Towards Rapid-Acting Treatments for OCD C AROLY N R ODRIGUE Z , M.D - - PowerPoint PPT Presentation

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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

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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

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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

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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

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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

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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

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Study Design (Flow)

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Rodriguez et al., Neuropsychopharmacology, 2013

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First Phase Only

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PHASE 1

Rodriguez et al., Neuropsychopharmacology, 2013

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Ketamine Rapidly Reduces OCD

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IN INFU FUSI SION

1 2 3 4 5 6 7 8 9 10

Baseline 90min 230min Day 2 Day 4 Day 6

OCD Visual Analog Scale

** ** * * * *

SALINE n=7 KETAMINE n=8

Rodriguez et al., Neuropsychopharmacology, 2013

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First Phase

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Proportion Responders (35% reduction in YBOCS Score) Ketamine Saline

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

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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

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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 25% 0% Nausea 1 12.5% 0% Vomiting 1 12.5% 0% Headache 1 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

  • f less than 20 mm Hg systolic and 10 mm Hg diastolic.
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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-acting therapeutic target for OCD

Rodriguez et al., Neuropsychopharmacology, 2013

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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

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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

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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

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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

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Summary #2

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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

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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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Impact

Demonstrate Rapidly Acting Tx Possible Shed light on severity of OCD Decrease Stigma

  • cdresearch@stanford.edu

1 Million Steps 4 OCD Walk Oakland, CA, June 4, 2016 Sacramento, CA, June 10, 2017