抗抑郁药的方向——多模式作用机制

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抑郁症是一种复杂、多维度、临床异质性的疾病。作为当前主流指南推荐的一线治疗药物，选择性5-羟色胺再摄取抑制剂（SSRIs）和5-羟色胺−去甲肾上腺素再摄取抑制剂（SNRI）仅通过一种主要的MoA（抑制神经递质再摄取）发挥作用¹ 。随着抗抑郁药研发进程的不断推进，具有多模式作用机制的抗抑郁药（如Vilazodone、伏硫西汀）逐渐应运而生（图1）。

图1：过去60年抗抑郁药研发的演变进程

一、何为多模式抗抑郁药？

通常认为，至少通过两种作用模式（MoA）发挥抗抑郁作用，作用于两个不同药理学靶点的药物为多模式抗抑郁药 ^2,3 。SSRI类抗抑郁药具有一种MoA（5-HT再摄取抑制）和一个药理学靶点即5-HT转运体（SERT）^3,4, ；SNRI类抗抑郁药虽然具有两个药理学作用靶点（SERT和去甲肾上腺素转运体），但它也仅以单一模式发挥作用 ^3,5 ；同样，阿戈美拉汀也是具有一种MoA和三个药理学靶点的抗抑郁药，也不属于多模式作用机制药物^3,6,7 。

多模式药物的代表伏硫西汀具有受体活性和再摄取抑制两种MoA，并同时作用于6个药理学靶点。伏硫西汀是SERT抑制剂、5-HT3、5-HT7和5-HT1D拮抗剂、5-HT1B部分激动剂以及5-HT1A激动剂^3,8,8,10。另一种多模式药物Vilazodone则是SERT抑制和5-HT1A激动双重作用机制^3,11。

二、多模式作用机制为伏硫西汀抗抑郁和改善患者认知症状奠定了基础

我们知道，所有神经递质都受负反馈机制的调控，5-HT1A、5-HT1B和5-HT3受体参与SERT抑制剂引发的负反馈机制^12,13。但负反馈机制阻碍了5-HT升高引起的潜在益处^14,15，引起多巴胺、去甲肾上腺素、组胺和谷氨酸神经传递同时下调。伏硫西汀具有SERT抑制及5-HT受体活性的调控能力，减弱神经递质系统的负反馈抑制，从而使治疗效果最大化^18,16。伏硫西汀的多模式药理学活性是其发挥抗抑郁和改善认知症状的基础¹⁷。

1. 伏硫西汀的抗抑郁作用 

伏硫西汀的抗抑郁效果是基于多模式作用机制。其在标准的临床前模型中具有良好抗抑郁作用，包括小鼠和大鼠强迫游泳试验¹³以及小鼠悬尾试验¹³。另外，在大鼠社交互动试验中，仅需短期给予伏硫西汀就可以获得中长期给予SSRI或SNRI治疗的同样疗效。在临床前模型中，相比于氟西汀，伏硫西汀的抗抑郁效应更强，并且临床前模型中可在更低的SERT结合率下发挥效果¹⁸。 

2. 伏硫西汀改善认知症状

认知症状是抑郁症治疗中未满足的需求，临床前研究证实了伏硫西汀具有改善认知症状的功效。 

● 能有效增强情景记忆（图3）¹⁹。

● 与SSRI类药物、SNRI类药物度洛西汀相比，伏硫西汀可显著改善PCPA（对氯苯丙氨酸）导致的5-HT耗竭大鼠识别功能和空间记忆缺陷（图3）^20,21。

● 可显著改善老年大鼠空间记忆（图4）²²。

图3：伏硫西汀改善5-HT耗竭大鼠记忆缺陷

图4：伏硫西汀改善老年大鼠空间记忆 (>12个月) 

三、总结

无论是SSRI，还是SNRI，作用机制模式相对单一。近年来研发的抗抑郁药物转向多模式作用机制。伏硫西汀是一种新型多模式抗抑郁药，具有两种MoA，作用于6个药理学靶点。伏硫西汀在改善抑郁症状的同时，可以改善患者的认知症状，能够全面满足抑郁症患者的治疗需求。

参考文献：

 1. Nutt DJ, Attridge J. CNS drug development in Europe—past progress and future challenges. Neurobiol Dis 2014; 61: 6–20.

 2. Nutt DJ. Beyond psychoanaleptics - can we improve antidepressant drug nomenclature? J Psychopharmacol 2009; 23: 343–345.

 3. Zohar J, Nutt DJ, Kupfer DJ, Moller H-J, Yamawaki S, Spedding M, Stahl SM. A proposal for an updated neuropsychopharmacological nomenclature. Eur Neuropsychopharmacol 2014; 24: 1005–1014.

  4.Fagius J, Osterman PO, Sidén A, Wiholm BE. Guillain-Barré syndrome following zimeldine treatment.  J Neurol Neurosurg Psychiatry. 1985;48(1): 65–69.

  5.Sansone RA, Sansone LA. Serotonin norepinephrine reuptake inhibitors: a pharmacological comparison. Innov Clin Neurosci. 2014;11(3–4):37–42.

  6.Fornaro M, Prestia D, Colicchio S, Perugi G. A systematic, updated review on the antidepressant agomelatine focusing on its melatonergic modulation. Curr Neuropsychopharmacol 2010;8(3):287–304.

7.Agomelatine EPAR. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000915/WC500046224.pdf

  8.Bang-Andersen B, Ruhland T, Jørgensen M, Smith G, Frederiksen K, Jensen KG, Zhong H, Nielsen SM, Hogg S, Mørk A, Stensbøl TB. Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder. J Med Chem 2011;54(9)3206–3221.

  9.Westrich L, Pehrson A, Zhong H, Nielsen SM, Frederiksen K, Stensbøl TB, Boyle N, Hentzer M, Sanchez C. In vitro and in vivo effects of the multimodal antidepressant vortioxetine (Lu AA21004) at human and rat targets. Int J Psychiatry Clin Pract 2012; 16 (Suppl 1): 47, abs P71.

  10.Vortioxetine Prescribing Information (last accessed June 2016) http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204447s000lbl.pdf

  11.Cruz MP. Vilazodone HCl (Viibryd): A Serotonin Partial Agonist and Reuptake Inhibitor For the Treatment of Major Depressive Disorder. Pharmacy and Therapeutics 2012;37(1): 28–31.

  12.Barnes NM, Sharp T. A review of central 5-HT receptors and their function. Neuropharmacology 1999; 38: 1083–1152.

  13.Blier P, Ward NM. Is there a role for 5-HT1A agonists in the treatment of depression? Biol Psychiatry 2003; 53:193–203.

 14.Blier P, El Mansari M. Serotonin and beyond: therapeutics for major depression. Philos Trans R Soc Lond

 B Biol Sci. 2013 Feb 25;368(1615):20120536.

  15.Komlósi G, Molnár G, Rózsa M, Oláh S, Barzó P, Tamás G. Fluoxetine (prozac) and serotonin act on excitatory synaptic transmission to suppress single layer 2/3 pyramidal neuron-triggered cell assemblies in the human prefrontal cortex. J Neurosci. 2012 Nov 14;32(46):16369-78.

  16.Dale E, Bang-Andersen B, Sánchez C. Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs. Biochem Pharmacol. 2015 May 15;95(2):81-97.

  17.European Medicines Agency. Brintellix (vortioxetine). Assessment report for an initial marketing authorisation application. Available at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002717/WC500159447.pdf. Last updated 24 October 2013. Accessed 1 July 2014.

  18.Guilloux J-P, Mendez-David I, Pehrson A, Guiard BP, Repérant C, Orvoën S, Gardier AM, Hen R, Ebert B, Miller S, Sanchez C, David DJ. Antidepressant and anxiolytic potential of the multimodal antidepressant vortioxetine (Lu AA21004) assessed by behavioural and neurogenesis outcomes in mice. Neuropharmacology 2013; 73: 147–159.

  19.Haddjeri N, Etievant A, Pehrson A, Sánchez C, Bétry C. Effect of the multimodal antidepressant Lu AA21004 on rat hippocampal plasticity and recognition memory. Poster NR9-32 presented at the 165th American Psychiatric Association Annual Meeting, Philadelphia, Pennsylvania, USA, 5–9 May, 2012.

  20.Du Jardin KG, Jensen JB, Sanchez C, Pehrson AL. Vortioxetine dose-dependently reverses 5-HT depletion-induced deficits in spatial working and object recognition memory: a potential role for 5-HT1A receptor agonism and 5-HT3 receptor antagonism. Eur Neuropsychopharmacol 2014; 24:160–171.

  21.Jensen JB, Du Jardin KG, Song D, Budac D, Smagin G, Sanchez C, Pehrson AL. Vortioxetine, but not escitalopram or duloxetine, reverses memory impairment induced by central 5-HT depletion in rats: evidence for direct 5-HT receptor modulation. Eur Neuropsychopharmacol 2014; 24:148–159.

  22.Li Y, Sánchez C, Gulinello M. Memory impairment in old mice is differentially sensitive to different classes of antidepressants. Poster P.1.j.002 presented at the 26th ECNP Congress, Barcelona, Spain, 5–9 October, 2013.

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