Uncovering the Underlying Mechanisms of Ketamine as a Novel Antidepressant

Summary & key facts

This paper is a review that looks at ways ketamine might work as a fast-acting antidepressant. Ketamine has been shown to lift depressive symptoms quickly in people and in animals, but it can also cause dissociation and psychosis-like experiences that limit its use. The authors summarize ideas that ketamine changes how certain brain receptors talk to each other and may trigger growth and strengthening of brain connections, which could help restore brain circuits that are disrupted in depression. They say these are current hypotheses and that understanding them could help make safer, effective drugs in the future.

Key facts:

• Major depressive disorder is a serious condition that causes large personal and social costs, and researchers are looking for faster, better treatments.
• Ketamine is a drug that blocks a brain receptor called N-methyl-D-aspartate receptor, often shortened to NMDAR; blocking this receptor is linked to fast antidepressant effects.
• Studies in people and in animals have found that ketamine can reduce depressive symptoms quickly and with effects that last beyond the immediate dose.
• Ketamine can cause dissociation (a sense of being detached from yourself or reality) and psychosis-like experiences, and these side effects limit its use as a regular psychiatric treatment.
• One idea is that ketamine boosts signaling through another receptor type called AMPA by reducing the activity of inhibitory brain cells or by blocking spontaneous NMDAR activity; in plain terms, it may let certain nerve cells fire more stro
• Another idea is that ketamine activates biological pathways that help brain cells grow and form connections, involving proteins like brain-derived neurotrophic factor (BDNF) and a cell-growth regulator called mTOR; these help build and stre
• Together, the changes in receptor activity and the growth pathways might rebalance excitatory and inhibitory signals in the brain and restore networks that don’t work properly in depression.
• These explanations are current hypotheses, not proven facts, and the paper says that figuring out exactly how ketamine works at the cell and circuit level could lead to safer medicines that keep the fast antidepressant benefits without the

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.

Topics

Neuroscience and Neuropharmacology Research Treatment of Major Depression Tryptophan and brain disorders

Categories

Health Sciences Medicine Pharmacology

Tags

Antidepressant Biochemistry Biology Brain-derived neurotrophic factor Cognition Disinhibition Hippocampus Internal medicine Ketamine Major depressive disorder Medicine Neuroscience Neurotrophic factors NMDA receptor PI3K/AKT/mTOR pathway Psychology Psychotomimetic Receptor Signal transduction Synaptogenesis

Substances

Ketamine

Conditions & symptoms

Depression Lack of energy or motivation Sadness or low mood