Boosting and Guiding Neuroplasticity by Combining Ketamine with Neurofeedback-assisted Learning - Towards an Individualized and Integrated Pharmaco-psychotherapy for Cocaine Addiction
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 120
- 试验地点
- 1
- 主要终点
- Decrease in proportion of cocaine use days
研究概览
简要总结
The goal of this clinical trial is to learn about the effects of the combination of ketamine and realtime functional magnetic resonance imaging (fMRI) neurofeedback training in individuals with cocaine use disorder. The main questions the investigators aim to answer are:
- Can the investigators observe a positive, significant effect on percentage of cocaine use days of both interventions combined as well as stand alone interventions?
- Is there a significant transfer effect of the neurofeedback training?
- Is there a significant, ketamine-dependent change in glutamate levels in the nucleus accumbens?
Participants will be given ketamine and a realtime fMRI neurofeedback training. Both interventions are placebo-controlled. The investigators will compare the four intervention groups to investigate the effects of the stand-alone effects of the intervention and the combination of it.
详细描述
Cocaine is the most frequently used stimulant worldwide, and its consumption rate in Europe indicates a continuing upward trend. Cocaine use is associated with great harms for affected individuals, their families, and the society. Unfortunately, until today no pharmacotherapy has been approved for the treatment of cocaine use disorder (CUD) due to lack of efficacy of tested compounds.
The investigators therefore propose, to use latest advancements in proton magnetic resonance spectroscopy (1H-MRS) and real time functional magnetic resonance imaging neurofeedback training (rt-fMRI NFT) to develop a neurobiologically informed experimental approach for an individualized and integrated pharmaco-psychotherapy that has the potential to open new avenues for the treatment of CUD, and in addition, to be transferable to other neuropsychiatric conditions.
To improve the efficacy of psychotherapeutic interventions in individuals with CUD, the investigators recently developed an rt-fMRI NFT paradigm based on reward imagery to specifically modify maladaptive reward sensitivity by self-regulating the brain's reward circuits.
Furthermore, using a 1H-MRS technique, the investigators recently demonstrated that a disturbed glutamate homeostasis in the nucleus accumbens (NAcc), an important hub in the brain's reward system, characterizes cue-induced craving in CUD. This indicates that urgently needed novel pharmacotherapies for addiction treatment should target the glutamatergic system.
Thus, to restore the glutamate homeostasis and to boost learning effect of the reward imagery training, the investigators propose to combine reward imagery rt- fMRI NFT with the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine, which has direct effects both on glutamatergic signaling and neuroplasticity and has shown therapeutic potential to reduce cocaine craving and cocaine us.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Informed Consent as documented by signature
- •Male and female cocaine users 18 to 55 years of age
- •diagnostic and statisical manual (DSM)-5 diagnosis of CUD
- •Willingness to comply with the study protocol as explained by investigator
- •Normal level of language comprehension (German or Swiss-German)
排除标准
- •Current or lifetime psychotic disorders
- •History of severe substance-induced psychosis
- •Current or lifetime bipolar I or II disorders
- •Current suicidality
- •Previous suicide attempts during the last 2 years
- •Current severe alcohol use disorder
- •Current severe cannabis use disorder
- •Current moderate or severe stimulant use disorder (other than cocaine)
- •Current moderate or severe benzodiazepine use disorder
- •Current opioid use disorder
- •First-degree relatives with psychotic disorders
- •Beck Depression Inventory Score greater than 25
- •Unmedicated or unstable hypertension
- •Severe illness (e. g. myocardial ischemia or arrythmias, severe pulmonary secretions, glaucoma, congestive heart failure or angina, significant renal or hepatic impairment)
- •Acute infection (e. g. pulmonary or upper respiratory tract infection)
- •Insufficient treated or uncorrected hyperthyroidism
- •Severe central nervous system related traumas or disorders (e. g. stroke, cerebral trauma with loss of consciousness over more than 24h, epilepsy)
- •Increased intracranial pressure
- •Medication directly affecting glutamate signaling (e. g. anticonvulsant medication)
- •Any unstable psychoactive medication (no changes in compounds within last 4 weeks before start of study)
- •Pregnancy or lactation
- •Women of childbearing potential with no use of medically accepted contraceptive (e. g.
- •condoms, contraceptive diaphragm, birth control pill, hormone injection, intrauterine device)
- •Allergy, hypersensitivity, or other adverse reaction to previous use of ketamine
- •Contradictions to magnetic resonance imaging
- •Concurrent participation in other clinical study
研究组 & 干预措施
rt-fMRI NFT / Placebo
Participants get real time neurofeedback based on an experimental regions' activity and receive a 0.9% saline solution (i.v.) over 40 minutes.
干预措施: Placebo (Drug)
rt-fMRI NFT / Placebo
Participants get real time neurofeedback based on an experimental regions' activity and receive a 0.9% saline solution (i.v.) over 40 minutes.
干预措施: real-time fMRI neurofeedback training (Behavioral)
rt-fMRI NFT / Ketamine
Participants get real time neurofeedback based on an experimental regions' activity and receive 0.71mg ketamine (i.v.) per kilogram bodyweight.
干预措施: Ketamine (Drug)
rt-fMRI NFT / Ketamine
Participants get real time neurofeedback based on an experimental regions' activity and receive 0.71mg ketamine (i.v.) per kilogram bodyweight.
干预措施: real-time fMRI neurofeedback training (Behavioral)
sham NFT / Placebo
Participants get a real time neurofeedback based on a control regions' activity, which serves as a sham region and receive a 0.9% saline solution (i.v.) over 40 minutes.
干预措施: Placebo (Drug)
sham NFT / Placebo
Participants get a real time neurofeedback based on a control regions' activity, which serves as a sham region and receive a 0.9% saline solution (i.v.) over 40 minutes.
干预措施: sham real-time fMRI neurofeedback training (Behavioral)
sham NFT / Ketamine
Participants get a real time neurofeedback based on a control regions' activity, which serves as a sham region and receive 0.71mg ketamine (i.v.) per kilogram bodyweight.
干预措施: Ketamine (Drug)
sham NFT / Ketamine
Participants get a real time neurofeedback based on a control regions' activity, which serves as a sham region and receive 0.71mg ketamine (i.v.) per kilogram bodyweight.
干预措施: sham real-time fMRI neurofeedback training (Behavioral)
结局指标
主要结局
Decrease in proportion of cocaine use days
时间窗: Between 5 and 7 weeks after baseline (the first intervention visit)
Between-group comparison of proportion of cocaine use days measured with Time-Line Follow-Back questionnaire for cocaine use on follow-up visit (t3).
Changes in fMRI signal of neurofeedback training
时间窗: Between 1 and 2 weeks after baseline (the first neurofeedback training)
Signal changes assessed with fMRI between the non-neurofeedback run 1 on Interention Visit I (t1) and run 3 on Intervention Visit II (t2).
Changes in accumbal glutamate levels
时间窗: Before and during infusion (same day)
Baseline and acute accumbal glutamate levels assessed with 1H-MRS on Intervention Visit I (t1).
次要结局
- Changes in urine cocaine and cocaine metabolites(Baseline (screening visit) up to 19 weeks later (Follow-up Visit))
- Cocaine craving(From baseline (screening visit) until 38 weeks later (Follow-up Survey))
- Severity of cocaine use disorder(From baseline (screening visit) until 38 weeks later (Follow-up Survey))
- Current motivation to change cocaine use behaviour(From baseline (screening visit) until 38 weeks later (Follow-up Survey))
- Hedonic capacity(From baseline (screening visit) until 38 weeks later (Follow-up Survey))
- Experience of pleasure across different domains(From baseline (screening visit) until 38 weeks later (Follow-up Survey))
- Emotion regulation skills(Baseline (screening visit) and up to 19 weeks later (Follow-up Visit))
- Depressive symptoms(Baseline (screening visit), up to 14 weeks later (Intervention Visit II), and up to 19 weeks later (Follow-up Visit))
- Perceived stress(Baseline (screening visit), up to 19 weeks later (Follow-up Visit), and up to 38 weeks later (Follow-up Survey))
- Self-esteem(Baseline (screening visit), up to 14 weeks later (Intervention Visit II), up to 19 weeks later (Follow-up Visit), and up to 38 weeks later (Follow-up Survey))
- Self-efficacy, optimism, and pessimism(Baseline (screening visit), up to 14 weeks later (Intervention Visit II), up to 19 weeks later (Follow-up Visit), and up to 38 weeks later (Follow-up Survey))
- Subjective effects of ketamine infusion(2 hours post infusion)
- Effects of ketamine infusion on mystic experiences(2 hours post infusion)
- Sustained changes in accumbal glutamate levels(Baseline (pre infusion, Intervention Visit I) and up to 2 weeks after infusion and neurofeedback training (Intervention Visit II))
- Glutamate levels during craving paradigm(Up to 2 weeks post infusion and neurofeedback training)
- Changes in Brain Derived Neurotrophic Factor(0.5 hours pre infusion and 2 hours post infusion)
研究者
Dr. med. Marcus Herdener
Dr. med.
Psychiatric University Hospital, Zurich