Reduced Energy Per Cycle, a Marker of Glutamatergic Synaptic Strength, in Individuals Diagnosed with PTSD and Depression

Trauma and chronic stress are believed to induce and exacerbate psychopathology by disrupting glutamate synaptic connectivity. In this pilot study, we utilized energy-per-cycle (EPC), a novel putative biomarker of glutamatergic synaptic strength, to investigate the role of prefrontal neurotransmission in trauma psychopathology. Healthy control (n=18) and patients with comorbid posttraumatic stress and major depressive disorders (PTSD+MDD; n=16) completed 13C-acetate magnetic resonance spectroscopy scans to estimate prefrontal EPC, which is the ratio of neuronal energetic needs per glutamate neurotransmission cycle (VTCA/VCycle). Patients with PTSD+MDD were found to have 28% reduction in prefrontal EPC (t=3.0; df=32, p=0.005). There was no effect of sex on EPC, but age was negatively associated with prefrontal EPC across groups (r=-0.46, n=34, p=0.006). Controlling for age did not affect the study results. Exploratory analyses found antidepressants to have statistically significant effects (F(2,30)=5.3, p=0.01), with the lowest EPC in the unmedicated PTSD+MDD participants (p=0.003). Patients with comorbid PTSD and MDD have reduced prefrontal glutamatergic synaptic strength, as estimated by EPC. Antidepressant treatment appears to partially normalize the prefrontal EPC deficits. These findings suggest that reduced glutamatergic synaptic strength may contribute to the pathophysiology of comorbid PTSD and MDD and might be targeted by novel treatments.