Recent studies demonstrate that a single dose of ketamine, a glutamate NMDA receptor antagonist, produces rapid antidepressant actions in treatment-resistant patients, one of the most significant advances in the field of depression in recent years. Preclinical studies demonstrate that the rapid antidepressant actions of ketamine are mediated by the induction of synaptic proteins and increased number and function of new spine synapses in the prefrontal cortex (PFC; Duman and Aghajanian, 2012). In addition, the behavioral and synaptogenic effects of ketamine require brain-derived neurotrophic factor (BDNF) and stimulation of the mechanistic target of rapamycin complex 1 (mTORC1), which is involved in protein synthesis-dependent synaptic plasticity. Surprisingly, we have also found that scopolamine, a muscarinic receptor antagonist that produces rapid antidepressant effects, also increases mTORC1 and induces synaptogenesis in the PFC (Voleti et al, 2013).

Although ketamine is an NMDA receptor antagonist, it paradoxically increases glutamate transmission in the PFC. This is thought to occur via blockade of tonic firing GABAergic interneurons, resulting in disinhibition of glutamate release. The resulting ‘burst of glutamate’ contributes to activity-dependent release of BDNF and increased synaptogenesis (Duman and Aghajanian, 2012). A functional BDNF polymorphism, Val66Met, has provided an approach to examine the role of BDNF in depressed patients, as well as rodent models. We have found that the rapid actions of ketamine are blocked in mice with a knockin of the Met allele, which prevents the processing and release of BDNF (Liu et al, 2012). Moreover, depressed patients who are carriers of the Met allele show a significantly decreased response to ketamine, indicating that the Met allele is a marker of nonresponders (Laje et al, 2012).

Log in or create a free account to read this content

Gain free access to this article, as well as selected content from this journal and more on nature.com

Access through your institution

or

Sign in or create an account
Continue with Google
Continue with ORCiD