SYNERGISTIC POTENTIAL OF ACCELERATED NEUROMODULATION AND KETAMINE IN A SUPER-RESISTANT RAT MODEL OF DEPRESSION

Treatment-resistant depression (TRD) remains a major clinical challenge, with a substantial proportion of patients failing to respond to first-line antidepressants. Although neuromodulation (accelerated rTMS) and glutamatergic agents (ketamine/esketamine) have broadened therapeutic options, non-response still occurs, pointing to a super-resistant phenotype. This condition is poorly characterized, warranting dedicated preclinical models. We evaluated the effects of combined a-rTMS and ketamine in a super-resistant rat model of depression to assess potential synergy on depressive-/anxiety-like behaviors. Wistar–Kyoto rats (endogenous depression model) were first screened for ketamine response (15mg/kg) using the novelty-suppressed feeding test (NSFT) administered 24h later. After a 2-week washout, ketamine non-responders underwent a 2-day a-rTMS protocol (10Hz; 1600 pulses/session; 4 sessions/day; 55-min intersession-interval) and were re-assessed with the NSFT to identify a-rTMS non-responders. Animals resistant to both interventions were classified as super-resistant and allocated to combined a-rTMS+ketamine or sham a-rTMS+vehicle. Co-administration of a-rTMS+ketamine (vs. sham a-rTMS+ vehicle), reduced apathy-like state in the splash test, normalized heightened anxiety/reduced motivation, showing significant effects in the NSFT and a trend in the novelty-seeking test, promoted recovery from anhedonia in the female urine sniffing test, normalized altered emotionality in the dark–light test, partially improved active coping-related behavior in the forced-swim test, and produced mixed effects on social behavior. This study provides preliminary evidence that combining a-rTMS with ketamine may yield augmentative benefits across multiple behavioral domains in a super-resistant depression model. These findings support further work to optimize integrated protocols and to assess underlying mechanisms, with the long-term goal of informing clinical strategies.