment less than 72 h or depot neurolcptics less than
`3 Weeks before the start of treatment:
`. patients committed to a mental hospital (Den-
`mark only); and
`0 women of reproductive age without adequate con-
`traception; pregnant or lactating women.
`
`Medeation
`
`Tablets of identical appearance, containing either
`2.5 mg RIS or 8 mg PER, were used. The starting
`dose was one tablet twice daily, that is to say, 5 mg
`RI S or 16 mg PER daily. During the first 4 weeks the
`dose was titrated according to the individual needs
`of the patient, to a maximum dose of 3 tablets twice
`daily (15 mg R18, 48 mg PER). During the last 4
`weeks of the trial the dose was to be kept unchanged
`if possible. However, if adverse efi'ects occurred dur-
`ing this fixed—dose period. the dose could be reduced.
`
`(9). This rating scale consists of 3 subscales: the
`positive subscalc. the negative subscale and the gen-
`eral psychopathology subscalc. All 18 items of the
`Brief Psychiatric Rating Scale (BPRS) ( 10) occur in
`the PANSS, so that the BPRS total score and fac-
`tor scores can be derived from it. The overall severity
`of illness was also assessed with the 7»point Clini—
`cal Global lmprcssions (CG!) scale. severity ver—
`sion. and the overall improvement since baseline with
`the CGI, improvement version. All ratings were per-
`formed immediately before start of trial medication.
`and after 1. 2. 4, 6 and 8 weeks.
`Parkinsonian symptoms were evaluated by means
`of the Extrapyramidal Symptom Rating Scale
`(ESRS) (1 1). Other adverse events were assessed by
`the UKU Side Effect Rating Scale (12).
`
`Statistical analysis
`
`In order not to increase the risk of Type 1 error
`(accepting a difference as “true" when in fact it is
`only due to chance), only one single improvement
`variable was chosen for statistical comparisons be-
`tween the two drug groups: the patients' improve-
`ment at endpoint compared with baseline. All pa-
`tients in whom at least one clinical assessment had
`
`been performed after inclusion (50 patients on R18
`and 51 on PER) were included in the intention-to-
`treat or endpoint analysis. The results at other time
`points are presented but not statistically analysed.
`Two—tail parametric significance tests were used,
`with a level of significance set at 5%,, for total and
`subtotal scores on PANSS. total and factor scores
`on BPRS and the CG] scores of severity and im-
`provement. The chi-square test was used to compare
`the number of improved patients at endpoint (with
`at least 20‘}!o reduction in total score on PANSS).
`
`Results
`
`Patient population
`
`A total of 107 patients entered the trial (Norway: 54.
`Denmark: 53); 55 were allocated to treatment with
`R15, 52 to PER. The mean age of the patients was
`36 years (range 20—67); 77 patients (72% ) were men
`and 30 women. The two treatment groups were very
`similar with respect
`to demography and baseline
`characteristics such as sex, weight. height, diagnosis
`and other data (Table I). For 10 patients (4 RIS,
`6 PER) a concomitant disease was recorded at se-
`lection.
`
`Assessment
`
`The key efficacy variable was the Positive and Nega-
`tive Syndrome Scale for Schizophrenia (PANSS)
`
`Seventy-eight patients (7331,) completed the 8-week
`trial period (RlS 41, PER 37). Thus, 14 patients
`withdrew prematurely in the R18 group and 15 in the
`
`Premature withdrawal
`
`396
`
`

`

`Risperidone versus perphenazine in chronic schizophrenia
`
`Table 1. Demographic and baselne c'raractensucs ot all patients
`
`
`
`fitspendone Perphertazrm
`
`Total no. of patients lWFl
`Median age in teas irangei
`Median weight in kg lrangel
`Median height in an lrangel
`Diagnosis acmrding to DSM-It/
`Sch'zopnrenia
`Disurganized
`Paranoc
`Catatonia
`Undfierentrated
`Patterns tan with perm treatments’
`Neuroleptres
`fiutyroohenones
`Dibenzoxazeprnes
`Diphenymtylpiperidnes
`Prenothtaznes
`Thoxantlems
`Other neurolepttcs
`Antidepressants
`Anhdyskmtics
`Benzooiatepnes
`Antihistamines
`Antiasthmatits
`Corticosterords
`Diuretics
`Nonstoreordal anti-inflammatory drugs
`0rd contraceptives
`Thyroid preparations
`Vitamins or minerais
`
`55 (40/151
`38 l21—61l
`75 (50-117l
`176 (154- 192)
`
`52 (37/ 15)
`35 (20457)
`76 (43-1201
`175 (160—190)
`
`l
`1
`32
`
`12
`5183961“
`
`17
`23
`t
`11
`49194961‘
`
`—-wJI-Nw‘sb
`
`1
`
`N—u—‘bmw
`
`2
`1
`
`—-wu—ow——-ura:ut—-—-
`
`—‘
`
`2
`
`The treatment groups are comparable with respect to democratic and basetne dur-
`acterist‘rcs: P>0.05 (the cit—squat rest or Fisher‘s exact ptobdility test for nom‘nat
`var'ebbs. the Codrrm-Mantelvilaenszel test stratified by country for ordinal wiables,
`two-way amtysis ol tartar-toe with effects lot grotto, oomtry and hteraet'on for con-
`tinuous vo'iatrlesl ‘ No information miable in one r’spendone-treated patient.
`" 25
`patimts received more than one treatment. ‘ 22 patients received me than one treat-
`merit.
`
`PER group. Of these, 8 patients on R18 and 6 on
`PER were withdrawn because of adverse events.
`
`Two patients on RIS were withdrawn due to lack of
`therapeutic effect (after 15 and 28 days); 3 patients
`on PER were withdrawn for the same reason (after
`13, 31. and 4] days). Four patients on R15 and 6 on
`PER were withdrawn because they stopped coming
`to the control visits.
`
`All prematurely withdrawn patients are included
`in the side effect analysis, whereas endpoint analy-
`sis of therapeutic cfl'ect comprises only patients who
`were assessed at
`least once after initiation of trial
`
`medication (50 on RIS. 51 on PER). Hence, 9 of the
`14 prematurely withdrawn patients on R18 and 14
`of the 15 on PER are included in the endpoint analy-
`SIS.
`
`Medication
`
`Previous medication. Before entering the wash-out
`phase of the trial, 93 “/0 of the patients had been using
`
`drugs of diverse categories. Phenothiazines and
`thioxanthcnes were the most commonly used antipv
`sychotics. Twenty-two patients [21 °.,,) had used ben-
`zodiazepines. The two groups were comparable re-
`garding previous medication (Table 1).
`
`Trial medication. The mean daily dose of trial medi-
`cation al endpoint was 8.5 mg for rispcridonc and
`28 mg for pcrphcnazine.
`
`Concomitant medication. During the entire treatment
`period, 42 patients (763;) in the rispcridone group
`and 38 patients (73 ‘30) in the perphenazinc group
`used one or more concomitant medicines. Benzodi-
`
`azepincs and orphett adrine were the most frequently
`used concomitant drugs. There were no significant
`differences in the use of concomitant drugs between
`the two treatment groups.
`
`Cl'nical results: efficacy
`
`The total treatment groups. Table 2 shows the total
`and subtotal PANSS scores and the total and clus-
`
`ter scores for BPRS for the treatment groups at
`baseline, after 8 weeks and at endpoint. There is only
`one significant difference in the endpoint analysis:
`the hostility cluster of BPRS is improved more on
`RlS than on PER (P< 0.005). There is a nonsignifi-
`cant tendency for R15 to be better than PER also on
`the positive subscale of PANSS.
`The reduction in mean total PANSS score at the
`various time points is shown in Fig. 1. There is a
`tendency for greater improvement in the R18 than in
`the PER group at weeks 2, 4, en 6. Corresponding
`results were recorded for the 3 PANSS subscales
`(not shown).
`Clinical improvement, defined as at least 20% re-
`duction in total PANSS score at endpoint, was seen
`in 74% on R18 and 59°/0 on PER (NS). If clinical
`improvement is instead defined as at least 20% re-
`duction in total BPRS score. then improvement oc-
`curred in 7831, on R18 and 59%, on PER (P<0.05)
`(Table 3). The CG] severity scores were comparable
`between the 2 treatment groups at every time point
`during the treatment period. The mean CG] im-
`provement scores, on the other hand, showed a
`(n onsignificant) tendency for more favourable results
`in the RIS group: the number of patients showing
`any degree ofimprovement at endpoint was 80"/0 in
`the R18 group and 672;, in the PER group.
`
`Negative and positive subtypes according to PANSS.
`At baseline, 76 patients had a higher score on the
`negative than on the positive PANSS subscale,
`whereas the opposite was the case for 31 patients.
`In the positive subgroup, there was no significant
`difference in improvement at endpoint between those
`
`397
`
`

`

`Hoyherg et al.
`
`
`Table 2. PANSS and PANSS-oe'ivec BPRS: mean scores at baseline and mean charges from baselme alters weeks am: at enchant. by treatment group
`
`Baseline
`
`8 weeks
`
`Endpomt
`
`ltem
`
`Treatment
`Mean values
`Mean change versus
`
`settemle
`n
`(range)
`n
`baseline (rage)
`
`
`n
`
`Mean change versus
`baseline Hangs!
`
`ANDVA'
`
`PAWS scale
`
`Positive srbsa‘ale
`
`Negatwe subsoa‘e
`
`General psychopathology
`smscale
`
`Total PANSS score
`
`PANSS-der‘rved sedes
`
`Activity
`
`Anerge
`
`Anxiety or deprmion
`
`Rsperdone
`Perplterezrne
`
`Risoeridone
`Perpltenezme
`
`R'spermne
`Perohenazrne
`
`Rispendone
`Perphemzlne
`
`Risperdone
`Perphenazme
`
`R'speridooe
`Perphemame
`
`55
`‘52
`
`55
`52
`
`55
`52
`
`55
`52
`
`55
`52
`
`55
`52
`
`2219—36)
`21112738)
`
`26111-42)
`2618—43)
`
`47129-67)
`46130—741
`
`96158-136)
`93150—1511
`
`813-15)
`813—15]
`
`1215—23)
`1215—20]
`
`41
`37
`
`41
`37
`
`41
`37
`
`41
`37
`
`41
`37
`
`41
`37
`
`-8 1-23—31
`-7 I-26~3)
`
`-7 I‘ -24-6)
`-7 |-33»4)
`
`- 12 I-34~11)
`-121-43-4l
`
`‘ 27 1-80—1 31
`-261'102—8)
`
`-2 I-9—2l
`41-9421
`
`-31-14—2)
`-31-12—31
`
`-31-9-5)
`-41-11~~5)
`
`50
`51
`
`50
`5|
`
`50
`51
`
`50
`51
`
`50
`51
`
`50
`51
`
`50
`51
`
`-7 123-7)
`-5 1-26—61
`
`-61-24—61
`-5 I-33-61
`
`- 11 1—34-11}
`-9 1-43-16)
`
`- 24 I- 80—141
`-201-101-26)
`
`-2 1-9-2)
`-2 !-9-41
`
`-2 1-14—21
`-31-12—6)
`
`-3 l-9-5)
`-3 1-11-51
`
`NS
`
`“5
`I
`
`NS
`
`NS
`
`NS
`
`NS
`
`NS
`
`Hostility
`
`W1 drsturbanoes
`
`Total BPRS score
`
`Risperidone
`Perphenazine
`
`Risperidone
`Perpbemzine
`
`Esperbone
`Perphenazrno
`
`Risoeridone
`Perpltenazinc
`
`55
`52
`
`55
`52
`
`55
`52
`
`55
`52
`
`1215-19)
`1115-201
`
`813-18)
`713—141
`
`1314-241
`1314-24)
`
`54133—771
`52130-82)
`
`41
`37
`
`41
`37
`
`41
`37
`
`41
`37
`
`
`
`-31'11-2)
`41.7.2)
`
`-4 1-13-1l
`-51-20—1l
`
`50
`51
`
`50
`51
`
`-31-11—41
`-1 1-7—4)
`
`~41-13—51
`-31-20—41
`
`~151-39—11)
`‘151-51—5)
`
`-14 1-39-11)
`50
`
`51
`-12 1-51—11)
`
`P<0 01
`‘
`
`NS
`
`NS
`
`‘ Variables being treatment schedule and country; sigmlicmce levels for the va'iable treatment schedUe are grven; no srgniheont differences tor the variable country.
`
`treated with R15 and those treated with PER. This
`
`applied to total or subtotal PANSS scores, BPRS
`total or cluster scores and the number of patients
`showing at least 20 ‘31, reduction in PANSS or BPRS
`total scores at endpoint.
`In the negative subgroup, there was also no sig-
`nificant difference between the two treatment groups
`in improvement at endpoint according to total or
`subtotal PANSS scores or in BPRS total score. But
`
`there was a significantly greater improvement on RIS
`than on PER in the BPRS hostility score (P<U.01).
`
`Also the number of patients improved was signifi-
`cantly larger in the R18 than in the PER group (76%,
`vs 5352,, P<0.05. according to total PANSS score,
`and 78??0 vs 53%,, P<0.05, according to total BPRS
`score (Table 4)).
`
`130183. Clinical improvement. defined as a reduction of the total PMS score and
`PANSS-derrvad BPRS score by 20% or more. by treatment group
`
`Cinical improvement on the told PM smre
`
`8 weeks
`
`Endpoht
`
`Treatment
`group
`
`II
`
`No. 01
`responders'
`196)
`
`No. oi
`responders“
`1%)
`
`Chi-mare
`MtHaM
`probobiity
`
`n
`
`Hisperidone
`41
`33181)
`50
`37174)
`NS
`
`Pemhmazine
`37
`28176)
`51
`30159)
`
`Cinicd mprovement on the PANSSduived BPRS score
`
`8 weeks
`
`Enrbo'nr
`
`Treatment
`gram
`
`(1
`
`No. of
`respmders'
`1’6)
`
`No. 01
`responders“
`1%)
`
`Chi‘square
`MlHaM
`probabiily
`
`17
`
`39 178)
`50
`34 183)
`41
`Hispentione
`
`
` 5128176) ”005 Perphenazine 301591
`37
`
`
`
`
`7
`
`14
`
`42
`23
`Time (days)
`
`56
`
`Enrboint
`
`
`
`
`
`
`
`MoanchangeintotalPANSSscore
`
`fig. 1. Mean 1: SEM) changes in total PANSS score (analysis
`includes all patients).
`
`' Responders = patient showing clinics mprovement, dst‘ned as at least 20% reduction
`from baseline.
`
`398
`
`

`

`Tabb 4. Claim! improvement groan defined as a reducton at the total PANSS score and PANSS-derived total BPRS score by 20% or more. by treatment group and dinical subtype
`Totat BPRS score
`Total PANSS score
`
`Risperidone versus perphenazine in chronic schizophrenia
`
`Stbtype
`
`Positive
`
`Negative
`
`
`Treatment
`you)
`
`Risper'done
`Perphenaztne
`R'sperrbne
`Perpltenazino
`
`It
`
`13
`35
`37
`36
`
` Endpont
`
`No. 01
`responders“
`%
`
`9 (69)
`11 173)
`28 176)
`19 1531
`
`Chi-square
`twnrtailed
`pmoahiity
`
`NS
`
`P< 0.05
`
`n
`
`13
`15
`37
`36
`
`Endpomt
`
`No 01
`remders‘
`1%}
`
`10 (77)
`1 l 173)
`29 178)
`19 [53)
`
`Chi-senate
`two tailed
`probaoitty
`
`NS
`
`I’< 0.05
`
`' Rosponders=patrents showmg cl'nul mprovement. defned as at least 20% reduction from baselne.
`
`Clirical resuts: side effects
`
`E‘xtram'ramt'dal swnptoms. Parkinsonian symptoms
`were assessed with the parkinsonism subscalc of the
`ES RS (1 l). This scale comprises a number of single
`symptoms arranged in 2 clusters: hypokinetic symp-
`toms (expressive automatic movements. bradykine-
`sia. rigidity. gait and posture and sialorrhoea) and
`hyperkinetic symptoms (tremor and akathisia); the
`first cluster can range from a total score of 0 (absent)
`to an extreme of 48. the second from O to 54. A
`parkinsonism total score combines both clusters plus
`postural stability.
`Table 5 shows the mean of these scores at base-
`line and the mean shift from baseline to maximum
`
`score during treatment. There is a somewhat larger
`increase in hypokinetic symptoms and parkinsonism
`total score in the R13 group than in the PER group.
`but the differences are far from significant.
`During the trial period, use of antiparkinson drugs
`was required by 15 patients (27%) in the R18 and
`17 (33 {70) in the PER group.
`
`UKU Side Eflect Rating Scale. On this scale (12), the
`single symptoms are rated on a scale ranging from
`
`0 (absent) to 3 (maximal). regardless of cause; in
`addition, a judgement is given on how likely the
`symptom in question is drug-induced. Table 6 shows
`the most important results from use of the UKU
`scale during the trial: (a) The percentage of patients
`showing (any degree) of the various symptoms at
`baseline and after 1 and 8 weeks (for brevity. the
`results after 2, 4 and 6 weeks are not shown), and
`(b) the percentage of patients who at least once dur-
`ing the trial were given a higher score on the symp-
`tom in question than at baseline.
`As is usually seen in a drug trial, the picture is
`complex: the overall frequency of many symptoms
`(such as depression) is markedly reduced during the
`treatment period, but there are always some patients
`who at some time show deterioration. In general, the
`percentage of patients who reported an increase in
`severity of symptoms in this study was similar in
`both treatment groups for most items, with some
`exceptions. An increase in severity of asthenia was
`more frequently observed in the R15 group (44%)
`than in the PER group (28%). This effect was also
`seen in the item sleepiness or sedation (40‘?" with
`R18, 24% with PER). Other items with at least lO"/o
`more patients reporting a deterioration in the ris-
`
`Table 5. Rating of attrapyramidal symptom at baseline and exiting the trial period See text for MB! explantiort
`
`Shift of maxinum
`score versus
`baseline some
`Item
`—- Treatment
`'
`——
`
`Cluster
`group
`It
`Mean
`Rarge
`ANOVA‘
`n
`Meat
`Range
`ANOVA'
`
`Mean score of
`baseine
`
`
`
`Hyperltinetic symptom racial“
`
`Hypokinet'r; symoms lactorC
`
`Parkrtsonistn told score
`
`Risperidme
`Perphenazhe
`
`Rquetidom
`Perphenazne
`Risperida‘e
`Perphenazne
`
`55
`52
`
`55
`52
`55
`52
`
`1.7
`1.2
`
`3.4
`3.6
`5.5
`5.2
`
`0-7
`0—8
`
`0—14
`0—12
`0—20
`0—22
`
`NS
`
`NS
`
`NS
`
`so
`51
`
`50
`51
`50
`51
`
`0.9
`1.0
`
`1.9
`1.2
`2.6
`2.0
`
`-4—5
`-1—9
`
`~2-12
`-3-7
`-5-18
`-4—-11
`
`"s
`
`NS
`
`NS
`
`' Variable being treatment scheme and country signlicanee lovds tor the varid>le treatment schedule are given: tor the vandile wintry, P< 0.05 tot expressive automatic mea-
`surements. ° vaerk'netic symptoms factor includes the imms traitor and altathisia. = Hypolt'met'c syrtploms factor includes the items expressive automatic trovernents, bradyiunese.
`rigidity. gar and posture and smitten.
`
`399
`
`

`

`Hnybcrg et al.
`
`
`Table 6. Side effects rateo on the UKU Side Eilect Rating Scale
`
`
`
`Pacentage 01 patients wrth side eiiects
`-----—— —-—————— 56 patients who
`A1 start
`During weak 1
`hiring week 8
`deteriorated
`
`Rispen-
`Perphs
`Risperi
`Pephe-
`Risphe
`Pephe‘
`Rispen-
`Perphe—
`done
`nazine
`done
`nazine
`done
`nazine
`ome
`nazine
`
`
`Psychic soc effects
`Concentration diificultias
`Asthenia/lassitudefncreased latiguabil'ty
`Sleepness oi sedation
`Failing memory
`Deutesston
`Tersion
`increased 61111101 015194)
`Reduced duration 01 sleep
`Increased dream activity
`Emotional hdilierenoe
`Neural side effects
`Drstonia
`Paraesthesia
`Hyperiinesia
`Autonomic s‘de eflects
`Accormtothtion d‘sturbances
`Rediceo salivatim
`Nausea or vom't'ng
`Diarrhoea
`Custipation
`Mauritian osturbanoss
`011110313111: dizziness
`Papitations or tachywdia
`Increased tendany to sweating
`Other side effects
`flash
`Prun'tus
`Wow gain
`W1 loss
`Nanorrhao'a'
`Amsnonhoea‘
`Galactorrhoea
`Gyraeoomastia
`17
`Diminished sand desire
`8
`increased mud com
`14
`Emile drsfunotion'
`5
`Ejaculatofv minimum"
`2
`Orgsstic dysftmtion
`15
`Headache- tsnson headadia
`2
`Headed: - migraine
`2
`5
`3
`4
`2
`2
`4
`Headache — other forms
`
`
`
`
`
`
`9 6 6 9 10None 9
`
`46
`41
`26
`18
`28
`44
`18
`8
`13
`28
`
`5
`5
`8
`
`9
`
`13
`5
`13
`
`15
`23
`15
`
`5
`8
`39
`5
`9
`9
`5
`5
`5
`5
`14
`14
`8
`10
`
`49
`40
`29
`23
`37
`43
`20
`14
`20
`29
`
`14
`3
`20
`
`16
`6
`9
`
`3
`14
`14
`9
`
`3
`6
`20
`11
`
`5
`6
`13
`4
`3
`6
`
`14
`44
`40
`14
`3O
`14
`24
`14
`32
`20
`
`10
`5
`14
`
`12
`16
`20
`10
`14
`
`22
`18
`20
`
`8
`12
`52
`8
`8
`15
`4
`2
`8
`10
`11
`is
`14
`12
`
`IE
`28
`24
`12
`22
`37
`14
`31
`22
`20
`
`8
`2
`22
`
`14
`20
`8
`4
`14
`12
`10
`20
`
`8
`10
`24
`12
`
`1
`
`8
`14
`3
`
`6
`
`73
`54
`27
`31
`52
`65
`25
`21
`15
`44
`
`12
`4
`8
`
`410
`B
`12
`2
`12
`2
`23
`19
`15
`
`2
`12
`10
`15
`
`13
`
`7|
`36
`20
`33
`55
`76
`20
`27
`15
`62
`
`6
`6
`13
`
`4
`7
`9
`6
`7
`6
`20
`20
`16
`
`6
`13
`I 1
`15
`
`13
`4
`2
`15
`6
`s
`10
`6
`9
`
`67
`49
`39
`29
`51
`71
`27
`20
`25
`53
`
`4
`6
`10
`
`6
`12
`12
`6
`12
`
`25
`20
`23
`
`12
`18
`6
`
`8
`2
`4
`10
`6
`a
`14
`8
`12
`
`62
`51
`21
`26
`34
`60
`13
`23
`17
`30
`
`13
`4
`13
`
`IS
`15
`9
`11
`6
`28
`21
`17
`
`1 1
`6
`
`7
`
`17
`2
`12
`5
`2
`4
`
`‘ The percentage 5 waisted on the total number of wmm “ The pamage ‘s mumbled on 11! total number of men.
`
`pcridone group were: increased duration of sleep,
`increased dream activity, constipation, weight gain,
`orthostatic dizziness and ejaculatory and orgastic
`dysfunction. Tension was reported to aggravate in
`37% of the perphenazine-treated patients and in
`143/" ofthe risperidone-treated subjects. Micturition
`disturbances increased in severity under PER (in
`14% of patients); this item was not reported in pa-
`tients treated with risperidonc. Reduced duration of
`sleep was reported to deteriorate in 31 "/0 of the pa-
`
`tients in the perphenazine group; this was the case
`in only 142‘, of the risperidone-treated patients.
`Due to the increased risk of Type II error when
`performing multiple. selected significance tests, we
`refrained from calculating the significance levels of
`the observed difl'erences in single side effects.
`
`Laboratory tests. No increase in abnormality was
`observed in any of the laboratory tests during the
`trial.
`
`400
`
`

`

`Risperidone versus perphenazine in chronic schizophrenia
`
`Discussion
`
`The results of this study would appear to confirm
`that R15 is. like PER. a potent antipsychotic agent.
`Moreover. comparative efi‘icacy evaluations suggest
`that RlS is at least as effective as PER. and in some
`respects even better. Although not all efficacy vari-
`ables assumed statistical significance. :1 number did
`so: the number of patients showing at least 20%
`improvement on total BPRS score was significantly
`larger on RlS than on PER. Risperidone was also
`significantly better than perphcnazine on the hostil-
`ity cluster of BPRS. In the subgroup of‘patients with
`predominantly negative symptoms. risperidonc was
`significantly better than perphenazine with respect
`to the number of patients reaching clinical improve-
`ntent on the PANSS and BPRS total scores.
`The mean daily dose ofrisperidone during the last
`4 weeks ofthis study was 8.5 mg. In previous open
`dose-finding trials, the mean dose at endpoint var-
`ied between 3 mg and 9 mg (5. 6, 13-17).
`Front
`the side effect evaluation in this trial,
`patients" tolerance to both drugs is comparable for
`ntost items of the UKU Side Effect Rating Scale.
`The orthostatic dizziness and increased heart rate
`
`reported with RlS in the first week of the trial might
`be explained by the adrenolytic properties of the
`drug. Those symptoms are expected to occur mostly
`at the start of the administration. and they can be
`avoided by starting with a low dose (1 mg twice
`daily) and gradually increasing it. Although there
`was a statistically greater decrease in systolic blood
`pressure in the perphenazine-treated patients. there
`were less complaints of orthostatic dizziness and
`palpitations in this group. The erection and ejacu-
`latory disturbances seen in the risperidone treatment
`group are probably also related to the adrenolytie
`properties of the compound.
`The weight gain observed with rispcridonc in the
`present trial has been reported in several trials with
`risperidonc; a linear dose relationship is reported in
`the fixed dose trials. Thus, with the use of R18 doses
`within the assumed optimal dose range of 4—8 mg.
`the weight increase is expected to be minor. The
`clinical laboratory evaluations give further reassur—
`ance that the drug poses no laboratory safety prob-
`lems.
`
`Conclusion
`
`This study in chronic schizophrenic patients with
`exacerbation has demonstrated that the combined
`
`serotonin 5-HT2 and dopamine-Dz antagonist ris-
`peridone is an antipsychotic at least as efi'ective as
`perphettazine. Risperidone is more effective than
`perplten azine in bringing about clinical improvement
`in patients with predominantly negative symptoms.
`
`Risperidone causes few extrapyramidal symptoms
`and has a tolerability comparable to that of per—
`pltenazine.
`
`Acknowledgements
`The following people participated in the study: A Aan'old.
`H. S. Andersen. M. Birket-Smith. F. Bjorndal. M.Christcnscn.
`W Eggert. O. Garsdal. A. Gjerris. H. H. Godt. H. Hansen.
`P. M. Isakscn. L Jensen. O.Jorgcnsen. M. Kelner. J. Krabbc.
`J Krag. M. B. Kruger. O. Laigaard.
`.l. K. Larsen. K Michecls-
`en. A. Naess. K. Pedersen. P. Poulsen. M. Reiner. J. U. Roald-
`set. K. Stems. R. Sorensen. S. Tiesan. Welner. A. K. Wersland
`and K. Westlye.
`
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