Ketamine and Serotonergic Psychedelics: Common Mechanisms Underlying the Effects of Rapid-Acting Antidepressants

Summary & key facts

This review looked at studies of ketamine and classic serotonergic psychedelics, like psilocybin, to see what they might have in common as fast-acting antidepressants. The authors found evidence that both kinds of drugs can lift mood quickly and keep helping after the intense drug effects fade. The review suggests they may work in similar ways by changing how the glutamate brain system drives quick, short-term reorganization of brain circuits. But the link between the unusual mental experiences people have on these drugs and the mood improvements is not proven, and the authors say more careful studies are needed.

Key facts:

• Ketamine has become a model for studying new fast-acting antidepressant drugs.
• Recent studies suggest classic serotonergic psychedelics, such as psilocybin, may also reduce depressive symptoms quickly and for a lasting time after the brief psychoactive effects pass.
• The review finds overlapping evidence from cells, brain recordings, and brain scans that both ketamine and serotonergic psychedelics may trigger rapid increases in neuroplasticity, which means the brain's ability to rewire or change.
• Both types of drugs seem to work through the glutamate system, a chemical network in the brain that helps neurons communicate and can drive changes in brain circuits.
• Both ketamine and serotonergic psychedelics produce short-term changes in how the cortex, the brain's outer layer, communicates; those acute changes may lead to milder, longer-lasting improvements in how brain networks work.
• The connection between the subjective psychoactive experience (the hallucinations or altered consciousness people feel) and the antidepressant benefit is unclear and needs more rigorous research.
• Because ketamine research has been a prototype, the authors suggest using this research platform to explore entirely new classes of rapid antidepressants.

Abstract

BACKGROUND: The glutamatergic modulator ketamine has created a blueprint for studying novel pharmaceuticals in the field. Recent studies suggest that "classic" serotonergic psychedelics (SPs) may also have antidepressant efficacy. Both ketamine and SPs appear to produce rapid, sustained antidepressant effects after a transient psychoactive period. METHODS: This review summarizes areas of overlap between SP and ketamine research and considers the possibility of a common, downstream mechanism of action. The therapeutic relevance of the psychoactive state, overlapping cellular and molecular effects, and overlapping electrophysiological and neuroimaging observations are all reviewed. RESULTS: Taken together, the evidence suggests a potentially shared mechanism wherein both ketamine and SPs may engender rapid neuroplastic effects in a glutamatergic activity-dependent manner. It is postulated that, though distinct, both ketamine and SPs appear to produce acute alterations in cortical network activity that may initially produce psychoactive effects and later produce milder, sustained changes in network efficiency associated with therapeutic response. However, despite some commonalities between the psychoactive component of these pharmacologically distinct therapies-such as engagement of the downstream glutamatergic pathway-the connection between psychoactive impact and antidepressant efficacy remains unclear and requires more rigorous research. CONCLUSIONS: Rapid-acting antidepressants currently under investigation may share some downstream pharmacological effects, suggesting that their antidepressant effects may come about via related mechanisms. Given the prototypic nature of ketamine research and recent progress in this area, this platform could be used to investigate entirely new classes of antidepressants with rapid and robust actions.

Topics

Neurotransmitter Receptor Influence on Behavior Psychedelics and Drug Studies Treatment of Major Depression

Categories

Clinical Psychology Psychology Social Sciences

Tags

Internal medicine Ketamine Medicine Neuroscience Psychiatry Psychology Receptor Serotonergic Serotonin

Substances

Ketamine

Conditions & symptoms

Depression Sadness or low mood