Effects of Esketamine Challenge on Brain Glutamate Release (fMRS), Resting State Connectivity (BOLD-rs-fMRI), and Neuroplasticity (Visual Task)
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 16
- 试验地点
- 1
- 主要终点
- Brain Glutamate Dynamic Change
研究概览
简要总结
Esketamine is the S-enantiomer of racemic ketamine, a N-methyl-D-aspartate (NMDA) receptor antagonist. Esketamine and other antidepressant NMDA receptor antagonists are hypothesised to act by producing a rapid increase in brain glutamate release, which then stimulates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. This activity in turn is thought to restore synaptic functioning, neuroplasticity, and connectivity in brain regions involved in mood regulation, which would be ultimately responsible for the antidepressant effect of esketamine. However, the effect of esketamine on glutamate release in humans has not previously been studied. In this study we therefore aim to ascertain the effect of esketamine on dynamic brain glutamate release, resting state connectivity, and neuroplasticity as measured via fMRS, BOLD-rs-fMRI, and a behavioural computerised visual task respectively.
详细描述
There is growing interest in the use of antagonists at the glutamate N-methyl-D-aspartate (NMDA) receptor in patients with treatment-resistant depression (TRD). Work in animal studies suggests that NMDA receptor antagonists act initially by increasing brain glutamate release, but whether such an action occurs in humans is not established.
Esketamine is the S-enantiomer of racemic ketamine: a non-selective, non-competitive, antagonist of the ionotropic glutamate NMDA receptor. It is the only NMDA receptor antagonist licensed in the UK for the treatment of patients with TRD. Esketamine is administered intranasally: it is rapidly absorbed by the nasal mucosa following nasal administration and can be measured in plasma within 7 minutes following a 28 mg dose. The time to reach maximum plasma concentration (tmax) is typically 20 to 40 minutes after the last nasal spray of a treatment session. It is hypothesised that through NMDA receptor antagonism, esketamine produces a transient increase in glutamate release leading to increases in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor stimulation and subsequently to increases in neurotrophic signalling which may contribute to the restoration of synaptic function, neuroplasticity, and connectivity in brain regions involved with the regulation of mood.
Glutamate is the primary excitatory neurotransmitter in the brain and has been implicated in several neuropsychiatric disorders. "Gold-standard" methods to assess glutamate activity in the living human brain are expensive and involve radioactive injections and invasive blood sampling. More recently, preliminary work in our Clinical Psychopharmacology laboratory (Department of Psychiatry, University of Oxford) has shown that 7T fMRS (a more widely available, non-invasive, safe technique) that uses a visual stimulus ("flickering checkerboard") can reliably and sensitively measure changes in brain glutamate release. No prior study however has shown whether this effect is susceptible to pharmacological challenge. We therefore propose to assess whether through its NMDA/AMPA-mediated activity, esketamine induced glutamate increase can be measured via this fMRS technique.
The aims of this study are to investigate the effect of esketamine on brain glutamate release and resting state connectivity, and on vision. Therefore, the primary objective of this study is to assess the effect of a single dose of esketamine 56mg intranasal vs placebo on brain glutamate release changes measured via 7T fMRS "flickering checkerboard" stimulus. Secondary objectives include the investigation of the effects of esketamine on brain resting state connectivity changes measured via 7T BOLD-rs-fMRI, and on vision measured via a behavioural computerised visual task. Psychological questionnaires will also be measured to check for possible correlations with the outcomes measured.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- Double (Participant, Outcomes Assessor)
盲法说明
Self-administered by the participant wearing an eye mask, following instructions and under supervision of appropriately trained medical staff where resuscitation facilities are available, via a single-use device delivering 28 mg as two sprays (i.e., one spray per nostril).
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Aged 18 to 50 years
- •Body Mass Index in the range of 18-30
- •Sufficiently fluent in English to understand the study instructions
- •Willing and able to give informed consent for participation in the research
排除标准
- •Currently on any regular prescribed medications (except the contraceptive pill), unless unlikely to compromise safety or affect data quality in the opinion of the Investigator
- •Known hypersensitivity to the study drug (i.e., esketamine)
- •History of, or current significant alcohol or substance misuse disorder
- •Any use of recreational drugs over the last 3 months
- •Any lifetime use of ketamine or phencyclidine (PCP)
- •Currently smoking >/=20 cigarettes/day
- •History of, or current significant cardiovascular disorder (e.g., hypertension, myocardial infarction)
- •History of, or current significant neurological disorder (e.g., epilepsy, migraine) or cerebrovascular disorder (e.g., haemorrhagic or ischemic stroke, aneurysmal vascular disease, raised intracranial pressure)
- •History of, or current significant respiratory, hepatic, urinary tract, or thyroid disorders
- •History of, or current acute porphyria
- •History of, or current significant psychiatric disorder (e.g., psychosis, mania, depression)
- •History of, or current eye disorder, not including refractive error that can be corrected with glasses or contact lenses)
- •Pregnant, breast feeding, women of child-bearing potential not using appropriate contraceptive measures
- •Any contraindication to 7T MRI
研究组 & 干预措施
Esketamine
Nasal spray solution, 56mg (28mg per nostril), intranasal
干预措施: Esketamine nasal spray (Drug)
Placebo
Nasal spray solution, 0.9% NaCl, intranasal
干预措施: Placebo (Other)
结局指标
主要结局
Brain Glutamate Dynamic Change
时间窗: Acute (40-60 minutes after nasal spray application)
From the functional magnetic resonance spectroscopy (fMRS), calculating the glutamate concentration change in response to flickering checkerboard stimulation (by the difference in the rest concentrations to the stimulation concentrations). This dynamic glutamate change will be compared between individuals on ketamine and placebo, in a within subject cross over design.
次要结局
- Exploratory Analysis of Other Metabolite Concentrations at Baseline or Changes After Stimulation(Acute (40-60 minutes after nasal spray application))
- Brain Resting State Connectivity(Acute (40-60 minutes after nasal spray application))
- Brain Glutamate Baseline Change(Acute (40-60 minutes after nasal spray application))
- Visual response(Post-Acute (60-120 minutes after nasal spray application))
- Excitatory-Inhibitory Ratio Change(Acute (40-60 minutes after nasal spray application))
- Exploratory Investigation of the Influence of Age, Gender, and Questionnaire Scores on Metabolite Concentration Change(Acute (40-60 minutes after nasal spray application))