The effects of ketamine and classic hallucinogens on neurotrophic and inflammatory markers in unipolar treatment-resistant depression: a systematic review of clinical trials

Introduction

Major depressive disorder (MDD) is a leading cause of disability worldwide and current first-line treatments such as selective serotonin reuptake inhibitors are limited by delayed onset and incomplete response, leaving a substantial proportion of patients with treatment-resistant depression (TRD). Rossi and colleagues frame an urgent need for faster-acting antidepressants and note that both classical hallucinogens (psychedelics such as LSD, psilocybin and DMT/ayahuasca) and ketamine have shown preliminary rapid antidepressant effects, with different putative pharmacological mechanisms (5-HT2A agonism for classical hallucinogens; NMDA receptor antagonism and downstream glutamatergic signalling for ketamine). The introduction also summarises biological hypotheses linking depression to altered neuroinflammatory and neurotrophic signalling, naming markers such as proinflammatory cytokines (IL-1β, IL-6, TNF-α) and neurotrophic factors (BDNF, VEGF, FGF-2, NGF) that have been proposed as mechanistic mediators or potential biomarkers. This systematic review set out to gather and synthesise clinical-trial evidence examining whether ketamine and classical hallucinogens, when administered to adult patients with unipolar TRD, produce reliable changes in peripheral neurotrophic or inflammatory biomarkers and whether such changes relate to antidepressant response. The authors aimed to evaluate trial designs, measured biomarkers, and the consistency of reported effects, with a view to determining whether peripheral biomarkers can currently serve as indicators or outcome measures for these rapid-acting treatments.