Antidepressant therapy is still associated with delays in symptomatic improvement and low response rates. Incomplete understanding of molecular mechanisms underlying antidepressant effects hampered the identification of objective biomarkers for antidepressant response. In this work, we studied transcriptome-wide expression followed by pathway analysis in lymphoblastoid cell lines (LCLs) derived from 17 patients documented for response to SSRI antidepressants from the Munich Antidepressant Response Signatures (MARS) study upon short-term incubation (24 and 48 h) with citalopram. Candidate transcripts were further validated with qPCR in MARS LCLs from responders (n = 33) vs. non-responders (n = 36) and afterward in an independent cohort of treatment-resistant patients (n = 20) vs. first-line responders (n = 24) from the STAR*D study. In MARS cohort we observed significant associations of GAD1 (glutamate decarboxylase 1; p = 0.045), TBC1D9 (TBC1 Domain Family Member 9; p = 0.014–0.021) and NFIB (nuclear factor I B; p = 0.015–0.025) expression with response status, remission status and improvement in depression scale, respectively. Pathway analysis of citalopram-altered gene expression indicated response-status-dependent transcriptional reactions. Whereas in clinical responders neural function pathways were primarily up- or downregulated after incubation with citalopram, deregulated pathways in non-responders LCLs mainly involved cell adhesion and immune response. Results from the STAR*D study showed a marginal association of treatment-resistant depression with NFIB (p = 0.068) but not with GAD1 (p = 0.23) and TBC1D9 (p = 0.27). Our results propose the existence of distinct pathway regulation mechanisms in responders vs. non-responders and suggest GAD1, TBC1D9, and NFIB as tentative predictors for clinical response, full remission, and improvement in depression scale, respectively, with only a weak overlap in predictors of different therapy outcome phenotypes.

抗抑郁治疗仍然与症状改善延迟和反应率低有关。对潜在抗抑郁作用的分子机制的不完全理解阻碍了对抗抑郁反应的客观生物标志物的识别。在这项工作中，我们研究了转录组范围内的表达，然后对来自 17 名患者的淋巴母细胞系 (LCL) 进行了通路分析，这些患者在短期孵育时记录了对 SSRI 抗抑郁药的反应，这些患者来自慕尼黑抗抑郁反应特征 (MARS) 研究（24 和 48 h) 与西酞普兰。候选转录本在 MARS LCL 中从响应者 ( n  = 33) 与非响应者 ( n  = 36) 中进一步验证，然后在一个独立的耐药患者队列中 ( n = 20) 与来自 STAR*D 研究 的一线响应者 ( n = 24)。在 MARS 队列中，我们观察到GAD1（谷氨酸脱羧酶 1；p  = 0.045）、TBC1D9（TBC1 域家族成员 9；p  = 0.014-0.021）和NFIB（核因子 IB；p = 0.015–0.025) 分别表示响应状态、缓解状态和抑郁量表的改善。西酞普兰改变基因表达的通路分析表明反应状态依赖性转录反应。临床反应者的神经功能通路在与西酞普兰孵育后主要上调或下调，而无反应者 LCL 中的失调通路主要涉及细胞粘附和免疫反应。STAR*D 研究的结果显示，难治性抑郁症与NFIB ( p  = 0.068) 存在边际关联，但与GAD1 ( p  = 0.23) 和TBC1D9 ( p = 0.27)。我们的研究结果表明，应答者与非应答者存在不同的通路调节机制，并建议GAD1、TBC1D9和NFIB 分别作为临床反应、完全缓解和抑郁量表改善的暂定预测因子，预测因子只有微弱的重叠不同的治疗结果表型。