Clinical Predictors of Intravenous Ketamine Response in Treatment-Resistant Depression: A Randomized, Double-Blind, Midazolam-Controlled Pilot Study
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 40
- 试验地点
- 2
- 主要终点
- Change in Montgomery Åsberg Depression Rating Scale Score
研究概览
简要总结
For patients with treatment-resistant depression (TRD), a single low dose of intravenous (IV) ketamine can help relieve symptoms as quickly as 24 hours later.
The main problem with IV ketamine for TRD is that the effect is short-lived, lasting only days to 1 or 2 weeks. Furthermore, IV ketamine is a resource-intensive treatment, and the safety of long-term, repeated use for depression is unknown. To provide this treatment in a safe and cost-effective way, Investigators must allocate it efficiently to those patients who have the greatest need and probability of benefit. Therefore, this project aims to find clinical features (signs, symptoms, and parts of a patient's history) that will help predict which patients are most likely to respond to a single dose of IV ketamine for TRD. This will help guide patient selection and triaging.
Investigators will recruit 40 participants with TRD, and randomize them to one of two conditions (ketamine followed by an active placebo 3-weeks later, or vice versa). With clinical data collected through detailed interviews, questionnaires, actigraphy, speech sampling, electroencephalography (EEG), and computerized tasks, this study design will let us evaluate how well such factors predict (A) rapid response at 24-hours, and (B) sustained response at 7 and 14 days.
详细描述
Study Design:
This will be a randomized, double-blinded, midazolam-controlled crossover trial. There is no perfect control agent for studies of subanaesthetic IV ketamine, but midazolam is generally thought to be superior to normal saline since it is not an antidepressant, yet is psychoactive and thus should better preserve blinding. Participants will undergo psychiatric assessment to establish diagnosis and determine suitability. After providing informed consent for participation, participants will wear a GENEActive accelerometer on the non-dominant wrist for the duration of the trial, beginning 21 days prior to the first infusion. Participants will complete a set of rating scales, anhedonia measures and computerized tasks. On Day 0 (infusion day), participants will receive either a single infusion of IV ketamine (KET) (KET; 0.5mg/kg over 40 minutes) or midazolam (MID) (MID; 30μg/kg over 40 minutes) diluted in 0.9% NaCl by an intravenous pump. Investigators will randomize infusion sequences in a 1-to-1 ratio: KET followed by MID (K→M) or vice versa (M→K). Infusions will be administered on Days 0 and 21, separated by a 20-day washout period. This duration balances the need to establish comparable baselines at each crossover phase and the ethical consideration of not allowing depressive symptoms to remain untreated for an unreasonable amount of time.
Investigators will obtain objective depression ratings with the Montgomery-Åsberg Depression Rating Scale (MADRS) on Days -1, 1, 7, 14, 20, 22, 28, 35, and 41. Participants will provide weekly self-ratings of depressive symptoms (using the Quick Inventory of Depressive Symptoms 16-item self-rated version; QIDS 16-SR). Weekly symptom monitoring will continue for 20 days following the second infusion. Anhedonia will be measured using both self-reported rating scale measures as well as behavioural task. Patients will provide self-ratings using the Snaith-Hamilton Pleasure Scale - 14 items (SHAPS), the Dimensional Anhedonia Rating Scale - 17 items (DARS), and Positive Valence System Scale - 21 items (PVSS-21). Several aspects of subjective sleep and circadian rhythms will be measured via self-report questionnaires. The Pittsburgh Sleep Quality Index (PSQI) will measure general sleep quality and sleep disturbance, and the Basic Language Morningness Scale (BALM) will be used to measure subjective chronotype (morningness-eveningness) of patients. Both will be completed by participants prior to the first infusion and 14 days after each infusion.
Participants will complete the Epworth Sleepiness Scale (ESS) to measure daytime sleepiness symptoms, as well as the Fatigue Scale Severity Scale (FSS) to measure symptoms of fatigue. Both ESS and FSS will be completed the day before and after each infusion, and every 7 days.
Study Groups:
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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
- •Able to fluently read in English with or without optical correction
- •Ability to understand and comply with the study requirements
- •This is determined by the investigators
- •Provision of written informed consent
- •Documented diagnosis of MDD or bipolar disorder meeting DSM-5 criteria (as confirmed by the Diagnostic Assessment Research Tool), currently in a single or recurrent episode without psychotic features
- •Failure of at least two antidepressant medications from different pharmacological classes, as well as at least one augmentation agent, each of which must have been given at adequate doses for at least 6 weeks (recorded using the Antidepressant Treatment History Form - Short Form).
- •Augmentation strategies include those listed in the 2016 Canadian Network for Mood and Anxiety Treatments (CANMAT) depression guidelines, including a 12-week course of cognitive behavioural therapy or interpersonal therapy.
- •MADRS score of ≥25 at initial assessment and Day -
- •For premenopausal females who are currently sexually active with male partners:
- •Negative serum beta-HCG test at enrolment
- •AND commitment to using an appropriate birth control method of their choice throughout the duration of the study, including
- •Intrauterine device
- •Oral contraceptive
- •Long-term injectable contraceptive
- •Double-barrier method
- •Dermal contraception
- •Tubal ligation
- •Abstinence from grapefruit juice consumption on the day of infusion
- •Abstinence from benzodiazepine use within 24 hours of infusion
- •Adherence to maintaining current antidepressant management
排除标准
- •Pregnant or breastfeeding
- •Allergies to ketamine or midazolam
- •Body mass less than 50kg
- •Concomitant use of medications with the potential for clinically significant interactions with either ketamine or midazolam (e.g., monoamine oxidase inhibitors, methylene blue)
- •Substance related exclusion criteria:
- •Concomitant use of naltrexone or narcotics
- •Positive urine drug screen or history of DSM-5 substance use disorder (SUD) in the past 3 months (except nicotine, and recreational cannabis use that doesn't meet the criteria for DSM-5 substance use disorder). History of SUD with significant severity that investigators believe warrant exclusion based on clinical judgment.
- •Previous or current benzodiazepine abuse history
- •Psychiatric exclusion criteria:
- •Previous ketamine use (therapeutic or recreational)
- •Comorbid DSM-5 personality disorder with a major impact on mental status
- •Secondary depressive disorders
- •E.g. secondary to stroke, cancer, or other somatic pathology
- •Subjects who will be starting psychotherapy during the trial period, or have only recently started psychotherapy within 2 months of the trial
- •Participants who have had ECT within 6 weeks prior to enrollment and/or have ECT during the trial period.
- •Medical comorbidity related exclusion criteria:
- •Evidence on history or chart review of any of the following:
- •Any current or historical occurrence of renal disease
- •Clinically significant abnormalities of liver function tests (total bilirubin, albumin, prothrombin time and international normalized ratio [PT/INR], gamma-glutamyl transferase [GGT], alkaline phosphatase [ALP]). Clinical significance of any abnormal liver function tests will be evaluated by the study anesthesiologists. Patients with clinically significant abnormalities suggesting hepatic disease will be excluded.
- •Liver enzymes (AST, ALT) three times the upper normal limit at screening
- •Exception: of history of acute kidney injury or transient reductions in glomerular filtration rate that have fully resolved for at least three months
- •Any current or historical occurrence of hepatic disease
- •Abnormal liver function tests
- •Liver enzymes three times the upper normal limit at screening
- •Exception: History of transient elevations of liver enzymes or reduction in liver function that have re-normalized for the past three months (as per criteria above concerning function/enzymes)
- •Myocardial infarct within a year prior to initial randomization
- •Chronic obstructive pulmonary disease
- •Untreated obstructive sleep apnea
- •Cerebrovascular disease (including history of cerebrovascular accident)
- •Intracerebral structural lesions
- •Viral hepatitis B or C
- •Acquired immunodeficiency syndrome
- •Interstitial cystitis
- •Uncontrolled hypertension
- •Decompensated heart failure
- •Current uncorrected thyroid pathology or recent correction within 30 days (correction of thyroid function for longer than 1 month is admissible).
- •Any unstable somatic pathology or clinically significant investigational abnormality (biochemical, ECG) that investigators believe would be negatively impacted by study procedures or that would negatively impact study procedures
研究组 & 干预措施
Ketamine
Participants will be randomly assigned to receive Ketamine or Midazolam
干预措施: Ketamine (Drug)
Midazolam
Participants will receive either Ketamine or Midazolam based on what they initially received
干预措施: Midazolam (Drug)
结局指标
主要结局
Change in Montgomery Åsberg Depression Rating Scale Score
时间窗: 24 hours, 7 days, 14 days, 20 days
Montgomery Åsberg Depression Rating Scale (MADRS) measures depressive symptoms. The scores for each item ranges from 0 to 6 and total scores range from 0 to 60, with higher scores indicating more severe depression. Researchers will investigate the degree to which each clinical feature predicts Days 1, 7, 14, and 20 post-infusion MADRS using a biomarker prediction model.
次要结局
- Weekly self-ratings of Generalized Anxiety Disorder 7 Scale(24 hours, 7 days, 14 days, 20 days)
- The Snaith-Hamilton Pleasure Scale(24 hours, 20 days)
- Dimensional Anhedonia Rating Scale(24 hours, 20 days)
- The Positive Valence Systems Scale(24 hours, 20 days)
- Fatigue Severity Scale(24 hours, 7 days, 14 days, 20 days)
- Basic Language Morningness Scale(24 hours, 7 days, 14 days, 20 days)
- Epworth Sleepiness Scale(24 hours, 7 days, 14 days, 20 days)
- Probabilistic Reward Task(24 hours after each infusion, 20 days after each infusion)
研究者
Abraham Nunes
Psychiatrist/Assistant Professor
Nova Scotia Health Authority