NEW YORK (Reuters Health) - Researchers from Harvard Medical School suggest that inhibiting the extraneuronal monoamine transporter, known as uptake 2, could speed up the clinical effects of norepinephrine reuptake inhibitor antidepressant drugs, according to a review in the May issue of the American Journal of Psychiatry.
Two to six weeks are often required after initial administration of norepinephrine reuptake inhibitor antidepressant drugs before clinical antidepressant effects are seen, the authors point out. These effects occur after a gradual increase in the release of norepinephrine and the output of normetanephrine.
Dr. Joseph J. Schildkraut and Dr. John J. Mooney from Harvard Medical School at Massachusetts Mental Health Center, Chestnut Hill, Massachusetts examined the literature on noradrenergic neurotransmission in an effort to develop a hypothesis regarding this delayed antidepressant effect.
They report that recent studies have confirmed the importance of glia in the reuptake of norepinephrine in the synapse or other extraneuronal spaces via uptake 2.
Within the glia, norepinephrine is converted to normetanephrine, a potent inhibitor of uptake 2. The rising levels of normetanephrine produce marked increases in norepinephrine levels in the synapse.
In depressed patients treated with desipramine, the investigators note, the sum of urinary norepinephrine and normetanephrine increases significantly over time, as does the ratio of urinary norepinephrine to normetanephrine.
“These findings are compatible with the hypothesis that normetanephrine is indeed blocking uptake 2,” the researchers write, “thereby decreasing the access of norepinephrine to catechol O-methyltransferase (COMT) and, thus, the inactivation of norepinephrine by enzymatic conversion to normetanephrine.”
“Therefore,” the authors suggest, “drugs or other agents that increase levels of normetanephrine or otherwise inhibit the extraneuronal monoamine transporter, uptake 2, in the brain will produce a marked increase in levels of norepinephrine in the synapse and thus speed up the clinical effects of norepinephrine reuptake inhibitor antidepressant drugs.”
Source: Am J Psychiatry 2004;161:909-911. [ Google search on this article ]
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