BACKGROUND: Psychedelics are emerging as promising treatments for major depressive disorder (MDD) and treatment-resistant depression (TRD). Functional magnetic resonance imaging (fMRI) offers a powerful tool to study neural mechanisms underlying therapeutic response.
METHODS: This systematic review (PROSPERO #CRD42024557973) examined neuroimaging studies of psilocybin in MDD and TRD, with a focus on the temporal evolution of neuroimaging changes post-treatment. A secondary aim was to correlate imaging findings with validated clinical outcomes to assess their relevance in predicting treatment response.
RESULTS: Eleven eligible studies were included, using diverse fMRI modalities such as resting-state functional connectivity, task-based BOLD imaging, amplitude of low-frequency fluctuations (ALFF), dynamic functional connectivity, and magnetic resonance spectroscopy. Early (0-4 weeks) post-treatment changes included reduced network modularity and increased global brain integration, alongside modulation of affective circuits involving the amygdala, default mode network, and prefrontal regions. These changes were significantly associated with reductions in BDI, QIDS, and SHAPS scores, reflecting improvements in mood and anhedonia. Longer-term changes (5+ weeks) involved sustained reorganization of large-scale networks, particularly increased connectivity between the prefrontal and parietal cortices and salience network.
CONCLUSIONS: Although these findings suggest psilocybin is associated with dynamic and temporally distinct neuroplastic changes linked to clinical improvement, several limitations must be acknowledged. Many studies reused overlapping datasets with high exploratory flexibility and risk of bias. The generalizability of results is therefore constrained. Future research should emphasize independent datasets, pre-registered imaging endpoints, and longitudinal designs to clarify the mechanisms underlying psychedelic therapy for depression.
