35 Primary Psychiatry Lithium Augmentation for Refractory Depression: A Critical Reappraisal Lawrence H. Price, MD, Linda L. Carpenter, MD, Audrey R. Tyrka, MD, PhD ABSTRACT Lithium augmentation, first described in 1981, is considered one of the best-supported strategies for treating refractory depression. However, clinical use of this approach has fallen dramatically in recent years, and some recent studies have cast doubt over its efficacy. This article reviews published findings in order to clarify the current role of lithium augmenta- tion in treating refractory depression. Ten placebo-controlled studies, eight comparator-controlled studies, and 13 uncontrolled large-scale prospec- tive studies of acute efficacy were reviewed in addition to six studies of effects on long-term outcome. Detailed examination found that controlled studies of lithium augmentation suffer from inadequate criteria for refractoriness, marked variability in duration of augmentation, variability in lithium levels, inadequate criteria for evaluating response, and idiosyn- cratic designs. Even more recent studies, while methodologically superior to earlier trials, have significant limitations, especially with respect to vari- ability in lithium levels. “True” response rates to lithium augmentation are likely between 30% to 40%, rather than the 50% assumed by clinicians. A more balanced appraisal of the benefits and risks of this underutilized approach might encourage its wider use by clinicians. INTRODUCTION Numerous groups in the 1970s studied the effects of combining lithium with tricyclic antidepressants (TCAs) or monoamine oxidase inhibitors (MAOIs), 1,2 but broad interest Needs Assessment: Despite numerous published efficacy studies, use of lithium augmentation for the treatment of refractory depression has declined markedly among clinicians. This paper critically reviews the literature in order to clarify the current role of this strategy in light of emerging trends and findings in managing treatment- resistant depressed patients. Learning Objectives: • Be familiar with the controlled and large-scale uncontrolled acute efficacy studies on lithium augmentation. • Be aware of data concerning the effects of lithium augmentation on long-term outcome. • Understand the strengths and limitations of the clinical database on lithium aug- mentation. • Appreciate the role of lithium augmentation in contemporary practice. Target Audience: Primary care physicians and psychiatrists. CME Accreditation Statement: This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation: The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s) TM . Physicians should only claim credit commensurate with the extent of their participation in the activity. Faculty Disclosure Policy Statement: It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the plan- ning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclo- sure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material. This activity has been peer-reviewed and approved by James C.-Y. Chou, MD, associate professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: October 6, 2008. Dr. Sussman reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Chou receives honoraria from AstraZeneca, Bristol- Myers Squibb, Eli Lilly, Janssen, and Pfizer. To receive credit for this activity: Read this article and the two CME-des- ignated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation found on page 72. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by November 1, 2010 to be eligible for credit. Release date: November 1, 2008. Termination date: November 30, 2010. The estimated time to com- plete all three articles and the posttest is 3 hours. CLINICAL FOCUS Primary Psychiatry. 2008;15(11):35-42 3 CME November 2008 Dr. Price is professor of psychiatry and human behavior, Dr. Carpenter is associate professor of psychiatry and human behavior, and Dr. Tyrka is assistant professor of psychiatry and human behavior, all at the Warren Alpert Medical School of Brown University in Providence, Rhode Island. Dr. Price is director of research and clinical director, Dr. Carpenter is chief, and Dr. Tyrka is associate chief of the Mood Disorders Research program, all at Butler Hospital in Providence. Disclosures: Dr. Price is consultant to Gerson Lehrman, Oxford University Press, Springer, and Wiley; serves on the speaker’s bureau for Jazz; and receives research support from Cyberonics, the National Institutes of Health (NIH), Sepracor, UCB Pharma, and the United States Department of Defense. Dr. Carpenter is consultant to AstraZeneca, Cyberonics, Novartis, and Wyeth; is on the speaker’s bureau for Cyberonics; and receives research support from Cyberonics, National Alliance for Research on Schizophrenia and Depression, the NIH, Sepracor, and UCB Pharma. Dr. Tyrka receives research support from Cyberonics, Sepracor, UCB Pharma, and the US Department of Defense. Please direct all correspondence to: Lawrence H. Price, MD, Butler Hospital, 345 Blackstone Blvd, Providence, RI 02906; Tel: 401-455-6533; Fax: 401-455-6534; E-mail: Lawrence_Price_MD@Brown.edu. © MBL Communications