Abstract：
OBJECTIVE: Accumulating studies have assessed mortality risk associated with mood-stabilizers, the mainstay treatment for bipolar disorder (BD). However, existing data were mostly restricted to suicide risk, focused on lithium and valproate and rarely adequately adjusted for potential confounders. This study aimed to assess comparative mortality risk with all, natural and unnatural causes between lithium, valproate and three frequently prescribed second-generation antipsychotics (SGA), with adjustment for important confounders.
METHODS: This population-based cohort study identified 8137 patients with first-diagnosed BD, who had exposed to lithium (n = 1028), valproate (n = 3580), olanzapine (n = 797), quetiapine (n = 1975) or risperidone (n = 757) between 2002 and 2018. Data were retrieved from territory-wide medical-record database of public healthcare services in Hong Kong. Propensity-score (PS)-weighting method was applied to optimize control for potential confounders including pre-existing chronic physical diseases, substance/alcohol use disorders and other psychotropic medications. PS-weighted Cox proportional-hazards regression was conducted to assess risk of all-, natural- and unnatural-cause mortality related to each mood-stabilizer, compared to lithium. Three sets of sensitivity analyses were conducted by restricting to patients with (i) length of cumulative exposure to specified mood-stabilizer ≥90 days and its medication possession ratio (MPR) ≥90%, (ii) MPR of specified mood-stabilizer ≥80% and MPR of other studied mood-stabilizers <20% and (iii) monotherapy.
RESULTS: Incidence rates of all-cause mortality per 1000 person-years were 5.9 (95% confidence interval [CI]: 4.5-7.6), 8.4 (7.4-9.5), 11.1 (8.3-14.9), 7.4 (6.0-9.2) and 12.0 (9.3-15.6) for lithium-, valproate-, olanzapine-, quetiapine- and risperidone-treated groups, respectively. BD patients treated with olanzapine (PS-weighted hazard ratio = 2.07 [95% CI: 1.33-3.22]) and risperidone (1.66 [1.08-2.55]) had significantly higher all-cause mortality rate than lithium-treated group. Olanzapine was associated with increased risk of natural-cause mortality (3.04 [1.54-6.00]) and risperidone was related to elevated risk of unnatural-cause mortality (3.33 [1.62-6.86]), relative to lithium. The association between olanzapine and increased natural-cause mortality rate was consistently affirmed in sensitivity analyses. Relationship between risperidone and elevated unnatural-cause mortality became non-significant in sensitivity analyses restricted to low MPR in other mood-stabilizers and monotherapy. Valproate- and lithium-treated groups did not show significant differences in all-, natural- or unnatural-cause mortality risk.
CONCLUSIONS: Our data showed that olanzapine and risperidone were associated with higher mortality risk than lithium, and further supported the clinical guidelines recommending lithium as the first-line mood-stabilizer for BD. Future research is required to further clarify comparative mortality risk associated with individual SGA agents to facilitate risk-benefit evaluation of alternative mood-stabilizers to minimize avoidable premature mortality in BD.
METHODS: This population-based cohort study identified 8137 patients with first-diagnosed BD, who had exposed to lithium (n = 1028), valproate (n = 3580), olanzapine (n = 797), quetiapine (n = 1975) or risperidone (n = 757) between 2002 and 2018. Data were retrieved from territory-wide medical-record database of public healthcare services in Hong Kong. Propensity-score (PS)-weighting method was applied to optimize control for potential confounders including pre-existing chronic physical diseases, substance/alcohol use disorders and other psychotropic medications. PS-weighted Cox proportional-hazards regression was conducted to assess risk of all-, natural- and unnatural-cause mortality related to each mood-stabilizer, compared to lithium. Three sets of sensitivity analyses were conducted by restricting to patients with (i) length of cumulative exposure to specified mood-stabilizer ≥90 days and its medication possession ratio (MPR) ≥90%, (ii) MPR of specified mood-stabilizer ≥80% and MPR of other studied mood-stabilizers <20% and (iii) monotherapy.
RESULTS: Incidence rates of all-cause mortality per 1000 person-years were 5.9 (95% confidence interval [CI]: 4.5-7.6), 8.4 (7.4-9.5), 11.1 (8.3-14.9), 7.4 (6.0-9.2) and 12.0 (9.3-15.6) for lithium-, valproate-, olanzapine-, quetiapine- and risperidone-treated groups, respectively. BD patients treated with olanzapine (PS-weighted hazard ratio = 2.07 [95% CI: 1.33-3.22]) and risperidone (1.66 [1.08-2.55]) had significantly higher all-cause mortality rate than lithium-treated group. Olanzapine was associated with increased risk of natural-cause mortality (3.04 [1.54-6.00]) and risperidone was related to elevated risk of unnatural-cause mortality (3.33 [1.62-6.86]), relative to lithium. The association between olanzapine and increased natural-cause mortality rate was consistently affirmed in sensitivity analyses. Relationship between risperidone and elevated unnatural-cause mortality became non-significant in sensitivity analyses restricted to low MPR in other mood-stabilizers and monotherapy. Valproate- and lithium-treated groups did not show significant differences in all-, natural- or unnatural-cause mortality risk.
CONCLUSIONS: Our data showed that olanzapine and risperidone were associated with higher mortality risk than lithium, and further supported the clinical guidelines recommending lithium as the first-line mood-stabilizer for BD. Future research is required to further clarify comparative mortality risk associated with individual SGA agents to facilitate risk-benefit evaluation of alternative mood-stabilizers to minimize avoidable premature mortality in BD.
摘要：
目的：越来越多的研究已经评估了与情绪稳定相关的死亡风险，双相情感障碍（BD）的主要治疗方法。然而,现有数据大多仅限于自杀风险，专注于锂和丙戊酸，很少对潜在的混杂因素进行充分调整。这项研究旨在评估所有人的相对死亡风险，锂之间的自然和非自然原因，丙戊酸盐和三种常用的第二代抗精神病药（SGA），对重要混杂因素进行调整。
方法：这项基于人群的队列研究确定了8137例首次诊断为BD的患者，暴露于锂的人(n=1028)，丙戊酸盐（n=3580），奥氮平（n=797），2002年至2018年期间，喹硫平（n=1975）或利培酮（n=757）。数据是从香港公共医疗服务的全港医疗记录数据库中检索的。倾向评分（PS）加权方法用于优化控制潜在的混杂因素，包括预先存在的慢性身体疾病，物质/酒精使用障碍和其他精神药物。进行PS加权Cox比例风险回归评估所有风险，与每种情绪稳定剂相关的自然和非自然原因死亡率，与锂相比。通过限制以下患者进行三组敏感性分析：（i）累积暴露于指定情绪稳定剂的时间≥90天，其药物占有率（MPR）≥90％，（ii）指定的情绪稳定剂的MPR≥80％，其他研究的情绪稳定剂的MPR<20％和（iii）单一疗法。
结果：每1000人年的全因死亡率发生率为5.9（95％置信区间[CI]：4.5-7.6），8.4(7.4-9.5),11.1(8.3-14.9),锂-7.4（6.0-9.2）和12.0（9.3-15.6），丙戊酸钠-,奥氮平-,喹硫平和利培酮治疗组，分别。奥氮平治疗的BD患者（PS加权风险比=2.07[95％CI：1.33-3.22]）和利培酮（1.66[1.08-2.55]）的全因死亡率明显高于锂治疗组。奥氮平与自然原因死亡风险增加相关（3.04[1.54-6.00]），利培酮与非自然原因死亡风险增加相关（3.33[1.62-6.86]），相对于锂。在敏感性分析中，一致确认了奥氮平与自然原因死亡率增加之间的关联。利培酮与非自然原因死亡率升高之间的关系在其他情绪稳定剂和单一疗法中仅限于低MPR的敏感性分析中变得不显著。丙戊酸和锂治疗组没有显示所有的显着差异，自然或非自然原因死亡风险。
结论：我们的数据表明，奥氮平和利培酮比锂盐具有更高的死亡风险，并进一步支持临床指南推荐锂作为BD的一线情绪稳定剂。未来的研究需要进一步澄清与单个SGA药物相关的比较死亡率风险，以促进替代情绪稳定剂的风险收益评估，以最大程度地减少BD中可避免的过早死亡率。
方法：这项基于人群的队列研究确定了8137例首次诊断为BD的患者，暴露于锂的人(n=1028)，丙戊酸盐（n=3580），奥氮平（n=797），2002年至2018年期间，喹硫平（n=1975）或利培酮（n=757）。数据是从香港公共医疗服务的全港医疗记录数据库中检索的。倾向评分（PS）加权方法用于优化控制潜在的混杂因素，包括预先存在的慢性身体疾病，物质/酒精使用障碍和其他精神药物。进行PS加权Cox比例风险回归评估所有风险，与每种情绪稳定剂相关的自然和非自然原因死亡率，与锂相比。通过限制以下患者进行三组敏感性分析：（i）累积暴露于指定情绪稳定剂的时间≥90天，其药物占有率（MPR）≥90％，（ii）指定的情绪稳定剂的MPR≥80％，其他研究的情绪稳定剂的MPR<20％和（iii）单一疗法。
结果：每1000人年的全因死亡率发生率为5.9（95％置信区间[CI]：4.5-7.6），8.4(7.4-9.5),11.1(8.3-14.9),锂-7.4（6.0-9.2）和12.0（9.3-15.6），丙戊酸钠-,奥氮平-,喹硫平和利培酮治疗组，分别。奥氮平治疗的BD患者（PS加权风险比=2.07[95％CI：1.33-3.22]）和利培酮（1.66[1.08-2.55]）的全因死亡率明显高于锂治疗组。奥氮平与自然原因死亡风险增加相关（3.04[1.54-6.00]），利培酮与非自然原因死亡风险增加相关（3.33[1.62-6.86]），相对于锂。在敏感性分析中，一致确认了奥氮平与自然原因死亡率增加之间的关联。利培酮与非自然原因死亡率升高之间的关系在其他情绪稳定剂和单一疗法中仅限于低MPR的敏感性分析中变得不显著。丙戊酸和锂治疗组没有显示所有的显着差异，自然或非自然原因死亡风险。
结论：我们的数据表明，奥氮平和利培酮比锂盐具有更高的死亡风险，并进一步支持临床指南推荐锂作为BD的一线情绪稳定剂。未来的研究需要进一步澄清与单个SGA药物相关的比较死亡率风险，以促进替代情绪稳定剂的风险收益评估，以最大程度地减少BD中可避免的过早死亡率。
