Back to the Future: Psilocybin Trials in Treatment Resistant Depression in the UK.

Transcription

1 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 james.rucker@kcl.ac.uk

2 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

3 Two Questions 1 2 Can psilocybin be developed into a medicine? Will psilocybin be developed into a medicine?

4 Two Questions Can psilocybin be developed into a medicine? Will psilocybin be developed into a medicine? Yes Only if the evidence supports it.

5 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)

6 SCHEDULE 1 UK Misuse of Drugs Act (1971) SCHEDULE I UN Convention on Drugs (1967)

7 PSYCHEDELIC PUBLICATIONS (PROPORTION OF TOTAL PUBMED PUBLICATIONS) Pre Schedule I Post Schedule I Year

8 Phase 1 trials (Switzerland)

9 Phase 1 Trials 2011, United Kingdom (Imperial College London)

10 Early Phase 2 Psilocybin Trial in TRD, UK, 2016, Imperial College London

11 Drug Development & Clinical Trials Olanzapine Pre Clin Ph. 1 Ph. 2 Ph. 3 Approval PMS/Phase 4 Sativex (THC/CBD) Esketamine MDMA (also Schedule 1) Psilocybin Main obstacles: 1. Money 2. Stigma 3. GMP source of drug 4. (Schedule 1) 7 17 years $350,000,000 8%

12 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 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

13 Participant Demographics Number Sex Age (yrs) Ethnicity Employment status Illness duration (yrs) BDI 1 Female 43 Black Employed Male 40 Hispanic Unemployed Male 37 White Employed Female 30 White Studying Male 34 White Unemployed Female 57 White Unemployed Male 52 White Unemployed Female 37 White Employed Male 37 White Unemployed Female 36 Black Unemployed Female 64 White Employed Male 45 White Employed Male 27 White Employed Male 49 White Unemployed Male 56 Black Unemployed Male 42 White Unemployed Male 31 Asian Unemployed Male 58 White Part retired Male 62 White Retired Male 44 White Unemployed Mean illness duration = 17.7 years (7 30) Mean medications tried = 4.6 (2 11) 13/20 were psilocybin naïve

14 Variable 1 week 1 week 1 week 1 week 1 week 1 week 3 months START END Telephone and face to face psychiatric screening Preparation 1 2 hours Preparation 1 2 hours Psilocybin session (10mg) 6 8 hours Psilocybin session (25mg) 6 8 hours Integration 1 2 hours Integration 1 2 hours Telephone follow up Clinical measures Clinical measures MRI + Clinical measures Clinical measures Clinical measures MRI + Clinical measures Clinical measures Clinical measures Study Design 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

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16 Details of adverse events No serious adverse events Transient adverse events (expected) 15/20 reported mild anxiety ( mins) 5/20 reported mild nausea (1 3 hours) 3 instances of mild paranoia responsive to reassurance: subsided after 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

17 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

18 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),

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21 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.

22 Psilocybin RCTs What are we Testing? BEFORE MADRS/QIDS Psilocybin + Psychological Support MADRS/QIDS AFTER Randomise No difference Vs. Null hypothesis = No difference Alternative hypothesis = Improvement MADRS/QIDS Placebo + Psychological Support MADRS/QIDS

23 Current UK Phase 2 Trials Inception Authorisation Completion Publication King s College London PsiDeR (TRD) (NIHR) P TRD (TRD) (also Newcastle, Manchester and 9 other EU sites) (COMPASS) P HV (Healthy volunteers) (COMPASS) Imperial College London PsiloDEP (TRD) (MRC) PsiloDEP RCT (non TRD) (Alex Mosley Charitable Trust)

24 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.

25 P TRD Recruitment Criteria 1. Age 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 psilocybin@kcl.ac.uk

26 P TRD Basic Design Up To 8 weeks 1 day 12 weeks 1mg psilocybin Recruit Taper ADx Randomise 10mg psilocybin Follow Up Study End 25mg psilocybin Visit Description Screening Visit Baseline Visit Treatment Visit 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 weeks Location King s College Hospital Clinical Research Facility Length of hours 8 hours 4 hours 4 hours 2 hours 2 hours Visit hours hours

27 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)

28 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 Inbetween primary and secondary care Delivered in specialist centres only

29 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 psilocybin@kcl.ac.uk

30 Thank you

31 Other Clinical Psychedelic Studies

32 Psilocybin Phenethylamine Mescaline CLASSICAL PSYCHEDELICS 5 HT/Serotonin Tryptamines DMT LSD Ergolide

33 Type 2a Serotonin Receptors (5 HT 2a R) Mediate the Psychedelic Effect 5 HT 2A R affinity LSD Potency 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),

34 Where is the 5 HT 2a Receptor? Hot colours = 5 HT 2A 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),

35 Acknowledgements: Prof Allan Young, Prof David Nutt, Dr Robin Carhart Harris, Dr Nefize Yalin, Dr Dilveer Sually, Prof Mitul Mehta, Dr Luke Jelen, Dr Simon Ruffell, Dr Robert Lawrence, Prof Anthony Cleare, Dr James Stone, Dr Paul Stokes, Dr Roland Zahn, Dr Camilla Day, Prof Peter McGuffin, Dr Gerome Breen.and last (but BY NO MEANS least) the inestimable Mrs Caroline Loveland