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Back to the Future: Psilocybin Trials in Treatment Resistant Depression in the UK.
James Rucker MBBS BSc MRCPsych PhD
Consultant Psychiatrist. South London & Maudsley NHS Trust
Senior Clinical Lecturer in Mood Disorders & Psychopharmacology. King’s College
London
NIHR Clinician Scientist Fellow
Conflicts of Interest
• I have no financial interest in the development of psilocybin as a treatment.
• I was a clinician in clinical trials of psilocybin at Imperial College London.
• I currently hold an NIHR fellowship (UK government funding) to investigate psilocybin. This pays the entirety of my salary and associated trial costs.
• The IoPPN receives money from Compass Pathways Ltd, to perform phase 1 and 2 clinical trials with psilocybin.
• I have attended trial related meetings for these trials, paid for by Compass Pathways Ltd.
• I receive no other pharma money
Two Questions
Can psilocybin be developed into a medicine?
1Will psilocybin be developed into a medicine?
2
Two Questions
Can psilocybin be developed into a medicine?
Yes
Will psilocybin be developed into a medicine?
Only if the evidence supports it.
Overview
• This talk will focus on the evidence for psilocybin in TRD thus far
• An RCT of psilocybin in TRD that will shortly start in 3 centres in the UK (London, Newcastle & Manchester)
SCHEDULE 1 – UK Misuse of Drugs Act (1971)
SCHEDULE I – UN Convention on Drugs
(1967)
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PSYCHEDELIC PUBLICATIONS (PROPORTION OF TOTAL PUBMED PUBLICATIONS)
Pre Schedule I Post Schedule I
Phase 1 trials1996 – 2008 (Switzerland)
Phase 1 Trials2011, United Kingdom (Imperial College London)
Early Phase 2 Psilocybin Trial in TRD, UK, 2016, Imperial College London
Drug Development & Clinical TrialsPre‐Clin Ph. 1 Ph. 2 Ph. 3 Approval
Sativex(THC/CBD)
MDMA (also Schedule 1)
Psilocybin
PMS/Phase 4
7 – 17 years
$350,000,000
Olanzapine
8%
Main obstacles: 1. Money 2. Stigma3. GMP source of drug4. (Schedule 1)
Esketamine
PsiloDep Trial – Psilocybin in Treatment Resistant Depression• Open label, feasibility trial of psilocybin with psychological support in resistant depression.
• Funded – Medical Research Council. 3 years.• Patients seen at Imperial College London clinical research facility (the Hammersmith Hospital) between May 2015 and April 2016.
• N=20 (6 female), current moderate or severe depression (HAMD > 17). Failed at least two antidepressant treatments.
• Primary Outcome• Quick Inventory of Depressive Symptoms (QIDS) – self rated
Number Sex Age (yrs) Ethnicity Employment status Illness duration (yrs) BDI1 Female 43 Black Employed 30 362 Male 40 Hispanic Unemployed 25 333 Male 37 White Employed 17 224 Female 30 White Studying 10 265 Male 34 White Unemployed 12 386 Female 57 White Unemployed 29 397 Male 52 White Unemployed 27 338 Female 37 White Employed 17 399 Male 37 White Unemployed 15 32
10 Female 36 Black Unemployed 8 4711 Female 64 White Employed 15 2412 Male 45 White Employed 8 3513 Male 27 White Employed 7 2914 Male 49 White Unemployed 30 3615 Male 56 Black Unemployed 30 4416 Male 42 White Unemployed 22 4517 Male 31 Asian Unemployed 7 4418 Male 58 White Part retired 10 2819 Male 62 White Retired 15 4220 Male 44 White Unemployed 20 27
Mean illness duration = 17.7 years (7‐30)Mean medications tried = 4.6 (2‐11)13/20 were psilocybin naïve
Participant Demographics
Telephone and face‐to‐face psychiatric screening
Preparation1‐2 hours
Preparation1‐2 hours
Psilocybin session (10mg)6‐8 hours
Psilocybin session (25mg)6‐8 hours
Integration1‐2 hours
Integration1‐2 hours
Telephone follow up
1 week
1 week
1 week
1 week
1 week
1 week –3 months
• Patients withdrawn from current antidepressants
• Day patient design – no overnight hospital stays
• 2 people (at least one psychiatrist) with patient at all times
• Patients accompanied home• Rescue medications (never used)
• Oral lorazepam and risperidone• No patient received additional antidepressant treatments in the 5 weeks after psilocybin treatment
• 1 patient dropped out after 25mg session, citing lack of efficacy. He provided 6 month follow up data (depression scores largely unchanged)
• 6/20 patients started new courses of antidepressants between 5 weeks and 6 months
Study Design
Varia‐ble
START
END
Clinical measures
Clinical measures
MRI + Clinical measures
Clinical measures
Clinical measures
MRI + Clinical measures
Clinical measures
Clinical measures
Details of adverse events
• No serious adverse events
• Transient adverse events (expected)• 15/20 reported mild anxiety (30‐150 mins)
• 5/20 reported mild nausea (1‐3 hours)
• 3 instances of mild paranoia responsive to reassurance: subsided after 30‐60 minutes
• 1 prolonged experience (10 hours) ‐ required us to stay with the participant until the early evening.
• 8/20 reported post psilocybin headache (< 1 day)
• No prolonged psychosis or mania
Trial criticisms…
• Low sample number (20)• Pilot trial ‐> feasibility & safety. Not a test of efficacy
• Unblinded, uncontrolled, early phase trial ‐> inflation of effect size
• Almost all self‐referrals to the trial ‐> selection bias• Hawthorne effect• Depression trials have notoriously large placebo effects
The biggest problem in this trial was obtaining GMP (good manufacturing practice) quality psilocybin.
Why? Schedule 1.
Nutt, D. J., King, L. A., & Nichols, D. E. (2013). Nature Reviews Neuroscience, 14(8), 577–585.
Essential Clinical Info About Psilocybin Therapy
• Existing antidepressants should be withdrawn prior to psilocybin therapy ‐> risks vs benefits of this.
• Single dose treatment. No ongoing medication.
• Day hospital treatment. 9am – 5pm, then home.
• Psychological support before, during and after.
• Psilocybin itself is physiologically non‐toxic• The objective pharmacological effect is mediated by 5HT2a agonism
• The subjective effect is likened to a ‘waking dream’ ‐> high entropy brain state leading to a temporary disintegration of ego‐function.
• Because of this, the set and setting of the therapy is critical.
• Thus, we are testing drug plus psychological support vs. placebo plus psychological support.
• Like ketamine, the initial evidence suggests a rapid antidepressant effect relative to established antidepressants.
Psilocybin RCTs ‐What are we Testing?
Psilocybin +Psychological Support
Vs.
Placebo +Psychological Support
MADRS/QIDS MADRS/QIDS
MADRS/QIDS MADRS/QIDS
Randomise ‐No difference
Null hypothesis = No differenceAlternative hypothesis = Improvement
BEFORE AFTER
Current UK Phase 2 TrialsInception Authorisation Completion Publication
King’s College LondonPsiDeR (TRD) (NIHR)
P‐TRD (TRD) (also Newcastle, Manchester and 9 other EU sites) (COMPASS)
P‐HV (Healthy volunteers) (COMPASS)
Imperial College LondonPsiloDEP (TRD) (MRC)
PsiloDEP RCT (non TRD) (Alex Mosley Charitable Trust)
P‐TRD (Psilocybin in Treatment Resistant Depression)
• Phase 2b, randomised, controlled trial.
• Start October 2018
• Funder – Compass Pathways.
• Double blind, 3 arm trial
• 216 adult patients with treatment resistant depression
• 1mg vs 10mg vs 25mg psilocybin
• This is not an efficacy trial. Phase 2b trials are generally about feasibility of treatment delivery and drug safety
• Phase 2b trials aim to estimate the variance in the primary outcome measure ‐> allows an estimate of sample size required for a phase 3 trial.
P‐TRD –Recruitment Criteria
1. Age 18+
2. Current ≥ moderate depression (HAM‐D ≥ 18)
3. Failed ≥ 2 antidepressants but ≤ 4. No ECT.
4. Duration of current episode 3 months to 2 years
5. No past history of mania or psychosis
6. No current drug/alcohol dependence
7. No serious suicide attempts in the past year (requiring hospitalisation)
8. In practice we are also likely to exclude people with EUPD and strong family histories of psychosis.
9. Those who fail criteria 3 & 4 may be eligible for my NIHR trial
10. Discussion of potential participants –[email protected]
P‐TRD ‐ Basic Design
Recruit TaperADx Randomise
25mg psilocybin
10mg psilocybin
1mg psilocybin
Follow Up Study End
Up To 8 weeks 1 day 12 weeks
Visit 1 2 3 4 5 6 7 8
Description ScreeningVisit
BaselineVisit
TreatmentVisit
Follow Up Visit 1
Follow Up Visit 2
Follow Up Visit 3
Follow Up Visit 4
Follow Up Visit 5
Time 1‐8 weeks 1 day 12 weeksLocation King’s College Hospital Clinical Research FacilityLength of
Visit 4 hours 4‐6 hours 8 hours 4 hours 4‐6
hours 4 hours 2 hours 2 hours
Statistical Analysis
• Performed by an institution independent from the Sponsor (Compass)
• Primary outcome measure – MADRS
• Primary outcome taken by independent, blinded raters
• Primary end point ‐ 3 weeks post treatment
• Primary statistical analysis – mixed model for repeated measures with treatment, visit, study site, prior psychedelic experience, treatment by visit interaction, participant as a random effect, and baseline MADRS total score included.
• Comparator is 1mg psilocybin vs. optimal dose (10mg or 25mg)
Longer Term
• Phase 3 trials ‐> Licensing of ‘drug plus specialist delivery context’
• Reschedule to Schedule 2 with restrictions to specialist prescribers and centres
• Cost model ‐ Psilocybin therapy ‘cheaper than a course of CBT’
• Care Pathway Point – In‐between primary and secondary care
• Delivered in specialist centres only
Summary
• Psilocybin is now being manufactured to GMP standard in the UK, with matching placebo capsules
• Significant trial funding and government approvals are now in place
• This should allow deliver good quality clinical trials that may evidence the licensing of psilocybin as a treatment for resistant depression
• However, many drugs fail and there are particular problems fitting psilocybin into the established drug development and clinical trials models
• To discuss referrals please email [email protected]
Thank you
Other Clinical Psychedelic Studies
LSD
Mescaline
Psilocybin
DMT
5‐HT/Serotonin
Phenethylamine
Ergolide
CLASSICALPSYCHEDELICS Tryptamines
Type 2a Serotonin Receptors (5‐HT2aR) Mediate the Psychedelic Effect
↑5‐HT2ARaffinity
Potency →
LSD
Glennon, R. A., Titeler, M., & McKenney, J. D. (1984). Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sciences, 35(25), 2505–2511.
Where is the 5‐HT2a Receptor?
Hot colours = 5‐HT2A in cortex
Erritzoe, D., Frokjaer, V. G., Holst, K. K., Christoffersen, M., Johansen, S. S., Svarer, C., et al. (2011). In Vivo Imaging of Cerebral Serotonin Transporter and Serotonin2A Receptor Binding in 3,4-Methylenedioxymethamphetamine (MDMA or “Ecstasy”) and Hallucinogen Users. Archives of General Psychiatry, 68(6), 562. http://doi.org/10.1001/archgenpsychiatry.2011.56
Acknowledgements: Prof Allan Young, Prof David Nutt, Dr Robin Carhart‐Harris, Dr NefizeYalin, Dr Dilveer Sually, Prof Mitul Mehta, Dr Luke Jelen, Dr Simon Ruffell, Dr Robert Lawrence, Prof Anthony Cleare, Dr James Stone, DrPaul Stokes, Dr Roland Zahn, Dr Camilla Day, Prof Peter McGuffin, DrGerome Breen….and last (but BY NO MEANS least) the inestimable Mrs Caroline Loveland