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Brain-derived neurotrophic factor (BDNF)-tyrosine receptor kinase B (TrkB) signaling is thought to influence antidepressant efficacy and hippocampal volumes, robust predictors of treatment resistance. We therefore hypothesized the possible role of BDNF and neurotrophic receptor tyrosine kinase 2 (NTRK2)-related polymorphisms in affecting both hippocampal volumes and treatment resistance in MDD. A total of 121 MDD inpatients underwent 3T structural MRI scanning and blood sampling to obtain genotype information. General linear models and binary logistic regressions were employed to test the effect of genetic variations related to BDNF and NTRK2 on bilateral hippocampal volumes and treatment resistance, respectively. Finally, the possible mediating role of hippocampal volumes on the relationship between genetic markers and treatment response was investigated. A significant association between one NTRK2 polymorphism with hippocampal volumes and antidepressant response was found, with significant indirect effects. Our results highlight a possible mechanistic explanation of antidepressant action, possibly contributing to the understanding of MDD pathophysiology.<\/jats:p>","DOI":"10.3390\/genes14112037","type":"journal-article","created":{"date-parts":[[2023,11,3]],"date-time":"2023-11-03T02:41:56Z","timestamp":1698979316000},"page":"2037","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Association between NTRK2 Polymorphisms, Hippocampal Volumes and Treatment Resistance in Major Depressive Disorder"],"prefix":"10.3390","volume":"14","author":[{"given":"Marco","family":"Paolini","sequence":"first","affiliation":[{"name":"Psychiatry and Clinical Psychobiology Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lidia","family":"Fortaner-Uy\u00e0","sequence":"additional","affiliation":[{"name":"Psychiatry and Clinical Psychobiology Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Lorenzi","sequence":"additional","affiliation":[{"name":"Psychiatry and Clinical Psychobiology Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7059-8242","authenticated-orcid":false,"given":"Sara","family":"Spadini","sequence":"additional","affiliation":[{"name":"Psychiatry and Clinical Psychobiology Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melania","family":"Maccario","sequence":"additional","affiliation":[{"name":"Mood Disorders Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"},{"name":"Faculty of Medicine, Vita-Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5941-5663","authenticated-orcid":false,"given":"Raffaella","family":"Zanardi","sequence":"additional","affiliation":[{"name":"Mood Disorders Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Colombo","sequence":"additional","affiliation":[{"name":"Mood Disorders Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"},{"name":"Faculty of Medicine, Vita-Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Poletti","sequence":"additional","affiliation":[{"name":"Psychiatry and Clinical Psychobiology Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"},{"name":"Faculty of Psychology, Vita-Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Benedetti","sequence":"additional","affiliation":[{"name":"Psychiatry and Clinical Psychobiology Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"},{"name":"Faculty of Psychology, Vita-Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/s41572-023-00454-1","article-title":"Major depressive disorder","volume":"9","author":"Marx","year":"2023","journal-title":"Nat. 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