A double-blind comparison of raclopride and haloperidol in the acute phase of schizophrenia The British Isles Raclopride Study Group. A double-blind comparison of raclopride and haloperidol in the acute phase of schizophrenia. Acta Psychiatr Scand 1992: 86: 391-398. 0 Munksgaard 1992. This is the first comparative double-blind study of raclopride. Ninety-one patients with acute schizophrenia received either raclopride 2-8 mg twice daily or haloperidol 5-20 mg twice daily for 4 weeks. Both neuroleptics produced clinical improvements. There were no significant between-drug differences in overall efficacy measurements as assessed by the schizophrenia change sub-scale of the Comprehensive Psychopathological Rating Scale and the Krawiecka (Manchester) Rating Scale. Assessment by the Clinical Global Impression scale found haloperidol to be more effective. There were significantly fewer extrapyramidal symptoms with raclopride and a significantly lower incidence of acute dystonia. The results suggest that raclopride has an antipsychotic effect with a low incidence of extrapyramidal side effects.
Raclopride((-)-( S)-3,5-dichloro-N- [ ( 1-ethyl-2-pyrrolidinyl) methyl]-2-hydroxy-6-methoxybenzamide( + )-tartrate) is a potential neuroleptic of the benzamide type, which in animal studies blocks D2dopamine receptors in low doses. Raclopride has no other potent pharmacological effects that would suggest interaction with other receptor systems (1). In rats, raclopride shows a marked separation between the dose that blocks apomorphine-induced hyperactivity and the dose causing catalepsy; this suggests a separation between doses exerting antipsychotic effect and doses inducing extrapyramidal symptoms (EPS) in patients (2). The development of positron emission tomography (PET) has made it possible to study receptor binding in the living human brain. 11 C-raclopride passes rapidly through the bloodbrain barrier and accumulates in brain structures with a high density of D2-dopamine receptors. The high specificity of raclopride has been confirmed in the living human brain (3).
* Charing Cross and Westminster Research Group, London: Professor S.R. Hirsch, Dr T.R.E. Barnes, Dr M. Dickinson, Dr M. Fernandez, Dr A. Jolley, Dr L. Pusavat, Dr M. Riccio, Dr J. Speller. Crichton Royal Hospital, Dumfries: Dr R.G. McCreadie, Dr M. Stewart. Epsom Hospital, Epsom: Dr H. Standish-Barry, Dr H.V. Goppinath, Mrs M. Metcalfe. Hope Hospital, Salford: Dr S. Soni, Dr P. Davidson. Royal London Hospital, London: Dr J. Cookson. St Batholomews Hospital, London: Professor T. Silverstone, Dr P. Mallett. St James Hospital, Dublin: Dr T.G. Dinan. Astra Clinical Research Unit, Edinburgh: Dr A. Chanas, Ms G. Uppfeldt, Mrs B. Mathie.
The British Isles Raclopride Study Group'
Key words: raclopride; haloperidol; schizophrenia Dr. R.G. McCreadie, Crichton Royal Hospital, Dumfries, Scotland, United Kingdom, DGl 4TG Accepted for publication July 19, 1992
In open studies (3,4) raclopride was well tolerated in the tested dose range of 4-16 mg daily. Treatment response justified further controlled comparative clinical studies. We report the first doubleblind controlled study of raclopride in schizophrenia. The main objectives were to evaluate the efficacy, safety and tolerance of raclopride in comparison with haloperidol. We also report plasma drug concentrations at steady-state and plasma prolactin changes. Material and methods Patients
Patients aged 18-65 years of either sex were eligible for recruitment provided the following conditions were fulfilled: clinical diagnosis of schizophrenia; acute phase of illness according to the Research Diagnostic Criteria (5); not known to be nonresponders to neuroleptic treatment; at the start of active treatment disease severity of at least moderate on the Clinical Global Impression scale (CGI) (6) and a total score of at least 6 on the schizophrenia change sub-scale of the Comprehensive Psychopathological Rating Scale for schizophrenia (CPRSSCS) (7). Exclusion criteria were: a primary mental disorder other than schizophrenia; significant concurrent somatic disease; alcoholism or other drug dependence; lactation, pregnancy or the possibility of pregnancy during the study; and receiving depot neuroleptics, unless at least one normal dose inter-
39 1
The British Isles Raclopride Study Group val had elapsed since the last injection prior to the start of active treatment. Medication
A drug-free washout period of 1 to 7 days followed initial assessment. Patients were randomly and blindly allocated to receive either raclopride or haloperidol. The starting dose of raclopride was 2 mg twice daily and of haloperidol 5 mg twice daily. The dosage could be increased to a maximum of 8 mg twice daily of raclopride or 20 mg twice daily of haloperidol. Dosage was adjusted according to the patient’s clinical response. An interval of 3 days between increases was recommended. The duration of active treatment was 4 weeks. Compliance was assessed by repeated measurement of plasma drug concentrations. No other antipsychotic or antidepressant medication (including lithium) or electroconvulsive treatment was given during the treatment period. Temazepam could be given for night-time sedation and diazepam for grossly disturbed behaviour. If EP S requiring anticholinergic therapy appeared, treatment with procyclidine was initiated; its need was reviewed at least weekly. Ratings of movement disorders were performed before anticholinergic medication was started. If a patient was taking an anticholinergic on entry to the study, this was withdrawn during the washout period. Assessment
The patient’s mental state was assessed by the schizophrenia change subscale of the CPRS-SCS, the CGI and the Krawiecka Scale (8) at the initial assessment, at the end of the washout period and weekly during treatment. The global usefulness (9) of the study drug for each patient was rated at the end of the study period using a 5-point scale ranging from markedly useful to harmful. Efficacy, tolerability and safety aspects were considered when making this rating. EPS were assessed at the same time using the Barnes Akathisia Scale (lo), the Simpson-Angus Scale (11) and the Abnormal Involuntary Movements Scale (AIMS) (12). Dystonic reactions, if they occurred, were rated mild, moderate or severe. Adverse events were also recorded by medical event recording and open questioning. Symptoms were recorded as present or absent since the last evaluation or during the previous week, together with an assessment of severity. Blood pressure and pulse rate measurements were taken at every assessment. An electrocardiogram (ECG) was recorded on admission and after 2 and 4 weeks of treatment. Laboratory tests (haematology
392
and clinical chemistry) were conducted on admission and then after 1, 2 and 4 weeks. Body weight was recorded on admission and the end of the study. Blood samples were taken at baseline and then at weekly intervals immediately before the morning dose to measure plasma raclopride ( I 3), haloperidol (14) and prolactin (commercial radioimmunoassay kit, Diagnostic Prod Corporation, Los Angeles, CA, USA). Psychiatrists from participating hospitals met regularly to examine patients before and during the study to ensure agreement on patient assessment. Statistics
Early withdrawals were included in the statistical safety evaluation to the extent that valid information was available and for efficacy in the evaluation of all patients treated. For the main efficacy analysis, data were used if a patient was treated for at least 12 days. Multiple hypotheses were tested. In the analysis of change, the difference from baseline to last valid rating (last rating carried forward) was considered equally relevant as using the baseline value as a covariate. The Wilcoxon rank-sum test was used in the former (1 5 ) and analysis of covariance in the latter case. In the analysis of the outcome of adverse symptoms, chi-square with contingency tables were used. When an adverse symptom was very rare (expected number in any individual cell less than 5), Fisher’s exact test was used in 2 x 2 tables (15). Blood pressure, pulse, ECG, clinical chemistry and haematology data were not subjected to a formal statistical analysis. The SAS system, version 5, was used to present and analyse data in this study (1618). Ethical considerations
The study was performed in accordance with the principles of the Declaration of Helsinki and the Declaration of Hawaii. Local ethics committees gave approval in all centres. Results
Patients
A total of 91 patients from 8 hospitals were randomized to trial treatment; 44 patients to raclopride and 47 to haloperidol (Table 1). In one patient in the raclopride group and 4 in the haloperidol group there was a protocol violation. They were therefore excluded from the main efficacy analysis, but included in the end safety evaluations and an analysis of psychopathological ratings of all patients treated. The two drug groups were well matched in the
Raclopride and haloperidol in schizophrenia Table 1. Validity status of patients
Table 3. Patients receiving concomitant medication at any time during the study Raclopride (n)
Haloperidol ( ni
Total
44 43
47 47
91 90
6 1
10 4
16 5
36
33
69
Enrolled Valid for safety analysis Excluded from the main efficacy analysis - treatment < 12 days Other protocol violation Valid for the main efficacy analysis
Type of medication
Raclopride group (n=43) 1%)
Haloperidol group (n=47) (%)
Sedative (diazepam) Hypnotic (temazepam or nitrazepam) Anticholinergic Other
18 (42) 13 (301 lo* (231 23 153)
13 (28) 14 (30) 24* (5 1) 21 (45)
* Pt0.02.
main (Table 2). A relatively high proportion of men (62%) were included in the study. When patients valid for the main efficacy analysis were considered, 70% (26/37) were male in the raclopride group compared with 52% (17/33) in the haloperidol group. Of 15 patients who had previously had a “virtual recovery” following treatment, 11 were randomized to raclopride and 4 to haloperidol (NS). Medication
The main dose (i.e. the mean of the dose used longest for each patient) was 10.7 mg of raclopride (67% of the maximum allowed) and 19.5 mg of haloperido1 (49% of the maximum allowed). There were an average of 3.9 and 3.5 dose changes in the two groups respectively. The patients considered in this calculation were those valid for the efficacy analysis only.
The most frequently prescribed concomitant drugs were anticholinergics, sedatives or hypnotics (Table 3). There were no significant between-group differences in the number of patients receiving sedatives or hypnotics. More patients in the haloperidol group received anticholinergic medication at some time during treatment. Early withdrawals
Twenty-nine patients (32 %) were withdrawn from the study before completing 4 weeks of treatment with the study drug (Fig. 1). The mean duration of treatment for withdrawals was 15 days in the raclopride group and 8 days in the haloperidol group. Patients with premature treatment termination
I
-t
Table 2. Demographic and clinical characteristics of the patients Raclopride group (n=44)
Haloperidol group (n=47)
(n=91)
Age (years) Mean SD
35.6 12.5
39.0 12.0
37.4 12.3
Sex (no. of patients) (%) Male Female
29 (66) 15 (34)
28 (60) 19 (40)
57 (63) 34 (37)
Weight (kg) Mean SD
64.1 11.0
68.2 14.5
66.2 13.0
Duration of current episode (no. of patients) (%) < 1 month 1-3 months 3-6 months > 6 months
10 (23) 23 (52) 4 (9) 7 (16)
14 (30) 23 (49) 6 (13) 4 (9)
24 (26) 46 (51) 10 (1 1) 11 (12)
Current episode (no. of patients) (%I Indistinguishable from past Exacerbation Recurrence Significantly different First occurrence
Raclopride
Haloperidol
I
Day No.
Total
4 mg b.d. Elevated
bilirubin
El
I
Drowsiness 5 mg 0.d. EPS, akathisia 10 mg b.d.
2 mg b.d. Postural hypotension
I
8 mg b.d. Neutrophiis 35% (reference4075%)
II 2 (5) 9 (20) 25 157) 0 (0) 8 (18)
1 (2) 12 (26) 26 (55) 1 (2) 7 (15)
3 (3) 21 (23) 51 (56) 1 (1) 15 (16)
Adverse event
Ineffectiveness
Refusal
m o t h e r reason
Fig. 1. Patients with premature treatment termination. Each square represents one patient.
393
The British Isles Raclopride Study Group
Other reasons for withdrawal (Fig. 1) in the raclopride group were suspected intercurrent illness, pregnancy and cannabis abuse. The most common reason for withdrawal for haloperidol-treated patients was an adverse reaction; 3 patients withdrew due to acute dystonic reactions during the first days of treatment.
""1 701
Efficacy
CPRS-SCS scores. The mean total CPRS-SCS scores for those who were treated for at least 12 days are shown in Fig. 2. No statistically significant difference was found between the treatment groups. Analysis of covariance for CPRS-SCS total score at last rating with total CPRS-SCS at baseline as covariate for patients valid for the main efficacy analysis resulted in 1.33 units of difference to the advantage of haloperidol ( S E M = 1.05, NS). The same analysis with the all-patients-treated group gave a difference of 0.8 1 units to the advantage of haloperido1 (SEM = 1.02, NS). For total CPRS-SCS scores, 4 response categories were constructed based on the relative change in total score (
Raclopride((-)-( S)-3,5-dichloro-N- [ ( 1-ethyl-2-pyrrolidinyl) methyl]-2-hydroxy-6-methoxybenzamide( + )-tartrate) is a potential neuroleptic of the benzamide type, which in animal studies blocks D2dopamine receptors in low doses. Raclopride has no other potent pharmacological effects that would suggest interaction with other receptor systems (1). In rats, raclopride shows a marked separation between the dose that blocks apomorphine-induced hyperactivity and the dose causing catalepsy; this suggests a separation between doses exerting antipsychotic effect and doses inducing extrapyramidal symptoms (EPS) in patients (2). The development of positron emission tomography (PET) has made it possible to study receptor binding in the living human brain. 11 C-raclopride passes rapidly through the bloodbrain barrier and accumulates in brain structures with a high density of D2-dopamine receptors. The high specificity of raclopride has been confirmed in the living human brain (3).
* Charing Cross and Westminster Research Group, London: Professor S.R. Hirsch, Dr T.R.E. Barnes, Dr M. Dickinson, Dr M. Fernandez, Dr A. Jolley, Dr L. Pusavat, Dr M. Riccio, Dr J. Speller. Crichton Royal Hospital, Dumfries: Dr R.G. McCreadie, Dr M. Stewart. Epsom Hospital, Epsom: Dr H. Standish-Barry, Dr H.V. Goppinath, Mrs M. Metcalfe. Hope Hospital, Salford: Dr S. Soni, Dr P. Davidson. Royal London Hospital, London: Dr J. Cookson. St Batholomews Hospital, London: Professor T. Silverstone, Dr P. Mallett. St James Hospital, Dublin: Dr T.G. Dinan. Astra Clinical Research Unit, Edinburgh: Dr A. Chanas, Ms G. Uppfeldt, Mrs B. Mathie.
The British Isles Raclopride Study Group'
Key words: raclopride; haloperidol; schizophrenia Dr. R.G. McCreadie, Crichton Royal Hospital, Dumfries, Scotland, United Kingdom, DGl 4TG Accepted for publication July 19, 1992
In open studies (3,4) raclopride was well tolerated in the tested dose range of 4-16 mg daily. Treatment response justified further controlled comparative clinical studies. We report the first doubleblind controlled study of raclopride in schizophrenia. The main objectives were to evaluate the efficacy, safety and tolerance of raclopride in comparison with haloperidol. We also report plasma drug concentrations at steady-state and plasma prolactin changes. Material and methods Patients
Patients aged 18-65 years of either sex were eligible for recruitment provided the following conditions were fulfilled: clinical diagnosis of schizophrenia; acute phase of illness according to the Research Diagnostic Criteria (5); not known to be nonresponders to neuroleptic treatment; at the start of active treatment disease severity of at least moderate on the Clinical Global Impression scale (CGI) (6) and a total score of at least 6 on the schizophrenia change sub-scale of the Comprehensive Psychopathological Rating Scale for schizophrenia (CPRSSCS) (7). Exclusion criteria were: a primary mental disorder other than schizophrenia; significant concurrent somatic disease; alcoholism or other drug dependence; lactation, pregnancy or the possibility of pregnancy during the study; and receiving depot neuroleptics, unless at least one normal dose inter-
39 1
The British Isles Raclopride Study Group val had elapsed since the last injection prior to the start of active treatment. Medication
A drug-free washout period of 1 to 7 days followed initial assessment. Patients were randomly and blindly allocated to receive either raclopride or haloperidol. The starting dose of raclopride was 2 mg twice daily and of haloperidol 5 mg twice daily. The dosage could be increased to a maximum of 8 mg twice daily of raclopride or 20 mg twice daily of haloperidol. Dosage was adjusted according to the patient’s clinical response. An interval of 3 days between increases was recommended. The duration of active treatment was 4 weeks. Compliance was assessed by repeated measurement of plasma drug concentrations. No other antipsychotic or antidepressant medication (including lithium) or electroconvulsive treatment was given during the treatment period. Temazepam could be given for night-time sedation and diazepam for grossly disturbed behaviour. If EP S requiring anticholinergic therapy appeared, treatment with procyclidine was initiated; its need was reviewed at least weekly. Ratings of movement disorders were performed before anticholinergic medication was started. If a patient was taking an anticholinergic on entry to the study, this was withdrawn during the washout period. Assessment
The patient’s mental state was assessed by the schizophrenia change subscale of the CPRS-SCS, the CGI and the Krawiecka Scale (8) at the initial assessment, at the end of the washout period and weekly during treatment. The global usefulness (9) of the study drug for each patient was rated at the end of the study period using a 5-point scale ranging from markedly useful to harmful. Efficacy, tolerability and safety aspects were considered when making this rating. EPS were assessed at the same time using the Barnes Akathisia Scale (lo), the Simpson-Angus Scale (11) and the Abnormal Involuntary Movements Scale (AIMS) (12). Dystonic reactions, if they occurred, were rated mild, moderate or severe. Adverse events were also recorded by medical event recording and open questioning. Symptoms were recorded as present or absent since the last evaluation or during the previous week, together with an assessment of severity. Blood pressure and pulse rate measurements were taken at every assessment. An electrocardiogram (ECG) was recorded on admission and after 2 and 4 weeks of treatment. Laboratory tests (haematology
392
and clinical chemistry) were conducted on admission and then after 1, 2 and 4 weeks. Body weight was recorded on admission and the end of the study. Blood samples were taken at baseline and then at weekly intervals immediately before the morning dose to measure plasma raclopride ( I 3), haloperidol (14) and prolactin (commercial radioimmunoassay kit, Diagnostic Prod Corporation, Los Angeles, CA, USA). Psychiatrists from participating hospitals met regularly to examine patients before and during the study to ensure agreement on patient assessment. Statistics
Early withdrawals were included in the statistical safety evaluation to the extent that valid information was available and for efficacy in the evaluation of all patients treated. For the main efficacy analysis, data were used if a patient was treated for at least 12 days. Multiple hypotheses were tested. In the analysis of change, the difference from baseline to last valid rating (last rating carried forward) was considered equally relevant as using the baseline value as a covariate. The Wilcoxon rank-sum test was used in the former (1 5 ) and analysis of covariance in the latter case. In the analysis of the outcome of adverse symptoms, chi-square with contingency tables were used. When an adverse symptom was very rare (expected number in any individual cell less than 5), Fisher’s exact test was used in 2 x 2 tables (15). Blood pressure, pulse, ECG, clinical chemistry and haematology data were not subjected to a formal statistical analysis. The SAS system, version 5, was used to present and analyse data in this study (1618). Ethical considerations
The study was performed in accordance with the principles of the Declaration of Helsinki and the Declaration of Hawaii. Local ethics committees gave approval in all centres. Results
Patients
A total of 91 patients from 8 hospitals were randomized to trial treatment; 44 patients to raclopride and 47 to haloperidol (Table 1). In one patient in the raclopride group and 4 in the haloperidol group there was a protocol violation. They were therefore excluded from the main efficacy analysis, but included in the end safety evaluations and an analysis of psychopathological ratings of all patients treated. The two drug groups were well matched in the
Raclopride and haloperidol in schizophrenia Table 1. Validity status of patients
Table 3. Patients receiving concomitant medication at any time during the study Raclopride (n)
Haloperidol ( ni
Total
44 43
47 47
91 90
6 1
10 4
16 5
36
33
69
Enrolled Valid for safety analysis Excluded from the main efficacy analysis - treatment < 12 days Other protocol violation Valid for the main efficacy analysis
Type of medication
Raclopride group (n=43) 1%)
Haloperidol group (n=47) (%)
Sedative (diazepam) Hypnotic (temazepam or nitrazepam) Anticholinergic Other
18 (42) 13 (301 lo* (231 23 153)
13 (28) 14 (30) 24* (5 1) 21 (45)
* Pt0.02.
main (Table 2). A relatively high proportion of men (62%) were included in the study. When patients valid for the main efficacy analysis were considered, 70% (26/37) were male in the raclopride group compared with 52% (17/33) in the haloperidol group. Of 15 patients who had previously had a “virtual recovery” following treatment, 11 were randomized to raclopride and 4 to haloperidol (NS). Medication
The main dose (i.e. the mean of the dose used longest for each patient) was 10.7 mg of raclopride (67% of the maximum allowed) and 19.5 mg of haloperido1 (49% of the maximum allowed). There were an average of 3.9 and 3.5 dose changes in the two groups respectively. The patients considered in this calculation were those valid for the efficacy analysis only.
The most frequently prescribed concomitant drugs were anticholinergics, sedatives or hypnotics (Table 3). There were no significant between-group differences in the number of patients receiving sedatives or hypnotics. More patients in the haloperidol group received anticholinergic medication at some time during treatment. Early withdrawals
Twenty-nine patients (32 %) were withdrawn from the study before completing 4 weeks of treatment with the study drug (Fig. 1). The mean duration of treatment for withdrawals was 15 days in the raclopride group and 8 days in the haloperidol group. Patients with premature treatment termination
I
-t
Table 2. Demographic and clinical characteristics of the patients Raclopride group (n=44)
Haloperidol group (n=47)
(n=91)
Age (years) Mean SD
35.6 12.5
39.0 12.0
37.4 12.3
Sex (no. of patients) (%) Male Female
29 (66) 15 (34)
28 (60) 19 (40)
57 (63) 34 (37)
Weight (kg) Mean SD
64.1 11.0
68.2 14.5
66.2 13.0
Duration of current episode (no. of patients) (%) < 1 month 1-3 months 3-6 months > 6 months
10 (23) 23 (52) 4 (9) 7 (16)
14 (30) 23 (49) 6 (13) 4 (9)
24 (26) 46 (51) 10 (1 1) 11 (12)
Current episode (no. of patients) (%I Indistinguishable from past Exacerbation Recurrence Significantly different First occurrence
Raclopride
Haloperidol
I
Day No.
Total
4 mg b.d. Elevated
bilirubin
El
I
Drowsiness 5 mg 0.d. EPS, akathisia 10 mg b.d.
2 mg b.d. Postural hypotension
I
8 mg b.d. Neutrophiis 35% (reference4075%)
II 2 (5) 9 (20) 25 157) 0 (0) 8 (18)
1 (2) 12 (26) 26 (55) 1 (2) 7 (15)
3 (3) 21 (23) 51 (56) 1 (1) 15 (16)
Adverse event
Ineffectiveness
Refusal
m o t h e r reason
Fig. 1. Patients with premature treatment termination. Each square represents one patient.
393
The British Isles Raclopride Study Group
Other reasons for withdrawal (Fig. 1) in the raclopride group were suspected intercurrent illness, pregnancy and cannabis abuse. The most common reason for withdrawal for haloperidol-treated patients was an adverse reaction; 3 patients withdrew due to acute dystonic reactions during the first days of treatment.
""1 701
Efficacy
CPRS-SCS scores. The mean total CPRS-SCS scores for those who were treated for at least 12 days are shown in Fig. 2. No statistically significant difference was found between the treatment groups. Analysis of covariance for CPRS-SCS total score at last rating with total CPRS-SCS at baseline as covariate for patients valid for the main efficacy analysis resulted in 1.33 units of difference to the advantage of haloperidol ( S E M = 1.05, NS). The same analysis with the all-patients-treated group gave a difference of 0.8 1 units to the advantage of haloperido1 (SEM = 1.02, NS). For total CPRS-SCS scores, 4 response categories were constructed based on the relative change in total score (
