Early trauma is linked to stronger glutamatergic synaptic strength in people with PTSD, measured via a novel in vivo marker called energy per cycle (EPC). In a sample of 34 adults (16 with PTSD, 18 healthy controls), higher early trauma correlated with higher EPC only in the PTSD group. Greater synaptic strength was associated with reduced behavioral inhibition, and EPC mediated stronger links between reward responsiveness and early trauma. These findings suggest that trauma-induced changes in synaptic plasticity may underlie psychiatric risk and point to potential targets for treatments like ketamine and psilocybin.
Ketamine's discovery as a rapid antidepressant has transformed drug development and understanding of chronic stress pathology. This review covers the history of NMDA receptor modulators leading to ketamine's psychiatric use, its rapid antidepressant and antisuicidal effects, a model of synaptic loss and dysconnectivity underlying chronic stress pathology, clinically relevant biomarkers and mechanisms, and how ketamine may both reverse chronic stress pathology and serve as a research tool. The authors discuss outstanding questions and the ongoing debate between optimism and concern about ketamine's widespread use.
A robust and reproducible brain connectivity fingerprint (CFP) was identified during ketamine infusion in healthy participants, characterized by reduced connectivity within primary cortices and the executive network, but increased connectivity between the executive network and the rest of the brain. This same CFP measured one week after treatment in major depressive disorder patients predicted response to eight weeks of sertraline, but not placebo. The findings suggest a brain network biomarker that links ketamine's acute effects to the mechanisms of conventional antidepressants.