Lithium’s Antisuicidal Efﬁcacy: Elucidation of Neurobiological Targets Using Endophenotype Strategies Colleen E. Kovacsics, 1 Irving I. Gottesman, 2 and Todd D. Gould 1 1 Department of Psychiatry, Mood and Anxiety Disorders Program, University of Maryland School of Medicine, Baltimore, Maryland; email: tgould@psych.umaryland.edu 2 Department of Psychiatry, University of Minnesota Medical School, and Department of Psychology, University of Minnesota, Minneapolis, Minnesota Annu. Rev. Pharmacol. Toxicol. 2009. 49:175–98 First published online as a Review in Advance on October 3, 2008 The Annual Review of Pharmacology and Toxicology is online at pharmtox.annualreviews.org This article’s doi: 10.1146/annurev.pharmtox.011008.145557 Copyright c  2009 by Annual Reviews. All rights reserved 0362-1642/09/0210-0175$20.00 Key Words aggression, impulsivity, mood stabilizer, suicidal behavior, personality traits, pharmacotherapy Abstract Lithium used as a drug treatment for major mental disorders such as bipolar disorder and depression is effective in reducing the risk of both attempted and completed suicide. However, the mechanisms underlying lithium’s antisui- cidal actions are not yet known, limiting the development of novel lithium- mimetic compounds that may help reduce suicide risk with fewer undesirable side effects. Suicide is a complex behavior, complicated to study in humans, and impossible to fully reproduce in animal models. The endophenotype ap- proach, by which quantitative measures of neurobiological function are used to assess and subclassify psychiatric illness, may present a path to new dis- coveries. Aggression and impulsivity are candidate endophenotypes strongly associated with suicide; we review the evidence supporting aggression and impulsivity as suicide endophenotypes, as well as the effects of lithium on these constructs in both humans and rodents. Examining the mechanisms that contribute to lithium’s antiaggressive and antiimpulsive effects may as- sist in understanding how lithium acts to reduce the risk of suicide and in elucidating the neurobiological underpinnings of suicidal behavior. 175 Annu. Rev. Pharmacol. Toxicol. 2009.49:175-198. Downloaded from arjournals.annualreviews.org by National Institute of Health Library on 01/06/09. For personal use only.