Abstract
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.
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Acknowledgements
Mihran J Bakalian assisted with graph preparation and data management and Jennifer Lau with stereological analysis. This study was supported by PHS grants MH40210, MH62185, MH64168, and MH083862, the American Foundation for Suicide Prevention, the Diane Goldberg Foundation, and the Janssen Fellowship in Translational Neuroscience.
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The authors Maura Boldrini, Mark D Underwood, Andrew J Dwork, Gorazd B Rosoklija and Victoria Arango declare that, except for income received from their primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service, and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. Dr Rene' Hen receives compensation as a consultant for BrainCells Inc, PsychoGenics Inc, and AstraZeneca in relation to the generation of novel antidepressants. Dr J John Mann received grants from GlaxoSmithKline and Novartis.
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Boldrini, M., Underwood, M., Hen, R. et al. Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacol 34, 2376–2389 (2009). https://doi.org/10.1038/npp.2009.75
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