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UPDATE ON EVIDENCEBASED PHARMACOLOGICAL APPROACHES IN PTSD Dr Mat Hoskins MBBCh MSc MRCPsych Psychiatrist, Traumatic Stress Service, Cardiff & Vale NHS University Health Board Clinical Lecturer, Cardiff University Pharmacological approaches in PTSD • Monotherapy • Augmentation • Drug-assisted psychological therapy • Cardiff fMRI MDMA RCT I have no commercial conflicts of interest Our MDMA study is part funded by two non-profit psychedelic research charities All Multidisciplinary Association for Psychedelic Studies (MAPS) The Beckley Foundation slides are annotated and fully referenced Available on request from : [email protected] Treating PTSD • • • Trauma-focused Psychological Therapies (TFPT) (Bisson et al 2016) • TF-CBT • EMDR Effective for >50% • Difficult work • Optimal window of arousal • High drop-outs Not available or suitable Monotherapy (Hoskins et al 2015) • Systematic review and meta-analysis • 51 studies • • • • Paroxetine Venlafaxine Sertraline Fluoxetine • Small +ve impact on PTSD Sx • No SSRI class effect Emerging monotherapy evidence • Single small +ve studies • Phenelzine • Mirtazepine • Amitriptyline • ?Topiramate • No evidence from 2 monotherapy RCTs when metaanalysed • Other +ve reviews included drug-augmentation (Jonas et al 2016) • ?Quetiapine • ?Ketamine Augmentation • Prazosin • α-1 blocker • Augments re-experiencing Sx and daytime hyperarousal • 1-16mg, PO ON or split • Case series describing Sx improvement at high doses • Usually well tolerated • SEs – injury from syncope, dizziness, nausea • ?not suitable alongside TFPT • Impede access to nightmares Emerging augmentation evidence • Mirtazepine + sertraline • Effective, tolerable • Risperidone • 3 studies, with and w/o psychosis • Very small benefit and med-high risk of bias • Topiramate w/ alcohol dependence dual ∆ • Reduced PTSD Sx and drinking Drug-assisted therapy • D-cycloserine (DCS) – a new hope? • NMDA-partial agonist • ↑ fear extinction – animals • Used in other anxiety disorders 5 RCTs – none were treatment resistant • De Kleine et al 2012 – • “lack of overall augmentation effect” • Difede et al 2014 • “statistically and clinically significantly DCS … improvement” • Litz et al 2012 • “less symptom reduction in DCS group than placebo” • Rothbaum et al 2014 • “no advantage” • Scheeringa 2013 • “no significant difference” Drug-assisted therapy: D-cycloserine • McGuire meta-analysis (2016) • DCS in prolonged exposure (PE) for anxiety disorders • Included moderators • Age, gender, co-morbidity, SSRIs, short or full-course PE, dose, time of administration • Small to moderate, albeit non-significant effect in PTSD • Greater effect in co-morbid anxiety, number of sessions, higher DCS dose, concurrent SSRIs • No strong evidence for DCS augmenting PE in PTSD • Caution against premature dismissal • Further studies needed So what does that leave us with? • Not much, unfortunately Antidepressants Anticonvulsants Antipsychotics Anxiolytics • Don’t raise hope for conventional drugs > TFPT • New psychotherapies? • 3MDR • Still trauma-focussed We urgently need new approaches We have a moral obligation to our patients to look at all options If you were to design a drug to assist TFPT, what characteristics would it have? Consider effects on: • • • • • • Arousal Relaxation Level of consciousness Memory consolidation Fear circuitry Therapeutic alliance MDMA 3,4-methylenedioxymethylamphetamine Unique psychopharmacological profile Appears First ideally suited to TFPT used as psychotherapeutic tool in late 1970s Recreational Class A illegal Stringent ecstasy ≠ clinical MDMA drug UK Home Office restrictions on research MDMA acute effects Effects last 2-5 hours Marked well being Euphoria Extroversion Empathic social engagement Decreased fear There’s a reason they call it “ecstasy” Mithoefer et al 2010 • Chronic, treatment-resistant • Average duration Sx 19.5 years • MDMA (n=12) vs placebo (n=8) • Clinically and statistically significant drop in CAPS • No drug related adverse events Mithoefer © 2009 16 Mithoefer et al 2013 • Long term follow-up data • 17-24 months • maintained statistically and clinically significant gains • No subjects reporting harm • 2 relapsed Oehen et al 2013 • Chronic, treatment-resistant • Full dose MDMA (n=9) vs low dose active-placebo MDMA (n=5) • 12 subjects reached 0.066 significance (Clinician rated) • Clinically and statistically significant self-reported improvement. • Effect size similar to Mithoefer et al 2010. • 3 MDMA sessions > 2 • No adverse events Drug-assisted therapy: MDMA-AP • Meta-analysis MDMA vs PE (Amoroso & Workman 2016) • 2 MDMA RCTs, n=40 • All treatment resistant • 13 PE RCTs, n=658 (Powers et al 2010) • Not treatment resistant on entering • MDMA-AP • Larger clinician effect size • Larger self reported effect size • Better tolerated THE NEUROCIRCUITRY OF PTSD Structural and functional abnormalities Amygdala Insula Medial prefrontal cortex Rostral anterior cingulate Hippocampus Areas associated with fear conditioning, fear extinction, and emotional regulation THE AMYGDALA AND INSULA Hyperactive in response to trauma script provocation and when processing fearful vs happy faces Positive correlation between activation and PTSD Sx severity Successful exposure therapy associated with decreased amygdala activation THE ACC, MPFC Reduced activation of mPFC in PTSD Sx provocation Diminished mPFC and ACC activation in response to fearful faces Negative correlation between mPFC, ACC activation and PTSD Sx severity Succesful exposure therapy associated with increased ACC activation THE HIPPOCAMPUS Disturbances Intrusive in memory in PTSD recollections, flashbacks Hippocampus modulates memories according to context during fear conditioning Conflicting reports Meta-analysis suggests overall reduced activity In particular, reduced activity in traumatic script provocation Successful Rx (sub-threshold PTSD) found increased hippocampal activation RESTING STATE FUNCTIONAL CONNECTIVITY (RSFC) Increased RSFC between amygdala and insula Reduced positive connectivity between amygdala and hippocampus Negative correlations between amygdala and mPFC and between rostral ACC and dorsal ACC Supports hypothesis of inhibitory role of mPFC on the amygdala MDMA IN HEALTHY CONTROLS Intensity of euphoric effect correlated with reductions of cerebral blood flow (CBF) to amygdala Amygdala Decreased Increased response to fearful faces also reduced RSFC between hippocampus and mPFC RSFC between hippocampus and amygdala Suggests MDMA exerts therapeutic effect by decreasing coupling between mPFC and hippocampus THE NEUROBIOLOGICAL EFFECTS OF MDMA Unique psychopharmacological profile Exerts main effect through release of pre-synaptic serotonin To a lesser extent dopamine, noradrenaline and cortisol Rapid The and robust release of oxytocin love hormone Receptors or site in the brain where MDMA acts: Increased 5-HT1A Serotonin: 5-HT1B (POSITIVE MOOD + CREATIVE THINKING) What are the effects? 5-HT2A Why this helps with psychotherapy? ↓ depression Less anxiety and ↓ anxiety aggression improves ↓fear (at the amygdala) relationship with ↓ aggression and therapist defensiveness Allows patient to focus ↑ self-confidence on trauma without being overwhelmed by negative affect Alterations in perception of meaning Facilitates new ways of thinking of old experiences Receptors or site in the brain where MDMA acts: What are the effects? Why this helps with psychotherapy? Increased Dopamine, ↑ level of alertness Improved behavioural Noradrenaline and cortisol ↑ arousal readiness ↑ conscious registration Improved recall of (STIMULATION) of external stimuli (at state-dependent LC) memories of stressful Increase fear extinction events Provides ‘Optimum Arousal Zone’ Receptors or site in the What are the effects? brain where MDMA acts: Increased alpha-2 activity (RELAXATION) ↑ calmness and relaxation ↓hypervigilance Why this helps with psychotherapy? Provides improved mental state for exploring negative cognitions Provides ‘Optimum Arousal Zone’ Receptors or site in the What are the effects? brain where MDMA acts: At the hypothalamus Release of oxytocin (EMPATHY / BONDING) Why this helps with psychotherapy? Improved attachment with therapist Improved empathy, trust and closeness Empathogen • A substance that produces profound feelings of empathy, trust and intimacy MDMA APPEARS IDEALLY SUITED FOR TFPT Positive mood and creative thinking New insights Stimulation Window of optimal arousal Relaxation Paroxysmal Empathy and Bonding Therapeutic alliance Cardiff fMRI MDMA study Acute effects of MDMA in pts with PTSD have never been investigated £200k funding secured Double blind, crossover, fMRI RCT Explore mechanism of therapeutic effect MDMA full dose (125mg) Vs placebo • Resting state functional connectivity • Response to non-trauma related emotional stimuli • PTSD sx provocation • Cognitive and emotional empathy Cardiff fMRI MDMA study N=10 • Screening • Enrolment • Baseline assessment s • CAPS5 >40 • Chronic, treatment resistant • Medication washout • Preparatory sessions MDMA Placebo N=20 C A P S 5 N=10 C A P S 5 Placebo 2 weeks C A P S 5 C A P S 5 MDMA Follow up Data analysis Hypothesis under MDMA condition Distress and arousal will be lower during Sx provocation Correlating with ↓ amygdala and ↑ mPRC activation Similar change to fearful faces Reversed RSFC correlations between amygdala and mPFC Increased cognitive and emotional empathy • MDMA Therapist training • Charleston, South Carolina • November 2016 • 2 x 8 hour therapy sessions • Placebo • 125mg + 62.5mg MDMA 2 hours later • Eye masks, music, nonverbal • No “comedown” • No adverse reactions We hope that the results from this study will add to the understanding of how MDMA could assist TFTP Develop into an NHS model Lay the groundwork for a future phase 3 RCT in Cardiff University of TFPT versus MDMA-assisted TFPT several international phase 2 RCTs Many thanks, diolch yn fawr iawn.
