加用螺内酯作为NRG1-ERBB4信号通路拮抗剂治疗精神分裂症：一项多中心随机、安慰剂对照试验的研究设计与方法
Add-on spironolactone as antagonist of the NRG1-ERBB4 signaling pathway for the treatment of schizophrenia: Study design and methodology of a multicenter randomized, placebo-controlled trial.
作者信息
Hasan Alkomiet, Roeh Astrid, Leucht Stefan, Langguth Berthold, Hansbauer Maximilian, Oviedo-Salcedo Tatiana, Kirchner Sophie K, Papazova Irina, Löhrs Lisa, Wagner Elias, Maurus Isabel, Strube Wolfgang, Rossner Moritz J, Wehr Michael C, Bauer Ingrid, Heres Stephan, Leucht Claudia, Kreuzer Peter M, Zimmermann Stephanie, Schneider-Axmann Thomas, Görlitz Thomas, Karch Susanne, Egert-Schwender Silvia, Schossow Beate, Rothe Philipp, Falkai Peter
机构信息
Department of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians University München, Germany.
Department of Psychiatry, Psychotherapy and Psychosomatics of the University Augsburg, Bezirkskrankenhaus Augsburg, University of Augsburg, Augsburg, Germany.
出版信息
Contemp Clin Trials Commun. 2020 Jan 28;17:100537. doi: 10.1016/j.conctc.2020.100537. eCollection 2020 Mar.
BACKGROUND
Preclinical studies recently showed that the mineralocorticoid antagonist spironolactone acts also as an antagonist of the NRG1-ERBB4 signaling pathway and improves schizophrenia-like behaviour in Nrg1 transgenic mouse model. As this signaling pathway is critically linked to the pathophysiology of schizophrenia, especially in the context of working-memory dysfunction, spironolactone may be a novel treatment option for patients with schizophrenia targeting cognitive impairments.
AIMS
To evaluate whether spironolactone added to an ongoing antipsychotic treatment improves cognitive functioning in schizophrenia.
METHODS
The add-on spironolactone for the treatment of schizophrenia trial (SPIRO-TREAT) is a multicenter randomized, placebo-controlled trial with three arms (spironolactone 100 mg, spironolactone 200 mg and placebo). Schizophrenia patients are treated for three weeks and then followed-up for additional nine weeks. As primary outcome, we investigate changes in working memory before and at the end of the intervention phase. We will randomize 90 patients. Eighty-one patients are intended to reach the primary endpoint measure at the end of the three-week intervention period. Secondary endpoints include other measures of cognition, psychopathology, safety measures and biological measures.
CONCLUSIONS
SPIRO-TREAT is the first study evaluating the efficacy of the mineralocorticoid receptor antagonist spironolactone to improve cognitive impairments in schizophrenia patients targeting the NRG1-ERBB4 signaling pathway. With SPIRO-TREAT, we intend to investigate a novel treatment option for cognitive impairments in schizophrenia that goes beyond the established concepts of interfering with dopaminergic neurotransmission as key pathway in schizophrenia treatment.
CLINICAL TRIAL REGISTRATION
International Clinical Trials Registry Platform: http://apps.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2014-001968-35-DE.
背景
临床前研究最近表明，盐皮质激素拮抗剂螺内酯还可作为神经调节蛋白1（NRG1）-表皮生长因子受体4（ERBB4）信号通路的拮抗剂，并改善Nrg1转基因小鼠模型中的精神分裂症样行为。由于该信号通路与精神分裂症的病理生理学密切相关，尤其是在工作记忆功能障碍的背景下，螺内酯可能是针对认知障碍的精神分裂症患者的一种新型治疗选择。
目的
评估在正在进行的抗精神病治疗中添加螺内酯是否能改善精神分裂症患者的认知功能。
方法
螺内酯治疗精神分裂症附加试验（SPIRO-TREAT）是一项多中心随机、安慰剂对照试验，分为三组（螺内酯100毫克、螺内酯200毫克和安慰剂）。精神分裂症患者接受为期三周的治疗，然后再随访九周。作为主要结局，我们研究干预阶段开始前和结束时工作记忆的变化。我们将随机分配90名患者。81名患者预计在三周干预期结束时达到主要终点指标。次要终点包括其他认知指标、精神病理学指标、安全指标和生物学指标。
结论
SPIRO-TREAT是第一项评估盐皮质激素受体拮抗剂螺内酯针对NRG1-ERBB4信号通路改善精神分裂症患者认知障碍疗效的研究。通过SPIRO-TREAT，我们打算研究一种针对精神分裂症认知障碍的新型治疗选择，该选择超越了将干扰多巴胺能神经传递作为精神分裂症治疗关键途径的既定概念。
临床试验注册
国际临床试验注册平台：http://apps.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2014-001968-35-DE 。
Zotero 插件