Valproic acid, valproate and divalproex in the maintenance treatment of bipolar
disorder.
Author(s): Cipriani A(1), Reid K, Young AH, Macritchie K, Geddes J.
Affiliation(s): Author information:
(1)Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK,
OX3 7JX.
Publication date & source: 2013, Cochrane Database Syst Rev. , 10:CD003196
BACKGROUND: Bipolar disorder is a recurrent illness that is amongst the top 30
causes of disability worldwide and is associated with significant healthcare
costs. In the past, emphasis was placed solely on the treatment of acute episodes
of bipolar disorder; recently, the importance of episode prevention and of
minimisation of iatrogenicity has been recognised. For many years, lithium was
the only mood stabiliser in common use, and it remains an agent of first choice
in the preventative treatment of bipolar disorder. However, an estimated 20% to
40% of patients may not respond adequately to lithium. Valproate is an
anticonvulsant drug that has been shown to be effective in acute mania and is
frequently used in maintenance treatment of bipolar disorder. When the
acceptability of long-term treatment is considered, together with efficacy, the
adverse event profile of a medication is also important. This is an update of a
Cochrane review first published in 2001 and last updated in 2009.
OBJECTIVES: 1. To determine the efficacy of valproate continuation and
maintenance treatment:a) in preventing or attenuating manic, depressive and mixed
episodes of bipolar disorder;b) in preventing or attenuating episodes of bipolar
disorder in patients with rapid cycling disorder; and; c) in improving patients'
general health and social functioning, as measured by global clinical impression,
employment and marital stability.2. To review the acceptability to patients of
long-term valproate treatment, as measured by numbers of dropouts and reasons for
dropping out, by compliance and by reference to patients' expressed views
regarding treatment.3. To investigate the adverse effects of valproate treatment
(including general prevalence of side effects) and overall mortality rates.
SEARCH METHODS: Search of the Cochrane Register of Controlled Trials and the
Cochrane Depression, Anxiety and Neurosis Group Register (CCDANCTR) (to January
2013), which includes relevant randomised controlled trials from the following
bibliographic databases: The Cochrane Library (all years), EMBASE, (1974 to
date), MEDLINE (1950 to date) and PsycINFO (1967 to date). No language
restrictions were applied. Reference lists of relevant papers and previous
systematic reviews were handsearched. Pharmaceutical companies marketing
valproate and experts in this field were contacted for supplemental data.
SELECTION CRITERIA: Randomised controlled trials allocating participants with
bipolar disorder to long-term treatment with valproate or any other mood
stabiliser, or antipsychotic drugs, or placebo. Maintenance treatment was defined
as treatment instituted specifically or mainly to prevent further episodes of
illness.
DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data.
A double-entry procedure was employed by two review authors. Information
extracted included study characteristics, participant characteristics,
intervention details and outcome measures in terms of efficacy, acceptability and
tolerability. For dichotomous data, risk ratios were calculated with 95%
confidence intervals (CIs). For statistically significant results, we calculated
the number needed to treat for an additional beneficial outcome (NNTB) and the
number needed to treat for an additional harmful outcome (NNTH). For continuous
data, mean differences (MDs) or standardised mean differences (SMDs) were
calculated along with 95% CIs. MDs were used when the same scale was used to
measure an outcome; SMDs were employed when different scales were used to measure
the same outcome. The primary analysis used a fixed-effect model. Binary outcomes
were calculated on a strict intention-to-treat (ITT) basis; dropouts were
included in this analysis. When data were missing and the method of "last
observation carried forward" (LOCF) had been used to do an ITT analysis, then the
LOCF data were used.
MAIN RESULTS: Six randomised controlled trials (overall 876 participants) lasting
6 to 24 months were included. Two studies (overall 312 participants) compared
valproate with placebo, four studies (overall 618 participants) valproate with
lithium, one study (overall 23 participants) valproate with olanzapine and one
study (overall 220 participants) valproate with the combination of valproate plus
lithium. In terms of study quality, most studies reported the methods used to
generate random sequence; however, only one study reported enough details on
allocation concealment. Four of six included studies described their design as
"double blind", but only two trials reported full details about blinding.
Valproate was more effective than placebo in preventing study withdrawal due to
any mood episode (RR 0.68, 95% CI 0.49 to 0.93; NNTB 8), but no difference in
efficacy was found between valproate and lithium (RR 1.02, 95% CI 0.87 to 1.20).
Valproate was associated with fewer participants dropping out of treatment for
any cause when compared with placebo or lithium (RR 0.82, 95% CI 0.71 to 0.95 and
RR 0.87, 95% CI 0.77 to 0.98, respectively). However, combination therapy with
lithium plus valproate was more likely to prevent relapse than was monotherapy
with valproate (RR 0.78, 95% CI 0.63 to 0.96). Significant differences in adverse
event frequencies were found, and lithium was associated with more frequent
diarrhoea, polyuria, increased thirst and enuresis, whereas valproate was
associated with increased sedation and infection.
AUTHORS' CONCLUSIONS: Limited evidence supports the efficacy of valproate in the
long-term treatment of bipolar disorder. Clinicians and patients should consider
acceptability and tolerability profile when choosing between lithium and
valproate-their combination or other agents-as long-term treatment for bipolar
disorder.
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