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Potential Phenotypic Vulnerability Marker?

Robert M. Berman, MD; Meera Narasimhan, MD; Helen L. Miller, MD; Amit Anand, MD; Angela Cappiello, MD, PhD; Dan A. Oren, MD; George R. Heninger, MD; Dennis S. Charney, MD

Arch Gen Psychiatry. 1999;56:395-403.

Background  Although state-related alterations in catecholamine function have been well-described in depressed subjects, enduring abnormalities have been less reliably identified. In our study, medication-free subjects with fully remitted major depression underwent a paradigm of catecholamine depletion, via use of the tyrosine hydroxylase inhibitor -methylparatyrosine.

Method  Subjects underwent 2 sets of testing conditions in a double-blind, random-ordered, crossover design, approximately 1 week apart. They underwent active catecholamine depletion (via oral administration of 5 g -methylparatyrosine) or sedation-controlled, sham catecholamine depletion (via oral administration of 250 mg diphenhydramine hydrochloride), during a 2-day observation. Serial mood ratings and blood samples were obtained.

Results  Fourteen subjects completed the active testing condition; 13 completed sham testing. Subjects experienced marked, transient increases in core depressive and anxiety symptoms, as demonstrated by a mean 21-point increase on Hamilton Depression Rating Scale scores. Furthermore, 10 (71%) of 14 subjects fulfilled relapse criteria during active testing, whereas 1 (8%) of 13 subjects did so during sham testing. The severity of the depressive reaction correlated with baseline plasma cortisol levels (r=0.59; P=.04).

Conclusions  Euthymic, medication-free subjects with a history of major depression demonstrate significant depressive symptoms when undergoing testing with -methylparatyrosine. This depressive reaction may represent a reliable marker for a history of depression. Further work is needed to clarify the significance of this finding.

From the Clinical Neuroscience Research Unit, Connecticut Mental Health Center (Drs Berman, Heninger, and Charney), the West Haven Veterans Affairs Medical Center (Drs Berman, Narasimhan, Miller, Anand, Cappiello, Oren, and Charney), and the Department of Psychiatry, Yale University School of Medicine (Drs Berman, Narasimhan, Miller, Anand, Cappiello, Oren, Heninger, and Charney), New Haven, Conn.

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