James W Murrough1, Elizabeth Wade2, Sehrish Sayed2, Gabriella Ahle3, Drew D Kiraly4, Alison Welch5, Katherine A Collins2, Laili Soleimani5, Dan V Iosifescu6, Dennis S Charney7. 1. Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States. Electronic address: james.murrough@mssm.edu. 2. Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States. 3. Thomas Jefferson University, Jefferson College of Biomedical Sciences, Philadelphia, PA, United States. 4. Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States. 5. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States. 6. Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States. 7. Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
Abstract
BACKGROUND: At least one-third of patients with major depressive disorder (MDD) have treatment-resistant depression (TRD), defined as lack of response to two or more adequate antidepressant trials. For these patients, novel antidepressant treatments are urgently needed. METHODS: The current study is a phase IIa open label clinical trial examining the efficacy and tolerability of a combination of dextromethorphan (DM) and the CYP2D6 enzyme inhibitor quinidine (Q) in patients with TRD. Dextromethorphan acts as an antagonist at the glutamate N-methyl-d-aspartate (NMDA) receptor, in addition to other pharmacodynamics properties that include activity at sigma-1 receptors. Twenty patients with unipolar TRD who completed informed consent and met all eligibility criteria we enrolled in an open-label study of DM/Q up to 45/10mg by mouth administered every 12h over the course of a 10-week period, and constitute the intention to treat (ITT) sample. Six patients discontinued prior to study completion. RESULTS: There was no treatment-emergent suicidal ideation, psychotomimetic or dissociative symptoms. Montgomery-Asberg Depression Rating Scale (MADRS) score was reduced from baseline to the 10-week primary outcome (mean change: -13.0±11.5, t19=5.0, p<0.001), as was QIDS-SR score (mean change: -5.9±6.6, t19=4.0, p<0.001). The response and remission rates in the ITT sample were 45% and 35%, respectively. LIMITATIONS: Open-label, proof-of-concept design. CONCLUSIONS: Herein we report acceptable tolerability and preliminary efficacy of DM/Q up to 45/10mg administered every 12h in patients with TRD. Future larger placebo controlled randomized trials in this population are warranted.
BACKGROUND: At least one-third of patients with major depressive disorder (MDD) have treatment-resistant depression (TRD), defined as lack of response to two or more adequate antidepressant trials. For these patients, novel antidepressant treatments are urgently needed. METHODS: The current study is a phase IIa open label clinical trial examining the efficacy and tolerability of a combination of dextromethorphan (DM) and the CYP2D6 enzyme inhibitor quinidine (Q) in patients with TRD. Dextromethorphan acts as an antagonist at the glutamate N-methyl-d-aspartate (NMDA) receptor, in addition to other pharmacodynamics properties that include activity at sigma-1 receptors. Twenty patients with unipolar TRD who completed informed consent and met all eligibility criteria we enrolled in an open-label study of DM/Q up to 45/10mg by mouth administered every 12h over the course of a 10-week period, and constitute the intention to treat (ITT) sample. Six patients discontinued prior to study completion. RESULTS: There was no treatment-emergent suicidal ideation, psychotomimetic or dissociative symptoms. Montgomery-Asberg Depression Rating Scale (MADRS) score was reduced from baseline to the 10-week primary outcome (mean change: -13.0±11.5, t19=5.0, p<0.001), as was QIDS-SR score (mean change: -5.9±6.6, t19=4.0, p<0.001). The response and remission rates in the ITT sample were 45% and 35%, respectively. LIMITATIONS: Open-label, proof-of-concept design. CONCLUSIONS: Herein we report acceptable tolerability and preliminary efficacy of DM/Q up to 45/10mg administered every 12h in patients with TRD. Future larger placebo controlled randomized trials in this population are warranted.
Authors: Gabriela D Colpo; Marion Leboyer; Robert Dantzer; Mahdukar H Trivedi; Antonio L Teixeira Journal: Expert Rev Neurother Date: 2017-11-27 Impact factor: 4.618
Authors: Sema G Quadir; Sean M Tanino; Yasmine N Sami; Margaret A Minnig; Malliga R Iyer; Kenner C Rice; Pietro Cottone; Valentina Sabino Journal: Alcohol Clin Exp Res Date: 2021-07-05 Impact factor: 3.928