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Risperidone in long-term treatment for bipolar disorder (Review)
Rendell JM, Geddes J
Rendell JM, Geddes J.
Risperidone in long-term treatment for bipolar disorder.
Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD004999.
DOI: 10.1002/14651858.CD004999.pub2.
www.cochranelibrary.com
Risperidone in long-term treatment for bipolar disorder (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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TABLE OF CONTENTS
HEADER......................................................................................................................................................................................................... 1
ABSTRACT..................................................................................................................................................................................................... 1
PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 1
BACKGROUND.............................................................................................................................................................................................. 3
OBJECTIVES.................................................................................................................................................................................................. 3
METHODS..................................................................................................................................................................................................... 3
RESULTS........................................................................................................................................................................................................ 5
DISCUSSION.................................................................................................................................................................................................. 5
AUTHORS' CONCLUSIONS........................................................................................................................................................................... 5
ACKNOWLEDGEMENTS................................................................................................................................................................................ 5
REFERENCES................................................................................................................................................................................................ 6
WHAT'S NEW................................................................................................................................................................................................. 6
HISTORY........................................................................................................................................................................................................ 6
CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 7
DECLARATIONS OF INTEREST..................................................................................................................................................................... 7
SOURCES OF SUPPORT............................................................................................................................................................................... 7
INDEX TERMS............................................................................................................................................................................................... 7
Risperidone in long-term treatment for bipolar disorder (Review) i
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[Intervention Review]
Risperidone in long-term treatment for bipolar disorder
Jennifer M Rendell1, John Geddes1
1Department of Psychiatry, University of Oxford, Oxford, UK
Contact address: Jennifer M Rendell, Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, OX3 7JX, UK.
[email protected].
Editorial group: Cochrane Common Mental Disorders Group
Publication status and date: Edited (no change to conclusions), published in Issue 1, 2010.
Citation: Rendell JM, Geddes J. Risperidone in long-term treatment for bipolar disorder. Cochrane Database of Systematic Reviews 2006,
Issue 4. Art. No.: CD004999. DOI: 10.1002/14651858.CD004999.pub2.
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ABSTRACT
Background
Risperidone, an atypical antipsychotic, is used to treat acute manic episodes, particularly when psychotic symptoms are present. Drugs
used to treat mania are often continued as long-term treatment to prevent relapse. There is a need for evidence of the effectiveness and
safety of risperidone as long-term treatment.
Objectives
To assess the randomised evidence for the efficacy and tolerability of risperidone compared with placebo or other active pharmacological
treatments as long-term treatment for prevention or attenuation of further episodes of mood disorder in patients with bipolar disorder.
Search methods
The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR-Studies) was search on 12/10/2005,
The Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, MEDLINE, CINAHL and PsycINFO were searched in October 2005.
Reference lists and English language textbooks were searched; researchers in the field were contacted.
Selection criteria
Randomised trials comparing risperidone with placebo or other drug in long-term treatment for prevention of depressive or manic
relapses.
Data collection and analysis
Not applicable.
Main results
No randomised trials comparing risperidone with other treatments for the prevention of manic and depressive relapses were identified.
Authors' conclusions
There is a need for randomised controlled trials comparing risperidone and other treatments for the prevention of relapse in bipolar
disorder. The trials should involve randomisation of treatment for relapse prevention and involve long-term follow up.
PLAIN LANGUAGE SUMMARY
Risperidone in the long-term treatment for bipolar disorder
Risperidone in long-term treatment for bipolar disorder (Review) 1
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No studies involving risperidone were identified which randomly assigned treatment for long-term relapse prevention. Trials involving
random assignment of risperidone and other treatments for long-term treatment are needed.
Risperidone in long-term treatment for bipolar disorder (Review) 2
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BACKGROUND treatment were included in the review. Long-term treatment was
defined as treatment instituted specifically or mainly to prevent
Bipolar disorder is a chronic and recurrent mental disorder which further episodes of illness.
has a lifetime prevalence in the order of 0.5% to 1.5% (Kessler 1997).
It is characterised by episodes of elevated or irritable mood (manic Types of participants
or hypomanic episodes) and episodes of low mood, loss of energy Patients of both sexes and all ages with a diagnosis of bipolar
and sadness (depressive episodes) interspersed with periods of disorder were included:
normal mood. Drugs are commonly used both as acute treatment
for manic and depressive episodes and as long-term treatment to (1) Patients with depressive episodes with or without psychotic
prevent recurrence. Current treatment guidelines (Goodwin 2003) symptoms.
recommend that long-term treatment be considered following a
single severe manic episode to try to ameliorate the future course of (2) Patients with a diagnosis of mixed affective disorder with or
the illness by preventing syndromal relapse. In addition to relapse without psychotic symptoms.
prevention, there is increasing recognition of the need for long-
term treatments to reduce subsyndromal, minor depressive and (3) Patients with a diagnosis of hypomania or mania with or without
hypomanic symptoms which are both persistent (Judd 2002; Judd psychotic symptoms.
2003) and associated with significant morbidity and functional
All subtypes of bipolar disorder (Type I and II, rapid cycling and
impairment (MacQueen, 2003). An effective long-term treatment
other) were included. Trials exclusively studying patients with
for bipolar disorder should therefore both prevent relapse into
cyclothymia and bipolar III disorder were excluded.
mania or depression and reduce subsyndromal symptoms and
neurocognitive impairment. Types of interventions
Drugs used to treat mania are commonly continued as long- Risperidone in comparison with placebo or other pharmacological
term treatment. These include lithium, anticonvulsants and treatment, either as monotherapy or as add-on treatment to
antipsychotics. However, treatments that are safe and tolerable in lithium, valproate or other adjunctive compounds, as long-term
the short-term may be less so in the long-term. Lithium, which has treatment for bipolar disorder.
been shown to be effective in prevention of mania and may prevent
depression (Geddes 2004), has troublesome adverse effects which Types of outcome measures
can lead to low rates of adherence and to abrupt discontinuation (1) Efficacy in terms of prevention of attenuation of further episodes
which is associated with increased risk of manic relapse (Goodwin of affective disorder. This was analysed in relation to recurrence of
1994). The evidence for efficacy and safety of anticonvulsants in any mood episodes, recurrence of manic or depressive episodes
long-term treatment is less clear. A number of studies (e.g. Sernyak and recurrence of mixed affective states. Lack of efficacy measures
1994) have shown that antipsychotics are frequently used as long- included:
term treatment despite concerns that older antipsychotics can
cause tardive dyskinesia (TD) and extrapyramidal symptoms (EPS). (a) Study withdrawal due to mood episode.
(b) Admission to hospital: time to next admission and average
More recently, atypical antipsychotics such as olanzapine and number of admissions during trial period.
risperidone have been used to treat mania and it is possible that, (c) Initiation of additional treatment for single affective episode/
because they are associated with lower risk of TD and EPS, they state and time to initiation.
might have a role as long-term treatments. However, there are (d) Average number of episodes during trial period.
concerns that atypical antipsychotics may cause other adverse
effects, in particular weight gain and prolactin elevation. There is (2) General health and social functioning - measures included:
some evidence that weight gain may be less for risperidone than
for olanzapine or clozapine (Allison 1999) and in a recent, non- (a) Clinical global impression of the clinician.
randomised study (Vieta 2001) risperidone combined with a mood (b) Global impression of the subject, family or significant other(s).
stabiliser appeared to be both effective and well tolerated over a six (c) Scores on mania or depression symptom scales
month period. (d) Employment during the study period.
OBJECTIVES (3) Acceptability of risperidone treatment - measures included:
To assess the randomised evidence for the efficacy and (a) Completion of trial treatment, which included elements of
tolerability of risperidone compared with placebo or other active tolerability and efficacy, were used as an indicator of the overall
pharmacological treatments as long-term treatment for prevention acceptability of treatments.
or attenuation of further episodes of mood disorder in patients with (b) Adherence to treatment.
bipolar disorder. (c) Participants' reports of satisfaction or otherwise with treatment.
METHODS (4) Specific adverse effects as reported in the trials, including
weight gain and metabolic disturbances
Criteria for considering studies for this review
(5) Mortality rates during treatment:
Types of studies
(a) Overall mortality rates during the trials
Prospective randomised control trials comparing risperidone with (b) Cause specific mortality rates
placebo or other active pharmacological treatment for long-term
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Search methods for identification of studies category C will be excluded. In addition, a general appraisal of
study quality will be made by assessing key methodological issues
Electronic searches: such as blinding of participants, providers, outcome evaluators
The CCDAN Controlled Trials Register (CCDANCTR-studies) register and analysts, completeness of follow up and reporting of study
was searched with the following search strategy: withdrawals. Where inadequate details of randomisation and other
characteristics of trials are provided, the authors will be contacted
CCDANCTR-Studies - searched on 12/10/2005
in order to obtain further information.
Diagnosis = ("Bipolar III Disorder" or "Unipolar Mania" or "Rapid
Cycling Disorder" or "Affective Disorders" or "Affective Psychosis,
(c) Data analysis
Bipolar" or "Bipolar Disorder " or "Bipolar I Disorder" or "Bipolar
Data will be entered into Revman 4.2.2 software by one reviewer.
II Disorder" or "Cyclothymic Disorder " or "Depression " or
Intention-to-treat data (ITT) data will be used when available.
"Depressive Psychosis" or "Excited Psychosis" or "Hypomania"
Where ITT data are not available, end-point data for trial completers
or "Mania" or "Manic-Depressive" or "Manic Disorder" or "Manic
will be used.
Episode" or "Melancholia" or "Mixed Depression" or "Mood
Disorders" or "Bipolar Affective Disorder " or "Bipolar Not Continuous data will be analysed using weighted mean differences
Otherwise Specified " or "Dysphoric Mania" or "Manic Episode" or (with 95% confidence intervals) or standardised mean differences
"Manic Symptoms" or "Schizoaffective Disorder" or "Psychoses" (where different measurement scales are used).
or "Psychotic Disorders" or "Puerpal Psychosis " or "Reactive
Depressive Psychosis") For dichotomous, or event-like, data, relative risks will be
and calculated with 95% confidence intervals.
Intervention = Risperidone
Count data: Where available, data on rare events (which could
To supplement the above search, the following specified electronic include precipitation of mania) will be analysed in terms of the ratio
databases were searched with the subject headings "bipolar of rates per person per year. Data on more common events (which
disorder" (exploded) "manic depressive psychosis", "bipolar could include relapse into affective episode) will be analysed in
depression" and "risperidone" and the text words "bipolar terms of the mean difference in the number of events per group
disorder*", "bipolar depress*", "manic depress*" and "risperidone". over a specified time period.
The Cochrane Central Register of Controlled Trials (CENTRAL)
EMBASE (1980-October 2005) Time to event data: The way in which time to event data will be
MEDLINE (1966-October 2005) handled will depend on the data reported. Where appropriate,
CINAHL (1982-October 2005) authors of papers will be asked to provide data in a format that
PsycINFO (1872-October 2005) allows meta-analysis.
Reference checking Where reported, analyses of data according to subgroups identified
The reference lists of all identified randomised controlled trials, a priori will be included in the review.
other relevant papers and major textbooks of affective disorder
written in English were checked. Heterogeneity between studies will be assessed using the chi-
squared test with a P-value of less than or equal to 0.1 being
Personal communication taken to indicate heterogeneity and a value for I-squared of
The authors of significant papers were identified from authorship greater that 50% taken to indicate substantial heterogeneity. Where
lists over the last five years. They, and other experts in the field, heterogeneity is identified, potential sources will be considered
were contacted and asked for their knowledge of other studies, in terms of the clinical characteristics (participants, interventions
published or unpublished, relevant to the review article. and outcomes) and methodological characteristics of the studies.
Fixed and random-effects analyses will be done routinely to
Data collection and analysis investigate the effect of the choice of method on the estimates
and material differences between the models will be reported.
The searches did not identify any trials that met the inclusion
Where heterogeneity is identified, random-effects analyses will be
criteria. The following section outlines the way in which future trials
reported.
will be analysed in updates of this review.
Where sample sizes are small and the lowest and/or highest
(a) Selection of trials and data extraction
possible value is known, skewness will be assessed by calculating
Studies relating to risperidone generated by the search strategies
the observed mean minus the lowest possible value (or highest
will be checked to identify those that meet the previously defined
possible value minus the observed mean) and dividing this by the
inclusion criteria. Two reviewers will independently extract data
standard deviation. A ratio of less than two will be regarded as
concerning participant characteristics, intervention details and
suggestive and a ratio of less than one as strong evidence of a
outcome measures from the included studies. Subgroup analyses
skewed distribution (Altman 1996). Where skewness is identified or
in the trials will be recorded where the subgroups were defined a
cannot be assessed this will be reported as a limitation of the data.
priori.
Monotherapy and adjunctive treatment trials will be analysed
(b) Quality assessment
separately and, where appropriate, combined results will also be
Allocation concealment will be reported in the Included Studies
reported.
tables according to the criteria outlined in the Cochrane Handbook
Continuation trials, i.e. those in which randomised treatment
for Systematic Reviewers (Anderson 2004, Section six) as A
was given for an acute episode and then continued as long-
(adequate), B (unclear), and C (inadequate) and any trials assigned
Risperidone in long-term treatment for bipolar disorder (Review) 4
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term treatment, will be analysed separately. If data are available, There is thus a need for adequately powered well designed
analysis by length of treatment will be performed to ascertain trials investigating the benefits and costs of risperidone. This
whether any treatment differences detected varied with time. absence of evidence will also influence short-term treatment
decisions. Clinicians and patients, when considering using an
(d) Publication bias and outcome selection bias. atypical antipsychotic in mania, may be better off choosing an
The possibility of publication bias will be investigated using funnel agent for which there is evidence of the long-term effects.
plots and the Egger Test for funnel plot asymmetry (Egger 1997).
In addition to this a comparison will be made between the a priori AUTHORS' CONCLUSIONS
defined outcome measures and the outcomes reported.
Implications for practice
RESULTS
There is no randomised evidence to inform the use of risperidone
Description of studies for long-term treatment to prevent relapse.
The search for randomised controlled trials of risperidone Implications for research
identified 610 papers. No studies involving risperidone which
randomly assigned treatment for long-term relapse prevention There is a need for randomised controlled trials comparing
treatment were identified. risperidone and other treatments for which there is evidence
concerning efficacy in prevention of relapse in bipolar disorder. The
Risk of bias in included studies trials should involve randomisation of long-term treatment
None ACKNOWLEDGEMENTS
Effects of interventions We thank Heather Wilder and Sarah Stockton, Information
Scientists, Centre for Evidence Based Mental Health and the
None
Cochrane Depression, Anxiety and Neurosis Group editorial staff
DISCUSSION for assistance in developing the search strategy, the review and for
conducting several of the database searches.
We found no randomised evidence to inform the use of risperidone
for long-term treatment to prevent relapse in bipolar disorder.
Risperidone in long-term treatment for bipolar disorder (Review) 5
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REFERENCES
Additional references Judd 2002
Allison 1999 Judd LL, Akiskal HS, Schettler PJ, Endicott J, Maser J,
Solomon DA, et al. The long-term natural history of the weekly
Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC,
symptomatic status of bipolar I disorder. Archives of General
Infante MC, et al. Antipsychotic-induced weight gain: a
Psychiatry 2002;59(6):530-7.
comprehensive research synthesis. American Journal of
Psychiatry 1999;156(11):1686-96. Judd 2003
Altman 1996 Judd LL, Akiskal HS, Schettler PJ, Coryell W, Endicott J,
Maser JD, et al. A prospective investigation of the natural
Altman DG, Bland JM. Detecting skewness from summary
history of the long-term weekly symptomatic status of bipolar II
information. BMJ 1996;313(7066):1200.
disorder. Archives of General Psychiatry 2003;60(3):261-9.
Anderson 2004
Kessler 1997
Alderson P, Green S, Higgins JPT, editors. Cochrane Reviewers'
Kessler RC, Rubinow DR, Holmes C, Abelson JM, Zhao S. The
Handbook 4.2.2 [updated March 2004). The Cochrane Library,
epidemiology of DSM-III-R bipolar I disorder in a general
Issue 1. Chichester: John Wiley & Sons, Ltd, 2004.
population survey. Psychological Medicine 1997;27(5):1079-89.
Egger 1997
MacQueen, 2003
Egger M, Davey Smith G, Schneider M, Minder C. Bias in
MacQueen GM, Marriott M, Begin H, Robb J, Joffe RT, Young LT.
meta-analysis detected by a simple graphical test. BMJ
Subsyndromal symptoms assessed in longitudinal, prospective
1997;315(7109):629-34.
follow up of a cohort of patients with bipolar disorder. Bipolar
Geddes 2004 Disorders 2003;5(5):349-55.
Geddes JR, Burgess S, Hawton K, Jamison K, Goodwin GM. Sernyak 1994
Long-term lithium therapy for bipolar disorder: Systematic
Sernyak MJ, Griffin RA, Johnson RM, Pearsall HR, Wexler BE,
review and meta-analysis of randomized controlled trials.
Woods SW. Neuroleptic exposure following inpatient treatment
American Journal of Psychiatry 2004;161(2):217-22.
of acute mania with lithium and neuroleptic. American Journal
Goodwin 1994 of Psychiatry 1994;151(1):133-5.
Goodwin GM. Recurrence of mania after lithium withdrawal. Smeeth 1999
Implications for the use of lithium in the treatment of bipolar
Smeeth L, Haines A, Ebrahim S. Numbers needed to treat
affective disorder. British Journal of Psychiatry 1994;164:149-52.
derived from meta-analyses - sometimes informative, usually
Goodwin 2003 misleading. BMJ 1999;318(7197):1548-51.
Goodwin GM. Evidence-based guidelines for treating bipolar Vieta 2001
disorder: Recommendations from the British Association
Vieta E, Goikolea JM, Corbella B, Benabarre A, Reinares M,
for Psychopharmacology. Journal of Psychopharmacology
Martinez G, et al. Risperidone safety and efficacy in the
2003;17(2):149-73.
treatment of bipolar and schizoaffective disorders: Results
from a 6-month, multicenter, open study. Journal of Clinical
Psychiatry 2001;62(10):818-25.
WHAT'S NEW
Date Event Description
5 November 2008 Amended Converted to new review format.
HISTORY
Protocol first published: Issue 4, 2004
Review first published: Issue 4, 2006
Risperidone in long-term treatment for bipolar disorder (Review) 6
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Date Event Description
22 August 2006 New citation required and conclusions Substantive amendment
have changed
CONTRIBUTIONS OF AUTHORS
Jennifer Rendell co-wrote the review
John Geddes co-wrote the review
DECLARATIONS OF INTEREST
John Geddes has received research funding and support from GlaxoSmithKline, Sanofi-Aventis, UK Government Department of Health, UK
Medical Research Council and the Stanley Medical Research Institute.
Jennifer Rendell has no conflicts of interest.
SOURCES OF SUPPORT
Internal sources
• Department of Psychiatry, University of Oxford, UK.
External sources
• No sources of support supplied
INDEX TERMS
Medical Subject Headings (MeSH)
Antipsychotic Agents [*therapeutic use]; Bipolar Disorder [*drug therapy]; Long-Term Care; Risperidone [*therapeutic use]
MeSH check words
Humans
Risperidone in long-term treatment for bipolar disorder (Review) 7
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