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The initiators of inflammatory pathways in the <jats:styled-content style=\"fixed-case\">CNS<\/jats:styled-content> are microglia activated in response to acute ischemic stress, and anti\u2010depressants have been shown to have anti\u2010inflammatory effects in the <jats:styled-content style=\"fixed-case\">CNS<\/jats:styled-content>, promoting neuronal survival following ischemic insult. We have previously shown that the selective serotonin reuptake inhibitors (<jats:styled-content style=\"fixed-case\">SSRI<\/jats:styled-content>s) fluoxetine and citalopram promote neuronal survival after oxygen\u2010glucose deprivation, an <jats:italic>in\u00a0vitro<\/jats:italic> model of ischemia, by attenuating the release of glutamate and D\u2010serine from activated microglia. Interestingly, we found that fluoxetine\u2010treated microglial cultures contained fewer numbers of cells compared to other groups and hypothesized that fluoxetine and citalopram attenuated the release of glutamate and D\u2010serine by promoting the apoptosis of microglia. The present study aimed to test and compare antidepressants from three distinct classes (tricyclics, monoamine oxidase inhibitors, and <jats:styled-content style=\"fixed-case\">SSRI<\/jats:styled-content>s) on microglial apoptosis. Primary microglia were treated with 1\u00a0\u03bcg\/mL lipopolysaccharide and\/or 10\u00a0\u03bcM antidepressants, and various apoptotic markers were assayed. Fluoxetine and its metabolite norfluoxetine decreased protein levels in cell lysates, decreased cell viability of microglia, and increased the expression of the apoptotic marker cleaved\u2010caspase 3 in microglia. Live\/dead nuclear staining also showed that fluoxetine\u2010 or norfluoxetine\u2010treated cultures contained greater numbers of dying microglial cells compared to vehicle\u2010treated cultures. Cultures treated with citalopram, phenelzine, or imipramine showed no evidence of inducing microglial apoptosis. Our results demonstrate that fluoxetine and norfluoxetine induce the apoptotic death of microglia, which may serve as a mechanism to attenuate the release of glutamate and D\u2010serine from activated microglia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Open Science Badges<\/jats:title><jats:p><jats:inline-graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"graphic\/jnc14661-gra-0001.png\" xlink:title=\"image\"\/><\/jats:p><jats:p>This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/cos.io\/our-services\/open-science-badges\/\">https:\/\/cos.io\/our-services\/open-science-badges\/<\/jats:ext-link>.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc14661-fig-0008-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.14661","type":"journal-article","created":{"date-parts":[[2019,1,7]],"date-time":"2019-01-07T02:35:55Z","timestamp":1546828555000},"page":"761-778","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Fluoxetine and its metabolite 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