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Substantial evidence supports a role for dysfunction of brain serotonergic (5-HT) systems in the pathogenesis of major affective disorder, both unipolar (recurrent major depression) and bipolar. 1 Modification of serotonergic neurotransmission is pivotally implicated in the mechanism of action of antidepressant drugs 2 and also in the action of mood stabilizing agents, particularly lithium carbonate. 3 Accordingly, genes that code for the multiple subtypes of serotonin receptors that have been cloned and are expressed in brain, 4 are strong candidates for a role in the genetic etiology of affective illness. We examined a structural variant of the serotonin 2C (5-HT2C) receptor gene (HTR2C) that gives rise to a cysteine to serine substitution in the N terminal extracellular domain of the receptor protein (cys23ser), 5 in 513 patients with recurrent major depression (MDD-R), 649 patients with bipolar (BP) affective disorder and …