Psilocybin-Assisted Therapy in Treatment-Resistant Depression

Induction Protocol for Psilocybin-Assisted Therapy in Treatment-Resistant Depression (TRD): A Pilot Study

The goal of this clinical trial is to test how well psilocybin-assisted therapy works in treating people with depression. The main questions this study aims to answer are:

• Does psilocybin with assisted therapy help improve symptoms for people with depression?
• How long do the effects of this treatment last?

Participants will:

• Take part in a couple of screening and preparation visits.
• Be given psilocybin in one or two treatment sessions.
• Attend a series of follow-up sessions over the following year.
• Complete forms and surveys to test how their symptoms have changed and what they thought of their experience.

Researchers will also compare whether one treatment or two treatments help improve symptoms more for participants.

Study Overview

• Status: Recruiting
• Conditions: Treatment Resistant Depression; Refractory Depression
• Intervention / Treatment: Drug: psilocybin

Detailed Description

Major depressive disorder (MDD) ranks fourth in global disease burden and has significant morbidity, mortality, societal and financial costs. However, few adequate and effective treatments exist with 60% of MDD patients not responding sufficiently to an initial oral antidepressant treatment. These patients who experience treatment resistant depression (TRD), defined as an intolerance or lack of response to two antidepressants of different classes, have limited treatment options beyond the antidepressant treatments that often yield insufficient results or relapse. Psilocybin, a novel treatment, has been found to relieve symptoms of TRD, but there are limited studies on specific dosing and long term treatment follow-up. In this study, the investigators will look closer at the effectiveness of one treatment with psilocybin versus two treatments with psilocybin, as well as the long term effectiveness over the first 12 months after treatment.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Mary Pruden; Phone Number: 9849741004; Email: PilotPAT_study@med.unc.edu
• Study Contact Backup: Name: Robert K McClure, MD; Phone Number: 9199286381; Email: robert_mcclure@med.unc.edu

Study Locations

• United States
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • Recruiting
      • UNC Chapel Hill Medical Center
      • Contact: Mary Pruden, BA
      • Principal Investigator: Robert K McClure, MD
      • Sub-Investigator: Amanda Tow, MD, PhD
      • Sub-Investigator: Lindley Reynolds, MSW

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Provision of signed and dated informed consent form.
• Willingness to comply with all study procedures and availability for the study.
• Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-V) diagnosis of major depressive disorder.
• Currently experiencing a major depressive episode, lasting at least 3 months
• Failure to respond or inability to tolerate at least 2 guideline-concordant pharmacological treatments from different pharmacologic classes during the current major depressive episode
• Good health evidenced by medical history and routine lab tests
• No central nervous system (CNS) or neurocognitive impairment
• Ability to take oral medication and to follow to the psilocybin-assisted therapy protocol
• Identified support person to accompany patient home after dosing
• Use of effective contraception throughout the study by those with child-bearing potential
• Use of condoms or other effective contraceptive methods by males with reproductive potential
• Fully vaccinated and up to date on vaccination against COVID-19, as defined by Center for Disease Control guidelines
• Following Lifestyle Considerations throughout study (no nicotine containing products in clinical unit, refrain from operating heavy machinery for the duration of treatment day, no more than two servings 8 hours prior to treatment, no psychoactive drugs 72 hours before treatment, refrain from consuming foods that would interfere with drug absorption, minimize interaction with household immunocompromised contacts)

Exclusion Criteria:

• Family history (first- or second-degree relatives) or diagnosis of bipolar disorder with psychotic features, schizophrenia, schizoaffective disorder, hallucinogen-induced psychosis, anti-social personality disorder, or other psychotic disorder.
• Borderline personality disorder, defined by DSM-V criteria, that in the judgement of the Investigator is likely to complicate the assessment of clinical response to study treatments or limits the patient's ability to comply with study procedures.
• Alcohol or other substance use disorder (except tobacco/nicotine) that has been active within the 6 months prior to enrollment.
• Recent use (within past 6 months) of esketamine, ketamine or classic hallucinogens (psilocybin-containing mushrooms or LSD) or use of psychedelics more than 10 times in lifetime.
• Participants with active suicidal ideation or plan with a Columbia Suicide Severity Rating Scale (C-SSRS) score greater than or equal to 4.
• Current active self-injurious behavior, requiring medical attention or per investigator discretion.
• Diagnosis of Obsessive-compulsive disorder or post-traumatic stress disorder.
• Within 72 hours of psilocybin administration, use of nicotine, alcohol, or other controlled substances.
• Current delirium, dementia, amnestic disorder, or other cognitive disorders.
• Any current or past medical or neurological illness (including chronic pain syndromes and/or history of cerebrovascular event (excluding migraine)) that, in the opinion of the investigator, may confound the interpretation of study assessments
• Known allergic reactions to components of psilocybin.
• Medically instability at screening, including hepatic, renal, circulatory, cardiac (arrhythmia, uncontrolled hypertension, systolic BP > 140 mmHg or diastolic BP > 90 mmHg, abnormal QTc), pulmonary or CNS (seizure disorder or treatment with antiepileptic drugs) impairment.
• Current pregnancy or lactation.
• Febrile illness in last 3 weeks.
• Current use or use within 4 weeks of psilocybin administration of Monoamine oxidase inhibitors (MAOIs), alcohol dehydrogenase inhibitors and antipsychotics (concomitant medications will be allowed per investigator discretion).
• Current treatment with buproprion greater than 300mg/day.
• Current use of tramadol.
• Prior participation in psilocybin-assisted therapy trial and or regular use of hallucinogens
• Treatment with another investigational drug or other intervention during study period.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Single Psilocybin Treatment; Participants will be administered one dose of a 25mg capsule of psilocybin. This will be administered one time.	Drug: psilocybin; 25mg of psilocybin administered during treatment session, accompanied by preparation before, integration after, and assistive therapy during the session.
Active Comparator: Two Psilocybin Treatments; Participants will be administered one dose of a 25mg capsule of psilocybin. Two weeks later, the participant will be administered one more dose of a 25mg capsule of psilocybin.	Drug: psilocybin; 25mg of psilocybin administered during treatment session, accompanied by preparation before, integration after, and assistive therapy during the session.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in HAM-D-17 Scores between Baseline and 2 Weeks after Treatment	The change in Hamilton Depression Rating Scale 17 item (HAM-D-17) scores between baseline and 2 weeks after treatment The HAM-D-17 is a 17-item questionnaire used to measure severity of depression. The score ranges from 0 to 52. Higher scores indicate more severe depression.	Baseline, 2 weeks
Change in QIDS SR-16 Scores between Baseline and 2 Weeks after Treatment	The change between depression scores as reported by Quick Inventory of Depressive Symptomatology Short Response-16 (QIDS SR-16) scores between baseline and 2 weeks after treatment The QIDS SR-16 is a 16-item questionnaire used to measure severity of depression. The scores range from 0 to 45. Higher scores indicate more severe depression.	Baseline, 2 weeks
Number of Participants Achieving Remission 2 Weeks after Treatment	Number of participants achieving remission (defined as a HAM-D-17 score less than 10) 2 weeks after treatment	up to 2 weeks
Number of Participants Achieving Response 2 weeks after treatment	Number of participants achieving response (defined as a HAM-D-17 score that has decreased by greater than or equal to 50 percent compared to baseline) 2 weeks after treatment	up to 2 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Achieving Remission at 6 Weeks	Number of participants achieving remission (defined as a HAM-D-17 score less than 10) 6 weeks after treatment	up to 6 weeks
Number of Participants Achieving Response at 6 Weeks	Estimate the number of participants achieving response (defined as a HAM-D-17 score that has decreased by greater than or equal to 50 percent compared to baseline) at 6 weeks after treatment	up to 6 weeks
Number of Participants Achieving Remission at 3 Months	Number of participants achieving remission (defined as a HAM-D-17 score less than 10) 3 months after treatment	up to 3 months
Number of Participants Achieving Response at 3 Months	Estimate the number of participants achieving response (defined as a HAM-D-17 score that has decreased by greater than or equal to 50 percent compared to baseline) at 3 months after treatment	up to 3 months
Number of Participants Achieving Remission at 6 Months	Number of participants achieving remission (defined as a HAM-D-17 score less than 10) 6 months after treatment	up to 6 months
Number of Participants Achieving Response at 6 Months	Estimate the number of participants achieving response (defined as a HAM-D-17 score that has decreased by greater than or equal to 50 percent compared to baseline) at 6 months after treatment	up to 6 months
Number of Participants Achieving Remission at 9 Months	Number of participants achieving remission (defined as a HAM-D-17 score less than 10) 9 months after treatment	up to 9 months
Number of Participants Achieving Response at 9 Months	Estimate the number of participants achieving response (defined as a HAM-D-17 score that has decreased by greater than or equal to 50 percent compared to baseline) at 9 months after treatment	up to 9 months
Number of Participants Achieving Remission at 12 Months	Number of participants achieving remission (defined as a HAM-D-17 score less than 10) 12 months after treatment	up to 12 months
Number of Participants Achieving Response at 12 Months	Estimate the number of participants achieving response (defined as a HAM-D-17 score that has decreased by greater than or equal to 50 percent compared to baseline) at 12 months after treatment	up to 12 months
Time to Relapse in Participants Who Showed Remission at 2 weeks	Of the number of participants achieving remission (defined as a HAM-D-17 score less than 10) 2 weeks after treatment, the amount of time until a relapse occurring thereafter occurs. Relapse is defined as a HAM-D-17 score greater than or equal to 17 and will be measured up to the study follow-up visit at 1 year.	up to 1 year after treatment
Time to Relapse in Participants Who Showed Response at 2 Weeks	Of the number of participants achieving remission (defined as a HAM-D-17 score that has decreased by greater than or equal to 50 percent compared to baseline) 2 weeks after treatment, the amount of time until a relapse occurring thereafter occurs. Relapse is defined as a HAM-D-17 score greater than or equal to 17 and will be measured up to the study follow-up visit at 1 year.	up to 1 year after treatment
Change in HAM-D-17 Scores between Baseline and 6 Weeks after Treatment	The change in HAM-D-17 scores between baseline and 2 weeks after treatment The HAM-D-17 is a 17-item questionnaire used to measure severity of depression. The score ranges from 0 to 52. Higher scores indicate more severe depression.	Baseline, 6 weeks
Change in HAM-D-17 Scores between Baseline and 3 Months after Treatment	The change in HAM-D-17 scores between baseline and 2 weeks after treatment The HAM-D-17 is a 17-item questionnaire used to measure severity of depression. The score ranges from 0 to 52. Higher scores indicate more severe depression.	Baseline, 3 Months
Change in HAM-D-17 Scores between Baseline and 6 Months after Treatment	The change in HAM-D-17 scores between baseline and 2 weeks after treatment The HAM-D-17 is a 17-item questionnaire used to measure severity of depression. The score ranges from 0 to 52. Higher scores indicate more severe depression.	Baseline, 6 Months
Change in HAM-D-17 Scores between Baseline and 9 Months after Treatment	The change in HAM-D-17 scores between baseline and 2 weeks after treatment The HAM-D-17 is a 17-item questionnaire used to measure severity of depression. The score ranges from 0 to 52. Higher scores indicate more severe depression.	Baseline, 9 Months
Change in HAM-D-17 Scores between Baseline and 12 Months after Treatment	The change in HAM-D-17 scores between baseline and 2 weeks after treatment The HAM-D-17 is a 17-item questionnaire used to measure severity of depression. The score ranges from 0 to 52. Higher scores indicate more severe depression.	Baseline, 12 months
Change in QIDS SR-16 Scores between Baseline and 6 Weeks after Treatment	The change between depression scores as reported by QIDS SR-16 scores between baseline and 2 weeks after treatment The QIDS SR-16 is a 16-item questionnaire used to measure severity of depression. The scores range from 0 to 45. Higher scores indicate more severe depression.	Baseline, 6 weeks
Change in QIDS SR-16 Scores between Baseline and 3 Months after Treatment	The change between depression scores as reported by QIDS SR-16 scores between baseline and 2 weeks after treatment The QIDS SR-16 is a 16-item questionnaire used to measure severity of depression. The scores range from 0 to 45. Higher scores indicate more severe depression.	Baseline, 3 Months
Change in QIDS SR-16 Scores between Baseline and 6 Months after Treatment	The change between depression scores as reported by QIDS SR-16 scores between baseline and 2 weeks after treatment The QIDS SR-16 is a 16-item questionnaire used to measure severity of depression. The scores range from 0 to 45. Higher scores indicate more severe depression.	Baseline, 6 Months
Change in QIDS SR-16 Scores between Baseline and 9 Months after Treatment	The change between depression scores as reported by QIDS SR-16 scores between baseline and 2 weeks after treatment The QIDS SR-16 is a 16-item questionnaire used to measure severity of depression. The scores range from 0 to 45. Higher scores indicate more severe depression.	Baseline, 9 Months
Change in QIDS SR-16 Scores between Baseline and 12 Months after Treatment	The change between depression scores as reported by QIDS SR-16 scores between baseline and 2 weeks after treatment The QIDS SR-16 is a 16-item questionnaire used to measure severity of depression. The scores range from 0 to 45. Higher scores indicate more severe depression.	Baseline, 12 Months

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Collaborators: Foundation of Hope, North Carolina
• Investigators: Principal Investigator: Robert K McClure, MD, Director of Interventional Psychiatry

Publications and helpful links

General Publications

• Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006 Nov;163(11):1905-17. doi: 10.1176/ajp.2006.163.11.1905.
• Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA, Richards BD, Cosimano MP, Klinedinst MA. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol. 2016 Dec;30(12):1181-1197. doi: 10.1177/0269881116675513.
• Ross S, Bossis A, Guss J, Agin-Liebes G, Malone T, Cohen B, Mennenga SE, Belser A, Kalliontzi K, Babb J, Su Z, Corby P, Schmidt BL. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol. 2016 Dec;30(12):1165-1180. doi: 10.1177/0269881116675512.
• Carhart-Harris RL, Bolstridge M, Rucker J, Day CM, Erritzoe D, Kaelen M, Bloomfield M, Rickard JA, Forbes B, Feilding A, Taylor D, Pilling S, Curran VH, Nutt DJ. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry. 2016 Jul;3(7):619-27. doi: 10.1016/S2215-0366(16)30065-7. Epub 2016 May 17.
• Bond FW, Hayes SC, Baer RA, Carpenter KM, Guenole N, Orcutt HK, Waltz T, Zettle RD. Preliminary psychometric properties of the Acceptance and Action Questionnaire-II: a revised measure of psychological inflexibility and experiential avoidance. Behav Ther. 2011 Dec;42(4):676-88. doi: 10.1016/j.beth.2011.03.007. Epub 2011 May 25.
• Davis AK, Barrett FS, May DG, Cosimano MP, Sepeda ND, Johnson MW, Finan PH, Griffiths RR. Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2021 May 1;78(5):481-489. doi: 10.1001/jamapsychiatry.2020.3285. Erratum In: JAMA Psychiatry. 2021 Feb 10;:
• Barrett FS, Johnson MW, Griffiths RR. Validation of the revised Mystical Experience Questionnaire in experimental sessions with psilocybin. J Psychopharmacol. 2015 Nov;29(11):1182-90. doi: 10.1177/0269881115609019. Epub 2015 Oct 6.
• Carhart-Harris RL, Bolstridge M, Day CMJ, Rucker J, Watts R, Erritzoe DE, Kaelen M, Giribaldi B, Bloomfield M, Pilling S, Rickard JA, Forbes B, Feilding A, Taylor D, Curran HV, Nutt DJ. Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology (Berl). 2018 Feb;235(2):399-408. doi: 10.1007/s00213-017-4771-x. Epub 2017 Nov 8.
• Demyttenaere K, Van Duppen Z. The Impact of (the Concept of) Treatment-Resistant Depression: An Opinion Review. Int J Neuropsychopharmacol. 2019 Feb 1;22(2):85-92. doi: 10.1093/ijnp/pyy052.
• Carhart-Harris R, Giribaldi B, Watts R, Baker-Jones M, Murphy-Beiner A, Murphy R, Martell J, Blemings A, Erritzoe D, Nutt DJ. Trial of Psilocybin versus Escitalopram for Depression. N Engl J Med. 2021 Apr 15;384(15):1402-1411. doi: 10.1056/NEJMoa2032994.
• Dold M, Kasper S. Evidence-based pharmacotherapy of treatment-resistant unipolar depression. Int J Psychiatry Clin Pract. 2017 Mar;21(1):13-23. doi: 10.1080/13651501.2016.1248852. Epub 2016 Nov 16.
• Keller MB, Shapiro RW, Lavori PW, Wolfe N. Recovery in major depressive disorder: analysis with the life table and regression models. Arch Gen Psychiatry. 1982 Aug;39(8):905-10. doi: 10.1001/archpsyc.1982.04290080025004.
• Gukasyan N, Davis AK, Barrett FS, Cosimano MP, Sepeda ND, Johnson MW, Griffiths RR. Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up. J Psychopharmacol. 2022 Feb;36(2):151-158. doi: 10.1177/02698811211073759.
• Maclean KA, Leoutsakos JM, Johnson MW, Griffiths RR. Factor Analysis of the Mystical Experience Questionnaire: A Study of Experiences Occasioned by the Hallucinogen Psilocybin. J Sci Study Relig. 2012 Dec;51(4):721-737. doi: 10.1111/j.1468-5906.2012.01685.x.
• Murphy R, Kettner H, Zeifman R, Giribaldi B, Kartner L, Martell J, Read T, Murphy-Beiner A, Baker-Jones M, Nutt D, Erritzoe D, Watts R, Carhart-Harris R. Therapeutic Alliance and Rapport Modulate Responses to Psilocybin Assisted Therapy for Depression. Front Pharmacol. 2022 Mar 31;12:788155. doi: 10.3389/fphar.2021.788155. eCollection 2021.

Study record dates

Study Major Dates

• Study Start (Actual): April 19, 2024
• Primary Completion (Estimated): September 1, 2025
• Study Completion (Estimated): September 1, 2026

Study Registration Dates

• First Submitted: February 27, 2024
• First Submitted That Met QC Criteria: March 4, 2024
• First Posted (Actual): March 12, 2024

Study Record Updates

• Last Update Posted (Actual): April 23, 2024
• Last Update Submitted That Met QC Criteria: April 22, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: depression; psilocybin; treatment-resistant depression; TRD; psychedelic; psychedelic-assisted therapy; refractory depression
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Depression; Depressive Disorder; Depressive Disorder, Treatment-Resistant; Physiological Effects of Drugs; Psychotropic Drugs; Hallucinogens; Psilocybin
• Other Study ID Numbers: 22-1421

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Deidentified individual data that supports the results will be shared beginning 9 to 36 months following publication provided the investigator who proposes to use the data has approval from an Institutional Review Board (IRB), Independent Ethics Committee (IEC), or Research Ethics Board (REB), as applicable, and executes a data use/sharing agreement with UNC.
• IPD Sharing Time Frame: Data will be provided beginning 9 and continuing for 36 months following publication.
• IPD Sharing Access Criteria: Investigator has approved IRB, IEC, or REB and an executed data use/sharing agreement with UNC.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No