Ketamine Sustains and Enhances the Protective Effects of a Ketogenic Diet Against Relapses in an Anorexia Mouse Model

Anorexia nervosa (AN) has high mortality and relapse rates, yet no accepted pharmacotherapies. Reports based on six individuals suggest that ketogenic diet (KGD) combined with sub-anesthetic ketamine (KET) is an effective treatment. The animal model, Activity-Based Anorexia (ABA), captures AN's maladaptive behaviors of voluntary food restriction, excessive exercise, severe weight loss, heightened anxiety and relapse vulnerability. Using ABA, we tested whether (1) KGD, alone, can protect against relapses after a severe anorexia-like experience; (2) KGD must be maintained to prevent relapses; (3) sub-anesthetic KET combined with KGD is more ameliorative than KGD alone. We also (4) explored KGD's mechanism for protecting against relapses by electron microscopic (EM) analysis of synapses in the hippocampus. To simulate AN relapses, we imposed ABA induction twice (ABA1, ABA2), with 10 recovery days in between. Animals were fed a standard diet (SD, pellet plus wet food) during ABA1 and KGD during ABA2 (SD ➔ KGD). ABA vulnerability, measured by food restriction-evoked hyperactivity and weight loss, was severe during ABA1 but significantly less during ABA2, compared to those fed SD throughout ABA1 and ABA2 (SD ➔ SD). KGD withdrawal after ABA1 (KGD ➔ SD) caused vulnerability during ABA2 to become as severe as for the SD ➔ SD, indicating that KGD must be maintained to be protective. We tested whether KET plus KGD during ABA1 can protect against ABA2 relapse in the absence of KGD or KET (KGD + KET ➔ SD). During ABA2, KGD + KET ➔ SD exhibited low maladaptive behaviors, similarly to those maintained on KGD throughout ABA1 and ABA2 (KGD ➔KGD), with greater weight during recovery. Thus, KET sustains and boosts KGD's benefits for > 10 days, supporting clinical findings that short-term KGD + KET may be an effective treatment for preventing AN relapses. EM revealed that KGD increases GABAergic synapse lengths and may reduce ABA vulnerability by increasing excitatory synaptic drive of GABAergic interneurons and increasing E-to-E synapses' role in body weight regulation.