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Valproate for keeping people with bipolar disorder well, after mood episodes

Cipriani A, Reid K, Young AH, Macritchie K, Geddes J
Published Online: 
17 October 2013

Bipolar disorder is a common and important disorder that includes episodes of depression, mixed states or mania. Depression includes low mood and energy, as well as lack of enjoyment, often combined with other problems such as sleep disturbance. Mania includes the opposite, with 'too much' energy and problems with high mood or irritation. In mixed states, the symptoms of depression and mania are combined. These mood episodes usually happen several times in an individual's life, so long-term treatment (maintenance treatment) can be very important in preventing relapse and recurrence. As valproate is a drug that may be useful in treating the acute phase of bipolar disorder, in this review we wanted to answer the following question: Is valproate useful as maintenance treatment for bipolar disorder?

We searched, in a wide-ranging way, for all the useful studies (randomised controlled trials, or RCTs) we could find on long-term treatment of people with bipolar disorder using valproate or any other mood stabiliser, or antipsychotic drugs, or placebo. Three of us looked at RCTs to make sure they were fair experiments. We extracted data from the studies, put all of the evidence together and carried out a statistical analysis to look for significant results.

We conducted these searches to 11 January 2013 and found six studies, including a total of 876 participants. The quality of the studies in terms of design was not good, which means that the effects of some drugs might have been overestimated. All of the trials taken together suggest that valproate might help to prevent relapse in bipolar disorder, especially depressive episodes. However, because of limited available evidence, conclusions on valproate compared with placebo and lithium (or other active drugs) cannot be made with any reliable degree of confidence. Lithium is an important drug to compare with valproate because lithium is already known to be effective in preventing relapses of bipolar disorder. When we combined the findings of all studies comparing valproate with lithium, the evidence did not favour valproate or lithium in terms of efficacy. People taking valproate over a long time were more likely than patients given lithium to keep taking their allocated medication. Clinicians and patients should consider the side effects of valproate, including alopecia, tremor and weight gain.

We also found a study that compared valproate taken alone with valproate combination therapy (two drugs taken at the same time). This study compared people who took lithium only or valproate only with people who took valproate and lithium together. No evidence showed that use of valproate and lithium compared with lithium alone helped to ensure that patients kept taking their allocated medication.

This record should be cited as: 
Cipriani A, Reid K, Young AH, Macritchie K, Geddes J. Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder. Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD003196. DOI: 10.1002/14651858.CD003196.pub2
Assessed as up to date: 
11 January 2013
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