Tiihonen Jari, Tanskanen Antti, Hoti Fabian, Vattulainen Pia, Taipale Heidi, Mehtälä Juha, Lähteenvuo Markku
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Forensic Psychiatry, Niuvanniemi Hospital, University of Eastern Finland, Kuopio, Finland.
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Forensic Psychiatry, Niuvanniemi Hospital, University of Eastern Finland, Kuopio, Finland; National Institute for Health and Welfare, Impact Assessment Unit, Helsinki, Finland.
Lancet Psychiatry. 2017 Jul;4(7):547-553. doi: 10.1016/S2215-0366(17)30134-7. Epub 2017 Jun 1.
Little is known about the comparative effectiveness of long-term pharmacological treatments for severe unipolar depression. We aimed to study the effectiveness of pharmacological treatments in relapse prevention in a nationwide cohort of patients who had been admitted to hospital at least once as a result of unipolar depression.
Our nationwide cohort study investigated the risk of readmission to hospital in 1996-2012 in all patients in Finland who had been admitted to hospital at least once for unipolar depression (without a diagnosis of schizophrenia or bipolar disorder) in Finland between Jan 1, 1987, and Dec 31, 2012. We used nationwide databases to obtain data for hospital admission, mortality, and dispensed medications. Exposure and non-exposure periods for medications were established using the PRE2DUP method. The primary analysis was within-individual analysis of readmission to hospital in the total cohort, in which each individual was used as his or her own control to eliminate selection bias. Putative survival and protopathic biases were controlled in sensitivity analyses. Since 33 independent statistical comparisons were done for specific medications, the level of statistical significance was set at p<0·0015.
Data from 123 712 patients were included in the total cohort, with a mean follow-up time of 7·9 years (SD 5·3). Lithium use was associated with a lower risk of re-admission to hospital for mental illness than was no lithium use (hazard ratio [HR] 0·47 [95% CI 0·40-0·55]; p<0·0001), whereas the groups of antidepressants (HR 1·10 [1·06-1·13]; p<0·0001) and antipsychotics (HR 1·16 [1·12-1·20]; p<0·0001) were not associated with a reduced risk of readmission to hospital. Risk of hospital readmission was lower during lithium therapy alone (HR 0·31 [0·21-0·47]; p<0·0001) than during use of lithium with antidepressants (HR 0·50 [0·43-0·59]; p<0·0001). After lithium, clozapine (HR 0·65 [0·46-0·90]; p=0·010) and amitriptyline (HR 0·75 [0·70-0·81]; p<0·0001) were the specific agents associated with the next lowest risk of readmission. In the sensitivity analyses controlling for survival and protopathic biases, all drugs were associated with lower rates of readmission to hospital than they were in the primary analysis, showing the same rank order in comparative effectiveness. The lowest mortality was observed during antidepressant use (HR 0·56 [0·54-0·58]; p<0·0001).
Our results indicate that lithium, especially without concomitant antidepressant use, is the pharmacological treatment associated with the lowest risk of hospital readmission for mental illness in patients with severe unipolar depression, and the outcomes for this measure related to antidepressants and antipsychotics are poorer than lithium. Lithium treatment should be considered for a wider population of severely depressed patients than those currently considered, taking into account its potential risks and side-effects.
The Finnish Ministry of Health.
关于重度单相抑郁症长期药物治疗的比较有效性，人们了解甚少。我们旨在研究药物治疗对全国范围内因单相抑郁症至少住院一次的患者预防复发的有效性。
我们的全国队列研究调查了1987年1月1日至2012年12月31日期间芬兰所有因单相抑郁症（无精神分裂症或双相情感障碍诊断）至少住院一次的患者在1996 - 2012年再次住院的风险。我们使用全国性数据库获取住院、死亡率和配药数据。使用PRE2DUP方法确定药物的暴露和非暴露期。主要分析是对整个队列中再次住院情况进行个体内分析，其中每个个体作为自身对照以消除选择偏倚。在敏感性分析中控制了假定的生存偏倚和原发病偏倚。由于针对特定药物进行了33次独立的统计比较，统计学显著性水平设定为p<0.0015。
整个队列纳入了123712例患者的数据，平均随访时间为7.9年（标准差5.3）。与未使用锂盐相比，使用锂盐与因精神疾病再次住院的风险较低相关（风险比[HR]0.47[95%CI 0.40 - 0.55]；p<0.0001），而抗抑郁药组（HR 1.10[1.06 - 1.13]；p<0.0001）和抗精神病药组（HR 1.16[1.12 - 1.20]；p<0.0001）与再次住院风险降低无关。单独使用锂盐治疗期间再次住院风险（HR 0.31[0.21 - 0.47]；p<0.0001）低于锂盐与抗抑郁药联合使用期间（HR 0.50[0.43 - 0.59]；p<0.0001）。在锂盐之后，氯氮平（HR 0.65[0.46 - 0.90]；p = 0.010）和阿米替林（HR 0.75[0.70 - 0.81]；p<0.0001）是与再次住院风险次低相关的特定药物。在控制生存偏倚和原发病偏倚的敏感性分析中，所有药物与再次住院率的关联均低于主要分析中的情况，在比较有效性方面显示出相同的排序。在使用抗抑郁药期间观察到最低的死亡率（HR 0.56[0.54 - 0.58]；p<0.0001）。
我们的结果表明，锂盐，尤其是不与抗抑郁药联合使用时，是与重度单相抑郁症患者因精神疾病再次住院风险最低相关的药物治疗，而抗抑郁药和抗精神病药在这方面的效果比锂盐差。考虑到锂盐的潜在风险和副作用，对于重度抑郁症患者，应考虑将锂盐治疗应用于比目前更广泛的人群。
芬兰卫生部。
