Ketamine and Neurofeedback as Combined Therapeutic Interventions to Target Glutamatergic Neurotransmission in Alcohol Use Disorder

Официальное название

Phase II, Randomised, Placebo-controlled, Double Blind, Parallel Group, Single Centre Study Investigating Ketamine and Neurofeedback as Combined Therapeutic Interventions to Target Glutamatergic Neurotransmission in Alcohol Use Disorder

Обзор

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 on the treatment of individuals with alcohol use disorder (AUD). The main questions the investigators aim to answer are: * Can the investigators observe a positive, significant therapeutic effect by comparing changes in alcohol use via i) mean alcohol use per day, ii) heavy drinking days one month after the last treatment intervention? * Are changes in glutamatergic neurotransmission in the nucleus accumbens related to cue-induced cravings in individuals with AUD? * Is there a significant, ketamine-dependent change in glutamate levels in the nucleus accumbens? Participants will be given ketamine or placebo and real-time fMRI neurofeedback (rt-fMRI NFT) or sham rt-fMRI NFT. The investigators will compare three intervention groups to investigate the effects of the stand-alone effects as well as potential synergies between the combination of pharmacological and non-pharmacological intervention.

Подробное описание

For decades, addiction research has focused predominantly on the dopaminergic system. However, preclinical research suggests that alterations of glutamatergic neurotransmission within the nucleus accumbens (NAcc) are crucial for cue-induced drug-seeking behavior, at least in animal models of addiction (Kalivas, 2009). In line with this, three randomized controlled trials have been conducted exploring ketamine as a treatment for alcohol use disorder (AUD) or harmful drinking, each combining ketamine with either memory retrieval destabilization procedures or psychological therapy (Dakwar et al., 2020a; Das et al., 2019a; Grabski et al., 2022a). While ketamine consistently reduced alcohol use in these studies, the variability in treatment responses highlights the need for further investigation into the role of the glutamate system in AUD as well as optimal treatment approaches that maximize safety and efficacy for patients.

Given the significant need to advance both mechanistic and clinical understanding of AUD, this study aims to: (1) explore the role of glutamatergic neurotransmission in AUD; (2) determine whether ketamine can modulate potentially pathophysiological altered glutamate neurotransmission, and how such modulation may be influenced by ketamine metabolism ; and (3) optimize ketamine as a treatment for AUD by leveraging synergies between the additional biological mechanism of action of ketamine (i.e., induced neuroplasticity) and a targeted non-pharmacological neuromodulatory intervention, such as neurofeedback training (NFT), to maximize clinical outcomes.

To evaluate both the mechanistic and therapeutic effects of a single ketamine infusion and rt-fMRI NFT as well as their combined application on AUD, we will assess glutamatergic signalling in the NAcc, changes in neuroplasticity via BDNF, inter-individual differences in the metabolism of ketamine, and clinical symptoms in individuals with AUD.

Therefore, in this randomized, placebo-controlled, double blind, parallel group, single centre study we investigate the extend to which a single administration of ketamine and neurofeedback training, as well as the combination of the two interventions can restore neurobiological changes related to alcoholism and what effect this new treatment method has on the symptoms of AUD.

Вмешательства

• Препарат Ketamine
  A single dose of ketamine 0.8 mg ketamine (i.v.) per kilogram bodyweight
• Поведенческое Real-time fMRI Neurofeedback Training
  Participants will undergo a closed-loop rt-fMRI paradigm over 25 minutes. Participants will be instructed to use strategies to downregulate cue-induced cravings. The Intensity of cues will adjust based on the participants neural activity in response to cues. This dynamic feedback mechanism allows for personalized training aimed at improving the participant's ability to manage cravings.
• Препарат Placebo
  Single dose of placebo (0.9% NaCl infusion)
• Поведенческое Sham Neurofeedback Training/ Ketamine
  Participants get a real time neurofeedback based on a control regions' activity, which serves as a sham region and receive 0.8 mg ketamine (i.v.) per kilogram bodyweight. The use of sham-NFT allows for a rigorous assessment of the specific effects of combined rt-fMRI NFT and ketamine by controlling for non-specific factors such as expectancy effects or the therapeutic context.

Первичные конечные точки

• Change in mean alcohol use per day [Срок оценки: Starting immediately after the intervention visit 2 and ending 4 weeks later (integration visit).]
• Change in heavy drinking days [Срок оценки: Starting immediately after the intervention visit 2 and ending 4 weeks later (integration visit).]

Вторичные конечные точки (12)

• Changes in glutamat levels during craving [Срок оценки: During the intervention visit 1a and 1 week later during the intervention visit 2.]
• Changes in Brain Derived Neurotrophic Factor [Срок оценки: During the intervention visit 2 at baseline 30 minutes before and 2 hours after infusion start.]
• Individual variations in ketamine pharmacokinetics [Срок оценки: During the intervention visit 2 at baseline, 45 minutes, 1 hour 30 minutes before, and 2 hours 30 minutes after infusion start.]
• Predictive value of baseline rs-fMRI for treatment response [Срок оценки: Between 1 and 2 weeks after baseline (screening visit) during the intervention visit 1a.]
• Changes in alcohol use in blood alcohol metabolites [Срок оценки: At baseline (screening visit) and 4 weeks later (integration visit).]
• Severity of alcohol use disorder [Срок оценки: From baseline (screening visit) until 6 months later (follow-up survey II).]
• Changes in alcohol abstinence ability [Срок оценки: From baseline (screening visit) until 6 months later (follow-up survey II).]
• Experience of alcohol craving [Срок оценки: From baseline (screening visit) until 6 months later (follow-up survey II).]
• Depressive symptoms [Срок оценки: From baseline (screening visit) until 6 months later (follow-up survey II).]
• Experience of pleasure across different domains [Срок оценки: From baseline (screening visit) until 6 months later (follow-up survey II).]
• Hedonic capacity [Срок оценки: From baseline (screening visit) until 6 months later (follow-up survey II).]
• Perceived quality of life [Срок оценки: From baseline (screening visit) until 6 months later (follow-up survey II).]

Критерии участия

Критерии включения

• Informed Consent as documented by signature
• In- and outpatients aged 18 to 65 years of all sexes.
• DSM-IV diagnosis of alcohol use disorder (mild - severe).
• Motivation to reduce or stop alcohol use
• Normal level of language comprehension (German or Swiss-German)
• Good physical health with no unstable medical conditions
• Participants of childbearing potential must use an effective and established method of contraception for the entire study duration
• Comply with the study protocol as explained by investigator

Критерии исключения

• History of DSM-IV severe drug dependence other than alcohol (except for caffeine or nicotine) and any opiod use disorder within two months prior to enrolment.
• Hallucinogen and ketamine use 3 months prior to study participation (including regular microdosing).
• Alcohol withdrawal symptoms at any of the treatment visits (V2 and V3) (CIWA-Ar Scale >9).
• 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
• High risk of adverse emotional and behavioral reactions
• 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)
• During the study, new use or dose changes of already existing concomitant medication without prior informing the investigators.
• Taking medications that are known to modualte uridine diphosphate glucuronosyltransferase-enzyme
• Medication directly affecting glutamate signaling (e. g. anticonvulsant medication)
• Inhibitors of UGT1A9 and 1A10 should be discontinued at least five half-lives prior to the administration of ketamine.
• Monoamine oxidase and aldehyde or alcohol dehydrogenase inhibitors should be discontinued at least 5 half-lives prior to the dose of ketamine.
• 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)
• BMI < 17 or > 35
• Allergy, hypersensitivity, or other adverse reaction to previous use of ketamine
• Contradictions to magnetic resonance imaging
• Concurrent participation in other clinical study

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Тройное слепое

Основная цель

Лечение

Центры проведения

Швейцария · 1 центр

• Psychiatric University Zurich, University of Zurich — Zurich

Идентификаторы

NCT: NCT06969937 · 2024-02294

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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