Hippocampal and Prefrontal MRI Alterations as Candidate Severity Biomarkers in Schizophrenia and Treatment Resistant Depression: A critical review with structured synthesis of published meta analyses

Resumen

Hippocampal and prefrontal abnormalities are repeatedly observed in psychiatric neuroimaging, but their value as individual markers of severity remains uncertain. This review synthesizes PubMed-indexed structural and functional MRI evidence in schizophrenia and treatment-resistant depression, with bibliographic verification on 7 October 2026. Published meta-analyses, large harmonized imaging studies, and selected treatment-response reports were examined through a framework separating case-control differences, symptom associations, functional outcomes, and prospective prediction. No new cross-disorder pooled effect was calculated. Large schizophrenia analyses reported reduced hippocampal volume and cortical thickness, whereas major-depression studies generally reported smaller structural effects. These major-depression findings were treated as contextual evidence rather than as treatment-resistant-depression estimates. Direct treatment-resistance reviews identified hippocampal and network alterations but showed substantial methodological variability; an exploratory coordinate-based meta-analysis produced limited modality-specific convergence. Functional connectivity and prefrontal treatment-target studies suggest clinically relevant circuits, yet response prediction differs from severity measurement. Medication exposure, illness duration, motion, clinical heterogeneity, and overlapping cohorts constrain interpretation. Hippocampal and prefrontal measures are therefore credible research candidates, but a reproducible group association does not establish a calibrated individual severity test. Clinical translation requires explicit target outcomes, longitudinal reliability, independent validation, comparison with clinical assessment, and demonstrated decision benefit.