Barcelona snapshots

Prof. Sanjay J. Mathew

Sanjay J. Mathew psiquiatra Controversias Psiquiatria Barcelona
Baylor College of Medicine, EUA
Ponència Funció glutamatèrgica i nous enfocaments per a la depressió resistent al tractament
Data Divendres, 26 d'Abril, 2019
Hora 15:15 a 16:00
Taula rodona Resistència al tractament en trastorns afectius


Sanjay J. Mathew, M.D. is the Marjorie Bintliff Johnson and Raleigh White Johnson, Jr. Chair for Research in Psychiatry, Professor and Vice Chair for Research in the Menninger Department of Psychiatry & Behavioral Sciences at Baylor College of Medicine, and staff psychiatrist at the Michael E. Debakey VA Medical Center (MEDVAMC) in Houston, Texas. He attended medical school at Baylor College of Medicine and completed his psychiatric residency at Columbia University and the New York State Psychiatric Institute, where he also completed a NIH-funded research fellowship in affective and anxiety disorders. Dr. Mathew began his faculty career at the Mount Sinai School of Medicine, where he co-founded and directed the Mood and Anxiety Disorders Program. In 2010, Dr. Mathew was recruited back to his hometown of Houston to direct Baylor and VA's Mood & Anxiety Disorders Program. His research program focuses on developing novel therapies for patients with serious, treatment-resistant mood and anxiety disorders and PTSD, with a particular focus on rapid-acting glutamate-modulating agents.

Dr. Mathew's research program is currently funded by NIMH, Department of Veterans Affairs, Patient-Centered Outcomes Research Institute (PCORI), and industry in the areas of experimental therapeutics and pathophysiology of treatment-resistant depression, suicide, and PTSD. He has authored or co-authored over 120 manuscripts and book chapters, and serves on the editorial board of several journals. He is an elected member of the American College of Neuropsychopharmacology, was elected to the Board of the American Society of Clinical Psychopharmacology, and was formerly Chair of the Program Committee for the Anxiety and Depression Association of America.

Dr. Mathew is a frequent grant reviewer for NIMH, and previously served a 4-year term on the NIMH Interventions Committee for Adult Disorders. He currently serves on a standing VA Merit Review Committee, and on the Data Safety and Monitoring Board for the VA/Dept of Defense Consortium to Alleviate PTSD.

Dr. Mathew serves on the NAMI Greater Houston Advisory Board and the Board of Depelchin Psychiatric Services, and has served as a Medical Advisor to re: MIND (formerly greater Houston Depression and Bipolar Support Alliance) since 2010. An active clinician, Dr. Mathew has been selected by his peers as a "Best Doctor" every year since 2011.


Glutamate is the primary excitatory amino acid neurotransmitter in CNS with important functions in regulating cognition and mood. Converging preclinical and human studies support alterations in glutamate signaling in the pathophysiology of major depressive disorder (MDD). The N-methyl-D-aspartate (NMDA) receptor, along with AMPA, are key ionotropic glutamate receptors which have been extensively investigated as targets for drug development across CNS indications. Ketamine, used for many years as an anesthetic agent, acts as a non-selective, non-competitive antagonist within the NMDA receptor channel. Since an initial report by the Yale group in 2000 showing a rapid and robust antidepressant effect of a single subanethetic ketamine dose, there have been numerous studies of ketamine (administered primarily as an intravenous infusion, but also via the subcutaneous, oral, intranasal, and intramuscular routes) repurposed as the prototypical rapid-acting antidepressant (RAAD).

This talk will provide an overview of efficacy and safety data for ketamine and S-ketamine (the S-isomer of racemic ketamine) as a RAAD, with a focus on patients with treatment-resistant depression (TRD). An intranasal spray version of esketamine recently received U.S. regulatory approval for TRD, signifying the first non-monoaminergic antidepressant approved in the U.S. While there is substantial evidence for ketamine and esketamine's rapid antidepressant efficacy (often within 24 hours), there is more limited information about its longer term efficacy over several months. As a scheduled drug of potential abuse, there are also concerns about the safety and abuse liability associated with longer term administration. Notable side effects include dissociation, elevations in blood pressure, and sedation, which have mandated a post-approval risk mitigation programme including a 2 hour post-treatment monitoring period and driving restrictions. Several unanswered questions for ketamine/esketamine to be addressed include: 1) mechanisms of antidepressant action (including controversial data regarding mu-opiate receptor activity); 2) methods to prolong and extend the transient benefit; 3) comparative effectiveness in TRD compared to established treatments such as ECT; 4) efficacy in specific subgroups of patients such as the elderly.

Given the need for alternatives to ketamine and esketamine, several drug development programmes have focused on discovering NMDAR modulators which may retain ketamine's rapid onset of activity but could be associated with considerably fewer adverse effects. These approaches include drugs which primarily target the glycine binding site of the NMDA receptor (AV-101, rapastinel), drugs which combine NMDAR channel blockers with monoaminergic drugs (AXS-05), and “low-trapping” NMDA receptor channel antagonists (lanicemine). More recent drug development initiatives also include arketamine (R-isomer of ketamine), which was found in preclinical models to have antidepressant activity and potentially less abuse liability, and hydroxynorketamine (HNK), a metabolite of ketamine, which was found to bypass the NMDAR channel entirely and work via AMPA receptor potentiating mechanisms.


[PDF] Wilkinson ST, Farmer C, Ballard ED, Mathew SJ et al (2019). Impact of midazolam vs. saline on effect size estimates in controlled trials of ketamine as a rapid-acting antidepressant. Neuropsychopharmacology. 2019 Jan 17. doi: 10.1038/s41386-019-0317-8

[web] Fava M et al (2018). Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in Treatment-Resistant Depression (TRD). Mol Psychiatry. 2018 Oct 3. doi: 10.1038/s41380-018-0256-5.

[PDF] Mathew S et al (2018). ELEctroconvulsive therapy (ECT) vs. Ketamine in patients with treatment-resistant Depression: The ELEKT-D study protocol. Contemp Clin Trials. 2019 Feb;77:19-26. doi: 10.1016/j.cct.2018.12.009. Epub 2018 Dec 17.

[PDF] Murrough JW, Abdallah CG, Mathew SJ (2017). Targeting glutamate signalling in depression: progress and prospects. Nat Rev Drug Discov. 2017 Jul;16(7):472-486. doi: 10.1038/nrd.2017.16