title: Mortality associated with lithium and valproate treatment of US Veterans Health Administration patients with mental disorders.
abstract: BackgroundThe mood stabilisers lithium and valproate might plausibly have differing associations with mortality because of differing effects on mental health and various physiological indicators.AimsTo assess associations between lithium, valproate and non-suicide mortality.MethodIntention-to-treat, propensity score-matched cohort study.ResultsLithium was associated with significantly reduced non-suicide mortality in the intent-to-treat cohort over 0-90 days (hazard ratio (HR) = 0.67, 95% CI 0.51-0.87) but not longer. In secondary analyses, a sizeable reduction in mortality was observed during active treatment with lithium across all time periods studied (for example 365-day HR = 0.62, 95% CI 0.45-0.84), but significantly increased risks were observed among patients discontinuing lithium by 180 days (HR = 1.54, 95% CI 1.01-2.37).ConclusionsPatients initiating lithium had lower non-suicide mortality over 0-90 days than patients initiating valproate and consistently lower non-suicide mortality among patients maintaining treatment, but elevated risk among patients discontinuing treatment by 180 days. Although residual confounding or selection effects cannot be excluded, this study suggests potential benefits to enhancing lithium treatment persistence and the monitoring of patients discontinuing lithium. There is a need for further research.
authors.affiliation: Eric G. Smith, MD, PhD, MPH, VA Center for Healthcare Organization and Implementation Research, Department of Veterans Affairs VA Medical Center, Bedford, Massachusetts, and Departments of Psychiatry and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, Massachusetts; Karen L. Austin, MPH, Serious Mental Illness Treatment Resource and Evaluation Center, Department of Veterans Affairs, Ann Arbor, Michigan; Hyungjin Myra Kim, ScD, VA Center for Clinical Management Research, Department of Veterans Affairs VA Medical Center, Ann Arbor, Michigan, and Center for Statistical Consultation and Research, University of Michigan, Ann Arbor, Michigan; Susan V. Eisen, PhD, VA Center for Healthcare Organization and Implementation Research, Department of Veterans Affairs VA Medical Center, Bedford, Massachusetts, and Department of Health Policy and Management, Boston University School of Public Health, Boston, Massachusetts; Amy M. Kilbourne, PhD, MPH, Quality Enhancement Research Initiative (QUERI), Department of Veterans Affairs, Washington DC, and Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan; Donald R. Miller, ScD, VA Center for Healthcare Organization and Implementation Research, Department of Veterans Affairs VA Medical Center, Bedford, Massachusetts; Kara Zivin, PhD, VA Center for Clinical Management Research, Department of Veterans Affairs VA Medical Center, Ann Arbor, Michigan, and Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan; Claire Hannemann, MPH, Serious Mental Illness Treatment Resource and Evaluation Center, Department of Veterans Affairs, Ann Arbor, Michigan; Brian C. Sauer, PhD, VA IDEAS2.0 Center and Health Services Research and Development Researcher Enhancement Award Program, Department of Veterans Affairs, Salt Lake City, Utah, and Department of Internal Medicine, University of Utah, Salt Lake City, Utah; Marcia Valenstein, MD, MS, VA Center for Clin
authors.forename: Eric G
authors.initials: EG
authors.lastname: Smith
authors.affiliation: Eric G. Smith, MD, PhD, MPH, VA Center for Healthcare Organization and Implementation Research, Department of Veterans Affairs VA Medical Center, Bedford, Massachusetts, and Departments of Psychiatry and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, Massachusetts; Karen L. Austin, MPH, Serious Mental Illness Treatment Resource and Evaluation Center, Department of Veterans Affairs, Ann Arbor, Michigan; Hyungjin Myra Kim, ScD, VA Center for Clinical Management Research, Department of Veterans Affairs VA Medical Center, Ann Arbor, Michigan, and Center for Statistical Consultation and Research, University of Michigan, Ann Arbor, Michigan; Susan V. Eisen, PhD, VA Center for Healthcare Organization and Implementation Research, Department of Veterans Affairs VA Medical Center, Bedford, Massachusetts, and Department of Health Policy and Management, Boston University School of Public Health, Boston, Massachusetts; Amy M. Kilbourne, PhD, MPH, Quality Enhancement Research Initiative (QUERI), Department of Veterans Affairs, Washington DC, and Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan; Donald R. Miller, ScD, VA Center for Healthcare Organization and Implementation Research, Department of Veterans Affairs VA Medical Center, Bedford, Massachusetts; Kara Zivin, PhD, VA Center for Clinical Management Research, Department of Veterans Affairs VA Medical Center, Ann Arbor, Michigan, and Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan; Claire Hannemann, MPH, Serious Mental Illness Treatment Resource and Evaluation Center, Department of Veterans Affairs, Ann Arbor, Michigan; Brian C. Sauer, PhD, VA IDEAS2.0 Center and Health Services Research and Development Researcher Enhancement Award Program, Department of Veterans Affairs, Salt Lake City, Utah, and Department of Internal Medicine, University of Utah, Salt Lake City, Utah; Marcia Valenstein, MD, MS, VA Center for Clin
authors.forename: Karen L
authors.initials: KL
authors.lastname: Austin
authors.affiliation: Eric G. Smith, MD, PhD, MPH, VA Center for Healthcare Organization and Implementation Research, Department of Veterans Affairs VA Medical Center, Bedford, Massachusetts, and Departments of Psychiatry and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, Massachusetts; Karen L. Austin, MPH, Serious Mental Illness Treatment Resource and Evaluation Center, Department of Veterans Affairs, Ann Arbor, Michigan; Hyungjin Myra Kim, ScD, VA Center for Clinical Management Research, Department of Veterans Affairs VA Medical Center, Ann Arbor, Michigan, and Center for Statistical Consultation and Research, University of Michigan, Ann Arbor, Michigan; Susan V. Eisen, PhD, VA Center for Healthcare Organization and Implementation Research, Department of Veterans Affairs VA Medical Center, Bedford, Massachusetts, and Department of Health Policy and Management, Boston University School of Public Health, Boston, Massachusetts; Amy M. Kilbourne, PhD, MPH, Quality Enhancement Research Initiative (QUERI), Department of Veterans Affairs, Washington DC, and Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan; Donald R. Miller, ScD, VA Center for Healthcare Organization and Implementation Research, Department of Veterans Affairs VA Medical Center, Bedford, Massachusetts; Kara Zivin, PhD, VA Center for Clinical Management Research, Department of Veterans Affairs VA Medical Center, Ann Arbor, Michigan, and Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan; Claire Hannemann, MPH, Serious Mental Illness Treatment Resource and Evaluation Center, Department of Veterans Affairs, Ann Arbor, Michigan; Brian C. Sauer, PhD, VA IDEAS2.0 Center and Health Services Research and Development Researcher Enhancement Award Program, Department of Veterans Affairs, Salt Lake City, Utah, and Department of Internal Medicine, University of Utah, Salt Lake City, Utah; Marcia Valenstein, MD, MS, VA Center for Clin
authors.forename: Hyungjin Myra
authors.initials: HM
authors.lastname: Kim
authors.affiliation: Eric G. Smith, MD, PhD, MPH, VA Center for Healthcare Organization and Implementation Research, Department of Veterans Affairs VA Medical Center, Bedford, Massachusetts, and Departments of Psychiatry and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, Massachusetts; Karen L. Austin, MPH, Serious Mental Illness Treatment Resource and Evaluation Center, Department of Veterans Affairs, Ann Arbor, Michigan; Hyungjin Myra Kim, ScD, VA Center for Clinical Management Research, Department of Veterans Affairs VA Medical Center, Ann Arbor, Michigan, and Center for Statistical Consultation and Research, University of Michigan, Ann Arbor, Michigan; Susan V. Eisen, PhD, VA Center for Healthcare Organization and Implementation Research, Department of Veterans Affairs VA Medical Center, Bedford, Massachusetts, and Department of Health Policy and Management, Boston University School of Public Health, Boston, Massachusetts; Amy M. Kilbourne, PhD, MPH, Quality Enhancement Research Initiative (QUERI), Department of Veterans Affairs, Washington DC, and Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan; Donald R. Miller, ScD, VA Center for Healthcare Organization and Implementation Research, Department of Veterans Affairs VA Medical Center, Bedford, Massachusetts; Kara Zivin, PhD, VA Center for Clinical Management Research, Department of Veterans Affairs VA Medical Center, Ann Arbor, Michigan, and Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan; Claire Hannemann, MPH, Serious Mental Illness Treatment Resource and Evaluation Center, Department of Veterans Affairs, Ann Arbor, Michigan; Brian C. Sauer, PhD, VA IDEAS2.0 Center and Health Services Research and Development Researcher Enhancement Award Program, Department of Veterans Affairs, Salt Lake City, Utah, and Department of Internal Medicine, University of Utah, Salt Lake City, Utah; Marcia Valenstein, MD, MS, VA Center for Clin
authors.forename: Susan V
authors.initials: SV
authors.lastname: Eisen
authors.affiliation: Eric G. Smith, MD, PhD, MPH, VA Center for Healthcare Organization and Implementation Research, Department of Veterans Affairs VA Medical Center, Bedford, Massachusetts, and Departments of Psychiatry and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, Massachusetts; Karen L. Austin, MPH, Serious Mental Illness Treatment Resource and Evaluation Center, Department of Veterans Affairs, Ann Arbor, Michigan; Hyungjin Myra Kim, ScD, VA Center for Clinical Management Research, Department of Veterans Affairs VA Medical Center, Ann Arbor, Michigan, and Center for Statistical Consultation and Research, University of Michigan, Ann Arbor, Michigan; Susan V. Eisen, PhD, VA Center for Healthcare Organization and Implementation Research, Department of Veterans Affairs VA Medical Center, Bedford, Massachusetts, and Department of Health Policy and Management, Boston University School of Public Health, Boston, Massachusetts; Amy M. Kilbourne, PhD, MPH, Quality Enhancement Research Initiative (QUERI), Department of Veterans Affairs, Washington DC, and Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan; Donald R. Miller, ScD, VA Center for Healthcare Organization and Implementation Research, Department of Veterans Affairs VA Medical Center, Bedford, Massachusetts; Kara Zivin, PhD, VA Center for Clinical Management Research, Department of Veterans Affairs VA Medical Center, Ann Arbor, Michigan, and Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan; Claire Hannemann, MPH, Serious Mental Illness Treatment Resource and Evaluation Center, Department of Veterans Affairs, Ann Arbor, Michigan; Brian C. Sauer, PhD, VA IDEAS2.0 Center and Health Services Research and Development Researcher Enhancement Award Program, Department of Veterans Affairs, Salt Lake City, Utah, and Department of Internal Medicine, University of Utah, Salt Lake City, Utah; Marcia Valenstein, MD, MS, VA Center for Clin
authors.forename: Amy M
authors.initials: AM
authors.lastname: Kilbourne
authors.affiliation: Eric G. Smith, MD, PhD, MPH, VA Center for Healthcare Organization and Implementation Research, Department of Veterans Affairs VA Medical Center, Bedford, Massachusetts, and Departments of Psychiatry and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, Massachusetts; Karen L. Austin, MPH, Serious Mental Illness Treatment Resource and Evaluation Center, Department of Veterans Affairs, Ann Arbor, Michigan; Hyungjin Myra Kim, ScD, VA Center for Clinical Management Research, Department of Veterans Affairs VA Medical Center, Ann Arbor, Michigan, and Center for Statistical Consultation and Research, University of Michigan, Ann Arbor, Michigan; Susan V. Eisen, PhD, VA Center for Healthcare Organization and Implementation Research, Department of Veterans Affairs VA Medical Center, Bedford, Massachusetts, and Department of Health Policy and Management, Boston University School of Public Health, Boston, Massachusetts; Amy M. Kilbourne, PhD, MPH, Quality Enhancement Research Initiative (QUERI), Department of Veterans Affairs, Washington DC, and Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan; Donald R. Miller, ScD, VA Center for Healthcare Organization and Implementation Research, Department of Veterans Affairs VA Medical Center, Bedford, Massachusetts; Kara Zivin, PhD, VA Center for Clinical Management Research, Department of Veterans Affairs VA Medical Center, Ann Arbor, Michigan, and Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan; Claire Hannemann, MPH, Serious Mental Illness Treatment Resource and Evaluation Center, Department of Veterans Affairs, Ann Arbor, Michigan; Brian C. Sauer, PhD, VA IDEAS2.0 Center and Health Services Research and Development Researcher Enhancement Award Program, Department of Veterans Affairs, Salt Lake City, Utah, and Department of Internal Medicine, University of Utah, Salt Lake City, Utah; Marcia Valenstein, MD, MS, VA Center for Clin
authors.forename: Donald R
authors.initials: DR
authors.lastname: Miller
authors.affiliation: Eric G. Smith, MD, PhD, MPH, VA Center for Healthcare Organization and Implementation Research, Department of Veterans Affairs VA Medical Center, Bedford, Massachusetts, and Departments of Psychiatry and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, Massachusetts; Karen L. Austin, MPH, Serious Mental Illness Treatment Resource and Evaluation Center, Department of Veterans Affairs, Ann Arbor, Michigan; Hyungjin Myra Kim, ScD, VA Center for Clinical Management Research, Department of Veterans Affairs VA Medical Center, Ann Arbor, Michigan, and Center for Statistical Consultation and Research, University of Michigan, Ann Arbor, Michigan; Susan V. Eisen, PhD, VA Center for Healthcare Organization and Implementation Research, Department of Veterans Affairs VA Medical Center, Bedford, Massachusetts, and Department of Health Policy and Management, Boston University School of Public Health, Boston, Massachusetts; Amy M. Kilbourne, PhD, MPH, Quality Enhancement Research Initiative (QUERI), Department of Veterans Affairs, Washington DC, and Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan; Donald R. Miller, ScD, VA Center for Healthcare Organization and Implementation Research, Department of Veterans Affairs VA Medical Center, Bedford, Massachusetts; Kara Zivin, PhD, VA Center for Clinical Management Research, Department of Veterans Affairs VA Medical Center, Ann Arbor, Michigan, and Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan; Claire Hannemann, MPH, Serious Mental Illness Treatment Resource and Evaluation Center, Department of Veterans Affairs, Ann Arbor, Michigan; Brian C. Sauer, PhD, VA IDEAS2.0 Center and Health Services Research and Development Researcher Enhancement Award Program, Department of Veterans Affairs, Salt Lake City, Utah, and Department of Internal Medicine, University of Utah, Salt Lake City, Utah; Marcia Valenstein, MD, MS, VA Center for Clin
authors.forename: Kara
authors.initials: K
authors.lastname: Zivin
authors.affiliation: Eric G. Smith, MD, PhD, MPH, VA Center for Healthcare Organization and Implementation Research, Department of Veterans Affairs VA Medical Center, Bedford, Massachusetts, and Departments of Psychiatry and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, Massachusetts; Karen L. Austin, MPH, Serious Mental Illness Treatment Resource and Evaluation Center, Department of Veterans Affairs, Ann Arbor, Michigan; Hyungjin Myra Kim, ScD, VA Center for Clinical Management Research, Department of Veterans Affairs VA Medical Center, Ann Arbor, Michigan, and Center for Statistical Consultation and Research, University of Michigan, Ann Arbor, Michigan; Susan V. Eisen, PhD, VA Center for Healthcare Organization and Implementation Research, Department of Veterans Affairs VA Medical Center, Bedford, Massachusetts, and Department of Health Policy and Management, Boston University School of Public Health, Boston, Massachusetts; Amy M. Kilbourne, PhD, MPH, Quality Enhancement Research Initiative (QUERI), Department of Veterans Affairs, Washington DC, and Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan; Donald R. Miller, ScD, VA Center for Healthcare Organization and Implementation Research, Department of Veterans Affairs VA Medical Center, Bedford, Massachusetts; Kara Zivin, PhD, VA Center for Clinical Management Research, Department of Veterans Affairs VA Medical Center, Ann Arbor, Michigan, and Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan; Claire Hannemann, MPH, Serious Mental Illness Treatment Resource and Evaluation Center, Department of Veterans Affairs, Ann Arbor, Michigan; Brian C. Sauer, PhD, VA IDEAS2.0 Center and Health Services Research and Development Researcher Enhancement Award Program, Department of Veterans Affairs, Salt Lake City, Utah, and Department of Internal Medicine, University of Utah, Salt Lake City, Utah; Marcia Valenstein, MD, MS, VA Center for Clin
authors.forename: Claire
authors.initials: C
authors.lastname: Hannemann
authors.affiliation: Eric G. Smith, MD, PhD, MPH, VA Center for Healthcare Organization and Implementation Research, Department of Veterans Affairs VA Medical Center, Bedford, Massachusetts, and Departments of Psychiatry and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, Massachusetts; Karen L. Austin, MPH, Serious Mental Illness Treatment Resource and Evaluation Center, Department of Veterans Affairs, Ann Arbor, Michigan; Hyungjin Myra Kim, ScD, VA Center for Clinical Management Research, Department of Veterans Affairs VA Medical Center, Ann Arbor, Michigan, and Center for Statistical Consultation and Research, University of Michigan, Ann Arbor, Michigan; Susan V. Eisen, PhD, VA Center for Healthcare Organization and Implementation Research, Department of Veterans Affairs VA Medical Center, Bedford, Massachusetts, and Department of Health Policy and Management, Boston University School of Public Health, Boston, Massachusetts; Amy M. Kilbourne, PhD, MPH, Quality Enhancement Research Initiative (QUERI), Department of Veterans Affairs, Washington DC, and Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan; Donald R. Miller, ScD, VA Center for Healthcare Organization and Implementation Research, Department of Veterans Affairs VA Medical Center, Bedford, Massachusetts; Kara Zivin, PhD, VA Center for Clinical Management Research, Department of Veterans Affairs VA Medical Center, Ann Arbor, Michigan, and Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan; Claire Hannemann, MPH, Serious Mental Illness Treatment Resource and Evaluation Center, Department of Veterans Affairs, Ann Arbor, Michigan; Brian C. Sauer, PhD, VA IDEAS2.0 Center and Health Services Research and Development Researcher Enhancement Award Program, Department of Veterans Affairs, Salt Lake City, Utah, and Department of Internal Medicine, University of Utah, Salt Lake City, Utah; Marcia Valenstein, MD, MS, VA Center for Clin
authors.forename: Brian C
authors.initials: BC
authors.lastname: Sauer
authors.affiliation: Eric G. Smith, MD, PhD, MPH, VA Center for Healthcare Organization and Implementation Research, Department of Veterans Affairs VA Medical Center, Bedford, Massachusetts, and Departments of Psychiatry and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, Massachusetts; Karen L. Austin, MPH, Serious Mental Illness Treatment Resource and Evaluation Center, Department of Veterans Affairs, Ann Arbor, Michigan; Hyungjin Myra Kim, ScD, VA Center for Clinical Management Research, Department of Veterans Affairs VA Medical Center, Ann Arbor, Michigan, and Center for Statistical Consultation and Research, University of Michigan, Ann Arbor, Michigan; Susan V. Eisen, PhD, VA Center for Healthcare Organization and Implementation Research, Department of Veterans Affairs VA Medical Center, Bedford, Massachusetts, and Department of Health Policy and Management, Boston University School of Public Health, Boston, Massachusetts; Amy M. Kilbourne, PhD, MPH, Quality Enhancement Research Initiative (QUERI), Department of Veterans Affairs, Washington DC, and Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan; Donald R. Miller, ScD, VA Center for Healthcare Organization and Implementation Research, Department of Veterans Affairs VA Medical Center, Bedford, Massachusetts; Kara Zivin, PhD, VA Center for Clinical Management Research, Department of Veterans Affairs VA Medical Center, Ann Arbor, Michigan, and Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan; Claire Hannemann, MPH, Serious Mental Illness Treatment Resource and Evaluation Center, Department of Veterans Affairs, Ann Arbor, Michigan; Brian C. Sauer, PhD, VA IDEAS2.0 Center and Health Services Research and Development Researcher Enhancement Award Program, Department of Veterans Affairs, Salt Lake City, Utah, and Department of Internal Medicine, University of Utah, Salt Lake City, Utah; Marcia Valenstein, MD, MS, VA Center for Clin
authors.forename: Marcia
authors.initials: M
authors.lastname: Valenstein
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018692:Antimanic Agents / Q000627:therapeutic use*; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008094:Lithium / Q000627:therapeutic use*; D008297:Male; D001523:Mental Disorders / Q000188:drug therapy* / Q000401:mortality*; D008603:Mental Health; D012044:Regression Analysis; D012307:Risk Factors; D014635:Valproic Acid / Q000627:therapeutic use*; D058014:Veterans Health
chemical_list: D018692:Antimanic Agents; D014150:Antipsychotic Agents; D014635:Valproic Acid; D008094:Lithium