Acute Neurophysiologic Effects of Intravenous (IV) Citalopram Hydrochloride During Transcranial Magnetic Stimulation in Major Depressive Disorder (MDD)
试验速览
- 阶段
- 早期 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Percent change in Hamilton Depression Scale
研究概览
简要总结
This study will recruit 30 subjects diagnosed with Major Depressive Disorder (MDD). Subjects will be recieve one infusion treatment of citalopram or placebo and 10 treatments of a form of transcranial magnetic stimulation, theta burst stimulation (TBS). Subjects will also undergo brain scans, quantitative electroencephalography (qEEG) brain activity recordings, and mood surveys. Study activities will be performed over the course of 4 weeks.
详细描述
Repetitive Transcranial Magnetic Stimulation (rTMS) is an increasingly common treatment for Major Depressive Disorder (MDD). rTMS applied to dorsolateral prefrontal cortex (DLPFC), the most common treatment target, appears to change neuronal excitability in this region. rTMS also changes function of brain circuits connected to DLPFC. This application proposes an innovative approach to elucidating the mechanism of action (MOA) underlying these circuit changes, using MDD as a significant translational model.
One form of rTMS, theta burst stimulation (TBS), has particularly strong effects on cortical excitability: intermittent pulsing over left DLPFC (iTBS) increases excitability, while continuous pulsing over right DLPFC (cTBS) reduces excitability. TBS applied to DLPFC alters functional connectivity with the anterior cingulate, medial frontal, and orbitofrontal cortices (ACC, MFC, and OFC); however, the MOA underlying these changes in connectivity is incompletely understood. Pilot data will be obtained for a larger grant application that will test the hypothesis that changes in local excitability underlie the changes in functional connectivity and the therapeutic efficacy of TBS for MDD.
TBS modulation of cortical excitability may be modulated in turn by the serotonergic (5HT) neurotransmitter system, which is also a key target of classical antidepressant medications. The investigators will use the 5HT transport inhibitor citalopram (CIT), a widely-used clinical antidepressant agent, to investigate the serotonergic modulation of functional connectivity and neurophysiologic measures of excitability.
Intravenous citalopram hydrochloride has been available for prescription to patients with treatment-refractory major depression and anxiety disorders in most of continental Europe for more than 30 years. In the U.S., it has been used extensively as an investigational drug to study human neurochemistry and in clinical trials for depressive disorders. An IND for the University of Pittsburgh has utilized this compound safely as a research tool for more than 10 years (Smith et al., 2009).
This double-blinded study will recruit 30 subjects diagnosed with Major Depressive Disorder (MDD). Subjects will be randomized to acute (single-dose) citalopram (CIT) 40 mg iv treatment or placebo, counterbalanced and combined with one of two forms of unblinded Transcranial Magnetic Stimulation, i.e., either intermittent Theta Burst Stimulation or continuous Theta Burst Stimulation. Assessments for this study include brain scans, qEEG recordings, and cognitive and mood scales. One citalopram/placebo infusion and 10 TBS treatments will be administered over the course of approximately two weeks.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- Double (Participant, Care Provider)
入排标准
- 年龄范围
- 21 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •21-55 years of age. MDD currently depressed subjects will meet DSM-V criteria for MDD based on the Mini-International Neuropsychiatric Interview (MINI) (http://www.medicaloutcomes.com/index/mini7fororganizations) with a 17-item Hamilton Depression Rating Scale (HamD17) (Hamilton, 1960) score >
- •Subjects must have failed to enter remission with at least two prior antidepressant medications in the current episode (Vasavada et al., 2016)
- •Must have been free of any medications known to significantly affect brain function for at least ten days prior to enrollment (except fluoxetine, which will require a five-week washout).
排除标准
- •No unstable medical illness that would prevent completion of participation in the trial (determined as needed from physical examination, ECG, laboratory safety tests, as well as a review of systems).
- •Clinically significant physical abnormalities as indicated by physical examination, hematological laboratory assay, or urinalysis, defined as:
- •hematology and chemistry laboratory tests that are within normal (+/- 10%) limits with the following exceptions: a) liver function tests (total bilirubin, ALT, AST, and alkaline phosphatase) < 3 x the upper limit of normal, and b) kidney function tests (creatinine and BUN) < 2 x the upper limit of normal;
- •A screening ECG that demonstrates anything other than normal sinus rhythm, normal conduction, and no clinically significant arrhythmias
- •History of epilepsy, seizures, or severe head trauma;
- •Resting vital signs on any study visit outside of acceptable parameters (i.e., pulse of 60-100 bpm, blood pressures of 90-150 mm Hg systolic, 50- 90 mm Hg diastolic);
- •Any indication of suicidal ideation (e.g. as assessed by the suicidality question on the HamD17or the Columbia Suicide Severity Rating Scale.
- •Baseline QT prolongation (QTc> 450 ms): Given that citalopram has been found to be associated with a dose-dependent risk of ECG QT interval prolongation, in order to avoid the potential risk of causing ventricular arrhythmias including Torsades de Pointes, we will exclude participants from the study who exhibit baseline QTc prolongation.
- •For women of childbearing age, a positive urine pregnancy test, as well as women who are currently breastfeeding or not using a medically acceptable method of birth control
- •Presence of any implanted medical device or metal in the body that would render it unsafe to perform TMS or an MRI.
- •Axis I: the presence of any other primary mood, anxiety, or psychotic disorder, depression secondary to a general medical condition, or substance- induced illness. Subjects also will be excluded if they have current suicidal intent or plan, a history of substance abuse or dependence within the past six months (except nicotine and caffeine), Bipolar Disorder or psychotic disorder (lifetime), eating disorder (current or within the past year), Obsessive Compulsive Disorder (lifetime), Post-Traumatic Stress Disorder (PTSD, current or within the past year);
- •Axis III: active medical illness known to significantly affect brain function or that could be etiologically related to the ongoing depression (e.g., untreated hypothyroidism);
- •Current treatment with a medication known to affect brain function. This would include both psychiatric and centrally-acting neurological agents.
- •The investigators have chosen to exclude these subjects because current medication could affect measures of brain function as well as introduce an uncontrolled treatment effect into the study. Prospective subjects who are currently taking psychiatric medications will also be excluded as the risk of antidepressant discontinuation outweighs the potential benefit of study participation. A history of prior treatment with IV CIT. We have chosen to exclude subjects who have received this treatment because they may have a degree of treatment resistance that would make it less likely for them to respond to treatment in the current protocol. Additionally, if they previously have received CIT the PBO treatment blind in the current protocol may not be effective;
- •Current treatment with a medication known to affect brain function. We have chosen to exclude these subjects because current medication could affect measures of brain function as well as introduce an uncontrolled treatment effect into the study. These medications include: antidepressants, barbiturates, anticonvulsants/mood stabilizers, benzodiazepines, anticholinergics, herbal preparations, antipsychotics, muscle relaxants, antimigraine, psychostimulants, anti-Parkinsonian medications, sedating antihistamines, corticosteroids (oral; topical preparations OK), Zyban (bupropion for use in smoking cessation);
- •Treatment with any of the following medications within the last 30 days prior to randomization: antidepressants, anticonvulsants, hypnotics, antipsychotics, psychomotor stimulants, anti-anxiety agents, or cimetidine;
- •Current illicit drug use. We will perform urine toxicology screens at baseline;
- •History of stroke, skull fracture, brain surgery, or transient ischemic attacks, or other brain disease that could affect results;
- •For women of childbearing age, a positive urine pregnancy test, as well as women who are currently breastfeeding or not using a medically acceptable method of birth control;
- •History of allergic reaction or intolerance to citalopram (any formulation); and,
- •History of ECT within the past six months, or history of failure to benefit from prior TMS treatment of MDD.
研究组 & 干预措施
Placebo infusion
Placebo comparator to active study drug
干预措施: Placebo (Drug)
intravenous citalopram hydrochloride (CIT)
A single 40 mg dose of CIT diluted in 60 cc normal saline will be delivered intravenously under double-blind conditions via pump over a 40-minute period.
干预措施: intravenous citalopram hydrochloride (CIT) (Drug)
intermittent Theta Burst Stimulation
- 10 sessions of treatment with cTBS to right DLPFC
- TBS consists of three TMS pulses given at 50 Hz, with this triplet repeated at a frequency of 5 Hz (every 200 ms).
- iTBS paradigm of a 2 s train repeated every 10 seconds
干预措施: intermittent theta burst stimulation (Device)
continuous Theta Burst Stimulation
- 10 sessions of treatment with iTBS to left or cTBS to right DLPFC
- TBS consists of three TMS pulses given at 50 Hz, with this triplet repeated at a frequency of 5 Hz (every 200 ms).
- 1800 pulses of cTBS will be delivered
干预措施: continuous theta burst stimulation (Device)
结局指标
主要结局
Percent change in Hamilton Depression Scale
时间窗: through study completion, an average of 10 days
A 17-item, clinician-administered depression assessment scale pertaining to symptoms of depression experienced over the past week. Each item is scored between 0-4 points. Scoring is based on the 17-item scale and scores of 0-7 are considered as being normal, 8-16 suggest mild depression, 17-23 moderate depression and scores over 24 are indicative of severe depression; the maximum score being 52 on the 17-point scale.
次要结局
- Percent. change in The Inventory of Depressive Symptomatology-Self Report(through study completion, an average of 10 days)
研究者
Andrew F. Leuchter
Principal Investigator
University of California, Los Angeles