Action of Ketamine in Treatment-Resistant Depression
Depression carries the largest burden of all medical disorders in middle to high income countries, as determined by the World Health Organization. Despite many antidepressant strategies, only a third of patients get well after their first treatment and a third remain ill after several treatments. Moreover, antidepressant treatments all have a delayed action ranging up to several weeks.
Ketamine (KET) has been used for decades as a sedative and anesthetic. In treatment-resistant depressed patients(TRD), an intravenous dose much lower than necessary for anesthesia may produce a robust antidepressant effect and may even abolish suicidal thoughts within hours, peaking within 24 hours. But, its antidepressant effect generally lasts only days.Previous studies examining KET in TRD have been critiqued for lack of an effective placebo measure due to brief perceptual experiences associated with KET. Thus, the current study compares KET against a short-acting sedative. The phases of this study compare response to a single KET injection to 6 injections over 2 weeks. Next, KET responders are given 1 injection a week for 3 weeks of either KET or the sedative agent to determine if beneficial effects of KET are maintained, and to assess duration of its benefits after repeated administration. The genetic profile of patients for a substance promoting contacts between cells and brain will be determined to investigate if response to KET could be predicted with that blood test. This substance, as well as several chemicals that produce inflammation, will also be measured in the blood to investigate their role in the effect of KET. Patients will receive, in total, no more than the equivalent of two to three anesthetic dose of KET. Results from this study will help establish the beneficial effects of a single KET injection as a rapid intervention for major depression, and to investigate the possibility of obtaining a prolonged antidepressant effect with repeated injections.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
|Official Title:||Phase 2 Optimization of the Antidepressant Action of Ketamine in Treatment-Resistant Depression and Investigations on Its Mechanism of Action|
- Efficacy of Ketamine over Midazolam in double blind study for efficacy of relief for Major Depressive Disorder [ Time Frame: 2 weeks ] [ Designated as safety issue: Yes ]Phase 1 double blind treatment with Ketamine or Midazolam then crossover. Will assess efficacy of each for relief of Major Depressive Symptoms through assessment using the HAMD17.
- Ketamine for use in relief of Major Depressive Disorder over repeated administration [ Time Frame: 6 weeks ] [ Designated as safety issue: Yes ]Repeated infusion of ketamine in phases 2 and 3 to determine efficacy over extended treatment period.We will assess effectiveness for treatment of depression by administering the Montgomery-Asberg Depression Rating Scale (MADRS)to assess severity of depressive symptoms. MADRS will be given before and after each infusion and at follow up visits to monitor changes.
- To determine the role of genetic polymorphisms in the participants response to ketamine infusion [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]Patients will be genotyped for a VAL/MET polymorphism for the brain-derived neutrophic factor (BDNF)gene to see whether presence or absence of the polymorphism mediates their antidepressant response.
- Cortisol, melatonin, and inflammatory mediators will be assessed to examine changes occurring during treatment with ketamine [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
Pro-inflammatory mediators and cortisol are generally elevated in depression while melatonin is decreased. These anomalies are typically restored with effective treatments. This will be investigated in the light of the rapid antidepressant effect of ketamine.
During phase 1, patients will provide samples of saliva for morning melatonin and salivary cortisol at 1)Randomization, 2)Phase 2,infusion 6, 3)Phase 3, infusion 4. Collected for 2 days: Immediately upon waking;30 minutes later;1 hour later;Mid-day.
Inflammatory mediators will be assessed to determine changes occurring throughout treatment. Two blood samples will be drawn at each of the following study visits: Randomization;Phase 2, infusion 6;Phase 3, infusion 4 We will examine C-reactive protein, IL-1β, IL-2, IL-6, IL-8, IL-12, IFN-γ, TNF-α, and anti-inflammatory factors IL-4 and IL-10.
- Effects of ketamine infusion compared to midazolam [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]A clinician will evaluate their clinical status prior to the infusion, using the Montgomery-Asberg Depression Rating Scale (MADRS) and the Clinical Global Intensity-Severity (CGI-S) and the patients will rate themselves using the Quick Inventory Depressive Symptoms-Self-report (QIDS-SR)105 and a self-report questionnaire rating suicidality. The patients will be assessed using the Brief Psychiatric Rating Scale-positive symptom scale at baseline (before the infusion), time 0 (immediately after infusion is complete), then at 60 and 120 minutes post time 0. The CGI-Improvement (CGI-I) will be used to obtain a clinical evaluation of overall change of their condition after two hours before discharging the patients two hours after the infusion. We will compare the scores on the scales used in ketamine infusion verses midazolam to evaluate whether ketamine is superior but also whether midazolam is an effective control (patients feel some effects similar to ketamine infusion)
|Study Start Date:||May 2013|
|Estimated Study Completion Date:||December 2015|
|Estimated Primary Completion Date:||May 2015 (Final data collection date for primary outcome measure)|
During Phase 1 patients will be randomly assigned to receive ketamine or active placebo.
Intravenous Bolus infusion Ketamine Hydrochloride 0.50 mg/mL over 40 minutes
Active Comparator: Midazolam
In phase 1 patients will be randomized to receive active placebo
Bolus infusion of Midazolam Hydrochloride 1 mg/mL over 40 minutes
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01945047
|Contact: Wendy Fusee, RN||613-722-6521 ext firstname.lastname@example.org|
|Contact: Lisa Batten, Master||613-722-6521 ext email@example.com|
|Institute of Mental Health Research, Royal Ottawa Hospital||Recruiting|
|Ottawa, Ontario, Canada, K1Z 7K4|
|Contact: Wendy Fusee, RN 613-722-6521 ext 7828 firstname.lastname@example.org|
|Contact: Lisa batten, Master 613-722-6521 ext 6971 email@example.com|
|Principal Investigator: Pierre Blier, M.D. Ph.D|
|Principal Investigator:||Pierre Blier, M.D, Ph.D||University of Ottawa, Institute of Mental Health Research|