Elucidating the Neurocircuitry of Irritability With High-Field Neuroimaging to Identify Novel
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 165
- 试验地点
- 1
- 主要终点
- Treatment-related change in striatum-habenula functional connectivity.
研究概览
简要总结
The study is investigating dysfunctions in neurocircuitry in regards to irritability with healthy controls (HC) and individuals with Major Depressive Disorder (MDD) by performing MRIs. The MDD group will also be randomized to receive ketamine or midazolam to investigate changes post-treatment in neurocircuitry with regards to irritability.
详细描述
The proposed study aims to 1 (Aim 1) identify dysfunctions in neurocircuitry that engender irritability, and (Aim 2) determine how changes in neurocircuit function related to change in irritability. We will accomplish Aim 1 with resting-state and frustrative nonreward (FNR) task-based fMRI data from n=30 HCs and n=60 subjects with MDD ((Fig 3). For Aim 2, we will randomize the MDD cohort (n=60; same as Aim 1) to 2 weeks of twice-weekly 40-minutes long intravenous infusion of either ketamine (0.5 mg/kg) or midazolam (0.02 mg/kg) in a double-blind parallel-arm fashion, and by repeating clinical assessments and fMRI scans after the last infusion. The central hypothesis of the proposed study is that striatum is a key hub in the neurocircuitry of irritability, and that treatment-related improvement in irritability is associated with normalization of these neurocircuit functioning.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Subjects and study team members, including the PI, study-affiliated physicians, coordinator, nursing staff, and data analysts will be blinded to the drug assignment until the completion of the proposed project. Only the research pharmacist and study members involved in safety monitoring (medical monitor, independent safety monitor, and data analyst responsible for generating safety reports) will know the identity of the drug.
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
- 是
入选标准
- •Male or female subjects, 18-65 years of age and body weight less than or equal to 120 kg on baseline visit.
- •Participants must have a level of understanding of the English language sufficient to agree to all tests and examinations required by the study and must be able to participate fully in the informed consent process.
- •For Healthy Controls: Subjects must be free of any lifetime psychiatric condition based on the Mini-International Neuropsychiatric Interview (MINI). For MDD: Subjects must meet Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for current unipolar depression [major depressive disorder (MDD) or persistent depressive disorder (PDD) in a current major depressive episode (MDE)] based on MINI.
- •A woman of childbearing potential who is sexually active with a male must agree to use an acceptable method of contraception [defined as either one highly effective (permanent sterilization, intrauterine device or hormonal implant) or two other forms of contraception (such as oral contraceptive pill and condom)] to avoid pregnancy throughout the study. Throughout the study and for 90 days (one spermatogenesis cycle) after receiving the last dose of study drug (ketamine/midazolam) man who is sexually active with a woman of childbearing potential must use an acceptable method of contraception (described above) with his female partner and must agree not to donate sperm.
- •Subjects must either be free of psychotropic medications (including antidepressants, antipsychotics, benzodiazepines, mood stabilizers, sedative/hypnotics, dopamine agonists, stimulants, buspirone, and triptans) and certain anticonvulsants (topiramate and levetiracetam) or be stable on these medications for four weeks prior to the baseline visit [first magnetic resonance imaging (MRI) scan].
- •Subjects with MDD should be willing to participate in neuroimaging scans before and after infusions, and be willing to undergo infusions with study drug.
排除标准
- •Lifetime diagnosis of schizophrenia or any psychotic disorder, bipolar disorder, pervasive developmental disorder or intellectual development disorder.
- •Current diagnosis of obsessive-compulsive disorder, anorexia nervosa or bulimia. Comorbid anxiety, stress and trauma-related disorders are permitted as long as unipolar depression is the primary diagnosis.
- •Diagnosis of a moderate or severe substance use disorder within the past 6 months per MINI; all subjects must have a negative urine toxicology test on the day of the MRI, prior to the scan.
- •Female subjects who are pregnant, nursing, for may become pregnant. Women of childbearing potential must have a negative urine pregnancy test on the day of the fMRI, prior to scan, and on days of study drug infusion, prior to infusion.
- •Any unstable medical illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, immunologic, or hematologic disease.
- •Inadequately treated obstructive sleep apnea (STOP-Bang score of 5-8 if untreated, if using positive airway pressure device then past-month apnea hypopnea index ≥ 15 per hour representing moderate or higher severity).
- •Presence of a significant neurological disease such as Parkinson's disease, primary or secondary seizure disorders, intracranial tumors, or severe head trauma.
- •Presence of neurocognitive or dementing disorders.
- •Clinically significant abnormalities of laboratories, physical examination (including unstable hypertension - systolic blood pressure >170, diastolic blood pressure >100), or electrocardiogram at screening visit.
- •Subjects judged to be at serious and imminent suicidal or homicidal risk by the PI or another study-affiliated psychiatrist.
- •Any contraindications to MRI, including pacemakers or metallic objects in the body.
- •Any claustrophobia or other conditions which may result in inability to lie still in the MRI scanner for 1 hour or more.
- •Allergy to ketamine or midazolam in subjects with MDD.
- •Must not be on any prohibited concomitant medication.
研究组 & 干预措施
MDD - Ketamine
Participants with MDD who have completed all baseline assessments including pre-treatment fMRI scan randomly allocated to receive four ketamine infusions.
干预措施: Ketamine Hydrochloride (Drug)
MDD - Midazolam
Participants with MDD who have completed all baseline assessments including pre-treatment fMRI scan randomly allocated to receive four midazolam infusions.
干预措施: Midazolam injection (Drug)
结局指标
主要结局
Treatment-related change in striatum-habenula functional connectivity.
时间窗: Baseline, at 14 days
Striatum-habenula functional connectivity is the standardized correlation between resting state BOLD signal of the striatum and habenula regions of the brain measured on a fMRI. Unit is the standardized correlation ranges from -1 to 1. MDD participants only.
Treatment-related change in striatal response to FNR.
时间窗: Baseline, at 14 days
Striatal response to FNR is the standardized correlation between resting state BOLD signal of the striatum and habenula regions of the brain measured on a fMRI. Unit is the standardized correlation ranges from -1 to 1. MDD participants only.
Resting state functional connectivity.
时间窗: Baseline
Resting-state functional connectivity between striatum and habenula will be measured by functional magnetic resonance imaging (fMRI) in healthy controls and in adults with major depressive disorder (MDD). Functional connectivity refers to the standardized correlation between resting state BOLD signal of the striatum and habenula regions of the brain.
Striatal response to frustrative nonreward (FNR).
时间窗: Baseline
Striatal response to frustrative nonreward (FNR) as measured by the BOLD (Blood Oxygen Level Dependent) signal within the striatum region of the brain on a functional MRI behavioral task of FNR in healthy controls and in adults with MDD. BOLD signal is the unit of measure of this outcome.
次要结局
- Acute behavioral changes measured by Brief Psychiatric Rating Scale (BPRS)(Baseline, at 14 days)
- Change in patient reported side effects measured by PRISE Adverse Event scores(Baseline, at 14 days)
- Change in symptoms of depression (including suicidal ideation) measured by MADR scale(Baseline, at 14 days)
- Change in symptoms of depression measured by QIDS report(Baseline, at 14 days)
- Change in symptoms including anxious arousal measured by MAS questionnaire(Baseline, at 14 days)
- Change in severity of dissociative symptoms associated with study drug administration measured by CADS scale(Baseline, at 14 days)
- Change in symptoms of irritability after two weeks of twice-weekly infusions of ketamine versus midazolam.(Baseline, at 14 days)
- Change in behavior (including anger attacks) measured by AAQ(Baseline, at 14 days)
研究者
Manish Jha
Associate Professor
University of Texas Southwestern Medical Center