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

Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortexin vivo

“…Of note, the timing of psilocybin's effect on the neural architecture is reminiscent of ketamine, which at subanesthetic dose causes similar rapid increase in spine density and elevation of spine formation rate in the medial frontal cortex (Moda-Sava et al, 2019;Phoumthipphavong et al, 2016). However, still unknown is how drugs with disparate molecular targets may yield comparable modifications on neural architecture and behavior (Kadriu et al, 2021;Savalia et al, 2021). Elucidating the mechanisms will be crucial towards unraveling the neurobiology of rapid-acting antidepressants.…”

Inflammatory signaling mechanisms in bipolar disorder

“…Emerging evidence with other rapid-acting antidepressants may provide further support for this hypothesis. Specifically, serotonergic hallucinogens (SH) appear to provide potent antidepressant responses starting the first day after treatment, even in refractory populations, though broader clinical validation is needed [ 185 ]. Currently, a phase I trial using psilocybin in bipolar II depression is underway at the University of Maryland in The United States [ 188 ].…”

“…Both compounds also appear to exert part of their antidepressant activity via serotonin signaling [ 189 ].Similar patterns of downstream neuroplastic growth factor upregulation (particularly BDNF) have been reported, though SHs appear far more potent in that regard. With a few exceptions, in human studies, increasing levels of BDNF appear to correlate with acute antidepressant effects for both ketamine and SHs as well [ 185 ].…”

“…Unlike the short-lived effects of ketamine however, SHs have been reported to induce responses which last six months or more after just one to two sessions [ 185 ]. While superior growth factor stimulation may contribute to this phenomenon, repeated acute-phase administration of ketamine still confers relapse in the vast majority of patients within the first month following their final infusion [ 190 ].…”

“…In contrast to ketamine, SHs as a class exhibit potent anti-inflammatory effects across a myriad of disease models and cell lines [ 191 – 194 ]. The most studied SH with regards to inflammation, 2,5-dimethoxy-4-iodoamphetamine (DOI), has been shown to profoundly suppresses TNF-α mediated inflammation in rodent tissues at picomolar concentrations—equating to a dose in humans at least two orders of magnitude below what is necessary to produce hallucinogenic effects [ 185 , 193 , 194 ]. With the exception of a few natural toxins (i.e.…”