Control-Interoception Attention Team, Paris Brain Institute, Sorbonne University, National Institute of Health and Medical Research, French National Centre for Scientific Research, Assistance Publique-Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, DMU Neuroscience, Paris, France.
Department of Psychiatry, Pitié-Salpêtrière Hospital, DMU Neuroscience, Sorbonne University, Assistance Publique-Hôpitaux de Paris, Paris, France.
JAMA Psychiatry. 2022 Nov 1;79(11):1124-1132. doi: 10.1001/jamapsychiatry.2022.2996.
Clinical research has shown that persistent negative beliefs maintain depression and that subanesthetic ketamine infusions induce rapid antidepressant responses.
To evaluate whether ketamine alters belief updating and how such cognitive effects are associated with the clinical effects of ketamine.
DESIGN, SETTING, AND PARTICIPANTS: This study used an observational case-control protocol with a mixed-effects design that nested 2 groups by 2 testing time points. Observers were not blinded. Patients with treatment-resistant depression (TRD) and healthy volunteer participants aged 34 to 68 years were included. Patients with TRD were diagnosed with major depressive disorder or bipolar depression, had a Montgomery-Åsberg Depression Rating Scale score greater than 20, a Maudsley Staging Method score greater than 7, and failed to respond to at least 2 prior antidepressant trials. Exclusion criteria were any other psychiatric, neurological, or neurosurgical comorbidities, substance use or addictive disorders, and recreational ketamine consumption. Data were collected from January to February 2019 and from May to December 2019, and data were analyzed from January 2020 to July 2021.
Patients with TRD were observed 24 hours before single ketamine infusion, 4 hours after the infusion, and 4 hours after the third infusion, which was 1 week after the first infusion. Healthy control participants were observed twice 1 week apart without ketamine exposure.
Montgomery-Åsberg Depression Rating Scale score and belief updating after belief updating when patients received good news and bad news measured by a cognitive belief-updating task and mathematically formalized by a computational reinforcement learning model.
Of 56 included participants, 29 (52%) were male, and the mean (SEM) age was 52.3 (1.2) years. A total of 26 patients with TRD and 30 control participants were included. A significant group × testing time point × news valence interaction showed that patients with TRD updated their beliefs more after good than bad news following a single ketamine infusion (controlled for age and education: β = -0.91; 95% CI, -1.58 to -0.24; t216 = -2.67; P = .008) than controls. Computational modeling showed that this effect was associated with asymmetrical learning rates (LRs) after ketamine treatment (good news LRs after ketamine, 0.51 [SEM, 0.04]; bad news LRs after ketamine 0.36 [SEM, 0.03], t25 = 3.8; P < .001) and partially mediated early antidepressant responses (path a*b: β = -1.00 [SEM, 0.66]; t26 = -1.53; z = -1.98; P = .04).
These findings provide novel insights into the cognitive mechanisms of the action of ketamine in patients with TRD, with promising perspectives for augmented psychotherapy for individuals with mood disorders.
临床研究表明，持续的负面信念会导致抑郁持续存在，而亚麻醉剂量的氯胺酮输注会引发快速的抗抑郁反应。
评估氯胺酮是否会改变信念更新，以及这种认知效应如何与氯胺酮的临床效果相关。
设计、设置和参与者：本研究采用了观察性病例对照方案和混合效应设计，通过 2 个测试时间点对 2 个组进行嵌套。观察者没有被蒙蔽。纳入了年龄在 34 至 68 岁之间的治疗抵抗性抑郁症（TRD）患者和健康志愿者参与者。TRD 患者被诊断为重度抑郁症或双相抑郁症，蒙哥马利-阿斯伯格抑郁评定量表评分大于 20，莫兹利分期方法评分大于 7，且对至少 2 种先前的抗抑郁药物治疗无反应。排除标准为任何其他精神、神经或神经外科合并症、物质使用或成瘾障碍，以及娱乐性氯胺酮使用。数据于 2019 年 1 月至 2 月和 2019 年 5 月至 12 月收集，数据于 2020 年 1 月至 2021 年 7 月进行分析。
TRD 患者在单次氯胺酮输注前 24 小时、输注后 4 小时和第三次输注后 4 小时（即第一次输注后 1 周）接受观察。健康对照参与者在没有氯胺酮暴露的情况下，2 次间隔 1 周接受观察。
当患者接受好消息和坏消息时，使用认知信念更新任务对蒙哥马利-阿斯伯格抑郁评定量表评分和信念更新进行测量，并通过计算强化学习模型对其进行数学形式化。
在纳入的 56 名参与者中，有 29 名（52%）为男性，平均（SEM）年龄为 52.3（1.2）岁。共有 26 名 TRD 患者和 30 名对照参与者被纳入。一个显著的组×测试时间点×消息效价的交互作用表明，与对照组相比，TRD 患者在单次氯胺酮输注后，对好消息的信念更新比对坏消息的信念更新更多（控制年龄和教育：β=-0.91；95%CI，-1.58 至-0.24；t216=-2.67；P=0.008）。计算模型显示，这种效应与氯胺酮治疗后的不对称学习率（LRs）有关（氯胺酮治疗后的好消息 LRs，0.51[SEM，0.04]；氯胺酮治疗后的坏消息 LRs，0.36[SEM，0.03]，t25=3.8；P<0.001），并部分介导了早期抗抑郁反应（路径 a*b：β=-1.00[SEM，0.66]；t26=-1.53；z=-1.98；P=0.04）。
这些发现为氯胺酮在 TRD 患者中的作用的认知机制提供了新的见解，为情绪障碍患者的增强型心理治疗提供了有前景的视角。
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