精神分裂症阴性症状管理中国专家共识（2026）

方案与建议

# 精神分裂症阴性症状管理中国专家共识(2026)

马相宜*& 翟兆琳*& 薛菁心* 石川$\triangle$® 刘登堂*⊙

上海市神经科学学会精神医学分会 中国人民健康科技促进会精神卫生科技转化专业委员会

【摘要】 阴性症状是精神分裂症的核心表现之一,贯穿疾病全程,严重损害患者的社会功能和长期预后,但在既往临床实践中常被忽视。本共识在指导委员会的指导下,经过28位精神科专家反复讨论及2轮改良德尔菲(Delphi)法匿名调研,最终形成了11条针对精神分裂症阴性症状管理的推荐意见,涉及原发性与继发性阴性症状的危险因素识别、规范化量表评估与相关诊断标准、药物治疗策略(包括部分第二代抗精神病药物、新型靶向毒蕈碱型胆碱能受体药物,以及抗抑郁药物联合治疗方案)、神经调控以及心理社会干预等方面。本共识结合国内外的循证医学证据,有助于指导我国精神分裂症患者阴性症状的管理工作并推动其水平更新,促进患者功能康复及生活质量改善。

【关键词】精神分裂症 阴性症状 评估 干预 专家共识

【中图分类号】R749.3

【文献标识码】 A

Chinese experts consensus on the management of negative symptoms of schizophrenia (2026). MA Xiangyi, ZHAI Zhaolin, XUE Jingxin, SHI Chuan, LIU Dengtang. Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing 100191, China. E-mail: shichuan@bjmu.edu.cn. Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Clinical Center for Psychotic Disorders, National Center for Mental Disorders, Shanghai 200030, China. E-mail: liudengtang@smhc.org.cn.

[Abstract] Negative symptoms represent one of the core manifestations of schizophrenia, persisting throughout the disease course and significantly impairing patients' social functioning and long-term prognosis. However, these symptoms have frequently been overlooked in past clinical practice. Under the guidance of the steering committee, this expert consensus was formed by integrating domestic and international evidence-based medical evidence after repeated discussions by 28 psychiatric experts and 2 rounds of anonymous modified Delphi surveys. Ultimately, 11 consensus recommendations in the management of negative symptoms of schizophrenia were established. The recommendations cover the identification of risk factors of primary and secondary negative symptoms, standardized scale assessment and operational diagnostic criteria, pharmacological treatment strategies (including second-generation antipsychotics, novel muscarinic cholinergic agent and antidepressants augmentation strategy), neuromodulation interventions, and psychosocial interventions. This consensus aims to update the diagnostic and therapeutic concepts regarding negative symptoms among psychiatrists in China and standardize clinical practice, thereby promoting patients' functional recovery and improving their quality of life.

【Keywords】 Schizophrenia Negative symptoms Assessment Intervention Expert consensus

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精神分裂症的阴性症状是指患者正常精神活动功能的减退或缺失[1]。自尤金·布鲁勒(Eugen Bleuler)对精神分裂症“4A症状”中情感淡漠及内向性的描述起,阴性症状即被视为精神分裂症的核心症状之一[2]。相较于幻觉、妄想等阳性症状,阴性症状起病时间更早且较隐匿,在阳性症状好转后可持续存在,贯穿于疾病全程[3]。最新的国际疾病分类系统(包括 DSM-5 及 ICD-11)均认为,阴性症状属于精神分裂症的独立症状维度。临床实践及研究结果发现,阴性症状是影响精神分裂症患者功能预后的重要因素之一[4],但在识别与治疗上存在较多困难。

本共识以临床问题为导向,系统梳理了精神分裂症阴性症状的危险因素、评估及诊断、预防及干预等内容,并结合专家意见及循证证据提出推荐意见,旨在更新我国精神科医生对阴性症状的认识,提高阴性症状的诊断及干预水平,从而改善精神分裂症的功能预后及生活质量。

1 共识形成过程

本共识由上海市神经科学学会精神医学分会、中国人体健康科技促进会精神卫生科技转化专业委员会发起,由上海交通大学医学院附属精神卫生中心刘登堂教授和北京大学第六医院石川教授联合牵头组织,专家共识意见的形成采用改良德尔菲(Delphi)法[5],通过2轮次匿名投票表决,以及反馈修改,形成最终意见。本共识已在国际实践指南注册与透明化平台完成注册(注册号:PREPARE-2025CN1477)。江开达教授、李涛教授及俞斌教授(方法学专家)组成指导委员会,指导共识形成的全过程。由来自全国各省市的28位专家(均为副高及以上职称)组成专家组并参与匿名投票。投票使用利克特(Likert)5点法,分为“1-强烈反对,2-反对,3-中立,4-同意,5-强烈同意”,若持“强烈反对+反对”或“强烈同意+同意”态度的专家比例≥70%,则认为达成共识,形成专家推荐意见[5]。指导委员会、专家组及工作组成员均不存在与本共识相

关的利益冲突。专家组共进行了2轮投票,问卷回收率均为100%。除此之外,本共识使用澳大利亚乔安娜布里格斯研究所(Joanna Briggs Institute, JBI)证据预分级系统[6-7]对相关循证证据进行质量等级评定(表1),由2名具有循证证据评定经验的工作组成员独立进行,具有争议处经另1名成员参与讨论商定。

首先,工作组以“schizophrenia OR psychosis OR psychotic”“negative symptoms”作为关键词,按照PICO(P:研究对象,I:干预措施,C:对照措施,O:研究结局)原则组合后,在PubMed、Embase、中国知网与万方数据等国内外多个数据库进行系统文献检索与筛选,检索时间截至2025年5月。在循证证据基础上,指导委员会及工作组结合临床需求初步提炼出精神分裂症阴性症状的3大临床问题,并组织研讨会进行讨论,形成第一轮调研问卷,共包含11条推荐意见、26个子条目。根据第一轮反馈结果,有22个子条目达成共识,而4个治疗相关子条目未达成共识。指导委员会及工作组经过讨论及进一步查阅文献后,删除了4个未达成共识的子条目,修改了1项已达成共识的评估相关推荐意见表述(推荐意见5),形成第二轮调研问卷,包含1个修改过的子条目。经过2轮投票后,最终共11项推荐意见达成共识。图1为专家共识意见形成流程图。

# 2 精神分裂症阴性症状管理的临床问题及专家建议

# 临床问题1:精神分裂症阴性症状的危险因素

精神分裂症阴性症状按来源可分为原发性与继发性2种,原发性阴性症状是精神分裂症自身病理过程的表现之一[11],而继发性阴性症状则是由其他因素所诱发或加重,例如被害妄想导致患者因恐惧被伤害而出现社会退缩,过度镇静导致患者显得言语减少、意志缺乏等[11]。

推荐意见1:原发性阴性症状的危险因素包括精神病未治疗时间较长、男性、病前社会适应差、社

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Tab.1 JBI levels of evidence and grades of recommendation system

表1 JBI证据预分级及证据推荐级别系统

|证据等级|研究设计类型|具体描述| |---|---|---| |治疗有效性||| |级别1|RCT/实验性研究|1a:多项RCT的系统评价 1b:多项RCT及其他干预性研究的系统评价 1c:单项RCT 1d:准RCT| |级别2|类实验性研究|2a:多项类实验性研究的系统评价 2b:多项类实验性研究及其他低质量干预性研究的系统评价 2c:单项前瞻性有对照组的类实验性研究 2d:前后对照/回顾性对照的类实验性研究 3a:多项队列研究的系统评价 3b:多项队列研究及其他低质量观察性研究的系统评价 3c:单项有对照组的队列研究 3d:单项病例对照研究 3e:单项无对照组的观察性研究 4a:多项描述性研究的系统评价 4b:单项横断面研究 4c:病例系列研究 4d:个案研究 5a:对专家意见的系统评价 5b:专家共识 5c:单项专家意见/基础研究| |级别3|观察性-分析性研究|| |级别4|观察性-描述性研究|| |级别5|专家意见/基础研究|| |诊断试验||| |级别1|连续性患者的诊断准确度检验|1a:多项连续性患者诊断准确度检验的系统评价 1b:单项连续性患者诊断准确度检验的研究 2a:多项非连续性患者的诊断准确度检验研究的系统评价 2b:单项非连续性患者的诊断准确度检验研究 3a:多项诊断性病例对照研究的系统评价 3b:单项诊断性病例对照研究 4a:多项诊断率研究的系统评价 4b:单项诊断性病例对照研究 5a:对专家意见的系统评价 4b:专家共识 5c:单个专家意见/基础研究| |级别2|非连续性患者的诊断准确度检验|| |级别3|诊断性病例对照研究|| |级别4|诊断率研究|| |级别5|专家意见/基础研究|| |预测研究||| |级别1|起始队列研究|1a:起始队列研究的系统评价 1b:起始队列研究 2a:多项观察结果为“全或无”的研究的系统评价 2b:单项观察结果为“全或无”的研究| |级别2|观察结果为“全或无”的研究|3a:多项队列研究的系统评价 3b:单项队列研究 3a:多项队列研究的系统评价 3b:单项队列研究| |级别3|队列研究|4a:多项病例系列研究、病例对照研究、历史对照研究的系统评价 4b:单项病例系列研究、病例对照研究、历史对照研究| |级别4|病例系列研究、病例对照研究、历史对照研究|5a:对专家意见的系统评价 4b:单项病例系列研究、病例对照研究、历史对照研究| |级别5|专家意见/基础研究|5c:单个专家意见/基础研究|

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![graph TD\n A1[组建指导委员会（2位精神科专家、1位方法学专家），提名专家组（28位）及工作组] --> A2[系统文献检索与评价（截至2025年5月），初步提炼3大临床问题]\n A2 --> A3[专家研讨会就文献检索结果讨论，形成第一轮匿名调研问卷（11条推荐意见、26个子条目）]\n A3 --> A4[第一轮匿名投票]\n A4 --> A5[22个子条目达成共识]\n A4 --> A6[4个子条目未达成共识]\n A4 --> A7[指导委员会及工作组根据第一轮结果删改条目，删除4个未达成共识条目，修改1条已达成共识推荐意见形成第二轮匿名问卷（1条推荐意见，包含1个修改过的子条目）]\n A7 --> A8[第二轮匿名投票]\n A8 --> A9[1个子条目达成共识]\n A8 --> A10[最终共形成11条专家推荐意见]\n](1/parseimages/figure0ce4df23b3ee4ec78334c30353acb7cc_0_2.png) Fig.1 Flowchart of expert consensus formation

图 1 专家共识意见形成流程图

交局限、社会支持系统较弱、生活质量差、失业、治疗依从性差、精神分裂症阳性家族史、儿童期创伤(如身体虐待、情感忽视)、代谢异常(如糖耐量异常等)。(专家共识度100%,证据等级1a~4b)

精神病未治疗时间(duration of untreated psychosis, DUP)作为危险因素的证据最为充分,2项基于首发精神病患者队列的大型 meta分析显示,DUP较长与患者的阴性症状(基线及随访)较重显著相关[8-9](证据等级1a)。3项队列研究证实病前社会适应差与阴性症状持续存在相关[10-12](证据等级1b~3b)。原发性阴性症状的其他危险因素均仅有个别证据支持,包括男性[11]、失业[111](证据等级1b)、精神分裂症阳性家族史(证据等级1b)[13]、社交局限[14](证据等级2a)、社会支持系统较弱[15](证据等级4b)及代谢异常[16](证据等级4a)等,治疗依从性差与阴性症状可能存在相互影响[17-18](证据等级4b),儿童期创伤对阴性症状的影响在不同证据中存在差异(证据等级4a~4b)[19-21]。

此外,有证据揭示原发性阴性症状可能存在一定的遗传背景[3],如特定单核苷酸多态性可能与阴性症状严重程度相关,提示阴性症状的发生发展与精神分裂症的神经发育异常假说存在相关性,但尚无统一结论。

推荐意见2:继发性阴性症状的危险因素包括使用第一代抗精神病药物(如氟哌啶醇)、抗精神病药物所致不良反应(如锥体外系反应、镇静过度、体

质量增加等)、阳性症状、抑郁症状、疾病反复发作及社会参与度减少等。(专家共识度86%,证据等级1b~5c)

继发性症状危险因素研究证据总体偏少、质量偏低。1项纳入25例健康志愿者的短程药理学试验发现,单次使用利培酮2.5mg可直接导致动机缺乏,也可以通过锥体外系反应(extrapyramidal symptoms,EPS)介导情感淡漠及言语减少等症状;单次使用氟哌醇5mg也可直接导致动机缺乏[22](证据等级2c)。1项RCT队列事后分析发现阴性症状变化与EPS、抑郁症状或阳性症状的变化显著相关,其中动机/愉快感缺乏与三者均相关,而表达缺陷主要与EPS相关[23](证据等级3b)。1项基于定性研究的系统综述揭示,患者对阴性症状的主观体验(subjective experience of negative symptoms)受到阳性症状、认知症状、抑郁症状、药物治疗所致镇静过度及体质量增加等影响,更换第二代抗精神病药可能具有改善作用[24](证据等级5a)。

罹患精神分裂症显著影响患者的社会交往意愿及能力,而社会参与度减少又进一步加剧患者的阴性症状[25](证据等级5c),首发患者的随访研究显示发病后就业不佳与持续性阴性症状相关[11](证据等级1b)。疾病反复发作同样是继发性阴性症状的危险因素,1项RCT研究事后分析揭示复发患者的阴性症状较首发患者更重[26](证据等级3b)。

推荐意见3: 阴性症状与认知缺陷症状均属于精神分裂症的独立症状维度, 但两者关系较为密切, 认知功能较差与阴性症状较重存在一定相关性。(专家共识度100%, 证据等级3a~4b)

认知缺陷症状是精神分裂症的另一重要症状维度,涉及注意、处理速度、工作记忆、词语和视觉学习、推理和问题解决、执行功能及社会认知等诸多领域[27]。与阴性症状类似,认知缺陷症状在患者首次发病前已存在[27],且显著影响患者的功能预后[28]。1项队列研究 meta分析报道,阴性症状与认知缺陷症状严重程度显著相关(r=0.24)[29](证据等级3a)。1项中国首发患者横断面研究证实,阴性

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症状为主患者相对于阳性症状为主者的认知缺陷更显著,且认知缺陷症状与阴性症状的严重程度呈正相关(不同认知分测验相关系数r为0.121~0.227)[30](证据等级4b)。2项20年随访研究发现在较长时间跨度中,精神分裂症的认知功能下降与阴性症状恶化显著相关[28,31](证据等级3b)。然而,阴性症状与认知缺陷症状的内在关联尚未被阐明,二者可能具有相同或类似的神经机制,需要进一步研究[29,32-33]。

临床问题2:精神分裂症阴性症状的评估及诊断

推荐意见4: 阴性症状是指正常精神活动功能的减退或缺失,主要表现为情感淡漠、言语减少、快感缺失、动机缺乏与社会退缩等5大领域。第二代评估量表通过因子分析将阴性症状划分为动机/愉快感缺乏和表达缺陷2大因子。(专家共识度93%,证据等级1b~5b)

2006年,美国国立精神卫生研究院(National Institute of Mental Health, NIMH)的阴性症状专家共识指出,精神分裂症阴性症状指患者正常精神活动功能的减退或缺失,属独立症状维度,涵盖情感淡漠、言语减少、快感缺失、动机缺乏与社会退缩5个核心症状领域[34](证据等级5b),并建议据此开发新评估工具。此后,基于第二代阴性症状评估量表的因子分析验证了上述5因子模型[35-36](证据等级1b),并进一步将其凝练为“动机/愉快感缺乏(motivation and pleasure, MAP)”与“表达缺陷(expression, EXP)”2因子模型[37-38](证据等级1b)。

尽管2因子模型的结构稳定性已在不同人群样本中获广泛验证[39-42](证据等级1b),且能够有效预测患者功能预后[43-45](证据等级3b),但也有研究指出其模型拟合度劣于5因子模型,难以充分解释阴性症状的复杂结构[42,46](证据等级1b)。目前,阴性症状的最佳因子模型尚无定论,虽有研究探索了3、5、6因子等其他模型[42,47],但证据尚不充分,凸显了阴性症状的多维度复杂性。少数证据表明,动机缺乏可能在阴性症状结构中居核心地位,或为改善

阴性症状的关键治疗靶点[48-51],但仍需进一步探究。

推荐意见5:建议使用标准化量表对阴性症状严重程度进行评估,包括第一代评估量表(SANS、PANSS 阴性症状分量表、PANSS Marder 阴性因子分、NSA)和第二代评估量表(BNSS、CAINS)等。建议对阴性症状进行全程纵向监测,如半年评估1次。(专家共识度100%,证据等级1a~5c)

阴性症状的标准化量表评估对规范临床诊治与新药、治疗手段研发均有裨益。第一代量表中,阳性与阴性症状量表(positive and negative symptoms scale,PANSS)最常用于精神分裂症患者症状评估,信度良好,但研究发现其阳性症状、阴性症状及一般精神病理症状的3因子模型结构效度欠佳(证据等级1a)[52-53]。后续通过PANSS Marder 5因子模型改进,阴性因子分结构效度稍有提升(去除了原量表中N5抽象思维困难、N7刻板思维,增加了G7动作迟缓、G16主动回避社交)[54](证据等级1a),但未覆盖快感缺失症状维度,内容效度仍有缺陷[52,55](证据等级1a-5c)。阴性症状评定量表(scale for the assessment of negative symptoms,SANS)是早期评估量表之一,原版及缩短版信度良好[56](证据等级1b~2b),但同样存在内容效度问题,即部分量表条目与当下阴性症状领域描述不符(如注意障碍、情感不适切等条目)[55]。首轮投票后,专家建议在推荐意见中增加阴性症状评估量表(negative symptom assessment scale,NSA),其信效度、辨别力及对变化的响应良好,且具有4个条目缩短版本,便于临床应用[57-61](证据等级2b~4b),经工作组讨论予以纳入推荐意见,并经第二轮投票达成共识。

第二代评估量表基于2006年NIMH阴性症状专家共识[34]的5个核心症状领域研发,包括简明阴性症状评定量表(brief negative symptom scale, BNSS)与临床阴性症状评估访谈量表(clinical assessment interview for negative symptoms, CAINS)。两者均包含13个条目,内部一致性、重测信度以及结构、聚合与区分效度良好,支持动机/愉快感缺乏和表达缺陷的2因子模型[38, 62-63],且均有经验证的

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中文版本[64-65](证据等级1a~1b),推荐用于临床及研究中的定量评估。

ICD-11 诊断标准同样包含阴性症状分级标准,要求在排除药物或抑郁等继发因素后,按过去1周情感-语言-动机功能损害程度,将严重度分为无、轻度、中度、重度4级,可作为简便评估工具,暂无相关循证证据。

阴性症状评估频率尚无公认标准,鉴于其对患者预后影响且易被忽视,本共识推荐全病程纵向评估。1项首发精神病队列随访发现,急性期后0、6、12个月随访可提高持续性阴性症状识别率[66](证据等级4b),但仍需更多研究探索。

推荐意见6:阴性症状相关诊断标准

推荐意见6-1:阴性症状为主(predominant)的精神分裂症,指阳性症状完全缓解或轻微,阴性症状仍显著的精神分裂症(如PANSS 阴性症状分量表或PANSS Marder 阴性因子分≥18分等),对原发性或继发性阴性症状做不做区分。(专家共识度79%,证据等级3b~5c)

推荐意见6-2:持续性阴性症状(persistent negative symptoms, PNS),指疾病稳定阶段仍然存在的阴性症状,可包含原发性阴性症状及常规积极处理后仍未好转的继发性阴性症状,总体严重程度经标准化量表评估达到中度及以上,且影响患者正常功能,达到一定时间(如6个月)。(专家共识度96%,证据等级4b~5c)

临床实践与研究中,需界定阴性症状相关的操作性诊断标准以明确目标人群。本共识纳入上述2种诊断标准进行投票并达成共识,此外还有其他相关标准,各有侧重。阴性症状显著(prominent)的精神分裂症仅要求阴性症状达一定严重程度,而阴性症状为主(predominant)的精神分裂症则同时强调阳性症状轻微,对于是否排除继发性阴性症状、是否持续一定时间,不同研究间差异较大[11](证据等级5c)。队列研究证实,二者均与更差的社会功能相关[67-68](证据等级3b),而后者排除急性期阳性症状的干扰,能更好地判断治疗手段对阴性症状的疗

效[69](证据等级4a),故被纳入投票。

持续性阴性症状(PNS)涵盖急性期抗精神病疗效不佳的原发性阴性症状,以及积极治疗后仍存在的继发性阴性症状,强调无论原发或继发,持续存在的阴性症状均不利于患者预后,应积极干预[70](证据等级5c)。1项中国香港首发队列3年随访研究报道,PNS发病率约24%[111](证据等级4b)。早期有学者提出“缺陷综合征(deficit syndrome, DS)”概念[71],要求排除继发性阴性症状后,在5项阴性症状领域中至少有2项达重度(经标准化量表评估),且在疾病稳定阶段持续超过12个月(含慢性精神病状态)。尽管DS与患者功能预后显著相关[71],但原发与继发阴性症状在实际操作中区分困难,故逐渐少用。部分学者提出原发性持续性 primary and persistent)阴性症状概念,试图用不良反应及抑郁症状量表等排除继发患者[72],但可能排除过多病例,目前应用较少。

临床问题3:精神分裂症阴性症状的预防及干预

推荐意见7:阴性症状是精神分裂症功能预后的重要影响因素,应积极预防及干预。(专家共识度100%,证据等级1b~3b)

多项基于首发精神病患者的前瞻性初始队列随访证实,基线阴性症状的严重程度与长期功能预后显著相关[73-77](证据等级1b),阴性症状早期好转是社会功能恢复的最有力预测因素(OR为3.4~5.5)[78](证据等级1b)。阴性症状为主或显著的精神分裂症患者功能预后显著更差[68](证据等级3b),在早发型及难治性精神分裂症等特殊群体中阴性症状的严重程度亦与功能结局不良相关[79-80](证据等级3a~3b)。对阴性症状的早期预防及干预对改善患者功能预后至关重要。

推荐意见8:积极识别及预防阴性症状的危险因素,如缩短DUP,预防疾病复发,减少阳性症状残留,改善抑郁症状,积极识别并处理药物不良反应,调整可能诱发或加重阴性症状的抗精神病药物,加强社会支持系统,鼓励社会参与等。(专家共

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识度100%,证据等级2c~5c)

阴性症状的预防主要针对可干预的危险因素。原发性阴性症状危险因素中,仅DUP可通过早期筛查与诊断进行干预。1项前瞻性队列研究发现,社区筛查可显著缩短DUP,首次就诊时阴性症状更轻,提示其作为可干预危险因素的价值[81](证据等级2c)。

继发性阴性症状的可干预危险因素较多,多国指南推荐对其进行针对性处理[82-84](证据等级5c),包括:规范治疗以尽可能缓解阳性症状并预防复发,调整抗精神病药物方案并对症处理EPS、过度镇静及代谢相关不良反应,识别并治疗可能存在的抑郁症状,加强社会支持,鼓励社会参与等。然而,目前尚无直接证据支持上述措施可改善阴性症状总体严重程度。

推荐意见9:对阴性症状具有一定疗效的抗精神病药物及其他药物治疗方案,包括阿立哌唑(专家共识度96%,证据等级1a~5b)、氨磺必利(专家共识度93%,证据等级1a~1c)、呎诺美林曲司氯铵(X/T)(专家共识度82%,证据等级1a~2a)、奥氮平(专家共识度79%,证据等级1a~1c)、氯氮平(专家共识度79%,证据等级2c~3a)、布瑞哌唑(专家共识度71%,证据等级1a~2a),以及抗精神病药物与抗抑郁药物联合治疗方案(专家共识度75%,证据等级1a~1c)。

结合现有循证证据,第一轮德尔菲投票共纳入8种抗精神病药物(奥氮平、阿立哌唑、氨磺必利、布南色林、布瑞哌唑、氯氮平、齐拉西酮及咕诺美林曲司氯铵)和1种联合治疗方案(抗精神病药物与抗抑郁药物联合治疗方案),经过专家投票后,6种抗精神病药物及1种联合治疗方案达成共识,而布南色林和齐拉西酮并未达成共识。表2列出了6种达成共识的抗精神病药物在精神分裂症急性期改善阴性症状的效应值及95%有效剂量。

氨磺必利和奥氮平改善阴性症状的证据相对充分。2项meta分析发现,氨磺必利急性期改善阴性症状效应值靠前[85, 88](证据等级1a)。急性期阴

|药物|效应值(相对于安慰剂)|95%有效剂量(mg/d)$^{3)}$| |---|---|---| |阿立哌唑|0.33(0.24~0.41)$^{1)}$|11.9| |氨磺必利|0.50(0.37~0.64)$^{1)}$|481| |呫诺美林曲司氯铵|0.42或1.$18^{2)}$|/| |奥氮平|0.45(0.39~0.51)$^{1)}$|15.5| |氯氮平|0.62(0.39~0.84)$^{1)}$|/| |布瑞哌唑|0.25(0.14~0.36)$^{1)}$|2.1|

注:1)数据来源于文献[85].急性期治疗阴性症状效应值为标准化均值差(SMD),括号内为95%置信区间;2)数据来源于文献[86],急性期治疗阴性症状效应值为Cohen'sd,在所有患者中为0.42,在阴性症状显著患者中为1.18;3)数据来源于文献[87]。

性症状可能受到阳性症状等其他因素干扰,故有meta分析针对阴性症状为主或阴性症状显著患者进行比较,同样发现氨磺必利疗效显著优于安慰剂(SMD=0.47)[89](证据等级1a),且阴性症状越重,其相对安慰剂的优势越明显[90](证据等级1a)。奥氮平急性期改善阴性症状效应值也靠前[85,88](证据等级1a),且在阴性症状为主及阴性症状显著患者中分别优于氟哌啶醇和利培酮,但仅基于小样本RCT研究[89](证据等级1c)。1项在日本人群比较药物治疗精神分裂症急性期疗效与安全性的网络meta分析发现,奥氮平是纳入的9种药物中唯一对阴性症状改善显著优于安慰剂的药物[91](证据等级1a)。在较早的1项meta分析中,奥氮平也在改善阴性症状方面表现出相比其他第二代抗精神病药物的潜在优势,但未达统计学意义[92](证据等级1a)。

阿立哌唑和布瑞哌唑同属5-羟色胺/多巴胺活性调节剂,有meta分析及系统综述支持该类药物改善阴性症状相比安慰剂具有小而稳定的优势[93-94](证据等级1a)。阿立哌唑在本次专家共识投票中共识度最高,布瑞哌唑亦达成共识。在大型网状meta分析中,二者在急性期改善阴性症状效应值仅排名中等及靠后[85](证据等级1a)。阿立哌唑相比利培酮及氯氮平具有部分优势,但研究质量偏低[95](证据等级2a)。3项meta分析提示布瑞哌唑在急

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性期改善阴性症状优于安慰剂[96-98](证据等级1a)。针对阴性症状为主及显著患者,阿立哌唑和布瑞哌唑暂无高级别证据支持。

氯氮平对阴性症状的改善作用同样获得较多专家支持。在急性期meta分析中,其改善阴性症状效应值排名靠前(SMD=0.62),但纳入研究样本量小且发表年份较早,证据质量被评为极低,且未纳入难治性精神分裂症患者,与氯氮平适应证人群不符[85](证据等级2c)。2项 Cochrane图书馆 meta分析补充了难治性患者的证据,发现氯氮平改善阴性症状优于第一代抗精神病药物,但与利培酮无显著差异,劣于喹硫平,且研究样本量较小[99-100](证据等级3a)。综上,氯氮平在治疗阴性症状中的价值仍需更多研究探索。

咕诺美林曲司氯铵(X/T)是靶向毒蕈碱型胆碱能受体(M1/M4)的新型抗精神病药物,目前国内已获批上市。基于现有循证证据,专家组对其改善阴性症状的作用持积极态度,并达成共识。2项 meta分析揭示X/T对精神分裂症阴性症状的疗效显著优于安慰剂(Cohen's d=0.42),且亚组分析发现这种疗效优势对于阴性症状显著的患者更加突出(Cohen's d=1.18)[86, 101](证据等级1a~2a)。另有1项meta分析比较了X/T和几种常用第二代抗精神病药物(利培酮、奥氮平、阿立哌唑)对急性期阴性症状的疗效,结果发现这些药物均优于安慰剂,但彼此之间无显著差异[102](证据等级1a)。基于X/T对阳性、阴性及认知症状的改善作用,胆碱能机制在精神分裂症中的作用受到持续关注[103-104]。

此外,也有研究报道布南色林[88, 91, 105-106]、卡利拉嗪[93-94]、齐拉西酮[107-108]及鲁拉西酮[109, 110]等药物对精神分裂症阴性症状可能具有改善作用,但存在结论不一致或证据等级偏低的局限,需要进一步研究,本次专家共识未纳入投票或未达成共识。

联合治疗方案可以作为抗精神病药物的补充, 本次投票结果支持抗精神病药物与抗抑郁药物的联合治疗方案。多项 meta分析提示抗精神病药物与抗抑郁药物联合治疗方案可为阴性症状带来轻

至中度获益[111-113](证据等级1a),且抗抑郁药对精神分裂症总体症状的改善主要来源于阴性症状改善(SMD=0.25)[111]。另有 meta分析发现联合抗抑郁药物对慢性精神分裂症患者(SMD=0.48)[113]及难治性精神分裂症患者[114-115]的阴性症状也具有改善作用(证据等级1a)。其他联合治疗方案总体证据尚不充分或存在矛盾[116],本次共识未纳入投票。

推荐意见10:对阴性症状具有一定疗效的神经调控干预方案包括重复经颅磁刺激(repetitive transcranial magnetic stimulation, rTMS)等。(专家共识度71%,证据等级1a)

神经调控技术是精神分裂症阴性症状的重要干预手段,目前多用于稳定期患者。本共识对重复经颅磁刺激(rTMS)、经颅电刺激(transcranial electrical stimulation, tES)、改良电抽搐治疗(modified electroconvulsive therapy, MECT)这3种主要神经调控干预方案进行投票,仅rTMS达成共识,tES与MECT未达成共识。

rTMS 借助线圈产生快速变化的磁场,在大脑皮质(如背外侧前额叶皮质)诱发电流,调控皮质兴奋性及相关神经环路活动。既往研究对rTMS改善阴性症状的疗效存在争议[117],但近期1篇纳入26项meta 分析的综述指出,更多证据支持rTMS能显著改善阴性症状[118](证图等级1a),且耐受性良好[119](证据等级1a)。治疗参数可显著影响疗效,选择左侧背外侧前额叶为刺激靶点、10~20 Hz 高频刺激、刺激强度>100%~110%运动阈值、持续至少3周等,对改善阴性症状疗效更优[118](间歇性θ脉冲刺激(intermittent theta burst stimulation, iTBS)是rTMS的特殊类型,meta分析显示其能改善阴性症状(SMD=0.89)[120],且疗效显著优于其他rTMS方案(SMD=0.43)[121-122](证据等级1a)。专家组认为,阴性症状的神经调控方案总体缺乏长期证据,是主要短板,有待进一步研究。

未达共识的干预方案中,tES通过头皮电极输入低强度电流,以阈下刺激调节神经元膜电位和网络活动,可分为经颅直流电刺激(transcranial direct

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current stimulation, tDCS)和经颅交流电刺激(transcranial alternating current stimulation, tACS)。meta分析提示两者均能有效改善阴性症状,其中tDCS证据较多(SMD为0.51~0.80)[123],而tACS证据相对较少(SMD=0.65)[124]。本次未达共识,原因可能是目前其临床可及性较差及缺少统一治疗规范等,但有潜在应用前景。MECT是较成熟的神经调控手段,其主要优势在于缓解阳性症状,但存在公认的认知不良反应风险,少量证据表明其对缓解阴性症状无效[125-127],投票结果与研究证据相符。此外,经颅随机噪声刺激(transcranial random noise stimulation, tRNS)、经皮迷走神经刺激(transcutaneous vagus nerve stimulation, tVNS)、经颅超声刺激(transcranial ultrasound stimulation, tUS)等新兴治疗手段在部分研究中有一定疗效,但总体证据不足[122,128-129],故未纳入投票。

推荐意见11:联合社交技能训练(专家共识度100%,证据等级1a~1b)、运动疗法(专家共识度89%,证据等级1a~1b)、工娱疗法(专家共识度86%,证据等级1c)、认知增强治疗(专家共识度79%,证据等级1c)及认知行为疗法(专家共识度75%,证据等级1a~1b)等心理社会干预方法有助于改善精神分裂症的阴性症状。

心理社会干预是改善精神分裂症阴性症状的重要补充手段。1篇汇总了31项 meta分析的系统综述表明,与常规治疗(treatment-as-usual, TAU)相比,包括运动疗法、认知行为疗法、社交技能训练、音乐疗法、正念疗法、团体治疗、认知矫正治疗、家庭治疗、整合治疗在内的大部分心理社会干预手段对阴性症状有小至中等改善作用[130](证据等级1a)。经工作组讨论,本共识共纳入5种干预方法进行投票,并都达成共识。

认知行为疗法(cognitive behavioral therapy, CBT)的证据最为充分,使用也较广泛。1项横断面研究 meta分析发现,患者功能障碍相关负性信念与阴性症状显著相关[131],CBT可聚焦负性信念,通过认知重构、行为激活和问题解决训练,促使患者逐

步增加有意义的活动,改善阴性症状。多项 meta分析证实,相比TAU,CBT对阴性症状的改善在短期及长期随访中均更优,且在首发精神病人群中有效[130,132-135](证据等级1a~1b)。社交技能训练(social skills training, SST)通过示范、角色扮演、反馈与家庭作业等方式,系统训练患者在实际情境中的情绪表达、对话及冲突处理能力,4项meta分析支持其对阴性症状的改善作用[130](证据等级1a~1b)。运动疗法近年来受到关注,包括瑜伽、太极、有氧运动、阻抗运动等形式,其通过改善体能、提升神经可塑性等机制改善阴性症状[130,136-140](证据等级1a)。工娱疗法以有目的的劳动和文体娱乐活动为核心,包含工作治疗(又称职业康复)及娱乐治疗,在完成工作或作品的过程中促进表达及社会参与,1项RCT研究证实,职业康复可显著改善稳定期患者阴性症状[141](证据等级1c),虽证据较少,但实施简便。认知增强治疗(cognitive enhancement therapy,CET)则通过结构化、重复性的认知训练任务(纸笔或计算机化),针对性干预注意、记忆和执行功能等认知功能,2项RCT研究报告其能够改善患者的阴性症状[142-143](证据等级1c)。

尽管证据及专家意见均推荐心理社会干预方法改善阴性症状,但经济及普及性等因素可能限制其广泛应用,可根据患者偏好及可用资源进行选择。

3 总结与展望

本共识围绕精神分裂症阴性症状的临床相关问题展开,涵盖了阴性症状的危险因素、评估及诊断、预防及干预等多个方面,希望加强我国各级医疗机构对阴性症状的关注及干预,从而改善精神分裂症患者的功能预后。总体来说,阴性症状内涵及主要症状尚不十分明确,病因及病理机制不明,且干预效果不理想。未来亟待更多临床及基础研究,深入探索阴性症状的内涵及其病理机制,厘清其与其他症状的关联,构建阴性症状客观量化评估体系,开展大型RCT研究优化药物治疗策略等。此

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外,神经调控、心理社会干预、人工智能[144-146]及数字疗法[144,147-149]等,在精神分裂症阴性症状的治疗与管理中也可能发挥重要作用。本共识将在未来持续更新,以更好地满足临床需求。

指导委员会:江开达(上海交通大学医学院附属精神卫生中心),李涛(杭州市第七人民医院),俞斌(武汉大学公共卫生学院)

专家组成员(以姓氏汉语拼音字母排序):薄奇静(首都医科大学附属北京安定医院),丛伟东(福建医科大学附属福州神经精神病医院),程宇琪(杭州市第七人民医院),董芳(首都医科大学附属北京安定医院),胡少华(浙江大学医学院附属第一医院),黄满丽(浙江大学医学院附属第一医院),黄兢(中南大学湘雅二医院),何红波(广东省人民医院、广东省精神卫生中心),李安宁(首都医科大学附属北京安定医院),李冠军(上海市精神卫生中心),李乐华(中南大学湘雅二医院),李伟(北京回龙观医院),李先宾(首都医科大学附属北京安定医院),李则挚(广州医科大学附属脑科医院),刘铁桥(中南大学湘雅二医院),马现仓(西安交通大学第一附属医院),蒲城城(北京大学第六医院),孙静(南京医科大学附属南京脑科医院),宋学勤(郑州大学第一附属医院),隋毓秀(南京医科大学附属南京脑科医院),谭淑平(北京回龙观医院),王惠玲(武汉大学人民医院),王继军(上海市精神卫生中心),王强(四川大学华西医院),易正辉(上海市精神卫生中心),袁勇贵(东南大学附属中大医院),郑英君(广州医科大学附属脑科医院),朱刚(中国医科大学附属第一医院)

工作组/执笔组成员:马相宜(上海交通大学医学院附属精神卫生中心),翟兆琳(上海交通大学医学院附属精神卫生中心),薛菁心(上海交通大学医学院附属精神卫生中心),石川(北京大学第六医院),刘登堂(上海交通大学医学院附属精神卫生中心)

利益冲突 所有作者声明无利益冲突

致谢 北京医学奖励基金会资助本共识

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