¹Keio University School of Medicine, Department of Neuropsychiatry, Tokyo, Japan, ²Kanazawa University, Department of Clinical Cognitive Neuroscience, Kanazawa, Japan, ³Monash University, Turner Institute for Brain and Mental Health, Clayton, VIC, Australia

Background: Cognitive dysfunction is associated with impaired psychosocial functioning in patients with major depressive disorder (MDD). Patients with treatment-resistant depression (TRD) exhibit more pronounced cognitive dysfunction than those with non-resistant MDD, underscoring the need for effective therapeutic strategies. Psilocybin has emerged as a promising treatment for depression due to its rapid onset and sustained antidepressant effects. However, the previous study examining the effects of psilocybin on cognition in TRD reported only non-significant improvement in global cognitive performance. That study was used a single screening measure, and comprehensive assessments of cognitive function are lacking. Moreover, it remains unclear whether cognitive changes following psilocybin therapy reflect a direct pharmacological effect or are secondary to improvements in depressive symptoms.

Aims & Objectives: This study aimed to examine the effects of psilocybin treatment on cognitive function in Japanese patients with TRD and to clarify the relationship between changes in cognitive function and depressive symptoms.

Method: This single-arm, open-label feasibility study was conducted at Keio University Hospital in Tokyo, Japan (clinical trial registration number: jRCTs031230351). Twelve Japanese adults aged 20–59 years with a DSM-5 diagnosis of MDD who showed insufficient treatment response to at least two antidepressants during the current episode were enrolled. Participants received two courses of psilocybin therapy with psychological support. Psilocybin was administered orally at 10 mg (the former six participants) or 25 mg (the latter six participants) with the same dose used for both dosing sessions. The two dosing sessions were administered approximately 2–3 weeks apart in an inpatient setting under the supervision of a psychiatrist and a clinical psychologist. Follow-up continued for up to eight weeks after the second dosing session.
Cognitive function was assessed using the Japanese translation of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Letter-Number Sequencing, Stroop Neuropsychological Screening Test, and Trail Making Test. The RBANS is a repeatable battery that evaluates immediate and delayed memory, attention, language, and processing speed. Depression symptoms severity was assessed using the Montgomery-Åsberg Depression Rating Scale, the Hamilton Depression Rating Scale, and the Quick Inventory of Depressive Symptomatology-Self Report. Changes in cognitive function before and after treatment were analyzed using paired t-tests. Path analysis was conducted to examine whether changes in cognitive function were directly attributable to psilocybin treatment or mediated by improvements in depressive symptoms.

Results: As of December 14, 2025, 12 participants have been enrolled: 10 completed all the assessments, 1 withdrew from the study, and 1 is currently undergoing the treatment. The final participant is scheduled to complete all the study procedures in February. Detailed results regarding changes in cognitive function following psilocybin treatment will be presented at the congress.

Discussion & Conclusions: This study will provide preliminary evidence on the effects of psilocybin treatment on cognitive function comprehensively in Japanese patients with TRD, including domains such as language and delayed memory. Furthermore, path analysis will help clarify whether observed cognitive changes are directly attributable to psilocybin or mediated by improvements in depressive symptoms, thereby offering insight into the mechanisms underlying psilocybin therapy.