Research Interests

Dr. Ordway’s principal area of research is the study of the biological basis of clinical depression. This research utilizes brain tissues from individuals who have either committed suicide or have died from accidental or natural causes, all of whom have had psychiatric diagnoses made post-mortem using a rigorous retrospective psychological examination through first-degree family members. Brain tissues are studied at the biochemical and molecular level in an attempt to understand the relationship between brain biology and psychiatric illnesses that lead to suicide, particularly depressive disorders. Recently, this laboratory has discovered specific protein abnormalities in a discrete area of the human brain, the noradrenergic locus coeruleus, that are associated with severe depression. In particular, levels of specific proteins are altered in the locus coeruleus of depressive subjects relative to psychiatrically normal control subjects. The biochemical alterations observed in humans with depression can be induced in laboratory animals by depleting brain norepinephrine either pharmacologically or by exposing animals to environmental stimuli that chronically activate the locus coeruleus. These findings strongly implicate that at least one aspect of the pathophysiology of major depression/suicide is a deficiency of norepinephrine, possibly secondary to over-activity or over-stimulation of central noradrenergic neurons. Research is ongoing to determine the extent to which brain noradrenergic neurochemistry is altered and to investigate potential causes of this disruption. Another brain neurotransmitter of great interest to Dr. Ordway’s laboratory is dopamine. Animal studies of depression and psychoactive substance use have revealed that central dopamine-containing systems are neuronal substrates of a broad spectrum of behaviors including reward-seeking, motivation, and mechanisms of environmental responsibility. Disruption of these behaviors leads to anhedonia, social isolation, and psychomotor disturbances - behaviors that form core symptoms of depression. Hence, another area of research activity in this laboratory is the study of the putative dysfunction of the limbic dopaminergic system in major depression. As for the study of the brain noradrenergic system, brain tissues from psychiatrically characterized human subjects are used in conjunction with sophisticated neuroimaging and biochemical/molecular techniques to investigate dopaminergic dysfunction in depression. This research is funded by the National Institute of Mental Health, grants MH46692, MH63187, and MH/AG 02031.


Selected Publications

Bissette, G., Klimek, V., Pan, J., Stockmeier, C.A., and Ordway, G.A.: Elevated concentrations of CRF in the locus coeruleus of depressed subjects. Neuropsychopharmacology, 28:1328-1335, 2003.

Ordway, G.A., Klimek, V. and Mann, J.J.: Neurocircuitry of mood disorders. In Psychopharmacology. The Fifth Generation of Progress. (K.L. Davis, D. Charney, J.T. Coyle, C. Nemeroff, eds), Lippincott-Williams & Wilken, 1051-1064, 2002.

Klimek, V., Schenk, J.E., Han, H., Stockmeier, C.A. and Ordway, G.A.: Dopaminergic abnormalities in amygdaloid nuclei in major depression. A postmortem study. Biological Psychiatry, 52:740-748, 2002.

Klimek, V., Zhu, M.-Y., Dilley, G., Konick, L., Overholser, J., Meltzer, H.Y., May, W.L., Stockmeier, C.A., and Ordway, G.A.: Effects of long-term cigarette smoking on the human locus coeruleus. Arch. Gen. Psychiatry, 58:821-827, 2001.

Zhu, M.-Y., Shamburger, S., Li, J. and Ordway, G.A.: Regulation of the human norepinephrine transporter by cocaine and amphetamine. J. Pharmacol. Exp. Therap., 295:951-959, 2000.

Klimek, V., Stockmeier, C.A., Overholser, J., Meltzer, H.Y., Kalka, S., Dilley, G. and Ordway, G.A.: Reduced levels of norepinephrine transporters in the locus coeruleus in major depression. J. Neurosci., 17:8451-8458, 1997.