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Review
. 2019 Oct 7;10(10):CD004052.
doi: 10.1002/14651858.CD004052.pub2.

Valproate for acute mania

Janina Jochim #  1 , Raphael P Rifkin-Zybutz #, John Geddes, Andrea Cipriani
Affiliations
Review

Valproate for acute mania

Janina Jochim et al. Cochrane Database Syst Rev. .

Abstract

Background: Bipolar disorder is a severe and common mental disorder where patients experience recurrent symptoms of elevated or irritable mood, depression, or a combination of both. Treatment is usually with psychiatric medication, including mood stabilisers, antidepressants and antipsychotics. Valproate is an effective maintenance treatment for bipolar disorder. However, evidence assessing the efficacy of valproate in the treatment of acute mania is less robust, especially when comparing it to some of the newer antipsychotic agents. This review is an update of a previous Cochrane Review (last published 2003) on the role of valproate in acute mania.

Objectives: To assess the efficacy and tolerability of valproate for acute manic episodes in bipolar disorder compared to placebo, alternative pharmacological treatments, or a combination pharmacological treatments, as measured by the treatment of symptoms on specific rating scales for individual episodes in paediatric, adolescent and adult populations.

Search methods: We searched Ovid MEDLINE (1950- ), Embase (1974- ), PsycINFO (1967- ) and the Cochrane Central Register of Controlled Trials (CENTRAL) to 28 September 2018. We had also conducted an earlier search of these databases in the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR) (all years to 6 June 2016). We also searched the World Health Organization (WHO) trials portal (ICTRP) and clinicaltrials.gov in September 2018, to identify any additional unpublished or ongoing studies.

Selection criteria: Single- and double-blind, randomised controlled trials comparing valproate with placebo, alternative antimanic treatments, or a combination of pharmacological treatments. We also considered studies where valproate was used as an adjunctive treatment in combination with another agent separately from studies where it was used in monotherapy. We included male and female patients of all ages and ethnicity with bipolar disorder.

Data collection and analysis: Two review authors independently performed data extraction and methodological quality assessment. For analysis, we used the odds ratio (OR) for binary efficacy outcomes and the mean difference (MD) or standardised mean difference (SMD) for continuously distributed outcomes.

Main results: Twenty-five trials (3252 participants) compared valproate with either placebo or alternative antimanic treatments to alleviate the symptoms of acute mania. For efficacy, our primary outcome was response rate. For tolerability, our primary outcome was the number of participants with any adverse effect. This meta-analysis included studies focusing on children, adolescents, as well as adults with a range of severity of manic symptoms. The majority of studies focused on adult men and women (aged 18 and above), were conducted in inpatient settings and completed in the US. Five studies in this review focused on children and adolescents (aged 18 and under) so that the review covers an age range from 3 - 82 years. Seven studies contained outpatient participants in some form. Nine studies included data that has been collected outside the US, namely Iran (4 studies), India (3 studies), China (1 study), or across several international countries (1 study).In adults, high-quality evidence found that valproate induces a slightly higher response compared to placebo (45% vs 29%, OR 2.05, 95% CI 1.32 to 3.20; 4 studies, 869 participants). Moderate-quality evidence found there was probably little or no difference in response rates between valproate and lithium (56% vs 62%, OR 0.80, 95% CI 0.48 to 1.35; 3 studies, 356 participants). In adults, low-quality evidence found there may be little or no difference in response rate between valproate and olanzapine (38% vs 44%, OR 0.77, 95% CI 0.48 to 1.25; 2 studies, 667 participants).In the children and adolescent population, the evidence regarding any difference in response rates between valproate and placebo was uncertain (23% vs 22%, OR 1.11, 95% CI 0.51 to 2.38; 1 study, 151 participants, very low-quality evidence). Low-quality evidence found that the response rate of participants receiving valproate may be lower compared to risperidone (23% vs 66%, OR 0.16, 95% CI 0.08 to 0.29; 1 study, 197 participants). The evidence regarding any difference in response rates between valproate and lithium was uncertain (23% vs 34%, OR 0.57, 95% CI 0.31 to 1.07; 1 study, 197 participants, very low-quality evidence).In terms of tolerability in adults, moderate-quality evidence found that there are probably more participants receiving valproate who experienced any adverse events compared to placebo (83% vs 75%, OR 1.63, 95% CI 1.13 to 2.36; 3 studies, 745 participants). Low-quality evidence found there may be little or no difference in tolerability between valproate and lithium (78% vs 86%, OR 0.61, 95% CI 0.25 to 1.50; 2 studies, 164 participants). We did not obtain primary tolerability outcome data on the olanzapine comparison.Within the children and adolescent population, the evidence regarding any difference between valproate or placebo was uncertain (67% vs 60%, OR 1.39, 95% CI 0.71 to 2.71; 1 study, 150 participants, very low-quality evidence). We did not obtain primary tolerability outcome data on the lithium or risperidone comparisons.

Authors' conclusions: There is evidence that valproate is an efficacious treatment for acute mania in adults when compared to placebo. By contrast, there is no evidence of a difference in efficacy between valproate and placebo for children and adolescents. Valproate may be less efficacious than olanzapine in adults, and may also be inferior to risperidone as a monotherapy treatment for paediatric mania. Generally, there is uncertain evidence regarding whether valproate causes more or less side effects than the other main antimanic therapies. However, evidence suggests that valproate causes less weight gain and sedation than olanzapine.

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Conflict of interest statement

Conflict of interests: Janina Jochim: no conflicts of interest Raphael Rifkin‐Zybutz: no conflicts of interest Andrea Cipriani: no conflicts of interest John Geddes: no conflicts of interest

Figures

1
1
study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1 Valproate vs placebo, Outcome 1 Response rate (adults).
1.2
1.2. Analysis
Comparison 1 Valproate vs placebo, Outcome 2 Response rate (children and adolescents).
1.3
1.3. Analysis
Comparison 1 Valproate vs placebo, Outcome 3 Number with any adverse event (adults; children and adolescents).
1.4
1.4. Analysis
Comparison 1 Valproate vs placebo, Outcome 4 Individual adverse events (adults).
1.5
1.5. Analysis
Comparison 1 Valproate vs placebo, Outcome 5 Individual adverse events (children and adolescents).
1.6
1.6. Analysis
Comparison 1 Valproate vs placebo, Outcome 6 Remission rate (adults).
1.7
1.7. Analysis
Comparison 1 Valproate vs placebo, Outcome 7 Remission rate (children and adolescents).
1.8
1.8. Analysis
Comparison 1 Valproate vs placebo, Outcome 8 Change in symptom severity (adults).
1.9
1.9. Analysis
Comparison 1 Valproate vs placebo, Outcome 9 Change in symptom severity (children and adolescents).
1.10
1.10. Analysis
Comparison 1 Valproate vs placebo, Outcome 10 Dropout rate (adults).
1.11
1.11. Analysis
Comparison 1 Valproate vs placebo, Outcome 11 Dropout rate (children and adolescents).
1.12
1.12. Analysis
Comparison 1 Valproate vs placebo, Outcome 12 Global Functioning (children and adolescents).
2.1
2.1. Analysis
Comparison 2 Valproate vs carbamazepine, Outcome 1 Response rate (adults).
2.2
2.2. Analysis
Comparison 2 Valproate vs carbamazepine, Outcome 2 Number with any adverse event (adults).
2.3
2.3. Analysis
Comparison 2 Valproate vs carbamazepine, Outcome 3 Individual adverse events (adults).
2.4
2.4. Analysis
Comparison 2 Valproate vs carbamazepine, Outcome 4 Change in symptom severity (adults).
2.5
2.5. Analysis
Comparison 2 Valproate vs carbamazepine, Outcome 5 Dropout rate (adults).
3.1
3.1. Analysis
Comparison 3 Valproate vs endoxifen, Outcome 1 Response rate (adults).
3.2
3.2. Analysis
Comparison 3 Valproate vs endoxifen, Outcome 2 Number with any adverse event (adults).
3.3
3.3. Analysis
Comparison 3 Valproate vs endoxifen, Outcome 3 Individual adverse events (adults).
4.1
4.1. Analysis
Comparison 4 Valproate vs haloperidol, Outcome 1 Response rate (adults).
4.2
4.2. Analysis
Comparison 4 Valproate vs haloperidol, Outcome 2 Individual adverse events (adults).
4.3
4.3. Analysis
Comparison 4 Valproate vs haloperidol, Outcome 3 Change in symptom severity (adults).
5.1
5.1. Analysis
Comparison 5 Valproate vs lithium, Outcome 1 Response rate (adults).
5.2
5.2. Analysis
Comparison 5 Valproate vs lithium, Outcome 2 Response rate (children and adolescents).
5.3
5.3. Analysis
Comparison 5 Valproate vs lithium, Outcome 3 Number with any adverse event (adults).
5.4
5.4. Analysis
Comparison 5 Valproate vs lithium, Outcome 4 Individual adverse events (adults).
5.5
5.5. Analysis
Comparison 5 Valproate vs lithium, Outcome 5 Individual adverse events (children and adolescents).
5.6
5.6. Analysis
Comparison 5 Valproate vs lithium, Outcome 6 Change in symptom severity (adults).
5.7
5.7. Analysis
Comparison 5 Valproate vs lithium, Outcome 7 Clinical response on MSRS ‐ Frequency (adults).
5.8
5.8. Analysis
Comparison 5 Valproate vs lithium, Outcome 8 Change in symptom severity (children and adolescents).
5.9
5.9. Analysis
Comparison 5 Valproate vs lithium, Outcome 9 Dropout rate (adults).
5.10
5.10. Analysis
Comparison 5 Valproate vs lithium, Outcome 10 Dropout rate (children and adolescents).
6.1
6.1. Analysis
Comparison 6 Valproate vs olanzapine, Outcome 1 Response rate (adults).
6.2
6.2. Analysis
Comparison 6 Valproate vs olanzapine, Outcome 2 Individual adverse events (adults).
6.3
6.3. Analysis
Comparison 6 Valproate vs olanzapine, Outcome 3 Remission rate (adults).
6.4
6.4. Analysis
Comparison 6 Valproate vs olanzapine, Outcome 4 Change in symptom severity (adults).
6.5
6.5. Analysis
Comparison 6 Valproate vs olanzapine, Outcome 5 Dropout rate (adults).
7.1
7.1. Analysis
Comparison 7 Valproate + olanzapine vs olanzapine alone, Outcome 1 Individual adverse events (adults).
7.2
7.2. Analysis
Comparison 7 Valproate + olanzapine vs olanzapine alone, Outcome 2 Change in symptom severity (adults).
7.3
7.3. Analysis
Comparison 7 Valproate + olanzapine vs olanzapine alone, Outcome 3 Dropout (adults).
8.1
8.1. Analysis
Comparison 8 Valproate vs oxcarbazepine, Outcome 1 Number with any adverse event (adults).
8.2
8.2. Analysis
Comparison 8 Valproate vs oxcarbazepine, Outcome 2 Individual adverse events (adults).
8.3
8.3. Analysis
Comparison 8 Valproate vs oxcarbazepine, Outcome 3 Remission rate (adults).
8.4
8.4. Analysis
Comparison 8 Valproate vs oxcarbazepine, Outcome 4 Change in symptom severity (adults).
9.1
9.1. Analysis
Comparison 9 Valproate vs quetiapine, Outcome 1 Individual adverse events (adults).
9.2
9.2. Analysis
Comparison 9 Valproate vs quetiapine, Outcome 2 Individual adverse events (children and adolescents).
9.3
9.3. Analysis
Comparison 9 Valproate vs quetiapine, Outcome 3 Remission rate (children and adolescents).
9.4
9.4. Analysis
Comparison 9 Valproate vs quetiapine, Outcome 4 Change in symptom severity (children and adolescents).
9.5
9.5. Analysis
Comparison 9 Valproate vs quetiapine, Outcome 5 Dropout rate (adults).
9.6
9.6. Analysis
Comparison 9 Valproate vs quetiapine, Outcome 6 Dropout rate (children and adolescents).
9.7
9.7. Analysis
Comparison 9 Valproate vs quetiapine, Outcome 7 Global functioning (children and adolescents).
10.1
10.1. Analysis
Comparison 10 Valproate vs risperidone, Outcome 1 Response rate (children and adolescents).
10.2
10.2. Analysis
Comparison 10 Valproate vs risperidone, Outcome 2 Individual adverse events (children and adolescents).
10.3
10.3. Analysis
Comparison 10 Valproate vs risperidone, Outcome 3 Change in symptom severity (children and adolescents).
10.4
10.4. Analysis
Comparison 10 Valproate vs risperidone, Outcome 4 Dropout rate (children and adolescents).
10.5
10.5. Analysis
Comparison 10 Valproate vs risperidone, Outcome 5 Global functioning (children and adolescents).
11.1
11.1. Analysis
Comparison 11 Valproate + risperidone vs risperidone alone, Outcome 1 Total number with any adverse events (adults).
11.2
11.2. Analysis
Comparison 11 Valproate + risperidone vs risperidone alone, Outcome 2 Remission (adults).
11.3
11.3. Analysis
Comparison 11 Valproate + risperidone vs risperidone alone, Outcome 3 Partial or full remission (adults).
12.1
12.1. Analysis
Comparison 12 Valproate vs topiramate, Outcome 1 Individual adverse events (children and adolescents).
12.2
12.2. Analysis
Comparison 12 Valproate vs topiramate, Outcome 2 Change in symptom severity (children and adolescents).
12.3
12.3. Analysis
Comparison 12 Valproate vs topiramate, Outcome 3 Dropout rates (children and adolescents).
13.1
13.1. Analysis
Comparison 13 Valproate vs placebo (sensitivity analysis treatment resistant mania removed), Outcome 1 Response rate (adults).
14.1
14.1. Analysis
Comparison 14 Valproate vs lithium (sensitivity analysis treatment resistant mania removed), Outcome 1 Response rate (adults).
15.1
15.1. Analysis
Comparison 15 Valproate vs placebo (sensitivity analysis any unclear blinding/allocation concealment removed), Outcome 1 Response rate (adults).
15.2
15.2. Analysis
Comparison 15 Valproate vs placebo (sensitivity analysis any unclear blinding/allocation concealment removed), Outcome 2 Number with any adverse event (primary tolerability outcome).
16.1
16.1. Analysis
Comparison 16 Valproate vs lithium (sensitivity analysis unclear blinding/allocation concealment removed), Outcome 1 Response rate (adults).
16.2
16.2. Analysis
Comparison 16 Valproate vs lithium (sensitivity analysis unclear blinding/allocation concealment removed), Outcome 2 Number with any adverse effect (primary tolerability outcome).
17.1
17.1. Analysis
Comparison 17 Valproate vs placebo (sensitivity analysis ‐ estimated standard deviation removed), Outcome 1 Change in symptom severity (adults).
18.1
18.1. Analysis
Comparison 18 Valproate vs placebo (sensitivity analysis excluding psychotic features), Outcome 1 Response rate (adults).
19.1
19.1. Analysis
Comparison 19 Valproate vs olanzapine (sensitivity analysis removing psychotic features), Outcome 1 Response rate (adults).
19.2
19.2. Analysis
Comparison 19 Valproate vs olanzapine (sensitivity analysis removing psychotic features), Outcome 2 Change in symptom severity (secondary efficacy outcome).
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