Valproate in bipolar disorder: 2000 onwards.
OBJECTIVE
To describe the evidence for the efficacy and tolerability of valproate in treatment of bipolar disorders, as well as factors associated with favorable or unfavorable outcomes.


METHODS
Studies published from 2000 onwards were reviewed, as well as published abstracts. For clinical trials, randomized, prospective studies were emphasized.


RESULTS
Several mechanisms of action of valproate on central nervous system neurons that may be relevant to its actions in bipolar disorders have been recently reported. These include inhibition of glycogen synthase kinase and activation of extracellular signal-regulated kinase. Several of the actions overlap those observed from lithium. Valproate is effective in treatment of mania, and somewhat more effective in certain patient subgroups than other treatments, e.g. mixed mania, and mania with prominent irritability. Valproate is comparable with olanzapine in maintenance treatment, and somewhat better tolerated. Higher serum levels, particularly above 110 microg/ml, are associated with more reports of weight gain, sedation, and reductions in platelet count. Valproate may be associated with an increased rate of polycystic ovarian syndrome, with increased weight contributing to the risk. Valproate reduces total cholesterol levels, particularly among patients with baseline elevations of cholesterol. Several studies indicate that valproate can be beneficially combined with antipsychotic drugs and other treatments for bipolar disorder.


CONCLUSIONS
Valproate continues to be studied in further clarification of its mechanisms, efficacy, risks, and spectrum of benefits in bipolar disorder. It is a major treatment for bipolar disorder, both in monotherapy and combination therapy regimens.
Bowden
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Department of Psychiatry, The University of Texas Health Science Center at San Antonio, TX 78229, USA. bowdenc@uthscsa.edu
Singh
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D018692:Antimanic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D006801:Humans; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016032:Randomized Controlled Trials as Topic; D014635:Valproic Acid / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
D018692:Antimanic Agents; D014635:Valproic Acid; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3