Dam Vibeke H, Köhler-Forsberg Kristin, Ozenne Brice, Larsen Søren V, Ip Cheng-Teng, Jorgensen Anders, Stenbæk Dea S, Madsen Jacob, Svarer Claus, Jørgensen Martin B, Knudsen Gitte M, Frokjaer Vibe G
Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Psychiatric Center Copenhagen, Copenhagen, Denmark.
Biol Psychiatry. 2025 Feb 1;97(3):261-268. doi: 10.1016/j.biopsych.2024.08.009. Epub 2024 Aug 22.
Brain serotonin 4 receptor (5-HTR) levels are lower in untreated patients with major depressive disorder (MDD) and are linked to verbal memory. Here, we investigated the relationship between 5-HTR levels, clinical outcomes, and cognitive function in patients with MDD who initiated selective serotonin reuptake inhibitor drug treatment.
Ninety patients with moderate to severe depression underwent molecular brain imaging to measure 5-HTR binding prior to antidepressant treatment with escitalopram. Pretreatment 5-HTR binding was assessed for its ability to predict treatment outcome at weeks 4, 8, or 12. In 40 patients who were rescanned 8 weeks posttreatment, change in cerebral 5-HTR binding was correlated with change in verbal memory and with change in depressive symptoms, as evaluated by the 6-item Hamilton Depression Rating Scale.
After 8 weeks of serotonergic intervention, neostriatal 5-HTR binding was reduced by 9%. Global change in 5-HTR binding from baseline was associated with verbal memory outcomes, but not with overall clinical depressive symptom outcomes. Pretreatment 5-HTR binding did not predict clinical recovery status at week 8 and was not associated with change in the 6-item Hamilton Depression Rating Scale scores.
In patients with moderate to severe MDD, treatment with selective serotonin reuptake inhibitors downregulated neostriatal 5-HTR levels, which is consistent with the notion that the drugs increase cerebral extracellular serotonin. The less global brain 5-HTR levels were downregulated after selective serotonin reuptake inhibitors, the more verbal memory improved, highlighting the potential importance of 5-HTR as a treatment target in MDD. The findings offer insights into mechanisms that underlie antidepressant effects and point to new directions for precision medicine treatments for MDD.
在未经治疗的重度抑郁症（MDD）患者中，脑内5-羟色胺4受体（5-HTR）水平较低，且与言语记忆有关。在此，我们研究了开始选择性5-羟色胺再摄取抑制剂药物治疗的MDD患者中5-HTR水平、临床结局和认知功能之间的关系。
90例中度至重度抑郁症患者在接受艾司西酞普兰抗抑郁治疗前，进行分子脑成像以测量5-HTR结合情况。评估治疗前5-HTR结合情况预测第4、8或12周治疗结局的能力。在40例治疗后8周再次扫描的患者中，通过6项汉密尔顿抑郁量表评估，脑内5-HTR结合变化与言语记忆变化及抑郁症状变化相关。
经过8周的5-羟色胺能干预后，新纹状体5-HTR结合减少了9%。5-HTR结合相对于基线的总体变化与言语记忆结局相关，但与总体临床抑郁症状结局无关。治疗前5-HTR结合不能预测第8周的临床恢复状态，且与6项汉密尔顿抑郁量表评分变化无关。
在中度至重度MDD患者中，选择性5-羟色胺再摄取抑制剂治疗使新纹状体5-HTR水平下调，这与该药物增加脑内细胞外5-羟色胺的观点一致。选择性5-羟色胺再摄取抑制剂治疗后脑内5-HTR水平下调越少，言语记忆改善越明显，突出了5-HTR作为MDD治疗靶点的潜在重要性。这些发现为抗抑郁作用的潜在机制提供了见解，并为MDD的精准医学治疗指明了新方向。
