Multimodal microglial and kynurenine pathway alterations across the affective-psychosis spectrum: a systematic review of patterns, heterogeneity, and dimensional implications
Abstract
Immune dysregulation is implicated in patient subgroups in major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SCZ), but the role of microglia across affective and psychotic illnesses remains unclear. 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 TSPO-PET comprised a single study reporting hippocampal increases, and postmortem 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…
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