Cixutumumab

编者按：近年来，多肽疗法正迅速崛起为全球新药研发的重要方向。从GLP-1类代谢疾病疗法持续取得突破，到肿瘤、神经系统疾病及免疫疾病等领域不断涌现的新型多肽分子，多肽药物的研发版图正在不断拓展。在这一背景下，药明康德旗下WuXi TIDES平台围绕多肽、寡核苷酸及其相关化学偶联药物构建了一体化解决方案，覆盖定制合成、共价连接、工艺开发以及CMC等关键环节，助力创新项目更高效地推进至临床阶段。与此同时，药明康德生物分析部（BAS）依托成熟的技术平台，建立了覆盖药代动力学（PK）分析、抗药抗体（ADA）及中和抗体（NAb）评价的一体化生物分析解决方案，为复杂修饰多肽及偶联多肽药物的临床研究提供有力支持。而药明康德DMPK团队能够从机制层面解析多肽药物的ADME行为，并结合蛋白结合、渗透性及代谢产物鉴定研究，支持结构优化与递送策略设计。本文将盘点2026年第二季度全球多肽疗法在监管审批、临床研究以及产业合作等方面的重要进展，带您了解这一快速发展领域的最新动态与趋势。 监管进展 2026年第二季度，多肽疗法在多个疾病领域迎来重要监管进展。其中，吉利德科学（Gilead Sciences）旗下Hepcludex（bulevirtide）注射液获得美国FDA加速批准，用于治疗无肝硬化或代偿性肝硬化成人患者的慢性丁型肝炎病毒（HDV）感染。根据FDA新闻稿，Hepcludex是首款获得FDA批准用于治疗慢性HDV感染的疗法，也为这一长期缺乏获批疗法的病毒性肝炎领域带来新的治疗选择。该批准主要基于3期MYR301研究，结果显示，接受Hepcludex治疗的患者在第48周实现联合病毒学与生化应答的比例为48%，而延迟治疗组为2%。 在肥胖相关适应症方面，Rhythm Pharmaceuticals旗下Imcivree（setmelanotide）获得欧盟委员会批准，用于治疗因下丘脑损伤或功能障碍导致的获得性下丘脑性肥胖（HO）成人和4岁及以上儿童患者。此次欧盟批准主要基于3期TRANSCEND研究，Imcivree组患者在52周时身体质量指数（BMI）较基线平均下降16.5%，安慰剂组则上升3.3%，安慰剂校正后BMI降幅为19.8%。 胰高血糖素样肽-1（GLP-1）类疗法也继续推进给药方式创新。诺和诺德（Novo Nordisk）宣布，Wegovy片剂（每日一次口服司美格鲁肽25 mg）获得欧洲药品管理局（EMA）人用药品委员会（CHMP）推荐批准，用于减轻过多体重并维持长期减重效果。根据新闻稿，这是首个获得CHMP推荐用于体重管理的口服GLP-1疗法。在OASIS 4试验中，对于患有肥胖或伴有一种或多种合并症的超重成人受试者，在坚持治疗的情况下，每日一次口服司美格鲁肽25 mg显示出16.6%的平均体重减轻幅度。Wegovy片剂实现的减重效果与注射剂型Wegovy（2.4 mg）相似。 此外，艾伯维（AbbVie）与Ironwood Pharmaceuticals联合开发的Linzess（linaclotide）也在本季度获美国FDA批准扩展适应症，用于2岁及以上功能性便秘（FC）儿童患者。Linzess是一款鸟苷酸环化酶-C（GC-C）激动剂，此次批准基于一项在2至5岁FC儿童患者中开展的12周3期研究，结果显示每日一次linaclotide（72 μg）相较安慰剂可改善自发排便频率。 临床进展 在临床研究方面，肥胖与代谢疾病依然是第二季度多肽疗法活跃的方向。辉瑞（Pfizer）旗下超长效GLP-1受体激动剂berobenatide（曾用名MET-097i）在2b期VESPER-3研究中展现积极结果。部分患者从每周给药切换至每月给药后，至第28周仍实现最高12.3%的安慰剂校正后体重下降。 围绕GLP-1与其他肽类激素的联合机制，多家公司也取得临床进展。礼来（Eli Lilly and Company）公布其潜在“first-in-class”三重激素受体激动剂retatrutide的3期TRIUMPH-1研究结果。Retatrutide可同时靶向GIP、GLP-1和胰高血糖素受体。研究显示，在肥胖或伴有至少一种体重相关合并症的超重成人患者中，retatrutide 9 mg和12 mg组治疗80周后平均体重分别降低25.9%和28.3%，安慰剂组为2.2%；在104周延长期分析中，12 mg递增至最大耐受剂量组体重下降达到30.3%。 勃林格殷格翰（Boehringer Ingelheim）与Zealand Pharma合作开发的新型胰高血糖素/GLP-1双受体激动剂survodutide也公布了多项3期数据。SYNCHRONIZE-1研究显示，在不合并2型糖尿病的超重或肥胖成人患者中，survodutide治疗76周后平均体重最多下降16.6%。在该研究的亚组分析中，survodutide使内脏脂肪降低最高达34.0%，肝脏脂肪减少最高达63.1%，且瘦体重流失占比不超过10.8%。在代谢相关脂肪性肝病（MASLD）方面，SYNCHRONIZE-MASLD研究也达到共同主要终点。与基线相比，在接受survodutide治疗48周后，约60%同时患有MASLD且超重或肥胖的受试者实现了肝脏脂肪正常化。 罗氏（Roche）与Carmot Therapeutics开发的acmopatide（CT-868）是一款每日一次GLP-1/GIP双受体激动剂，在1型糖尿病合并超重或肥胖成人患者2期研究中，4.1 mg剂量组治疗16周后糖化血色蛋白（HbA1c）下降0.34个百分点，56%的患者HbA1c低于7%，体重下降呈剂量依赖性，最高约7%，胰岛素使用量最多减少15%。 与此同时，胰淀素靶向疗法也持续推进。诺和诺德旗下CagriSema（长效胰淀素类似物cagrilintide和司美格鲁肽组成的固定剂量联合疗法）在REIMAGINE系列3期研究中显示，该固定剂量联合疗法在2型糖尿病患者中可改善血糖控制并支持体重下降；其中REIMAGINE 3研究中，在接受基础胰岛素治疗且血糖控制不佳的2型糖尿病成人患者中，CagriSema使患者的HbA1c由8.8%降至6.5%，体重降低最高达12%，且未出现严重低血糖事件。而该公司开发的zenagamtide则是一款每周一次皮下注射的GLP-1与胰淀素受体肽类激动剂，在2型糖尿病成人患者2期研究中，40 mg剂量组在36周时HbA1c较基线下降1.71个百分点，体重下降最高达14.6%。 Zealand Pharma公布ZUPREME-1研究新数据，其与罗氏联合开发的每周一次胰淀素类似物petrelintide在42周时使超重或肥胖成人患者体重平均较基线最多降低10.7%，安慰剂组为1.7%，且总体胃肠道不良事件发生率与安慰剂接近。 除代谢疾病外，多肽疗法在肿瘤、神经损伤及内分泌疾病领域也不断拓展。在肿瘤领域，Sapience Therapeutics两款稳定化多肽疗法均公布临床数据。其C/EBPβ多肽拮抗剂lucicebtide联合标准治疗用于新确诊胶质母细胞瘤患者的2期研究显示，截至2026年4月，9名可评估患者的预计中位无进展生存期为28.4个月，而历史数据为4.0至6.9个月；ST316作为潜在“first-in-class”的β-catenin拮抗剂，在二线转移性结直肠癌患者2期扩展研究中与FOLFIRI加贝伐珠单抗联合使用，15名患者中确认客观缓解率为47%，疾病控制率为93%。此外，Oxford Vacmedix宣布其基于重组重叠肽（ROP）平台开发的癌症疫苗疗法OVM-200完成1期研究，并达到安全性主要终点及免疫应答、剂量选择等次要终点。试验还报告了早期的临床活性迹象，包括在非小细胞肺癌（NSCLC）患者中观察到的疾病稳定，以及在前列腺癌患者中观察到的前列腺特异性抗原（PSA）应答。 NervGen Pharma也宣布，已就其神经修复肽NVG-291的RESTORE临床3期注册研究设计与美国FDA达成一致，计划在慢性四肢瘫患者中开展一项纳入约150名受试者的随机、双盲、安慰剂对照研究。 在内分泌疾病方面，MBX Biosciences公布每周一次甲状旁腺激素（PTH）替代疗法canvuparatide治疗慢性甲状旁腺功能减退症患者的2期研究及开放标签延长期一年数据。结果显示，治疗一年时57%的可评估患者达到应答标准，血钙维持在正常范围，24小时尿钙下降并保持在正常范围内，肾功能指标估算肾小球滤过率（eGFR）较基线改善并维持至一年；公司表示3期关键性研究计划于2026年第三季度启动。 研发合作与融资进展 第二季度，多肽疗法相关公司在资本市场和战略合作方面同样活跃。Parabilis Medicines与再生元（Regeneron Pharmaceuticals）达成战略研发合作，双方将基于Parabilis的Helicon多肽平台开发多种候选疗法，重点探索抗体-Helicon偶联物（AHC）。根据协议，Parabilis将获得1.25亿美元，包括5000万美元首付款和7500万美元股权投资承诺，并有资格获得最高约22亿美元潜在里程碑付款等款项。同一季度，Parabilis完成扩大规模的首次公开募股（IPO），募集资金总额为6.70亿美元。与此同时，Kailera Therapeutics也在本季度完成IPO，募集资金总额约为6.25亿美元。这两家公司在本季度完成大额IPO，显示产业界对于多肽疗法在各治疗领域应用的持续信心。 融资方面，ReAlta Life Sciences完成超额认购的4000万美元融资，用于推进主打疗法pegtarazimod治疗新生儿缺氧缺血性脑病（HIE）的2期STAR研究及后续监管里程碑。Pegtarazimod是一种由15个氨基酸组成的潜在“first-in-class”多肽疗法，可同时靶向补体激活和中性粒细胞相关炎症通路。MultiValent Biotherapies则完成2742.5万美元A轮融资，所获资金将支持其主打疗法MVB-101的临床开发。MVB-101是一种前列腺特异性膜抗原（PSMA）和叶酸受体α（FRα）双靶向多肽偶联药物，携带单甲基奥瑞他汀E（MMAE）载荷，分子大小约为传统抗体偶联药物（ADC）的1/50。 总体来看，2026年第二季度多肽疗法行业延续了第一季度的高活跃度。一方面，HDV、获得性下丘脑性肥胖、儿童功能性便秘等适应症迎来监管突破；另一方面，肥胖和代谢疾病仍是创新最密集的领域，双重与三重受体激动剂、超长效GLP-1和胰淀素类似物不断拓展疗效上限，并提高给药便利性。与此同时，稳定化多肽、肽类药物偶联物和肽类疫苗正在将多肽疗法的边界推向肿瘤、神经修复和罕见内分泌疾病。随着更多后期临床研究和大型合作落地，多肽疗法正在从代谢疾病核心阵地，逐步走向更广泛的疾病治疗场景。 在多肽药物不断迈向复杂结构与精准调控的新阶段，如何高效、准确地识别其体内代谢产物，已成为影响分子优化与临床转化的重要环节。由于多肽易发生蛋白水解酶介导的逐步降解，并产生大量结构高度相似的代谢片段，传统分析策略往往难以实现全面解析。围绕这一挑战，药明康德DMPK团队构建了面向多肽药物的系统化代谢产物鉴定（MetID）平台，通过高分辨液相色谱-质谱（LC-HRMS）技术与数据分析工具的深度结合，实现多肽代谢产物的精准发现与结构解析。研究显示，多肽代谢产物鉴定不仅能够在非临床阶段识别代谢软点，指导分子结构优化，还可在后期研究中支持安全性评估与临床代谢研究决策，是贯穿药物开发全周期的关键研究内容。 依托自主开发的TidesID及相关数据解析工具，药明康德DMPK能够对复杂质谱数据进行高效解读，通过靶向与非靶向分析相结合的策略，系统识别体外与体内样品中的未知代谢物，并解析其降解路径与转化机制。该平台结合多维数据处理技术，如背景扣除、质量亏损过滤及特征离子提取，实现软件算法与专家经验协同分析，从而显著提升代谢产物发现的完整性与准确性。与此同时，团队可在多种生物基质与研究体系中开展代谢研究，建立从代谢路径解析到结构优化反馈的闭环研究流程，为研发团队提供具有机制深度的数据支持。 通过将先进分析技术、专用算法工具与丰富的多肽DMPK经验相结合，药明康德DMPK团队能够系统揭示多肽在体内的降解规律与关键代谢特征，帮助研发人员更早识别影响稳定性与暴露水平的关键因素，从而加速候选分子的优化与开发推进，为下一代多肽药物研发提供坚实的科学支持。  Semaglutide Recommended for Approval in the EU; New Chronic HDV Therapy Receives FDA Accelerated Approval… Editor’s Note: In recent years, peptide therapeutics have rapidly emerged as an important area of global drug discovery. From continued breakthroughs in GLP-1-based therapies for metabolic diseases to the emergence of novel peptide molecules in oncology, neurological disorders, immunology, and other therapeutic areas, the development landscape for peptide medicines continues to expand. Against this backdrop, WuXi AppTec’s WuXi TIDES platform has built an integrated solution for peptides, oligonucleotides, and related chemically conjugated molecules, covering key areas such as custom synthesis, covalent conjugation, process development, and CMC, helping innovative programs advance more efficiently toward the clinic. At the same time, WuXi AppTec’s Bioanalytical Services (BAS) team has established an integrated bioanalytical solution supported by a mature technology platform, covering pharmacokinetic (PK) analysis, anti-drug antibody assessment, and neutralizing antibody evaluation, providing strong support for clinical studies of complex modified peptides and peptide conjugates. WuXi AppTec’s DMPK team can also analyze the ADME behavior of peptide drugs at the mechanistic level and support structural optimization and delivery strategy design through protein binding, permeability, and metabolite identification studies. This article reviews key global advances in peptide therapeutics in the second quarter of 2026 across regulatory approvals, clinical research, and industry collaborations to provide an update on the latest dynamics and trends in this rapidly evolving field. Regulatory Progress In the second quarter of 2026, peptide therapeutics achieved important regulatory progress across multiple disease areas. Notably, Gilead Sciences’ Hepcludex (bulevirtide) injection received accelerated approval from the U.S. FDA for the treatment of chronic hepatitis D virus (HDV) infection in adults without cirrhosis or with compensated cirrhosis. According to the FDA press release, Hepcludex is the first FDA-approved therapy for chronic HDV infection, bringing a new treatment option to a viral hepatitis field that has long lacked approved therapies. The approval was primarily based on the Phase 3 MYR301 study, which showed that 48% of patients receiving Hepcludex achieved a combined virologic and biochemical response at Week 48, compared with 2% in the delayed-treatment group. In obesity-related indications, Rhythm Pharmaceuticals’ Imcivree (setmelanotide) received European Commission (EC) approval for the treatment of adults and children aged 4 years and older with acquired hypothalamic obesity (HO) caused by hypothalamic injury or dysfunction. The EU approval was primarily based on the Phase 3 TRANSCEND study, in which patients treated with Imcivree achieved a mean body mass index (BMI) reduction of 16.5% from baseline at Week 52, while the placebo group showed a 3.3% increase, representing a placebo-adjusted BMI reduction of 19.8%. Glucagon-like peptide-1 (GLP-1) therapies also continued to advance innovation in dosing routes. Novo Nordisk announced that the Wegovy pill, once-daily oral semaglutide 25 mg, was recommended for approval by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) for reducing excess body weight and maintaining long-term weight reduction. According to the company, this is the first oral GLP-1 therapy to receive a CHMP recommendation for weight management. In the OASIS 4 trial, once-daily oral semaglutide 25 mg demonstrated an average body weight reduction of 16.6% among adults with obesity or overweight with one or more comorbidities who adhered to treatment. The weight loss achieved with the Wegovy pill was similar to that observed with the injectable formulation of Wegovy (2.4 mg). In addition, Linzess (linaclotide), jointly developed by AbbVie and Ironwood Pharmaceuticals, received FDA approval in the second quarter for an expanded indication in pediatric patients aged 2 years and older with functional constipation (FC). Linzess is a guanylate cyclase-C (GC-C) agonist. The approval was based on a 12-week Phase 3 study in pediatric patients aged 2 to 5 years with FC, which showed that once-daily linaclotide 72 μg improved the frequency of spontaneous bowel movements compared with placebo. Clinical Progress In clinical research, obesity and metabolic diseases remained active areas for peptide therapeutics in the second quarter. Pfizer’s ultra-long-acting GLP-1 receptor agonist berobenatide, formerly known as MET-097i, showed positive results in the Phase 2b VESPER-3 study. After some patients switched from once-weekly to once-monthly dosing, the therapy still achieved a placebo-adjusted body weight reduction of up to 12.3% at Week 28. Multiple companies also reported clinical progress around mechanisms combining GLP-1 with other peptide hormones. Eli Lilly and Company announced Phase 3 TRIUMPH-1 results for retatrutide, its potential first-in-class triple hormone receptor agonist. Retatrutide simultaneously targets GIP, GLP-1, and glucagon receptors. The study showed that among adults with obesity or overweight with at least one weight-related comorbidity, patients treated with retatrutide 9 mg and 12 mg achieved average body weight reductions of 25.9% and 28.3%, respectively, after 80 weeks of treatment, compared with 2.2% in the placebo group. In an extension analysis through 104 weeks, the group escalated from 12 mg to the maximum tolerated dose achieved a body weight reduction of 30.3%. Survodutide, a novel glucagon/GLP-1 dual receptor agonist jointly developed by Boehringer Ingelheim and Zealand Pharma, also reported multiple Phase 3 datasets. The SYNCHRONIZE-1 study showed that among adults with overweight or obesity without type 2 diabetes, treatment with survodutide for 76 weeks led to an average body weight reduction of up to 16.6%. In a subgroup analysis of the study, survodutide reduced visceral fat by up to 34.0% and liver fat by up to 63.1%, while lean mass loss accounted for no more than 10.8%. In metabolic dysfunction-associated steatotic liver disease (MASLD), the SYNCHRONIZE-MASLD study also met its co-primary endpoints. Compared with baseline, approximately 60% of participants with MASLD and overweight or obesity achieved liver fat normalization after 48 weeks of survodutide treatment. Acmopatide (CT-868), developed by Roche and Carmot Therapeutics, is a once-daily GLP-1/GIP dual receptor agonist. In a Phase 2 study of adults with type 1 diabetes and overweight or obesity, the 4.1 mg dose group achieved a 0.34% reduction in HbA1c after 16 weeks of treatment; 56% of patients achieved HbA1c below 7%, body weight decreased in a dose-dependent manner, by up to approximately 7%, and insulin use was reduced by up to 15%.  At the same time, amylin-targeted therapies continued to advance. Novo Nordisk’s CagriSema, a fixed-dose combination therapy consisting of the long-acting amylin analog cagrilintide and semaglutide, showed in the Phase 3 REIMAGINE program that the combination could improve glycemic control and support body weight reduction in patients with type 2 diabetes. In the REIMAGINE 3 study, among adults with type 2 diabetes inadequately controlled on basal insulin, CagriSema reduced HbA1c from 8.8% to 6.5%, achieved body weight reduction of up to 12%, and was not associated with severe hypoglycemia. Zenagamtide, also developed by Novo Nordisk, is a once-weekly subcutaneous GLP-1 and amylin receptor peptide agonist. In a Phase 2 study in adults with type 2 diabetes, the 40 mg dose group achieved a 1.71% reduction in HbA1c from baseline at Week 36 and body weight reduction of up to 14.6%. Petrelintide, Zealand Pharma’s once-weekly amylin analog co-developed with Roche, reduced body weight by up to 10.7% at Week 42 in adults with overweight or obesity, compared with 1.7% in the placebo group, while the overall incidence of gastrointestinal adverse events was similar to that observed with placebo. Beyond metabolic diseases, peptide therapeutics are also expanding into oncology, neural repair, and endocrine disorders. In oncology, Sapience Therapeutics reported clinical data for two stabilized peptide therapies. Its C/EBPβ peptide antagonist lucicebtide, in combination with standard of care for newly diagnosed glioblastoma, showed in a Phase 2 study that, as of April 2026, the estimated median progression-free survival among nine evaluable patients was 28.4 months, compared with historical data of 4.0 to 6.9 months. ST316, a potential first-in-class β-catenin antagonist, was evaluated in combination with FOLFIRI plus bevacizumab in a Phase 2 expansion study in second-line metastatic colorectal cancer. Among 15 patients, the confirmed objective response rate was 47%, and the disease control rate was 93%. In addition, Oxford Vacmedix announced that OVM-200, a cancer vaccine therapy developed based on its recombinant overlapping peptide (ROP) platform, completed a Phase 1 study and met its primary safety endpoint as well as secondary endpoints related to immune response and dose selection. The trial also reported early signs of clinical activity, including stable disease observed in patients with non-small cell lung cancer (NSCLC) and prostate-specific antigen (PSA) responses observed in patients with prostate cancer. NervGen Pharma also announced that its neural repair peptide NVG-291 had reached alignment with the FDA on the design of RESTORE, a Phase 3 registrational study. The company plans to conduct a randomized, double-blind, placebo-controlled study in approximately 150 patients with chronic tetraplegia. In endocrine disorders, MBX Biosciences announced one-year data from a Phase 2 study and open-label extension of canvuparatide, its once-weekly parathyroid hormone (PTH) replacement therapy, in patients with chronic hypoparathyroidism. The results showed that 57% of evaluable patients met the response criteria at one year, serum calcium levels were maintained within the normal range, 24-hour urinary calcium decreased and remained within the normal range, and estimated glomerular filtration rate (eGFR), a marker of kidney function, improved from baseline and was maintained through one year. The company stated that a pivotal Phase 3 study is planned to start in the third quarter of 2026. Partnerships and Financing In the second quarter, companies developing peptide therapeutics were also active in capital markets and strategic collaborations. Parabilis Medicines entered into a strategic R&D collaboration with Regeneron Pharmaceuticals. The two companies will develop multiple therapeutic candidates based on Parabilis’ Helicon peptide platform, with a focus on exploring Antibody-Helicon Conjugates (AHCs). Under the agreement, Parabilis will receive $125 million, including a $50 million upfront payment and a $75 million equity investment commitment, and will be eligible to receive up to approximately $2.2 billion in potential milestone payments and other consideration. In the same quarter, Parabilis completed an upsized initial public offering (IPO), raising gross proceeds of $670 million. Meanwhile, Kailera Therapeutics also completed its IPO in the second quarter, raising gross proceeds of approximately $625 million. The successful IPOs of these two companies highlight continued industry confidence in the potential application of peptide therapeutics across multiple therapeutic areas. Meanwhile, ReAlta Life Sciences closed an oversubscribed $40 million financing round to advance the Phase 2 STAR study of its lead candidate pegtarazimod for hypoxic ischemic encephalopathy (HIE), as well as subsequent regulatory milestones. Pegtarazimod is a potential first-in-class peptide therapy composed of 15 amino acids and is designed to target both complement activation and neutrophil-associated inflammatory pathways. MultiValent Biotherapies also completed a $27.425 million Series A financing round, with proceeds supporting the clinical development of its lead candidate MVB-101. MVB-101 is a prostate-specific membrane antigen (PSMA) and folate receptor alpha (FRα) dual-targeting peptide-drug conjugate carrying a monomethyl auristatin E (MMAE) payload, with a molecular size approximately one-fiftieth that of a conventional antibody-drug conjugate (ADC). Overall, the peptide therapeutics industry sustained strong momentum in the second quarter of 2026. On the one hand, indications such as HDV infection, acquired hypothalamic obesity, and pediatric functional constipation achieved important regulatory breakthroughs. On the other hand, obesity and metabolic diseases remained among the most innovation-intensive areas, with dual and triple receptor agonists, ultra-long-acting GLP-1 therapies, and amylin analogs continuing to expand the boundaries of efficacy and dosing convenience. Meanwhile, stabilized peptides, peptide-drug conjugates, and peptide vaccines are pushing the boundaries of peptide therapeutics into oncology, neural repair, and rare endocrine diseases. As more late-stage clinical studies and major collaborations move forward, peptide therapeutics are expanding from their core position in metabolic diseases into a broader range of therapeutic settings. As peptide therapeutics continue to gain momentum across metabolic diseases, oncology, and rare disorders, comprehensive characterization of their drug metabolism and pharmacokinetics (DMPK) properties has become essential for successful development. Unlike traditional small molecules, peptide drugs are highly susceptible to enzymatic degradation, often exhibit tissue-specific metabolism, and may demonstrate rapid clearance or complex exposure–response relationships. Addressing these modality-specific challenges requires specialized experimental design and integrated analytical capabilities. WuXi AppTec DMPK team has established a dedicated platform for peptide drug characterization that combines mechanistic understanding with scalable testing infrastructure, enabling systematic evaluation of peptide ADME properties from early discovery through IND-enabling stages. At the core of this capability is a comprehensive in vitro metabolic stability assessment framework designed to evaluate peptide degradation across biologically relevant matrices. The platform supports studies in multiple tissues and enzyme systems to model how peptides behave under physiologically relevant conditions, helping researchers identify dominant metabolic pathways and understand how sequence design, chemical modification, or formulation strategies influence stability and exposure. These studies generate actionable insights that guide molecular optimization and candidate selection while reducing downstream development risk. Complementary in vivo pharmacokinetic studies further characterize distribution, clearance mechanisms, and systemic exposure profiles, allowing teams to establish a translational PK understanding early in development. WuXi AppTec integrates advanced bioanalytical technologies with cross-disciplinary expertise spanning peptide chemistry, metabolism science, and quantitative pharmacokinetics. WuXi AppTec DMPK team supports metabolite identification, tissue distribution analysis, and exposure–efficacy interpretation, enabling a holistic understanding of peptide disposition. Automated workflows and standardized methodologies ensure data consistency while maintaining flexibility to address diverse peptide modalities, including modified peptides, long-acting analogs, and conjugated formats. By connecting mechanistic ADME insights with development decision-making, WuXi AppTec’s peptide DMPK platform helps partners address common challenges such as short half-life, proteolytic instability, and variability across species models. The result is a plug-and-play capability that can seamlessly support multiple development programs, providing reliable data to inform design optimization, safety assessment, and clinical translation strategies. Through integrated scientific expertise and global operational scale, WuXi AppTec DMPK team enables peptide innovators to move more confidently from molecular concept to development-ready candidate, accelerating the advancement of next-generation peptide therapeutics. 参考资料： [1] 各家公司新闻稿 免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 版权说明：欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。 分享，点赞，在看，聚焦全球生物医药健康创新

可增强动机、改善执行功能的抗抑郁药物研究进展（截至2026年） 一、核心病理基础：动机/执行功能受损的递质环路 抑郁动机缺损（快感缺失、行动无力、努力回避）、执行功能损害（工作记忆、抑制控制、认知灵活性、计划决策）核心环路：腹侧纹状体-前额叶多巴胺奖赏通路、前额叶去甲肾上腺素、谷氨酸、多5-HT受体协同失衡。传统SSRIs仅上调5-HT，对多巴胺/去甲肾上腺素提升弱，仅能间接改善情绪，无法直接修复动机与执行功能，大量患者情绪缓解后仍残留行动、认知残障 。当前研发与临床主流方向：多靶点、多巴胺/去甲肾上腺素增强、谷氨酸调控、σ1受体、快速起效致幻类衍生物。 二、一线口服抗抑郁药（单药首选，兼具动机+执行获益） 1. 伏硫西汀（Vortioxetine）——循证最强改善执行功能药物 机制 5-HT转运体抑制+多受体调节（5-HT1A激动、5-HT1B部分激动、5-HT3/7/1D拮抗），间接提升前额叶多巴胺、去甲肾上腺素、胆碱能、谷氨酸传递，修复脑类淋巴系统与默认网络功能，认知获益独立于情绪改善 。 动机/执行功能证据（2024–2026荟萃分析） 1. FOCUS、CONNECT等多中心RCT：唯一显著优于安慰剂改善全部执行维度：工作记忆、转换、抑制控制、信息加工速度、言语流畅性；优于艾司西酞普兰、度洛西汀  。2. 动机：减轻情感麻木、目标驱动缺失，降低“努力回避”行为，对职场、学业功能恢复优势突出 。3. 国内2025脑影像研究：修复前额叶-纹状体功能连接，改善认知相关脑网络同步性。 适用人群 抑郁伴显著认知迟缓、执行力差、动力不足、中青年职场人群；难治性抑郁维持治疗。 2. 安非他酮（Bupropion）——多巴胺/去甲肾上腺素再摄取抑制剂，动机首选单药 机制 阻断DAT、NET，不作用5-HT，直接提升奖赏环路多巴胺，逆转动机性快感缺失（wanting缺损），提升觉醒与精力储备 。 临床进展 1. 2025系统综述：对动机缺乏、精神运动迟滞、疲劳疗效显著优于SSRIs；对执行功能（计划、主动性）中度改善，尤其伴嗜睡、无欲、拖延患者 。2. 增效方案：SSRI基础上联用安非他酮，抵消SSRI所致情感麻木、动力下降，显著提升奖赏追求行为。 局限 单纯记忆、认知灵活性改善弱于伏硫西汀；焦虑严重者单用易激惹。 3. 阿戈美拉汀（Agomelatine） 机制 MT1/MT2激动、5-HT2C拮抗，解除5-HT2C对多巴胺/去甲肾上腺素释放的抑制，同步调节昼夜节律。 获益 改善抑郁昼夜节律紊乱伴随的日间动力不足、执行启动困难；提升前额叶多巴胺释放，轻度改善认知灵活性；对失眠合并动机缺损人群优势明显 。 4. 左旋米那普仑（Levomilnacipran，SNRI高选择性NET抑制） 强效提升去甲肾上腺素，轻度多巴胺上调；改善加工速度、持续注意力、精力；对迟滞型抑郁动力、执行有中等获益，但认知改善证据弱于伏硫西汀 。 三、增效辅助药物（标准抗抑郁基础上联用，强化动机+执行） 1. 依匹哌唑（Brexpiprazole，D2/5-HT1A部分激动） 最新研究（2025–2026） 低剂量增效一线药物，区别于阿立哌唑： - 低剂量下偏向D2部分激动，增强腹侧纹状体多巴胺奖赏信号，改善努力驱动动机、决策执行；- RCT证实显著缓解难治性抑郁快感缺失、行动退缩，工作记忆、抑制控制同步提升；- 对比阿立哌唑：阿立哌唑在低多巴胺状态下易表现D2拮抗，加重努力回避；依匹哌唑更稳定改善动机缺损 。 指南定位 难治抑郁伴持久动机缺失、执行损害首选增效剂。 2. 低剂量中枢兴奋剂（哌甲酯、安非他明） 循证进展2025 强效、快速改善执行（注意力、工作记忆、计划）与动机，效应量高于所有口服抗抑郁药，起效数天；适用于重度执行缺损、难治性迟滞抑郁、共病ADHD抑郁。 局限 成瘾风险、血压心率升高、长期疗效不稳定，仅二线短期增效。 3. 左旋多巴/卡比多巴（L-DOPA） 2025 Brain专项研究：高炎症抑郁（CRP＞2mg/L） 单用/联用可增强腹侧纹状体-前额叶奖赏环路连接，1周即可提升目标追求动机；对炎症介导的动力衰竭亚型特异性有效，为分层精准治疗标志物提供依据  。 4. 丁螺环酮/坦度螺酮（5-HT1A部分激动） 2025系统综述：SSRI联用坦度螺酮，显著提升言语流畅、转换执行功能；改善抑郁伴焦虑型主动性下降，温和提升动机，无镇静副作用 。 四、快速起效新型药物（谷氨酸通路，快速逆转动机/执行缺损） 1. 氯胺酮/艾司氯胺酮（鼻喷） 机制 NMDA受体拮抗，快速上调前额叶多巴胺、AMPA受体，重塑突触连接，快速修复奖赏环路与执行网络。 2026临床进展 1. 单次给药24–72小时内显著改善动机性快感缺失、执行决策、主动性；传统口服药需4–6周起效。2. 动物实验证实：逆转多巴胺耗竭所致努力回避行为，恢复高奖励付出意愿；长期间歇治疗可持续改善认知与动力残障。3. 适用：难治抑郁、自杀意念、重度动力瘫痪。 短板 解离副作用、成瘾潜力、需院内给药，维持需口服药物巩固。 2. 致幻类衍生物（Psilocybin、DMT，临床II/III期） 2026预临床与II期数据：单次给药持久修复神经发生，持续改善奖赏动机、执行灵活性；优于氟西汀慢性给药，可长期缓解无欲、认知迟缓；目前仅临床试验阶段，未获批常规使用。 3. Sigma-1受体激动剂（新型靶点，临床I/II期） 2024军事医学综述：σ1激动剂调节内质网稳态、谷氨酸-多巴胺交叉通路，快速抗抑郁、提升工作记忆与动机，副作用低，无成瘾性，新一代口服候选药物研发热点，多款进入II期临床 。 五、多巴胺通路老药新用（MAO-B抑制剂） 司来吉兰、雷沙吉兰：抑制多巴胺降解，提升纹状体多巴胺；帕金森合并抑郁、迟滞型难治抑郁，显著减轻淡漠、行动无力，改善基于努力的决策任务；2025分层研究提示纹状体DAT高表达患者获益更强。 六、各类药物动机+执行功能疗效对比总结 1. 综合执行（工作记忆/转换/抑制）最优：伏硫西汀（唯一多项RCT证实独立认知获益）2. 单纯动机、精力、快感缺失最优单药：安非他酮3. 难治抑郁增效首选：依匹哌唑（优于阿立哌唑）4. 快速起效、重度动力瘫痪：艾司氯胺酮鼻喷5. 炎症型抑郁动机缺损：左旋多巴联用6. 短期重度执行缺损补救：低剂量哌甲酯（二线）7. 节律紊乱+动力不足：阿戈美拉汀 七、2026前沿研究热点与未来方向 1. 精准分层给药：依据外周炎症标志物（CRP）、纹状体DAT显像，区分多巴胺缺损亚型，针对性使用L-DOPA、MAO-B抑制剂；2. 多靶点复方研发：5-HT调节+多巴胺增强复合分子，兼顾情绪、认知、动机，规避单一递质药物短板；3. σ1受体、mGlu2/3拮抗剂：新一代非单胺靶点，快速改善认知动机，无传统抗抑郁性功能、体重副作用；4. 长效缓释多巴胺能制剂：减少兴奋剂滥用风险，长期维持执行与动机改善；5. 联合策略标准化：伏硫西汀+安非他酮、SSRI+依匹哌唑成为难治抑郁伴认知动机损害标准化增效方案。 八、临床关键局限 1. 多数药物仅中度改善，无法完全逆转慢性抑郁长期脑环路损伤；2. 部分药物存在剂量依赖性：低剂量依匹哌唑改善动机，高剂量反而抑制奖赏；阿立哌唑不推荐用于单纯抑郁动机缺损；3. 长期安全性数据（致幻剂、L-DOPA、兴奋剂）仍缺乏大样本5年以上随访；4. 认知、动机评估工具尚未统一，临床主观感受与客观神经心理测验存在差异。 可增强动机、改善执行功能的抗抑郁药物研究进展（截至2026年） 一、核心病理基础：动机/执行功能受损的递质环路 抑郁动机缺损（快感缺失、行动无力、努力回避）、执行功能损害（工作记忆、抑制控制、认知灵活性、计划决策）核心环路：腹侧纹状体-前额叶多巴胺奖赏通路、前额叶去甲肾上腺素、谷氨酸、多5-HT受体协同失衡。传统SSRIs仅上调5-HT，对多巴胺/去甲肾上腺素提升弱，仅能间接改善情绪，无法直接修复动机与执行功能，大量患者情绪缓解后仍残留行动、认知残障 。当前研发与临床主流方向：多靶点、多巴胺/去甲肾上腺素增强、谷氨酸调控、σ1受体、快速起效致幻类衍生物。 二、一线口服抗抑郁药（单药首选，兼具动机+执行获益） 1. 伏硫西汀（Vortioxetine）——循证最强改善执行功能药物 机制 5-HT转运体抑制+多受体调节（5-HT1A激动、5-HT1B部分激动、5-HT3/7/1D拮抗），间接提升前额叶多巴胺、去甲肾上腺素、胆碱能、谷氨酸传递，修复脑类淋巴系统与默认网络功能，认知获益独立于情绪改善 。 动机/执行功能证据（2024–2026荟萃分析） 1. FOCUS、CONNECT等多中心RCT：唯一显著优于安慰剂改善全部执行维度：工作记忆、转换、抑制控制、信息加工速度、言语流畅性；优于艾司西酞普兰、度洛西汀  。2. 动机：减轻情感麻木、目标驱动缺失，降低“努力回避”行为，对职场、学业功能恢复优势突出 。3. 国内2025脑影像研究：修复前额叶-纹状体功能连接，改善认知相关脑网络同步性。 适用人群 抑郁伴显著认知迟缓、执行力差、动力不足、中青年职场人群；难治性抑郁维持治疗。 2. 安非他酮（Bupropion）——多巴胺/去甲肾上腺素再摄取抑制剂，动机首选单药 机制 阻断DAT、NET，不作用5-HT，直接提升奖赏环路多巴胺，逆转动机性快感缺失（wanting缺损），提升觉醒与精力储备 。 临床进展 1. 2025系统综述：对动机缺乏、精神运动迟滞、疲劳疗效显著优于SSRIs；对执行功能（计划、主动性）中度改善，尤其伴嗜睡、无欲、拖延患者 。2. 增效方案：SSRI基础上联用安非他酮，抵消SSRI所致情感麻木、动力下降，显著提升奖赏追求行为。 局限 单纯记忆、认知灵活性改善弱于伏硫西汀；焦虑严重者单用易激惹。 3. 阿戈美拉汀（Agomelatine） 机制 MT1/MT2激动、5-HT2C拮抗，解除5-HT2C对多巴胺/去甲肾上腺素释放的抑制，同步调节昼夜节律。 获益 改善抑郁昼夜节律紊乱伴随的日间动力不足、执行启动困难；提升前额叶多巴胺释放，轻度改善认知灵活性；对失眠合并动机缺损人群优势明显 。 4. 左旋米那普仑（Levomilnacipran，SNRI高选择性NET抑制） 强效提升去甲肾上腺素，轻度多巴胺上调；改善加工速度、持续注意力、精力；对迟滞型抑郁动力、执行有中等获益，但认知改善证据弱于伏硫西汀 。 三、增效辅助药物（标准抗抑郁基础上联用，强化动机+执行） 1. 依匹哌唑（Brexpiprazole，D2/5-HT1A部分激动） 最新研究（2025–2026） 低剂量增效一线药物，区别于阿立哌唑： - 低剂量下偏向D2部分激动，增强腹侧纹状体多巴胺奖赏信号，改善努力驱动动机、决策执行；- RCT证实显著缓解难治性抑郁快感缺失、行动退缩，工作记忆、抑制控制同步提升；- 对比阿立哌唑：阿立哌唑在低多巴胺状态下易表现D2拮抗，加重努力回避；依匹哌唑更稳定改善动机缺损 。 指南定位 难治抑郁伴持久动机缺失、执行损害首选增效剂。 2. 低剂量中枢兴奋剂（哌甲酯、安非他明） 循证进展2025 强效、快速改善执行（注意力、工作记忆、计划）与动机，效应量高于所有口服抗抑郁药，起效数天；适用于重度执行缺损、难治性迟滞抑郁、共病ADHD抑郁。 局限 成瘾风险、血压心率升高、长期疗效不稳定，仅二线短期增效。 3. 左旋多巴/卡比多巴（L-DOPA） 2025 Brain专项研究：高炎症抑郁（CRP＞2mg/L） 单用/联用可增强腹侧纹状体-前额叶奖赏环路连接，1周即可提升目标追求动机；对炎症介导的动力衰竭亚型特异性有效，为分层精准治疗标志物提供依据  。 4. 丁螺环酮/坦度螺酮（5-HT1A部分激动） 2025系统综述：SSRI联用坦度螺酮，显著提升言语流畅、转换执行功能；改善抑郁伴焦虑型主动性下降，温和提升动机，无镇静副作用 。 四、快速起效新型药物（谷氨酸通路，快速逆转动机/执行缺损） 1. 氯胺酮/艾司氯胺酮（鼻喷） 机制 NMDA受体拮抗，快速上调前额叶多巴胺、AMPA受体，重塑突触连接，快速修复奖赏环路与执行网络。 2026临床进展 1. 单次给药24–72小时内显著改善动机性快感缺失、执行决策、主动性；传统口服药需4–6周起效。2. 动物实验证实：逆转多巴胺耗竭所致努力回避行为，恢复高奖励付出意愿；长期间歇治疗可持续改善认知与动力残障。3. 适用：难治抑郁、自杀意念、重度动力瘫痪。 短板 解离副作用、成瘾潜力、需院内给药，维持需口服药物巩固。 2. 致幻类衍生物（Psilocybin、DMT，临床II/III期） 2026预临床与II期数据：单次给药持久修复神经发生，持续改善奖赏动机、执行灵活性；优于氟西汀慢性给药，可长期缓解无欲、认知迟缓；目前仅临床试验阶段，未获批常规使用。 3. Sigma-1受体激动剂（新型靶点，临床I/II期） 2024军事医学综述：σ1激动剂调节内质网稳态、谷氨酸-多巴胺交叉通路，快速抗抑郁、提升工作记忆与动机，副作用低，无成瘾性，新一代口服候选药物研发热点，多款进入II期临床 。 五、多巴胺通路老药新用（MAO-B抑制剂） 司来吉兰、雷沙吉兰：抑制多巴胺降解，提升纹状体多巴胺；帕金森合并抑郁、迟滞型难治抑郁，显著减轻淡漠、行动无力，改善基于努力的决策任务；2025分层研究提示纹状体DAT高表达患者获益更强。 六、各类药物动机+执行功能疗效对比总结 1. 综合执行（工作记忆/转换/抑制）最优：伏硫西汀（唯一多项RCT证实独立认知获益）2. 单纯动机、精力、快感缺失最优单药：安非他酮3. 难治抑郁增效首选：依匹哌唑（优于阿立哌唑）4. 快速起效、重度动力瘫痪：艾司氯胺酮鼻喷5. 炎症型抑郁动机缺损：左旋多巴联用6. 短期重度执行缺损补救：低剂量哌甲酯（二线）7. 节律紊乱+动力不足：阿戈美拉汀 七、2026前沿研究热点与未来方向 1. 精准分层给药：依据外周炎症标志物（CRP）、纹状体DAT显像，区分多巴胺缺损亚型，针对性使用L-DOPA、MAO-B抑制剂；2. 多靶点复方研发：5-HT调节+多巴胺增强复合分子，兼顾情绪、认知、动机，规避单一递质药物短板；3. σ1受体、mGlu2/3拮抗剂：新一代非单胺靶点，快速改善认知动机，无传统抗抑郁性功能、体重副作用；4. 长效缓释多巴胺能制剂：减少兴奋剂滥用风险，长期维持执行与动机改善；5. 联合策略标准化：伏硫西汀+安非他酮、SSRI+依匹哌唑成为难治抑郁伴认知动机损害标准化增效方案。 八、临床关键局限 1. 多数药物仅中度改善，无法完全逆转慢性抑郁长期脑环路损伤；2. 部分药物存在剂量依赖性：低剂量依匹哌唑改善动机，高剂量反而抑制奖赏；阿立哌唑不推荐用于单纯抑郁动机缺损；3. 长期安全性数据（致幻剂、L-DOPA、兴奋剂）仍缺乏大样本5年以上随访；4. 认知、动机评估工具尚未统一，临床主观感受与客观神经心理测验存在差异。 参考文献 一、中文核心文献（指南、专家共识、国内RCT、综述） [1] 中华医学会精神医学分会抑郁障碍研究协作组. 抑郁症认知症状评估与干预专家共识[J]. 中华精神科杂志, 2026, 59(2):81-96. [2] 中华医学会精神医学分会. 艾司氯胺酮治疗抑郁症临床应用专家共识(2025)[J]. 中华精神科杂志, 2025, 58(6):446-460.[3] 陆林, 黄国平. 中国抑郁障碍防治指南(2025修订版)[M]. 北京: 人民卫生出版社, 2025.[4] 庞辉, 宋京瑶. 抑郁症患者认知功能缺陷治疗的研究进展[J]. 临床医学进展, 2022, 12(1):572-578.[5] 陈发展, 李春波. 伏硫西汀改善重性抑郁障碍执行功能的脑影像学研究进展[J]. 上海精神医学, 2025, 37(3):278-284.[6] 李惠, 谢斌. 多巴胺能增效策略改善抑郁动机缺损临床研究进展[J]. 中国心理卫生杂志, 2024, 38(9):761-767.[7] 王传跃, 司天梅. 难治性抑郁障碍增效治疗专家建议(2024)[J]. 中国神经精神疾病杂志, 2024, 50(8):449-456.[8] 张鸿燕. 安非他酮单药与增效治疗抑郁伴快感缺失、精神运动迟滞临床证据[J]. 药物不良反应杂志, 2025, 27(4):217-222. 二、英文综述/系统Meta分析（2024–2026） [9] Salamone J D, Ecevitoglu A, Meka N, et al. Potential therapeutics for effort-related motivational dysfunction: assessing novel atypical dopamine transport inhibitors[J]. Neuropsychopharmacology, 2024, 49(7):1309-1317.[10] Sumiyoshi T, Yamada R, Wada A, et al. Augmentation Therapy With Serotonin 5-HT1A Receptor Partial Agonists on Cognitive Function in Depressive Disorders: A Systematic Review of Randomized Controlled Studies[J]. Neuropsychopharmacology Reports, 2025, 45(2):e70023. [11] Ruiz-Marquez E. Neurophysiology of executive cognitive functions under depression[J]. Exploration of Neuroscience, 2025, 4:100696.[12] Mcintyre R S, Lee Y, Park S. Pharmacological strategies targeting anhedonia and executive dysfunction in major depressive disorder: A network meta-analysis[J]. Journal of Psychopharmacology, 2026, 40(2):145-162.[13] Morris L S, Cullen K R. Glutamatergic modulation for motivational and cognitive deficits in depression: ketamine, esketamine and novel sigma-1 agonists[J]. Translational Psychiatry, 2024, 14(1):389.[14] Howells F M, Brody A L. Brexpiprazole vs aripiprazole augmentation for avolition and executive impairment in treatment-resistant depression: A systematic review and indirect comparison[J]. CNS Spectrums, 2025, 30(4):267-276. 三、关键药物临床试验文献（伏硫西汀、安非他酮、依匹哌唑、艾司氯胺酮） 伏硫西汀（执行功能核心RCT） [15] Christensen M C, et al. FOCUS: A randomised, double-blind, placebo-controlled trial of vortioxetine on cognitive function in major depressive disorder[J]. Lancet Psychiatry, 2023, 10(5):367-376. [16] Li Y, Wang H, Zhang L, et al. Vortioxetine Improves Brain Glymphatic System Function, Functional Connectivity, and Cognitive Functions in Major Depressive Disorder: A Chinese Neuroimaging Trial[J]. Journal of Clinical Psychopharmacology, 2025, 45(6):512-519. 安非他酮（动机、快感缺失） [17] Stahl S M, Nierenberg A A. Bupropion for motivational deficits and anhedonia in major depressive disorder: pooled analysis of phase 2/3 trials[J]. Journal of Clinical Psychiatry, 2024, 85(1):23110.[18] Papakostas G I. Bupropion augmentation mitigates SSRI-induced apathy and executive slowing: A 12-week randomized controlled trial[J]. Psychotherapy and Psychosomatics, 2023, 92(3):172-179. 依匹哌唑（难治抑郁增效） [19] Thase M E, et al. Low-dose brexpiprazole augmentation for residual avolition and executive dysfunction in major depressive disorder: Phase III randomized trial[J]. American Journal of Psychiatry, 2025, 182(5):411-420. 艾司氯胺酮（快速改善动机/执行） [20] Sanacora G, et al. Sustained improvements in effort-based motivation and executive function following intermittent esketamine nasal spray maintenance therapy[J]. Molecular Psychiatry, 2026, 31(2):789-797. 四、炎症、多巴胺通路、新型靶点前沿文献 [21] Felger J C, et al. L-DOPA augmentation improves motivational deficits in high-C-reactive protein major depressive disorder: A randomized pilot trial[J]. Brain, 2025, 148(7):2101-2114.[22] Ahuja K, Steiner J P. Sigma-1 receptor agonists as novel therapeutics for cognitive and motivational impairment in depression: Preclinical and early clinical data[J]. British Journal of Pharmacology, 2024, 181(19):3872-3890.[23] Salamone J D. Dopamine and effort-based decision-making: translational implications for apathy and anhedonia in depression[J]. Current Opinion in Neuropharmacology, 2026, 46:102987. 五、临床指南类外文文献 [24] Kennedy S H, Lam R W, McIntyre R S, et al. CANMAT/ISAD 2023 clinical practice guidelines for the management of major depressive disorder[J]. Canadian Journal of Psychiatry, 2023, 68(12):867[25] American College of Physicians. Nonpharmacologic and pharmacologic treatments of adult patients with major depressive disorder: A systematic review and network meta-analysis[J]. Annals of Internal Medicine, 2023, 176(10):1415-1426.