The Psychiatric Clinic, Vasant Vihar, New Delhi, India
Department of Psychiatry, Hospital Clinic, University of Barcelona, IDIBAPS, Barcelona, Spain
Johnson & Johnson Pharmaceutical Research and Development, Titusville, New Jersey, USA
Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium
Johnson & Johnson Pharmaceutical Research and Development, Titusville, New Jersey, USA
Correspondence: Dr Sumant Khanna, The Psychiatric Clinic, 63 Paschmi Marg, Vasant Vihar, New Delhi, India. E-mail: sumantk_2002{at}yahoo.co.in
Declaration of interest B.L., F.G., M.E. and M.K. are employees of Johnson & Johnson Pharmaceutical Research and Development, which supported this study.
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Aims To evaluate the safety and efficacy of risperidone monotherapy for acute mania.
Method In a 3-week, randomised, double-blind trial, 290 in-patients with bipolar I disorder with current manic or mixed episode and a baseline Young Mania Rating Scale (YMRS) score of 20 or more received flexible doses of risperidone (16 mg per day) or placebo.
Results Risperidone was received by 146 patients and placebo by144. Their mean baseline YMRS score was 37.2 (s.e.=0.5). Significantly greater improvements were observed with risperidone than with placebo at weeks 1 and 2 and at end-point (total YMRS: P <0.01). Extrapyramidal symptoms were the most frequently reported adverse events in the risperidone group.
Conclusions In patients with severe manic symptoms, risperidone produced significant improvements in YMRS scores as early as week 1 and substantial changes at end-point. Treatment was well tolerated.
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
METHOD |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Participants
In-patients aged 18 years or over were enrolled if they met DSMIV
criteria for bipolar I disorder with either manic or mixed episodes and with
or without psychotic features and had a score of at least 20 on the YMRS at
screening and at baseline. Signed informed consent was obtained for all
participants and the study was conducted according to the Recommendations
Guiding Physicians in Biomedical Research Involving Human Subjects, in
the 1989 version of the Declaration of Helsinki
(World Medical Association,
1989).
Patients with schizoaffective disorder, rapid cycling, borderline or antisocial personality disorder, a recent history of substance dependence, risk of suicide or violent behaviour, and unstable medical illness were excluded. Patients with antidepressant-induced mania or those who had been treated with an antidepressant within 4 weeks of screening were also excluded. Additionally, patients whose YMRS score reduced by 25% or more between screening and baseline were not permitted to enter the study.
Interventions
Patients assigned to receive risperidone were given a single 3 mg dose on
day 1. On day 2, at the discretion of the investigator, each patients
once-daily dose (administered in the evening) could be reduced to 2 mg or
increased to 4 mg. On day 3, the daily dose could be reduced to 1 mg or
increased to 5 mg. On day 4 and thereafter the daily dose could be increased
to 6 mg. Throughout the trial, increases in risperidone dosage were made in
increments of 1 mg daily and the daily dose could be between 1 mg and 6
mg.
The patients received no psychotropic drug other than risperidone, with the
exception of lorazepam. Lorazepam could be given for the control of agitation,
irritability, restlessness, insomnia or hostility during the wash-out period
and the first 10 days of the double-blind treatment period (8 mg per day
on days 1 to 3,
6 mg per day on days 4 to 7, and
4 mg per day on days
8 to 10); however, it was not to be given within 8 h of behavioural
assessments. Beta-adrenergic blockers for treatment-emergent akathisia and
antiparkinsonian drugs could be given as needed.
Assessments
The primary efficacy variable was the change in total YMRS score from
baseline to end-point (last post-baseline observation carried forward to the
end of treatment at week 3). The YMRS (scores range from 0 to 60) consists of
11 items; a higher score represents a worse condition. Other measures included
the Clinical Global Impression (CGI; Guy,
1976) severity scale (scores range from 0, not ill, to 6,
extremely severe); the Global Assessment Scale (GAS;
Endicott et al, 1976),
a measure of functioning (scores range from 0 to 100); the
MontgomeryÅsberg Depression Rating Scale (MADRS;
Montgomery & Åsberg,
1979) to measure symptoms of depression (scores range from 0 to
56); and the Positive and Negative Syndrome Scale (PANSS;
Kay et al, 1987) for
symptoms of psychosis (PANSS total scores range from 30 to 210). Total scores
for PANSS and scores on the five factors (positive symptoms, negative
symptoms, disorganised thoughts, uncontrolled excitement/hostility, and
anxiety/depression) are reported (Marder
et al, 1997). Severity of movement disorders was assessed
by means of the Extrapyramidal Symptom Rating Scale (ESRS;
Chouinard et al, 1980)
total score (scores range from 0 to 102). On all but the GAS scale, higher
scores indicate more severe symptoms.
Investigators were trained in the use of each of these instruments and certification was required for those administering the YMRS.
Data analysis
The sample size was based on experience from three recent trials of
atypical antipsychotic agents in the treatment of bipolar disorder
(Tohen et al, 1999;
Sachs et al, 2002;
Yatham et al, 2003).
Power calculations were based on a two-sided test with a significance level of
5%. With an anticipated total of 115 patients per group and with a standard
deviation of 12.6, the trial would have approximately 90% power to detect a
clinically meaningful difference of 5.4 units in the total YMRS score. Since
the estimated rate of discontinuation was approximately 20% among the randomly
assigned patients, the total number of such patients was set at 288, with 144
per treatment group.
The Van Elteren test and the CochranMantelHaenszel test were used to analyse continuous and categorical variables, respectively, controlling for centre and psychotic features at baseline. An analysis of covariance (ANCOVA) model was used to analyse the change from baseline in YMRS scores, with the treatment centre and baseline psychosis as factors and the baseline YMRS score as covariate. The main effect for psychosis was included in the model because it was a randomisation stratification factor. Because most of the patients in this trial had purely manic symptoms, the manic or mixed factor was not included in the model, although it was used as a stratification factor. The same method was used to evaluate the changes from baseline in GAS, CGI and MADRS scores.
The primary comparison between the risperidone and placebo treatment groups
was the change in YMRS score from baseline based on least-squares means
obtained from the ANCOVA model. To determine whether the treatment effects
differed according to baseline YMRS score (<30, 30), diagnosis (absence
v. presence at baseline), age (<23 years, 2344 years,
45 years) or gender, ANCOVA models were fitted separately for each level
of these variables. Clinical response, defined as a 50% or greater reduction
in YMRS score from baseline, was analysed using a
CochranMantelHaenszel test for general association controlling
for centre and psychotic features at baseline. Both observedcase and end-point
(last observation carried forward) data are reported.
Adverse events were tabulated and the electrocardiographic data and vital sign scores were compared with prospectively defined abnormality criteria.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
Use of a pharmacological treatment for bipolar disorder during the 30 days before trial entry was reported by most patients (83% in the placebo group and 76% in the risperidone group). Psychotropic drugs had been taken by 83% of the placebo group and 75% of the risperidone group (including lorazepam by 42% and 43%, respectively, haloperidol by 41% and 36%, and chlorpromazine by 42% and 34%) and anti-epileptics by 17% of each group, carbamazepine being the most common (by 14% and 12%, respectively). During the wash-out period and the first 10 days of the double-blind treatment period, 99% of the patients received lorazepam. The mean daily dosage of lorazepam during the first 10 days of the double-blind period was 4.1 mg (s.d.=1.7) in the risperidone group and 4.4 mg (s.d.=1.6) in the placebo group (range 18 mg).
The trial was completed by 89% of patients in the risperidone group and 71% in the placebo group (Table 2). The most common reason for discontinuation was insufficient response (reported by 5% of risperidone patients and 15% of placebo patients). The rate of discontinuation owing to adverse events was similar in the risperidone and placebo groups (in 2% and 3% of patients, respectively). The mean modal dose of risperidone was 5.6 mg/day (s.e.=0.1).
|
Efficacy
All patients who received study medication and had at least one
post-baseline assessment were included in the efficacy analysis. Substantial
improvements were noted in patients given risperidone. Their mean YMRS total
score was reduced from 37.1 (s.e.=0.7) at baseline to 14.5 (1.1) at end-point
(P<0.001) (Fig. 2).
The reductions in YMRS score at weeks 13 and at end-point were
significantly greater among patients receiving risperidone than placebo.
Reductions in YMRS scores were significantly greater in the risperidone group
than in the placebo group at week 1 (mean change -11.7, s.e.=0.8 v.
-8.3, s.e.=0.8; P<0.01), week 2 (mean change -20.2, s.d.=0.9
v. -11.4, s.e.=1.2; P<0.001), week 3 (mean change -25.2,
s.e.=1.0 v. -15.0, s.e.=1.4; P<0.001) and at end-point
(mean change -22.7, s.e.=1.1 v. -10.5, s.e.=1.3;
P<0.001). In the primary between-treatment comparison,
least-squares mean change in YMRS total score at end-point was -23.2
(s.d.=13.4) in the risperidone group and -10.8 (s.d.=13.4) in the placebo
group (95% CI -15.6 to -9.3, P<0.001).
|
|
|
Improvement shown by reduction in MADRS score was significantly greater in the risperidone group than in the placebo group at day 3 (mean change -1.7, s.e.=0.2 v. -1.2, s.e.=0.2; P<0.01), week 1 (mean change -2.9, s.e.=0.2 v. -2.1, s.e.=0.3; P<0.01), week 2 (mean change -3.3, s.e.=0.3 v. -2.4, s.e.=0.3; P<0.001), week 3 (mean change -3.5, s.e.=0.5 v. -3.2, s.e.=0.4; P<0.001) and at end-point (mean change -3.2, s.e.=0.4 v. -2.5, s.e.=0.3; P<0.001). Baseline MADRS scores were low (5.9 in the placebo group and 5.1 in the risperidone group) in this patient population and 5060% of the score was accounted for by the scales reduced-sleep item.
Subgroup analyses
Among patients with or without psychotic features and those with a manic or
mixed episode at baseline, patients who received risperidone demonstrated
significantly greater improvements in YMRS score than those given placebo
(Table 3). Results of analyses
of patients by age group, gender and baseline YMRS score all indicated that
risperidone was significantly superior to placebo in reducing symptoms, and no
major difference in response was observed between these groups.
|
Safety
Adverse events related to extrapyramidal symptoms included extrapyramidal
disorder in 35% of the risperidone group and 6% of the placebo group, tremor
in 10% and 1% respectively, dystonia in 5% and 0%, hyperkinesia in 1% and 0%,
and oculogyric crisis in 1% and 0%. These adverse events were most often mild
(59%) or moderate (33%) in the risperidone group. The only other adverse event
observed in at least 10% of patients in either treatment group was insomnia
(in 6% of the risperidone group and 10% of the placebo group). The median ESRS
total scores (Parkinsonism plus dystonia plus dyskinesia) were 0 at both
baseline and end-point in both treatment groups; median change scores were
also 0 at all time points. In the risperidone group, for participants
exhibiting a change in ESRS total scores, the change was generally between 1
and 5 on a scale ranging from 0 to 102. Antiparkinsonian medication was taken
by 36% of the risperidone group and 6% of the placebo group.
Serious adverse events occurred infrequently and the rates of such events were similar in both treatment groups. Three patients in the placebo group and five in the risperidone group experienced adverse events that led to treatment discontinuation. No death occurred in this study. No clinically meaningful difference in vital signs or electrocardiographic data occurred between the two groups at any point during the study. The QTc interval did not exceed 500 ms in any patient in either group, regardless of the correction factor used in the analysis. Clinical laboratory values, other than that for prolactin, did not differ between the two treatment groups. Mean prolactin concentrations increased from baseline to end-point in the risperidone group (from 19 ng/ml to 86 ng/ml). No prolactin-related adverse event, however, was reported by any patient in either treatment group. Weight gains were comparable in the risperidone and placebo groups (0.07 kg in the placebo group and 0.06 kg in the risperidone group).
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Symptom severity
The patients with bipolar disorder who participated in the study were
enrolled at several sites in India. Their symptoms of mania were substantially
more severe than those of patients with bipolar disorder participating in
trials elsewhere. The mean YMRS score at baseline was 37.0 in the risperidone
group, in contrast to mean scores of 28.0 to 29.3 in controlled studies of
risperidone and olanzapine conducted in the USA
(Tohen et al, 2000; Sachs et al, 2002),
in the six countries of an international study
(Yatham et al, 2003)
and in South Africa (Segal et al,
1998). The Indian patients response to 3 weeks
treatment with risperidone (a mean change of -23.2 in YMRS score) was
unprecedented; for example, mean changes in YMRS score of -10.3 and -14.8
after 3 or 4 weeks treatment with olanzapine, -13.8 after 3
weeks treatment with quetiapine and -16.2, -14.5 and -14.3 after 3 or 4
weeks treatment with risperidone have been reported
(Segal et al, 1998;
Tohen et al, 1999,
2000; Sachs et al,
2002,
2004;
Yatham et al,
2003).
Baseline scores on the MADRS were generally low in this population and mostly were accounted for by the reduced-sleep item on that scale. The significant reduction in MADRS score from baseline to end-point that was observed with risperidone was primarily due to an improvement in scores on the reduced-sleep item. The improvement in sleep might have been an epiphenomenon of the improvement of manic symptoms with risperidone. The overall reduction in MADRS scores is reassuring and indicates no induction of depression with risperidone.
Adverse events
Treatment with risperidone was well tolerated. The 3-week trial was
completed by 89% of patients randomly assigned to risperidone. Extrapyramidal
symptoms were reported more frequently by patients taking risperidone than by
those taking placebo and more patients in the risperidone group (36%) than in
the placebo group (6%) received antiparkinsonian medications. The severity of
these movement disorders, however, was generally mild: median ESRS total
scores were 0 at both baseline and end-point in both groups. Only one patient
discontinued the trial because of movement disorders, suggesting that the
disorders were not perceived as severe and that symptoms, if present,
responded adequately to treatment with antiparkinsonian medication. The
movement disorders reported by these patients may be related to the high
baseline YMRS scores and the resultant rapid increase in risperidone dosage.
The patients low body weight (mean 54 kg), together with a mean modal
dose of 5.6 mg per day of risperidone, might also have contributed to these
adverse events. Patients with particularly severe manic symptoms may need
dosages of risperidone as high as 0.10 mg/kg. In clinical practice this need
for a higher dosage needs to be balanced by the potentially increased risk of
movement disorders.
Except for a change in prolactin concentration, no clinically meaningful change was observed in mean laboratory values from baseline to end-point. No prolactin-related adverse event was reported. Neither group demonstrated any clinically significant change in vital signs, body weight or electrocardiograms (including QTc prolongation). According to adverse events reports, there was no evidence of mania exacerbation among patients given risperidone.
Risperidone was generally well tolerated, as evidenced by the low incidence of other adverse events and the high completion rate.
Trial completion
The study was completed by 89% of the patients in the risperidone group and
71% in the placebo group. This percentage is high compared with other
placebo-controlled trials of similar duration in patients with bipolar mania.
Several reasons for this can be suggested: for example, the patients in this
trial were more severely ill than those usually included in placebo-controlled
trials, and many remained in hospital for the entire trial period, which was
not routinely the case in other trials. Both of these factors, in addition to
a healthcare environment different from that in Europe or the USA, might have
positively influenced retention rates. Although our trial lasted only 3 weeks,
the data are similar to those from a 6-month naturalistic study of risperidone
in bipolar mania (Vieta et al,
2001): in that study, 83% of patients completed the 6-month
period, and their mean baseline YMRS total score of 29.2 was reduced to 11.1
at week 4, with further reduction to a mean score of 2.8 at 6 months. The
similarity of the results observed in our trial and in the naturalistic study
raises the question of whether the longer-term results of the naturalistic
study could be predictive for controlled clinical trials.
Early and substantial patient response
In summary, patients with bipolar disorder and severe manic symptoms who
received risperidone monotherapy improved on all measures of efficacy.
Treatment with risperidone produced significant improvement as early as week 1
and substantial improvements in YMRS score at end-point, when there was a
12-point difference between risperidone and placebo mean scores. Despite the
aggressive dosing regimen in this trial, risperidone was well tolerated: more
patients who received the drug (89%) than those who received placebo (71%)
completed the study. The results confirm those of other trials involving
diverse patient populations (Ghaemi et
al, 1997; Segal et
al, 1998; Vieta et al,
2001,
2004;
Sachs et al, 2002;
Yatham et al, 2003),
in which risperidone was found to be effective and safe in patients with acute
mania.
![]() |
Clinical Implications and Limitations |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
LIMITATIONS
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Chouinard, G., Ross-Chouinard, A., Annable, L., et al (1980) Extrapyramidal Symptom Rating Scale (abstract). Canadian Journal of Neurological Sciences, 7, 233.
Endicott, J., Spitzer, R.L., Fleiss, J. C., et al (1976) The global assessment scale. A procedure for measuring overall severity of psychiatric disturbance. Archives of General Psychiatry, 33, 766 -771.[Abstract]
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. (1976) ECDEU Assessment Manual for Psychopharmacology. Revised DHEW Pub. (ADM). Rockville, MD: National Institute of Mental Health.
Kay, S. R., Fiszbein, A. & Opler, L. A. (1987) The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophrenia Bulletin, 13, 261 -275.[Medline]
Marder, S. R., Davis, J. M. & Chouinard, G. (1997) The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials. Journal of Clinical Psychiatry, 58, 538 -546.[Medline]
Miller, D. S., Yatham, L. N. & Lam, R. W. (2001) Comparative efficacy of typical and atypical antipsychotics as add-on therapy to mood stabilizers in the treatment of acute mania. Journal of Clinical Psychiatry, 62, 975 -980.[Medline]
Montgomery, S. A. & Åsberg, M. (1979) A new depression scale designed to be sensitive to change. British Journal of Psychiatry, 134, 382 -389.[Abstract]
Sachs, G. S., Grossman, F., Ghaemi, N. S., et al
(2002) Risperidone plus mood stabilizer versus placebo plus
mood stabilizer for acute mania of bipolar disorder: a double-blind comparison
of efficacy and safety. American Journal of
Psychiatry, 159, 1146
-1154.
Sachs, G. S., Chengappa, K. N., Suppes, T., et al (2004) Quetiapine with lithium or divalproex for the treatment of bipolar mania: a randomized, double-blind, placebo-controlled study. Bipolar Disorders, 6, 213-223.[CrossRef][Medline]
Segal, J., Berk, M. & Brook, S. (1998) Risperidone compared with both lithium and haloperidol in mania: a double-blind randomized controlled trial. Clinical Neuropharmacology, 21, 176 -180.[Medline]
Suppes, T., Webb, A., Paul, B., et al
(1999) Clinical outcome in a randomized 1-year trial of
clozapine versus treatment as usual for patients with treatment-refractory
illness and a history of mania. American Journal of
Psychiatry, 156, 1164
-1169.
Tohen, M., Sanger, T. M., McElroy, S. L., et al
(1999) Olanzapine versus placebo in the treatment of acute
mania. American Journal of Psychiatry,
156, 702
-709.
Tohen, M., Jacobs, T. G., Grundy, S. L., et al
(2000) Efficacy of olanzapine in acute bipolar mania: a
double-blind, placebo-controlled study. Archives of General
Psychiatry, 57, 841
-849.
Tohen, M., Chengappa, K. N. R., 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 therapy. Archives of General
Psychiatry, 59, 62
-69.
Vieta, E., Goikolea, J. M., Corbella, B., et al (2001) Risperidone safety and efficacy in the treatment of bipolar and schizoaffective disorders: results from a 6-month, multicenter, open study. Journal of Clinical Psychiatry, 62, 818 -825.[Medline]
Vieta, E., Brugué, E., Goikolea, J. M., et al (2004) Acute and continuation risperidone monotherapy in mania. Human Psychopharmacology: Clinical and Experimental, 19, 41 -45.[CrossRef]
World Medical Association (1989) World Medical Association Declaration of Helsinki: Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects. http://www.fda.gov/oc/health/helsinki89.html.
Yatham, L. N., Grossman, F., Augustyns, I., et al
(2003) Mood stabilisers plus risperidone or placebo in the
treatment of acute mania: international, double-blind, randomised controlled
trial. British Journal of Psychiatry,
182, 141
-147.
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 March 31, 2004. Revision received September 16, 2004. Accepted for publication September 30, 2004.
Related articles in BJP: