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Modulating NMDA, Opiate, and 5HT-2A Receptors for Antidepressant Effects

Explore the potential of drugs targeting the NMDA receptor, opiate system, and 5HT-2A receptors to provide new options for antidepressant treatment.

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Modulating NMDA, Opiate, and 5HT-2A Receptors for Antidepressant Effects

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  1. Beyond SSRIs and SNRIs: Are Drugs that Target the NMDA receptor, Opiate System, or Modulate Serotonin 5HT-2A Receptors on the Horizon? joseph f. Goldberg, md Icahn school of medicine at mount sinai New York, ny

  2. Financial disclosures • Dr. Goldberg is a consultant for Lundbeck, Neurocrine, Otsuka, Sunovion, and WebMD; is a member of the speakers/advisory boards for Allergan, Neurocrine, Otsuka, Sunovion, and Takeda-Lundbeck; and has received royalties from American Psychiatric Publishing, Inc.

  3. Learning Objectives 1. To recognize the role of NMDA and other glutamatergic receptor targets as contributing to the antidepressant effects of ketamine and its active metabolites 2. To describe the rationale and emerging role of 5HT2A antagonists and opiate receptor modulators in the pharmacotherapy of depression

  4. GLUTAMATERGIC MODULATION OF ANTIDEPRESSANT RESPONSE • Ketamine: suspected antidepressant MOA(s): • Disinhibition of GABA interneurons via NMDA receptor blockade → • Disinhibition of pyramidal neurons → • Enhanced glutamate firing → • glu binding to AMPA • Inhibits spontaneous NMDA receptor transmission • Induces hippocampal BDNF • Enhanced glutamate throughput at AMPA • receptors via HNK metabolite Kadriu et al., Int J Neuropsychopharmacol2019; 22: 19-135

  5. Diverse Mechanisms of Action of Ketamine Newport et al., Am J Psychiatry 2015; 172: 950-966

  6. Is Ketamine Antidepressant Response Mediated by Opioid System? Naltrexone pretreatment blocks antidepressant response Williams et al., Am J Psychiatry 2018; 175: 1205-1215

  7. Open data: naltrexone does not diminish ANTIDEPRESSANT RESPONSE TO iv ketamine in depressed alcoholics Yoon et al., JAMA Psychiatry 2019 Jan 9. doi: 10.1001/jamapsychiatry.2018.3990. [Epub ahead of print]

  8. Opioid system and depression: the failure of alks-5461 (buprenorphine/samidorphan) • Rationale: • Buprenorphine=partial μ opioid agonist • Samidorphan= μ opioid antagonist • Effectively=kappa opioid receptor antagonist • 2/1/19 FDA complete response letter (advisory board: 21-1 rejection): • only one of three Phase 3 trials were significant on 1o endpoint • Additional design concerns re safety and efficacy

  9. What’s NMDA Got to Do With It?Hydroxynorketamine (HNK) HNK requires AMPA activation and does not involve NMDA receptor blockade Learned helplessness: Antidepressant-like responses in rat after single 75 mg/kg HNK injection Forced swim test: Antidepressant-like responses in rat after Single 25 mg/kg HNK injection N-demethyl- ation AMPA= α-amino-3-hydroxy-5-methyl-4-isoxazold-propionic cid Zanos et al., Nature 2016; 633: 481-486

  10. Meta-analysis: IV Ketamine in Treatment-Resistant Depression Newport et al., Am J Psychiatry 2015; 172: 950-966

  11. IN Esketamine in MDD Open label continuation: esketamine 56 mg administered on Day 15, then if/as needed up to 2x/week for weeks 1-2, weekly for weeks 3-5, then once/week thereafter Daly et al., JAMA Psychiatry 2018; 75: 139-148

  12. FDA-Recommended dosing for intranasal esketamine in mdd

  13. Impact of single dose iv ketamine on suicidal ideation Meta-analysis of 10 RCTs of IV ketamine vs. midazolam or saline placebo in 167 MDD patients with baseline SI • ES ranges from • 0.48-0.85 • Significant • effect on SI • after control- • ling for changes • in depressive • sx severity (MADRS and HAM-D) (QIDS-SR and BDI) Wilkinson et al., Am J Psychiatry 2018; 175: 150-158

  14. Other glutamatergic modulators: rct data 1Preskorn et al., J PsychiatrPract2015; 21: 140-149; 2https://www.allergan.com/News/News/Thomson-Reuters/Allergan-Announces-Phase-3-Results-for-Rapastinel; 3Heresco-Levy et al., Int J Neuropsychopharmacol2013; 16: 501-506 4 Mathew et al., Int J Neuropsychopharmacol2010; 13: 71-82 5 Mathew et al., Neuropsychopharmacol 2017; 42: 2567-2574

  15. Other glutamatergic modulators: rct data 1 Zarate et al., Am J Psychiatry 2006; 163: 153-155; 2 Smith et al., J Clin Psychiatry2013; 74: 966-973; 3 Anand et al., Bipolar Disord2012; 14: 64-70; 4Sanacora et al., Molec Psychiatry 2014; 19: 978-985; 5Sanacora et al., Neuropsychopharmacol2017; 42: 844-853; 6Preskorn et al., J Clin Psychopharmacol2008; 28: 631-617; 7 Ibrahim et al., J Clin Psychopharmacol2012; 32: 551-557

  16. 5HT2A Receptor Modulation • High postsynaptic density associated with depression, suicide completions 1 • High concentration in apical dendrites of cortical layer V pyramidal neurons • Antagonism ↑’s PFC DA release 1Eison & Mullins. Behav Brain Res 1996; 73: 177-181

  17. Pimavanserin in mdd • Phase 2 trial (“CLARITY”): n=207 MDD patients unresponsive to a first-line SSRI or SNRI • 28-site 10 week RCT of pimavanserin 34 mg/day vs. placebo • Pimavanserin (n=51) > placebo (n=123) on 1o endpoint (∆ HAM-D17 from baseline; p=.039) • Post hoc: significant separation from placebo weeks 2-10 7/11 2o outcome measures nominally significant: “Response” (p=.0075), SDS (p=.004), CGI-S (p=.0084), CGI-I (p=.0289), Barratt Impulsiveness Scale, Karlolinska Sleepiness Scale (p=.0075), MGH Sexual Functioning Index (p=.0003) http://www.acadia-pharm.com/pipeline/pimavanserin-major-depressive-disorder/

  18. Conclusions • Ketamine and esketamine both have growing database suggesting rapid efficacy for substantial majority of MDD patients • Antiglutamatergic mechanisms may contribute to observed antidepressant benefits of ketamine and esketamine; ? role of opiate modulation • Uncertainty about opiate modulation more broadly as a robust antidepressant target • Class effects of NMDA receptor antagonists as antidepressants are not well-established • Uncertainties about optimal “protocol” and necessity for repeated dosing to sustain benefit and prevent relapse • Emerging role for 5HT2A antagonism in treatment of depression

  19. Case-Based Question • A 43-year-old mid-career academic molecular neurobiologist with 3 lifetime major depressive episodes since college (never manic, psychotic, or hospitalized) now presents with a recurrence involving anhedonia, anxiety, and passive but distressing suicidal thoughts. He previously had suboptimal responses to adequate trials of SSRIs, SNRIs, adjunctive mirtazapine or aripiprazole or lithium but never had ECT, rTMS, or tried an MAOI. He asks your opinion about novel or experimental antiglutamatergic agents with putative AMPA receptor modulation for depression. With an “aha!” you say “you must be referring to:” • rapastinel • Pimavanserin • Ketamine • Hydroxynorketamine • riluzole

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