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

Depression is the world's leading cause of disability, yet classical antidepressants offer limited relief. Ketamine and psychedelics have shown promise and received Breakthrough Therapy designation. Their precise mechanisms remain unclear, but shared features include promoting structural, functional, and behavioral plasticity and increasing Brain-Derived Neurotrophic Factor (BDNF) via mTOR activation. This review connects pharmacological pathways of 5-HT2AR agonists and NMDA antagonists to neurobiological and psychological responses. It suggests that BDNF-driven plasticity alters connectivity in high-level cognitive networks like the Default Mode Network, fostering lasting psychological flexibility. Verifying these hypotheses could guide development of safer antidepressants and biomarkers for treatment response.

Study at a glance

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.