Selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) increase neurogenesis in the dentate gyrus (DG) of rodents and nonhuman primates. We determined whether SSRIs or TCAs increase neural progenitor (NPCs) and dividing cells in the human DG in major depressive disorder (MDD). Whole frozen hippocampi from untreated subjects with MDD (N=5), antidepressant-treated MDD (MDDT, N=7), and controls (C, N=7) were fixed, sectioned, and immunostained for NPCs and dividing cell markers (nestin and Ki-67, respectively), NeuN and GFAP, in single and double labeling. NPC and dividing cell numbers in the DG were estimated by stereology. Clinical data were obtained by psychological autopsy, and by toxicological and neuropathological examination performed on all subjects. NPCs decreased with age (p=0.034). Females had more NPCs than males (p=0.023). Correcting for age and sex, MDDT receiving SSRIs had more NPCs than untreated MDD (p⩽0.001) and controls (p⩽0.001), NPCs were not different in SSRI- and TCA-treated MDDT (p=0.169). Dividing cell number, unaffected by age or sex, was greater in MDDT receiving TCAs than in untreated MDD (p⩽0.001), SSRI-treated MDD (p=0.001), and controls (p⩽0.001). The increase of NPCs and dividing cells in MDDT was localized to the rostral DG. MDDT had a larger DG volume compared with untreated MDD or controls (p=0.009). Antidepressants increase NPC number in the anterior human DG. Whether this finding is critical or necessary for the antidepressants effect remains to be determined.

MAJOR DEPRESSION^1-25 and suicidal behavior^16,26-46 are independently related to altered serotonergic system indices in the brain, cerebrospinal fluid (CSF), and platelets.^47-51 Two questions arise: Do serotonergic abnormalities in major depression involve different brain regions compared with the diathesis for suicide? Second, what factors cause these alterations in serotonergic function? Genetic factors partly explain the risks for major depression⁵² and for suicide.^53,54 It is not known which genes are involved. Candidate genes that warrant investigation are those related to the serotonergic system. Genetic factors affect serotonergic activity, as indicated by the heritability of CSF levels of 5-hydroxyindoleacetic acid in nonhuman primates⁵⁵ and the reported association of suicidal acts and serotonergic indices, such as CSF levels of 5-hydroxyindoleacetic acid and the prolactin response to fenfluramine hydrochloride therapy, with an intronic polymorphism in the gene for tryptophan hydroxylase.^56-59 The most widely reported serotonergic abnormality in major depression and suicide involves the serotonin transporter (5-HTT).⁵¹ Fewer platelet 5-HTT sites and reduced platelet serotonin uptake have been reported.^49,51 Both functional imaging and postmortem brain studies indicate less 5-HTT binding in the brain in depressed patients.^60,61 Because platelet 5-HTT binding seems to be unrelated to levels of brain 5-HTT binding,^51,61 direct studies of the brain are necessary to determine the state of 5-HTT binding in major depression.

Altered serotonin indices have been reported in the brain of suicide victims. We sought to localize the changes in presynaptic and postsynaptic serotonin receptors and identify an area of prefrontal cortex that may influence suicide risk. Quantitative autoradiography was performed in coronal sections of prefrontal cortex to determine whether serotonin 5-HT1A receptor (postsynaptic in cortex) and serotonin transporter (presynaptic) binding are different in suicide victims compared to matched controls. 5-HT1A receptor binding was higher in 85 of the 103 sampled areas in the suicide group (n = 18 pairs; P < 0.0001). The increase ranged from 17 to 30%. The increase was more pronounced in the ventrolateral prefrontal cortex. Serotonin transporter binding was found to be lower in the suicide group in all but one of the 43 sampled regions (n = 22 pairs; P < 0.0001). The reduction in binding was most pronounced in the ventrolateral prefrontal cortex, where the difference between suicides and controls ranged between 15 and 27%. Serotonin transporter and 5-HT1A binding were negatively correlated (r = -0.35 to -0.44, P = 0.04 to 0.007) within the same brain areas, suggesting common regulatory factors with opposite effects on binding to the two receptors. We conclude that suicide victims have an abnormality in the serotonin system involving predominantly the ventrolateral prefrontal cortex, and hypothesize that the serotonergic dysfunction in this brain region contributes to the risk for suicidal behavior.