雙極性患者使用鋰鹽和癌症發生之相關性探討

The Association between Lithium used and Cancer Occurrence in Bipolar Disorder

黃如玉(Ru-Yu Huang)

指導教授 ： 楊奕馨

高雄醫學大學/藥學院/藥學系臨床藥學碩士班/碩士(2015年)

摘要

背景：
肝醣合成酶激酶-3在過去的體外試驗和動物實驗中已經證實和許多人類疾病有關，其中包括癌症，然而其對腫瘤細胞生長是呈現正向或負向調節則會因細胞組織有所不同。鋰鹽被視為是一種肝醣合成酶激酶-3抑制劑，目前肝醣合成酶激酶-3抑制劑和癌症發生的臨床研究有限，因此本研究之目的為探討肝醣合成酶激酶-3抑制劑對於雙極性情感疾患病患發生癌症之相關性，並進一步探討是否有累積劑量相關性。
方法：
本研究採回溯性世代研究，以國家衛生研究院之台灣健保研究資料庫西元2005年之百萬歸人檔，擷取1998-2009年間18-99歲新診斷雙極性情感疾患且同時使用一種以上治療藥物的病患，追蹤期間自開始用藥持續至癌症發生或2010年止。研究組別分成鋰鹽、抗癲癇藥、鋰鹽/抗癲癇藥三組，各組分別計算累積使用量及累積使用天數；統計分析先利用傾向分數(propensity score)計算接受治療的機率，再用治療權重倒數機率(IPTW, inverse probability of treatment weighting)方法計算統計分析模式的權數，利用Cox迴歸分析估算病患得到癌症的風險比(hazard ratios, HRs)，且同時調整時間相依變項(time-dependent covariates) 和其他可能預防癌症藥物使用等變項。
結果：
本研究納入4079位新診斷雙極性情感疾患病患(鋰鹽組370人，鋰鹽/抗癲抗癲癇藥組1479人，抗癲癇藥組3250人)；在追蹤期間得到癌症人數共115位(鋰鹽組6人，鋰鹽/抗癲癇藥組23人，抗癲癇藥組86人)。在治療權重倒數機率加權之Cox迴歸分析下，鋰鹽/抗癲癇藥組(aHR=0.712, 95%CI=0.518-0.979)、高累積劑量(≥ 215 DDD)的鋰鹽(高累積劑量aHR=0.594, 95%CI=0.394-0.898)相較於只用抗癲癇藥有統計上顯著地較低癌症風險。單用鋰鹽組雖然未達統計顯著性，但具有風險較低的趨勢(aHR=0.311, 95%CI= 0.548-1.200)。若合併鋰鹽組和鋰鹽/抗癲癇藥組增加樣本數，可達統計顯著性(aHR=0.742, 95%CI= 0.557-0.989)。分析鋰鹽累積使用天數則未發現統計上顯著相關性(p value for trends =0.1239),
結論：
鋰鹽為一種肝醣合成酶激酶-3抑制劑，對於癌症發生的相關研究侷限於體內/體外試驗。本研究採用具人口代表性之資料以流行病學研究設計了解鋰鹽和癌症的相關性，研究結果顯示雙極性情感疾患患者使用鋰鹽相較於抗癲癇藥物有較低的癌症發生風險，且具有劑量反應相關性。但未來仍需進一步針對不同型態的腫瘤作分析。

關鍵字

鋰鹽 ； 癌症 ； 肝醣合成酶激酶-3抑制劑

並列摘要

Background:
The use of glycogen synthase kinase-3 (GSK-3) is associated with several human diseases including cancer in in vitro studies or animal models. Whether the impact of GSK-3 is positive or negative on tumor development is speculated on the type of tumor tissue. Lithium is one of the GSK-3 inhibitors. Clinical studies on the association between the GSK-3 inhibitor and cancer occurrence are still limited. The aim of this study was to determine the lithium effect on cancer occurrence, and further to investigate whether there is a dose-response association on the usage of lithium in bipolar disorder patients.
Methods:
We conducted a population-based retrospective cohort study using the Taiwan Longitudinal Health Insurance Database 2005. Newly-diagnosed bipolar disorder patients during 1998-2009 were first extracted. We further included patients with at least one medication for bipolar disorder in the study cohort. The study population was then divided into 3 groups: lithium only, anticonvulsants only, and ever exposure to lithium and anticonvulsants. The cumulative define daily dose (DDD) and prescription days were computed for the 3 groups. The inverse probability of treatment weighted (IPTW) method based on the propensity score was used to balance confounding factors between the groups. The Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for the occurrence of cancer. Analysis covariates also included time-dependent covariates and co-medications.
Results:
There were 115 cancers (86, 6 and 23 in the anticonvulsants, lithium, and lithium?yanticonvulsant group, respectively) identified by the registry dataset for catastrophic illness patients from 4729 bipolar disorder patients (3250, 370 and 1109 in the anticonvulsants, lithium and lithium?yanticonvulsant group, respectively). The results of univariate analysis showed a significant decreased in HR (HR=0.426, 95%CI=0.186-0.975 for lithium only group; HR=0.511, 95%CI=0.322-0.812 for lithium ?yanticonvulsants group). After weighted by IPTW and adjusted for additional cofounders, the Cox regression analysis showed that lithium ?banticonvulsants group (HR=0.742, 95%CI=0.557-0.989), high cumulative dose of lithium (HR=0.594, 95%CI=0.394-0.898) were significantly associated with a decreased cancer risk. The result of cumulative prescription days did not show a trend for decreased cancer risk.
Conclusion:
Lithium as a GSK-3 inhibitor has been investigated to have an effect on the cancer development on both in vivo and in vitro studies. We investigate the relationship between lithium and cancer risk base on large-scale population database. Our result implies that the lithium use was negatively associated with incidence of overall cancer in bipolar disorder. There is a dose-response relationship in the lithium usage and risk reduction. Further studies could focus on the various tissue type of cancer.

並列關鍵字

Lithium ； Cancer ； Glycogen Synthase Kinase-3 ； GSK-3

參考文獻

1. Merikangas KR, Jin R, He JP, Kessler RC, Lee S, Sampson NA, et al. Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch Gen Psychiatry. 2011;68(3):241-51.

2. Yutzy SH, Woofter CR, Abbott CC, Melhem IM, Parish BS. The increasing frequency of mania and bipolar disorder: causes and potential negative impacts. J Nerv Ment Dis. 2012;200(5):380-7.

3. Bih SH, Chien IC, Chou YJ, Lin CH, Lee CH, Chou P. The treated prevalence and incidence of bipolar disorder among national health insurance enrollees in Taiwan, 1996-2003. Soc Psychiatry Psychiatr Epidemiol. 2008;43(11):860-5.

4. Chien IC, Chou YJ, Lin CH, Bih SH, Chou P. Prevalence of psychiatric disorders among National Health Insurance enrollees in Taiwan. Psychiatr Serv. 2004;55(6):691-7.

5. Jope RS. Anti-bipolar therapy: mechanism of action of lithium. Mol Psychiatry. 1999;4(2):117-28.