提示: 手机请竖屏浏览!

一种治疗精神分裂症的非D2受体结合药物
A Non–D2-Receptor-Binding Drug for the Treatment of Schizophrenia


Kenneth S. Koblan ... 其他 • 2020.04.16
相关阅读
• 精神分裂症

摘要


背景

口服化合物SEP-363856不作用于多巴胺D2受体,但对痕量胺相关受体1(TAAR1)和5-羟色胺1A型(5-HT1A)受体具有激动活性,可能是治疗精神分裂症患者精神病的一类新型精神药物。

 

方法

我们开展了一项随机、对照试验,在精神分裂症急性发作的成人患者中评估了SEP-363856的疗效和安全性。我们以1∶1的比例将患者随机分组,分别接受为期4周的每日1次SEP-363856(50 mg或75 mg)或安慰剂治疗。主要终点是第4周时的阳性和阴性症状量表(Positive and Negative Symptom Scale,PANSS;范围,30~210分;评分较高表示精神病症状较严重)总分相对于基线的变化。本研究有8项次要终点,包括临床总体印象-严重程度量表(Clinical Global Impressions Severity,CGI-S)和简明阴性症状量表(Brief Negative Symptom Scale,BNSS)评分相对于基线的变化。

 

结果

共计120例患者被分配至SEP-363856组,125例被分配至安慰剂组。在SEP-363856组和安慰剂组中,基线时的平均PANSS总分分别为101.4分和99.7分,第4周时的平均变化分别为-17.2分和-9.7分(最小二乘均值差异,-7.5分;95%置信区间[CI],-11.9~-3.0;P=0.001)。第4周时,CGI-S和BNSS评分的降低与主要结局的变化方向总体相同,但未对结果进行多重比较校正。SEP-363856的不良事件包括嗜睡和胃肠道症状;SEP-363856组有1例心脏性猝死。两组的锥体外系症状发生率以及血脂、糖化血红蛋白和催乳素水平的变化相似。

 

结论

在对精神分裂症急性发作患者开展的这项为期4周的试验中,与安慰剂相比,SEP-363856(一种非D2受体结合抗精神病药)使PANSS总分相对于基线有较大幅下降。为了证实SEP-363856的效应和副作用,以及与现有药物相比SEP-363856对精神分裂症的疗效,我们需要开展时间更长、规模更大的试验(由Sunovion制药公司资助,在ClinicalTrials.gov注册号为NCT02969382)。





作者信息

Kenneth S. Koblan, Ph.D., Justine Kent, M.D., Seth C. Hopkins, Ph.D., John H. Krystal, M.D., Hailong Cheng, Ph.D., Robert Goldman, Ph.D., and Antony Loebel, M.D.
From Sunovion Pharmaceuticals, Marlborough, MA (K.S.K., J.K., S.C.H., H.C., R.G., A.L.); and the Department of Psychiatry, Yale University, the Department of Neuroscience, Yale University School of Medicine, and Behavioral Health Services, Yale New Haven Hospital, New Haven (J.H.K.), and the Clinical Neurosciences Division, Veterans Affairs National Center for PTSD, Veterans Affairs Connecticut Healthcare System, West Haven (J.H.K.) — all in Connecticut. Address reprint requests to Dr. Koblan at Sunovion Pharmaceuticals, 84 Waterford Dr., Marlborough, MA 01752, or at kenneth.koblan@sunovion.com.

 

参考文献

1. Kaar SJ, Natesan S, McCutcheon R, Howes OD. Antipsychotics: mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology. Neuropharmacology 2019 July 9 (Epub ahead of print).

2. Leucht S, Leucht C, Huhn M, et al. Sixty years of placebo-controlled antipsychotic drug trials in acute schizophrenia: systematic review, Bayesian meta-analysis, and meta-regression of efficacy predictors. Am J Psychiatry 2017;174:927-942.

3. Keefe RS, Bilder RM, Davis SM, et al. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Arch Gen Psychiatry 2007;64:633-647.

4. Stahl SM, Buckley PF. Negative symptoms of schizophrenia: a problem that will not go away. Acta Psychiatr Scand 2007;115:4-11.

5. Krause M, Zhu Y, Huhn M, et al. Antipsychotic drugs for patients with schizophrenia and predominant or prominent negative symptoms: a systematic review and meta-analysis. Eur Arch Psychiatry Clin Neurosci 2018;268:625-639.

6. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353:1209-1223.

7. Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013;382:951-962.

8. Laursen TM, Nordentoft M, Mortensen PB. Excess early mortality in schizophrenia. Annu Rev Clin Psychol 2014;10:425-448.

9. Cooper SJ, Reynolds GP, Barnes T, et al. BAP guidelines on the management of weight gain, metabolic disturbances and cardiovascular risk associated with psychosis and antipsychotic drug treatment. J Psychopharmacol 2016;30:717-748.

10. Taipale H, Mittendorfer-Rutz E, Alexanderson K, et al. Antipsychotics and mortality in a nationwide cohort of 29,823 patients with schizophrenia. Schizophr Res 2018;197:274-280.

11. Dedic N, Jones PG, Hopkins SC, et al. SEP-363856, a novel psychotropic agent with a unique, non-D2 receptor mechanism of action. J Pharmacol Exp Ther 2019;371:1-14.

12. Shao L, Campbell UC, Fang QK, et al. In vivo phenotypic drug discovery: applying a behavioral assay to the discovery and optimization of novel antipsychotic agents. MedChemComm 2016;7:1093-1101.

13. Revel FG, Moreau J-L, Gainetdinov RR, et al. TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity. Proc Natl Acad Sci U S A 2011;108:8485-8490.

14. Lindemann L, Meyer CA, Jeanneau K, et al. Trace amine-associated receptor 1 modulates dopaminergic activity. J Pharmacol Exp Ther 2008;324:948-956.

15. Rutigliano G, Accorroni A, Zucchi R. The case for TAAR1 as a modulator of central nervous system function. Front Pharmacol 2018;8:987-987.

16. Schwartz MD, Canales JJ, Zucchi R, Espinoza S, Sukhanov I, Gainetdinov RR. Trace amine-associated receptor 1: a multimodal therapeutic target for neuropsychiatric diseases. Expert Opin Ther Targets 2018;22:513-526.

17. Kokkinou M, Irvine EE, Bonsall DR, et al. Mesocorticolimbic circuit mechanisms underlying the effects of ketamine on dopamine: a translational imaging study. bioRxiv (in press) (https://www.biorxiv.org/content/10.1101/748665v1. opens in new tab).

18. McCutcheon R, Beck K, Jauhar S, Howes OD. Defining the locus of dopaminergic dysfunction in schizophrenia: a meta-analysis and test of the mesolimbic hypothesis. Schizophr Bull 2018;44:1301-1311.

19. Miyamoto S, Duncan GE, Marx CE, Lieberman JA. Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry 2005;10:79-104.

20. Celada P, Bortolozzi A, Artigas F. Serotonin 5-HT1A receptors as targets for agents to treat psychiatric disorders: rationale and current status of research. CNS Drugs 2013;27:703-716.

21. Newman-Tancredi A. The importance of 5-HT1A receptor agonism in antipsychotic drug action: rationale and perspectives. Curr Opin Investig Drugs 2010;11:802-812.

22. Diagnostic and statistical manual of mental disorders, 5th ed.: DSM V. Washington, DC: American Psychiatric Association, 2013.

23. First MB, Williams JBW, Karg RS, Spitzer RL. Structured clinical interview for DSM-5 disorders: clinical trials version (SCID-5-CT). Washington, DC: American Psychiatric Association, 2015.

24. Ruikar V. Interactive voice/Web response system in clinical research. Perspect Clin Res 2016;7:15-20.

25. Guy W, ed. ECDEU assessment manual for psychopharmacology. Rockville, MD: Department of Health, Education, and Welfare, 1976.

26. Kirkpatrick B, Strauss GP, Nguyen L, et al. The Brief Negative Symptom Scale: psychometric properties. Schizophr Bull 2011;37:300-305.

27. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979;134:382-389.

28. Hopkins SC, Ogirala A, Loebel A, Koblan KS. Transformed PANSS factors intended to reduce pseudospecificity among symptom domains and enhance understanding of symptom change in antipsychotic-treated patients with schizophrenia. Schizophr Bull 2018;44:593-602.

29. Simpson GM, Angus JWS. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl 1970;212:11-19.

30. Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry 1989;154:672-676.

31. Rush AJ Jr, ed. Handbook of psychiatric measures. Washington, DC: American Psychiatric Association, 2000:166-8.

32. Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry 2011;168:1266-1277.

33. Buysse DJ, Reynolds CF III, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 1989;28:193-213.

34. Kemmler G, Hummer M, Widschwendter C, Fleischhacker WW. Dropout rates in placebo-controlled and active-control clinical trials of antipsychotic drugs: a meta-analysis. Arch Gen Psychiatry 2005;62:1305-1312.

服务条款 | 隐私政策 | 联系我们