Acta Psvchiawr Scand 1993; 88: 395-402
`Printed in Belgium — all rights reserved
`
`Copyright O Munksgaard 1993
`ACTA PSYCHTATRICA
`
`SCANDINAVICA
`ISSN (HO) -690N
`
`Risperidone versus perphenazine in the
`treatment of chronic schizophrenic patients
`with acute exacerbations
`
`Hoyberg OJ, Fensbo C, Remvig J, Lingjzrde O, Sloth-Nielsen M,
`Salvesen I. Risperidone versus perphenazine in the treatment of chronic
`schizophrenic patients with acute exacerbations.
`Acta Psychiatr Scand 1993: 88: 395-402. © Munksgaard 1993.
`
`Risperidone (RIS), a new neuroleptic with 5-HT,- and dopamine D,
`receptor-blocking properties, was compared with perphenazine (PER) in a
`double-blind, multicentre, parallel-group study in 107 chronic
`schizophrenics with acute exacerbation. RIS 5-15 mg or PER 16-48 mg
`daily was given for 8 weeks. Psychopathology was assessed with the Positive
`and Negative Syndrome Scale (PANSS) 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
`RIS and 28 mg PER. The reduction in total PANSS score to endpoint did
`notdiffer significantly, although there was a tendency in favour of RIS.
`The numberof patients with predominantly negative symptoms who showed
`at least 20%, reduction in total PANSS score was significantly larger in
`the RIS group. Furthermore, the number of patients showing at least 20”,
`reduction in Brief Psychiatric Rating Scale (BPRS) score (BPRS being a
`subscale of PANSS) wassignificantly larger in the RIS group. The hostility
`, cluster of BPRS improved more on RIS than on PERin the endpoint
`| analysis. The overall prevalence of side effects wasfairly similar in the two
`groups.
`
`0. J. Hoyberg', C. Fensbo”, J. Remvig’,
`0. Lingjaerde*, M. Sloth-Nielsen®,
`|, Salvesen®
`* Central Hospital, Department of Psychiatry.
`Aalesund, Norway, * Psychiatric Hospital,
`Aalborg, * Glostrup Hospital, Copenhagen,
`Denmark, * Gaustad Hospital, Oslo, Norway,
`5 Janssen Pharma, Denmark. © Janssen Pharma,
`Oslo, Norway
`
`Key words: risperidone; perphenazine; serotonin
`antagonism: schizophrenia; negative
`symptom; antipsychotic drug
`Irene Salvesen, Medical Department, Janssen
`Pharma, Postboks 143 Holmlia, N-1203 Osio,
`Norway
`Accepted for publication July 17, 1993
`
`Neuroleptics are today regarded as a cornerstonein
`the treatment of schizophrenia. However, conven-
`tional neuroleptics are mainly effective against posi-
`tive symptoms, andit is often difficult to avoid ex-
`trapyramidal symptoms whengivingeffective dosage.
`Thereis thus a need to develop newneuroleptics that
`are moreeffective 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 D,-receptors, and one way to search for
`better neuroleptics is to develop compoundsthatare
`more selective against these receptors or perhaps
`against a subgroup of D,-receptors. These com-
`pounds include sulpiride, remoxipride and raclo-
`pride. However, interference with other receptors in
`the brain mayalso be oftherapeutic value in schizo-
`phrenia, and perhapsespecially with regard to nega-
`tive symptoms.This is indicated by the remarkable
`antischizophrenic effect of clozapine, which has a
`modest affinity for D,-receptors, but a rather high
`
`affinity to, for example, serotonin 5-HT,-receptors.
`However, the relatively high frequency of agranulo-
`cytosis limits the use of clozapine.
`Risperidone is a benzisoxazole derivative with
`relatively strong blocking effect on both dopamine
`D, receptors and 5-HT, receptors (1, 2). Risperi-
`done binds also to %,, «2 and H, receptors. It is a
`potent LSD antagonist, whereasit is practically de-
`void of anticholinergic effect. Animal experiments
`have indicated its low potency in inducing extrapy-
`ramidal symptoms(3, 4), andall things considered,
`risperidone thus seems to be a promising drug for
`use in schizophrenia. Early clinicaltrials 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 efficacy andside effects ofrisperidone with that
`of another potent neuroleptic, perphenazine,
`in
`chronic schizophrenic patients suffering from an
`acute exacerbation.
`
`395
`
`Exhibit 2052
`Slayback v. Sumitomo
`IPR2020-01053
`
`Exhibit 2052
`Slayback v. Sumitomo
`IPR2020-01053
`
`

`

`Hoyberg etal.
`
`Material and methods
`
`This was a multicentre double-blind parallel group
`studythat wascarried 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 II.
`
`Inclusion criteria
`
`Patients were eligible for this study if they met the
`following criteria:
`® age between 18 and 65;
`® diagnosis according to DSM-III-R of chronic
`schizophrenic disorder with acute exacerbation
`(295.14/295.24/295.34/295.94); and
`e 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;
`* patients with clinically significant organic disor-
`ders;
`e patients with clinically relevant abnormalities in
`laboratory tests before the start of the trial;
`¢ patients with a historyof alcohol or drug abuse as
`defined in DSM-III-R within the 12-month period
`preceding the study;
`¢ patients who had received oral neuroleptic treat-
`mentless than 72 h or depot neuroleptics less than
`3 weeks before the start of treatment;
`* patients committed to a mental hospital (Den-
`mark only); and
`e women of reproductive age without adequate con-
`traception; pregnant or lactating women.
`
`Medication
`
`Tablets of identical appearance, containing either
`2.5 mg RIS or 8 mg PER, were used. The starting
`dose was onetablet twice daily, that is to say, 5 mg
`RIS or 16 mg PERdaily. Duringthefirst 4 weeks the
`dose was titrated according to theindividual needs
`of the patient, to a maximum doseof3 tablets twice
`daily (15 mg RIS, 48 mg PER). During the last 4
`weeksofthe trial the dose wasto be kept unchanged
`if possible. However, if adverseeffects occurred dur-
`ing this fixed-dose period, the dose could be reduced.
`
`Assessment
`
`The keyefficacy variable was the Positive and Nega-
`tive Syndrome Scale for Schizophrenia (PANSS)
`
`396
`
`(9). This rating scale consists of 3 subscales: the
`positive subscale, the negative subscale and the gen-
`eral psychopathology subscale. 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 Impressions (CGI) scale, severity ver-
`sion, and the overall improvementsince baseline with
`the CGI, improvementversion. 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) (11). 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 factit is
`only due to chance), only one single improvement
`variable was chosenfor statistical comparisons be-
`tween the two drug groups: the patients’ improve-
`ment at endpoint compared with baseline. All pa-
`tients in whom atleast oneclinical assessment had
`been performed after inclusion (50 patients on RIS
`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 CGI 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°% 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
`RIS, 52 to PER. The mean age ofthe 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 1). For 10 patients (4 RIS,
`6 PER) a concomitant disease was recorded at se-
`lection.
`
`Premature withdrawal
`
`Seventy-cight patients (73% ) completed the 8-week
`trial period (RIS 41, PER 37). Thus, 14 patients
`withdrew prematurely in the RIS group and 15 in the
`
`

`

`Risperidone yersus perphenazine in chronic schizophrenia
`
`Table 1. Demographic and baseline characteristics ofall patients
`
`
`
`Risperidone Perphenazine
`
`Total no. of patients (M/F)
`Median agein years (range)
`Median weightin kg (range)
`Median height in om {range}
`Diagnosis according te OSM-At
`Schizophrenia
`Disorganized
`Paranoid
`Catatonic
`Undifferentiated
`Patients (%) with previous treatments*
`Neuroleptics
`Butyrophenones
`Dibenzoxazepines
`Diphenyibutyipiperidines
`Phenothiazines
`Thoxanthenes
`Other neuroleptics
`Antidepressants
`Antidyskinetics
`Benzodiazepines
`Antihistamines
`Antiasthmatics
`Corticosteroids
`Diuretics
`Nonstergoidal anti-intlammatory drugs
`Oral contraceptives
`Thyroid preparations
`Vitamins or minerals
`
`55 (40/15)
`38 (2 1-61}
`75 (50-117)
`176 (154-192)
`
`52 (37/15)
`35 (20-67)
`76 (43-120)
`175 (160-190)
`
`i
`32
`
`12
`51(93%)°
`
`17
`23
`1
`11
`49(94%)°
`
`—Wweea
`
`_
`
`2
`
`—wsor
`neh—-Rw
`
`2
`|
`
`The treatment groups are comperable with respect to demographic end baseline char-
`acteristics: P>O.05 (the chi-square test or Fisher's exact probability test for nominal
`variables, the Cochran-Mantel-Haenszel test stratified by country for ordinal variables,
`two-way analysis of variance with effects for group, country and interaction for con-
`tinuous variables). No information available in one risperdone-treated patient.
`” 25
`patients received more than one treatment. © 22 patients received more than one treat-
`ment,
`
`PER group. Ofthese, 8 patients on RIS and 6 on
`PER were withdrawn because of adverse events.
`Two patients on RIS were withdrawn dueto lack of
`therapeutic effect (after 15 and 28 days); 3 patients
`on PER were withdrawn for the same reason(after
`13, 31, and 41 days). Four patients on RIS 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 effect 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 RIS and 14
`of the 15 on PER are includedin the endpoint analy-
`sis.
`
`Medication
`
`Previous medication. Before entering the wash-out
`phase ofthe trial, 93°, of the patients had been using
`
`drugs of diverse categories. Phenothiazines and
`thioxanthenes were the most commonly used antip-
`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 oftrial medi-
`cation at endpoint was 8.5 mg for risperidone and
`28 mg for perphenazine.
`
`Concomitant medication. During the entire treatment
`period, 42 patients (76%) in the risperidone group
`and 38 patients (73%) in the perphenazine group
`used one or more concomitant medicines. Benzodi-
`azepines and orphenadrine were the most frequently
`used concomitant drugs. There were no significant
`differences in the use of concomitant drugs between
`the two treatment groups.
`
`Clinicalresults: efficacy
`
`The total treaiment groups. Table 2 showsthe 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. Thereis only
`one significant difference in the endpoint analysis:
`the hostility cluster of BPRS is improved more on
`RIS than on PER (P<0.005). There is a nonsignifi-
`cant tendency for RIS to be better than PERalso 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
`tendencyfor greater improvementin the RIS thanin
`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 scen
`in 74% on RIS and 59% on PER (NS).If clinical
`improvementis instead defined as at least 20% re-
`duction in total BPRS score, then improvement oc-
`curred in 78% on RIS and 59% on PER (P<0.05)
`(Table 3). The CGI severity scores were comparable
`between the 2 treatment groups at every time point
`during the treatment period. The mean CGI im-
`provement scores, on the other hand, showed a
`(nonsignificant) tendency for more favourable results
`in the RIS group: the number of patients showing
`any degree of improvementat endpoint was 80% in
`the RIS group and 67% 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 nosignificant
`difference in improvementat endpoint between those
`
`397
`
`

`

`Hoyberg et al.
`
`
`Table 2. PANSS and PANSS-derived SPRS: mean scores at baseline and mean changes from baseline after 8 weeks and at endpoint, by treatment group
`
`Baseline
`
`8 weeks
`
`Endpoint
`
`item
`
`Treatment
`Mean values
`Mean change versus
`
`schedule
`n
`(range)
`n
`baseline(range)
`n
`
`Mean change versus
`baseline (range)
`
`ANOVA"
`
`PANNS scale
`
`Positive subscale
`
`Negative subscale
`
`-7 (23-7)
`50
`-8 |-23-3)
`4)
`22 (9-36)
`55
`Risperidone
`5 (-26-6)
`51
`-7 (26-3)
`37
`21(12-36)
`§==952
`Perphenazine
`-6{-24-6)
`50
`-7(-24-6)
`4)
`26 141-42)
`55
`Risperidone
`-§ (-33-6)
`51
`-7 (-33~4)
`37
`26 (8-43)
`§2
`Perphenazine
`
`
`General psychopathology 55=47 (29-67}—Risperidone 4) —12(-34~11} 50 ~11(-34-11)
`
`
`
`
`NS
`Perphenazine
`subscale
`52
` 46(30-74)
`37
`~12(-43-4)}
`51
`9 (-43-16)
`Total PANSS score
`Risperidone
`55
`96(58-136)
`41
`-27 |- 80-13}
`50
`~24(-80-14)
`Perphenazine
`52
`93 (50-151)
`37
`— 26 |- 102-8}
`51
`-20 (- 102-26)
`
`NS
`
`NS
`
`NS
`
`-2(-9-2)
`50
`-2|-9-2)
`4)
`8 (3-15)
`55
`Risperidone
`-2(-9-4)
`51
`-3(-9-2}
`37
`8 (3-15)
`52
`Perphenazine
`-2(-14-2)
`50
`-3(-14~2)
`41
` 12(5-23)
`65
`Risperidone
`-3{-12-6)
`51
`-3(-12-3}
`37
` 12(5-20)
`§2
`Perphenzaine
`-3|-9-5)
`50
`-3(-9-5)
`41
`12 (5-19)
`55
`Risperidone
`Anxiety or depression
`NS
`
`Perphenazine=§2 11 (5-20) 37 -4(-11-5) 51 -3{-11-5]
`
`
`
`
`Hostility
`Risperidone
`55
`8 (3-18)
`41
`-3(-11-2)
`50
`-3{-11-4)
`P<0.01
`Perphenazine
`52
`7 (3-14)
`37
`-2{-7-2)
`51
`-1|-7-4)
`Risperidone
`65
`13(4-24)
`41
`-4(-13-1)
`50
`-4(- 13-5}
`Porphenazine
`§2
`13(4-24)
`37
`5 (-20-1)
`51
`-3{-20-4)
`Risperidone
`55
`54(33-77)
`44
`-15(-39-11)
`50
`-14|-39-11)
`
`Perphenazine
`§2
`52 (30-82)
`37
`15 (-51~5)
`51
`—12(-51-11)
`
`PANSS-derived scales
`
`Activity
`
`Anerga
`
`Thought disturbances
`
`Total BPRS score
`
`
`
`NS
`
`NS
`
`NS
`
`NS
`
`* Variables being treatment schedule and country; significance levels for the variable treatment schedule are given; no significant differences for the variable country.
`
`treated with RIS and those treated with PER. This
`applied to total or subtotal PANSS scores, BPRS
`total or cluster scores and the numberof patients
`showing at least 20%, reduction in PANSS or BPRS
`total scores at endpoint.
`In the negative subgroup, there was also nosig-
`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 <0.01).
`
`Also the number of patients improved wassignifi-
`cantly larger in the RIS than in the PER group (76%
`vs 53%, P<0.05, according to total PANSS score,
`and 78% vs 53%, P<0.05, according to total BPRS
`score (Table 4)).
`
`Table 3. Clinical improvement, defined as a reduction of the totel PANSS score and
`PANSS-derived BPRS score by 20% or more, by treatment group
`
`Cinical improvement on the total PANSS score
`
`8 weeks
`
`Endpoint
`
`Treatment
`group
`
`a
`
`No. of
`responders *
`(%)
`
`No.of
`responders”
`{%}
`
`Chi-square
`two-tailed
`probability
`
`a
`
`Risperidone
`4)
`33 (81)
`50
`37 (74)
`NS
`
`Perphenazine
`37
`28 (76)
`51
`30 (59)
`
`Clinical improvement on the PANSS-derived BPRS score
`
`8 weeks
`
`Endpoint
`
`Treatment
`group
`
`n
`
`No. of
`responders *
`(%)
`
`No.of
`responders ®
`(%)
`
`Chi-square
`two-tailed
`probability
`
`a
`
`
`
`
`
`
`
`
`
`MeanchangeintotalPANSSscore
`
`39 (78)
`50
`34 (83}
`41
`Risperidone
`56
`42
`28
`14
`.
`Endpoint
`
`
` 28(76) 30/69)4$0.08 Perphenazine 81
`37
`Time (days)
`
`Fig. 1. Mean (+ SEM) changes in total PANSS score (analysis
`includesall patients).
`
`* Responders = patient showing clinical improvement, defined as at least 20% reduction
`from baseline.
`
`398
`
`

`

`Table 4. Clinical improvement group, defined as a reduction ofthe total PANSS score and PANSS-cerived total BPRS score by 20% or more, by treatment group and clinical subtype
`Total BPRS score
`Total PANSS score
`
`Risperidone versus perphenazine in chronic schizophrenia
`
`Subtype
`
`Positive
`
`Negative
`
`
`Treatment
`group
`
`Risperidone
`Perphenazine
`Risperidone
`Perphenazine
`
`a
`
`13
`1
`37
`36
`
` Endpoint
`
`No.of
`responders*
`%
`
`9 (69)
`11 (73}
`28 (76)
`19 {53}
`
`Chi-square
`two-tailed
`probability
`
`NS
`P<0.05
`
`n
`
`13
`15
`37
`26
`
`Endpoint
`
`No. of
`responders *
`(%)
`
`10 (77)
`11(73)
`29 (78)
`19 (53)
`
`Chi-scuare
`two-tailed
`probabiity
`
`NS
`P<0.05
`
`* Responders=patients showing clinical improvement, defined asat least 20% reduction from baseline,
`
`Clinical results: side effects
`
`Extrapyramidal symptoms. Parkinsonian symptoms
`were assessed with the parkinsonismsubscale of the
`ESRS (11). This scale comprises a numberofsingle
`symptoms arrangedin 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 0 to 54. A
`parkinsonism total score combines both clusters plus
`postural! stability.
`Table 5 shows the mean ofthese 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 RIS 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 RIS and
`17 (33%) in the PER group.
`
`UKUSide Effect Rating Scale. On this scale (12), the
`single symptomsare 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 whoat 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 somepatients
`whoat sometime 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 RIS group (44%)
`than in the PER group (28%). This effect was also
`seen in the item sleepiness or sedation (40% with
`RIS, 24% with PER), Otheritems with at least 10%
`more patients reporting a deterioration in the ris-
`
`Table 5. Rating of extrapyramidal symptoms at baseline and during the trial period. See text for further explanation
`
`Item
`
`Mean score of
`baseline
`
`Shift of maximum
`score versus
`baseline socre
`
`
`
`Treatment
`:
`
`Cluster
`group
`n
`Mean
`Range
`ANOVA*
`n
`Mean
`Range
`ANOVA?
`
`Hyperkinetic symptoms factor”
`Hypokinetic symptoms factor®
`Parkinsonism total score
`
`Risperidone
`Perphenezing
`Risperidone
`Perphenazine
`Risperidone
`Perphenazine
`
`55
`52
`55
`52
`55
`52
`
`17
`1.2
`3.4
`3.6
`5.5
`5.2
`
`0-7
`0-8
`O-14
`0-12
`0-20
`0-22
`
`ws
`NS
`NS
`
`50
`§1
`50
`$1
`50
`$1
`
`09
`1.0
`19
`1.2
`2.6
`2.0
`
`-4-5
`-1-9
`-2-12
`-3-7
`-5-18
`4-11
`
`NS
`NS
`NS
`
`* Variable being treatment schedule and country; significance levels for the variable treatment schedule are given;for the variable country, P< 0.05 for expressive automatic mea-
`surements, ° Hyperkinetic symptomsfactor includes the items tremor and akathisia, ° Hypokinetic symptoms factor includes the items expressive automatic movements, bradykinesia,
`rigidity, gait and posture and sialorthoea.
`
`399
`
`

`

`Heyberg et al.
`
`
`Table 6. Side effects rated on the UKU Side Effect Rating Scale
`
`
`
`IT
`Atstart
`
`Percentage of patients with side effects
`
`During week 1
`
`During week 8
`
`% patients who
`deteriorated
`
`
`
`Rispert-
`done
`
`Perphe-
`Risper-
`Perphe-
`Risphe-
`Perphe-
`Risperi-
`Perphe-
`nazine
`done
`nazine
`done
`nazine
`cone
`nazine
`
`
`Psychic side effects
`Concentration difficulties
`Asthenia/lassitude/increased fatiquability
`Sleepness or sedation
`Failing memory
`Depression
`Tension
`increased duration of sleep
`Reduced duration of sleep
`Increased dream activity
`Emotional indifference
`Neural side effects
`Dystonia
`Paraesthesia
`Hyperkinesia
`Autonomic side effects
`Accommodation disturbances
`Reduced salivation
`Nausea or vomiting
`Diarrhoea
`Constipation
`Micturition disturbances
`Orthostatic dizziness
`Palpitations or tachycardia
`Increased tendency to sweating
`Other side effects
`Rash
`Pruritus
`Weight gain
`Weightloss
`Menorthagia”
`Amenorthoea®
`Gelactorrhoea
`Gynaecomastia
`17
`Diminished sexual desire
`8
`Increased sexual desire
`14
`Erectile dysfunction”
`5
`Ejaculatory dysfunction”
`2
`Orgastic dysfunction
`15
`Headache — tension headache
`2
`Headache — migraine
`2
`6
`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
`3
`9
`5
`5
`5
`5
`14
`4
`8
`10
`
`49
`40
`29
`23
`37
`43
`20
`14
`20
`29
`
`14
`3
`20
`
`16
`6
`9
`
`3
`4
`14
`9
`
`3
`6
`20
`"i
`
`6
`6
`13
`4
`3
`6
`
`14
`44
`40
`14
`30
`14
`24
`14
`32
`20
`
`10
`8
`14
`
`12
`16
`20
`10
`14
`
`22
`18
`20
`
`8
`12
`52
`8
`8
`5
`4
`2
`8
`10
`1
`16
`14
`12
`
`16
`28
`24
`12
`22
`37
`14
`31
`22
`20
`
`8
`2
`22
`
`{4
`20
`8
`4
`14
`12
`10
`20
`
`8
`10
`24
`12
`
`7
`
`8
`14
`3
`
`6
`
`73
`54
`27
`31
`§2
`65
`25
`21
`15
`44
`
`12
`4
`8
`
`410
`8
`12
`2
`12
`2
`23
`19
`15
`
`2
`12
`10
`15
`
`13
`
`71
`36
`20
`33
`55
`76
`20
`27
`15
`62
`
`6
`6
`13
`
`4
`7
`9
`6
`7
`6
`20
`20
`16
`
`6
`13
`"
`15
`
`13
`4
`2
`15
`6
`8
`10
`6
`9
`
`67
`49
`39
`29
`51
`71
`27
`20
`25
`53
`
`4
`6
`10
`
`6
`12
`12
`6
`12
`
`25
`20
`23
`
`6
`12
`18
`6
`
`8
`2
`4
`10
`6
`8
`4
`8
`12
`
`62
`51
`21
`26
`34
`60
`13
`23
`7
`30
`
`13
`4
`13
`
`15
`16
`9
`1
`6
`28
`21
`17
`
`6
`15
`
`7
`
`17
`2
`12
`6
`2
`4
`
`* The percentage 's calculated on the total number of women.” The percentage is calculated on the total number of men.
`
`peridone 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
`14% 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 risperidone. Reduced duration of
`sleep was reported to deteriorate in 31% of the pa-
`
`tients in the perphenazine group; this was the case
`in only 14%, of the risperidone-treated patients.
`Dueto the increased risk of Type II error when
`performing multiple, selected significance tests, we
`refrained from calculating the significance levels of
`the observed differences in single side effects.
`
`Laboratory testis. 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 RIS is, like PER, a potent antipsychotic agent.
`Moreover, comparative efficacy evaluations suggest
`that RIS is at least as effective as PER, and in some
`respects even better. Although not all efficacy vari-
`ables assumedstatistical significance, a number did
`so: the number of patients showing at least 20%,
`improvement on total BPRS score was significantly
`larger on RIS than on PER.Risperidone was also
`significantly better than perphenazine on the hostil-
`ity cluster of BPRS. In the subgroup ofpatients with
`predominantly negative symptoms, risperidone was
`significantly better than perphenazine with respect
`to the numberofpatients reaching clinical improve-
`ment on the PANSS and BPRS total scores.
`The meandaily dose ofrisperidone during the last
`4 weeks of this 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).
`From the side effect evaluation in this trial,
`patients’ tolerance to both drugs is comparable for
`most items of the UKU Side Effect Rating Scale.
`The orthostatic dizziness and increased heart rate
`reported with RIS 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
`wasa 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 adrenolytic
`properties of the compound.
`The weight gain observed with risperidone in the
`presenttrial has been reported in several trials with
`risperidone; a linear dose relationship is reported in
`the fixed dosetrials. Thus, with the use of RIS 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-HT, and dopamine-D, antagonist ris-
`peridone is an antipsychotic at least as effective as
`perphenazine. Risperidone is more effective than
`perphenazine 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-
`phenazine.
`
`Acknowledgements
`The following people participated in the study: A. Aarvold,
`H.S. Andersen, M. Birket-Smith, F. Bjorndal, M. Christensen,
`W. Eggert, O. Garsdal, A. Gjerris, H.H. Godt, H. Hansen,
`P. M. Isaksen, L. Jensen, O. Jorgensen, M. Ketner, J. Krabbe.
`J. Krag, M. B. Kroger, O. Laigaard, J. K. Larsen, K. Micheels-
`en, A. Naess, K. Pedersen, P. Poulsen, M. Reiner, J. O. Rould-
`set, K. Stevns, R. Sorensen, S. Tiesen, J. Welner, A. K. Wersland
`and K. Westlye.
`
`References
`
`2
`
`1. Leysen JE. GOMMEREN W, EENS A. DE CHAFFOY DE
`CourceLtes D, STOOF JC, JANSSEN PAJ. The biochemi-
`cal profile of risperidone, a newantipsychotic. J Pharmacol
`Exp Ther 1988; 247: 661-670.
`. JANSSEN PAJ, NIEMEGFERS CJE, AWOUTERS F, SCHELLE-
`KENS KHL, MEGENS AAHP,MEErt TF. Pharmacology of
`risperidone (R 64 766), a new antipsychotic with serotonin-S,,
`and dopamine D, antagonistic properties. J Pharmacol Exp
`Ther 1988: 244: 685-693.
`3, MEGENS AAHP, AwovuTers FHL, NIEMEGEERS CJE, Dif-
`ferential effects of the newantipsychotic risperidone onlarge
`and small motor movements in rats: a comparison with ha-
`loperidol. Psychopharmacology 1988: 95: 493-496.
`4. MEGENS AAHP, AwouTers FHL, NIEMEGEERS CJE.In-
`teraction of haloperidol and risperidone (R 64 766) with
`amphetamine-induced motility changes in rats, Drug Dev Res
`1989; 17: 23-33.
`5. ROOSE K, GELDERS Y, HEYLEN S. Risperidone (R 64 766)
`in psychotic patients: a first clinical therapeutic exploration.
`Acta Psychiatr Belg 1988: 88: 233-241.
`6. GeL_prers YG, HeyLen SLE, VANDEN BusscHe G, Rey-
`NTJENS AJM, JANSSEN PAJ, Pilot clinical investigation of
`risperidone in the treatment of psychotic patients. Pharma-
`copsychiatry 1990: 23: 206-211.
`7. HeyLen SLE, Getpers YG. Risperidone versus haloperi-
`dol in psychotic patients: a multicentre double-blind com-
`parative study. 1, Clinical report. Beerse: Janssen Research
`Foundation, December |988; Clinical Research Report RIS-
`BEL-7.
`8. CLaus A, BoLLeN J, De CuyrerH et al. Risperidone ver-
`sus haloperidol in the treatment of chronic schizophrenic in-
`patients: a multicentre double-blind comparative study. Acta
`Psychiatr Scand [992: 85: 295-305.
`9, Kay SR, Opter LA, LinpenMAYER JP. Reliability and
`validity of the Positive and Negative Syndrome Scale for
`Schizophrenics. Psychiatry Res 1988: 23: 99-110.
`10. OVERALL JF, GorHAM DR.TheBrief Psychiatric Rating
`Scale. Psychol Rep 1962: 10: 799-812.
`11, CHOUINARD G, Ross-CHOUINARD A, ANNABLEL, JONES
`BD. The Extrapyramidal Symptoms Rating Scale. Can J
`Neurol Sci 1980: 7 (3): 233.
`12. LINGJARDE O, AHLFORS UG, BEcH P, DENCER SJ,
`ELGEN K. The UKUSide Effect Rating Scale. Acta Psychi-
`atr Scand 1987: 76 (suppl 334); 81-94.
`13. CasTeLao JF, FERREIRA L, Getpers YG, HEYLEN SLE.
`The efficacy of the D, and 5-HT, antagonist risperidone (R
`64 766) in the treatment of chronic psychosis: an open dose-
`finding study. Schizophr Res 1989: 2: 411-415.
`14, MesoTren F, Suy E, Prerquin M, Burton P, HEYLEN
`S, GELDERS Y. Therapeutic effect and safety of increasing
`
`401
`
`

`

`Hoyberget al.
`
`doses of risperidone (R 64 766) in psychotic patients. Psy-
`chopharmacology 1989; 99; 445-449.
`. GeLDeR YG. Thymosthenic agents, a novel upproachin the
`treatmentof schizophrenia. Br J Psychiatry 1989: 155 (suppl.
`5): 33-36.
`Meco G. Bepini L. Bonirati ¥. Sonsini U. Risperidone
`in the treatment of chronic schizophrenia with tardive dysk-
`
`16.
`
`inesia: a single-blind crossover study versus placebo. Curr
`Ther Res 1989: 46: 876-883.
`. BeRSAN! G, BRESSA GM, MECO G, Marini S. Pozzi F.
`Combined scrotonin 5-HT, and dopamine-D, antagonism in
`schizophrenia: clinical, extrapyramidal and neuroendocrine
`response in a preliminary study with risperidone (R 64 766).
`Hum Psychopharmacol 1990: 5: 225-231.
`
`402
`
`