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Publication Briefs

Lithium or Valproate Associated with Better Outcomes Compared to Second-Generation Antipsychotics for Bipolar Disorder

While lithium and the anticonvulsants valproate, carbamazepine, and oxcarbazepine have been used for several decades to treat bipolar disorder, the last 15 years have seen explosive growth in the use of second-generation antipsychotics (SGAs) for acute mania, acute depression, and maintenance. Under carefully structured conditions, randomized clinical trials indicate equivalency or superiority of SGAs compared to older antimanic agents; however, little is known about their comparative effectiveness in general clinical practice – an important issue as several SGAs have concerning cardiometabolic side-effect profiles. SGAs also are among the most costly classes of medications. This historical cohort design study assessed a nationwide population of Veteran outpatients with bipolar disorder treated at VAMCs, who were newly initiated on an antimanic agent between 2003 and 2010 (n=27,727). The primary outcome was likelihood of all-cause hospitalization during the year after initiation. Using VA administrative data, investigators also controlled for numerous covariates, including demographics (i.e., gender, race/ethnicity), comorbidities, and treatment characteristics (i.e., number of mental health hospital days).


  • After extensive control for covariates, initiation of lithium or valproate alone – compared to initiation of an SGA alone – was associated with a significantly lower likelihood of all-cause hospitalization, a longer time to hospitalization, and fewer hospitalizations in the subsequent year.
  • Veterans receiving combination treatment (i.e., SGA + lithium, SGA + valproate) had a significantly higher likelihood of hospitalization, although they also had a longer time to addition of another antimanic agent or antidepressant.
  • Among monotherapies, the only significant differences were found in psychosis, with it being more likely in those initiated on SGAs rather than those initiated on lithium, valproate, or carbamazepine/oxcarbazepine.


  • Although various mechanisms may have been responsible for these results, the data support the use of lithium or valproate, rather than SGAs, for the initial treatment of bipolar disorder. Investigators suggest that a large-scale, randomized clinical trial comparing the initiation of SGA monotherapy to that of lithium or valproate monotherapy is a logical next step.


  • Administrative data may not capture all potential confounding due to differences in patient clinical status in this non-randomized study design.
  • Investigators could not exclude prior or concurrent use of medications from non-VA sources.

This study was funded by HSR&D (IIR 10-314). Drs. Bauer and Miller are part of HSR&D's Center for Healthcare Organization and Implementation Research (CHOIR) in Boson, MA.

PubMed Logo Bauer M, Miller C, Li M, Bajor L, and Lee A. A Population-based Study of the Comparative Effectiveness of Second-Generation Antipsychotics vs. Older Antimanic Agents in Bipolar Disorder. Bipolar Disorders. September 2016;18(6):481-89.

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What are HSR Publication Briefs?

HSR requires notification by HSR-funded investigators about all articles accepted for publication. These journal articles are reviewed by HSR and publication briefs or summaries are written for a select number of articles that are then forwarded to VHA Central Office leadership to keep them informed about important findings or information. Articles to be summarized are selected by HSR based on timeliness of the findings, interest of leadership, or potential impact on the organization. Publication briefs are written for only a small number of HSR published articles. Visit the HSR citations database for a complete listing of HSR articles and presentations.

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