情感性疾患之臨床結果與遺傳影響：睡眠表徵所扮演之角色

Abstract

睡眠障礙是重鬱症及躁鬱症常見的重要症狀之一，然而重鬱症及躁鬱症患者、其家屬與健康對照組的睡眠情形以及睡眠特性的家族聚集現象仍未詳盡探討。睡眠障礙不但造成病人重要生活品質及社會功能的損害，且增加情感性疾患的復發率以及導致許多不良的臨床後果。因此，瞭解睡眠和情緒之間的關係以及對於臨床後果的研究就更為重要，時間累積的影響也不容小覷。情感性疾患的睡眠障礙被視為是生理節律異常所導致，許多生理節律基因參與情感性疾患的致病機轉以及睡眠相關的問題，過去的研究顯示生理節律參與情緒的調控。因而瞭解睡眠障礙和生理節律失調是探討情感性疾患病理的關鍵要素，不僅貢獻於嚴重情感性疾患的病因探討，也是未來協助改善臨床治療療效的基礎。本研究計畫的個案為台灣地區之情感性疾患的家庭，計畫的主要目的即在於探討睡眠在情感性疾患之臨床結果與遺傳影響所扮演之角色，將透過以下數項目標來達成：一、比較重鬱症及躁鬱症患者、其家屬與健康對照組的睡眠情形，以及探討睡眠品質和生活品質及功能損傷的關聯；二、利用追蹤樣本，考慮時間效應在睡眠與情緒上對臨床後果的影響，以及睡眠障礙是否預測不良的臨床後果；三、探討生理節律基因的遺傳變異與躁鬱症及睡眠問題之間的關係。本研究招募約1300位受試者，約700位指標個案(約350位依據精神疾病診斷(DSM-IV)診斷為躁鬱症第一型患者，150位躁鬱症第二型患者，200位重鬱症患者)，618家屬和235位健康對照組，受試者除了接受完整的診斷性訪談外，睡眠測量包括匹茲堡睡眠問卷(Pittsburgh Sleep Quality Index, PSQI)和作息型態量表(Mornigness－Eveningness scale, M/E scale)；症狀嚴重程度的測量包括貝氏憂鬱量表(Beck Depression Inventory, BDI-II)和楊氏躁症量表(Young Mania Rating Scale, YMRS)；世界衛生組織生活品質問卷(World Health Organization Quality of Life brief version, WHOQOL)調查。利用Affymetrix漢民族全基因陣列基因分型檢測技術進行單核苷酸多態性基因定型分析。家族聚集現象使用混合回歸模型和組內相關係數(intraclass correlation coefficients, ICC)評估，追蹤六個月期間睡眠與情緒對臨床後果的影響使用混合回歸模型探討時間效應，基因相關性分析使用PLINK軟體。三分之二的情感性疾患有較差的睡眠情形，睡眠較差的患者伴隨較差的生活品質和功能障礙。相較於躁鬱症患者，重鬱症患者具有較差的睡眠品質，重鬱症與躁鬱症家屬的睡眠情形則與健康對照組沒有差異。在主觀睡眠品質、睡眠潛伏期和睡眠障礙有中度的家族聚集現象。有睡眠障礙的患者如：較差的睡眠品質以及頻繁的惡夢，會增加產生自殺想法和自殺意念的風險。經過六個月追蹤後，躁鬱症(77.8％)與重鬱症(82.60％)患者持續存在睡眠障礙。多元/邏輯思迴歸分析模型證實有睡眠障礙(較差的睡眠品質及頻繁的惡夢)的患者顯著增高六個月後憂鬱情形(OR=1.07-4.56)、自殺想法(OR= 1.25-3.35)與自殺計畫(OR= 1.20-6.21)的風險。在此追蹤樣本以及控制時間效應之下，長期睡眠變化情形與不良的臨床後果(除了躁症嚴重程度與躁症復發)皆存在顯著的相關性。約日型態偏好對憂鬱特質與自殺有顯著的影響力，夜晚型作息型態的患者有較嚴重的憂鬱情形及較高的自殺意念。在遺傳的相關性分析結果，有五個生理節律基因(ARNTL2, BHLHE41, CNR1, RORA, RORB)顯著與躁鬱症相關。本研究結果支持RORs家族的基因與躁鬱症的風險相關。在睡眠的相關性分析結果，ARNTL, ARNTL2, CNR1, CRY1, CSNK1E, CSNK2A1, GSK3b, NPAS2, PER3, RORA, RORB, TIMELESS, TIPIN基因與躁症患者的睡眠障礙具有相關性。本研究證實情感性疾患伴隨顯著的睡眠障礙，睡眠品質較差的患者有較高的復發率和自殺風險，因此睡眠的介入措施在情感性疾患的臨床治療上極具重要性。生理節律基因在躁鬱症的生理途徑占有重要的影響因素，未來實證研究還需要再進一步佐證，本研究計畫的結果預期能從睡眠特徵以及基因特徵兩方面，更加瞭解重鬱症及躁鬱症生理節律。

Sleep problems are commonly observed in mood disorder patients, the sleep profiles among subgroups (major depressive (MDD), bipolar disorder (BD) patients, their relatives, and controls) and the familiality of sleep problems in MDD and BD families have not been well known. Sleep disturbance is important because it impairs quality of life (QOL), contributes to relapse, and has adverse consequences. Moreover, less is known about the longitudinal time effect between sleep and mood change. Sleep disturbance has caused by abnormal circadian function in mood disorders. Several genes that are involved in the regulation of circadian rhythms implicated in the susceptibility to mood disorders and sleep related problems. This suggests a connection between proper mood regulation and a normal functioning circadian clock. While sleep disturbance and circadian dysregulation are critical pathophysiological elements in mood disorders, many questions about the sleep profiles and the mechanisms remain. The current study aimed to explore the role of sleep in clinical outcomes and genetic contribution in mood disorders. First, we compare the sleep disturbances among subgroups and evaluated familiality in MDD and BD families. We examined the associations of sleep quality and patients’ QOL and functional impairment. Second, we evaluated the time effects of sleep and mood, and whether poor sleepers predict poorer clinical outcomes at follow up period. Third, we investigated the relationships between genetic variants in circadian genes with BD and with sleep phenotypes in the Han Chinese population. We recruited around ~1300 participants, including around ~700 probands ( ~350 DSM-IV diagnosed BD-I, 150 BD-II, and 200 MDD), 618 relatives and 235 healthy controls were completed structural diagnostic interview, sleep measurements including Pittsburgh Sleep Quality Index (PSQI), and Mornigness－Eveningness scale (M/E scale); the severity of symptoms measurements including Beck Depression Inventory (BDI-II), and Young Mania Rating Scale (YMRS); and World Health Organization Quality of Life brief version (WHOQOL) questionnaires. Single nucleotide polymorphisms in the circadian genes were genotyped using Affymetrix Genome-Wide CHB Array. Familiality of components of sleep was evaluated using mixed regression models and intraclass correlation coefficients (ICC). The relation of sleep on symptom severity and impairments during the same interval longitudinally across the 6-month period was also examining by mixed regression models. Genetic association analyses were performed using PLINK software. Three-quarter of mood disorder patients divided to “poor sleepers”, and with worse QOL and more functional impairment (p<0.01) than good sleepers. MDD patients had significantly worse sleep quality than BD patients, whereas there was no difference between unaffected relatives and controls. Moderate familial aggregation observed in subjective sleep quality, sleep latency and disturbance. Sleep disturbances such as poor sleep quality and nightmares increased the risk for suicidal ideation and suicide attempts. After a six month follow up, the persistence rates of sleep disturbance were 77.8% and 82.60% in BD and MDD, respectively. Multivariate analyses in linear/logistic regression models revealed that sleep disturbances at baseline including global score and frequent nightmares were significantly increased the consequence of depression (OR=1.07-4.56), suicide ideation (OR= 1.25-3.35) and suicide plan (OR= 1.20-6.21). A longitudinal relationship was showed of global score with poor clinical outcomes expect mania during the follow up. Our data suggested the idea that chronotypes have an impact on depressive features, with higher severity of depressive and suicide ideation for the eveningness type. For genetic association analysis, there were five genes (ARNTL2, BHLHE41, CNR1, RORA, RORB) showed significant with BD. Our results support for the involvement of RORs family in the risk of developing BD. For sleep phenotypes, we found ARNTL, ARNTL2, CNR1, CRY1, CSNK1E, CSNK2A1, GSK3b, NPAS2, PER3, RORA, RORB, TIMELESS, TIPIN genes with positive associations. Due to the notable sleep problems in mood disorders and the patients with sleep disturbances heightened the risk of recurrence and suicidality was demonstrated in the study. The special sleep intervention in mood disorders is required in clinical settings. The genes in circadian pathway may be an important candidate. Further replication studies are needed to investigate the functional properties of the genes in studying the pathogenesis of mood disorders and sleep problems.