TreatingNegativeSymptomsinSchizophrenia

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,新进展：,治疗精神分裂症阴性症状,Treating Negative Symptoms in Schizophrenia: an Update,1. 引言,1990年代与第二代抗精神病药物（SGAs）出现平行的精神分裂症（SCH）定位的重要变化：,从定义为一种精神病演变成反映,多个症状域,的疾病。1980年代工作的兴趣：阴性症状认知症状,结局的讨论：历史上陷入解决,阳性症状,开始坚定地接受,功能与临床康复,的概念。,早期的证据表明，,新的药物,以其不同的药理学能有效地治疗其他症状域，认为它们比抗精神病药物更有效。,经过20多年的临床经验，对这些新药想法有进一步的变化。,根据积累的证据，对于SGAs超出精神病性之外的症状的临床疗效的热情已经大大减弱,1,。,在功能恢复方面，,阴性,和,认知症状,两者的关联,2,已经成为快速扩展的工作力度中心，集中于：,(a) 更好的理解这些症状域,(b) 建立有效的治疗方法,1.Fusar-Poli P, Kempton MJ, Rosenheck RA,.,Efficacy and safety of second-generation long-acting injections in schizophrenia: a meta-analysis of randomized-controlled trials.,Int Clin Psychopharmacol,. 2013;28(2):5766.,2 Meyer EC, et al. The relationship of neurocognition and negative symptoms to social and role functioning over time in individuals at clinical high risk in the first phase of the north american prodrome longitudinal study.,Schizophr Bull.,2014;40(6):145261.,2. 阴性症状,1980年代的工作中心是区别原发性和继发性的,阴性症状,*，但临床上可以难以区分。,最近，NIMH的改善SCH认知的测量和治疗研究（MATRICS）将注意力转向,阴性症状,。,从治疗的角度来看，值得注意的是MATRICS共识声明引用了,持续的阴性症状,和表明显示原发性和继发性,阴性症状,之间的区别并不重要*。,* Carpenter Jr WT, Heinrichs DW, Wagman AM. Deficit and nondeficit forms of schizophrenia: the concept.,Am J Psychiatry,. 1988;145(5):57883.,* Kirkpatrick B, et al. The NIMH-MATRICS consensus statement on negative symptoms.,Schizophr Bull.,2006;32(2):2149.,阴性症状是什么？,域,描述性的词,翻译,沟通障碍,失语症,言语贫乏；如少言、寡语,情感障碍,情感迟钝,情绪(感知、体验和表达)范围减少；如感觉麻木或内心空虚、回忆一些情感体验，好或坏,社会化障碍,无社会性,社交动力和互动减少，例如性兴趣小、朋友很少、很少有兴趣花时间（或花很少的时间）交朋友,快乐能力障碍,快感缺乏,体验快乐的能力降低；如发现以前的爱好或兴趣虚妄,动机障碍,动机缺乏,欲望、动机、毅力减少；如承担和完成日常任务能力降低；可能有个人卫生不良,虽然有关,阴性与认知,（包括社会认知和神经认知）症状对,功能障碍,的相互关系和贡献的争论还在持续，但很明显，其影响是巨大的。,阳性症状,的解决，甚至在SCH的早期，未必意味着功能恢复；数据显示, 功能/社交完全恢复发生在不足15%的SCH患者，与,阴性症状,一起发挥重大作用,1,。,专注于SCH前驱症状的工作表明，精神病首次发作时,缺陷症状,和,认知损害,是明显的,2, 3,，在大约25-30 %慢性SCH患者已识别持久的原发性,阴性症状,4,。,1.Austin SF, et al. Predictors of recovery in first episode psychosis: the opus cohort at 10 year follow-up.,Schizophr Res,. 2013;150(1):1638.,2. Bora E, et al. Cognitive deficits in youth with familial and clinical high risk to psychosis: a systematic review and metaanalysis.,Acta Psychiatr Scand,. 2014;130(1):115.,3. Piskulic D, et al. Negative symptoms in individuals at clinical high risk of psychosis.,Psychiatry Res,. 2012;196(23):2204.,4. Kirkpatrick B, et al. A separate disease within the syndrome of schizophrenia .,Arch Gen Psychiatry,. 2001;58(2):16571.,3. 治疗,阴性症状,的本质影响有关的病理生理学和治疗。,阳性症状,是框入过度活动（如多巴胺亢奋）的背景,阴性症状,至少从历史上看,概念化为反映功能损失*,* Jackson JH. Selected writings. New York:,Basic Books,; 1958.,该定位对于区别,阳性,和,阴性症状,的早期工作极为重要，,阴性症状与神经系统结构的变化有关。,结果，假定这些特征将无法接受与,阳性症状,相同方式的药物治疗,1,。,这表示，,阴性症状,如何概念化已经稍微变化，众多的研究已经进行到基于,躯体化,以及,非躯体化干预,概念可能会影响所谓的原发性,阴性症状,的较好的改善。,1. Crow TJ. Molecular pathology of schizophrenia:more than one disease process?,Br Med J.,1980;280(6207):668.,对该主题兴趣和热情的程度反映在过去的2年中综述数量,1,2,3,46,。,1.Chue P, Lalonde JK. Addressing the unmet needs of patients with persistent negative symptoms of schizophrenia: emerging pharmacological treatment options.,Neuropsychiatr Dis Treat,. 2014;10:77789.,2. Davis MC, Horan WP, Marder SR. Psychopharmacology of the negative symptoms: current status and prospects for progress.,Eur Neuropsychopharmacol,. 2014;24(5):78899.,3. Fusar-Poli P, et al. Treatments of negative symptoms in schizophrenia: meta-analysis of 168 randomized,placebo-controlled trials.,Schizophr Bull,. 2015;41D4:8929.,This represents the largest meta-analysis of negative symptom treatment to date. Included are different pharmacotherapeutic agents, brain stimulation, and psychological interventions.,4. Millan MJ, et al. Negative symptoms of schizophrenia: clinical characteristics, pathophysiological substrates, experimental models and prospects for improved treatment.,Eur Neuropsychopharmacol.,2014;24(5):64592.,5. Moller HJ, Czobor P. Pharmacological treatment of negative symptoms in schizophrenia.,Eur Arch Psychiatry Clin Neurosci.,2015;265(7):56778.,6.Tsapakis EM, Dimopoulou T, Tarazi FI. Clinical management of negative symptoms of schizophrenia: an update.,Pharmacol Ther.,2015;153:13547.,根据精神病类药物（抗精神病药、抗抑郁药、CNS兴奋剂、抗癫痫药物）或突出的作用位点/机理（谷氨酸、乙酰胆碱、5-羟色胺、性激素、炎症免疫学）研究总结和更新。,还有脑刺激，尽管不是非躯体治疗 *。,最后，重要的是要强调，作为一个规则，这些不同的干预措施要伴随抗精神病治疗进行，除了涉及新型抗精神病药物的试验。,* Millan MJ, et al. Negative symptoms of schizophrenia: clinical characteristics, pathophysiological substrates, experimental models and prospects for improved treatment.,Eur Neuropsychopharmacol.,2014;24(5):64592.,* Tsapakis EM, Dimopoulou T, Tarazi FI. Clinical management of negative symptoms of schizophrenia: an update.,Pharmacol Ther.,2015;153:13547.,3.1 抗精神病药物,在1980年代确定,氯氮平,为难治性精神分裂症(TRS)的唯一抗精神病药物的开创性工作中，药物治疗确能影响,阴性症状,的概念获得了立足点。,所谓的非典型抗精神病药物（AAP），此后一直被视为共享相同的特性，包括那些最近研究的强调更新作用机制的药物,1,。,1.Lieberman JA, et al. ITI-007 for the treatment of schizophrenia: A 4-week randomized, double-blind, controlled trial.,Biol Psychiatry,. 2015 Aug 31,假定不同的理论解释非典型，包括5-HT2/D2 拮抗和从D2受体快速解离；最近，已经认定第三代药物 ，,阿立哌唑,的原型，特征是多巴胺部分激动性质,1,。,比较新型抗精神病药物的继续研究结果并不支持AAP之间治疗,阴性症状,的显著差异,24,。,1. Remington G. Understanding antipsychotic atypicality: a clinical and pharmacological moving target.,J Psychiatry Neurosci,. 2003;28(4):27584.,2. Harvey RC, et al. A systematic review and networkmeta-analysis to assess the relative efficacy of antipsychotics for the treatment of positive and negative symptoms in early-onset schizophrenia.,CNS Drugs,. 2016;30(1):2739.,3 Moosavi SM, et al. Comparison of quetiapine and risperidone in treatment of acute psychosis: a double-blind, randomized-controlled study.,Global J Health Sci,. 2015;7(5):41952.,4. Shoja Shafti S, Fallah JP. A comparative study between olanzapine and risperidone regarding drug-induced electrocardiographic changes.,Cardiovasc Psychiatry Neurol,. 2014;2014:637016.,迄今为止，包括几份最近的荟萃分析,1, 2,的证据，与其他早期的研究表明：,(a)新型抗精神病药物在,阴性症状,治疗方面不优于传统的药物,(b)无论哪种情况效果都是适度的,1. Fusar-Poli P, et al. Treatments of negative symptoms in schizophrenia: meta-analysis of 168 randomized,placebo-controlled trials.,Schizophr Bull.,2015;41D4:8929.,This represents the largest meta-analysis of negative symptom treatment to date. Included are different pharmacotherapeutic agents, brain stimulation, and psychological interventions.,2. Harvey RC, James AC, Shields GE. A systematic review and networkmeta-analysis to assess the relative efficacy of antipsychotics for the treatment of positive and negative symptoms in early-onset schizophrenia.,CNS Drugs.,2016;30(1):2739.,3.2 抗抑郁药,临床上区分,阴性,和,抑郁症状,是挑战，但许多文献积累了有关,抗抑郁药,治疗,阴性症状,的疗效。,该主题的荟萃分析很多，其中一些考虑将,抗抑郁药,作为一类特殊药物和/或以作用机制分组。,两个早期的荟萃分析分别提供模棱两可的证据,1,和缺乏支持,2,，然而最近的报告已经支持药物之间不同疗效的一些证据,3,。,1. Rummel C, Kissling W, Leucht S. Antidepressants for the negative symptoms of schizophrenia.,Cochrane Database Syst Rev,. 2006;3, CD005581.,2. Sepehry AA, Potvin S, Elie R, Stip E. Selective serotonin reuptake inhibitor (ssri) add-on therapy for the negative symptoms of schizophrenia: ameta-analysis.,J Clin Psychiatry,. 2007;68(4):60410.,3. Singh SP, Singh V, Kar N, Chan K. Efficacy of antidepressants in treating the negative symptoms of chronic schizophrenia: meta-analysis.,Br J Psychiatry,. 2010;197(3):1749.,尽管试验还在继续，但综述得出的证据不足以支持它们的使用,1,。,例如，一项最近评估,安非他酮,的12周安慰剂对照研究,2,未能确定临床效果 。,相反，一项,瑞波西汀,与安慰剂对照12周RCT,3,报告,瑞波西汀,治疗组强有力的效应值，不过，值得注意的是，研究的所有受试者都是正在用,氟哌啶醇,治疗的慢性患者 。,最近发表的仅对,米氮平荟,萃分析,4,得出结论，其展现了治疗,阴性症状,的疗效，但,阴性症状,不是结局指标。,1. Barnes TR, Paton C.Do antidepressants improve negative symptoms in schizophrenia?,BMJ,. 2011;342:d3371.,2. Yassini M, Shariat N, Nadi M, Amini F, Vafaee M. The effects of bupropion on negative symptoms in schizophrenia.,Iran J Pharm Res,. 2014;13(4):122733.,3. Shoja Shafti S, Jafarabad MS, Azizi R. Amelioration of deficit syndrome of schizophrenia by norepinephrine reuptake inhibitor.,Ther Adv Psychopharmacol,. 2015;5(5):26370.,4. Vidal C, Reese C, Fischer BA, Chiapelli J, Himelhoch S. Meta-analysis of efficacy of mirtazapine as an adjunctive treatment of negative symptoms in schizophrenia.,Clin Schizophr Relat Psychoses,. 2015;9(2):8895.,3.3 CNS兴奋剂,因为这类药物诱发或加剧,阳性症状,的风险，历史上被视为精神病患者的禁忌。,的确，在一段时间内，这类药物被用作对确认复发风险的挑战,1,。,同时使用抗精神病药物治疗似乎是这个论点的关键；例如共患SCH和ADHD的儿童接受抗精神病药物和精神兴奋剂的临床数据表明，这种联合与精神病的风险增加无关,2,。,对,阴性症状,及其治疗越来越关注重新燃起了对这类药物的兴趣，一项最近的专题综述提出了有益的证据，加上,阳性症状,最小和伴随抗精神病药物治疗的临床稳定的患者这种风险降低,3,。,1. Lieberman JA, Kane JM, Alvir J. Provocative tests with psychostimulant drugs in schizophrenia.,Psychopharmacology (Berl).,1987;91(4):41533.,2. Tossell JW, et al. Stimulant drug treatment in childhood-onset schizophrenia with comorbid ADHD: an open-label case series.,J Child Adolesc Psychopharmacol.,2004;14(3):44854.,3.Lindenmayer JP, et al. A systematic review of psychostimulant treatment of negative symptoms of schizophrenia: challenges and therapeutic opportunities.,Schizophr Res.,2013;147(23):24152.,早期的试验采用常规用于ADHD的药物（如,哌醋甲酯,、,右旋苯丙胺,），最近转向用于治疗过度镇静药物（,莫达非尼,、,阿莫达非尼,）试验。,值得注意的是，这些药物构成上述综述的重大贡献,1,；然而，一项最近的荟萃分析,2,报告,莫达非尼,或,阿莫达非尼,之间的差异 ，但效应值很小。,此外，后来另一项,莫达非尼,RCT,3,记录没有任何好处。,1.Lindenmayer JP, et al. A systematic review of psychostimulant treatment of negative symptoms of schizophrenia: challenges and therapeutic opportunities.,Schizophr Res.,2013;147(23):24152.,2. Andrade C,et al.Antipsychotic augmentation with modafinil or armodafinil for negative symptoms of schizophrenia:systematic review and meta-analysis of randomized controlled trials.,J Psychiatr Res,.2015;60:1421.,3. Shoja Shafti S, Akbari S. Intractability of deficit syndrome of schizophrenia against adjunctivemodafinil.,J Clin Psychopharmacol.,2016;36(1):459.,最近，,二甲磺酸赖右苯丙胺,(LDX，一种批准用于ADHD的苯丙胺药物前体)一直在研究其可能治疗SCH的,阴性症状,。,有利结果的发表是基于一项非盲、随机的撤药阶段试验,1,，证明LDX改善,阴性症状,和其突然停药没有,阳性,或,阴性症状,恶化迹象。,然而，后来试验被终止。,1 Lasser RA, et al. Adjunctive lisdexamfetamine dimesylate therapy in adult outpatients with predominant negative symptoms of schizophrenia: open-label and randomized-withdrawal phases.,Neuropsychopharmacology.,2013;38(11):21409.,3.4,抗癫痫药物,参考了其它综述,1,2,中这类药物对,阴性症状,的作用 。,像 ECT一样，这类药物有悠久的历史用于SCH以及特殊亚群（例如耐,氯氮平,、攻击）的增效,3,4,。,在这种背景下，,阴性症状,的改善是作为许多结果测量之一报告的，但没有对照研究专门检查抗癫痫药物对,阴性症状,本身的效用。,1.Chue P, Lalonde JK. Addressing the unmet needs of patients with persistent negative symptoms of schizophrenia: emerging pharmacological treatment options.,Neuropsychiatr Dis Treat.,2014;10:77789.,2.Tsapakis EM, et al. Clinical management of negative symptoms of schizophrenia: an update.,Pharmacol Ther.,2015;153:13547.,3. Citrome L. Unmet needs in the treatment of schizophrenia: new targets to help different symptom domains.,J Clin Psychiatry.,2014;75 Suppl 1:216.,4. Tiihonen J, Wahlbeck K, Kiviniemi V. The efficacy of lamotrigine in clozapine-resistant schizophrenia: a systematic review and meta-analysis.,Schizophr Res,. 2009;109(13):104.,3.5 谷氨酸,这是近年来获得了相当大的关注几个领域之一，不论,阴性症状,，还在,阳性,和,认知症状,1,。,对,阴性症状,，过去的20年已经评估了涉及既有,离子移变,的又有,代谢型受体,的大量药物。,不是特定于,阴性症状,的两项荟萃分析显示支持增强NMDA受体功能的药物（例如，,D-丝氨酸,、,肌氨酸,、,N-乙酰半胱氨酸,、,D-环丝氨酸,）的疗效虽然小但有利的信号 ，但药物之间的疗效不同,2,3,。,1. Goff DC. Drug development in schizophrenia: are glutamatergic targets still worth aiming at?,Curr Opin Psychiatry.,2015;28D3:20715.,A useful summary of the work done to date in this area, as well as discussion of future directions.,2. Singh SP, Singh V. Meta-analysis of the efficacy of adjunctive nmda receptor modulators in chronic schizophrenia.,CNS Drugs,. 2011;25(10):85985.,3. Tsai GE, Lin PY. Strategies to enhance n-methyl-daspartate receptor-mediated neurotransmission in schizophrenia, a critical review andmeta-analysis.,Curr Pharm Des,. 2010;16(5):52237.,最近，这种思路至少在某种程度上引起了对目前正在研究的其他药物的兴趣，它们对,阴性症状,有益。,虽然试验继续下去，到目前为止结果喜忧参半。,值得注意的是，去年发表的一篇论文对,d-丝氨酸,提供持续支持,1,， 而研究的几种药物在早期发展阶段就停止了，包括含甘氨酸转运体1 (GlyT1)抑制(如,bitopertin,),2,和代谢型谷氨酸受体2/3-阳性变构调节 (如,LY2140023,),3,通过不同机制发挥作用的药物。,命名为NMDA受体拮抗剂的药物也成为研究的主题,4,。,这再一次说明谷氨酸能系统的复杂性和通过不同的作用机制起效的药物之间的差异。,与这些策略有关的结果也一直模棱两可。,1. Kantrowitz JT, et al. D-serine for the treatment of negative symptoms in individuals at clinical high risk of schizophrenia: a pilot, double-blind, placebocontrolled, randomised parallel group mechanistic proof-of-concept trial.,Lancet Psychiatry.,2015;2(5):40312.,2. Umbricht D, et al. Effect of bitopertin, a glycine reuptake inhibitor, on negative symptoms of schizophrenia: a randomized, double-blind, proof-of-concept study.,JAMA Psychiatry,. 2014;71(6):63746.,3. Stauffer VL, et al. Pomaglumetad methionil: no significant difference as an adjunctive treatment for patients with prominent negative symptoms of schizophrenia compared to placebo.,Schizophr Res,. 2013;150(23):43441.,4. Kishi T, Iwata N. NMDA receptor antagonists interventions in schizophrenia: meta-analysis of randomized, placebo-controlled trials.,J Psychiatr Res,. 2013;47(9):11439.,bitopertin,和,LY2140023,的结果令人失望，导致对这种适应症的终止,1,2,。,至于NMDA受体拮抗剂，一项,金刚烷胺,和,美金刚,的荟萃分析,3,不支持在治疗,阴性症状,方面的效用，虽然焦点不是特别在,阴性症状,。,随后发表的一个观察,阴性症状,为主的RCT结果报告,4,，,美金刚,在8周时导致显著改善，有一个很大的效应值 (Cohens d=1.5 95%CI 0.82.22)。,Cohen1988年定义，d效应大小标准（解释）： d=0.2,小;d=0.5,中;d=1.0,大,1. Davis MC, Horan WP, Marder SR. Psychopharmacology of the negative symptoms: current status and prospects for progress.,Eur Neuropsychopharmacol,. 2014;24(5):78899.,2. Singer P, Dubroqua S, Yee BK. Inhibition of glycine transporter 1: the yellow brick road to new schizophrenia therapy?,Curr Pharm Des.,2015;21(26):377187.,3. Kishi T, Iwata N. NMDA receptor antagonists interventions in schizophrenia: meta-analysis of randomized, placebo-controlled trials.,J Psychiatr Res.,2013;47(9):11439.,4. Rezaei F, et al. Memantine add-on to risperidone for treatment of negative symptoms in patients with stable schizophrenia: randomized, double-blind, placebo-controlled study.,J Clin Psychopharmacol,. 2013;33(3):33642.,支持谷氨酸对SCH过程的关键作用的证据持续增长,1,2,，这也许可以解释为什么，在面对模棱两可的临床证据时，开发新的药物努力还在继续。,推动领域前进的建议包括评估其他受体、细胞内路径、疾病亚型以及疾病阶段和生物标记/内表型,3,48,。,虽然，这项工作并不只局限于对于,阴性症状,或事实上SCH的疗效 。,1. LaCrosse AL, et al. mGluR5 positive allosteric modulation and its effects on MK-801 induced set-shifting impairments in a rat operant delayed matching/non-matching-to-sample,task. Psychopharmacol (Berl).,2015;232(1):2518.,2. Ohgi Y, Futamura T, Hashimoto K. Glutamate signaling in synaptogenesis andNMDAreceptors as potential therapeutic targets for psychiatric disorders.,Curr Mol Med,. 2015;15(3):20621.,3. Goff DC.,Drug development in schizophrenia: are glutamatergic targets still worth aiming at,?,Curr Opin Psychiatry.,2015;28D3:20715.,A useful summary of the work done to date in this area, as well as discussion of future directions.,4. Ellaithy A, Younkin J, Gonzalez-Maeso J, Logothetis DE. Positive allosteric modulators of metabotropic glutamate 2 receptors in schizophrenia treatment.,Trends Neurosci.,2015;38(8):50616.,5. Li ML, Hu XQ, Li F, Gao WJ. Perspectives on the mGluR2/3 agonists as a therapeutic target for schizophrenia: still promising or a dead end?,Prog Neuropsychopharmacol Biol Psychiatry,. 2015;60:6676.,6. Matosin N, Fernandez-Enright F, Lum JS, Newell KA. Shifting towards a model of mGluR5 dysregulation in schizophrenia: consequences for future schizophrenia treatment.,Neuropharmacology,. 2015 Sep 6.,7. Wieronska JM, Zorn SH, Doller D, Pilc A.Metabotropic glutamate receptors as targets for new antipsychotic drugs: historical perspective and critical comparative assessment.,Pharmacol Ther,. 2016;157:1027.,8. Zink M, Correll CU. Glutamatergic agents for schizophrenia: current evidence and perspectives.,Expert Rev Clin Pharmacol.,2015;8(3):33552.,3.6 乙酰胆碱,正如谷氨酸能药物那样，该领域的兴趣不是特定于,阴性症状,；主要以,认知症状,作为主要疗效指标。,一项评估SCH的乙酰胆碱酯酶抑制剂（,卡巴拉汀,、,多奈哌齐,、,加兰他敏,）的早期的荟萃分析,1,指出选定的,认知,措施的改善，但不是,阴性症状,。,随后的一项荟萃分析,2,也主要关注,认知症状,，另外评估谷氨酸能和和5-羟色胺能受体。,注意到有适应于治疗阿尔茨海默病的两个药物,多奈哌齐,和,加兰他敏,，影响,阴性症状,；,两个药共享作为胆碱酯酶抑制剂的共同作用，而后者也是尼古丁乙酰胆碱受体的变构调制剂。,1. Ribeiz SR, Bassitt DP, Arrais JA, Avila R, Steffens DC, Bottino CM. Cholinesterase inhibitors as adjunctive therapy in patients with schizophrenia and schizoaffective disorder: a review and meta-analysis of the literature.,CNS Drugs,. 2010;24(4):30317.,2. Choi KH, Wykes T, Kurtz MM. Adjunctive pharmacotherapy for cognitive deficits in schizophrenia: metaanalytical investigation of efficacy,. Br J Psychiatry,. 2013;203(3):1728.,大约在同时，针对SCH的胆碱酯酶抑制剂一项循证综述，也提出了一个,阴性症状,改善的信号,1,；但,阴性症状,并不是结局指标。,结果的更复杂的解释是需要厘清在,阴性症状,评分的其他范畴变化的影响,2,，还有其它的药理作用；例如，已经报告,加兰他敏,通过其尼古丁乙酰胆碱受体的变构调节增强多巴胺神经传递,3,。,迄今为止，尚无涉及胆碱酯酶抑制剂的,阴性症状,是结局指标的RCTs的报告。,1. Singh J, Kour K, Jayaram MB. Acetylcholinesterase inhibitors for schizophrenia.,Cochrane Database Syst Rev.,2012;1, CD007967.,2. Choi KH, Wykes T, Kurtz MM. Adjunctive pharmacotherapy for cognitive deficits in schizophrenia: metaanalytical investigation of efficacy,. Br J Psychiatry,. 2013;203(3):1728,3. Schilstrom B, et al. Galantamine enhances dopaminergic neurotransmission in vivo via allosteric potentiation of nicotinic acetylcholine receptors.,Neuropsychopharmacology.,2007;32(1):4353.,努力还包括许多新的7烟碱乙酰胆碱受体(7nAChR）激动剂/部分受体激动剂以及正变构调节剂,14,。,不过，对此很难评估调查这条线的临床益处。,最近一项,加兰他敏,/,胞二磷胆碱,双盲试验,5,没有改善,阴性症状,，最近的7nAChR激动剂TC-5619的二期试验,6,也没有。,对此补充的是其它几个这样的药物的早期终止,7,。,1. Beinat C, et al. The therapeutic potential of 7 nicotinic acetylcholine receptor (7 nAChR) agonists for the treatment of the cognitive deficits associated with schizophrenia.,CNS Drugs,. 2015;29(7):52942.,2. Pohanka M. Alpha7 nicotinic acetylcholine receptor is a target in pharmacology and toxicology,. Int J Mol Sci.,2012;13(2):221938.,3. Uteshev VV. The therapeutic promise of positive allosteric modulation of nicotinic receptors.,Eur J Pharmacol,. 2014;727:1815.,4. Wallace TL, Bertrand D. Neuronal 7 nicotinic receptors as a target for the treatment of schizophrenia.,Int Rev Neurobiol,. 2015;124:79111.,5. Deutsch SI, et al. Targeting alpha-7 nicotinic neurotransmission in schizophrenia: a novel agonist strategy.,Schizophr Res,. 2013;148(13):13844.,6. Walling D, et al. Phase 2 trial of an alpha-7 nicotinic receptor agonist (TC-5619) in negative and cognitive symptoms of schizophrenia.,Schizophr Bull,. 2016;42(2):33543.,7.Chue P, Lalonde JK. Addressing the unmet needs of patients with persistent negative symptoms of schizophrenia: emerging pharmacological treatment options.,Neuropsychiatr Dis Treat.,2014;10:77789.,此外，还有可能造成任何影响的其他作用机制的问题；例如，临床前的证据已经显示EVP-614（也是7 nAChR激动剂）增加皮质ACh和谷氨酸的释放，并且这还符合于多巴胺,1,。,说句题外话，也有人报告，增加多巴胺和去甲肾上腺素的活性与,胞二磷胆碱,的实施有关,2,。,1. Huang M, Felix AR, Flood DG, Bhuvaneswaran C, Hilt D, Koenig G, et al. The novel 7 nicotinic acetylcholine receptor agonist EVP-6124 enhances dopamine, acetylcholine, and glutamate efflux in rat cortex and nucleus accumbens.,Psychopharmacol (Berl).,2014;231(23):454151.,2. Secades JJ, Frontera G. CDP-choline: pharmacological and clinical review.,Methods Find Exp Clin Pharmacol.,1995;17(Suppl B):154.,4. 5-羟色胺,随着早期断言AAP（氯氮平的原型）治疗,阴性症状,优于传统抗精神病药物，认为5 -HT拮抗可能证明治疗,阴性症状,是有用的势头大增,1,。,假定伴随的5-HT2拮抗对此起了一定的作用，反过来，导致选择性5-HT2拮抗剂开发，然后进一步研究治疗,阴性,（以及,阳性,）,症状,（如,利坦色林,、,M100907,）。,虽然几项,利坦色林,RCTs支持对这条线研究,2,3,，但最近的焦点已经转向选择性5-HT3拮抗剂（例如，,昂丹司琼,、,托烷司琼,、,格拉司琼,）。,1. Schmidt CJ, Sorensen SM, Kehne JH, Carr AA, Palfreyman MG. The role of 5-HT2A receptors in antipsychotic activity. Life Sci. 1995;56(25):220922.,2. Akhondzadeh S,et al.Effect of ritanserin, a 5HT2A/2C antagonist, on negative symptoms of schizophrenia:a double-blind randomized placebo controlled study.,Prog Neuropsychopharmacol Biol Psychiatry,.2008;32(8):187983.,3. Duinkerke SJ, et al. Ritanserin, a selective 5-HT2/1C antagonist, and negative symptoms in schizophrenia. A placebo-controlled double-blind trial.Br J Psychiatry. 1993;163:4515.,特别专注于,阴性症状,的几项试验已经支持它们的疗效,1,2,，,最近的一项荟萃分析虽然评估其对SCH的作用，但结果一样,3,。,70. Khodaie-Ardakani MR, et al. Granisetronas an add-on to risperidone for treatment ofnegative symptoms in patients with stable schizophrenia: randomized double-blind placebocontrolledstudy.,J Psychiatr Res.,2013;47(4):4728.,71. Noroozian M, et al. A placebo-controlled study of tropisetron added to risperidone for the treatment of negative symptoms in chronic and stable schizophrenia.,Psychopharmacol (Berl)