Qureshi Mutahira, Silman Daniel, Gadelrab Romayne, Stein Hans-Christian, Carmellini Pietro, Duncan Graeme, Mehta Mitul A, Young Allan H, Reilly Carmel, Juruena Mario F
Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
South London and Maudsley NHS Foundation Trust, London, UK.
J Psychopharmacol. 2025 Jun;39(6):545-558. doi: 10.1177/02698811251340925. Epub 2025 Jun 20.
Ketamine, a rapid-acting N-methyl-D-aspartate receptor antagonist used as a therapeutic for treatment-resistant depression (TRD), is usually administered intravenously or intranasally.
This randomized, double-blind, placebo-controlled, Phase 1 study investigated safety and tolerability (primary endpoint), pharmacokinetics (PK) and pharmacodynamics (PD) of an immediate-release oral ketamine.
Healthy volunteers (18-55 years) were randomized to each receive two single doses of oral ketamine (40-240 mg) and one oral placebo dose. Treatment-emergent adverse events (TEAEs) and PK and PD assessments (e.g., Bond and Lader visual analogue scale, Modified Observer's Assessment of Alertness/Sedation Scale) were assessed up to 24 h after dosing. Descriptive statistics were used.
Nineteen participants were randomized (mean age: 31 years; male, 68%); 18 completed the study. Eighty mild or moderate TEAEs were reported following oral ketamine (40-240 mg) and five following placebo. There were no TEAE-related discontinuations. Most TEAEs (86%) were considered probably related to study drug. The most common TEAEs with oral ketamine were dissociation (26 events), dizziness (nine events) and headache (nine events). A positive relationship between increasing ketamine doses and dissociation events was observed. PK parameters (, AUC) of oral ketamine and its primary metabolites (2S,6S;2R,6R-hydroxynorketamine, R/S-norketamine) were dose proportional. Transient changes in mood and dissociation were detected 1 h postdose with a return to predose values after ~4 h.
There were no unexpected safety signals with oral ketamine. PK properties were consistent with those reported for other rapid-acting formulations. These findings warrant further investigation of oral ketamine capsules in TRD (EudraCT No. 2019-001019-22).
氯胺酮是一种起效迅速的N-甲基-D-天冬氨酸受体拮抗剂，用作难治性抑郁症（TRD）的治疗药物，通常通过静脉注射或鼻内给药。
这项随机、双盲、安慰剂对照的1期研究调查了速释口服氯胺酮的安全性和耐受性（主要终点）、药代动力学（PK）和药效学（PD）。
将健康志愿者（18 - 55岁）随机分组，每组接受两剂单剂量口服氯胺酮（40 - 240毫克）和一剂口服安慰剂。在给药后长达24小时内评估治疗中出现的不良事件（TEAE）以及PK和PD评估（例如，邦德和莱德视觉模拟量表、改良的观察者警觉性/镇静评估量表）。使用描述性统计方法。
19名参与者被随机分组（平均年龄：31岁；男性，68%）；18名完成了研究。口服氯胺酮（40 - 240毫克）后报告了80例轻度或中度TEAE，安慰剂组为5例。没有因TEAE而停药的情况。大多数TEAE（86%）被认为可能与研究药物有关。口服氯胺酮最常见的TEAE是解离感（26例）、头晕（9例）和头痛（9例）。观察到氯胺酮剂量增加与解离事件之间存在正相关关系。口服氯胺酮及其主要代谢物（2S,6S；2R,6R-羟基去甲氯胺酮、R/S-去甲氯胺酮）的PK参数（，AUC）与剂量成比例。给药后1小时检测到情绪和解离感的短暂变化，约4小时后恢复到给药前值。
口服氯胺酮没有出现意外的安全信号。PK特性与其他速效制剂报道的一致。这些发现值得对TRD患者进一步研究口服氯胺酮胶囊（欧洲临床试验注册号：2019 - 001019 - 22）。
