Phase 2 Optimization of the Antidepressant Action of Ketamine in Treatment-Resistant Depression and Investigations on Its Mechanism of Action
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 46
- 试验地点
- 1
- 主要终点
- Efficacy of Ketamine over Midazolam in double blind study for efficacy of relief for Major Depressive Disorder
研究概览
简要总结
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.
详细描述
Major depressive disorder (MDD) carries worldwide the largest burden of diseases among mental, neurological, and substance-use disorders measured in Disability Adjusted Life Years (DALYs), according to the World Health Organization (WHO).1 In turn, MDD has the highest DALYs in middle to high income countries, with ischemic cardiac diseases being second.2 Although there are effective treatments for MDD, a large proportion of patients do not achieve remission even after several attempts, and any significant response, when it manifests itself, takes place a delay of a few weeks.3,4 There is always urgency to treat MDD because although patients may have been ill for several weeks, months, and sometimes years, they are often in a crisis situation when they consult. The nature of the crisis may be familial, financial/professional, or the consultation may take place because of intense personal suffering, possibly involving suicidal ideation. Consequently, rapid therapeutic action and high remission rates represent the two major unmet needs for MDD.
In the last few years, considerable attention has been dedicated to the glutamate system as a possible contributor of the antidepressant response. The most striking breakthrough has been the rapid antidepressant response of intravenous ketamine using doses that are about a quarter of the routinely utilized anesthetic dose in children and adults.5,6 Unlike many anesthetic agents, ketamine does not depress cardiovascular and respiratory parameters.7 The primary action of ketamine is to block N-Methyl-D-Aspartate (NMDA) receptors. The antidepressant response to ketamine often manifests itself within a few hours, but is generally maximal after 24 hours.8 Importantly, a single infusion produces in the most subjects a robust decrease of suicidal ideation.9,10 The drawback of this approach is, however, that its benefits generally disappear within a week.6 Consequently, much clinical work remains to be carried out in order to better understand and maintain the antidepressant response of ketamine.
Specific aim #1: The first aim of this proposal is to characterize the antidepressant action of a single dose of ketamine in a truly double-blind paradigm. Indeed, even the low doses of ketamine (0.2-0.5 mg/kg)8,11 produce mild derealization and therefore the use a mere saline solution in prior studies has been inadequate as a control.
- To show that the infusion of a low dose of the short-acting benzodiazepine midazolam will serve as an adequate active control for ketamine. It is hypothesized that because midazolam produces marked sedation, it will serve as an adequate control.
- To determine if the brain-derived neutrophic factor (BDNF) mediates the antidepressant response. In mice, a VAL/MET polymorphism for the BDNF gene, ketamine is devoid of effects. The influence of this polymorphism will be evaluated in patients.
Specific aim #2: The second goal of this proposal is to attempt enhancing and prolonging the antidepressant effect of ketamine by giving it repeatedly at a rate of three infusions per week for two consecutive weeks.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Only participants from the Ottawa area will be considered
- •Provision of written informed consent before initiation of any study- related procedures.
- •Documented primary Axis I clinical diagnosis meeting criteria from the DSM-IV13 for MDD, as confirmed by the MINI.98
- •Failure to respond adequately to at least two antidepressant medication trials and two augmentation strategies. One augmentation strategy may include a noradrenergic dose of venlafaxine (225 mg/day) or duloxetine (120 mg/day), given their dual mechanism of action99,100 and a 12-week cognitive behavioural or interpersonal therapy
- •MADRS total score of ≥ 25 at screening and randomization, with no more than 20% improvement between these two visits.
- •Female subjects of childbearing potential must have a negative urine pregnancy test at enrolment (Visit 1) and be willing to use a reliable method of birth control (i.e., double-barrier method, oral contraceptive, implant, dermal contraception, long-term injectable contraceptive, intrauterine device, or tubal ligation) during the study.
- •Abstain from consuming grapefruit juice (a potent 3A4 cytochrome inhibitor) on the day of the infusions as it may slow down the elimination of midazolam and possibly ketamine.
- •Be able to understand and comply with the requirements of the study, as judged by the investigator(s).
排除标准
- •Subjects with a diagnosis of DSM-IV Axis II disorder which has a major impact on the subject's current psychiatric status.
- •Depression secondary to stroke, cancer or other severe medical illnesses.
- •Prior or current substance or alcohol abuse or dependence (except for caffeine or nicotine dependence), as defined in DSM-IV criteria.
- •A positive drug screen.
- •Unwilling to maintain their current antidepressant regimen. infusions.
- •Unwilling or able to hold benzodiazepines on the day prior and that of the Unwilling to discontinue any narcotic for a minimum of 5 drug half-lives prior to infusions.
- •Pregnant or lactating, or is of childbearing potential and not willing to use an approved method of contraception during the study.
- •Evidence of clinically relevant disease, e.g., renal or hepatic impairment, significant coronary artery disease (myocardial infarct within a year prior to initial randomization), cerebrovascular disease, viral hepatitis B or C, acquired immunodeficiency syndrome.
- •A clinical finding that is unstable or that, in the opinion of the investigator(s), would be negatively affected by the study medication or that would affect the study medication (e.g., diabetes mellitus, hypertension, unstable angina).
- •Liver function tests AST and ALT three times the upper normal limit at screening.
- •Uncorrected hypothyroidism or hyperthyroidism. Subjects needing a thyroid hormone supplement to treat hypothyroidism must have been on a stable dose of the medication for 30 days prior to enrolment (Visit 1).
- •Clinically significant deviation from the reference range in clinical laboratory test results as judged by the investigator(s).
- •ECG results considered clinically significant as determined by the investigator(s).
- •History of seizure disorder, except febrile convulsions.
- •Subjects who in the investigator(s) opinion will require psychotherapy (other than supportive psychotherapy) during the study period, unless psychotherapy has been ongoing for a minimum of 2 months prior to Visit
- •Known history of intolerance or hypersensitivity to ketamine or midazolam.
- •Any other condition that, in the opinion of the investigator(s) would adversely affect the subject's
研究组 & 干预措施
Ketamine
During Phase 1 patients will be randomly assigned to receive ketamine or active placebo.
干预措施: Ketamine (Drug)
Midazolam
In phase 1 patients will be randomized to receive active placebo
干预措施: Midazolam (Drug)
结局指标
主要结局
Efficacy of Ketamine over Midazolam in double blind study for efficacy of relief for Major Depressive Disorder
时间窗: 2 weeks
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.
次要结局
- Ketamine for use in relief of Major Depressive Disorder over repeated administration(6 weeks)
- To determine the role of genetic polymorphisms in the participants response to ketamine infusion(2 weeks)
研究者
Pierre Blier
Endowed Chair and Director of Mood Disorders Research Unit
University of Ottawa