Synaptic plasticity mechanisms of psychoplastogens in major depressive disorder: a systematic review of clinical studies

Introduction and aims

Major depressive disorder remains a leading cause of disability, and conventional monoaminergic antidepressants are limited by delayed onset and high non-response rates. Psychoplastogens are small molecules that rapidly induce structural and functional neural plasticity, and have emerged as fast-acting antidepressant candidates acting through synaptic remodelling [1]. Psychoplastogens are known to impact BDNF/TrkB signaling, but in contrast to traditional antidepressants, they do so rapidly after a single administration.This systematic review aimed to map the synaptic plasticity biomarkers reported in clinical studies of psychoplastogens in adult depression, and to identify which markers are shared across compounds and which remain compound-specific.

Methods

The review followed PRISMA 2020 guidance [2]. PubMed and Web of Science were searched using a Boolean string combining psychoplastogen compounds (including psilocybin, psilocin, LSD, DMT, 5-MeO-DMT, ibogaine, tabernanthalog, ketamine, esketamine) with plasticity-related terms (plasticity, synaptic, dendritic, BDNF, TrkB, mTOR, AMPA, NMDA, synaptogenesis, spinogenesis) and depression/antidepressant. Filters were applied for the last 10 years and English language. In PubMed, results were further restricted to the following design: Adaptive Clinical Trial, Clinical Trial, Clinical Trial Phase I, Clinical Trial Phase II, Clinical Trial Phase III, Clinical Trial Phase IV, Controlled Clinical Trial, and Pragmatic Clinical Trial. The search returned 2,145 PubMed and 1,423 Web of Science records, reduced after filters to 83 and 761 respectively. After removal of 51 duplicates, 793 unique records were screened in Rayyan against pre-specified inclusion criteria (clinical studies in humans assessing plasticity biomarkers) and exclusion criteria (reviews, exclusively behavioural studies, reports without objective measures). From included studies, extracted data included: compound, primary target, plasticity markers, design, sample, temporal window and statistical outcomes (p-values as reported).

Results

Of the 45 included studies, 31 were randomised controlled trials, conducted predominantly in the USA (n=16) and China (n=13). Ketamine accounted for 32 studies, esketamine for 7, psilocybin for 2, and one each for dextromethorphan, scopolamine, D-cycloserine and lanicemine. Only eight plasticity readouts were shared by at least two compounds: NMDA-related signalling), BDNF, dopamine, functional connectivity, IL-6, EEG theta, S100β and EEG gamma/HFO. Findings were most consistent for ketamine: enhanced visual long-term potentiation (p<0.05), increased glutamate–glutamine cycling in the pregenual anterior cingulate cortex at 24 h (p=0.001 and p=0.02 in two trials), normalisation of subgenual cingulate connectivity (p<0.01), and elevated phospho-mTOR and phospho-GSK3β (p=0.042). Peripheral BDNF responses were inconsistent: significant increases occurred with perioperative esketamine (two RCTs, p<0.05) and with psilocybin (p<0.001, persisting under escitalopram pre-treatment, p=0.002), whereas three ketamine trials reported no acute change in serum or plasma BDNF (p=0.587; p=0.756; p=0.295).

Conclusions

Across psychoplastogens, only NMDA-related and BDNF readouts emerge as broadly shared plasticity markers. Peripheral BDNF appears unreliable as a dynamic biomarker; while central readouts, cortical LTP, glutamate cycling, mTOR signalling and functional connectivity, track clinical response more consistently. The psychoplastogen framework remains only partially tested in humans, with mechanistic support concentrated almost exclusively in ketamine; for other compounds the evidence is insufficient to confirm or refute mechanistic convergence.

References

Olson DE. Psychoplastogens: A Promising Class of Plasticity-Promoting Neurotherapeutics. Journal of Experimental Neuroscience. 2018;12:1179069518800508. doi:10.1177/1179069518800508
Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. doi:10.1136/bmj.n71