Towards Rapid-Acting Treatments for OCD
C AR O LY N R O D R I G U E 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 T A 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
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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.
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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
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OCD: A Chronic, Disabling Disorder
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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
Imagine you are on a hike…
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…but the only water lies in a toilet bowl. Would you drink?
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Did you pause? Did you grimace?
Wilkerson and Rodriguez, American Journal of Psychiatry, 2016
OCD: Hyperactive Fronto-Striatal Brain Circuits
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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
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Circuit Neural
Networks
Behavior
Cortex
Striatum
Thalamus
Receptor
Ketamine
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Ketamine Decreases OCD
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Ketamine: NMDA glutamate receptor antagonist
Individuals with OCD (n=15) randomized to IV ketamine or saline
Receptor Behavior
Rodriguez et al., Neuropsychopharmacology, 2013
Study Design (Flow)
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Rodriguez et al., Neuropsychopharmacology, 2013
First Phase Only
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PHASE 1
Rodriguez et al., Neuropsychopharmacology, 2013
Ketamine Rapidly Reduces OCD
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INFUSION
0
1
2
3
4
5
6
7
8
9
10
Baseline 90min 230min Day 2 Day 4 Day 6
OC
D V
isu
al A
na
log
Sc
ale
**
**
*
*
*
*
SALINE n=7
KETAMINE n=8
Rodriguez et al., Neuropsychopharmacology, 2013
First Phase
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Proportion Responders
(35% reduction in YBOCS Score)
Ketamine Saline0
10
20
30
40
50
60
70
80
90
100
0%
50%
Proportion Responders 1 week post infusion (35% reduction in YBOCS Score)
* p < 0.05
*
Ketamine (N=8) Saline (N=7)
Rodriguez et al., Neuropsychopharmacology, 2013
Quotes from Responders after Ketamine
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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
Side Effects
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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%
Rodriguez et al., Neuropsychopharmacology, 2013
Murrough, et al., 2013
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.
Summary #1
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First study showing ketamine can decrease intrusive thoughts in the absence of SRIs
Glutamate modulation may be a rapid-actingtherapeutic target for OCD
Rodriguez et al., Neuropsychopharmacology, 2013
Challenge:
Ketamine Has Side Effects
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Rapastinel
Monoclonal antibody-derived neuropeptide (Glyxin family)
Invented by Dr. Joseph Moskal
Putative NMDAR modulator
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Moskal et al., 2005
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
Could Rapastinel be an OCD Therapeutic?
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Burgdorf, J. et al., 2013; Moskal, J. et al., 2014
Study Design
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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
Acute Effects of Rapastinel
Rodriguez et al, American Journal of Psychiatry, 2016
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Assessments of Sustained Effect
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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
Summary #2
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Rapastinel is well tolerated in unmedicatedOCD 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 dosingRodriguez et al, American Journal of Psychiatry, 2016
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Future Directions Next Generation NMDAR Modulators
Ketamine’s Mechanism of Action (NIMH R01)
Biomarkers of Ketamine’s Effects (Harold Amos – RWJ)
Cortex
Striatum
Thalamus
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Rodriguez Lab
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ImpactDemonstrate 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