University of British Columbia, Vancouver, British Columbia, Canada
Correspondence: Professor Lakshmi N. Yatham, Mood Disorders Clinical Research Unit, University of British Columbia, Vancouver, BC, V6T 2AI, Canada. Tel: 604 822 7325; fax: 604 822 7922; e-mail: yatham{at}interchange.ubc.ca
Declaration of interest Funded by Janssen Pharmaceutica Products, LP.
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ABSTRACT |
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Aims To determine the efficacy of risperidone in combination with a mood stabiliser in acute mania.
Method Patients taking a mood stabiliser were randomised to 3 weeks' treatment with risperidone (n=75) or placebo (n=76).
Results Young Mania Rating Scale (YMRS) scores improved rapidly with significantly greater reductions at week 1 in the risperidone group compared with the placebo group. At end-point YMRS scores decreased by 14.5 and 10.3 points in the risperidone and placebo groups, respectively. Significant improvements v. placebo (P<0.05) were noted in the risperidone group on several other clinically meaningful measures. Additionally, a post hoc analysis excluding carbamazepine-treated patients (plasma concentrations of risperidone active moiety were 40% lower in this group) revealed significantly greater reductions (P=0.047) in YMRS scores in the risperidone group than in the placebo group. Incidence of adverse events was similar in both groups.
Conclusions Risperidone is superior to placebo when used in combination with lithium or divalproex in acute mania.
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INTRODUCTION |
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METHOD |
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Inclusion and exclusion criteria
Eligible patients were 18-65 years old, had a DSM-IV bipolar disorder with
a manic or mixed episode (American
Psychiatric Association, 1994), with a minimum baseline score of
20 on the YMRS. Patients with concurrent symptoms of depression could be
entered. Patients were included if they had been receiving a mood stabiliser
lithium, divalproex (sodium valproate plus valproic acid) or
carbamazepine for a minimum of 2 weeks prior to screening; in the
event that the patient had not been receiving a mood stabiliser, one must have
been prescribed prior to randomisation. Patients were medically stable, and
were randomised within 7 days of hospital admission.
Patients were excluded if they had another DSMIV Axis I diagnosis other than nicotine or caffeine dependence, a seizure disorder requiring medication, or a history of alcohol or drug misuse or dependence within the 3 months prior to the study. People at imminent risk of causing injury to themselves or others or of causing property damage were also excluded, as were people with serious or unstable medical disease, clinically significant laboratory abnormalities, severe drug allergy or hypersensitivity, or a history of neuroleptic malignant syndrome. Pregnant or nursing women and those of childbearing potential without adequate contraception also were excluded.
Patient population
Participants with acute mania who fulfilled the entry criteria were
randomised to receive risperidone or placebo, with stratification for type of
mood stabiliser (lithium, divalproex or carbamazepine), site, and whether mood
stabiliser therapy had been initiated at the start of the trial or had been
given for at least 2 weeks before the patient's screening visit, using a
dynamic randomisation method. This method was based upon the minimisation
technique (White & Freedman,
1978) and was implemented by each site telephoning the
coordinating centre to obtain the randomisation number for each patient; it
ensured balanced treatment groups on the factors of mood stabiliser and time
of initiation of mood stabiliser therapy. Patients underwent a
wash-out period of 3 days, unless the investigator believed that
antipsychotic medication was needed sooner. During the wash-out period
antipsychotic, anti-Parkinsonian, anti-depressant, anxiolytic and other
centrally acting drugs were discontinued. Flurazepam, temazepam, oxazepam and
chloral hydrate were allowed as sleep aids. After initiation of double-blind
treatment, patients remained in hospital for at least 4 days. Study visits
were scheduled at screening, at baseline (day 1) and at days 3, 8, 15 and
22.
Patients were withdrawn from the study if they retracted consent, violated the randomisation code, discontinued mood stabiliser therapy for more than 4 consecutive days, or had a serious adverse event. After completion of the 3-week double-blind study or after completing at least 7 days of double-blind treatment participants were eligible to enter a 10-week, open-label extension study. The double-blind code was not broken, but every participant who entered the second phase of the study received open-label risperidone.
Study medication
All study participants were initially treated with 2 mg risperidone or
placebo (tablets) once daily on days 1 and 2. On days 3 and 4 the risperidone
dose could be increased to a maximum of 4 mg daily or decreased to 1 mg daily.
On days 5 to 21 the dose could be increased to a maximum of 6 mg daily or
decreased to a minimum of 1 mg. Venous blood samples were taken at baseline
and on day 22 to determine plasma concentrations of risperidone and its active
metabolite 9-hydroxyrisperidone, using a radioimmunoassay.
During the double-blind period of treatment all patients also received lithium, divalproex or carbamazepine. Only one mood stabiliser at a time was permitted; another drug could be substituted only for safety reasons, not for efficacy. The dosage of the mood stabiliser was reduced whenever an adverse event attributable to the drug occurred. If the adverse effect persisted, another mood stabiliser could be substituted with no more than a 2-day overlap. Patients whose mood stabiliser was switched retained their original prescription stratification for purposes of statistical analysis. Plasma drug concentrations were measured whenever clinically indicated and at screening, baseline and on days 3, 8, 15 and 22, and the doses of the mood stabilisers were adjusted to achieve therapeutic levels.
Prior and concomitant therapy
Medications not allowed during the study included antipsychotic agents
other than the trial medication; mood stabilisers other than lithium,
divalproex or carbamazepine; and benzodiazepines other than lorazepam,
oxazepam, temazepam or flurazepam. Patients were permitted to take up to 6 mg
lorazepam daily for agitation during the wash-out period and up to 4 mg daily
during the first 7 days of the double-blind period. Anti-Parkinsonian
medication was not permitted at baseline, but could be prescribed for
extrapyramidal symptoms after administration of the Extrapyramidal Symptom
Rating Scale (Chouinard et al,
1980). Antidepressant drugs were not permitted at the start of
double-blind treatment but could be prescribed if clinically significant
depression emerged, identified using the Hamilton Rating Scale for Depression
(HRSD; Hamilton, 1967), and if
the investigator believed that such treatment was unlikely to worsen manic
symptoms. Medication for ongoing medical conditions was continued.
Efficacy evaluations
Assessments using the YMRS (Young
et al, 1978), the Clinical Global Impression (CGI) scale
(Guy, 1976), the Brief
Psychiatric Rating Scale (BPRS; Overall
& Gorham, 1962) and a 21-item HRSD evaluation were completed
at baseline and on days 8, 15 and 22.
The primary measure of efficacy was the change in the YMRS score from baseline to end-point, which was the last available observation for each patient. Other parameters included the YMRS score change from baseline to day 8, the percentage of patients showing a 50% or greater improvement on the YMRS, and the time to onset of therapeutic response (in days) as represented by a reduction of at least 30% in the YMRS score. Further measures of efficacy included the changes from baseline in CGI, BPRS and HRSD scores, and the percentage of patients who used adjunctive lorazepam.
Safety evaluations
Vital signs were measured at screening, at baseline, and on days 8, 15 and
22. A physical examination including weight, ECG and laboratory evaluations
was performed at screening and on day 22. The Extrapyramidal Symptom Rating
Scale (ESRS), administered at baseline and on days 8, 15 and 22, consisted of
a questionnaire; parkinsonism, dystonia and dyskinesia sub-scales; a clinical
global impression of overall severity of dystonia, parkinsonism and
dyskinesia; and parkinsonism staging.
Statistical analysis
Assuming a standard deviation of 12.2, a total of 132 participants was
required to detect a six-point difference between groups in the mean YMRS
score change from baseline (0.05 significance, two-tailed, with 80% power). To
adjust for drop-outs, the total number of randomised participants was
increased to 150 (75 per group). No power calculation has been performed for
any of the secondary efficacy measures, nor have the P values been
adjusted for multiplicity.
For the change from baseline to end-point in YMRS score, an analysis of covariance model was used to test for differences between treatment groups including factors for treatment, country, strata (initiation of mood stabiliser therapy and type of drug), baseline score (as covariate), and their interactions with treatment. A similar analysis was used for changes from baseline in the BPRS and HRSD scores. Clinical Global Impression results are based on the van Elteren test, which evaluates the overall difference between treatments based on linear combinations of Wilcoxon statistics (van Elteren, 1960). For measures without a baseline response (e.g. percentage of days on which patients used adjunctive lorazepam) an analysis of variance (ANOVA) model was used, which contained treatment, country and strata factors.
The CochranMantelHaenszel test for general association, controlling for country, was used to test for treatment differences in the clinical response rates on the YMRS and in the percentage of patients who used adjunctive lorazepam. All statistical tests were interpreted at the 0.05 significance level (two-tailed).
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RESULTS |
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Medications
For each patient assigned to the risperidone group the modal daily dose of
risperidone was calculated (i.e. the most frequently used risperidone dose
throughout the treatment period). The median modal dose of risperidone was 4.0
mg. The treatment duration was as follows: for the placebo group, median 18
days (quartiles 7, 21, 28); for the risperidone group, median 21 days
(quartiles 12, 21, 24). The median plasma concentration of the active moiety
(sum of risperidone and 9-hydroxyrisperidone) at end-point was 17.2 µg/l
(first and third quartiles 0.0, 36) and the median dose normalised (dose
corrected with the 4 mg dose as a reference point, making it possible to
interpret certain effects by excluding the dose as a confounding factor)
concentration was 14.6 µg/l (quartiles 0.0, 25.9). The plasma
concentrations of risperidone, 9-hydroxyrisperidone and the active moiety were
similar when lithium or divalproex were taken concurrently; the median
dose-normalised concentrations for the active moiety were 17.1 µg/l
(quartiles 0.0, 40.6) or 23.4 µg/l (quartiles 0.0, 38.1), respectively.
When risperidone was co-administered with carbamazepine, however, median
dose-normalised plasma concentrations of the active moiety were approximately
40% lower (10 µg/l quartiles 5, 21.6) at the end of the 3-week double-blind
phase.
Fewer than half of the patients (43%) had been receiving a mood stabiliser before entering the trial. At baseline, 86 (57%) of the patients received lithium, 38 (25%) received divalproex and 26 (17%) received carbamazepine (Table 3). At weeks 1 to 3, plasma concentrations of mood-stabilising agents were within the targeted therapeutic range for all groups. Seven patients (five in the risperidone group, two in the placebo group) switched to a different mood stabiliser or, in the switching process, overlapped two different mood stabilisers during the study.
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Adjunctive lorazepam
Fifty-four patients (72%) in the risperidone group and 47 (63%) in the
placebo group used lorazepam during the first 7 days (mean difference 9%; 95%
CI - 5.9 to 23.9). The mean percentage of days that lorazepam was used was 44%
in the risperidone group and 58% in the placebo group (P=0.02;
between-group difference 13.5, 95% CI - 25.0 to - 1.9).
Efficacy based on YMRS
Baseline YMRS scores were similar in the two treatment groups
(Table 4). At week 1, the
risperidone group showed significantly greater improvement as indicated by
decreases in YMRS scores relative to baseline (- 10.2) compared with the
placebo group (- 6.7; 95% CI - 6.35 to - 0.35). On the efficacy measure of
mean change in YMRS scores from baseline to end-point, the risperidone group
had a mean decrease of 14.5 points (49%) in YMRS scores while the placebo
group had a mean decrease of 10.3 points (36%) in YMRS scores (mean difference
in change score - 4.2; 95% CI - 7.60 to 0.54)
(Table 4). At end-point, 40
patients (59%) in the risperidone group responded (defined as 50% or greater
reduction in YMRS scores from baseline) compared with 30 (41%) in the placebo
group (mean difference 17.7%, 95% CI 0.8-33.5; P < 0.05).
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Participants found to have psychotic features at baseline who received risperidone had a mean reduction in YMRS score of 15.1 from baseline to end-point, while those randomised to placebo had a mean reduction of 12.2. Among participants without psychotic features, those in the risperidone group had a mean reduction in YMRS score of 13.8 while those in the placebo group had a mean reduction of 9.2. Analysis of covariance showed no main effect of psychotic features on YMRS score change.
Patients who began taking a mood stabiliser at the start of the study and were randomised to risperidone (n=42) had a mean reduction in YMRS score of 14.9 from baseline to end-point, while patients randomised to placebo (n=39) had a mean reduction of 13.2 (mean difference 1.55; 95% CI - 3.78 to 6.87). In patients who had been taking a mood stabiliser for at least 2 weeks prior to screening, the mean reduction in YMRS score from baseline to end-point was 13.8 in the risperidone group (n=26) and 7.1 in the placebo group (n=34) (mean difference 6.30; 95% CI - 0.008 to 12.61).
Further measures of efficacy
Clinical Global Impression
The CGI severity ratings at baseline were comparable in both groups, with
most patients having marked or moderate manic symptoms. Both at the end of the
first week of treatment and at end-point, the distributions of entire CGI
improvement scores of the risperidone group were more concentrated on the
very much improved and much improved categories
compared with the placebo group (P=0.013 at week 1 and
P=0.022 at end-point using the van Elteren test to control for
country). For example, 48% (n=31) at week 1 and 61% (n=40)
at end-point of the risperidone group had much or very
much improvement on the CGI scale compared with 31% (n=21) at
week 1 and 43% (n=31) at end-point in the placebo group (mean
difference in responders at week 1 16.8%, 95% CI 0.7-32.9; mean difference in
responders at end-point 17.5%, 95% CI 1.1-33.9).
Brief Psychiatric Rating Scale
Both treatment groups had comparable baseline BPRS total and sub-scale
scores. Patients assigned to receive risperidone had significantly greater
improvement on total BPRS scores at week 1 and at end-point compared with the
placebo group (Table 5).
Furthermore, at end-point the risperidone group had significantly greater
improvement in the hostility and thought disturbance sub-scales of the BPRS
than did the placebo group (P < 0.05). In the analysis of activity
and anxiety/depression sub-scales, improvement with risperidone tended to be
greater than that with placebo.
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Hamilton Rating Scale for Depression
At baseline, the mean HRSD scores for the two groups were comparable
(risperidone 8.6, placebo 8.2). No significant difference was present between
the two groups in changes from baseline in total and cluster HRSD scores at
weeks 1, 2 and 3 or at end-point. At end-point the mean decreases in HRSD
total scores were 4.1 for the risperidone group and 2.1 for the placebo group.
Two patients in the placebo group and one patient in the risperidone group
experienced depressive symptoms during the study and were prescribed
antidepressants.
Post hoc analysis
The markedly lower plasma concentrations of the active moiety of
risperidone seen in patients who received carbamazepine prompted a post
hoc analysis of the YMRS change scores from baseline to end-point in
patients who received lithium or divalproex. In this analysis, which excluded
patients who received carbamazepine, the YMRS change scores of the risperidone
group were significantly greater than those of the placebo group at end-point
(P=0.047) and at week 1 (P=0.038)
(Table 6).
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Trial discontinuations
Twelve patients (16%) in the risperidone group and 14 (19%) in the placebo
group discontinued treatment early (difference in proportion discontinuing
early -3%; 95% CI -15.1 to 9.1). Another 15 patients (20%) in the risperidone
group and 25 patients (33%) in the placebo group left the 3-week double-blind
phase of the study early and entered the open-label extension phase
(difference in proportion -13%; 95% CI -26.9 to 0.9).
Safety
The incidence of adverse events was similar in the two groups: 57% of the
risperidone group and 51% of the placebo group reported at least one adverse
event (between-group difference in overall adverse event rate 6%; 95% CI -9.9
to 21.9). The most frequently reported adverse events, excluding
extrapyramidal-related adverse events, were headache (9% in the risperidone
group, 9% in the placebo group), insomnia (4% and 8%) and nausea (5% and 3%).
One patient in each group had worsening of manic symptoms.
Extrapyramidal-related adverse events were reported by 16 patients in the
risperidone group and 6 patients in the placebo group (P=0.013,
CochranMantelHaenszel test for general association controlling
for country, Table 7). Each
group had similar ESRS total scores at baseline and end-point (both groups had
a mean change from baseline of -0.1). Twelve patients in the risperidone group
and 6 in the placebo group used anti-Parkinsonian medication
(P=0.108, CochranMantelHaenszel test for general
association controlling for country). Among patients who received
anti-Parkinsonian medication, those in the risperidone group used it for 49%
of the study days; those in the placebo group used it for 64% of the study
days (P=0.236, ANOVA model with factors for treatment, stratification
and country).
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No clinically significant change in vital signs or laboratory values was observed in either group. At baseline, the mean body weight of the risperidone group was 76.5 kg and that of the placebo group was 74.3 kg. At end-point, the mean weight increase in the former group was 1.7 kg and in the latter 0.5 kg (P=0.012, ANOVA model with factors for treatment, stratification and country). Small fluctuations in the mean value of ECG parameters were observed during the course of the trial, none of which was considered clinically relevant. No significant between-group difference in ECG changes from baseline was observed.
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DISCUSSION |
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Further measures of efficacy
Risperidone in combination with mood-stabilising therapy was associated
with more rapid and significantly greater improvements in the BPRS and CGI
measures compared with placebo plus mood-stabilising therapy. More patients in
the risperidone group had much or very much improvement on the CGI improvement
scale compared with those in the placebo group. Furthermore, hostility,
thought disturbance and activity were better controlled with risperidone than
with placebo in combination with mood-stabilising therapy. This was further
supported by the observation that patients in the placebo group required
adjunctive lorazepam for a greater number of days than those in the
risperidone group. Thus, risperidone plus mood-stabilising treatment may
reduce the overall burden, staff time and other costs associated with acute
mania, particularly as many patients with bipolar disorder require long-term
treatment.
Risperidone plus a mood stabiliser was equally effective in patients with or without psychotic features, as indicated by similar magnitude of reductions in YMRS scores in both groups. This finding, supported by Ghaemi and colleagues (Ghaemi et al, 1997), suggests that risperidone like other atypical antipsychotic agents such as olanzapine (Tohen et al, 2000) has antimanic properties independent of its antipsychotic properties. In addition, improvement in measures of anxiety and depression in this study tended to be greater in patients who received risperidone rather than placebo in combination with a mood stabiliser.
Effect of carbamazepine on risperidone plasma levels and
efficacy
Reductions in YMRS score from baseline to end-point tended to be greater in
the risperidone group (14.5) than in the placebo group (10.3). The magnitude
of difference in YMRS change scores between the risperidone and placebo groups
(4.2) observed in this study was comparable to that reported between
olanzapine add-on and placebo add-on groups (4.01) in a similar study of 6
weeks' duration (Tohen et al,
2002). Furthermore, the magnitude of reduction in YMRS scores in
the risperidone group in this study might have been blunted by the conspicuous
effect of carbamazepine on risperidone plasma concentrations. This possibility
is supported by the observation that plasma levels of risperidone active
moiety were approximately 40% lower in the carbamazepine group compared with
those in the lithium or divalproex group and by the results of post
hoc analysis showing significant reductions in YMRS score from baseline
to end-point after exclusion of the carbamazepine group. Because risperidone
doses were not adjusted upwards in the carbamazepine group within the limited
period of this trial, optimal concentrations might not have been achieved in
that group. Based on our results and on those of others
(Freeman & Stoll, 1998),
patients who receive risperidone or other psychotropic agents concomitantly
with carbamazepine should be monitored closely, and dosages should be adjusted
if necessary.
Effect of risperidone on mania
Several case reports suggest an association between risperidone treatment
and hypomanic or manic episodes in patients with bipolar or schizoaffective
disorder (Aubrey et al,
2000). Patients who experienced these effects generally received
high doses of risperidone and concomitant mood stabilisers were abruptly
discontinued. The results of this placebo-controlled, double-blind trial
indicate that risperidone does not worsen mania. This is consistent with
results of a large, open-label study which showed that risperidone is not
associated with the induction of mania
(Vieta et al,
2001).
Adverse events
The risperidone and placebo combinations with a mood stabiliser were
equally well tolerated. Although patients in the risperidone group reported
extrapyramidal-related adverse events more frequently, the ESRS change scores
were similar in both groups suggesting that risperidone therapy at the dosages
used in this study was not associated with significant extrapyramidal
symptoms. This was supported by the absence of any significant difference in
the use of anti-Parkinsonian medication between the two groups.
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Clinical Implications and Limitations |
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LIMITATIONS
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REFERENCES |
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American Psychiatric Association (2002)
Practice guideline for the treatment of patients with bipolar disorder
(revision). American Journal of Psychiatry,
159 (suppl.),
1-50.
Aubrey, A. M., Simon, A. E. & Bertsky, C. (2000) Possible induction of mania and hypomania by olanzapine or risperidone: a critical review of reported cases. Journal of Clinical Psychiatry, 61, 649-655.
Chouinard, G., Ross-Chouinard, A., Annable, L., et al (1980) Extrapyramidal Symptom Rating Scale (abstract). Canadian Journal of Neurological Science, 7, 233.
Freeman, M. P. & Stoll, A. L. (1998) Mood
stabiliser combinations: a review of safety and efficacy. American
Journal of Psychiatry, 155,
12-21.
Ghaemi, S. N. & Sachs, G. S. (1997) Long-term risperidone treatment in bipolar disorder: 6-month follow-up. International Clinical Psychopharmacology, 12, 333-338.[Medline]
Ghaemi, S. N., Sachs, G. S., Baldassano, C. F., et al (1997) Acute treatment of bipolar disorder with adjunctive risperidone in outpatients. Canadian Journal of Psychiatry, 42, 196-199.[Medline]
Guy, W. (ed.) (1976) ECDEU Assessment Manual for Psychopharmacology, Revised. DHEW Publication No. (ADM) 76. Rockville, MD: DHEW.
Hamilton, M. (1967) Development of a rating scale for primary depressive illness. British Journal of Social and Clinical Psychology, 6, 278-296.
Overall, J. E. & Gorham, D. R. (1962) The Brief Psychiatric Rating Scale. Psychological Reports, 10, 799-812.
Sachs, G. S., Printz, D. J., Kahn, D. A., et al (2000) The Expert Consensus Guideline Series: Medication treatment of bipolar disorder. Postgraduate Medicine, April Special Report, 1-104.
Segal, J., Berk, M. & Brook, S. (1998) Risperidone compared with both lithium and haloperidol in mania: double-blind randomized controlled trial. Clinical Neuropharmacology, 21, 176-180.[Medline]
Tohen, M., Jacobs, T. G., Grundy, S. L., et al
(2000) Efficacy of olanzapine in acute bipolar mania: a
double blind, placebo-controlled study. The olanzapine HGGW Study Group.
Archives of General Psychiatry,
57,
841-849.
Tohen, M., Chengappa, K. N., Suppes, T., et al
(2002) Efficacy of olanzapine in combination with valproate
or lithium in the treatment of mania in patients partially nonresponsive to
valproate or lithium monotherapy. Archives of General
Psychiatry, 59,
62-69.
van Elteren, P. H. (1960) On the combination of independent two-sample tests of Wilcoxon. Bulletin of the International Statistical Institute, 37, 351-361.
Vieta, E., Corbella, B., Reinares, M., et al (2001) Risperidone safety and efficacy in the treatment of bipolar and schizoaffective disorder: results from a six-month, multicenter, open study. Journal of Clinical Psychiatry, 62, 818-825.
White, S. J. & Freedman, L. S. (1978) Allocation of patients to treatment groups in a controlled clinical study. British Journal of Cancer, 37, 849-857.[Medline]
Young, R. C., Biggs, J. T., Ziegler, V. E., et al (1978) A rating scale for mania: reliability, validity and sensitivity. British Journal of Psychiatry, 133, 429-435.[Abstract]
Received for publication January 7, 2002. Revision received August 29, 2002. Accepted for publication October 3, 2002.
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