Introduction

In a previously published randomized controlled trial, automated self-association training (ASAT), a novel digital intervention, was found to extend the rapid antidepressant effect of a single infusion of ketamine for at least 30 days. In this secondary analysis, we aimed to understand the potential role of implicit self-esteem in the combined antidepressant effect of ketamine and ASAT training, by investigating the novel synergistic treatment’s effects on implicit self-associations and their relation to symptom improvement.

Methods

A total of 154 adults (ages 18–60) with treatment-resistant unipolar depression and lower-than-normative explicit self-esteem were randomized in a double-blind, parallel-arm design to receive one of three treatment allocations: an active/active treatment combination consisting of one infusion of ketamine (0.5 mg/kg) followed by four days of ASAT ( ~ 30–40 min/day), or one of two control arms that lacked either the active drug or the active behavioral component. The Implicit Association Test (IAT) was used to behaviorally assess the strength of association between self-related stimuli and negative concepts. Linear regression models were used to test the relationship between group assignment, IAT scores acquired immediately post-treatment, and both acute and extended clinical outcomes (% change in Montgomery-Asberg Depression Rating Scale scores, relative to pre-treatment baseline) in the trial.

Results

The group assigned to ketamine + ASAT intervention, compared to the other groups, had a pattern of IAT scores indicating more positive self-associations immediately after treatment relative to the control arms (F(1, 131) = 3.979; p = 0.048). In regression models, IAT scores tracked with concurrent (acute post-treatment) % change in MADRS scores across all treatment arms (p = 0.001), and mediated more extended (Day 30) depression improvements specifically for the ketamine+ASAT arm (group * IAT interaction term: β = –0.201; p = 0.049).

Discussion

Our findings suggest that changing implicit self-worth during a post-ketamine ‘plasticity window’ is one key mechanism whereby the novel ketamine+ASAT treatment combination exerts its antidepressant benefit, confirming the intended treatment target at the level of implicit cognition. Future studies should seek to further enhance the reliability of the biobehavioral intervention’s impact on implicit cognition, as this mechanism appears linked to the intervention’s enduring clinical benefits.

中文翻译：

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内隐自尊的改善与新型协同干预后抗抑郁效果的延长有关

介绍

在之前发表的一项随机对照试验中，发现自动自我联想训练 (ASAT) 这种新型数字干预措施可以将单次注射氯胺酮的快速抗抑郁效果延长至少 30 天。在二次分析中，我们旨在通过研究新型协同治疗对内隐自我联想的影响及其与症状改善的关系，了解内隐自尊在氯胺酮和 ASAT 训练联合抗抑郁作用中的潜在作用。

方法

总共 154 名患有难治性单相抑郁症和外显自尊低于正常水平的成年人（18-60 岁）被随机分配到双盲平行组设计中，接受三种治疗分配之一：积极/积极的治疗组合包括输注一次氯胺酮（0.5 毫克/千克），然后进行四天的 ASAT（约 30-40 分钟/天），或两个缺乏活性药物或活性行为成分的对照组之一。内隐联想测试（IAT）用于行为评估自我相关刺激和消极概念之间的关联强度。线性回归模型用于测试试验中的分组、治疗后立即获得的 IAT 评分以及急性和长期临床结果（蒙哥马利-阿斯伯格抑郁量表评分相对于治疗前基线的变化百分比）之间的关系。

结果

与其他组相比，分配到氯胺酮 + ASAT 干预组的 IAT 评分模式表明，相对于对照组，治疗后立即出现更积极的自我关联（F(1, 131) = 3.979；p  = 0.048）。在回归模型中，IAT 评分与所有治疗组的 MADRS 评分同时（急性治疗后）% 变化进行跟踪（p  = 0.001），并且特别针对氯胺酮 + ASAT 组介导了更长期（第 30 天）的抑郁症改善（组 * IAT 交互项：β = –0.201；p  = 0.049）。

讨论

我们的研究结果表明，在氯胺酮后“可塑性窗口”期间改变内隐自我价值是一种关键机制，新型氯胺酮+ASAT治疗组合可以发挥其抗抑郁功效，从而在内隐认知水平上确认预期治疗目标。未来的研究应寻求进一步提高生物行为干预对内隐认知影响的可靠性，因为这种机制似乎与干预的持久临床益处有关。