Reflections On The Development Of

Glutamate-Based Antidepressants

Phil Skolnick, Ph.D., D.Sc. (hon.)

Chief Scientific Officer

ASCP, May 2018

1

Conflict of Interest

• I am a full time of employee of OpiantPharmaceuticals, Inc.

• I have no financial conflicts to declare related to the materials presented in this lecture.

• The opinions and conclusions in this presentation are my own, and do not reflect those of my employer.

Ketamine for

Depression:

The Most Important

Advance in Field in

50 Years?

Szalavitz, M. (2012, October 12). Ketamine for Depression: The Most Important Advance in Field in 50 Years? TIME.com. Retrieved

February 5, 2013, from http://healthland.time.com/2012/10/05/ketamine-for-depression-the-most-important-advance-in-field-in-50-years/

https://endpts.com/with-hits-and-misses-in-first-pivotal-trials-jj-confidently-maps-a-path-to-the-fda-with-its-major-depression-med-esketamine/ May, 2018

Drug Discovery Today, 2018 doi: 10.1016/j.drudis.2018.02.006.

5

Why Has It Taken So Long?

6

1990s: The Ascendancy of SSRIs

• Fluoxetine (Prozac) first marketed in 1988; sales of $350 mm by 1989.

• Sertraline (Zoloft) first marketed in 1992• Paroxetine (Paxil) first marketed in 1993• Citalopram (Celexa) first marketed in 1998• Escitalopram (Lexapro) first marketed in 2002

J. Neurobiology, 19927

Glutamate Antagonists: Emphasis on Neurologic

Indications (Stroke, TBI, AD) [late 1980s-1990s]

8

Nature Neuroscience (2002)

NMDA Receptors: A Family of Ligand-Gated Ion Channels

Porsolt, et al., Arch Int Pharmacodyn Ther. 1977

11

”Behavioral Despair”: A FST Used to Detect Potential Antidepressants

Porsolt, et al., Arch Int Pharmacodyn Ther. 1987

12

Tail Suspension: A Test Used to Detect Potential Antidepressants

Skolnick, et al., Eur. J. Pharmacol, 200313

FST (rats) TST (mice)

BIOGENIC AMINE BASED ANTIDEPRESSANTS REDUCE IMMOBILITY IN THE FORCED SWIM AND TAIL SUSPENSION TESTS

NMDA Antagonists Exhibit AD-Like Properties

in Behavioral Despair Measures (TST)

Trullas and Skolnick, Eur. J. Pharmacol. 1990

NMDA Antagonists Exhibit AD-Like Properties

in Behavioral Despair Measures (FST)

NR2B ANTAGONISM IS SUFFICIENT TO

PRODUCE AN AD-LIKE EFFECT

A COMPETITIVE NMDA ANTAGONIST (CGP 37849) REQUIRES>2

WEEKS OF TREATMENT IN THE CMS MODEL

Papp & Moryl, 1994

IMIPRAMINE

CGP 37849

Chronic Treatment With Conventional ADs Dampens NMDA

Receptor Function

Boyer, et al., 1998

BIOLOGICAL PSYCHIATRY, 200021

A Subanethetic Dose Of Ketamine (0.5 mg/kg, i.v.) Produces A

Rapid And Sustained AD Effect In TRD (Zarate, et al, 2006)

Within 24 h, 71% met response (≥50% ↓ in HAM-D) and 29%

remission (HAM-D scores ≤7) criteria; 35% of subjects

maintained a response for at least 1 week.

23

Phase II: IN Esketamine In TRD

Daly, et al., JAMA Psychiatry 2018;75:139-148

An NR2B Antagonist (Traxoprodil) Produces A

Rapid AD-Effect in TRD

Memantine Does Not Improve Depressive Symptomatology

Zarate, et al., 2006

28

Amidfar, et al., 201729

0

50

100

150

200

Mem 5 Mem 10 IMI

**

*

15

*

Mem 20

Mg/Kg

Imm

ob

ilit

y (

s)

Memantine Is Active In The FST (mice)

Li and Skolnick, unpublished

Repeated (7d) Administration of Memantine

Reverses ‘Anhedonia’ In A Rat CMS Paradigm

Reus, et al, 2012 [20 mg/kg memantine x 7d after 40 d CMS]

Zarate, et al., 2013

AZD 6765 ≠ Ketamine

AZD 6765 ≠ Ketamine

Sanacora, et al., 2013

Ketamine and Memantine More Closely Resemble One

Another (Than AZD 6765) As NMDA Antagonists

Mealing, et al., 1999

Ketamine’s “Hit and Run” Profile May Result In A Unique Pattern of

Intracellular Activation

36

Is There A Molecular Signature(s) That Differentiates Ketamine From Other NMDA Antagonists?

-Divergence of signaling pathways following NMDA receptor blockade (or actions in addition to NMDA receptor blockade) -- perhaps related to duration of NMDA receptor blockade

-Activation of multiple intracellular pathways related to strength/duration of NMDA receptor blockade may result in a very “sharp” inverted-U shaped dose response curve (“let’s go bowling”).

GARAY, ET AL., 2018, DRUG DISC. TODAY

37

IS THE FAILURE OF OTHER NMDA ANTAGONISTS IN DEPRESSION STUDIES DUE TO INADEQUATE TARGET ENGAGEMENT?

Luckenbaugh, et al., 2014

A SUBANESTHETIC DOSE OF KETAMINE PRODUCES

DISSOCIATIVE EFFECTS

….And it may all boil down to: Target Engagement, Target

Engagement, and Target Engagement

NMDA Receptors: A Family of Ligand-Gated Ion Channels

J. Psychiat. Practice 201541

A Glycine-Site Partial Agonist (Rapastinel) Elicits A Rapid Antidepressant Effect Without Dissociative Side Effects

42

Miller, et al., 2014

43

Conditional Removal Of The NR2B Subunit In Cortical Neurons Abolishes the AD-Like Actions of Ketamine

44

An NR2B Antagonist Is Active In the Absence of A Conditional AMPA Receptor (GluA1) Deletion

45

PERHAPS IT’S TIME TO REVISIT AMPA RECEPTOR ACTIVATION

Duman, et al., 2017

Vandergriff, et al. (2001)46

AMPA Receptor Potentiators: Selective Increase in AMPA Receptor Mediated Depolarization in Hippocampus

Bai, et al., 200147

AMPA Receptor Potentiators Are Active In Behavioral Despair Measures

LY 392098 Increases In BDNF Expression Are Mediated By

AMPA Receptors Activation

NMDA

Receptor

Activation is

NOT Required!

Legutko, et al., 2001

I. Acute treatment

B

C

D

A

E

CA1

CA3DG

CA

4

LY 451646 Increases BDNF mRNA in vivo

0.125 mg/kg + 6 h

0.125 mg/kg + 24 h

0.125 mg/kg + 24 h

Mackowiak, et al., 2002

Li, et al., 200350

Biogenic Amine-Based ADs Increase The Potency of ARPs

51

Nowak Paul Skolnick Layer Trullas Popik