Psilocybin vs Escitalopram for Major Depressive Disorder: Comparative Mechanisms (Psilodep-RCT)

This is a randomised double-blind clinical trial. The aim is to compare the efficacy and mechanisms of action of psilocybin, the primary psychoactive substance in 'magic mushrooms', with the selective serotonin reuptake inhibitor (SSRI) escitalopram for major depressive disorder (MDD).

Study Overview

• Status: Completed
• Conditions: Depressive Disorder, Major
• Intervention / Treatment: Drug: Psilocybin + Placebo; Drug: Psilocybin + Escitalopram

• Study Type: Interventional
• Enrollment (Actual): 59
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, W12 0NN
    • Imperial College Hammersmith campus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Major depressive disorder (DSM-IV)
2. Depression of moderate to severe degree (17+ on the 17-item Hamilton Depression Scale (HAM-D)).
3. No Magnetic Resonance Imaging (MRI) contraindications
4. No SSRI contraindications
5. Has a general practitioner (GP) or other mental healthcare professional who can confirm diagnosis
6. 18-80 years of age
7. Males and females
8. Sufficiently competent with English language

Key exclusion criteria:

1. Current or previously diagnosed psychotic disorder
2. Immediate family member with a diagnosed psychotic disorder
3. Medically significant condition rendering unsuitability for the study (e.g., diabetes, epilepsy, severe cardiovascular disease, hepatic or renal failure e.g. creatine clearance:renal clearance (CLRC) < 30 ml/min etc.)
4. History of serious suicide attempts requiring hospitalisation.
5. Significant history of mania (determined by study psychiatrist and medical records)
6. Psychiatric condition judged to be incompatible with establishment of rapport with therapy team and/or safe exposure to psilocybin, e.g. borderline personality disorder
7. Blood or needle phobia
8. Positive pregnancy test at screening or during the study, women who are planning a pregnancy and/or women who are nursing/breastfeeding.
9. Participants who do not agree to use an acceptable contraceptive method throughout their participation in study.
10. Current drug or alcohol dependence
11. No email access
12. Use of contraindicated medication
13. Patients presenting with abnormal QT interval prolongation at screening or with a history of this (QTc at screening above 440ms for men and above 470ms for women)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Psilocybin; Patients receive Psilocybin	Drug: Psilocybin + Placebo; Multiple dosing days psilocybin vs 6 weeks of daily placebo
Active Comparator: Escitalopram; Patients receive Escitalopram	Drug: Psilocybin + Escitalopram; Multiple dosing days psilocybin vs 6 weeks of daily escitalopram

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Change of the BOLD Signal	Patients were tested with functional magnetic resonance imaging (fMRI) to measure brain brain responses to emotional faces before and after the treatment. The 2 values of BOLD signal (before and after exposure to emotional faces) were used to estimate a percentage value per patient and then these were used to estimated a group percentage change.	Baseline measure vs 6 weeks post 1st psilocybin dosing
Change in QIDS-16: Quick Inventory of Depressive Symptomatology Self-Rated (QIDS-16)	Change in QIDS-16 (self-rated measure of depressive symptoms). Scale is composed of 16 items that correlate with the 9 Diagnostic Statistical Manual (DSM-IV) symptom criteria for depression. Each response is graded 0-4 (none-severe symptoms). Questions 1-4 concern sleep disturbances, Question 5 addresses sad mood, Questions 6-9 appetite/weight, Question 10 concentration, Question 11 self-criticism, Question 12 suicidal ideation, Question 13 interest, Q14 energy/fatigue and Questions 15-16 psychomotor agitation/retardation. All questions that address the same topic are grouped and only the highest score from each group is summed up together with the other questions in order to produce a total score. Scores can range from 0-27 and depression severity is graded based on the total score in the following way: 1-5 = No depression 6-10 = Mild depression 11-15 = Moderate depression 16-20 = Severe depression 21-27 = Very severe depression Lower score =better outcome (less depression)	Baseline vs 6 weeks post 1st psilocybin dosing

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Hamilton Depression Scale (HAMD-17)	HAMD-17: clinician rated Hamilton Depression Scale of depression severity. Range of scores: 0-52: where 0-7 is normal, 8-16 is mild, 17-23 is moderate, >23 is severe. A threshold score of 17 is the entry: a score of 17 or higher indicated moderate-severe depression and was a requirement for entry into this trial at the screening point. This baseline does not refer to the screening point, it refers to the HAMD conducted 7-10 days before psilocybin dosing. A higher decrease in the HAMD (larger negative change score) is a better outcome.	Change from baseline (7-10 days pre-dosing) to 6 weeks after the first psilocybin dose
Change in Beck Depression Inventory (BDI-IA)	BDI-IA: patient-rated Beck Depression Inventory, depressive symptomatology scale. Higher score = worse depression. The total score range is 0-63: where 0-13 is considered minimal range, 14-19 is mild, 20-28 is moderate, and 29-63 is severe Higher negative score = greater decrease in depression scores 6 weeks after each treatment arm = better outcome.	Change from baseline (7-10 days pre-dosing) to 6 weeks after the first psilocybin dose
Change in MADRS	MADRS - Montgomery-Asberg Depression Rating Scale, clinician-rated measure of depression. This scale is clinician-rated and consists of 10 items; each item is rated on a 0-6 scale, resulting in a maximum total score of 60 points, with higher scores indicative of greater depressive symptomology.36 The MADRS scoring instructions indicate that a total score ranging from 0 to 6 indicates that the patient is in the normal range (no depression), a score ranging from 7 to 19 indicates "mild depression," 20 to 34 indicates "moderate depression," a score of 35 and greater indicates "severe depression," and a total score of 60 or greater indicates "very severe depression." A higher decrease in the MADRS (larger negative change score) is a better outcome.	Change from baseline (7-10 days pre-dosing) to 6 weeks after the first psilocybin dose
Number of Patients Who "Responded": Quick Inventory of Depressive Symptomatology (QIDS-16) Response at 6 Weeks	Number of patients who "responded" on the QIDS-16 scale (Quick Inventory of Depressive Symptomatology, self-rated). "Response" is defined by a decrease in QIDS score of 50% from baseline. Higher number of patients who responded = better outcome for treatment arm.	Change from baseline (7-10 days pre-dosing) to 6 weeks after the first psilocybin dose
Number of Patients Who "Remitted": QIDS-16 Remission Rate	Number of patients who "remitted" on the QIDS-16 scale (Quick Inventory of Depressive Symptomatology, self-rated). "Remission" is defined by having a QIDS score below 5 at the 6 week point = no depression. Higher remission rate = better outcome (less depressed patients after treatment)	Change from baseline (7-10 days pre-dosing) to 6 weeks after the first psilocybin dose

Collaborators and Investigators

• Sponsor: Imperial College London
• Collaborators: Alexander Mosely Charitable Trust
• Investigators: Principal Investigator: David J Nutt, Medicine, Imperial College London

Publications and helpful links

General Publications

• 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.
• 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.
• Daws RE, Timmermann C, Giribaldi B, Sexton JD, Wall MB, Erritzoe D, Roseman L, Nutt D, Carhart-Harris R. Increased global integration in the brain after psilocybin therapy for depression. Nat Med. 2022 Apr;28(4):844-851. doi: 10.1038/s41591-022-01744-z. Epub 2022 Apr 11.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 7, 2019
• Primary Completion (Actual): April 17, 2020
• Study Completion (Actual): October 17, 2020

Study Registration Dates

• First Submitted: December 6, 2017
• First Submitted That Met QC Criteria: February 5, 2018
• First Posted (Actual): February 12, 2018

Study Record Updates

• Last Update Posted (Actual): October 24, 2024
• Last Update Submitted That Met QC Criteria: August 2, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: depression; major depressive disorder; psilocybin; escitalopram; major depression; psychedelics; psychedelic; ssri; unipolar depression; mdd
• Additional Relevant MeSH Terms: Mental Disorders; Behavioral Symptoms; Mood Disorders; Depression; Depressive Disorder; Depressive Disorder, Major; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Membrane Transport Modulators; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Serotonin Agents; Selective Serotonin Reuptake Inhibitors; Hallucinogens; Escitalopram; Psilocybin
• Other Study ID Numbers: 17HH3790; 2017-000219-18 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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