Nitric Oxide Gene Variant May Affect Depression Risk

Back in 1989, Solomon Snyder, M.D., a professor of neuroscience, pharmacology, and psychiatry at Johns Hopkins University, and colleagues reported a provocative discovery—that the gas nitric oxide functions as a neurotransmitter in the brain. Since then, nitric oxide has emerged as an important player in various cognitive, emotional, and behavioral processes.

Nitric oxide also seems to be implicated in depression. For example, major depression has been linked with increased expression of two enzymes that make nitric oxide—neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS)—as well as with increased nitric oxide levels in the brain. Inhibitors of nNOS and iNOS produced antidepressant-like effects in mice. And now a variant of the gene that makes nNOS and a variant of one that makes iNOS appear to increase depression susceptibility.

The findings were reported in the March Journal of Affective Disorders by a team of Polish scientists. The lead investigator was Piotr Galecki, M.D., Ph.D., vice chair of the Department of Adult Psychiatry at the Medical University of Lodz, Poland.

Galecki and his colleagues wanted to find out whether any variants in the genes that make nNOS and iNOS contribute to the risk of developing depression. They tested their hypothesis in a study that included 181 subjects being treated for recurrent depression and 149 control subjects. The former had had on average four depressive episodes over the prior eight years. The control subjects had never been diagnosed with depression or another psychiatric disorder.

The scientists found that a variant of genetic material within the gene that makes nNOS and a variant of genetic material within the gene that makes iNOS were present significantly more often in the depressed subjects than in the control subjects. Thus these variants appeared to contribute to the risk of developing depression, just as the variants that the controls possessed appeared to protect against the risk of developing depression.

Specifically, the T/T or T/C variant of the nNOS gene appeared to increase vulnerability to depression, whereas the C/C variant of that gene seemed to decrease risk for it. The G/G or G/A variant of the iNOS gene appeared to increase susceptibility to depression, whereas the A/A variant of that gene seemed to decrease risk for it.

The relationship between nitric oxide and depression is also interesting in that some variants of the genes that code for nNOS and iNOS have been linked to other illnesses—for example, Alzheimer's disease, autism, bipolar disorder, high blood pressure, Parkinson's disease, rheumatoid arthritis, and schizophrenia. Indeed, the iNOS gene variant that Galecki and his team found protective against depression—the A/A variant—has also been found by other researchers to be protective against Parkinson's.

The reason or reasons why nitric oxide is implicated in so many illnesses is not clear at this point. But inflammation could be one possible explanation, various lines of research suggest. For example, nitric oxide is a free radical that may contribute to the development of pro-inflammatory compounds. Rheumatoid arthritis and high blood pressure, like depression, are characterized by the overproduction of free radicals and inflammatory reactions, and in addition, depression often coexists with these disorders. The iNOS gene is located on chromosome 17, as is a gene involved in inflammation; a variant of the latter has also been linked with depression.

These findings, plus his own, suggest that "anti-inflammatory treatment should be seriously considered in the treatment of major depression," Galecki told Psychiatric News.

The study was funded by the Department of Psychiatry of the Medical University of Lodz.