THE CUTTING EDGE IN ANXIETY AND DEPRESSION TREATMENT. scott shannon, md university of colorado

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1 THE CUTTING EDGE IN ANXIETY AND DEPRESSION TREATMENT scott shannon, md university of colorado

2 DISCLOSURES I have published two textbooks on integrative mental health. I have published two books on parenting I receive royalties from these books I am a PI/researcher on The Phase III MDMA assisted psychotherapy in PTSD study and receive support for my clinical work from Multidisciplinary Association for Psychedelic Studies (MAPS), a 501c3 non profit through MAPS Public Benefit Corp Corp I have no other conflicts or financial relationships to disclose

3 AGENDA Why we need innovation in psychiatry: Ketamine MDMA Psychedelics Closure and comments

4 TREATMENT RESISTANT DEPRESSION About one third of patients with major depressive disorder have TRD. No new mechanisms of tx since SSRIs in 1980s Current treatments have delayed efficacy and response Remission rates typically below 30% in large studies We do not understand the pathophysiology of depression or any other psychiatric illness

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6 KETAMINE Anesthetic agent created in Approved in US in Used widely around the world A preferred battlefield and third world anesthetic. No cardiac or resp. depression Dissociative mechanism Extremely safe track record with medical use On WHO list of essential medicines

7 KETAMINE Drug of abuse-schedule III in US since 1999 Ulcerative cystitis found in daily abusers Nausea is the most common low dose issue Selective antagonist of NMDA receptor Anti-depressant effect noted for decades Multiple analogues under development. Short half life

8 KETAMINE IS DIFFERENT Response in few hours to few days Dramatic reduction in suicidal ideation almost immediately. Wide range of positive studies, mostly small Wide range of routes: IV, IM, SQ and Intranasal Generic drug-very cheap.

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10 KETAMINE AND DEPRESSION The marked acute antidepressant efficacy of ketamine, even in medication-refractory patients, now seems beyond doubt. A meta-analysis of 9 ketamine RCTs (pooled N = 234) found that ketamine attenuated depression significantly more than did control treatment. The antidepressant benefits were apparent at 40 minutes, peaked at day 1, and were lost by days Andrade, C J Clinical Psychiatry 2017 Apr;78(4):e415-e419.

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12 INTRANASAL ESKETAMINE S-enantiomer: higher affinity for NMDA receptor Phase II, DB, PC multisite study of 67 adults with TRD 4 Phases: screening, DB tx for 15 days, open label continuation for days and 8 weeks follow-up. Twice weekly in DB, once weekly in open label and then q 2 weeks 3 adverse events: dissociation, headache, syncope noted Daly, E et al JAMA Psychiatry 2017 Dec 27 epub ahead of print

13 INTRANASAL ESKETAMINE All 3 doses showed an effect size of over 2.0 A clear and significant ascending dose response relationship Response appeared to persist for over 2 months with reduced dosing frequency. Overall-well tolerated. Daly, E et al JAMA Psychiatry 2017 Dec 27 epub ahead of print

14 QUESTIONS How do we prolong the effect? Can we use SL lozenges or IM injections? Are there any long-term risks for patients? Are the effects cumulative? What is the ideal induction schedule? Which psychiatric medications limit the response? (lamotrigine and benzos are speculated)

15 MDMA A new use for an old medication

16 MDMA Ring-substituted phenylisoproylamine derivative Patented in 1914 by Merck. Now off-patent. Empathogen Closeness to others Empathy Well-being Insightfulness Little perceived loss of control vs. classical psychedelics

17 MDMA PHARMACOLOGY MDMA Increases release of: serotonin (5-HT) norepinephrine (NE) dopamine (DA) Enhances release of hormones: oxytocin prolactin vasopressin cortisol

18 LEGAL THERAPEUTIC USE, PRE-1985 SCHEDULING Greer and Tolbert (1986) Clinical experience and 2 year follow-up of 29 patients after MDMA-assisted psychotherapy. Grinspoon and Bakalar (1986) Review of therapeutic use with numerous cases Samuel Widmer, MD, Peter Gasser, MD, et.al Swiss Medical Society for Psycholytic Therapy permission from the Swiss Ministry of Health to administer MDMA to patients from 1988 to patients received MDMA, no significant adverse effects reported.

19 RESURGENCE OF MDMA CLINICAL RESEARCH

20 WHY STUDY MDMA? VA/DoD Clinical Practice Guidelines (2017): We recommend individual, manualized traumafocused psychotherapy over other pharmacologic and non-pharmacologic interventions for the primary treatment of PTSD. Psychotherapy is the definitive treatment, but doesn t always work What about a drug that could catalyze psychotherapy?

21 SURVEY OF PSYCHIATRISTS Survey: 20 psychiatrists with long term experience with MDMA Altered perception of time 90% Enhanced ability to be open 85% Decreased defensiveness 80% Decreased fear 65% Increased awareness of emotions 50% Less aggression 50% Liester, MB J Nervous Mental DO :345-52

22 STUDY DESIGN: PHASE 2 CHRONIC, TREATMENT-RESISTANT PTSD Stage 1 Unblind Assessment Screening Measures Prep Sessions Integrative Sessions Integrative Sessions Assessment Primary Endpoint Integrative Sessions Assessment Two Month Follow up Assessment Long-term Follow-up Experimental Session Experimental Session Stage 2 Experimental Session Open-label crossover for Low/Medium/Placebo Group

23 THERAPEUTIC APPROACH Non-directive, supporting emerging experience Inner healing intelligence Reclining, headphones with music, eyeshades Alternating inner focus & talking to therapists Allows for therapists individual variation Importance of preparation and integration

24 PHASE 2 CLINICAL TRIAL (MP-1) N = 20 Crime related PTSD Failed psychotherapy & psychopharmacology Required to taper off psychiatric meds Mithoefer MC et al. J Psychopharm. 2011;25(4):

25 STAGE 1: MEAN CAPS-4 SCORES BY GROUP Time*Group Interaction p=0.015 Mithoefer MC et al. J Psychopharm. 2011;25(4):

26 LONG-TERM FOLLOW-UP: GLOBAL MEAN CAPS Months Post Final MDMA Session (Mean = 45.4 Months, SD = 17.3 Months) Of 16 CAPS completers: 12% (2/16) relapsed 88% sustained benefit Assuming 3 CAPS non-completers relapsed: 26% relapsed (5/19) 74% sustained benefit Mithoefer MC et al. J Psychopharm. 2013; 27(1):28-39 * Error bars represent SD.

27 PTSD OUTCOME ANALYSIS Six MDMA/PTSD Studies at Long-Term Follow-Up Stage 1 All subjects who had full dose MDMA in Stage 1 or Stage 2 *** *** p < independent samples t-test Difference Scores (End of Stage- Baseline) Stage 2 ^^^ p < within subjects t-test (End of Stage 2- Baseline 2) ^^^ ### LTFU ### p < within subjects t-test (LTFU - Baseline) Primary Outcome across 6 studies at 5 sites pretest-posttest Cohen's d effect size for mg = mg = 0.6 Between group Cohen s d effect size: 0.9 Stage 1 Baseline Primary End of Stage 1 Stage 2 Baseline End of Stage 2 12-Month Follow-up

28 FEAR MEMORY IS THE KEY Conclusions: We validate enhancement of fear memory extinction by MDMA in a translational behavioral model, and reveal the importance of 5- HTT and 5-HT2A receptors to this effect. These observations support future clinical research of MDMA as an adjunct to exposure therapy, and provide important pharmacological considerations for clinical use in a population frequently treated with 5-HTT inhibitors. Acute and chronic treatment with a 5-HT transporter (5-HTT) inhibitor blocked MDMA's effect on fear memory extinction. Young, MB et al Psychopharmacology (19):

29 QUOTES FROM STUDY PARTICIPANT Iraq changed my brain, MDMA changed it back.

30 PSYCHEDELICS AND THE BRAIN What does this tell us about who we are?

31 INTRINSIC BRAIN ACTIVITY On-going resting demands The brains operating system Consumes 70 to 90% of the brain s energy demands DMN is by far the largest player Specific tasks add very little to energy demands Other related networks: salience and frontoparietal

32 DEFAULT MODE NETWORK (DMN) Network of interacting brain regions Functional hubs: posterior cingulate, precuneus, medial prefrontal cortex, temporal cortex and pole, etc. Changes with cognitive development Activates with mind wandering or rest De-activates with goal oriented tasks The CNS equivalent of our inner context

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34 DMN AND DEPRESSION Increased DMN activity in depression Meditation decreases DMN intensity All modes of meditation work Stronger connectivity in key areas for experienced meditators Brewer, JA PNAS (50):

35 DEPRESSIVE RUMINATION, DMN AND THE DARK MATTER OF NEUROSCIENCE Reliably increased connectivity between DMN and Subgenual PreFrontal Cortex in Maj Dep DO: predicts rumination Subgenual PFC is affectively laden content with increased activity in MDD Hamilton, JP Biol Psychiatry (4):

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37 Not unconsciousness or dissociation WHAT IF WE COULD TURN OFF OUR DMN?

38 PSYCHEDELICS Classical psychedelics: LSD, Mescaline (Peyote), DMT (Ayahausca), Psilocybin (mushrooms) Empathogens: MDA, MDMA, 3MMC Other psychedelics: Ibogaine, 2CB,

39 MORE IN THE PRESENT...

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41 Grob, Archives of General Psychiatry,

42 Krebs, Journal of Psychopharmacology, 2012

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45 SPIRITUAL AND MYSTICAL the big picture

46 ELEMENTS OF MYSTICAL EXPERIENCE Unity (core element) Ineffability Sacredness Transcendence of time Noetic Quality-ultimate reality

47 SPIRITUAL? Department of Neuroscience-John Hopkins U 30 subjects: psilocybin or methylphenidate DB RCT: 30 mg/70 kg and 40 mg/ 70 kg x months:..substantial personal meaning and spiritual significance and attributed to the experience sustained positive changes in attitudes and behavior consistent with changes rated by community observers. 61% in psilocybin group: complete mystical experience Griffiths, Psychopharmacology 2006, (187): 268.

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49 IT HAS POWER One month later 83%: This was a top five event in my life 89%: it created behavioral change Intensity of psilocybin exp not predictive Intensity of mystical experience is predictive Effects sustain for 14 months (self rated and outside validation) Griffiths, Psychopharmacology 2006, (187): 268.

50 OBSERVED EFFECTS Love of Others Decreased hatred Increased Reverence Increased Gratitude for Life Griffiths, Psychopharmacology 2006, (187): 268. Increased altruism

51 DRUG HARM SCALE NUTT, DAVID LANCET 2010, 376

52 Journal of Psychopharmacology, 2015

53 R o BRAIN STATES THAT STICK

54 TROUGHS AND ATTRACTORS

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56 SUMMARY Our current treatments for depression come up short Ketamine appears to work well and quickly for depression Sustained effect is the challenge MDMA shows early promise as a tool to treat PTSD Psychedelics possess strong potential as tools of inner change, spiritual awakening and personal growth

57 RESOURCES Grob, Charles Hallucinogens, 2002 Holland, Julie Ecstasy: The Complete Guide, 2001 Hyde, Steven Ketamine for Depression, 2015 Multidisciplinary Association for Psychedelic Studies (MAPS): Sessa, Ben Psychedelic Renaissance, 2012 Shroder, Tom Acid Test, 2014 Tupper, Ken Psychedelic Medicine, CMAJ DOI: /cmaj Wolfson and Hartelius The Ketamine Papers, 2016

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59 SCOTT SHANNON, MD Wholeness Center 2620 E Prospect Rd. #190 Fort Collins, Colorado scott@wholeness.com

60 SIX MOST COMMON REACTIONS DAY OF EXPERIMENTAL SESSIONS