Is the antidepressant effect of ketamine separate from its psychotomimetic effect? A review of rodent models.

Ketamine, an NMDA glutamate receptor antagonist, has dose-dependent effects including anesthesia, sedation, and analgesia. At subanesthetic doses, it uniquely both mimics schizophrenia symptoms and serves as the first fast-acting antidepressant. This overview describes ketamine's dual role as an antidepressant and as a pharmacological model of schizophrenia in animals and humans. Its mechanism involves NMDA receptors, triggering immediate and downstream effects. The authors discuss a unified approach linking the glutamatergic hypothesis of schizophrenia to ketamine's success in treating refractory depression.

Study at a glance

Abstract

Ketamine is an NMDA (N-methyl-d-aspartate) glutamate receptor antagonist, which has a myriad of dose-dependent pharmacological and behavioral effects, including anesthetic, sedative, amnestic, analgesic, and anti-inflammatory properties. Intriguingly, ketamine at subanesthetic doses displays a relevant profile both in mimicking symptoms of schizophrenia and also as the first fast-acting treatment for depression. Here, we present an overview of the state-of-the-art knowledge about ketamine as an antidepressant as well as a pharmacological model of schizophrenia in animal models and human participants. Ketamine's dual effect appears to arise from its mechanism of action involving NMDA receptors, with both immediate and downstream consequences being triggered as a result. Finally, we discuss the feasibility of a unified approach linking the glutamatergic hypothesis of schizophrenia to the promising preclinical and clinical success of ketamine in the treatment of refractory depression.