Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, USA.
University of Utah School of Medicine, Salt Lake City, UT, USA.
Mol Psychiatry. 2019 Jun;24(6):795-807. doi: 10.1038/s41380-019-0363-y. Epub 2019 Jan 30.
Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed antidepressants. They regulate serotonergic neurotransmission, but it remains unclear how altered serotonergic neurotransmission may contribute to the SSRI resistance observed in approximately 30% of major depressive disorder (MDD) patients. Patient stratification based on pharmacological responsiveness and the use of patient-derived neurons may make possible the discovery of disease-relevant neural phenotypes. In our study from a large cohort of well-characterized MDD patients, we have generated induced pluripotent stem cells (iPSCs) from SSRI-remitters and SSRI-nonremitters. We studied serotonergic neurotransmission in patient forebrain neurons in vitro and observed that nonremitter patient-derived neurons displayed serotonin-induced hyperactivity downstream of upregulated excitatory serotonergic receptors, in contrast to what is seen in healthy and remitter patient-derived neurons. Our data suggest that postsynaptic forebrain hyperactivity downstream of SSRI treatment may play a role in SSRI resistance in MDD.
选择性 5-羟色胺再摄取抑制剂（SSRIs）是最常被开的抗抑郁药。它们调节 5-羟色胺能神经传递，但目前尚不清楚改变的 5-羟色胺能神经传递如何导致大约 30%的重度抑郁症（MDD）患者出现 SSRIs 抵抗。基于药物反应性和使用患者来源的神经元进行患者分层，可能有助于发现与疾病相关的神经表型。在我们对一大组特征明确的 MDD 患者进行的研究中，我们从 SSRIs 缓解者和 SSRIs 非缓解者中生成了诱导多能干细胞（iPSCs）。我们在体外研究了患者前脑神经元中的 5-羟色胺能神经传递，观察到非缓解者患者来源的神经元表现出与健康和缓解者患者来源的神经元不同的上调兴奋性 5-羟色胺受体后 5-羟色胺诱导的过度活跃。我们的数据表明，SSRIs 治疗后的突触后前脑过度活跃可能在 MDD 的 SSRIs 抵抗中发挥作用。
