Reflections On The Development Of Glutamate-Based Antidepressants

Transcription

1 Reflections On The Development Of Glutamate-Based Antidepressants Phil Skolnick, Ph.D., D.Sc. (hon.) Chief Scientific Officer ASCP, May

2 Conflict of Interest I am a full time of employee of Opiant Pharmaceuticals, 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.

3 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

4 May, 2018

5 Why Has It Taken So Long? Drug Discovery Today, 2018 doi: /j.drudis

6 1990s: The Ascendancy of SSRIs Fluoxetine (Prozac) first marketed in 1988; sales of $350 mm by Sertraline (Zoloft) first marketed in 1992 Paroxetine (Paxil) first marketed in 1993 Citalopram (Celexa) first marketed in 1998 Escitalopram (Lexapro) first marketed in

7 Glutamate Antagonists: Emphasis on Neurologic Indications (Stroke, TBI, AD) [late 1980s-1990s] J. Neurobiology,

8 Nature Neuroscience (2002) 8

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10 NMDA Receptors: A Family of Ligand-Gated Ion Channels

11 Behavioral Despair : A FST Used to Detect Potential Antidepressants Porsolt, et al., Arch Int Pharmacodyn Ther

12 Tail Suspension: A Test Used to Detect Potential Antidepressants Porsolt, et al., Arch Int Pharmacodyn Ther

13 BIOGENIC AMINE BASED ANTIDEPRESSANTS REDUCE IMMOBILITY IN THE FORCED SWIM AND TAIL SUSPENSION TESTS FST (rats) TST (mice) Skolnick, et al., Eur. J. Pharmacol,

14 NMDA Antagonists Exhibit AD-Like Properties in Behavioral Despair Measures (TST) Trullas and Skolnick, Eur. J. Pharmacol. 1990

15 NMDA Antagonists Exhibit AD-Like Properties in Behavioral Despair Measures (FST)

16 NR2B ANTAGONISM IS SUFFICIENT TO PRODUCE AN AD-LIKE EFFECT

17 A COMPETITIVE NMDA ANTAGONIST (CGP 37849) REQUIRES>2 WEEKS OF TREATMENT IN THE CMS MODEL IMIPRAMINE CGP Papp & Moryl, 1994

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19 Chronic Treatment With Conventional ADs Dampens NMDA Receptor Function Boyer, et al., 1998

20 BIOLOGICAL PSYCHIATRY,

21 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.

22 Phase II: IN Esketamine In TRD Daly, et al., JAMA Psychiatry 2018;75:

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24 An NR2B Antagonist (Traxoprodil) Produces A Rapid AD-Effect in TRD

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26 Memantine Does Not Improve Depressive Symptomatology Zarate, et al., 2006

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28 Amidfar, et al.,

29 Immobility (s) Memantine Is Active In The FST (mice) * * * * 50 0 Mem 5 Mem 10 Mem 20 IMI 15 Mg/Kg Li and Skolnick, unpublished

30 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]

31 AZD 6765 Ketamine Zarate, et al., 2013

32 AZD 6765 Ketamine Sanacora, et al., 2013

33 Ketamine and Memantine More Closely Resemble One Another (Than AZD 6765) As NMDA Antagonists Mealing, et al., 1999

34 Ketamine s Hit and Run Profile May Result In A Unique Pattern of Intracellular Activation

35 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 ). 36

36 IS THE FAILURE OF OTHER NMDA ANTAGONISTS IN DEPRESSION STUDIES DUE TO INADEQUATE TARGET ENGAGEMENT? GARAY, ET AL., 2018, DRUG DISC. TODAY 37

37 A SUBANESTHETIC DOSE OF KETAMINE PRODUCES DISSOCIATIVE EFFECTS Luckenbaugh, et al., 2014

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

39 NMDA Receptors: A Family of Ligand-Gated Ion Channels

40 A Glycine-Site Partial Agonist (Rapastinel) Elicits A Rapid Antidepressant Effect Without Dissociative Side Effects J. Psychiat. Practice

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42 Conditional Removal Of The NR2B Subunit In Cortical Neurons Abolishes the AD-Like Actions of Ketamine Miller, et al.,

43 An NR2B Antagonist Is Active In the Absence of A Conditional AMPA Receptor (GluA1) Deletion 44

44 PERHAPS IT S TIME TO REVISIT AMPA RECEPTOR ACTIVATION Duman, et al.,

45 AMPA Receptor Potentiators: Selective Increase in AMPA Receptor Mediated Depolarization in Hippocampus Vandergriff, et al. (2001) 46

46 AMPA Receptor Potentiators Are Active In Behavioral Despair Measures Bai, et al.,

47 LY Increases In BDNF Expression Are Mediated By AMPA Receptors Activation Legutko, et al., 2001 NMDA Receptor Activation is NOT Required!

48 LY Increases BDNF mrna in vivo I. Acute treatment A CA1 B mg/kg + 6 h DG CA 4 CA3 C mg/kg + 24 h E D mg/kg + 24 h Mackowiak, et al., 2002

49 Biogenic Amine-Based ADs Increase The Potency of ARPs Li, et al.,

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51 Nowak Paul Skolnick Layer Trullas Popik