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Meta-Analysis
. 2013 Oct 17;2013(10):CD003196.
doi: 10.1002/14651858.CD003196.pub2.

Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder

Andrea Cipriani  1 , Keith Reid, Allan H Young, Karine Macritchie, John Geddes
Affiliations
Meta-Analysis

Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder

Andrea Cipriani et al. Cochrane Database Syst Rev. .

Abstract

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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Conflict of interest statement

Andrea Cipriani participated in the BALANCE trial as Italy's chief investigator.

Keith Reid declares no conflicting interests.

Allan H Young has sat on advisory boards and has received honoraria for lectures from sanofi‐aventis, makers of a form of valproate, and also participated in the BALANCE trial, for which sanofi‐aventis donated study medications.

Dr Karine Macritchie has worked on a project supported by an award NS‐EU‐166 from the Translational Medicine Research Collaboration. This consortium comprises the Universities of Aberdeen, Dundee, Edinburgh and Glasgow, the four associated NHS Health Boards (Grampian, Tayside, Lothian and Greater Glasgow and Clyde), Scottish Enterprise and Pfizer (formerly Wyeth). Several pharmaceutical companies have paid her institution for lectures, educational presentations/material and research.

John Geddes currently receives research funding from the UK Medical Research Council, the UK Economic and Social Research Council, the National Institute for Health Research, and the Stanley Medical Research Institute. He was expert witness for Dr Reddy's Laboratories, he is Chief Investigator on the CEQUEL trial to which GlaxoSmithKline has contributed and for which it has supplied investigational drugs and placebo. He is also the chief investigator of the BALANCE trial.

Figures

1
1
Study flow diagram showing study selection process.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Risk of bias graph: review authors' judgements about all risk of bias items presented as percentages across all included studies.
4
4
Forest plot of comparison: 1 Valproate versus placebo, outcome: 1.1 Study withdrawal due to episode of mood disorder.
5
5
Forest plot of comparison: 2 Valproate versus lithium, outcome: 2.1 Study withdrawal due to episode of mood disorder.
6
6
Forest plot of comparison: 5 Valproate plus lithium versus valproate alone, outcome: 5.1 Study withdrawal due to episode of mood disorder.
1.1
1.1. Analysis
Comparison 1 Valproate versus placebo, Outcome 1 Study withdrawal due to episode of mood disorder.
1.2
1.2. Analysis
Comparison 1 Valproate versus placebo, Outcome 2 Participant withdrawal from treatment—any cause.
1.3
1.3. Analysis
Comparison 1 Valproate versus placebo, Outcome 3 Participant withdrawal from treatment due to intolerance or non‐compliance.
1.4
1.4. Analysis
Comparison 1 Valproate versus placebo, Outcome 4 Adverse events.
2.1
2.1. Analysis
Comparison 2 Valproate versus lithium, Outcome 1 Study withdrawal due to episode of mood disorder.
2.2
2.2. Analysis
Comparison 2 Valproate versus lithium, Outcome 2 Number of hospital admissions.
2.3
2.3. Analysis
Comparison 2 Valproate versus lithium, Outcome 3 New drug treatment for mood episode.
2.4
2.4. Analysis
Comparison 2 Valproate versus lithium, Outcome 4 Time to relapse (days).
2.5
2.5. Analysis
Comparison 2 Valproate versus lithium, Outcome 5 Participant withdrawal from treatment—any cause.
2.6
2.6. Analysis
Comparison 2 Valproate versus lithium, Outcome 6 Participant withdrawal from treatment due to intolerance or non‐compliance.
2.7
2.7. Analysis
Comparison 2 Valproate versus lithium, Outcome 7 Adverse events.
2.8
2.8. Analysis
Comparison 2 Valproate versus lithium, Outcome 8 GAF—number of participants not responding at 24 months.
2.9
2.9. Analysis
Comparison 2 Valproate versus lithium, Outcome 9 Quality of life—number of participants not responding at 24 months.
2.10
2.10. Analysis
Comparison 2 Valproate versus lithium, Outcome 10 DSH—number of participants with at least one episode of deliberate self‐harm.
2.11
2.11. Analysis
Comparison 2 Valproate versus lithium, Outcome 11 Death.
3.1
3.1. Analysis
Comparison 3 Valproate versus olanzapine, Outcome 1 Study withdrawal due to episode of mood disorder.
3.2
3.2. Analysis
Comparison 3 Valproate versus olanzapine, Outcome 2 Participant withdrawal from treatment—any cause.
3.3
3.3. Analysis
Comparison 3 Valproate versus olanzapine, Outcome 3 Participant withdrawal from treatment due to intolerance or non‐compliance.
4.1
4.1. Analysis
Comparison 4 Valproate plus lithium versus lithium alone, Outcome 1 Study withdrawal due to episode of mood disorder.
4.2
4.2. Analysis
Comparison 4 Valproate plus lithium versus lithium alone, Outcome 2 Number of hospital admissions.
4.3
4.3. Analysis
Comparison 4 Valproate plus lithium versus lithium alone, Outcome 3 New drug treatment for mood episode.
4.4
4.4. Analysis
Comparison 4 Valproate plus lithium versus lithium alone, Outcome 4 Participant withdrawal from treatment—any cause.
4.5
4.5. Analysis
Comparison 4 Valproate plus lithium versus lithium alone, Outcome 5 Participant withdrawal from treatment due to intolerance or non‐compliance.
4.6
4.6. Analysis
Comparison 4 Valproate plus lithium versus lithium alone, Outcome 6 Serious adverse events.
4.7
4.7. Analysis
Comparison 4 Valproate plus lithium versus lithium alone, Outcome 7 GAF—number of participants not responding at 24 months.
4.8
4.8. Analysis
Comparison 4 Valproate plus lithium versus lithium alone, Outcome 8 Quality of life—number of participants not responding at 24 months.
4.9
4.9. Analysis
Comparison 4 Valproate plus lithium versus lithium alone, Outcome 9 DSH—number of participants with at least one episode of deliberate self‐harm.
4.10
4.10. Analysis
Comparison 4 Valproate plus lithium versus lithium alone, Outcome 10 Death.
5.1
5.1. Analysis
Comparison 5 Valproate plus lithium versus valproate alone, Outcome 1 Study withdrawal due to episode of mood disorder.
5.2
5.2. Analysis
Comparison 5 Valproate plus lithium versus valproate alone, Outcome 2 Number of hospital admissions.
5.3
5.3. Analysis
Comparison 5 Valproate plus lithium versus valproate alone, Outcome 3 New drug treatment for mood episode.
5.4
5.4. Analysis
Comparison 5 Valproate plus lithium versus valproate alone, Outcome 4 Participant withdrawal from treatment—any cause.
5.5
5.5. Analysis
Comparison 5 Valproate plus lithium versus valproate alone, Outcome 5 Participant withdrawal from treatment due to intolerance or non‐compliance.
5.6
5.6. Analysis
Comparison 5 Valproate plus lithium versus valproate alone, Outcome 6 Serious adverse events.
5.7
5.7. Analysis
Comparison 5 Valproate plus lithium versus valproate alone, Outcome 7 GAF—number of participants not responding at 24 months.
5.8
5.8. Analysis
Comparison 5 Valproate plus lithium versus valproate alone, Outcome 8 Quality of life—number of participants not responding at 24 months.
5.9
5.9. Analysis
Comparison 5 Valproate plus lithium versus valproate alone, Outcome 9 DSH—number of participants with at least one episode of deliberate self‐harm.
5.10
5.10. Analysis
Comparison 5 Valproate plus lithium versus valproate alone, Outcome 10 Death.
See this image and copyright information in PMC

Update of

References

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