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

Alkomiet Hasan; Astrid Roeh; Stefan Leucht; Berthold Langguth; Maximilian Hansbauer; Tatiana Oviedo-Salcedo; Sophie K Kirchner; Irina Papazova; Lisa Löhrs; Elias Wagner; Isabel Maurus; Wolfgang Strube; Moritz J Rossner; Michael C Wehr; Ingrid Bauer; Stephan Heres; Claudia Leucht; Peter M Kreuzer; Stephanie Zimmermann; Thomas Schneider-Axmann; Thomas Görlitz; Susanne Karch; Silvia Egert-Schwender; Beate Schossow; Philipp Rothe; Peter Falkai

doi:10.1016/j.conctc.2020.100537

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

Contemp Clin Trials Commun. 2020 Jan 28:17:100537. doi: 10.1016/j.conctc.2020.100537. eCollection 2020 Mar.

Authors

Alkomiet Hasan^{1

2}, Astrid Roeh¹, Stefan Leucht³, Berthold Langguth⁴, Maximilian Hansbauer¹, Tatiana Oviedo-Salcedo¹, Sophie K Kirchner¹, Irina Papazova¹, Lisa Löhrs¹, Elias Wagner¹, Isabel Maurus¹, Wolfgang Strube¹, Moritz J Rossner¹, Michael C Wehr¹, Ingrid Bauer³, Stephan Heres³, Claudia Leucht³, Peter M Kreuzer⁴, Stephanie Zimmermann⁴, Thomas Schneider-Axmann¹, Thomas Görlitz¹, Susanne Karch¹, Silvia Egert-Schwender⁵, Beate Schossow⁵, Philipp Rothe⁶, Peter Falkai¹

Affiliations

¹ Department of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians University München, Germany.
² Department of Psychiatry, Psychotherapy and Psychosomatics of the University Augsburg, Bezirkskrankenhaus Augsburg, University of Augsburg, Augsburg, Germany.
³ Department of Psychiatry and Psychotherapy, Technical University of Munich, Munich, Faculty of Medicine, Klinikum Rechts der Isar, Germany.
⁴ Department of Psychiatry and Psychotherapy, University of Regensburg, Germany.
⁵ Münchner Studienzentrum, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.
⁶ Department of Forensic Psychiatry and Psychotherapy, Ulm University, Ulm, Germany.

Abstract

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.

Keywords: Cognitive impairment; Drug repositioning; Drug repurposing; NRG1-ERBB4; Schizophrenia; Spironolactone.