How do serotonergic psychedelics treat depression: The potential role of neuroplasticity

Abstract

Depression is a common mental disorder and one of the leading causes of disability around the world. Monoaminergic antidepressants often take weeks to months to work and are not effective for all patients. This has led to a search for a better understanding of the pathogenesis of depression as well as to the development of novel antidepressants. One such novel antidepressant is ketamine, which has demonstrated both clinically promising results and contributed to new explanatory models of depression, including the potential role of neuroplasticity in depression. Early clinical trials are now showing promising results of serotonergic psychedelics for depression; however, their mechanism of action remains poorly understood. This paper seeks to review the effect of depression, classic antidepressants, ketamine, and serotonergic psychedelics on markers of neuroplasticity at a cellular, molecular, electrophysiological, functional, structural, and psychological level to explore the potential role that neuroplasticity plays in the treatment response of serotonergic psychedelics.

Keywords: Antidepressants; Depression; Hallucinogens; Ketamine; Neuroplasticity; Psychedelics; Serotonergic psychedelics.

Figure 1

Psychedelic effects on markers of neuroplasticity. At the molecular level serotonergic psychedelics have been associated with increases in brain derived neurotrophic factor protein; at the cellular level serotonergic psychedelics have been associated with increases in neuritogenesis, spinogenesis, and synaptogenesis; at the electrophysiological level serotonergic psychedelics have been shown to lead to cortical desynchronization acutely, less is known about the long term electrophysiological changes although; at the level of functional connectivity serotonergic psychedelics lead to a decrease in default mode network (DMN) integrity acutely but longer-term they may lead to a normalization of DMN integrity; less data exists about volumetric changes with serotonergic psychedelics although in rodents hippocampal neurogenesis has been observed and in long term ayahuasca users decreased thickness of the posterior cingulate cortex has been observed; at a psychological level serotonergic psychedelics have been associated with changes in emotional processing specifically: decreased negative affect, increased positive affect, and an increased sense of connection to the self, others, and the world. BDNF: Brain derived neurotrophic factor; DMN: Default mode network; PCC: Posterior cingulate cortex.