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bioRxiv · 10.64898/2026.04.27.721016

Do Symptom Domains Have Similar Cellular Underpinnings Across Psychiatric Diagnoses: Evidence from 3D Hippocampal MR Spectroscopy

Ruby, E.·Gonen, O.·Lotan, E.·Tal, A.·Rusinek, H.·Clemente, J. C.·Robinson-Papp, J.·Karlsgodt, K. H.·Malaspina, D.
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Abstract

Introduction: The NIMH Research Domain Criteria (RDoC) posits similar cellular pathologies for particular symptom domains across diagnostic categories. Conversely, knowledge that these differ could advance treatment discovery, especially for affective and non-affective psychoses, as studies usually intermix them. Methods: We tested this by comparing metabolite biomarker concentrations for cellular pathologies from whole hippocampal proton magnetic spectroscopic imaging (1H MRSI) with symptoms from the original and five factor PANSS, and the Hamilton Depression and Young Mania Scales. Participants were 26 healthy controls; 22 non-psychotic affective cases (NP-aff); and 33 with psychosis (including 20 schizophrenia (Scz) and 13 affective psychosis (aff-P) cases). Results: PANSS activation factor was related to reductions in all cellular component biomarkers in Scz, including glia, membrane turnover, neural integrity, glutaminergic neurotransmission, and energy metabolism (p's<.05), but only to energy metabolism in NP-aff (p=.03). Biomarkers for mood symptoms also varied across categories, suggesting gliosis for mania and depression in HC (p's[&le;].025), but increased membrane turnover for mania in aff-P (p=.015), and decreased neural integrity and energy metabolism for depression in Scz (p's<.05). In contrast, negative symptoms and autistic preoccupation were related to reduced glia in both NP-aff and aff-P (p's<.05). Autistic preoccupation in Scz was related to both reduced glia and membrane turnover (p's<.05). Only Scz showed a significant finding for positive symptoms, specifically reduced membrane turnover (p=.018). Discussion: These results suggest both distinct and similar cellular pathologies for symptoms across diagnoses, including affective and non-affective psychoses. The differences support categorizing disorders and stratifying different psychoses in research rather than transdiagnostic approaches.

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Ruby, E., Gonen, O., Lotan, E., Tal, A., Rusinek, H., Clemente, J. C., Robinson-Papp, J., Karlsgodt, K. H., Malaspina, D.. 2026-04-29. Do Symptom Domains Have Similar Cellular Underpinnings Across Psychiatric Diagnoses: Evidence from 3D Hippocampal MR Spectroscopy. https://doi.org/10.64898/2026.04.27.721016

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