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2015 HSR&D/QUERI National Conference Abstract

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3199 — Nonsuicide mortality associated with lithium and valproate treatment in Veterans Health Administration patients with mental health diagnoses

Smith EG, Center for Healthcare Organization and Implementation Research, ENRM VAMC, Bedford, MA, and UMass Medical School Dept. of Psychiatry, Worcester, MA; Austin KL, Center for Clinical Management Research, Ann Arbor, MI, VA Serious Mental Illness Treatment Resource & Evaluation Center; Kim HM, Center for Clinical Management Research, Ann Arbor, MI, and University of Michigan Center for Statistical Consultation and Research, Ann Arbor, MI; Eisen SV, Center for Healthcare Organization and Implementation Research, ENRM VAMC, Bedford, MA, & Dept. of Health Policy & Mngt, Boston Univ Sch Pub Health; Kilbourne AM, Quality Enhancement Research Initiative (QUERI), Washington, DC, & University of Michigan Dept of Psychiatry; Miller DR, Center for Healthcare Organization and Implementation Research, ENRM VAMC, Bedford, MA, & Dept. of Health Policy & Mngt, Boston Univ Sch Pub Health; Zivin K, Center for Clinical Management Research, Ann Arbor, MI, VA Serious Mental Illness Treatment Resource & Evaluation Ctr, & UMichigan Dept of Psychiatry; Hannemann C, Center for Clinical Management Research, Ann Arbor, MI, VA Serious Mental Illness Treatment Resource & Evaluation Center; Sauer BC, VA IDEAS2.0 Center, Salt Lake City, UT, & University of Utah Dept of Internal Medicine; Valenstein M

Objectives:
To examine the association between lithium and nonsuicide mortality.

Methods:
Historical prospective cohort study (1999-2008) of 93,000 Veterans Health Administration (VHA) patients with mental disorders newly initiating lithium or valproate. High-dimensional propensity score matching (1:1) was used to extensively balance the treatment groups on > 900 covariates drawn from VHA databases.

Results:
Lithium was associated with significantly reduced nonsuicide 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, and over 0-90, 0-180, and 0-365 days in secondary analyses of the period during which patients actively received prescriptions for lithium compared to valproate (e.g., 0-365 day HR 0.62 [0.45-0.84]). Significantly increased mortality risks were observed, however, over the first 0-180 days among patients discontinuing lithium compared to discontinuing valproate (HR 1.54, [1.01-2.37]).

Implications:
Significant differences in nonsuicide mortality were associated with patients initiating lithium versus valproate. Since this is a nonrandomized study, residual confounding cannot be excluded. Any residual confounding, however, is likely to be in the direction of decreased nonsuicide mortality risks for patients initiating lithium compared to valproate. It is difficult, therefore, to determine if active treatment with lithium is associated with significant reductions in nonsuicide mortality. In contrast, the significantly increased nonsuicide mortality risks observed over 0-180 days (but not over 0-365 days) among patients discontinuing lithium run counter to the expected overall direction of confounding. The possibility of some period of increased nonsuicide mortality risks occurring shortly after discontinuing lithium thus deserves strong consideration, and should be a high priority for additional research. Until then, our results suggest that efforts should be undertaken to maximize persistence with lithium once initiated. Patients initiating lithium should also be warned about the risks of discontinuing lithium, and monitored closely upon discontinuation when feasible.

Impacts:
This study may contribute to a new paradigm concerning the initiation and management of mental health treatments that gives increased weight to the associations of such treatments with overall physical health. This study will also help inform the VHA of potential health risks and benefits of lithium, a medication the VHA continues to investigate intensively as a potential approach to suicide prevention.