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Monoamine Oxidase A and Catechol-O-Methyltransferase Functional Polymorphisms and the Placebo Response in Major Depressive Disorder

Leuchter, Andrew F. MD*†; McCracken, James T. MD; Hunter, Aimee M. PhD*†; Cook, Ian A. MD*†; Alpert, Jonathan E. MD, PhD

Journal of Clinical Psychopharmacology: August 2009 - Volume 29 - Issue 4 - p 372-377
doi: 10.1097/JCP.0b013e3181ac4aaf
Brief Reports

The placebo response shows pronounced interindividual variability. Placebos are postulated to act through central reward pathways that are modulated by monoamines. Because monoaminergic signaling is under strong genetic control, we hypothesized that common functional polymorphisms modulating monoaminergic tone would be related to degree of improvement during placebo treatment of subjects with major depressive disorder. We examined polymorphisms in genes encoding the catabolic enzymes catechol-O-methyltransferase and monoamine oxidase A. Subjects with monoamine oxidase A G/T polymorphisms (rs6323) coding for the highest activity form of the enzyme (G or G/G) had a significantly lower magnitude of placebo response than those with other genotypes. Subjects with Val158Met catechol-O-methyltransferase polymorphisms coding for a lower-activity form of the enzyme (2 Met alleles) showed a statistical trend toward a lower magnitude of placebo response. These findings support the hypothesis that genetic polymorphisms modulating monoaminergic tone are related to degree of placebo responsiveness in major depressive disorder.

From the *Laboratory of Brain, Behavior, and Pharmacology, Semel Institute for Neuroscience and Human Behavior at UCLA; †Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA; and ‡Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA.

Received November 2, 2008; accepted after revision April 27, 2009.

Reprints: Andrew F. Leuchter, MD, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, 760 Westwood Plaza, Rm 37-452, Los Angeles, CA 90024-1759 (e-mail:

This work was supported by R01 AT002479 from the National Center for Complementary and Alternative Medicine of the NIH. Grant support was also received from Eli Lilly & Company and Pfizer, Inc.

© 2009 Lippincott Williams & Wilkins, Inc.