Beyond the Monoamines Neurotransmitters in the Etiology of

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

Disclosures ▶ Advisory Board / Consultation – Boehreinger Ingelheim, FSV 7, 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 anxiety disorders (Pending)

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 1. Burden and Neurobiology of Depression 2. Future Treatments: Beyond Monoamines 1. Glutamate / GABA 2. KCNQ Channels 3. Neuropeptide Y

Burden and Neurobiology of Depression

The Global Burden of 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 Whiteford et al. Lancet 2013 • 1 in 3 patients do not respond to available treatments

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

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

Future Treatments: Beyond Monoamines

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

Ketamine Discovery Sparks Paradigm Shift in Depression Charney and Manji, Science STKE 2004. • • Murrough and Charney, Nature Med 2010. 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

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

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

Glutamate Targets for Novel Drug Discovery for Depression 1. GABAR modulation 2. m. Glu. R 2/3 antagonism 3. Enhance presynaptic release 4. AMPAR potentiation 5. Enhance EAAT function 6. Gly. T 1 inhibition 7. Extra-synaptic NMDAR blockade 8. m. Glu. R 5 antagonism 9. Enhance protein translation Murrough, Abdallah and Mathew. Nat Rev Drug Disc 2017

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

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

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

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

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; Griebel and Holmes. Nat Rev Drug Disc, 2013; Kautz, Charney and Murrough. Neurosci Lett, 2017

Beyond Monoamines: The Future Treatment of Depression Glutamate Modulators NMDAR antagonists NMDAR PAMs m. Glu. R 2/3 antagonists m. Glu. R 5 antagonists AMPAR potentiators EAAT 2 potentiators Gly. T 1 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 Neurotophic Potentiators BDNF VEGF FGF-2

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: a) Augmentation of a monoamine agent with lithium b) Augmentation of a monoamine agent with esketamine c) Initiating a trial of r. TMS d) Initiating a trial of riluzole

Depression and Anxiety Center for Discovery and Treatment Core Faculty, Staff, Trainees Collaborators at Mount Sinai 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 Scott Russo Eric Nestler Ming-Hu Man Priti Balchandani Zahi Fayad Cheuk Tang Helen Mayberg Martijn Figee Sophia Frangou Amy Aloysi Matthew Majeske Emilia Bagiella Andrew Glasgow Jess Brallier