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We propose an integrative framework linking systemic immune drivers to microglia-related circuit engagement, cellular phenotype, and kynurenine pathway (KP) branch balance. We systematically reviewed human TSPO-PET, cerebrospinal fluid (CSF) KP metabolite, and postmortem microglial and KP studies. Quantitative synthesis focused on MDD versus SCZ. BD was integrated descriptively due to limited data. MDD showed the most reproducible in vivo signal, with increased TSPO binding in frontolimbic regions (cingulate cortex, hippocampus, prefrontal cortex), and had lower heterogeneity and higher precision than SCZ. Postmortem MDD findings were largely null for diagnosis-level increases in microglial density or classical activation markers, but suggested subtle homeostatic shifts. KP findings were localized and regionally dissociated, including cingulate QUIN-related microglial signals and reduced hippocampal QUIN immunoreactivity in single cohorts. BD evidence was sparse as\u00a0TSPO-PET comprised a single study reporting hippocampal increases, and\u00a0postmortem microglial markers were mostly unchanged at the diagnosis level, with suicide or psychosis stratification revealing subgroup effects. Also, BD KP data suggested anterior cingulate upstream activation with a psychosis-linked downstream signal (reduced prefrontal KMO) in a subgroup. In SCZ, TSPO-PET findings were heterogeneous with small decreases or no change, and\u00a0postmortem studies indicated either activation-marker increases or loss of homeostatic microglial signatures. In addition, the most consistent biochemical signal in SCZ\u00a0was a shift toward the KYNA branch (increased CSF KYNA and cortical KYNA), consistent with KP-linked glutamatergic dysregulation. Overall, microglia-related alterations appear better explained by biological subgroups and symptom dimensions than\u00a0by categorical diagnoses, motivating future transdiagnostic studies with\u00a0dimensional phenotyping, subgroup stratification, longitudinal designs, and microglia-specific biomarkers. Limitations include the\u00a0limited cellular specificity\u00a0of TSPO-PET, small sample sizes, and postmortem studies focusing on few cortical\/limbic regions rather than whole-brain coverage.<\/jats:p>","DOI":"10.1038\/s41380-026-03614-3","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T12:18:14Z","timestamp":1776773894000},"page":"5242-5264","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Multimodal microglial and kynurenine pathway alterations across the affective-psychosis spectrum: a systematic review of patterns, heterogeneity, and dimensional implications"],"prefix":"10.1038","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2775-7929","authenticated-orcid":false,"given":"Madeleine","family":"Nussbaumer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul C.","family":"Guest","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kolja","family":"Schiltz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0428-6757","authenticated-orcid":false,"given":"Leon","family":"Dudeck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leila Shokati","family":"Asl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"Meyer-Lotz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Dobrowolny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4934-4352","authenticated-orcid":false,"given":"Stefan","family":"Leucht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans-Gert","family":"Bernstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2616-6503","authenticated-orcid":false,"given":"Thomas","family":"Nickl-Jockschat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3797-7582","authenticated-orcid":false,"given":"Brisa S.","family":"Fernandes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2611-2268","authenticated-orcid":false,"given":"Johann","family":"Steiner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,21]]},"reference":[{"key":"3614_CR1","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1016\/j.schres.2011.09.005","volume":"133","author":"MS Keshavan","year":"2011","unstructured":"Keshavan MS, Morris DW, Sweeney JA, Pearlson G, Thaker G, Seidman LJ, et al. 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