Uncovering the Underlying Mechanisms of Ketamine as a Novel Antidepressant
Songbai Xu, Xiaoxiao Yao, Bingjin Li, R. Cui, Cuilin Zhu, Yao Wang, Wei Yang
Frontiers in Pharmacology July 7, 2022 DOI: 10.3389/fphar.2021.740996 via Semantic Scholar
Summary
Ketamine, a drug that blocks N-methyl-D-aspartate receptors, produces rapid and lasting antidepressant effects in people with major depressive disorder and in animal models, but its use is limited by side effects like dissociation and psychosis-like experiences. The drug may work by enhancing signaling through another receptor type, AMPA receptors, in brain cells, possibly by reducing inhibition or blocking spontaneous NMDAR activity. It also activates pathways linked to brain plasticity and synapse formation, such as BDNF/TrkB and mTOR signaling. These processes may help restore the balance of excitatory and inhibitory signals in brain circuits disrupted in depression. Understanding these mechanisms could guide development of safer, more effective treatments.
Study at a glance
| Characteristics | Review Peer reviewed |
|---|---|
| Keywords | Medicine |
| Citations | 50 |
| Key finding | Ketamine's antidepressant-like actions may involve potentiation of AMPA receptor transmission, activation of BDNF/TrkB and mTOR pathways, and restoration of excitatory/inhibitory balance in neural circuits. |
Abstract
Major depressive disorder (MDD) is a devastating psychiatric disorder which exacts enormous personal and social-economic burdens. Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, has been discovered to exert rapid and sustained antidepressant-like actions on MDD patients and animal models. However, the dissociation and psychotomimetic propensities of ketamine have limited its use for psychiatric indications. Here, we review recently proposed mechanistic hypotheses regarding how ketamine exerts antidepressant-like actions. Ketamine may potentiate α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR)-mediated transmission in pyramidal neurons by disinhibition and/or blockade of spontaneous NMDAR-mediated neurotransmission. Ketamine may also activate neuroplasticity- and synaptogenesis-relevant signaling pathways, which may converge on key components like brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) and mechanistic target of rapamycin (mTOR). These processes may subsequently rebalance the excitatory/inhibitory transmission and restore neural network integrity that is compromised in depression. Understanding the mechanisms underpinning ketamine’s antidepressant-like actions at cellular and neural circuit level will drive the development of safe and effective pharmacological interventions for the treatment of MDD.