Existing treatments for major depressive disorder (MDD) may require several weeks to months to exert their maximal benefit. Ketamine, a high-affinity NMDA glutamate receptor antagonist, is an anesthetic and analgesic medication commonly used in pediatric and adult patients. Ketamine has antidepressant properties in animal models, and may have rapid antidepressant activity for patients with severe mood disorders. A recent placebo-controlled investigation in patients with treatment-resistant unipolar depression (TRD) showed robust antidepressant efficacy of a single subanesthetic dose of intravenous (IV) ketamine (0.5 mg/kg), findings which replicated a previous small pilot trial. Strikingly, a high proportion of patients maintained the acute response to IV ketamine for several days or longer. In this 4-year single-site study, we will conduct a triple-masked, randomized, parallel-arm active control investigation of the acute efficacy and safety of IV ketamine in TRD.
Specific Aims : (1) To test whether a single IV infusion of ketamine has superior antidepressant efficacy compared to an active control agent (IV midazolam) in patients with TRD. (2) To characterize the durability of benefit and test whether IV ketamine is associated with superior antidepressant effects at the 7-day timepoint. (3) To examine the safety and tolerability of the interventions. The intent-to-treat sample is comprised of 64 TRD patients, conservatively defined as insufficient response to = 3 adequate antidepressant trials in the current episode. After a medication-free period = 2 weeks, patients are randomized to receive an infusion of either IV ketamine (0.5 mg/kg over 40 min) or IV midazolam (0.045 mg/kg over 40 min). Efficacy and safety is evaluated over the following 7 days. Non responders at the 7-day endpoint exit the study, while patients meeting response criteria are followed bi-weekly until relapse or for an additional 4 weeks. The primary efficacy measure is reduction in depression severity as assessed by the Montgomery- Asberg Depression Rating Scale (MADRS) scale 24 hours following IV infusion;additional outcome measures include response and remission rates, durability of benefit (7-day endpoint), side effects, and adverse events.

Public Health Relevance

There is an urgent public health imperative to develop safe, well-tolerated, and rapidly-acting treatments for MDD. This research application seeks to benefit the public health by identifying a novel therapy for highly symptomatic and treatment-resistant patients that may decrease the morbidity and mortality associated with this common and serious illness.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH081870-01A2
Application #
7728054
Study Section
Interventions Committee for Adult Mood and Anxiety Disorders (ITMA)
Program Officer
Hillefors, MI
Project Start
2009-07-23
Project End
2009-12-31
Budget Start
2009-07-23
Budget End
2009-12-31
Support Year
1
Fiscal Year
2009
Total Cost
$445,036
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Psychiatry
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Abdallah, Chadi G; Jackowski, Andrea; Salas, Ramiro et al. (2017) The Nucleus Accumbens and Ketamine Treatment in Major Depressive Disorder. Neuropsychopharmacology 42:1739-1746
Abdallah, Chadi G; Averill, Christopher L; Salas, Ramiro et al. (2017) Prefrontal Connectivity and Glutamate Transmission: Relevance to Depression Pathophysiology and Ketamine Treatment. Biol Psychiatry Cogn Neurosci Neuroimaging 2:566-574
Coplan, Jeremy D; Kolavennu, Venu; Abdallah, Chadi G et al. (2016) Patterns of anterior versus posterior white matter fractional anistotropy concordance in adult nonhuman primates: Effects of early life stress. J Affect Disord 192:167-75
Abdallah, Chadi G; Salas, Ramiro; Jackowski, Andrea et al. (2015) Hippocampal volume and the rapid antidepressant effect of ketamine. J Psychopharmacol 29:591-5
Price, Rebecca B; Mathew, Sanjay J (2015) Does ketamine have anti-suicidal properties? Current status and future directions. CNS Drugs 29:181-8
Wan, Le-Ben; Levitch, Cara F; Perez, Andrew M et al. (2015) Ketamine safety and tolerability in clinical trials for treatment-resistant depression. J Clin Psychiatry 76:247-52
Murrough, J W; Collins, K A; Fields, J et al. (2015) Regulation of neural responses to emotion perception by ketamine in individuals with treatment-resistant major depressive disorder. Transl Psychiatry 5:e509
Murrough, James W; Burdick, Katherine E; Levitch, Cara F et al. (2015) Neurocognitive effects of ketamine and association with antidepressant response in individuals with treatment-resistant depression: a randomized controlled trial. Neuropsychopharmacology 40:1084-90
Haile, C N; Murrough, J W; Iosifescu, D V et al. (2014) Plasma brain derived neurotrophic factor (BDNF) and response to ketamine in treatment-resistant depression. Int J Neuropsychopharmacol 17:331-6
Price, Rebecca B; Iosifescu, Dan V; Murrough, James W et al. (2014) Effects of ketamine on explicit and implicit suicidal cognition: a randomized controlled trial in treatment-resistant depression. Depress Anxiety 31:335-43

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