探討雙極性情感疾患認知功能及其中維生素D的角色

Abstract

背景: 雙極性情感疾患為一慢性精神疾病，病程常反覆發作而導致嚴重的疾病負擔。研究指出部分雙極性疾患患者伴有認知功能缺損，此認知缺損影響生活品質及預後，但縱貫性研究呈現其異質性的文獻仍相對稀少。此外針對雙極性情感疾患的認知缺損，生物治療的選擇仍不清楚。許多退化性神經及精神疾病被指出有高比例的維生素D低下，且維生素D缺乏和認知功能相關，但還未有研究探討在雙極性情感疾患中維生素D和認知表現的關聯以及介入補充的效果。 目的及方法: 招募雙極性情感疾患個案。以病歷回顧建立一回溯性世代，接著進行包含橫斷性研究並由其中部分特性者進入介入性研究。 1. 回溯性世代研究追蹤一年以上之認知功能變化以呈現縱貫性認知的差異。分析比較認知退化相關之危險因子及功能表現。 2. 針對雙極性情感疾患認知功能缺損的不同生物治療介入，進行網狀脈絡分析。 3. 探討雙極性情感疾患病人維生素D缺乏之危險因子，並探究維生素D濃度和整體認知或特定認知面向是否相關，同時探討和神經軸突完整性的交互作用 4. 量化確認維生素D介入對認知功能之實證。提出對雙極性情感疾患認知缺損適合之維生素D介入模式及病人特徵。 依上述研究結果未來可進行隨機雙盲實驗，探討補充維生素D對雙極性情感疾患穩定期之認知功能療效及影響的機轉。 結果: 回溯性世代研究指出部分的雙極性情感疾患其認知功能會逐步退化，且和較多的情緒發作伴隨精神病症狀有關。網狀脈絡分析作生物治療整合比較則呈現出紅血球生成素(erythropoietin)、睡茄(Withania somnifera)及加蘭他敏(galantamine)各別在注意力、工作記憶及語言學習上有顯著益處，但針對雙極性情感疾患認知功能之研究仍有許多異質性，分析結果顯示並無任一藥物或神經生理刺激能改善所有認知面向。在病例對照的相關性研究中發現，約百分之七十二的雙極性情感疾患病人有維生素D缺乏，且在成年晚期組病人中(45至65歲)，與較多住院次數及較低身體活動量相關。綜合認知能力及語意流暢呈現和維生素D及神經軸突完整性之交互作用相關；此外年齡亦在此相關中扮演效應修正因子。維生素D對認知功能的統合分析結果顯示在整體認知功能上有顯著益處，特別當研究族群為脆弱族群或伴隨維生素D缺乏時會呈現更大的益處。針對認知功能的效應，維生素D的介入亦建議須補足其維生素D濃度至足夠。因上述累積之研究發現，預期雙極性情感疾患患者伴隨維生素D缺乏者，後續接受維生素D補充對其認知功能應有其療效，值得下一步的臨床試驗。 結論: 本研究指出雙極性情感疾患認知功能退化的異質性，分別此次族群將有利於後續基因型及臨床研究。針對雙極性情感疾患的認知缺損，目前並無實證指出較佳的生物治療。由其他樣本之統合分析結果顯示維生素D對認知功能可為一安全有效的介入，且維生素D確實在雙極性情感疾患之認知功能上扮演部分角色，故值得進行下一步的隨機雙盲試驗。此系列針對雙極性情感疾患的認知研究，可作為未來個別化介入指引的藍圖。

Background: Bipolar disorder (BD) is a chronic mental disease related to recurrent episodes along with huge disease burden. Part of the BD patients who presented with cognitive deficits implied a poor prognosis and quality of life. The studies of cognitive function on longitudinal trajectory across the bipolar illness are scarce. In addition, comparing efficacy of biological interventions targeting to treat cognitive deficits in BD is unexplored. The majority of the observational studies demonstrate the high prevalence of hypovitamin D in wide ranges of neuropsychiatry diseases, and there was a significant association between compromised cognition and vitamin D deficiency; however, the effect of supplement and association between vitamin D and cognition in BD and the underlying mechanism is unclear. Aims and Methods: We enrolled patients with bipolar disorder. First, we established a retrospective cohort from medical chart review. Second, cross-sectional study was used for assessing the association between cognition and vitamin D levels. Third, part of the BD patients will be further enrolled in the randomized controlled trial (RCT). 1. To specify the subgroup of bipolar disorder patients with or without cognitive decline as their heterogeneity and to analysis the clinical risk factors and functional outcomes. 2. To perform network meta-analysis (NMA), to compare the efficacy of different biological interventions for cognition in BD patients. 3. To examine the risk factors of hypovitamin D and the interaction with neuro-axonal integrity in BD patients and the association with their cognitive profiles. 4. To reveal the evidence of vitamin D supplement model for cognitive function among different target populations, through meta-analysis. We will conduct RCT, to examine the efficacy of vitamin D supplement on cognitive performance and to dissect the related mechanism in euthymic BD. Results: The retrospective cohort study characterized the longitudinal cognitive heterogeneity in BD patients. We found that episodes with psychotic features was an independent risk factor for cognitive decline. The results from NMA implied that adjunctive of erythropoietin, Withania somnifera, and galantamine were beneficial for attention, working memory, and verbal learning in euthymic BD patients than treatment as usual, respectively. However, considerable variability in measurements of cognitive domains in BD was observed, and no intervention resulted in superior benefits across all cognitive domains. From cross-sectional study, we noted 72% of the BD patients were with vitamin D deficient. In the older age group (45< age <65), more frequent hospital admissions and lower physical activity levels were identified in the group with vitamin D deficiency than in that without. We identified the interaction effects between vitamin D and neurofilament light chain on composite neurocognitive score and domain of verbal fluency, and the effects were modified by age. The meta-analysis revealed a significant effect of vitamin D on global cognition but not on specific cognitive domains. Subgroup analysis indicated that the effect size of vitamin D increased for vulnerable populations and those with baseline vitamin D deficiency. In addition, we suggested that the intervention model should be applied for correcting the baseline vitamin D deficiency. Based on the aforementioned findings, we anticipated that subgroup of BD patients with cognitive deficits and vitamin D deficiency may benefit from vitamin D supplement for their cognitive deficits. Conclusion: Our results can specify and characterize the longitudinal cognitive heterogeneity in bipolar patients. These findings may potentially facilitate further genetic and biological studies to define more valid subtypes of bipolar disorder. Through the NMA, we first clarify the limitation and intervention effect from current available biological interventions. The meta-analysis provided the evidence about vitamin D model focusing on cognitive function. In addition, vitamin D plays a role to cognition in BD and interacts with the status of neuroaxonal integrity. From these results, further randomized trial will reveal the efficacy of vitamin D for cognitive deficits in BD patients. These series of studies can be a blueprint for future personalized intervention for cognitive deficits in BD patients and bring great impact on clinical care.