Evaluation of Early Ketamine Effects on Belief-Updating Biases in Patients With Treatment-Resistant Depression.
Evaluation of Early Ketamine Effects on Belief-Updating Biases in Patients With Treatment-Resistant Depression.
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DOI：
10.1001/jamapsychiatry.2022.2996
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发表时间：
2022-11-01
期刊：
影响因子：
25.8
通讯作者：
Schmidt, Liane
中科院分区：
文献类型：
--
作者：
Bottemanne, Hugo;Morlaas, Orphee;Claret, Anne;Sharot, Tali;Fossati, Philippe;Schmidt, Liane
氯胺酮对难治性抑郁症（TRD）患者的信念更新有何影响？
这项针对TRD患者的病例对照研究表明，在首次输注氯胺酮仅4小时后，信念更新就出现了更乐观的偏差。氯胺酮的这种早期认知效应通过更强的不对称强化学习得以形式化，并在治疗1周时介导了临床抗抑郁效果。
这些发现为理解速效抗抑郁药的认知效应提供了新的视角，这些效应可能被利用来促进持续的临床改善和治疗反应性。
这项病例对照研究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应相关联。
临床研究表明，持续的消极信念会维持抑郁状态，而亚麻醉剂量的氯胺酮输注会诱导快速的抗抑郁反应。
为了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应相关联。
本研究采用了一种观察性病例对照方案，采用混合效应设计，按2个测试时间点将2组进行嵌套。观察者未设盲。研究纳入了34至68岁的难治性抑郁症患者和健康志愿者参与者。TRD患者被诊断患有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得分大于20，莫兹利分期法得分大于7，且至少对2种先前的抗抑郁试验无反应。排除标准为任何其他精神、神经或神经外科合并症、物质使用或成瘾性障碍以及娱乐性氯胺酮使用。数据收集时间为2019年1月至2月以及2019年5月至12月，数据分析时间为2020年1月至2021年7月。
TRD患者在单次氯胺酮输注前24小时、输注后4小时以及第三次输注后4小时（首次输注后1周）进行观察。健康对照参与者在未接触氯胺酮的情况下，间隔1周观察两次。
蒙哥马利 - 阿斯伯格抑郁评定量表得分以及患者收到好消息和坏消息后的信念更新情况，通过认知信念更新任务进行测量，并通过计算强化学习模型进行数学形式化。
在56名纳入的参与者中，29人（52%）为男性，平均（标准误）年龄为52.3（1.2）岁。共纳入26名TRD患者和30名对照参与者。显著的组×测试时间点×消息效价交互作用表明，在单次氯胺酮输注后，TRD患者在收到好消息后的信念更新比收到坏消息后更多（校正年龄和教育因素后：β = -0.91；95%置信区间，-1.58至 -0.24；t216 = -2.67；P = 0.008），与对照组相比。计算建模显示，这种效应与氯胺酮治疗后的不对称学习率（LRs）相关（氯胺酮治疗后好消息的LRs为0.51[标准误，0.04]；氯胺酮治疗后坏消息的LRs为0.36[标准误，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[标准误，0.66]；t26 = -1.53；z = -1.98；P = 0.04）。
这些发现为氯胺酮在TRD患者中的作用认知机制提供了新的见解，为情绪障碍患者的强化心理治疗带来了有希望的前景。
What are the effects of ketamine on belief updating in patients with treatment-resistant depression (TRD)? This case-control study in patients with TRD showed that belief updating became more optimistically biased as soon as 4 hours after a first ketamine infusion. This early cognitive effect of ketamine was formalized by stronger asymmetrical reinforcement learning and mediated at 1 week of treatment the clinical antidepressant effect. These findings provide new perspectives for the understanding of the cognitive effects of fast-acting antidepressants that potentially can be leveraged to promote sustained clinical improvement and treatment responsiveness. This case-control study evaluates whether ketamine alters belief updating and how such cognitive effects are associated with the clinical effects of ketamine. 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. 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.
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