Rernoxipride and haloperidol in schizophrenia: a double-blind multicentre study. Ahlfors U G, Rimdn R, Appelberg B, et al. Remoxipride and haloperidol in schizophrenia: a double-blind multicentre study. Acta Psychiatr Scand 1990; 82 (Supp1.358): 99-103. Abstract: Ninety-two patients with schizophrenia were included in a doubleblind multicentre parallel-group trial comparing remoxipride and haloperidol. The mean daily dose during the last week of treatment was 316 mg (range, 150-600 mg) in the remoxipride group and 8.7 mg (range, 5-20 mg) in the haloperidol group. The study period was six weeks with at least one day of washout. Both Clinical Global Impression (CGI) rating, and Brief Psychiatric Rating Scale (BPRS) total scores declined at the end of the trial compared with pretreatment values in both groups. No significant differences were found between the remoxipride and haloperidol groups with regard to the treatment outcome. Treatment-emergent extrapyramidal symptoms were statistically more frequent and more severe during haloperidol than during remoxipride treatment. Haloperidol-treated patients reported also significantly more concentration difficulties. Severe extrapyramidal side effects in the haloperidol group and clinical ineffectiveness in the remoxipride group were the most frequent reasons for premature discontinuation of treatment.
Remoxipride (5-3-bromo-N-[(1-ethyl-2-pyrrolidinyl) methyl]- 2,6-dimethoxy benzamide hydrochloride monohydrate) is a dopamine D2 receptor blocking agent without effects on serotonin, noradrenaline, histamine, acetylcholine, or gamma-aminobutyric acid (GABA) receptors (1). It seems to have a preferential action on the mesolimbic compared to the nigrostriatal dopaminergic system in both behavioural and receptor binding studies in animals (2). The relative receptor specificity - not a characteristic of several other commonly used neuroleptic agents - suggests that the incidence of extrapyramidal side effects should be low (2). Open non-comparative and blind studies have indicated that remoxipride in doses ranging from 75-600 mglday exerts a beneficial therapeutic effect in patients with schizophrenia (3 - 5). McCreadie et al. (6) conducted the first double- blind study in which remoxipride was compared with thioridazine in acute treatment of schizophrenia. They showed that remoxipride had a clear-cut antipsychotic effect but that its clinical efflcacy was slightly although not statistically significantly inferior to that of thioridazine. Remoxipride,however, had significantly fewer side effects than thioridazine. The aim of the present study was to evaluate in a double-blind fashion the clinical efficacy, safety, and tolerability of remoxipride in comparison to haloperidol in schizophrenicpatients.
Patients and methods The study was carried out as arandomized, double-blind
U.G.Ahlfors', R.Rim,6n2,B.ApPelberg', U.Haqert3,P.Harma , H.Katila ,A.Mahlanen ,O-P.Mehtonen5, H.Naukkar$en2, J.Outakoski: HRantanen;, ASorri , T.Tamminen , E.Tolvanen , A X . Holm'. 'Hesperia Hospital, Helsinki, *Department of Psychiatry, University of Helsinki, 3Nikkila Hospital, Nikkila, 4Moisio Hospital, Mikkeli, 5PitkaniemiHos ital, Pitkaniemi, 60ulunsuu Hospital, Oulu, Psychiatric Clinic OUCH, Oulu,
P
'
Finland, 'Astra Research Centre, Sodertalje, Sweden
Key words: remoxipride - haloperidol schizophrenia. U.G. Ahlfors M.D., DSc., Hesperia Hospital, Helsinki, Finland
multicentre study, with a parallel design, in nine central mental hospitals in Finland. Altogether 92 inpatients (39 men, 53 women) who met the DSM-I11 criteria (7) for either schizophrenia or schizophreniform disorder were included. They had to be at least moderately ill according to the Clinical Global Impression (CGI) scale and to have a total score of at least 18 on the Brief Psychiatric Rating Scale (BPRS) at the start of the study. Patients with other primary psychiatric disorders or suffering from a major somatic illness were excluded from the study. The study was approved by the ethics committee of each hospital. Informed consent was obtained from the patients and/or their relatives after the purpose and the design of the study had been fully explained according to the Helsinki Declaration. The patients had the freedom to withdraw from the trial at any time.
Medication All psychotropic medication was discontinued on admission to the study. The study period was 6 weeks with at least one day of washout for neuroleptic drugs. Patients who had received depot neuroleptics had to be drug-free for at least one dose interval in order to be eligible for the study. Initially, the patients were given 150 mg or 300 mg/day of remoxipride or 5 mg or 10 mglday of haloperidol. At the discretion of the investigator the dosage was increased to a maximum of 600 mglday for remoxipride or 20 mg/day for haloperidol,
99
Ahlfors et al. or reduced to a minimum of 150 mg/day for remoxipride or 5 mg/day for haloperidol. The daily dosage was divided into two doses. The dosage was to be reduced either if harmful side effects appeared or if marked clinical improvement was observed. No other psychoactive drugs were allowed during the study period except for short-acting benzodiazepines (temazepam or oxazepam) and chloral hydrate for anxiety, agitation, and/or insomnia. An anticholinergic drug, preferably biperiden, was permitted to alleviate intolerable or severe extrapyramidal symptoms if the condition of the patient did not allow the dose of the antipsychotic study drug to be reduced. Patients who for any reason discontinued the study medication before the end of the study period were included in the statistical safety evaluation and an intention-to-treat analysis. For the main efficacy analyses data were used if the patient was treated for at least 12 days.
Assessment The patients were assessed on admission, after the washout period, and after 7,14,21,28, and 42 days by measurement of CGI and BPRS. Extrapyramidal symptoms were assessed according to the Simpson and Angus scale (8). Adverse symptoms were recorded using a 26-item checklist together with open questioning. Laboratory tests (haematology,clinical chemistry, electrocardiography (ECG), blood pressure, and pulse rate) were conducted on admission and thereafter biweekly. Samples for determination of plasma concentration of remoxipride and haloperidol were also taken bi-weekly.
Statistical methods The BPRS total scores, individual items and CGI scores in terms of differences from baseline to last rating were analysed using the Wilcoxon rank sum test (9). Nonparametric estimates of the distribution to reach a 50% reduction of the BPRS total scores were calculated. Comparisons of distribution were made using the log rank test (10). Analysis of covariance was used for some of the covariates (sex, duration of illness, outcome of previous neuroleptic treatment, type of schizophrenia). A repeated measurements analysis was performed on patients having completed the whole study period (11). A week-by-week analysis was performed on the BPRS total scores in terms of difference from baseline up to the timepoint in question. The difference in severity of illness on CGI from baseline and the global impression of change of illness were also analysed week-by-week. The Wilcoxon rank sum test was used to evaluate the statistical hypothesis. The Bonferroni-Holm sequentially rejective procedure was used controlling for multiplicity in the week-by-week analysis (1 l ) .
100
Adverse effects were analysed using the chi-squared test or Fisher’s exact test for evaluationof the hypotheses of equal incidences for each group of symptoms.
Results Of the 92 patients who entered the study,46 were treated with remoxipride and 46 with haloperidol. Their mean age was 36.9 years (range, 17-68 years) and the mean duration of illness was 12.5 years (range,< 1-39 years). About 40% of patients in both treatment groups discontinued treatment prematurely. Adverse reaction was more often (n=ll) observed in the haloperidol group, whereas clinical ineffectiveness was the most frequent reason for withdrawal in the remoxipride group (n=l 1). The mean duration of treatment for those who withdrew was 14 days (range, 3-33 days) for the remoxipride patients and 19 days (range, 4-37 days) for the haloperidol patients. The study medication was discontinued in 12 patients before day 12 of the study. Of the remaining 80 patients,38 received remoxipride and 42 haloperidol. The two groups were well-matched and there were no major differences with regard to age, sex distribution,duration of illness, age at first symptoms of illness, therapeutic outcome of previous treatments with neuroleptic drugs, the nature of the current psychotic episode, and/or course of the schizophrenic disease process.
Dosages of study drugs The mean daily dose of remoxipride during the last week of treatment was 316 mg (range, 150 - 600 mg). The corresponding dose of haloperidol was 8.7 mg (range 5-20 mg). Seven patients in the remoxipride group were receiving the maximum dose of 600 mg at the end of the trial, whereas only three patients in the haloperidol group were on the maximum dose of 20 mg.
Global therapeutic outcome (CGI) The overall therapeutic outcome in the two groups of patients as measured by CGI is shown in Table 1. The global impression of change of illness shows that 61% of the patients in the remoxipride and 71% in the haloperidol group had benefited at least minimally from the treatment. Forty-five percent of the patients in each treatment group were considered much or very much improved. There was no statistically significant difference between the two drugs as regards therapeutic outcome.
Changes of BPRS scores A clear-cut decrease in the BPRS total scores, reflecting clinical improvement, was observed in both groups. No statistically significant differences were found between
Remoxipride versus haloperidol Table 1. Global therapeutic outcome in 38 patients treated with remoxipride and 42 patients treated with haloperidol Therapeutic result Very much improved
Remoxipride n (%) 5 (13)
Haloperidol n (%) 2 (5)
12 (32)
17 (40)
6 (16)
11 (26)
4 (10) 11 (29)
2 (5) 10 (24)
Much improved Minimally improved Unchanged Deteriorated
the two groups of patients (Fig. 1). The time to reach a 50% reduction of the BPRS total score was almost identical for the two groups. Moreover, a repeated measurements' analysis was performed on patients having completed the whole study period. No statistically significant difference was found. Neither were there any statistically significant differences in the absolute change in positive or negative item total scores. Furthermore, there was no significant relationship between such variables as age, sex, duration of illness, subtype of schizophrenia, course of illness or previous response to treatment and therapeutic outcome.
Concomitant medication Anticholinergics were used clearly, although not significantly, more often by patients in the haloperidol group (39%) than by those in the remoxipride group (24%); this was due to more frequent extrapyramidal side effects in patients treated with haloperidol. Sedative and hypnotic drugs were used by 70% of the
-
remoxipride patients and by 85% of the haloperidol patients.
Adverse events and laboratory findings The incidences of treatment-emergent checklist symptoms during treatment are shown in Figs 2 and 3. Besides more concentration difficulties, there were also significantly more extrapyramidal symptoms of various degrees in the haloperidol group than in the remoxipride group. This finding was further confirmed by the Simpson and Angus rating scale (Fig.4). No statistically significant differences were observed between the two groups with regard to autonomic and endocrine side effects. The adverse effects were generally mild and, even in more severe cases, easily controlled. In 3 patients in the remoxipride group and 11 in the haloperidol group the seventy of the side effects led to premature discontinuation of treatment. Two patients in the remoxipride group and one in the haloperidol group showed treatment-emergent deviations of the white blood cell count below the reference limits. Deviations above the reference limit in the eosinophil court were observed in 7 and 9 patients in the remoxipride and haloperidol groups, respectively; in 1 and 4 cases, respectively, these were transient. Nevertheless, only one patient had evidence of allergy. This took the form of urticaria; however, no tests were carried out to determine whether it was drug related or not. Other haematological tests revealed no changes of clinical significance.
Remoxipride
o-----oHaloperidol
1
Drowrinessisomnolence R
45 45 45 45 45 45
H
Increased sleep
R H R H R
Headache
H R
Tiredoesslfatigue Insomnia
Concentralion difficulties
Dizzy on rising 01zziness other
1 I
iieline n (remoxipride) 38 38 n (haloperidol) 42
41
2
i i
I' 6
Time (weeks)
R H
Dry mouth
R H R
32
28
26
41
38
32
25
Fig. I. Median BPRS total scores in schizophrenic patients treated with remoxipride or haloperidol.
ISevere
a
Increased lhirst
Constipatlo"
45 45
45 45 45 45 45 45
R
R
H R H R H
sg
45 45
H Increased saliva1 on
Moderate Mild
45 45
H
Nausea
38
H R H R H R H
Blurred "1SlO"
Increased sweating
0
45 45
45 45 45
-1
45 45 45 45 45 45
Fig.2. Incidence of treatment-emergentchecklist symptoms during treatment. R = remoxipride; H = haloperidol. *p
Remoxipride (5-3-bromo-N-[(1-ethyl-2-pyrrolidinyl) methyl]- 2,6-dimethoxy benzamide hydrochloride monohydrate) is a dopamine D2 receptor blocking agent without effects on serotonin, noradrenaline, histamine, acetylcholine, or gamma-aminobutyric acid (GABA) receptors (1). It seems to have a preferential action on the mesolimbic compared to the nigrostriatal dopaminergic system in both behavioural and receptor binding studies in animals (2). The relative receptor specificity - not a characteristic of several other commonly used neuroleptic agents - suggests that the incidence of extrapyramidal side effects should be low (2). Open non-comparative and blind studies have indicated that remoxipride in doses ranging from 75-600 mglday exerts a beneficial therapeutic effect in patients with schizophrenia (3 - 5). McCreadie et al. (6) conducted the first double- blind study in which remoxipride was compared with thioridazine in acute treatment of schizophrenia. They showed that remoxipride had a clear-cut antipsychotic effect but that its clinical efflcacy was slightly although not statistically significantly inferior to that of thioridazine. Remoxipride,however, had significantly fewer side effects than thioridazine. The aim of the present study was to evaluate in a double-blind fashion the clinical efficacy, safety, and tolerability of remoxipride in comparison to haloperidol in schizophrenicpatients.
Patients and methods The study was carried out as arandomized, double-blind
U.G.Ahlfors', R.Rim,6n2,B.ApPelberg', U.Haqert3,P.Harma , H.Katila ,A.Mahlanen ,O-P.Mehtonen5, H.Naukkar$en2, J.Outakoski: HRantanen;, ASorri , T.Tamminen , E.Tolvanen , A X . Holm'. 'Hesperia Hospital, Helsinki, *Department of Psychiatry, University of Helsinki, 3Nikkila Hospital, Nikkila, 4Moisio Hospital, Mikkeli, 5PitkaniemiHos ital, Pitkaniemi, 60ulunsuu Hospital, Oulu, Psychiatric Clinic OUCH, Oulu,
P
'
Finland, 'Astra Research Centre, Sodertalje, Sweden
Key words: remoxipride - haloperidol schizophrenia. U.G. Ahlfors M.D., DSc., Hesperia Hospital, Helsinki, Finland
multicentre study, with a parallel design, in nine central mental hospitals in Finland. Altogether 92 inpatients (39 men, 53 women) who met the DSM-I11 criteria (7) for either schizophrenia or schizophreniform disorder were included. They had to be at least moderately ill according to the Clinical Global Impression (CGI) scale and to have a total score of at least 18 on the Brief Psychiatric Rating Scale (BPRS) at the start of the study. Patients with other primary psychiatric disorders or suffering from a major somatic illness were excluded from the study. The study was approved by the ethics committee of each hospital. Informed consent was obtained from the patients and/or their relatives after the purpose and the design of the study had been fully explained according to the Helsinki Declaration. The patients had the freedom to withdraw from the trial at any time.
Medication All psychotropic medication was discontinued on admission to the study. The study period was 6 weeks with at least one day of washout for neuroleptic drugs. Patients who had received depot neuroleptics had to be drug-free for at least one dose interval in order to be eligible for the study. Initially, the patients were given 150 mg or 300 mg/day of remoxipride or 5 mg or 10 mglday of haloperidol. At the discretion of the investigator the dosage was increased to a maximum of 600 mglday for remoxipride or 20 mg/day for haloperidol,
99
Ahlfors et al. or reduced to a minimum of 150 mg/day for remoxipride or 5 mg/day for haloperidol. The daily dosage was divided into two doses. The dosage was to be reduced either if harmful side effects appeared or if marked clinical improvement was observed. No other psychoactive drugs were allowed during the study period except for short-acting benzodiazepines (temazepam or oxazepam) and chloral hydrate for anxiety, agitation, and/or insomnia. An anticholinergic drug, preferably biperiden, was permitted to alleviate intolerable or severe extrapyramidal symptoms if the condition of the patient did not allow the dose of the antipsychotic study drug to be reduced. Patients who for any reason discontinued the study medication before the end of the study period were included in the statistical safety evaluation and an intention-to-treat analysis. For the main efficacy analyses data were used if the patient was treated for at least 12 days.
Assessment The patients were assessed on admission, after the washout period, and after 7,14,21,28, and 42 days by measurement of CGI and BPRS. Extrapyramidal symptoms were assessed according to the Simpson and Angus scale (8). Adverse symptoms were recorded using a 26-item checklist together with open questioning. Laboratory tests (haematology,clinical chemistry, electrocardiography (ECG), blood pressure, and pulse rate) were conducted on admission and thereafter biweekly. Samples for determination of plasma concentration of remoxipride and haloperidol were also taken bi-weekly.
Statistical methods The BPRS total scores, individual items and CGI scores in terms of differences from baseline to last rating were analysed using the Wilcoxon rank sum test (9). Nonparametric estimates of the distribution to reach a 50% reduction of the BPRS total scores were calculated. Comparisons of distribution were made using the log rank test (10). Analysis of covariance was used for some of the covariates (sex, duration of illness, outcome of previous neuroleptic treatment, type of schizophrenia). A repeated measurements analysis was performed on patients having completed the whole study period (11). A week-by-week analysis was performed on the BPRS total scores in terms of difference from baseline up to the timepoint in question. The difference in severity of illness on CGI from baseline and the global impression of change of illness were also analysed week-by-week. The Wilcoxon rank sum test was used to evaluate the statistical hypothesis. The Bonferroni-Holm sequentially rejective procedure was used controlling for multiplicity in the week-by-week analysis (1 l ) .
100
Adverse effects were analysed using the chi-squared test or Fisher’s exact test for evaluationof the hypotheses of equal incidences for each group of symptoms.
Results Of the 92 patients who entered the study,46 were treated with remoxipride and 46 with haloperidol. Their mean age was 36.9 years (range, 17-68 years) and the mean duration of illness was 12.5 years (range,< 1-39 years). About 40% of patients in both treatment groups discontinued treatment prematurely. Adverse reaction was more often (n=ll) observed in the haloperidol group, whereas clinical ineffectiveness was the most frequent reason for withdrawal in the remoxipride group (n=l 1). The mean duration of treatment for those who withdrew was 14 days (range, 3-33 days) for the remoxipride patients and 19 days (range, 4-37 days) for the haloperidol patients. The study medication was discontinued in 12 patients before day 12 of the study. Of the remaining 80 patients,38 received remoxipride and 42 haloperidol. The two groups were well-matched and there were no major differences with regard to age, sex distribution,duration of illness, age at first symptoms of illness, therapeutic outcome of previous treatments with neuroleptic drugs, the nature of the current psychotic episode, and/or course of the schizophrenic disease process.
Dosages of study drugs The mean daily dose of remoxipride during the last week of treatment was 316 mg (range, 150 - 600 mg). The corresponding dose of haloperidol was 8.7 mg (range 5-20 mg). Seven patients in the remoxipride group were receiving the maximum dose of 600 mg at the end of the trial, whereas only three patients in the haloperidol group were on the maximum dose of 20 mg.
Global therapeutic outcome (CGI) The overall therapeutic outcome in the two groups of patients as measured by CGI is shown in Table 1. The global impression of change of illness shows that 61% of the patients in the remoxipride and 71% in the haloperidol group had benefited at least minimally from the treatment. Forty-five percent of the patients in each treatment group were considered much or very much improved. There was no statistically significant difference between the two drugs as regards therapeutic outcome.
Changes of BPRS scores A clear-cut decrease in the BPRS total scores, reflecting clinical improvement, was observed in both groups. No statistically significant differences were found between
Remoxipride versus haloperidol Table 1. Global therapeutic outcome in 38 patients treated with remoxipride and 42 patients treated with haloperidol Therapeutic result Very much improved
Remoxipride n (%) 5 (13)
Haloperidol n (%) 2 (5)
12 (32)
17 (40)
6 (16)
11 (26)
4 (10) 11 (29)
2 (5) 10 (24)
Much improved Minimally improved Unchanged Deteriorated
the two groups of patients (Fig. 1). The time to reach a 50% reduction of the BPRS total score was almost identical for the two groups. Moreover, a repeated measurements' analysis was performed on patients having completed the whole study period. No statistically significant difference was found. Neither were there any statistically significant differences in the absolute change in positive or negative item total scores. Furthermore, there was no significant relationship between such variables as age, sex, duration of illness, subtype of schizophrenia, course of illness or previous response to treatment and therapeutic outcome.
Concomitant medication Anticholinergics were used clearly, although not significantly, more often by patients in the haloperidol group (39%) than by those in the remoxipride group (24%); this was due to more frequent extrapyramidal side effects in patients treated with haloperidol. Sedative and hypnotic drugs were used by 70% of the
-
remoxipride patients and by 85% of the haloperidol patients.
Adverse events and laboratory findings The incidences of treatment-emergent checklist symptoms during treatment are shown in Figs 2 and 3. Besides more concentration difficulties, there were also significantly more extrapyramidal symptoms of various degrees in the haloperidol group than in the remoxipride group. This finding was further confirmed by the Simpson and Angus rating scale (Fig.4). No statistically significant differences were observed between the two groups with regard to autonomic and endocrine side effects. The adverse effects were generally mild and, even in more severe cases, easily controlled. In 3 patients in the remoxipride group and 11 in the haloperidol group the seventy of the side effects led to premature discontinuation of treatment. Two patients in the remoxipride group and one in the haloperidol group showed treatment-emergent deviations of the white blood cell count below the reference limits. Deviations above the reference limit in the eosinophil court were observed in 7 and 9 patients in the remoxipride and haloperidol groups, respectively; in 1 and 4 cases, respectively, these were transient. Nevertheless, only one patient had evidence of allergy. This took the form of urticaria; however, no tests were carried out to determine whether it was drug related or not. Other haematological tests revealed no changes of clinical significance.
Remoxipride
o-----oHaloperidol
1
Drowrinessisomnolence R
45 45 45 45 45 45
H
Increased sleep
R H R H R
Headache
H R
Tiredoesslfatigue Insomnia
Concentralion difficulties
Dizzy on rising 01zziness other
1 I
iieline n (remoxipride) 38 38 n (haloperidol) 42
41
2
i i
I' 6
Time (weeks)
R H
Dry mouth
R H R
32
28
26
41
38
32
25
Fig. I. Median BPRS total scores in schizophrenic patients treated with remoxipride or haloperidol.
ISevere
a
Increased lhirst
Constipatlo"
45 45
45 45 45 45 45 45
R
R
H R H R H
sg
45 45
H Increased saliva1 on
Moderate Mild
45 45
H
Nausea
38
H R H R H R H
Blurred "1SlO"
Increased sweating
0
45 45
45 45 45
-1
45 45 45 45 45 45
Fig.2. Incidence of treatment-emergentchecklist symptoms during treatment. R = remoxipride; H = haloperidol. *p
