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

Summary & key facts

This paper looked over existing studies that test ketamine and classic serotonergic psychedelics like psilocybin and LSD for depression. The authors found that both kinds of drugs can lift depression quickly and for a while after a short mind-changing episode. They suggest this might happen because both drugs trigger similar changes in a brain chemical system called glutamate, which helps brain cells talk and lets the brain rewire itself. But the link between the mind-changing experience and the mood benefit is not yet clear, and more careful research is needed.

Key facts:

• The article is a review, which means the authors summarized results from many studies about ketamine and classic serotonergic psychedelics.
• Both ketamine and these psychedelics have been reported to produce rapid and lasting antidepressant effects after a short period of drug-induced mind changes.
• The authors suggest a shared downstream mechanism tied to glutamate, a brain chemical that helps nerve cells communicate, which may drive quick increases in the brain's ability to change its connections (neuroplasticity).
• Both types of drugs appear to cause immediate changes in how different brain regions communicate, and those immediate changes may later settle into milder, longer-lasting improvements in brain network efficiency linked to feeling better.
• The paper highlights that although some pharmacological effects overlap, the direct connection between the subjective, mind-changing experience and the antidepressant benefit is still unclear.
• Because ketamine research came first and is well developed, its research methods could serve as a model to study and develop other rapid-acting antidepressant drugs.

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 LSD Psilocybin

Conditions & symptoms

Depression Sadness or low mood