Early life stress and glutamate neurotransmission in major depressive disorder

Early life stress (ELS) and glutamate neurotransmission have been implicated in the pathophysiology of major depressive disorder (MDD). In non-human primates, ELS was positively correlated with cortical Glx (i.e., glutamate + glutamine). However, the relationship between ELS and cortical glutamate in adult patients with MDD is not fully known. Using ¹H Magnetic Resonance Spectroscopy (MRS), we conducted exploratory analyses measuring occipital cortical glutamate and glutamine levels in 36 medication-free patients with MDD. In a subsample (n=11), we measured dynamic glutamate/glutamine cycling (V_cycle) using advanced ¹³C MRS methods. ELS history was assessed using Early-life Trauma Inventory (ETI). Exploratory analyses suggest a relationship between ETI and glutamine as reflected by a significant positive correlation between ETI scores and occipital glutamine (r_s=0.39, p=0.017) but not glutamate. Post-hoc analyses showed that the association with glutamine was driven by the ETI emotional abuse (ETI-EA) subscale (r_s=0.39, p=0.02). V_cycle correlation with ETI was at trend level (r_s=0.55, p=0.087) and significantly correlated with ETI-EA (r_s=0.67, p=0.03). In this small sample of patients with MDD, those with childhood emotional abuse appear to have increased occipital glutamate neurotransmission as reflected by increased glutamate/glutamine cycling and glutamine level. Future studies would be needed to confirm this pilot evidence and to examine whether ELS effects on glutamate neurotransmission underlie the relationship between ELS and psychopathology.