AbstractPatients with schizophrenia receiving antipsychotic treatment present lower mortality rates than those who do not. However, the non-adherence rate is high, which can be partially addressed using long-acting injectable (LAI) antipsychotics. The impact of LAI treatments on all-cause mortality compared to oral antipsychotics remains unclear.

接受抗精神病药物治疗的精神分裂症患者死亡率低于未接受抗精神病药物治疗的患者。然而，不依从率很高，可以使用长效注射（LAI）抗精神病药物部分解决。与口服抗精神病药物相比，LAI治疗对全因死亡率的影响仍不清楚。

To fill that gap, a random effects meta-analysis was conducted to analyze the odds ratio (OR) of all-cause, suicidal, and non-suicidal mortality among patients taking LAI antipsychotics compared to oral antipsychotics (PROSPERO:CRD42023391352). Individual and pooled LAI antipsychotics were analyzed against pooled oral antipsychotics.

为了填补这一空白，进行了随机效应荟萃分析，以分析服用LAI抗精神病药物的患者与口服抗精神病药物（PROSPERO:CRD42023391352）相比，全因，自杀和非自杀死亡率的优势比（OR）。针对合并的口服抗精神病药物分析个体和合并的LAI抗精神病药物。

Sensitivity analyses were performed for study design, setting, and industry sponsorship. Meta-regressions were conducted for gender, age, antipsychotic dose, and race. Seventeen articles, total sample 12,042 patients (N = 5795 oral, N = 6247 LAI) were included. Lower risk of all-cause mortality for patients receiving LAI antipsychotics vs receiving oral antipsychotics was found (OR = 0.79; 95%CI = 0.66–0.95).

对研究设计，设置和行业赞助进行了敏感性分析。对性别，年龄，抗精神病药物剂量和种族进行荟萃回归。包括17篇文章，共12042名患者（N=5795口服，N=6247 LAI）。发现接受LAI抗精神病药物治疗的患者与接受口服抗精神病药物治疗的患者的全因死亡风险较低（OR＝0.79）；95%可信区间=0.66-0.95）。

Statistical significance was maintained when only studies comparing the same LAI and oral antipsychotic were included (OR = 0.79; 95%CI = 0.66–0.95; p = <0.01), as well as for non-suicidal mortality (OR = 0.77: 95%CI = 0.63–0.94; p = 0.01), but not for suicidal mortality (OR = 0.86; 95%CI = 0.59–1.26; p = 0.44).

当仅包括比较相同LAI和口服抗精神病药物的研究时，统计学显着性得以维持（OR=0.79；95%可信区间=0.66-0.95；p＜0.01），以及非自杀死亡率（OR＝0.77:95%CI＝0.63-0.94；p＝0.01），但不是自杀死亡率（OR＝0.86）；95%可信区间=0.59-1.26；p=0.44）。

Mortality reduction was more pronounced for LAI antipsychotics in first-episode psychosis (FEP) (OR = 0.79; 95%CI = 0.66–0.96) compared to chronic psychosis. No individual LAI reported statistically significant differences against all pooled oral antipsychotics. LAI antipsychotics are associated with a lower risk of all-cause and non-suicidal mortality in individuals with schizophrenia.

LAI抗精神病药物在首发精神病（FEP）中死亡率降低更为明显（OR＝0.79）；与慢性精神病相比，95%可信区间为0.66-0.96）。没有个人LAI报告与所有合并口服抗精神病药物的统计学显着差异。LAI抗精神病药物与精神分裂症患者全因和非自杀死亡风险较低有关。

IntroductionBackgroundSchizophrenia is a chronic and debilitating disorder characterized by positive, negative, and cognitive symptoms [1]. Individuals with schizophrenia experience a reduction in life expectancy of 15–20 years compared to the general population [2], with cardiovascular disease being the leading cause of death among this population [3].

引言背景精神分裂症是一种以阳性，阴性和认知症状为特征的慢性衰弱性疾病。与普通人群相比，精神分裂症患者的预期寿命缩短了15-20岁，心血管疾病是该人群的主要死亡原因。

This premature mortality is present even from the initial stages of the disorder [4], and has been consistently associated with modifiable factors, including poorer lifestyle conditions [5], limited access to healthcare services [6], and a high rate of comorbid disorders, both psychiatric [7, 8] and physical [9, 10].While there has been some controversy on the potential increase in cardiovascular deaths caused by long-term use of antipsychotics [11, 12], the protective effect of antipsychotic treatment has now been well-established, with a lower mortality rate in patients who received any antipsychotic treatment compared to those who did not [13, 14].

这种过早的死亡率甚至在疾病的初始阶段就存在，并且一直与可改变的因素有关，包括较差的生活方式条件，有限的医疗保健服务，以及精神疾病[7，8]和身体疾病[9，10]的高共病率。。

Furthermore, consistently, long-term treatment with antipsychotic medication dramatically reduces the risk of relapse in multiple-episode and first-episode psychosis (FEP) [15,16,17], along with the associated risk behaviours and stress increase. However, a significant percentage of patients discontinue their oral antipsychotic medication, with non-adherence rates from 30% [18] to up 77% [19, 20].Long-acting injectable antipsychotics (LAI-AP), including first and second-generation antipsychotics, were introduced in the 1960s to overcome non-adherence in psychotic disorders.

此外，长期服用抗精神病药物可显着降低多发性和首发精神病（FEP）复发的风险[15,16,17]，以及相关的风险行为和压力增加。然而，相当一部分患者停止口服抗精神病药物，不依从率从30%[18]上升到77%[19,20]。长效注射抗精神病药物（LAI-AP），包括第一代和第二代抗精神病药物，于20世纪60年代引入，以克服精神病性疾病的不依从性。

They have been shown to improve adherence, provide more stable antipsychotic blood levels and reduce relapses, all-cause hospitalizations and emergency department visits [21, 22]. However, potential adve.

它们已被证明可以提高依从性，提供更稳定的抗精神病药物血液水平，减少复发，全因住院和急诊就诊[21，22]。然而，潜在的优势。

1.

1.

Do people with schizophrenia receiving LAI antipsychotics present lower all-cause, suicidal, and non-suicidal mortality than those receiving oral antipsychotics?

接受LAI抗精神病药物治疗的精神分裂症患者的全因死亡率、自杀死亡率和非自杀死亡率是否低于口服抗精神病药物治疗的患者？

2.

2.

Is the difference in the all-cause mortality moderated by (a) the drug antipsychotic, age, sex, race, or type of sample (first-episode psychosis vs chronic schizophrenia), or (b) methodological factors, including the type of study (RCT vs cohort), length of follow-up, industry sponsorship, study quality, or publication bias?.

？。

MethodsThis study protocol was registered on PROSPERO (registration number: CRD42023391352). The study was conducted in accordance with 'Preferred Reporting Items for Systematic Reviews and Meta-Analyses' (PRISMA) [25] (Supplementary Table S1) and 'Meta-Analyses of Observational Studies in Epidemiology' (MOOSE) checklist [26] (Supplementary Table S2), following 'EQUATOR Reporting Guidelines' [27].Search strategy and selection criteriaA systematic literature search was carried out by two independent researchers (C.A.

。该研究是根据“系统评价和荟萃分析的首选报告项目”（PRISMA）[25]（补充表S1）和“流行病学观察性研究的荟萃分析”（MOOSE）清单[26]（补充表S2）进行的，遵循“赤道报告指南”[27]。搜索策略和选择标准两名独立研究人员（C.A.）进行了系统的文献检索。

and B.P.). Web of Science database (Clarivate Analytics) was searched, incorporating the Web of Science Core Collection, the BIOSIS Citation Index, the KCI-Korean Journal Database, MEDLINE®, the Russian Science Citation Index, and the SciELO Citation Index as well as Cochrane Central Register of Reviews, and Ovid/PsycINFO databases, from inception until January 12th, 2023.The following keywords were used: '(Antipsychotic OR neuroleptic OR aripiprazole OR bromperidol OR clopenthixol OR flupenthixol OR fluphenazine OR fluspirilene OR haloperidol OR iloperidone OR olanzapine OR paliperidone OR penfluridol OR perphenazine OR pipothiazine OR risperidone OR zuclopenthixol) AND (enanthate OR decanoate OR long-acting injection OR lai OR microsphere OR once monthly OR palmitate OR pamoate)'.Articles identified were first screened as abstracts, and after excluding those that did not meet the inclusion criteria, the full texts of the remaining articles were assessed for eligibility and inclusion.

和B.P.）。从开始到2023年1月12日，搜索了Web of Science数据库（Clarivate Analytics），其中包括Web of Science核心集合，BIOSIS引文索引，KCI韩国期刊数据库，MEDLINE®，俄罗斯科学引文索引和SciELO引文索引，以及Cochrane中央评论登记册和Ovid/PsycINFO数据库。使用了以下关键词：'（抗精神病药或精神病药或阿立哌唑或溴哌啶醇或氯苯噻醇或氟哌噻吨或氟苯那嗪或氟哌啶醇或伊洛哌酮或奥氮平或帕利哌酮或喷尼酮氟利多或奋乃静或哌噻嗪或利培酮或唑氯吡唑）和（庚酸酯或癸酸酯或长效注射剂或lai或微球或每月一次或棕榈酸酯或pamoate）”。首先将确定的文章筛选为摘要，排除不符合纳入标准的文章后，对其余文章的全文进行资格和纳入评估。

Inclusion criteria for the systematic review and meta-analyses were: (a) individual studies with original data, (b) comparing patient groups receiving any long-action injectable antipsychotic with patient groups receiving any oral antipsychotic, being followed during the same .

系统评价和荟萃分析的纳入标准是：（a）具有原始数据的个体研究，（b）比较接受任何长效可注射抗精神病药物的患者组与接受任何口服抗精神病药物的患者组，同时进行随访。

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Download referencesFundingThis research received funding from the Biobizkaia Health Research Institute for publication fees.Author informationAuthor notesThese authors contributed equally: Miguel Ángel González-Torres, Ana Catalán.Authors and AffiliationsDepartment of Psychiatry, Basurto University Hospital, Bilbao, SpainClaudia Aymerich, Malein Pacho, Lucía Andrés, Borja Pedruzo, Miguel Ángel González-Torres & Ana CatalánBiobizkaia Health Research Institute, Barakaldo, SpainClaudia Aymerich, Borja Pedruzo, Miguel Ángel González-Torres & Ana CatalánCIBERSAM.

下载参考文献资助该研究获得了Biobizkaia健康研究所的出版费资助。作者信息作者注意到这些作者做出了同样的贡献：米格尔·安格尔·冈萨雷斯·托雷斯，安娜·加泰罗尼亚。作者和附属机构巴苏尔托大学医院精神病学系，毕尔巴鄂，斯潘克劳迪亚·艾默里奇，马林·帕乔，卢卡·安德烈斯，博尔贾·佩德鲁佐，米格尔·安格尔·冈萨雷斯·托雷斯和安娜·加泰罗尼亚·比奥比斯凯亚健康研究所，巴拉卡多，斯潘克劳迪亚·艾默里奇，博尔贾·佩德鲁佐，米格尔·安格尔·冈萨雷斯·托雷斯和安娜·加泰罗尼伯萨姆。

Centro Investigación Biomédica en Red de Salud Mental, Madrid, SpainClaudia Aymerich, Borja Pedruzo, Iñaki Zorrilla, Ana González-Pinto, Miguel Ángel González-Torres & Ana CatalánUniversity of the Basque Country, UPV/EHU, Leioa, SpainClaudia Aymerich, Iñaki Zorrilla, Ana González-Pinto, Miguel Ángel González-Torres & Ana CatalánDepartment of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UKGonzalo Salazar de Pablo, Paolo Fusar-Poli & Ana CatalánDepartment of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UKGonzalo Salazar de PabloChild and Adolescent Mental Health Services, South London and Maudsley NHS Foundation Trust, London, UKGonzalo Salazar de PabloDepartment of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón School of Medicine, Madrid, SpainGonzalo Salazar de PabloSouth London and Maudsley NHS Foundation Trust (Southwark CAMHS), London, UKVioleta Pérez-RodríguezOsakidetza Basque Health Service, Basurto University Hospital, Research and Innovation Unit, Bilbao, SpainAmaia Bilbao, Idoia Castillo-Sin.

马德里红色萨卢德精神生物研究中心，西班牙艾默里奇，博尔加·佩德鲁佐，Iñaki Zorrilla，Ana González Pinto，米格尔·安格尔·冈萨雷斯·托雷斯和安娜·加泰罗尼亚大学巴斯克国家大学，UPV/EHU，莱约亚，西班牙艾默里奇，Iñaki Zorrilla，Ana González Pinto，米格尔·安格尔·冈萨雷斯·托雷斯和安娜·加泰罗尼亚精神病研究所伦敦国王学院心理学与神经科学系，伦敦国王学院精神病学、心理学与神经科学研究所儿童与青少年精神病学系，伦敦国王学院精神病学、心理学与神经科学研究所，UKGonzalo Salazar de PabloChild和青少年心理健康服务，南伦敦和Maudsley NHS基金会信托基金，伦敦，UKGonzalo Salazar de Pablod儿童与青少年精神病学系，马德里格雷戈里奥·马拉尼翁医学院综合医院精神病学与心理健康研究所，SpainGonzalo Salazar de PabloSouth London和Maudsley NHS Foundation Trust（Southwark CAMHS），伦敦，UKVioleta Pérez RodríguezOsakidetza巴斯克卫生服务，巴苏尔托大学医院，毕尔巴鄂研究与创新部，SpainAmaia Bilbao，Idoia Castillo Sin。

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PubMed Google ScholarContributionsCA (Conceptualization and protocol writing, original draft, methodology, systematic search); GSP (Conceptualization, original draft, methodology); MP (Systematic search, data extraction, writing—review and editing); VPR (Systematic search, data extraction, writing—review and editing); AB (Statistics, writing—review and editing); LA (Systematic search, data extraction); ICS (Statistics, writing—review and editing); NA (Statistics, figure design); PFP (Conceptualization and protocol writing, supervision, writing—review and editing); IZ (Methodology, writing—review and editing); AGP (Methodology, writing—review and editing); MAGT (Conceptualization and protocol writing, supervision, writing—review and editing); AC (Conceptualization and protocol writing, supervision, writing—review and editing)Corresponding authorCorrespondence to.

PubMed谷歌学术贡献SCA（概念化和协议撰写，原始草案，方法论，系统搜索）；普惠制（概念化，初稿，方法论）；MP（系统搜索，数据提取，写作评论和编辑）；VPR（系统搜索，数据提取，写作评论和编辑）；AB（统计，写作评论和编辑）；LA（系统搜索，数据提取）；ICS（统计，写作评论和编辑）；NA（统计，图形设计）；PFP（概念化和协议写作，监督，写作审查和编辑）；IZ（方法论，写作评论和编辑）；AGP（方法论，写作评论和编辑）；MAGT（概念化和协议写作，监督，写作审查和编辑）；。

Claudia Aymerich.Ethics declarations

克劳迪娅·艾默里奇。道德宣言

Competing interests

相互竞争的利益

CA received personal fees or grants from Janssen Cilag and Neuraxpharm outside the current work. GSP has received honoraria from Janssen Cilag, Lundbeck and Angelini outside the current work. PFP has received grant support from Lundbeck and honoraria fees from Angelini, Menarini, and Lundbeck outside the current work.

CA在当前工作之外收到了Janssen Cilag和Neuraxpharm的个人费用或赠款。GSP在当前工作之外收到了Janssen Cilag，Lundbeck和Angelini的酬金。PFP在当前工作之外收到了Lundbeck的赠款支持以及Angelini，Menarini和Lundbeck的酬金。

AGP has received grants and served as consultant, advisor or CME speaker for the following entities: Jannsen-Cilag, Lundbeck, Otsuka, Pfizer, Sanofi-Aventis, Exeltis, the Spanish Ministry of Science and Innovation (CIBERSAM), the Ministry of Science (Carlos III Institute), and the Basque Government.

AGP已获得资助，并担任以下实体的顾问、顾问或CME发言人：Jannsen Cilag、Lundbeck、Otsuka、辉瑞、赛诺菲-安万特、Exeltis、西班牙科学与创新部（CIBERSAM）、科学部（卡洛斯三世研究所）和巴斯克政府。

AC received personal fees or grants from Lundbeck, ROVI, and Janssen Cilag outside the current work. The rest of the authors reported no biomedical financial interests or potential conflicts of interest..

AC在当前工作之外收到了伦贝克（Lundbeck），罗维（ROVI）和詹森·西拉格（Janssen Cilag）的个人费用或赠款。其余作者报告没有生物医学财务利益或潜在的利益冲突。。

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Reprints and permissionsAbout this articleCite this articleAymerich, C., Salazar de Pablo, G., Pacho, M. et al. All-cause mortality risk in long-acting injectable versus oral antipsychotics in schizophrenia: a systematic review and meta-analysis.

转载和许可本文引用本文Aymerich，C.，Salazar de Pablo，G.，Pacho，M。等人。精神分裂症中长效注射与口服抗精神病药物的全因死亡风险：系统评价和荟萃分析。

Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02694-3Download citationReceived: 18 October 2023Revised: 01 August 2024Accepted: 05 August 2024Published: 22 August 2024DOI: https://doi.org/10.1038/s41380-024-02694-3Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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