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
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 pathophy...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2020-03-01
|
| Series: | Contemporary Clinical Trials Communications |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2451865420300211 |
| _version_ | 1818127405085097984 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Alkomiet Hasan |
| collection | DOAJ |
| description | 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: Schizophrenia, Cognitive impairment, Spironolactone, NRG1-ERBB4, Drug repositioning, Drug repurposing |
| first_indexed | 2024-12-11T07:16:50Z |
| format | Article |
| id | doaj.art-2fe8c8b6de264ff08cfd483cdb832053 |
| institution | Directory Open Access Journal |
| issn | 2451-8654 |
| language | English |
| last_indexed | 2024-12-11T07:16:50Z |
| publishDate | 2020-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Contemporary Clinical Trials Communications |
| spelling | doaj.art-2fe8c8b6de264ff08cfd483cdb8320532022-12-22T01:16:12ZengElsevierContemporary Clinical Trials Communications2451-86542020-03-0117Add-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 trialAlkomiet Hasan0Astrid Roeh1Stefan Leucht2Berthold Langguth3Maximilian Hansbauer4Tatiana Oviedo-Salcedo5Sophie K. Kirchner6Irina Papazova7Lisa Löhrs8Elias Wagner9Isabel Maurus10Wolfgang Strube11Moritz J. Rossner12Michael C. Wehr13Ingrid Bauer14Stephan Heres15Claudia Leucht16Peter M. Kreuzer17Stephanie Zimmermann18Thomas Schneider-Axmann19Thomas Görlitz20Susanne Karch21Silvia Egert-Schwender22Beate Schossow23Philipp Rothe24Peter Falkai25Department 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; Corresponding author. Department of Psychiatry & Psychotherapy, Klinikum der Universität München, Ludwig-Maximilians University Munich, Nußbaumstraße 7, D-80336, Munich, Germany.Department of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians University München, GermanyDepartment of Psychiatry and Psychotherapy, Technical University of Munich, Munich, Faculty of Medicine, Klinikum Rechts der Isar, GermanyDepartment of Psychiatry and Psychotherapy, University of Regensburg, GermanyDepartment of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians University München, GermanyDepartment of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians University München, GermanyDepartment of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians University München, GermanyDepartment of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians University München, GermanyDepartment of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians University München, GermanyDepartment of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians University München, GermanyDepartment of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians University München, GermanyDepartment of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians University München, GermanyDepartment of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians University München, GermanyDepartment of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians University München, GermanyDepartment of Psychiatry and Psychotherapy, Technical University of Munich, Munich, Faculty of Medicine, Klinikum Rechts der Isar, GermanyDepartment of Psychiatry and Psychotherapy, Technical University of Munich, Munich, Faculty of Medicine, Klinikum Rechts der Isar, GermanyDepartment of Psychiatry and Psychotherapy, Technical University of Munich, Munich, Faculty of Medicine, Klinikum Rechts der Isar, GermanyDepartment of Psychiatry and Psychotherapy, University of Regensburg, GermanyDepartment of Psychiatry and Psychotherapy, University of Regensburg, GermanyDepartment of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians University München, GermanyDepartment of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians University München, GermanyDepartment of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians University München, GermanyMünchner Studienzentrum, Klinikum Rechts der Isar, Technical University of Munich, Munich, GermanyMünchner Studienzentrum, Klinikum Rechts der Isar, Technical University of Munich, Munich, GermanyDepartment of Forensic Psychiatry and Psychotherapy, Ulm University, Ulm, GermanyDepartment of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians University München, GermanyBackground: 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: Schizophrenia, Cognitive impairment, Spironolactone, NRG1-ERBB4, Drug repositioning, Drug repurposinghttp://www.sciencedirect.com/science/article/pii/S2451865420300211 |
| spellingShingle | 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 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 Contemporary Clinical Trials Communications |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| url | http://www.sciencedirect.com/science/article/pii/S2451865420300211 |
| work_keys_str_mv | AT alkomiethasan addonspironolactoneasantagonistofthenrg1erbb4signalingpathwayforthetreatmentofschizophreniastudydesignandmethodologyofamulticenterrandomizedplacebocontrolledtrial AT astridroeh addonspironolactoneasantagonistofthenrg1erbb4signalingpathwayforthetreatmentofschizophreniastudydesignandmethodologyofamulticenterrandomizedplacebocontrolledtrial AT stefanleucht addonspironolactoneasantagonistofthenrg1erbb4signalingpathwayforthetreatmentofschizophreniastudydesignandmethodologyofamulticenterrandomizedplacebocontrolledtrial AT bertholdlangguth addonspironolactoneasantagonistofthenrg1erbb4signalingpathwayforthetreatmentofschizophreniastudydesignandmethodologyofamulticenterrandomizedplacebocontrolledtrial AT maximilianhansbauer addonspironolactoneasantagonistofthenrg1erbb4signalingpathwayforthetreatmentofschizophreniastudydesignandmethodologyofamulticenterrandomizedplacebocontrolledtrial AT tatianaoviedosalcedo addonspironolactoneasantagonistofthenrg1erbb4signalingpathwayforthetreatmentofschizophreniastudydesignandmethodologyofamulticenterrandomizedplacebocontrolledtrial AT sophiekkirchner addonspironolactoneasantagonistofthenrg1erbb4signalingpathwayforthetreatmentofschizophreniastudydesignandmethodologyofamulticenterrandomizedplacebocontrolledtrial AT irinapapazova addonspironolactoneasantagonistofthenrg1erbb4signalingpathwayforthetreatmentofschizophreniastudydesignandmethodologyofamulticenterrandomizedplacebocontrolledtrial AT lisalohrs addonspironolactoneasantagonistofthenrg1erbb4signalingpathwayforthetreatmentofschizophreniastudydesignandmethodologyofamulticenterrandomizedplacebocontrolledtrial AT eliaswagner addonspironolactoneasantagonistofthenrg1erbb4signalingpathwayforthetreatmentofschizophreniastudydesignandmethodologyofamulticenterrandomizedplacebocontrolledtrial AT isabelmaurus addonspironolactoneasantagonistofthenrg1erbb4signalingpathwayforthetreatmentofschizophreniastudydesignandmethodologyofamulticenterrandomizedplacebocontrolledtrial AT wolfgangstrube addonspironolactoneasantagonistofthenrg1erbb4signalingpathwayforthetreatmentofschizophreniastudydesignandmethodologyofamulticenterrandomizedplacebocontrolledtrial AT moritzjrossner addonspironolactoneasantagonistofthenrg1erbb4signalingpathwayforthetreatmentofschizophreniastudydesignandmethodologyofamulticenterrandomizedplacebocontrolledtrial AT michaelcwehr addonspironolactoneasantagonistofthenrg1erbb4signalingpathwayforthetreatmentofschizophreniastudydesignandmethodologyofamulticenterrandomizedplacebocontrolledtrial AT ingridbauer addonspironolactoneasantagonistofthenrg1erbb4signalingpathwayforthetreatmentofschizophreniastudydesignandmethodologyofamulticenterrandomizedplacebocontrolledtrial AT stephanheres addonspironolactoneasantagonistofthenrg1erbb4signalingpathwayforthetreatmentofschizophreniastudydesignandmethodologyofamulticenterrandomizedplacebocontrolledtrial AT claudialeucht addonspironolactoneasantagonistofthenrg1erbb4signalingpathwayforthetreatmentofschizophreniastudydesignandmethodologyofamulticenterrandomizedplacebocontrolledtrial AT petermkreuzer addonspironolactoneasantagonistofthenrg1erbb4signalingpathwayforthetreatmentofschizophreniastudydesignandmethodologyofamulticenterrandomizedplacebocontrolledtrial AT stephaniezimmermann addonspironolactoneasantagonistofthenrg1erbb4signalingpathwayforthetreatmentofschizophreniastudydesignandmethodologyofamulticenterrandomizedplacebocontrolledtrial AT thomasschneideraxmann addonspironolactoneasantagonistofthenrg1erbb4signalingpathwayforthetreatmentofschizophreniastudydesignandmethodologyofamulticenterrandomizedplacebocontrolledtrial AT thomasgorlitz addonspironolactoneasantagonistofthenrg1erbb4signalingpathwayforthetreatmentofschizophreniastudydesignandmethodologyofamulticenterrandomizedplacebocontrolledtrial AT susannekarch addonspironolactoneasantagonistofthenrg1erbb4signalingpathwayforthetreatmentofschizophreniastudydesignandmethodologyofamulticenterrandomizedplacebocontrolledtrial AT silviaegertschwender addonspironolactoneasantagonistofthenrg1erbb4signalingpathwayforthetreatmentofschizophreniastudydesignandmethodologyofamulticenterrandomizedplacebocontrolledtrial AT beateschossow addonspironolactoneasantagonistofthenrg1erbb4signalingpathwayforthetreatmentofschizophreniastudydesignandmethodologyofamulticenterrandomizedplacebocontrolledtrial AT philipprothe addonspironolactoneasantagonistofthenrg1erbb4signalingpathwayforthetreatmentofschizophreniastudydesignandmethodologyofamulticenterrandomizedplacebocontrolledtrial AT peterfalkai addonspironolactoneasantagonistofthenrg1erbb4signalingpathwayforthetreatmentofschizophreniastudydesignandmethodologyofamulticenterrandomizedplacebocontrolledtrial |