Bipolar disorders (BD), including types I (with mania and depression) and II (with depression and hypomania), are psychiatric illnesses that present as fluctuations (from mild to extreme) in mood with associated changes in thinking, speech, and behavior, often with impaired functioning and high risks of suicide.1,2 The cumulative prevalence of BD (types I and II) in the general population is approximately 2.4%,3 and BD is a prevalent source of disability worldwide.4 BD patients typically experience recurring pathological moods characterized as manic, hypomanic, depressive, or mixed with both depressive and manic features.1 In addition, BD, even aside from acute episodes, can include periods of sustained emotional instability and dysfunction, often associated with co-occurring substance abuse or anxiety disorders.5
Treatment of BD, particularly its acute manic phase and in reducing the risk of recurrences, was revolutionized by the introduction of lithium salts by Cade in 19496 and further development of prophylactic lithium treatment led by Schou,7 as well as by widespread use of antipsychotic drugs since the 1950s.8 In the 1960s and 1970s, it became apparent that certain anticonvulsants, notably carbamazepine and valproic acid and its sodium salts, exerted antimanic effects8–11 in addition to having antiepileptic activity.12
Valproic acid was first synthesized in the 1880s by Burton and used mainly as an industrial solvent.9 Its anticonvulsant activity was discovered by Eymard in 1962, and its psychotropic properties were recognized by Lambert in 1966.9,13 Several chemical preparations have been employed clinically, including free valproic acid (Depakene, Stavzor), its monosodium salt (Depacon, Epilim), the carboxamide (Depamide), and especially commonly, the sodium divalproate derivative divalproex (Depakote). Among its neuropharmacological effects, valproate can inhibit the transaminase that metabolizes the inhibitory amino acid neurotransmitter γ-amino-butyric acid (GABA), with resulting potentiation of the actions of GABA in the central nervous system.14
Based on substantial clinical research, valproic acid and divalproex received FDA approval for treating acute mania and mixed or dysphoric mania in 1995.15,16 Valproate, like antipsychotics, acts more rapidly than lithium, especially in high doses (about 20 mg/kg), encouraging its use to treat acute mania.17,18 Notably, however, valproate soon became widely used off-label for long-term maintenance treatment of BD patients despite a lack of regulatory approval or, indeed, of research evidence to support its prophylactic effectiveness. By the 2000s, valproate came to dominate the market of proposed “mood stabilizing” medicines, particularly in the United States.19–21 Again with little evidence of long-term effectiveness in BD, valproate has been accepted by international expert groups as a plausible treatment to limit recurrences of BD.22,23
Despite advances in therapeutics for BD in recent years,24 rates of recurrence remain high,25 and prevention of recurrences of bipolar depression remains unsatisfactory.26,27 Moreover, the long-term risks of suicide associated mainly with depressive phases of BD are among the highest in any psychiatric disorder—notably, despite evidence of anti-suicidal activity of lithium treatment.5,27 Given the clinical importance of treatments with potential prophylactic effectiveness in BD, the risk of adverse and especially of teratogenic effects of valproate (as discussed below), and its lack of regulatory approval for long-term use, it is of interest to update available evidence concerning the effectiveness of long-term treatment of BD with valproate.28–30
Accordingly, we sought to identify and update the available evidence bearing on the hypothesis that valproate has prophylactic effectiveness in the long-term treatment of BD patients. We undertook a systematic, computerized literature review with meta-analyses of results of clinical therapeutic trials in BD lasting at least 12 months and comparing valproate with placebo or with other approved or putative mood-stabilizing agents.
This systematic review followed PRISMA guidelines,31 based on searching several literature databases: Clinicaltrials.gov, Cochrane Library, EMBASE, Google Scholar, Ovid-MEDLINE, PsychiatryOnline, PsycInfo, and PubMed through June 2020. Bibliographies of identified reports were also searched for additional studies. Authors and pharmaceutical companies involved were contacted to seek missing data.
The search strategy employed combinations of the following keywords: anticonvulsant, antiepileptic, bipolar, divalproex, double-blind, efficacy or effectiveness, follow-up, long-term, maintenance, monotherapy, naturalistic, open-label, placebo, prevention, treatment, randomiz[s]ed, relapse or recurrence, treatment, trial, and valproate or valproic.
Retrieved reports were reviewed independently by two investigators (CSY and ERH). Initially, retrieved titles and abstracts were screened for eligibility, followed by review of full texts of apparently relevant reports. For multiple reports of the same study, the report considered most comprehensive, recent, or relevant was included.
Inclusion criteria included peer-reviewed, published reports of prospective studies (randomized controlled trials [RCTs], randomized open trials, nonrandomized open trials, naturalistic studies) evaluating prevention of new illness episodes during long-term, maintenance treatment of BD (mostly BD-I, with fewer cases of BD-II, usually not reported-on separately), involving valproic acid or sodium valproate versus placebo or an alternative pharmacological monotherapy. We included only prospective trials, from any year, published in English. Participants in the included studies were adults (aged ≥18 years), male or female, in trials with ≥15 subjects per treatment arm, with prospective treatment and assessment lasting ≥12 months. Outcome measures were the proportions of subjects with at least one new episode of BD illness (relapse or recurrence), based on standardized criteria and ratings or on the need either to change or add treatment or to be hospitalized. We excluded retrospective studies, chart reviews, case reports, commentaries, reviews, and short-term trials in acute episodes of illness, though such documents were searched for additional reports that met study criteria. Owing to the infrequency of trials qualifying for inclusion, we included studies that were broadly relevant, and classified them according to their methods (RCTs, open label, or prospective-naturalistic) and their main outcome measures.
Data Collection and Analysis
We developed a spreadsheet to record extracted study data. The following data were independently collected when available, and reviewed for accuracy and completeness by two investigators (CSY and ERH): report citation, authorship and year, study design, treatments assigned, subjects per treatment arm, proportion of female or male subjects, BD diagnostic types, approximate age at illness onset, current age, suicide attempt(s), co-occurring substance abuse or anxiety disorder(s), proportions starting in particular mood-states, outcomes as proportions of subjects with particular types of new BD episodes, and rates of early dropout from trials. A total of 21 authors and 2 industrial sponsors were contacted in regard to 14 reports with missing data; 10 responded. Data were finally rechecked for accuracy, and disagreements were resolved by consensus.
Data were summarized in tabulated form, and random-effects meta-analyses were carried out to compare valproate to placebo or to alternative active treatments. Data are presented as means or odds ratios (ORs) with 95% confidence intervals (CIs). Data were managed with Excel (Microsoft Corp, Redmond, WA) and Statview.5 (SAS Institute, Cary, NC) spreadsheets, and analyses were carried out with Stata.13 software (StataCorp, College Station, TX).
Computerized searching initially identified a total of 685 potentially relevant reports. Removing multiple presentations from the same study left 225 documents. An additional 171 reports were excluded for not meeting inclusion/exclusion criteria, leaving 54 full-text reports for detailed review. Of these, 41 were excluded for the following reasons: review articles (n = 13), insufficient data (n = 8), retrospective (n = 6), <12 months duration (n = 4), guidelines or commentaries (n = 4), too few subjects per trial arm (n = 3), or not in English (n = 3). This review process left a total of 13 included reports, representing a total of 21 distinct trials comparing valproate to placebo or other active treatments for at least a year. The report selection/exclusion process based on PRISMA guidelines is summarized in Supplemental Figure 1, http://links.lww.com/HRP/A146. Salient characteristics of the included studies are summarized in Supplemental Table 1, http://links.lww.com/HRP/A147.
Systematic searching yielded 13 included reports with 21 comparisons of valproate to other treatments.32–44 They included: 11 versus lithium,32–36,38–44 5 versus a second-generation antipsychotic (SGA; olanzapine,34 quetiapine,36,37 or olanzapine and quetiapine41), 3 versus placebo,32,33,38 and two versus another mood-stabilizing anticonvulsant (lamotrigine36 or carbamazepine42).
The total number of reported trial participants was 9240 (range, 37–5089/study), averaging 272 (95% confidence interval (CI), 114–430) per trial arm. Trials lasted a mean of 29.1 months (range, 12–124; CI, 10.4–47.7). Subject age averaged 42.4 years (CI, 40.6–44.2); age-at-onset of BD averaged 23.9 years (CI, 21.5–26.3), with a mean illness duration of 18.6 years (CI, 17.3–19.9) years. Of the adult subjects, 55.2% (CI, 52.1–58.1) were women.
Crude rates of premature dropouts from the 31 trials reporting such data all exceeded 30.0%, and did not differ (statistically) significantly among treatments (overall average = 46.2% [CI, 34.7–57.8]; t = 0.67; p = .77). However, when rates of early dropouts were adjusted for exposure times (percentage of subjects/month), they ranked as follows: MSAs (0.50 [CI, 0.00–4.44]) < SGAs (2.65 [CI, 0.00–6.68]) ≤ lithium (2.77 [CI, 0.82–4.72]) ≤ valproate (3.00 [CI, 1.41–4.58]) < placebo (5.93 [CI, 4.64–7.21]), and averaged 2.90%/month (CI, 1.94–3.86) overall. That is, the dropout rate with placebo was higher than with any active treatment, including valproate.
Valproate Versus Placebo
The three trials of valproate versus placebo32,33,38 were randomized and lasted 12 months. Two of these trials included the same subjects but considered either all new episodes32 or only new episodes of bipolar depression.33 Based on the proportions of subjects with at least one new episode of BD within a year of treatment, rates of new episodes of BD were 40.8% with placebo versus 26.8% with valproate (risk ratio = 0.657). Random-effects meta-analysis (Figure 1) indicated highly significant superiority of valproate over placebo (OR = 0.422 [CI, 0.295–0.602]; z = 4.75; p < .0001). The number needed to treat (NNT) was 6.8 (CI, 4.4–15), with very low intertrial variance (I2 < 1.00%). This very low intertrial variance suggested consideration of a fixed-effects meta-analytic model, which yielded a similar outcome (OR = 0.420 [CI, 0.295–0.599]; z = 4.79; p < .0001). In an additional sensitivity analysis based on omitting one of the reports with duplicate subjects and a different outcome measure,33 valproate remained highly significantly superior to placebo (OR = 0.362 [CI, 0.200–0.656]; z = 4.07; p < .0001; I2 < 1.00%; NNT = 5.4 [CI, 3.6–10]).
Valproate Versus Other Active Agents
Initial random-effects meta-analysis of all 18 comparisons of valproate to other active treatments (carbamazepine, lamotrigine, lithium, olanzapine, quetiapine) yielded pooled OR = 0.983 (CI, 0.751–1.29; z = 0.12; p = .90; I2 = 83.9%; NNT = 1385 [CI, 21–∞])—a nonsignificant difference between valproate and other active treatments. Sensitivity analysis based on omitting the unusually large study by Hayes and colleagues41 also yielded little difference from the overall comparison of valproate to other treatments (OR = 0.974 [CI, 0.679–1.40]; z = 0.14; p = .89). However, contingency analysis based on comparing the proportions of subjects with new episodes during treatment with valproate (66.3% [CI, 64.4–68.2]) versus all other active treatments (74.4% [CI, 73.3–75.4]) found 10.8% better protection with valproate (relative risk [RR] = 0.892; χ2 = 56.3; p < .0001).
Meta-regression modeling of factors associated with differences in response to valproate versus other treatments found no association with the following: year of reporting, total subject count, proportion of women subjects, or early dropout rate. Data were insufficient to compare effects with BD-I versus BD-II subjects, effects of co-occurring disorders or suicidal behavior, or demographic factors other than age and sex. However, there were associations of stronger therapeutic effects of valproate with older current age (β = 0.396 [CI, 0.171–0.622]; z = 3.44; p < .001), shorter treatment exposure (β = 0.218 [CI, 0.068–0.368]; z = 2.85; p = .004), and more years of BD illness (β = 0.611 [CI, 0.028–1.19]; z = 2.05; p = .04).
Valproate Versus Lithium
Head-to-head comparisons of valproate with lithium were made in 11 trials.32,33,35,36,38–44 Of these, 6 were randomized (5 blinded), and 5 were of open-label design, lasting an average of 42.2 months (CI, 10.6–73.8) (Supplemental Table 1, http://links.lww.com/HRP/A147). In these trials, rates of new episodes were 30.7% with valproate versus 24.9% with lithium (rate ratio = 1.23, indicating 23% apparent superiority of lithium). Random-effects meta-analysis found that the apparent superiority of lithium over valproate was not significant (OR = 1.057 [CI, 0.795–1.405]; z = 0.38; p = .70), with high heterogeneity (I2 = 82.4%) and a large NNT = 30 (CI, 29–∞) (Table 1 and Figure 2).
Table 1 -
Random-Effects Meta-analyses of Comparisons of Long-Term Treatment with Valproate
Versus Other Drugs or Placebo for Bipolar Disorder
||Rate of new episodes (%/year [CI])
||Odds ratio (CI)a
||Number needed to treat (CI)
Valproate vs. placebob
|All new episodes
Valproate vs. lithium
|All new episodes
Valproate vs. second-generation antipsychoticsc
|All new episodes
Valproate vs. other mood-stabilizing anticonvulsantsd
|All new episodes
Outcomes with valproatee
|Manias vs. depressions
CI, 95% confidence interval.
Note: Mean exposure = 38.6 months, or 3.22 years (CI, 24.1–53.1).
a Odds ratio (OR) <1.0 favors valproate (or depression).
In a sensitivity analysis, omitting the report by Gyulai et al. (2003),33
with data overlapping Bowden et al. (2000),32
the pooled outcome for valproate
vs. placebo in two studies yielded the pooled odds ratio = 0.362 (CI, 0.200–0.656; z = 4.07; p = .0001; I2
< 1.00%; NNT = 5.4 [CI, 3.6–10]).
c Second-generation antipsychotics were olanzapine (n = 2) and quetiapine (n = 3).
d Mood-stabilizing anticonvulsants were carbamazepine (n = 1) and lamotrigine (n = 1).
e Overall meta-analysis of valproate vs. all other active treatments (n = 18) found no difference (odds ratio = 0.983 [CI, 0.751–1.286]; z = 0.12; p = .90; I2 = 83.9%; NNT = 1385 [CI, 21–∞]).
For comparisons of valproate versus lithium, there were sufficient numbers of trials involving randomization to treatment (n = 6)32,33,35,38,39,44 or not (n = 5)36,40–43 to support use of contingency analysis to pool rates of new episodes of BD. With randomization, valproate yielded a pooled rate of 36.1% (CI, 32.6–39.7), and without randomization, a rate of 77.6% (CI, 75.3–79.8). Similarly, lithium yielded a rate of 50.3% with randomization (CI, 46.0–54.5) and 72.7% without (CI, 71.1–74.2). The markedly higher observed rates of new episodes without randomization are striking but unexplained.
Valproate Versus Second-Generation Antipsychotics
Four reports included five, direct, long-term comparisons of valproate to an SGA;34,36,37,41 three involved quetiapine,36,37,41 and two versus olanzapine.34,41 Two trials were randomized,34,37 and two others were of open-label design without randomization of treatment.36,41 The risk of a new episode of illness was 26.0% with valproate versus 31.9% with SGAs (RR = 0.815, Table 1). Random-effects meta-analysis found no difference in effects with valproate versus SGAs (OR = 0.961 [CI, 0.658–1.401]; z = 0.21; p = .84); and intertrial heterogeneity was high (I2 = 75.5%), as was NNT (26 [CI, 16–∞]; Table 1).
Valproate Versus Other Mood-Stabilizing Anticonvulsants
Two reports were identified that compared valproate to other mood-stabilizing anticonvulsants, either lamotrigine36 or carbamazepine.42 Both were of open-label design. Rates of subjects with new episodes of illness were relatively low, at 9.74% with valproate versus 8.54% with the other mood-stabilizing anticonvulsants (RR = 1.14) (Table 1). Based on random-effects meta-analysis, a tendency for somewhat superior prevention of new episodes of BD with other mood-stabilizing anticonvulsants was not significant (OR = 1.30 [CI, 0.752–2.26]; z = 0.95; p = .34; I2 < 1.00%; NNT = 15 [CI, 14–∞]) (Table 1).
Effects of Valproate Against New Episodes of Depression Versus Mania
Four trials reported on the polarity of initial outcome episodes with valproate treatment, enabling the meta-analysis of risks of new episodes of mania versus depression.34,36,43,44 In these trials, the risk of new episodes of bipolar depression was greater than for new mania (36.0% versus 29.3%; RR = 1.23) (Table 1). The meta-analytically pooled OR for this comparison was 1.49 (CI, 0.48–4.60; z = 0.69; p = .49; I2 = 89.0%; NNT = 13 [CI, 5.7–∞]), indicating a nonsignificantly greater effect versus mania (Table 1).
Empirical evidence pertaining to hypothesized efficacy of valproate monotherapy compared to other active mood-stabilizing agents or to placebo in the long-term treatment of BD remains strikingly scarce, especially considering the years of broad clinical acceptance of such treatment and the associated risks. The present systematic effort to identify long-term studies of valproate treatment for BD patients yielded only 13 reports that met broad and relatively liberal inclusion criteria. They include six RCTs, two randomized, unblinded studies, and five nonrandomized, unblinded (“open-label”) studies (Supplemental Table 1, http://links.lww.com/HRP/A147).
A particularly important outcome of this review was consistent evidence that valproate was significantly more effective at preventing BD recurrences than placebo in only three RCTs, all lasting one year (Table 1, Figure 1). This conclusion was further supported in a sensitivity analysis that excluded one trial33 involving the same subjects as a previous trial32 but a different outcome measure.
In addition, there were no significant differences between valproate and other active monotherapies (Table 1). These comparisons included 11 trials versus lithium (6 of which were randomized), in which lithium yielded an average rate of subjects with new episodes of BD 23.0% lower than with valproate, although without significance. In five other trials (Table 1), valproate was not significantly different in efficacy from two different SGAs (olanzapine, quetiapine). We found only two trials comparing valproate with another mood-stabilizing anticonvulsant (carbamazepine, lamotrigine), which both yielded very similar risks of new episodes with all treatments (Table 1). A pooled meta-analysis comparing valproate to all other active treatments in a total of 18 trials also found valproate and other active treatments not to differ significantly, although a contingency analysis of the same comparison, inexplicitly, found valproate to be modestly but significantly more effective.
Based on findings in four trials, there was a 23.0% greater efficacy of valproate against new episodes of mania than of depression. Although this tendency was not significant (Table 1), it accords with what has been found with most proposed mood-stabilizing agents, including lithium8 but with the notable exception of lamotrigine.8,24,45 However, this finding is not in accord with some previous observations suggesting greater long-term benefits of valproate against bipolar depression than mania.10,32
Overall, the present findings support the conclusion that valproate is more effective than placebo for long-term, prophylactic treatment of BD patients, and probably similar to other monotherapies with established or proposed mood-stabilizing effects. Nevertheless, the available research on this topic remains strikingly limited and involves some trials of less than ideal design. This conclusion seems remarkable in view of the widely clinically accepted and routine use of valproate for BD with long-term prophylactic intent in recent years—albeit without regulatory approval,24,46 though with support of prominent expert recommendations.22,23
In addition to the limited evidence supporting the effectiveness of long-term treatment with valproate to prevent illness recurrences in BD patients, this substance carries risks of adverse effects having a range of clinical significance.47 Particularly notable are risks to women of childbearing age. These include high rates of multiple teratogenic effects on fetal development, including cardiac and other malformations. Importantly, these effects include spina bifida, which arises very early in pregnancy, is disabling and incurable, and may not respond to supplemental folic acid, which has been found to reduce risk of spontaneous spina bifida.48,49 Young women also are at risk for valproate-associated masculinization with the polycystic ovarian syndrome.50,51 Additional risks include valproate-associated hyperammonemia that has been associated with encephalopathy.52 Valproate also can interfere with the metabolic clearance of several other drugs, notably including lamotrigine, consequently increasing its circulating concentrations and risk of dermatological toxicity.53
The limited evidence of long-term effectiveness, coupled with the risks of medically important adverse effects, calls for critical assessment of risk/benefit relationships in the long-term use of valproate with the intention of reducing the risk of recurrences of BD. The most suitable alternative, arguably, is lithium.54,55 Moreover, lithium and valproate can be used as a combined treatment when each monotherapy does not provide the desired benefits,39 and they can be given in moderate doses to limit the risk of adverse effects. In addition, a growing number of SGAs with both antimanic effects and short-term benefits against acute bipolar depression require further study to evaluate their long-term risks and potential benefits in the prophylactic treatment of BD.56,57
This review has notable limitations. Fewer than two-thirds of the identified studies (8/13) involved randomization to valproate or a comparator, although most (11/13) included at least 60 participants. The paucity of well-designed long-term trials encourages further studies if the use of valproate for prophylaxis in BD is to be supported adequately. Also requiring further study are the specific effects against recurrences of bipolar depression, mixed states, and mania, the benefits in clinical subgroups based on age and the presence of co-occurring psychiatric and other disorders, and comparisons involving types I and II BD. Finally, 6 of 13 studies (46.2%) received pharmaceutical corporate sponsorship.32–35,38,39 All of these yielded positive responses, raising the possibility of reporting bias.
The present comprehensive review of long-term clinical trials of valproate versus placebo or versus alternative active treatments given with prophylactic intent yielded only 13 reports involving 21 separate comparisons of valproate versus placebo (n = 3), lithium (11), SGAs (5), or other mood-stabilizing anticonvulsants (2). These trials varied greatly in the rigor of their design and in duration. Valproate was significantly superior in long-term efficacy to placebo—but in only three randomized trials. Other treatments commonly used to treat BD yielded no significant differences from valproate, to suggest possible noninferiority of valproate to alternatives.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.
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