Central and Peripheral GABA and Glutamate Modulation With Intravenous Ketamine for Treatment-Resistant Depression (G2K): A Randomized, Double-Blind, Placebo-Controlled Study
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- Mayo Clinic
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Peak (% change from baseline) Anterior Cingulate Cortex metabolites (Gamma-Aminobutyric Acid and Glutamate)
研究概览
简要总结
The purpose of this study is to to evaluate the relationships between peak (% change from baseline) central GABA and Glu levels during a 40-min IV ketamine or normal saline infusion utilizing fMRS, and change in peripheral GABA and Glu levels from baseline to 24-hr postinfusion utilizing LCMS, with baseline to 24-hr post-infusion change in depression (MADRS) in 30 TRD adults.
详细描述
This will be a randomized, double-blind, placebo-controlled, parallel-group study where adult subjects with treatment refractory major depressive disorder (MDD) will receive 1:1 single IV racemic ketamine (n=15) or normal saline (placebo) (n=15) infusion in an MRI scanner, followed by an optional open-label ketamine infusion. In this innovative comparative study utilizing novel dynamic sliding-window fMRS and liquid chromatography-mass spectrometry (LCMS), we will investigate the dynamic relationship between GABA and Glu levels measured centrally and peripherally, respectively, with change in depression symptoms utilizing the Montgomery Asberg Depression Rating Scale (MADRS).12 Given preclinical models of reduced ACs and glutamatergic function in depression, we will also include an exploratory analysis of ACs metabolomic markers associated with ketamine treatment response.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
MRI-tech, Radiologist, and Clinical Research Trial Unit Nurses. Any staff involved in the ratings will be blinded to the treatment of the subject for infusion. Only the study investigator present during infusion in the MRI will be unblinded for safety precautions during the infusion.
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
- •Ability to provide informed consent
- •Meets diagnostic criteria for major depressive disorder without psychotic features per the SCID DSM-IV-TR
- •PHQ-9 total score ≥ 15 at screening
- •Treatment-resistant depression, as defined by failure of at least two previous antidepressant treatments within the current depressive episode. Failed antidepressant treatments can include pharmacotherapy for depression at an adequate dose for at least 8 weeks, trial of transcranial magnetic stimulation (TMS) or an acute series of at least 6 administrations of electroconvulsive therapy (ECT)
- •Ability to pass a comprehension assessment test related to effects of ketamine and trial objectives and criteria
排除标准
- •Inability to speak English
- •Inability to provide consent or have a legal guardian
- •Patients with a BMI > 40 kg/m
- •Personality disorder being the primary diagnosis
- •Diagnosis of schizophrenia, schizoaffective disorder, bipolar disorder, or active psychotic symptoms
- •Active post-traumatic stress disorder symptoms based on clinical assessment
- •Ongoing prescription of > 2 mg lorazepam equivalents (total) daily, or morning dosing of any benzodiazepine at the time of assessment
- •Medications known to affect glutamate (i.e., Riluzole, Carbamazepine) or GABA (zaleplon, zolpidem, zopiclone, Valproate, Gabapentin, Pregabalin, tiagabine, and vigabatrin) are prohibited within two weeks prior to administration of study drug and at least 24 hours after last dose of study drug
- •Monoamine Oxidase Inhibitors (MAOIs) are prohibited two weeks prior to administration of study drug
- •Opioid antagonists (naltrexone, naloxone, nalmefene, methylnaltrexone, buprenorphine and naloxone combination) are prohibited within two weeks prior to administration of study drug and at least 24 hours after last dose of study drug
- •CYP3A4 inducers carbamazepine and modafinil are prohibited within two weeks prior to administration of study drug and at least 24 hours after last dose of study drug.
- •Currently undergoing TMS, vagal nerve stimulation, or deep brain stimulation as either an acute or maintenance treatment of depression
- •ECT in the past 6 months
- •Any active or unstable medical condition judged by the study psychiatrist as conferring too great a level of medical risk to allow inclusion in the study
- •A history of bleeding in the brain
- •Arteriovenous malformation or a history of aneurysm
- •Use of methamphetamine, cocaine, or cannabis. Abuse of stimulant (s) within the prior 12 months
- •Any current substance use disorder (excluding nicotine and caffeine). Note: Persons will be allowed to enroll in this study if their substance use is in complete (not partial) and sustained (> 1 year) remission
- •History of traumatic brain injury that resulted in loss of consciousness with brain bleeding
- •History of tonic-clonic (grand mal) seizures
- •Developmental delay, intellectual disability, or intellectual disorder
- •Clinical or self-reported diagnosis of delirium, encephalopathy, or related clinical diagnosis within the prior 12 months
- •Minor or Major Neurocognitive disorder
- •Received ketamine treatment for depression within the prior 2 months
- •History of either poor antidepressive response to or poor tolerability of ketamine (any route of administration) when previously administered
- •History of hypothyroidism unless taking a stable dose of thyroid medication and asymptomatic for 3 months
- •Hepatic insufficiency (2.5 X ULN for AST or ALT) within 3 months of consent, past liver transplant recipient, and/or clinical diagnosis of cirrhosis of the liver
- •Gastroesophageal reflux disease that is poorly managed
- •A diagnosis of Complex Regional Pain Syndrome (CRPS)
- •Pregnancy, or nursing
- •History of claustrophobia with active symptoms that would interfere with the MRI
- •Any contraindication to MRI safety questionnaire
- •Poorly controlled hypertension.
研究组 & 干预措施
Ketamine Group
Subjects will receive IV racemic ketamine at a dose of 0.5 mg per kg of the participant's actual body weight, with a maximum dose of 50 mg for individuals weighing over 100 kg.
干预措施: Ketamine (Drug)
Normal Saline/Placebo Group
Subjects will receive an IV infusion of normal saline over a duration of 40 minutes
干预措施: Normal Saline (Drug)
结局指标
主要结局
Peak (% change from baseline) Anterior Cingulate Cortex metabolites (Gamma-Aminobutyric Acid and Glutamate)
时间窗: Baseline to the end of 40-minute infusion
To measure peak (% change from baseline) Anterior Cingulate Cortex (ACC) Gamma-Aminobutyric Acid (GABA) and Glutamate (Glu) levels during a 40-minute IV ketamine or normal saline (0.9% sodium chloride) infusion utilizing fMRS (functional Magnetic Resonance Spectroscopy)
Change in peripheral Gamma-Aminobutyric Acid and Glutamate levels
时间窗: Baseline to the end of 40-minute infusion
Change in peripheral Gamma-Aminobutyric Acid (GABA) and Glutamate (Glu) levels measured utilizing liquid chromatography-mass spectrometry (LCMS) at baseline and the end of 40-minute infusion
Change in the Montgomery Asberg Depression Rating Scale
时间窗: Baseline to 24-hours post-infusion
Montgomery Asberg Depression Rating Scale (MADRS) is a 10-item clinician rating of depressive symptoms used in the previous ketamine research studies. Higher scores represent higher levels of depression.
Correlation between the percent change in central (anterior cingulate cortex) Gamma-Aminobutyric Acid and Glutamate levels and the change in depression severity measured using the Montgomery-Åsberg Depression Rating Scale
时间窗: Baseline to the end of 40-minute infusion for GABA and Glu. Baseline to 24 hours post-infusion for MADRS
Outcome measure: Changes in the total Montgomery-Asberg Depression Rating Scale (MADRS) scale from baseline (pre-infusion) to 24 hours post-infusion. MADRS will be compared by randomized arm as a continuous variable as well as defined by remission status (MADRS≤9). The total MADRS score can range from 0 to 60, with higher scores indicating a worse outcome. We aim to evaluate the correlation between the percent change in anterior cingulate cortex (ACC) Gamma-Aminobutyric Acid (GABA) and Glutamate (Glu) levels (from baseline to peak) during a 40-minute IV infusion of ketamine or normal saline (0.9% sodium chloride) using functional magnetic resonance spectroscopy (fMRS) and the change in MADRS scores (from baseline to 24 hours).
Correlation between the percent change in serum Gamma-Aminobutyric Acid and Glutamate levels and the change in depression severity measured using the Montgomery-Åsberg Depression Rating Scale
时间窗: Baseline to the end of 40-minute infusion for serum GABA and Glu. Baseline to 24 hours post-infusion for MADRS
Outcome measure: Changes in the total Montgomery-Asberg Depression Rating Scale (MADRS) scale from baseline (pre-infusion) to 24 hours post-infusion. MADRS scores will be compared by randomized arm as a continuous variable as well as defined by remission status (MADRS≤9). The total MADRS score can range from 0 to 60, with higher scores indicating a worse outcome. We aim to evaluate the correlation between the percent change in serum Gamma-Aminobutyric Acid (GABA) and Glutamate (Glu) levels during a 40-minute IV infusion of ketamine or normal saline (0.9% sodium chloride) using Liquid Chromatography-Mass Spectrometry (LCMS) and the change in MADRS scores (from baseline to 24 hours).
次要结局
- Change in McIntyre And Rosenblat Rapid Response Scale(Baseline to up to 24 hours post-infusion)
- Change in Quick Inventory of Depressive Symptomatology (Self-Report)(Baseline to up to 24 hours post-infusion)
- Changes in short chain acylcarnitine levels(Baseline to up to 24 hours post-infusion.)
- Changes in short-chain acylcarnitine levels and ketamine-related remission(Baseline to up to 24 hours post-infusion.)
- Changes in mTOR (mechanistic Target of Rapamycin)(Baseline to the end of 40-minute infusion)
- Change in the Snaith-Hamilton Pleasure Scale(Baseline to up to 24 hours post-infusion)
- Changes in neurocognitive functioning(Baseline to 24 hours post-infusion)
- Change in Beck Scale for Suicidal Ideation(Baseline to up to 24 hours post-infusion)
- Changes in Dimensional Anhedonia Rating Scale(Baseline to up to 24 hours post-infusion)
- Change in Clinical Global Impression(Baseline to up to 24 hours post-infusion)
- Perceived Stress(Baseline to up to 24 hours post-infusion)
- Resilience(Baseline to 24 hours post-infusion)
研究者
Balwinder Singh, MD, MS
Principal Investigator
Mayo Clinic