- A word to the wise about ketamine
by Alan Schatzberg
AJP 2014 171:262-264.
- The ketamine challenge: when practice leaps ahead of science
by Jeffrey Lieberman
February 3, 2015.
- Ketamine and Other NMDA Antagonists:
Early Clinical Trials and Possible Mechanisms in Depression
by Jeffrey Newport, Linda Carpenter, William McDonald, James Potash, Mauricio Tohen, Charles Nemeroff, and The APA Council of Research Task Force on Novel Biomarkers and Treatments
AJP 2015 172:950-966.
Intravenous Esketamine in Adult Treatment-Resistant Depression: A Double-Blind, Double-Randomization, Placebo-Controlled Studyby Jaskaran B. Singh , Maggie Fedgchin, Ella Daly, Liwen Xi, Caroline Melman, Geert De Bruecker, Andre Tadic, Pascal Sienaert, Frank Wiegand, Husseini Manji, Wayne C. Drevets, and Luc Van NuetenBiological Psychiatry. November 3, 2015. EPub ahead of print.
BACKGROUND: The purpose of this study was to assess the efficacy and safety and to explore the dose response of esketamine intravenous [IV] infusion in patients with treatment-resistant depression [TRD].METHODS: This multicenter, randomized, placebo-controlled trial was conducted in 30 patients with TRD. Patients were randomly assigned 1:1:1 to receive an IV infusion of .20 mg/kg or .40 mg/kg esketamine or placebo over 40 minutes on day 1. The primary end point was change in Montgomery-Åsberg Depression Rating Scale total score from day 1 [baseline] to day 2. Nonresponders who received placebo on day 1 were randomly assigned again 1:1 to IV esketamine .20 mg/kg or .40 mg/kg on day 4. Secondary efficacy and safety measures were also evaluated.RESULTS: Of the enrolled patients, 97% [29 of 30] completed the study. The least squares mean changes [SE] from baseline to day 2 in Montgomery-Åsberg Depression Rating Scale total score for the esketamine .20 mg/kg and .40 mg/kg dose groups were -16.8 [3.00] and -16.9 [2.61], respectively, and showed significant improvement [one-sided p = .001 for both groups] compared with placebo [-3.8 [2.97]]. Esketamine showed a rapid [within 2 hours] and robust antidepressant effect. Treatment-emergent adverse events were dose dependent. The most common treatment-emergent adverse events were headache, nausea, and dissociation; the last-mentioned was transient and did not persist beyond 4 hours from the start of the esketamine infusion.CONCLUSIONS: A rapid onset of robust antidepressant effects was observed in patients with TRD after a 40-min IV infusion of either .20 mg/kg or .40 mg/kg of esketamine. The lower dose may allow for better tolerability while maintaining efficacy
Esketamine Receives Breakthrough Therapy Designation from U.S. Food and Drug Administration for Major Depressive Disorder with Imminent Risk for SuicideJohnson and Johnson: Press ReleaseAugust 16, 2016
Janssen Research & Development, LLC, one of the Janssen Pharmaceutical Companies of Johnson & Johnson, announced today that the U.S. Food and Drug Administration [FDA] has granted a Breakthrough Therapy Designation for esketamine, an investigational antidepressant medication, for the indication of major depressive disorder with imminent risk for suicide. If approved by the FDA, esketamine would be one of the first new approaches to treat major depressive disorder available to patients in the last 50 years.
This also marks the second time esketamine has received a Breakthrough Therapy Designation from the U.S. regulatory authority. Esketamine was first granted this designation for treatment-resistant depression in November 2013. Breakthrough Therapy Designation is intended to expedite development and review timelines when preliminary clinical evidence indicates the drug may demonstrate substantial improvement on one or more clinically significant endpoints over available therapies for serious or life-threatening conditions.
The esketamine Phase 2 clinical trial data presented by Janssen in May 2016 at the Society of Biological Psychiatry 71st Annual Scientific Meeting in Atlanta, Georgia, provided preliminary clinical evidence to support the Breakthrough Therapy Designation for major depressive disorder with imminent risk for suicide.About EsketamineEsketamine for intranasal administration is an investigational compound being studied by Janssen as part of a global development program. Esketamine is a non-competitive and subtype non-selective activity-dependent N-methyl-D-aspartate [NMDA] receptor antagonist, which has a novel mechanism of action, meaning it works differently than currently available therapies for depression. The program in treatment-resistant depression is currently in Phase 3, with six ongoing clinical trials…[see also Party drug ketamine closer to approval for depression – CNN]
Here’s a roster of their Esketamine clinical trials from clinicaltrials.gov. As you can see, they’re going long on Esketamine. It’s a hungry market and they’re going after it. And then there’s that old saying, "The best predictor of future behavior is past behavior."
|NCT01394757||Network Dysfunction, Schizophrenia and Pharmacological Magnetic Resonance Imaging [phMRI]||Completed||–||08/2011|
|NCT00847418||Pharmacokinetics and Pharmacodynamics of Nasally Applied Esketamine||Completed||1||02/2009|
|NCT01780259||A Study to Assess the Pharmacokinetics, Safety, and Tolerability of Intranasally Administered Esketamine in Healthy Participants||Completed||1||12/2012|
|NCT02060929||A Study to Evaluate the Pharmacokinetics of Intranasal Esketamine Administered With and Without a Nasal Guide on the Intranasal Device||Completed||1||10/2013|
|NCT01980303||A Study to Assess the Pharmacokinetics of Intranasally Administered Esketamine in Healthy Japanese and Caucasian Volunteers||Completed||1||11/2013|
|NCT02129088||A Pharmacokinetic, Safety and Tolerability Study of Esketamine in Healthy Elderly and Adult Participants||Completed||1||03/2014|
|NCT02094378||A Study to Evaluate the Effect of Intranasal Esketamine on Cognitive Functioning in Healthy Subjects||Completed||1||06/2014|
|NCT02154334||Study to Assess the Effects of Allergic Rhinitis and Co-administration of Mometasone or Oxymetazoline on the Pharmacokinetics, Safety, and Tolerability of Intranasal Esketamine||Completed||1||06/2014|
|NCT02228239||Study to Assess the Effects of Esketamine on Safety of On-road Driving in Healthy Participants||Completed||1||09/2014|
|NCT02345148||Pharmacokinetic, Safety, and Tolerability Study of Intranasally Administered Esketamine in Elderly and and Healthy Younger Adult Participants||Completed||1||12/2014|
|NCT02343289||A Study to Evaluate the Absolute Bioavailability of Intranasal and Oral Esketamine and the Effects of Clarithromycin on the Pharmacokinetics of Intranasal Esketamine in Healthy Participants||Completed||1||01/2015|
|NCT02568176||Pharmacokinetic Study of Intranasal Esketamine and Its Effects on the Pharmacokinetics of Orally-Administered Midazolam and Bupropion in Healthy Participants||Completed||1||10/2015|
|NCT02611505||A Study to Assess the Effects of Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Intranasally Administered Esketamine||Recruiting||1||11/2015|
|NCT02606084||A Study to Assess the Effects of Renal Impairment on the Pharmacokinetics, Safety, and Tolerability of Intranasally Administered Esketamine||Recruiting||1||12/2015|
|NCT02846519||Pharmacokinetic, Safety, and Tolerability Study of Intranasally Administered Esketamine in Healthy Han Chinese, Korean, Japanese, and Caucasian Participants and the Effects of Rifampin on the Pharmacokinetics of Intranasally Administered Esketamine||Completed||1||02/2016|
|NCT02682225||Crossover Study to Evaluate the Abuse Potential of Intranasal Esketamine Compared to Racemic Intravenous Ketamine in Nondependent, Recreational Drug Users||Recruiting||1||03/2016|
|NCT02674295||A Mass Balance Study With a Microtracer Dose of 14C-esketamine in Healthy Male Participants||Recruiting||1||03/2016|
|NCT02737605||A Study to Evaluate the Effects of Esketamine on Cardiac Repolarization in Healthy Participants||Not yet recruiting||1||07/2016|
|NCT02857777||Pharmacokinetic, Safety, and Tolerability Study of Intranasally Administered Esketamine in Elderly Japanese, and Healthy Younger Adult Japanese Subjects||Not yet recruiting||1||08/2016|
|NCT01640080||A Study of the Efficacy of Intravenous Esketamine in Adult Patients With Treatment-Resistant Depression||Completed||2||06/2012|
|NCT01998958||A Study to Evaluate the Safety and Efficacy of Intranasal Esketamine in Treatment-resistant Depression||Completed||2||01/2014|
|NCT02133001||A Double-blind Study to Assess the Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of the Symptoms of Major Depressive Disorder, Including Suicidal Ideation, in Participants Who Are Assessed to be at Imminent Risk for Suicide||Completed||2||05/2014|
|NCT02417064||A Study to Evaluate the Efficacy, Safety, and Tolerability of Fixed Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With Treatment-resistant Depression||Recruiting||3||08/2015|
|NCT02418585||A Study to Evaluate the Efficacy, Safety, and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With Treatment-resistant Depression||Recruiting||3||08/2015|
|NCT02422186||A Study to Evaluate the Efficacy, Safety, and Tolerability of Intranasal Esketamine Plus an Oral Antidepressant in Elderly Participants With Treatment-resistant Depression||Recruiting||3||08/2015|
|NCT02497287||A Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression||Recruiting||3||09/2015|
|NCT02493868||A Study of Intranasal Esketamine Plus an Oral Antidepressant for Relapse Prevention in Adult Participants With Treatment-resistant Depression||Recruiting||3||10/2015|
|NCT02782104||A Long-term Safety Study of Intranasal Esketamine in Treatment-resistant Depression||Recruiting||3||06/2016|