towards rapid-acting treatments for ocd · rodriguez et al., neuropsychopharmacology, 2013...

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

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.

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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

4

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…

5

…but the only water lies in a toilet bowl. Would you drink?

6

7

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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First Phase Only

13

PHASE 1


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


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)


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”


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%


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


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


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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)


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

[email protected]

1 Million Steps 4 OCD Walk Oakland, CA, June 4, 2016

Sacramento, CA, June 10, 2017

towards rapid-acting treatments for ocd · rodriguez et al., neuropsychopharmacology, 2013...

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