Towards Rapid-Acting Treatments for OCD C AROLY N R ODRIGUE Z , M.D ., P H .D . A S S I S T A N T P R O F E S S O R O F P S Y C H I AT R Y A N D B E H AV I O R A L S C I E N C E S S TA N F O R D U N I V E R S I T Y S C H O O L O F M E D I C I N E 1
Funding and Disclosures (Rapastinel) Study Drug: Rapastinel (formerly GLYX-13) was supplied by Naurex at no cost (since drug donation Naurex has been acquired by Allergan) Funding: 2014 NARSAD Ellen Schapiro and Gerald Axelbaum Young Investigator Award, Brain and Behavior Research (PI: Rodriguez) New York Presbyterian Youth Anxiety Center K24MH9155 (PI: Simpson) K23MH092434 (PI: Rodriguez) Dr. Rodriguez was reimbursed for time and travel to present these findings at Allergan after submitting for publication. Dr. Moskal founder and owned stock in Naurex. Dr. Burch was an employee of Naurex when rapastinel was donated. 2
Funding and Disclosures NIMH (PI: Rodriguez) K23 Novel Interventions for Adults with OCD R01 NMDAR Modulation As A Therapeutic Target and Probe of Neural Dysfunction in OCD Foundations/Donors (PI: Rodriguez) Harold Amos Medical Faculty Development Award, Robert Wood Johnson Foundation 2009 & 2014 NARSAD, Brain and Behavior Research Foundation Black Family, Graham Arader, Youth Anxiety Center Initiative Other (PI: Rodriguez) New York State Office of Mental Health Provost’s Grants Award Program Irving Institute for Clinical and Translational Research Industry (Consultant: Rodriguez) Allergan Rugen Therapeutics BlackThorn Therapeutics 3
OCD: A Chronic, Disabling Disorder 2% Lifetime prevalence Half of cases start by age 19 Only FDA-approved medication: Serotonin-reuptake inhibitors Koran et al., 2007; Koran and Simpson 2013 Koran et al., 2007; Koran and Simpson, 2013 4
Imagine you are on a hike… 5
…but the only water lies in a toilet bowl. Would you drink? 6
Did you pause? Did you grimace? Wilkerson and Rodriguez, American Journal of Psychiatry, 2016 7
OCD: Hyperactive Fronto-Striatal Brain Circuits Known Abnormalities Hyperactive Circuit Neurotransimtters Glutamate GABA Rosenberg et al., 2000; Pittenger et al., 2011; Maia et al., 2008; Ahmari et al., 2013; Burguiere et al., 2013; Wood and Ahmari, 2015 8
Cortex Striatum Thalamus Neural Behavior Receptor Circuit Networks 9
Ketamine 10
Ketamine Decreases OCD Ketamine: NMDA glutamate receptor antagonist Individuals with OCD (n=15) randomized to IV ketamine or saline Behavior Receptor Rodriguez et al., Neuropsychopharmacology, 2013 11
Study Design (Flow) Rodriguez et al., Neuropsychopharmacology, 2013 12
First Phase Only PHASE 1 Rodriguez et al., Neuropsychopharmacology, 2013 13
Ketamine Rapidly Reduces OCD 10 IN INFU FUSI SION SALINE n=7 9 * 8 OCD Visual Analog Scale 7 ** * 6 KETAMINE n=8 5 * 4 * 3 ** 2 1 0 Baseline 90min 230min Day 2 Day 4 Day 6 Rodriguez et al., Neuropsychopharmacology, 2013 14
First Phase Proportion Responders 1 week post infusion Proportion Responders (35% reduction in YBOCS Score) (35% reduction in YBOCS Score) 100 90 80 70 50% 60 50 40 30 * 20 10 0% 0 Ketamine Saline Ketamine (N=8) Saline (N=7) * p < 0.05 Rodriguez et al., Neuropsychopharmacology, 2013 15
Quotes from Responders after Ketamine Responders (4 out of 8): 1. “I feel as if the weight of OCD has been lifted…I want to feel this way forever” 2. “I feel like someone is giving me an explanation [for my OCD]” 3. “I don’t have any intrusive thoughts. I was laughing when you couldn’t find the key, which normally is a trigger for me. This is amazing, unbelievable. This is right out of a movie.” 4. “I tried to have OCD thoughts, but I couldn’t” Rodriguez et al., Neuropsychopharmacology, 2013 16
Side Effects TOTAL N=15 (8 Ketamine, 7 Saline) n % Side effects in order of frequency Ketamine Saline Ketamine Saline Feelings of unreality/ Dissociation 8 1 100% 12.5% Dizziness 2 0 25% 0% Nausea 1 0 12.5% 0% Vomiting 1 0 12.5% 0% Headache 1 0 12.5% 0% Mild transient changes in blood pressure and heart rate observed on infusion day consistent with MDD studies that show mean change pre/post IV ketamine of less than 20 mm Hg systolic and 10 mm Hg diastolic. Rodriguez et al., Neuropsychopharmacology, 2013 Murrough, et al., 2013 17
Summary #1 First study showing ketamine can decrease intrusive thoughts in the absence of SRIs Glutamate modulation may be a rapid-acting therapeutic target for OCD Rodriguez et al., Neuropsychopharmacology, 2013 18
Challenge: Ketamine Has Side Effects 19
Rapastinel Monoclonal antibody-derived neuropeptide (Glyxin family) Invented by Dr. Joseph Moskal Putative NMDAR modulator Moskal et al., 2005 20
Could Rapastinel be an OCD Therapeutic? Shows rapid anti-depressant activity without ketamine-like effects in animal models Dosing: Phase IIa randomized, multiple-dose controlled (N = 116) Showed 10 mg/kg had significant anti- depressant effects vs placebo Effect lost at higher dose Burgdorf, J. et al., 2013; Moskal, J. et al. , 2014 21
Study Design Method: Open-label: Single 3-5 min push IV Rapastinel 10 mg/kg Inclusion: OCD at least moderate severity (YBOCS>16) Unmedicated Age 18-55 Exclusion: Severe depression (HDRS>25) Lifetime psychosis, bipolar, substance dependence Rodriguez et al, American Journal of Psychiatry , 2016 22
Acute Effects of Rapastinel Rodriguez et al, American Journal of Psychiatry , 2016 23
Assessments of Sustained Effect Sustained Effect: YBOCS (independent evaluator) Measures Obsessions and Compulsions Assessed over past week Responder > 35% reduction One week post-infusion: YBOCS = 0 out of 7 met response criteria for OCD Beck Depression Inventory = not significant (p=0.2) Beck Anxiety Inventory = significant (p=0.02) Rodriguez et al, American Journal of Psychiatry , 2016 24
Summary #2 Rapastinel is well tolerated in unmedicated OCD patients, as it is in patients with depression It did not increase psychotomimetic effects, unlike ketamine Acute effects on OCD, anxiety and depression, but no effects on OCD 1 week post infusion Next Steps: repeated dosing Rodriguez et al, American Journal of Psychiatry , 2016 25
Future Directions Next Generation NMDAR Modulators Ketamine’s Mechanism of Action (NIMH R01) Cortex Striatum Thalamus Biomarkers of Ketamine’s Effects (Harold Amos – RWJ) 26
Rodriguez Lab 27
Impact Demonstrate Rapidly Acting Tx Possible Shed light on severity of OCD Decrease Stigma 1 Million Steps 4 OCD Walk Oakland, CA, June 4, 2016 Sacramento, CA, June 10, 2017 ocdresearch@stanford.edu 28
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