Title: A Feasibility RCT of Single-Dose Psilocybin in Unipolar Depressive Disorder Resistant to Standard Treatments
Funder: Department of Health and Social Care

Abstract: Treatment resistant depression (TRD) is a common psychiatric disorder that confers high rates of personal disability, carer burden, socioeconomic costs and NHS costs associated both with the disorder itself and other physical health disorders that it is co-morbid with. TRD is strongly associated with completed suicide, and those with TRD contribute disproportionately to both the burden of morbidity/mortality and socioeconomic burden. The King's Fund estimates that combined costs for depression will exceed 15 billion annually by 2026. Despite this, there have been no breakthrough treatments for depression since the introduction of the specific serotonergic agents and cognitive behavioural forms of psychological therapy in the late 1980s. Patients with TRD are frequently prescribed multiple psychotropic agents, including antipsychotics and lithium, which often do not result in complete clinical remission and confer high side effect burden. The only other established therapy for TRD is electroconvulsive therapy, which is sufficiently stigmatised to result in many TRD patients to discount it entirely. Prior to prohibition in the early 1970s, the classical psychedelic drugs that include d-lysergic acid diethylamide, mescaline and psilocybin, were extensively used by psychiatrists in cases of depression, anxiety and addictions that were treatment resistant. Within a medically controlled and therapeutically supportive setting, the psychedelics were understood to act as pharmacological catalysts of mentally salutary change that led to clinically significant benefits in most, transformative experiences in some, and effects that often lasted long after the drug had left the body. In medically controlled settings, the rates of serious psychiatric side effects such as prolonged psychosis were noted not to be significantly different to that observed with placebos. We have recently completed a systematic review of pre-prohibition psychedelic use in broadly defined depressive disorder, which found that nearly 80% of patients were judged to have improved by their clinicians. We have also recently completed a pilot study at Imperial College London, in which 20 patients with TRD were withdrawn from their antidepressant medications and given two doses of psilocybin 1 week apart in a psychologically supportive setting under psychiatric supervision. Highly statistically significant reductions in depression relative to baseline, measured with the self-rated quick inventory of depressive symptoms (QIDS-SR) were observed at 1 week, 5 weeks, 3 months and 6 months, with the greatest reductions seen at 5 weeks. No serious adverse events occurred and the treatment was well tolerated, with high degrees of patient satisfaction. We now propose to conduct a feasibility randomised controlled trial (RCT) of psilocybin in 60 adult patients with TRD who are currently moderately-severely depressed (Hamilton Depression Rating Scale 14). Participants will be withdrawn from their antidepressant medications, and then randomised to one of two doses of psilocybin given as a single dose under the supervision of a psychiatrist and psychotherapist. Both participants and study team will be blind to treatment. The primary trial end point will be at 3-week follow-up; however, follow-up will continue for 6 months. The primary outcome measure will be the self-rated quick inventory of depressive symptoms (QIDS-SR). Pre and post-psilocybin blood samples and MRI data will also be collected for biomarker and mechanism analyses.The main aim is to assess the feasibility of the RCT design in this patient group and estimate variance in the primary outcome measure to allow a power calculation to estimate numbers required for a more definitive study. Recruitment rates, acceptance of randomisation, ease of blinding, follow-up and drop-out rates, rates of adverse events as well as the clinical practicality of withdrawing antidepressant regimens (necessary because almost all antidepressants and antipsychotics attenuate the effects of psychedelics) in this group will be assessed.

Lay abstract: Treatment resistant depression (TRD) is disabling depressive illness that does not improve despite treatment with multiple, established medical or psychological therapies. Sufferers have high rates of completed suicide, are frequently unable to work and suffer from other medical illnesses that are made worse by depression (e.g. diabetes and heart disease). The economic costs to sufferers, carers, the NHS and society is huge. Most of the treatments for TRD are either highly stigmatised (such as electroconvulsive therapy) have high side effect burdens (such as Lithium) or both. New treatments are badly needed, particularly those that have the potential to reduce the burden of medical therapy on patients.The psychedelic drugs, including psilocybin (the active component of so-called magic' mushrooms), were widely used in this patient group prior to politically motivated prohibition in 1970. In medically controlled settings, they were considered safe for use and understood to act as pharmacological catalysts of mentally salutary change in supportive, therapeutic settings. We have completed a systematic review of pre-prohibition era clinical studies using psychedelics that found that nearly 80% of patients with broadly defined depression were judged by their clinicians as improved after being treated with single or multiple doses of psychedelics. The nature of psychedelic drugs means that they are only taken as single doses, or very intermittently, unlike most antidepressant medications. Several modern pilot studies have suggested that psilocybin, taken as a single dose in a medically supported setting, is an effective antidepressant with long-lasting effects of up to 6 months. We have completed an open label pilot study using single doses of psilocybin in patients with TRD, which demonstrated both that use of psilocybin is safe in this patient group and that it may be effective when other treatments have failed.This project aims to extend this work by conducting a randomised controlled trial of psilocybin in patients with TRD to investigate whether such a trial design is feasible and practical in this patient group, and collect data needed to design future trials. Participants will be medically and psychiatrically screened before admission onto the trial. Participants will be withdrawn from their current medication regimens under the supervision of a psychiatrist. Participants will be randomised to receive 1 of 2 doses of psilocybin during 1 day at a clinical research facility, where they will be accompanied throughout by a psychiatrist and psychotherapist experienced with those under the influence of psychedelics. Participants will be allowed home at the end of the day. Participants will be followed up for 6 months and offered support to discuss any experiences that they may have had and monitor their mental health in collaboration with their usual care teams. Both participants and treating clinicians will be blind to treatment. Participants will be asked to provide a blood sample and undergo an MRI scan before and after treatment to investigate blood and neuroimaging based changes that may help develop biological markers of both depression and predictors of those that are more likely to respond to the treatment. The main aim of the trial will be to investigate the feasibility of the trial design. For example, we will measure recruitment rates, drop out rates and ease of adherence to trial protocols. There are some particular issues with this research that need to be addressed. For example, blinding of participants and treating clinicians to the treatment may be problematic because the drug has a noticeable psychoactive effect. Additionally, participants will need to be withdrawn from any current antidepressant medications before treatment (because these interfere with the effect of the treatment), and this may cause clinical problems that mean participants have to drop out before receiving the treatment. We need to measure how often this happens in practice to work out if this part of the trial protocol is feasible. We will also measure how much the primary outcome measure varies between participants. This data will allow an accurate estimation of the size and design of a more definitive trial to investigate whether psilocybin is an effective treatment in patients with depression that does not improve with standard therapies. Collection of MRI data and blood samples pre and post treatment will allow pre/post treatment comparison of the two treatment arms and investigation of blood-based and neuroimaging-based markers of illness and treatment. Linkage of participants in this trial to a larger case register of NHS patients and research participants will allow longer term follow up and economic analyses of whether the treatment is cost effective.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH