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Supplemental digital content is available in the text. Learning objective: After participating in this activity, learners should be better able to: • Evaluate the evidence regarding the effectiveness of long-term treatment of bipolar disorder with valproate Background: Prophylactic treatment is critical for bipolar disorder (BD) patients. Valproate is commonly used for this purpose but lacks regulatory approval and carries appreciable risks. Methods: Systematic literature searching through June 2020 sought prospective trials lasting ≥12 months with adults diagnosed with BD to support comparisons of risk of new illness episodes with valproate versus placebo or other agents. Results: Included were 13 reports involving 9240 subjects treated for an average of 29.1 months (range, 12–124) in 21 trials: 9 were blinded, randomized trials (RCTs) of valproate versus placebo (n = 3), lithium (5), or olanzapine (1); 2 were unblinded RCTs versus lithium (1) or quetiapine (1); and 10 were open-label trials versus lithium (5), quetiapine (2), carbamazepine (1), lamotrigine (1), or olanzapine (1). Random-effects meta-analysis found valproate superior to placebo in 3 trials (odds ratio [OR] = 0.42 [95% confidence level (CI), 0.30–0.60]; p <.0001). In 11 trials, protective effects with valproate and lithium were similar (OR = 1.20 [CI, 0.81–1.79]; p =.36), as well in 5 comparisons versus antipsychotics quetiapine and olanzapine (OR = 0.96 [CI, 0.66–1.40]; p =.84), and 2 versus other mood-stabilizing anticonvulsants (carbamazepine and lamotrigine) (OR = 1.30 [CI, 0.75–2.26]; p =.34). Valproate was nonsignificantly more effective versus new mania than depression (χ2 = 3.03; p =.08). Conclusions: Valproate was more effective than placebo in preventing new BD episodes of mania or depression, and not significantly different from lithium, second-generation antipsychotics, or other anticonvulsants. Overall benefits were nonsignificantly greater versus mania than bipolar depression. [ABSTRACT FROM AUTHOR]