16 Tryptophan depletion can lead to a depressive relapse in euthymic patients with a history of depression responsive to selective serotonin reuptake inhibitors (SSRIs).17,18 SERT availability has been shown to

be reduced in several brain regions in patients with major depression,19-21 though discordant findings have appeared.22 Abnormalities in SERT binding have been consistently identified in depression.23 Inhibitors,research,lifescience,medical Of paramount importance, all SSRIs are efficacious in the treatment of depression, and are generally considered first-line treatment for the illness. Many of the effects of serotonin on mood and behavior are thought to be mediated through action at postsynaptic 5-HT2 receptors.24 In unmedicated suicide victims with depression, an increased density of 5-HT2 receptors has been reported in the prefrontal cortex and amygdala,25 and, similar to findings with SERT, in platelets.26 Treatment with antidepressant medications is generally associated with decreased density of 5-HT2 receptors over a time course that Inhibitors,research,lifescience,medical corresponds to the onset of antidepressant efficacy- this finding

suggests that upregulation of 5-HT2 receptors in depression Inhibitors,research,lifescience,medical may be a compensatory response to a chronically low serotonergic state. However, other data suggest that 5-HT2 receptor Selleck WH 4023 activity may not completely normalize with antidepressant treatment.27 Also, using a radiolabled positron emission tomography (PET) ligand for the 5-HT2 receptor, Biver et Inhibitors,research,lifescience,medical al28 found reduced 5-HT2 activity in the right orbitofrontal and insular cortices. Another group found no difference in 5-HT2 activity in depressed patients versus normal controls29; however, this study excluded subjects with suicidal ideation. Depression

is a highly heritable illness, with one third of the risk for developing the disorder explained by genetic factors and two thirds of the risk attributable to the environment. A growing database suggests that the relationship of serotonin function and depression Inhibitors,research,lifescience,medical may be modulated in part by a gene-environment interaction. An early study showed an association Olopatadine between depression and a functional polymorphism of the promoter region for the SERT gene (5-HTTLPR).30 The 5-HTTLPR has two alleles: a “short” (s) version and a “long” (1) version; presence of an s allele is associated with a functionally significant decrease in SERT activity Other studies have shown an association between the presence of the s allele and the personality trait of neuroticism.31 A landmark study demonstrated that the 5-HTTLPR polymorphism moderated the influence of stressful life events on the development of depression.32 Specifically, this study showed that individuals homo- or heterozygous for the s allele were more likely to develop depressive syndromes after exposure to childhood abuse or neglect compared with subjects homozygous for the 1 allele.