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Beyond the Monoamines: Neurotransmitters in the Etiology of Major Depressive Disorder

Beyond the Monoamines: Neurotransmitters in the Etiology of Major Depressive Disorder. James W. Murrough, MD, PhD Associate Professor of Psychiatry and Neuroscience Director, Depression and Anxiety Center for Discovery and Treatment Icahn School of Medicine at Mount Sinai. Disclosures.

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Beyond the Monoamines: Neurotransmitters in the Etiology of Major Depressive Disorder

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  1. Beyond the Monoamines: Neurotransmitters in theEtiology of Major Depressive Disorder James W. Murrough, MD, PhD Associate Professor of Psychiatry and Neuroscience Director, Depression and Anxiety Center for Discovery and Treatment Icahn School of Medicine at Mount Sinai

  2. Disclosures • Advisory Board / Consultation • BoehreingerIngelheim, FSV7, Sage Therapeutics, Novartis, Medavante-Prophase, Fortress Biotech, Allergan, Global Medical Education • Research Support (Industry) • Avanir Pharmaceuticals • Research Support (Federal and Non-Profit) • NIH, NIMH, Brain and Behavior Research Foundation, Doris Duke Charitable Foundation, Charles A. Dana Foundation, American Foundation for Suicide Prevention • Patents • Ketamine for the treatment of depression (Mount Sinai - Licensed) • Neuropeptide Y for the treatment of mood and anxiety disorders (Pending)

  3. Learning Objectives: • To understand the current state of the field in terms of the neurotransmitters and neural systems that are implicated in the etiology of depression • To understand how new insights into the basic mechanisms of depression may advance novel antidepressant treatment development Mount Sinai / Presentation Name / Date

  4. Outline • Burden and Neurobiology of Depression • Future Treatments: Beyond Monoamines • Glutamate / GABA • KCNQ Channels • Neuropeptide Y

  5. Burden and Neurobiology of Depression

  6. The Global Burden of Depression Depression Accounts for Greatest Disability Among all CNS Disorders • Among most common and disabling condition worldwide • 70 million years lost to disability • 1 million suicides annually and rising • 1 in 3 patients do not respond to available treatments Whiteford et al. Lancet 2013

  7. Monoamine Targets of Current Pharmacotherapy for MDD Otte et al. Nature Rev Dis Primer, 2016

  8. Cellular Basis of Depression: Loss of Plasticity and Synaptic Function Above: Chronic stress causes atrophy of neuronal processes and decreases synapse number • Key Regulators of Synaptic Plasticity • Neurotransmitters • Neurotrophic Factors • Cytokines • Sex steroids • Glucocorticoids Above: Multiple signaling pathways that influence synapse formation and that could contribute to loss of synapses in depression Duman et al. Nat Med, 2016

  9. Future Treatments: Beyond Monoamines

  10. Role of the Glutamate Synapse in Stress and Depression Duman et al. Nat Med, 2016

  11. Ketamine Discovery Sparks Paradigm Shift in Depression Murrough and Charney, Nature Med 2010. Charney and Manji, Science STKE 2004. • Ketamine is first drug to show rapid antidepressant effects (within hours) • First to show rapid therapeutics effects in patients with treatment resistance • First to show rapid anti-suicidal effects • Re-directs drug discovery efforts to focus on the glutamate system

  12. Ketamine Rapidly Reverses Stress-Induced Synaptic Loss in Rodents Gerhard, Wohleb, Duman. Drug Disc Today, 2016

  13. Phase II Results of Intranasal Esketamine in Major Depression Efficacy of Adjunctive Esketamine in Treatment Resistant Depression Rapid Reductions in Depression and Suicidal Ideation in Acute Setting Canuso et al. Am J Psych, 2018 Daly et al. JAMA Psych, 2018

  14. Glutamate Targets for Novel Drug Discovery for Depression GABAR modulation mGluR2/3 antagonism Enhance presynaptic release AMPAR potentiation Enhance EAAT function GlyT1 inhibition Extra-synaptic NMDAR blockade mGluR5 antagonism Enhance protein translation Murrough, Abdallah and Mathew. Nat Rev Drug Disc 2017

  15. Rapid Antidepressant Effects of the GABA-A Modulator Brexanolone in Post-Partum Depression Meltzer-Brody et al. Lancet, 2018

  16. Role of GABA Signaling in Cortical Circuits and Glutamate Synapsis Fogaca and Duman. Front Cell Neuro, 2018

  17. Role of KCNQ Channels in Depression and Resilience to Stress Courtesy of Ming-Hu Han Russo et al. Nat Neurosci, 2011

  18. Reduced Ventral Striatum-Cingulate Connectivity Reduced Depression Severity Enhanced Reward Learning Tan et al. Mol Psych, 2018

  19. Role of Neuropeptide Y in Depression, Anxiety and Stress Resilience Effect of NPY on Anxiety in Response to Trauma Script in PTSD (N=26) Sayed et al. Int J Neuropsychopharm; Griebeland Holmes. Nat Rev Drug Disc, 2013; Kautz, Charney and Murrough. NeurosciLett, 2017

  20. Glutamate Modulators NMDAR antagonists NMDAR PAMs mGluR2/3 antagonists mGluR5 antagonists AMPAR potentiators EAAT2 potentiators GlyT1 inhibitors GABA Modulators GABAR PAMs Inflammatory Modulators COX inhibitors TNF-alpha MABs IL-6 MABs Neuropeptide Systems NPY Orexin Potassium Channels KCNQ HPA Axis Modulators GR antagonists CRF antagonists Opioid Modulators Kappa antagonists NeurotophicPotentiators BDNF VEGF FGF-2 Beyond Monoamines: The Future Treatment of Depression

  21. Case-Based Question Mr. A is a 47-year-old man with a history of recurrent major depressive disorder. His current episode is moderate to severe and has lasted for the past 2 years. He has had optimized treatment trials in the current episode that include 2 different SSRIs and 2 different SNRIs. All of the following would be an evidence-based next-step treatment choice except: • Augmentation of a monoamine agent with lithium • Augmentation of a monoamine agent with esketamine • Initiating a trial of rTMS • Initiating a trial of riluzole

  22. Depression and Anxiety Centerfor Discovery and Treatment Core Faculty, Staff, Trainees James Murrough Dennis Charney Manish Jha Adriana Feder Sara Costi Laura Bevilacqua Kate Collins Laurel Morris Daniel Brennan Jessica Ables Mora Grehl Abigail Collins Brittany Cho Molly Schneider Morgan Harnois Charlotte Pierce Derek Smith Collaborators at Mount Sinai Scott Russo Eric Nestler Ming-Hu Man PritiBalchandani ZahiFayad Cheuk Tang Helen Mayberg MartijnFigee Sophia Frangou Amy Aloysi Matthew Majeske Emilia Bagiella Andrew Glasgow Jess Brallier

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