促醒激素系統對睡眠品質與情緒障礙的影響

Abstract

目的：近90％的重度憂鬱症（MDD）的患者都有睡眠障礙。此外，睡眠問題往往持續出現在緩解期。促醒激素（Orexin）是一種神經傳導分子又名食慾素（Hypocretin），會調節睡眠與清醒週期，並可能和MDD的神經病理學相關。目前的研究在探討促醒激素受體的基因變異、重鬱症和睡眠特徵的關聯。此外，一些過去針對檢測促醒激素濃度在異質性情緒相關疾病患者的腦脊液中表現的研究出現相互矛盾的結果。我們也另外評估了血漿中促醒激素濃度和睡眠品質及情緒狀態之間的關係。 方法：個案的收集是包含臨床診斷為重鬱症患者和健康對照組。匹茲堡睡眠質量指數（PSQI）用來衡量睡眠品質，切點大於5表示睡眠質量差。貝克憂鬱量表第二版（BDI-II）針對MDD患者症狀的嚴重程度來進行評估。我們在619名受試者針對兩個在促醒激素的兩個受體基因（HCRTR1, HCRTR2）上的單點核甘酸多型性（SNP; rs2271933、 rs2653349）進行基因分型中的檢測。在132位受試者的血漿測定促醒激素濃度採用ELISA kit。根據疾病狀態和睡眠品質，受試者被分成4個子群體。我們用Kruskal-Wallis檢定，來評估各子群體的促醒激素濃度。用回歸模型來檢定在同時調整性別和年齡後促醒激素受體的基因變異與促醒激素濃度，對於睡眠變量（如睡眠時間，睡眠效率，睡眠延遲，和失眠相關的變項）以及貝克憂鬱量表第二版分數的影響。 結果：促醒激素的單點核甘酸多型性在rs2271933（HCRTR1）顯示與PSQI總分（P = 0.006）有關連。個體帶有G等位基因會增加MDD的風險（OR= 1.48，P= 0.014）及日間功能較差（OR= 1.46，P =0.0124）。血漿促醒激素濃度在對照組且有良好的睡眠品質（中位數：0.67 ng/ml，P = 0.04）明顯高於其他子群（最低濃度是MDD且睡眠品質差：0.058 ng/ml）。促醒激素濃度較高對於發生睡眠潛伏期較長（OR= 0.39，P = 0.014）以及發生長的睡眠潛伏期頻率較高（OR= 0.36，P = 0.019）有保護作用。更高的睡眠效率是與較高的血漿促醒激素濃度（β= 2.48，P = 0.027）相關。同時，促醒激素濃度與BDI-II得分呈現負相關（β= -4.129，P = 0.016）。 結論：促醒激素受體上的基因變異與血漿促醒激素濃度對於睡眠相關的功能和情緒紊亂都有影響。越低的血漿促醒激素濃度與睡眠質量較差及更嚴重的憂鬱症狀有關係。

Objective: Nearly 90% of patients with Major depressive Disorder (MDD) report sleep disturbances. Additionally, sleep problems often persist in the remission period. Orexins are neuropeptides also named hypocretins that have known to regulate sleep-wakeful cycle and might be involved in the psychopathology of MDD. The current study aimed to examine associations of genetic variants in the orexin receptor genes with MDD and sleep features. Furthermore, few previous studies that examined orexin level in the cerebrospinal fluid of patients with heterogeneous mood related disorders exhibit conflicting results. We also evaluated the relationships between plasma orexin level and sleep quality and mood status. Methods: We recruited clinical diagnosed MDD patients and healthy controls. Sleep quality was measured by Pittsburgh Sleep Quality Index (PSQI), with cut-off value 5 indicating poor sleep quality. Beck Depression Inventory II (BDI-II) was assessed for symptom severity in patients with MDD. We genotyped two markers in the orexin receptor genes (HCRTR1: rs2271933 and HCRTR2: rs2653349) in 619 subjects. Plasma orexin level was measured using an ELISA Kit in 132 individuals. They were divided into four subgroups according to disease status and sleep quality. We used Kruskal-Wallis test to evaluate orexin levels among subgroups. Regression models were used to test the effects of genetic variants and orexin level on sleep variables (e.g. sleep duration, efficiency, latency, and insomnia-related variables) and BDI-II while adjusted for sex and age. Results: Marker rs2271933 (HCRTR1) showed association with PSQI scores (p=0.006). Individuals carry G allele had increased risk for MDD (OR=1.48, p=0.014), and exhibited poor daytime function (OR=1.46, p=0.0124). Plasma orexin level was significantly higher (p=0.04) in the control group with good sleep quality (median: 0.67) than other subgroups (the lowest level in MDD with poor sleep quality: 0.058). Higher orexin level had protective effects on quantity (OR=0.39, p=0.014) and frequency (OR=0.36, p=0.019) of sleep latency. Longer sleep efficiency is associated with higher plasma orexin level (β=2.48, p=0.027). Meanwhile, orexin level was negatively correlated with BDI-II score (β= -4.129, p=0.016). Conclusion: Both genetic variants of orexin receptor genes and plasma orexin level show effects on sleep related features and mood disturbance. Lower plasma orexin level is associated with poor sleep quality and more severe depressive symptoms.