Compensatory neurochemical adaptation in first-episode, drug-naïve depression: Integrating cortical and systemic metabolism using multivoxel 1H-MRS.

Background

Major depressive disorder (MDD) involves both central neurotransmission and systemic metabolic disturbances. This study investigated how body mass index (BMI) modulates prefrontal neurometabolic profiles and their relationship with depressive severity in depression.

Methods

66 first-episode, drug-naïve Han Chinese patients with MDD and 79 Han Chinese healthy controls were recruited. Using multi-voxel proton magnetic resonance spectroscopy, we quantified tissue-corrected metabolite-to-creatine ratios in the anterior cingulate cortex (ACC) and bilateral dorsolateral prefrontal cortex (DLPFC). Serum lipid profiles and 17-item Hamilton Depression Rating Scale (HAMD) scores were collected. Patients were stratified into low-BMI and normal-BMI subgroups.

Results

Within the MDD cohort, the low-BMI subgroup showed lower HAMD-17 scores, triglyceride levels, and LDL-C levels and higher HDL-C levels than the normal-BMI subgroup. Nominally higher ACC GABA/Cr and DLPFC NAA/Cr ratios were observed in the low-BMI subgroup, although these differences did not survive FDR correction. In the additional comparison with low-BMI healthy controls, no neurometabolite difference survived false discovery rate correction. BMI subgroup significantly moderated the association between DLPFC Glu/Cr and HAMD-17 scores: the association was positive in the normal-BMI subgroup but negative in the low-BMI subgroup.

Conclusions

These findings suggest a possible compensatory neurochemical pattern associated with low BMI in depression. However, the cross-sectional design cannot determine whether this pattern reflects compensatory adaptation or a pre-existing neurobiological subtype, and low BMI alone should not be interpreted as evidence of metabolic stress. TRIAL REGISTRATION Chinese Clinical Trial Registry; URL: https://www.chictr.org.cn/; Registration number: ChiCTR2500109138.