Ketamine's Actions on Rumination Mechanisms as an Antidepressant
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 37
- 主要终点
- Ketamine's effects, 2h post infusion, on the activation of brain areas important for autobiographical emotional memory recall.
研究概览
简要总结
Rumination and anhedonia are two of the most common characteristics of depression that persist during remission and are not easily targeted by commonly prescribed antidepressants. Ketamine, an NMDA receptor antagonist, has emerged within the last decade as a potent, fast-acting antidepressant that can significantly improve anhedonia as early as two hours after a single infusion. The brain mechanisms, however, by which ketamine exerts its antidepressant action remain largely unknown. The aim of this study is to examine the early antidepressant action of ketamine, 2h post infusion, in patients who remitted from depression using fMRI. Participants are scanned while performing a personalised, autobiographical, emotional memory task and a monetary reward task. Ketamine is expected to reduce the activation of limbic areas such as the amygdala during emotional memory recall. Increased activations after ketamine are expected in reward processing areas, including striatal regions.
详细描述
Depression is one of the leading causes of disease worldwide with detrimental personal, interpersonal and societal impact.The current treatments available for depression involve psychotherapy as well as antidepressant medication. SSRIs (Selective Serotonin Reuptake Inhibitors) are the primary antidepressant medications considered for depression due to their relatively mild side effects and broad effect on depression symptoms. However, other drug types are also available and include tricyclic antidepressants and monoamine oxidase inhibitors. Despite the variety of psychotherapeutic approaches and antidepressant medication, 20% of patients suffering from depression fail to respond to any pharmacological or psychological treatment.
Recently and in an effort to overcome the limitations of the current antidepressant treatments, ketamine has emerged as an effective antidepressant with especially promising results in treatment resistant depression as well as a rather effective antidepressant maintenance strategy.Ketamine is not a novel drug and has used safely and effectively as a dissociative anaesthetic since its introduction in the 1960s. It is commonly used in medicine for starting and maintaining general anaesthesia, sedation in intensive care as well as a painkiller and is also known for its recreational use.
Several studies investigating the antidepressant effects of ketamine have shown that a single ketamine infusion produced a significant decrease in depressive symptoms in treatment resistant patients. This decrease occurred within approximately 2 hours after the infusion and the antidepressant effects of the drug persisted, in some cases, for up to 3 days after the drug administration.
The mechanism by which ketamine exercises its antidepressant effect is unknown. However, recent research has implicated the intracellular mTOR pathway, a signalling system that controls the translation of synaptic proteins. At the molecular level, ketamine is an uncompetitive antagonist of the NMDA receptor and can disrupt memory formation and retrieval. Animal research has shown that ketamine administration leads to proactive interference of spatial memory representations whereas in humans ketamine can modulate hippocampal activity during simple episodic memory tests.
Rumination and anhedonia are two of the most prevalent symptoms of depression that also persist in remission and are not easily targeted by commonly prescribed antidepressants.
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, Investigator)
盲法说明
Both the participants and the investigator are blind.
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
- •Right-handed male and female volunteers with a history of depression between the ages of 18 and 50 years.
- •Good command of the English language.
- •Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of and agrees to comply with all aspects of the study.
- •Willing and able to comply with scheduled visits, dosing plan, laboratory trials and any other necessary procedures.
- •Are willing for data to be shared and disseminated after being anonymised.
排除标准
- •Have a current or previously diagnosed psychiatric disorder except depression.
- •Have one or more immediate family members with a current or previously diagnosed psychotic disorder.
- •Have a medically significant condition which renders them unsuitable for the study (e.g., diabetes, severe cardiovascular disease, hepatic or renal failure etc.).
- •Show MR contraindications (e.g., metal implants, pacemakers, claustrophobia etc.) which would render them unsuitable for the study.
- •Have previously experienced an adverse response to ketamine.
- •Have excessive use of alcohol (in excess of 28 units a week), caffeine (>6 cups of coffee a day), or other drugs.
- •Have taken any other medication during the course of the study that has not been discussed - this should be documented by the investigators. (As an exception, 1g paracetamol/24 hours may be taken up to 24 hours prior to any MRI scan).
- •Have taken illicit drugs 7 days prior to admission, have consumed alcohol or caffeine within 24 hours prior to admission or have consumed nicotine within 4 hours prior to admission.
- •Have taken grapefruit juice- or Seville orange-containing products 24 hours prior to admission.
- •Use of any prescribed medication in the 3 weeks prior to enrolment or non-prescription medication (other than paracetamol) or herbal preparations in the previous 7 days.
- •Have a significant history of drugs of abuse (including benzodiazepines) or positive drugs of abuse test.
- •Had acute illness within 2 weeks before the start of study.
- •Have clinically significant abnormalities in clinical chemistry (including liver function tests), haematology or urinalysis results.
- •Have a history or presence of gastrointestinal, hepatic or renal disease or other condition known to interfere with absorption, distribution, metabolism or excretion of drugs.
- •Have been diagnosed hypertension, or supine systolic BP outside of the range of 90 to 140 mmHg and a supine diastolic BP outside the range of 40 to 90 mmHg, after a period of acclimatisation
- •Have a decrease in systolic BP of > 25 mmHg or a decrease in diastolic BP of > 15 mmHg when going from resting in bed to standing position, with or without symptoms such as dizziness or light-headedness. (For determination of orthostatic hypotension, lying and standing BP will be recorded after the subject has rested for 10 minutes and has had resting BP recorded followed by measurements taken at 1, 2 and 5 minutes after standing)
- •Had treatment in the previous 3 months with any drug known to have a well-defined potential for hepatotoxicity (e.g., halothane)
- •Subjects who, in the opinion of the investigator, should not participate in the study for reasons of safety
研究组 & 干预措施
Ketalar
0.5mg/kg of ketalar (ketamine). Single, intravenous, steady state infusion over 40min.
干预措施: Intravenous Infusion (Drug)
Saline
Single, intravenous, steady state infusion over 40min.
干预措施: Intravenous Infusion (Drug)
结局指标
主要结局
Ketamine's effects, 2h post infusion, on the activation of brain areas important for autobiographical emotional memory recall.
时间窗: 1 YEAR
To investigate the role of limbic areas and NMDA receptor blockade during autobiographical memory retrieval using fMRI
Ketamine's effects, 2h post infusion, on the activation of brain areas important for reward processing and anhedonia.
时间窗: 1 YEAR
To investigate the role of striatal areas and NMDA receptor blockade during a monetary reward task using fMRI.
次要结局
未报告次要终点