5-HT2A mediated plasticity as a target in major depression: a narrative review connecting the dots from neurobiology to cognition and psychology

TL;DR

This review explores how 5-HT2A receptor-mediated plasticity, involving BDNF and mTOR pathways, could be key to understanding and improving antidepressant therapies, especially psychedelics and ketamine.

Contribution

It connects neurobiological mechanisms of psychedelics and NMDA antagonists to cognitive and psychological effects, proposing new targets for antidepressant development.

Findings

BDNF overexpression mediates plasticity and connectivity changes

mTOR activation links to structural and functional brain plasticity

Enhanced psychological flexibility may result from these neurobiological processes

Abstract

As the world's first primary morbidity factor, depression has a considerable impact on both an individual as well as a societal level. despite their discovery several decades ago, classical antidepressants have been shown to provide limited benefits against this condition. However, substances such as ketamine and psychedelics have recently shown promising results and even received the grade of Breakthrough therapy for this indication. The accurate mechanisms of action underlying the efficacy of these substances are still to be defined, but some similarities appear to be shared on different levels across these substances. These include their structural, functional and behavioral plasticity promoting abilities, as well as their capacity to promote Brain-Derived Neurotrophic Factor overexpression, which seems to constitute a key element underlying their immediate and long-lasting action. From this observation, the present review aims to examine and connect the pharmacological pathways involved in these therapies to the neurobiological, cognitive and psychological responses that could be shared by both 5-HT2AR agonists and NMDA antagonists. It is suggested that BDNF overexpression resulting from mTOR activation mediates both structural and functional plasticity, resulting in connectivity changes among high-level cognitive networks such as the Default Mode Network, finally leading to an increased and long-lasting psychological flexibility. Connecting these pieces of evidence could provide insights about their precise mechanisms of action and help researchers to develop biomarkers for antidepressant response. If the hypotheses suggested in this review are verified by further trials, they could also constitute a starting point to developing safer and more efficient antidepressants, as well as provide information about the interactions that exist between different neurotransmitters systems.