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Examination of safety and efficacy of psilocybin treatment for treatment-resistant depression: a single-arm open-label trial

Psilocybin administration for treatment-resistant depression

12

The mean age of all study participants was 44.8 years (SD 9.0). There were 10 males (83.3%) and 2 females (16.7%), and all participants were Mongoloid. The mean age at onset was 30.1 years (SD 11.1), and the mean duration of illness was 14.8 years (SD 9.5). Mean height was 169.2 cm (SD 8.7), mean body weight was 73.3 kg (SD 17.8), mean body mass index (BMI) was 25.3 (SD 4.2), and the baseline Montgomery-Asberg Depression Rating Scale (MADRS) score was 32.3 (SD 8.7). All participants were treated in the outpatient setting. Eleven participants (91.7%) were right-handed and 1 participant (8.3%) was left-handed. Concomitant medications were used in all participants, and urine drug screening was negative in all participants. The baseline characteristics of the 10 mg group (n=6) and the 25 mg group (n=6) were as follows. The mean age was 43.3 years (SD 10.1) in the 10 mg group and 46.3 years (SD 8.4) in the 25 mg group. Both groups consisted of 5 males and 1 female. The mean age at onset was 27.5 years (SD 9.3) in the 10 mg group and 32.7 years (SD 13.0) in the 25 mg group. The mean duration of illness was 15.8 years (SD 10.2) in the 10 mg group and 13.7 years (SD 9.6) in the 25 mg group. The baseline MADRS score was 32.2 (SD 10.6) in the 10 mg group and 32.3 (SD 7.3) in the 25 mg group.

Enrollment 12, FAS 12, SAS 12, PPS 11, Completed 2 courses of psilocybin therapy 11.

Flushing 5 cases, 21.7%, 3 subjects, 25.0%; Difficulty concentrating 5 cases, 21.7%, 3 subjects, 25.0%; Increased blood pressure 4 cases, 17.4%, 2 subjects, 16.7%; Anxiety 3 cases, 13.0%, 2 subjects, 16.7%; Increased body temperature (<38 degrees) 3 cases, 13.0%, 2 subjects, 16.7%; Dysesthesia 2 cases, 8.7%, 2 subjects, 16.7%; Dizziness 2 cases, 8.7%, 2 subjects, 16.7%; Somnolence 2 cases, 8.7%, 2 subjects, 16.7%; Headache 2 cases, 8.7%, 2 subjects, 16.7%.

This study was a single-arm, open-label trial in patients with treatment-resistant depression, and the primary endpoint was the completion rate of the two-course psilocybin therapy regimen as a measure of feasibility. In the full analysis set (FAS), 11 of 12 participants completed the intervention, yielding a completion rate of 91.7% (95% confidence interval [CI], 61.5-99.8). In the per protocol set (PPS), all 11 participants completed the intervention, yielding a completion rate of 100.0% (95% CI, 71.5-100.0). Thus, the predefined feasibility criterion was met. Secondary endpoints were evaluated in the FAS. Depressive symptoms, assessed using the Montgomery-Asberg Depression Rating Scale (MADRS), 17-item Hamilton Depression Rating Scale (HDRS), and Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR), showed significant reductions from baseline at post-treatment, 4 weeks, and 8 weeks. The mean change in MADRS was -9.9 (SD 6.9) at post-treatment (p=0.0008), -9.8 (SD 6.8) at 4 weeks (p=0.0008), and -10.3 (SD 7.6) at 8 weeks (p=0.0012). The mean change in HDRS was -5.3 (SD 3.9) at post-treatment (p=0.0011), -4.2 (SD 3.2) at 4 weeks (p=0.0015), and -4.1 (SD 4.2) at 8 weeks (p=0.0091). The mean change in QIDS-SR was -3.7 (SD 4.4) at post-treatment (p=0.0177), -3.8 (SD 4.2) at 4 weeks (p=0.0132), and -4.2 (SD 4.9) at 8 weeks (p=0.0174). In contrast, no statistically significant changes were observed in the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Columbia-Suicide Severity Rating Scale (C-SSRS), Pittsburgh Sleep Quality Index (PSQI), Athens Insomnia Scale (AIS), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Letter-Number Sequencing (LNS), Stroop Neuropsychological Screening Test (SNST), Trail Making Test (TMT), Emotion Regulation Questionnaire (ERQ), Resilience Scale (RS), Life Orientation Test-Revised (LOT-R), or Sense of Coherence (SOC), although some fluctuations in mean values were observed. For the pharmacokinetic evaluation, plasma psilocin concentrations were measured after the second dosing session. In the 10 mg group, Cmax was 11.7, Tmax was 1 hour, t1/2 was 4.89 hours (SD 1.11), AUC was 42.1, and CL/F was 238. In the 25 mg group, Cmax was 14.3, Tmax was 2 hours, t1/2 was 3.99 hours (SD 0.86), AUC was 62.8, and CL/F was 399, indicating generally greater exposure in the 25 mg group.

A single-arm, open-label study consisting of two courses of psilocybin therapy was conducted in patients with treatment-resistant depression. The completion rate, which was the primary endpoint, was 91.7% (11/12) in the full analysis set (FAS), meeting the predefined feasibility criterion. For the secondary endpoints, significant improvements from baseline were observed in the MADRS, HDRS, and QIDS-SR at post-treatment, 4 weeks, and 8 weeks.

June. 01, 2026

No

N.A.

https://jrct.mhlw.go.jp/latest-detail/jRCTs031230351

Uchida Hiroyuki

Keio University Hospital

Shinanomachi 35, Shinjuku-ku, Tokyo

hiroyuki_uchida@keio.jp

Uchida Hiroyuki

Keio University Hospital

Shinanomachi 35, Shinjuku-ku, Tokyo

+81-3-3353-3971

hiroyuki_uchida@keio.jp

Complete

Sept. 21, 2023

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

1. Those who meet the criteria for depression according to Structured Clinical Interview for DSM-5 Disorders SCID-5-RV (ResearchVersion) Japanese Version
2. Male and female outpatients between the ages of 20 and 60 at the time of registration.
3. Inadequate response to 2 or more antidepressants at approved doses for 6 weeks or more for the current depressive episode
4. A Montgomery-Asberg Depression Rating Scale (MADRS) total score of 20 or higher at the time of screening
5. Being capable of providing informed consent confirmed with scores above 70% in the following four items: understanding, appreciation, reasoning, and the ability to express a choice in the MacArthur Competence Assessment Tool (MacCAT)
6. Written consent being provided by study participant

1. Having previously received psilocybin for the treatment of depression
2. Depression with psychotic features according to the diagnostic criteria of the DSM-5
3. Presence of other comorbidities according to the diagnostic criteria of the DSM-5
4. Presence of neurodevelopmental disorders according to the diagnostic criteria of the DSM-5
5. A history of schizophrenia spectrum and other psychotic disorders according to the diagnostic criteria of the DSM-5 in any of blood parents, children, and siblings
6. A history of self-harm or suicidal attempts
7. Taking a monoamine oxidase (MAO) inhibitor or uridine diphosphate glucuronosyltransferase enzyme modulator
8. Taking 5-hydroxytryptophan or St. John's wort
9. Being pregnant, breastfeeding, or hoping to become pregnant
10. A history of epilepsy or seizures
11. A history of cerebrovascular disease
12. High blood pressure (systolic pressure 160 mmHg or more, diastolic pressure 100 mmHg or more)
13. A history of ocular trauma
14. Receiving electroconvulsive therapy within 3
months prior to enrollment
15. Substance-related disorders (excluding nicotine and caffeine) within 6 months
16. Positive urine screening for dependent substances (except for those who are positive for drugs taken for treatment)
17. Having a metallic substance in the body or having a pacemaker
18. Size of the head, neck and body are not suitable for MRI scanners
19. Having tattoos that are larger than one point (including tattoos and art make-up)
20. A high degree of claustrophobia
21. Significant deformity of brain structure (including congenital and traumatic)
22. At the time of registration, any of the following abnormal laboratory values
eGFR < 60mL/min/1.73m2
AST > 60IU/L
ALT > 84IU/L (males), ALT > 46IU/L (females)
23. Participated in another clinical trial within 12
weeks prior to enrollment (limited to those with invasion/intervention)
24. Those deemed unsuitable as research subjects by the principal investigator, etc.

Both

Treatment-resistant depression

Psilocybin therapy (1 preparation session; 1 medication session, Psilocybin 10 mg or 25 mg orally; 2 reviewing sessions) for a total of 2 courses.

depression

psilocybin

D061218

D011562

Proportion of completers (those who completed 2 courses of psilocybin therapy)

- Adverse events
- Severity of mood symptoms assessed with Montgomery-Asberg Depression Rating Scale
- Severity of mood symptoms assessed with 24-item Hamilton Depression Rating Scale
- Severity of mood symptoms assessed with Quick Inventory of Depressive Symptomatology Self-Report
- Severity of obsessive symptoms assessed with YBOCS
- Cognitive function measured with Repeatable Battery for the Assessment of Neuropsychological Status
- Cognitive function measured with Letter Number Sequencing Test
- Cognitive function measured with Stroop - Cognitive function measured with Neuropsychological Screening Test
- Cognitive function measured with Trail Making Test
- Degree of suicidal ideation measured with Columbia-Suicide Severity Rating Scale
- Quality of sleep measured with Pittsburgh Sleep Quality Index
- Quality of sleep measured with Athens Insomnia Index
- Degree of emotional control measured with Emotion Regulation Questionnaire
- Degree of resilience measured with Resilience Scale
- Degree of optimism measured with Life Orientation Test-Revised
- Degree of emotional control measured with sense of coherence measured with Sense of Coherence Scale

+81-3-5363-3503

Aug. 31, 2023

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