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Recruitment of presently healthy individuals with a subsequent transition to MDD (converters) is extremely challenging but crucial to gain insights into neurobiological vulnerability. Hence, we compared converters to patients with MDD and sustained healthy controls (HC) to distinguish pre-existing neurobiological markers from those emerging later in the course of depression. Combining two clinical cohorts (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20091709), voxel-based morphometry was utilized to analyze GMV of\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200945 converters,\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009748 patients with MDD, and\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009916 HC\u00a0in a region-of-interest approach and exploratory whole-brain. By contrasting the subgroups and considering both remission state and reported recurrence at a 2-year clinical follow-up, we stepwise disentangled effects of (1) vulnerability, (2) the acute depressive state, and (3) an initial vs. a recurrent episode. Analyses revealed higher amygdala GMV in converters relative to HC (\n                    <jats:italic>p<\/jats:italic>\n                    <jats:sub>tfce-FWE<\/jats:sub>\n                    \u2009=\u20090.037,\n                    <jats:italic>d<\/jats:italic>\n                    \u2009=\u20090.447) and patients (\n                    <jats:italic>p<\/jats:italic>\n                    <jats:sub>tfce-FWE<\/jats:sub>\n                    \u2009=\u20090.005,\n                    <jats:italic>d<\/jats:italic>\n                    \u2009=\u20090.508), remaining significant when compared to remitted patients with imminent recurrence. Lower GMV in the dorsolateral prefrontal cortex (\n                    <jats:italic>p<\/jats:italic>\n                    <jats:sub>tfce-FWE<\/jats:sub>\n                    \u2009&lt;\u20090.001,\n                    <jats:italic>d<\/jats:italic>\n                    \u2009=\u20090.188) and insula (\n                    <jats:italic>p<\/jats:italic>\n                    <jats:sub>tfce-FWE<\/jats:sub>\n                    \u2009=\u20090.010,\n                    <jats:italic>d<\/jats:italic>\n                    \u2009=\u20090.186) emerged in patients relative to HC but not to converters, driven by patients with acute MDD. By examining one of the largest available converter samples in psychiatric neuroimaging, this study allowed a first determination of neural markers for an impending initial depressive episode. Our findings suggest a temporary vulnerability, which in combination with other common risk factors might facilitate prediction and in turn improve prevention of depression.\n                  <\/jats:p>","DOI":"10.1038\/s41386-025-02075-6","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T11:44:07Z","timestamp":1741779847000},"page":"1176-1185","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Brain structural correlates of an impending initial major depressive 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