Treatment-resistant depression (TRD) is a depressive disorder in which standard treatments have failed, and it is being studied both as a clinical target for psilocybin assisted psychotherapy and as a source of patient-derived iPSC models. In a translational study, neurons from individuals with TRD were compared with healthy volunteers to test rapid-acting antidepressants, including doi, hydroxynorketamine, lsd, and psilocybin, highlighting time-dependent effects in iPSC-derived neurons. TRD has also been evaluated in a clinical context using psilocybin assisted psychotherapy for anhedonia, with overall depression severity measured by the montgomery asberg depression rating scale (MADRS). Key mechanistic interest centers on rapid-acting antidepressant responses rather than conventional delayed-onset antidepressant pathways, with ketamine-treated healthy volunteers used as a translational CSF proteomics comparator. Recent literature includes a 2026 Journal of Affective Disorders study (PMID:41690631) and a 2026 Research Square preprint (PMID:41743330), both emphasizing rapid-acting interventions in TRD.
Clinical intervention
- psilocybin assisted psychotherapy was evaluated in participants with TRD, with effects on anhedonia reported in a 2026 Journal of Affective Disorders study. (PMID:41690631)
- Overall depression severity in the exploratory mediation analysis was measured with the montgomery asberg depression rating scale (MADRS). (PMID:41690631)
- The study focused on TRD as the target population for psilocybin-assisted psychotherapy. (PMID:41690631)
Patient-derived neuronal modeling
- TRD was used as a patient source for iPSC-derived neurons to model responses to rapid-acting antidepressants. (PMID:41743330)
- Neurons from individuals with TRD were compared with healthy volunteers, enabling direct disease-versus-control assessment. (PMID:41743330)
- doi was investigated as a rapid-acting antidepressant in neurons derived from individuals with TRD. (PMID:41743330)
- hydroxynorketamine was investigated in the same iPSC-derived neuronal system, supporting time-dependent pharmacologic profiling. (PMID:41743330)
- lsd and psilocybin were also tested as rapid-acting antidepressants in TRD-derived neurons. (PMID:41743330)
Translational pharmacology
- ketamine-treated healthy volunteers were used for CSF proteomics comparison in translational validation, linking cellular findings to human exposure. (PMID:41743330)
- The work emphasized rapid-acting antidepressant mechanisms in TRD rather than conventional antidepressant latency. (PMID:41743330)
- The 2026 Research Square study specifically framed the analysis as time-dependent effects of rapid-acting antidepressants in TRD-derived neurons. (PMID:41743330)