Psilocybin vs Escitalopram for Major Depressive Disorder: Comparative Mechanisms

Conditions

Depressive Disorder, Major

Keywords

depression, mdd, major depression, major depressive disorder, unipolar depression, psilocybin, psychedelics, psychedelic, escitalopram, ssri

Brief summary

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).

Paulina Clara Dagnino, Irene Acero-Pousa, Gorka Zamora‐López, Anira Escrichs, David Erritzøe et al. (10 authors)

bioRxiv (Cold Spring Harbor Laboratory)2026-06-16

10.64898/2026.06.12.731811

Effect of psilocybin versus escitalopram on depression symptom severity in patients with moderate-to-severe major depressive disorder: observational 6-month follow-up of a phase 2, double-blind, randomised, controlled trial.

Erritzoe D, Barba T, Greenway KT, Murphy R, Martell J, Giribaldi B, Timmermann C, Murphy-Beiner A, Jones MB, Nutt D, Weiss B, Carhart-Harris R.

2024-09-2122 citations

10.1016/j.eclinm.2024.102799

Different hierarchical reconfigurations in the brain by psilocybin and escitalopram for depression

Gustavo Deco, Yonatan Sanz Perl, Samuel Johnson, Niamh Bourke, Robin Carhart‐Harris et al. (6 authors)

Nature Mental Health2024-08-0527 citations

10.1038/s44220-024-00298-y

Assessing expectancy and suggestibility in a trial of escitalopram v. psilocybin for depression

Balázs Szigeti, Brandon Weiss, Fernando E. Rosas, David Erritzøe, David Nutt et al. (6 authors)

Psychological Medicine2024-01-2254 citations

10.1017/s0033291723003653

A Bayesian Reanalysis of a Trial of Psilocybin versus Escitalopram for Depression.

Nayak SM, Bari BA, Yaden DB, Spriggs MJ, Rosas FE, Peill JM, Giribaldi B, Erritzoe D, Nutt DJ, Carhart-Harris R.

2022-10-285 citations

10.1089/psymed.2022.0002

Increased global integration in the brain after psilocybin therapy for depression.

Daws RE, Timmermann C, Giribaldi B, Sexton JD, Wall MB, Erritzoe D, Roseman L, Nutt D, Carhart-Harris R.

2022-04-11262 citations

10.1038/s41591-022-01744-z

Therapeutic Alliance and Rapport Modulate Responses to Psilocybin Assisted Therapy for Depression

Roberta Murphy, Hannes Kettner, Rick Zeifman, Bruna Giribaldi, Laura Kärtner et al. (13 authors)

Frontiers in Pharmacology2022-03-31198 citations

10.3389/fphar.2021.788155

Trial of Psilocybin versus Escitalopram for Depression

Robin Carhart‐Harris, Bruna Giribaldi, Rosalind Watts, Michelle Baker-Jones, Ashleigh Murphy-Beiner et al. (10 authors)

New England Journal of Medicine2021-04-141,264 citations

10.1056/nejmoa2032994

Interventions

DRUGPsilocybin + Placebo

Multiple dosing days psilocybin vs 6 weeks of daily placebo

DRUGPsilocybin + Escitalopram

Multiple dosing days psilocybin vs 6 weeks of daily escitalopram

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to 80 Years

Healthy volunteers

No

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)

Design outcomes

Primary

Measure	Time frame	Description
Percentage Change of the BOLD Signal	Baseline measure vs 6 weeks post 1st psilocybin dosing	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.
Change in QIDS-16: Quick Inventory of Depressive Symptomatology Self-Rated (QIDS-16)	Baseline vs 6 weeks post 1st psilocybin dosing	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)

Secondary

Measure	Time frame	Description
Change in MADRS	Change from baseline (7-10 days pre-dosing) to 6 weeks after the first psilocybin dose	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 in Hamilton Depression Scale (HAMD-17)	Change from baseline (7-10 days pre-dosing) to 6 weeks after the first psilocybin dose	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.
Number of Patients Who Remitted: QIDS-16 Remission Rate	Change from baseline (7-10 days pre-dosing) to 6 weeks after the first psilocybin dose	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)
Number of Patients Who Responded: Quick Inventory of Depressive Symptomatology (QIDS-16) Response at 6 Weeks	Change from baseline (7-10 days pre-dosing) to 6 weeks after the first psilocybin dose	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 in Beck Depression Inventory (BDI-IA)	Change from baseline (7-10 days pre-dosing) to 6 weeks after the first psilocybin dose	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.

Countries

United Kingdom

Participant flow

Participants by arm

Arm	Count
Psilocybin Patients receive two doses of 25mg psilocybin, 3 weeks apart. After the first dose of 25mg psilocybin, patients start taking one daily placebo tablet every morning for 3 weeks. After their second 25mg psilocybin session, patients start taking two daily placebo tablets for another 3 weeks. All tablets are identical and visit procedures are identical otherwise.	30
Escitalopram Patients receive two doses of 1mg psilocybin (considered to be virtually placebo), 3 weeks apart. After the first dose of 1mg psilocybin, patients start taking one daily 10mg escitalopram tablet every morning for 3 weeks. After their second 1mg psilocybin session, patients start taking two daily tablets of escitalopram (10mg each, 20mg in total) for another 3 weeks. All tablets are identical and visit procedures are identical otherwise.	29
Total	59

Baseline characteristics

Characteristic	Psilocybin	Escitalopram	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	30 Participants	29 Participants	59 Participants
Age, Continuous	43.3 years STANDARD_DEVIATION 11.7	39.1 years STANDARD_DEVIATION 9.7	41.2 years STANDARD_DEVIATION 10.9
No previous psilocybin use	22 participants	21 participants	43 participants
Race/Ethnicity, Customized Asian	1 participants	4 participants	5 participants
Race/Ethnicity, Customized Mixed Asian + White	1 participants	1 participants	2 participants
Race/Ethnicity, Customized White	28 participants	24 participants	52 participants
Region of Enrollment United Kingdom	30 participants	29 participants	59 participants
Sex: Female, Male Female	11 Participants	9 Participants	20 Participants
Sex: Female, Male Male	19 Participants	20 Participants	39 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 30	0 / 29
other Total, other adverse events	26 / 30	24 / 29
serious Total, serious adverse events	0 / 30	0 / 29

Outcome results

Primary

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)

Time frame: Baseline vs 6 weeks post 1st psilocybin dosing

Arm	Measure	Value (MEAN)	Dispersion
Psilocybin	Change in QIDS-16: Quick Inventory of Depressive Symptomatology Self-Rated (QIDS-16)	-8 score on a scale	Standard Error 1
Escitalopram	Change in QIDS-16: Quick Inventory of Depressive Symptomatology Self-Rated (QIDS-16)	-6 score on a scale	Standard Error 1

p-value: 0.17ANCOVA

Primary

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.

Time frame: Baseline measure vs 6 weeks post 1st psilocybin dosing

Population: The data obtained from an imaging group in the trial, in which functional MRI was used to predict responses to the trial drugs, have not been analyzed.

Arm	Measure	Value (MEAN)	Dispersion
Psilocybin	Percentage Change of the BOLD Signal	-0.08 percentage change in BOLD signal	Standard Deviation 0.45
Escitalopram	Percentage Change of the BOLD Signal	0.43 percentage change in BOLD signal	Standard Deviation 0.62

Secondary

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.