Total N-acetylaspartate: A potential early biomarker of depression?

Depressive disorders are characterized by heterogeneous symptoms and variable treatment response. Current interventions primarily aim to manage symptoms, yet their effectiveness remains limited. This highlights the need for early neurobiological markers to improve understanding of depression pathophysiology and guide treatment development. In this study, 38 healthy participants aged 18-40 years (21 females and 17 males) completed the self-report version of the Montgomery-Åsberg Depression Rating Scale (MADRS-S), followed by proton magnetic resonance spectroscopy (¹H-MRS) data acquisition from the anterior cingulate cortex (ACC). Spectra were acquired from the dorsal (dACC) and pregenual (pgACC) subdivisions, and analyses focused on metabolite levels of γ-aminobutyric acid (GABA), glutamate + glutamine (Glx), total N-acetyl aspartate (tNAA), and total creatine (tCr). Simple and multiple linear regression analyses, controlling for age, sex, tobacco use, and alcohol consumption, revealed a negative association between depressive symptom scores and tNAA/tCr levels in both the pgACC and dACC. However, no significant associations were observed for GABA/tCr or Glx/tCr. These findings suggest that reduced tNAA/tCr levels in the dACC and pgACC may be associated with depressive symptom severity in non-clinical individuals. Given that tNAA reflects neuronal integrity and mitochondrial function, its reduction may reflect early neuronal and metabolic variation associated with depressive symptom scores. Thus, tNAA may represent an in vivo biomarker for early affective vulnerability, potentially enabling detection of depressive symptom scores in healthy individuals.