Psilocybin-assisted therapy for the treatment of resistant major depressive disorder (PsiDeR): protocol for a randomised, placebo-controlled feasibility trial

This paper (2021) lays out the protocol for a randomized, placebo-controlled trial exploring the safety and efficacy of using psilocybin-assisted therapy for the treatment of treatment-resistant major depressive disorder (MDD). Up to 60 participants will be selected and randomized to a single dosing session of 25mg psilocybin or placebo.

Abstract

“Introduction Psilocybin-assisted therapy may be a new treatment for major depressive disorder (MDD), with encouraging data from pilot trials. In this trial (short name: PsiDeR) we aimed to test the feasibility of a parallel-group, randomised, placebo-controlled design. The primary outcomes in this trial are measures of feasibility: recruitment rates, dropout rates and the variance of the primary outcome measure of depression.

Methods and analysis We are recruiting up to 60 participants at a single centre in London, UK who are unresponsive to, or intolerant of, at least two evidence-based treatments for MDD. Participants are randomised to receive a single dosing session of 25 mg psilocybin or a placebo. All participants receive a package of psychological therapy. The primary outcome measure for depression is the Montgomery Asberg Depression Rating Scale collected by blinded, independent raters. The primary endpoint is at 3 weeks, and the total follow-up is 6 weeks. With further informed consent, this study collects neuroimaging and omics data for mechanism and biomarker analyses and offers participants an open label extension consisting of a further, open label dose of 25 mg of psilocybin.

Ethics and dissemination All participants will be required to provide written informed consent. The trial has been authorised by the National Research Ethics Committee (20-LO/0206), Health Research Authority (252750) and Medicine’s and Healthcare Products Regulatory Agency (CTA 14523/0284/001-0001) in the UK. Dissemination of results will occur via a peer-reviewed publication and other relevant media.”

Authors: James Rucker, Hassan Jafari, Tim Mantingh, Catherine Bird, Nadav Liam Modlin, Gemma Knight, Frederick Reinholdt, Camilia Day, Ben Carter & Allan Young

Summary

Psilocybin- assisted therapy may be a new treatment for major depressive disorder. This trial aimed to test the feasibility of this treatment.

This study recruits participants who are unresponsive to or intolerant of at least two evidence-based treatments for MDD. They receive a package of psychological therapy and a single dosing session of 25 mg psilocybin.

All participants will be required to provide written informed consent, and results will be disseminated via a peer- reviewed publication and other relevant media.

NCT04959253.

INTRODUCTION

Major depressive disorder is a disabling and economically costly mental health problem. There have been no significant medical treatment developments for MDD since the introduction of selective serotonin reuptake inhibitors in the late 1980s.

Psychedelic drugs were marketed as treatments for depression before being classified in Schedule 1 of the Misuse of Drugs Regulations in 1971. Despite this classification, many patients with depression improved with psychedelic therapy.

Psilocybin was isolated and synthesised by Albert Hofmann in 1957 and 1958, and has subjective effects including heightened emotions, mystical experiences, misperceptions and blurring of conceptual boundaries.

In a phase 1 trial, 89 healthy volunteers were randomised to receive placebo, 10 mg of psilocybin or 25 mg of psilocybin. There were no serious adverse events and no negative effects on cognitive tasks.

20 adults were given two oral doses of psilocybin, 10 mg and 25 mg, 1 week apart in a clinical research facility with psychological support before, during and after the experience. The patients’ depression severity was markedly reduced, but the study was not blinded or have a placebo control group.

This trial compared the feasibility and safety of psilocybin-assisted therapy with placebo-assisted therapy in adult participants with treatment resistant MDD. It also estimated the variance in the primary depression outcome measure between groups to inform a power calculation for a future efficacy trial.

TRIAL OBJECTIVES

A phase 3 trial of psilocybin in treatment resistant MDD will be evaluated by measuring recruitment rates, dropout rates, and estimating the variance of the primary outcome measure.

The secondary objectives of this trial are to assess the clinician-rated efficacy of psilocybin 25 mg compared with placebo, to assess the participant-rated efficacy of psilocybin 25 mg compared with placebo, and to assess the safety and tolerability of psilocybin in participants with TRD.

Trial design

The trial is taking place in London, UK, between September 2020 and September 2023. It is a parallel group, double-blind, randomised, placebo-controlled, between- subjects, single centre, exploratory design.

The trial was funded by the National Institute for Health Research and was peer- reviewed by delegates on the sponsor.

Patient

Three participants from a similar pilot trial were engaged in the design of this trial, and five people with lived experience of mental health difficulty were recruited to the trial steering committee.

Since the study is exploratory, formal sample size calculations were not undertaken. However, 60 participants are considered sufficient to test the intervention and provide adequately reliable estimates of recruitment rate and loss to follow-up.

Trial activities

Recruitment occurs via referrals from primary and secondary care, psychological therapy services, established clinical trial registries, and advertising in the community.

Screening

Participants express interest in the trial by completing an online survey, which collects basic clinical and demographic data. Those who fulfil initial eligibility criteria are further assessed by telephone or video call.

Participants must be 25-80 years of age, fluent in English, able to give informed consent, and have a primary diagnosis of MDD of moderate severity but without psychotic features. They must also have failed to respond to two or more antidepressants prescribed at the minimum effective dose.

We define evidence based psychotherapy with reference to existing National Institute for Clinical Excellence guidelines for the treatment of depression. People with the following conditions are excluded from this trial: bipolar affective disorder type 1 or type 2, any psychotic disorder, any drug or alcohol dependence syndrome, any personality disorder or any dementia.

Preparation

Participants enter a preparatory phase of up to 8 weeks, during which they engage with a psychological therapist to establish processes of practical and interpersonal support for the dosing session.

The baseline visit occurs at the end of the preparation phase. Participants are randomised 1:1 to one of two study arms (treatment or placebo).

Randomisation is performed using a web-based service hosted at the sponsor’s Clinical Trials Unit. The sequence is concealed from researchers and the trial statistician.

Dosing

The dosing visit takes place 1 – 3 days after the baseline session and is conducted in a quiet, neutrally furnished room.

A psychological therapist helps participants relax by providing practical support, breathing and relaxation techniques, and encouraging an open curiosity around experiences as they arise.

Follow-up

The follow-up period is 6 weeks, and participants receive at least 4 hours of post dosing psychological support. This support consists of normalisation of emotional content and experiences, and emotional and experiential exploration of material relevant to depression.

Recruitment capability

We will evaluate the recruitment capabilities by reporting the number of patients screened, not found eligible, refusal rate before randomisation, excluded due to safety concerns, and numbers found eligible and recruitment rate at baseline (final eligibility).

Follow-up and adherence to the allocated treatment

The follow-up rate, withdrawals and reasons for withdrawal will be reported at each follow-up and by treatment arm. Descriptive statistics will be used to compare missing data with the complete follow-up.

Clinical outcomes

The primary outcome measure for depression will be the MADRS, and secondary outcomes will be the QIDS-SR- 16, GAD- 7, EQ- 5D-5L, and Work and Social Adjustment Scale.

Blinding

Psilocybin induces an altered state of consciousness that may allow participants to predict treatment allocation. Raters are independent of the immediate study team but not independent of the institution undertaking the trial.

Biological sample acquisition

Participants may consent to the collection of five sets of venous blood samples. The analysis of these samples is not intended.

Neuroimaging

Participants may consent to two 1-hour functional MRI scans, which include resting state, an emotional faces paradigm and magnetic resonance spectroscopy.

Open label extension

All eligible participants at 6-week follow-up are offered an open label extension to the main trial. This extension comprises a further single dosing session of 25 mg of psilocybin given in an identical setting.

Psychological therapist training

Psilocybin assisted therapy is a nascent field, and all therapists were professionally qualified and underwent a 3-day training course.

Trial monitoring

The King’s Health Partners Clinical Trials Office monitors the trial for regulatory compliance and quality. An independent data monitoring and ethics committee makes recommendations to the sponsor about continuing the trial.

Statistical analysis

Analysis of the primary outcome for depression will be done with fixed effects of treatment group in the model, and adjusted for baseline value of the outcome and other main baseline measures as covariates. Secondary outcomes will be done with linear and generalised linear mixed-effects models.

Ethics and dissemination

All participants will be required to provide written informed consent, and the trial was approved by the National Research Ethics Committee and Health Research Authority.

The results of this study will be published in a peer-reviewed journal, and may be discussed and publicised via other media.