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      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

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          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

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          Most cited references36

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          The positive and negative syndrome scale (PANSS) for schizophrenia.

          L Opler, Jennifer Kay, Paul Opler … (1986)
          The variable results of positive-negative research with schizophrenics underscore the importance of well-characterized, standardized measurement techniques. We report on the development and initial standardization of the Positive and Negative Syndrome Scale (PANSS) for typological and dimensional assessment. Based on two established psychiatric rating systems, the 30-item PANSS was conceived as an operationalized, drug-sensitive instrument that provides balanced representation of positive and negative symptoms and gauges their relationship to one another and to global psychopathology. It thus constitutes four scales measuring positive and negative syndromes, their differential, and general severity of illness. Study of 101 schizophrenics found the four scales to be normally distributed and supported their reliability and stability. Positive and negative scores were inversely correlated once their common association with general psychopathology was extracted, suggesting that they represent mutually exclusive constructs. Review of five studies involving the PANSS provided evidence of its criterion-related validity with antecedent, genealogical, and concurrent measures, its predictive validity, its drug sensitivity, and its utility for both typological and dimensional assessment.
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            Neuregulin 1 in neural development, synaptic plasticity and schizophrenia.

            Lin Mei, Wen-Cheng Xiong (2008)
            Schizophrenia is a highly debilitating mental disorder that affects approximately 1% of the general population, yet it continues to be poorly understood. Recent studies have identified variations in several genes that are associated with this disorder in diverse populations, including those that encode neuregulin 1 (NRG1) and its receptor ErbB4. The past few years have witnessed exciting progress in our knowledge of NRG1 and ErbB4 functions and the biological basis of the increased risk for schizophrenia that is potentially conferred by polymorphisms in the two genes. An improved understanding of the mechanisms by which altered function of NRG1 and ErbB4 contributes to schizophrenia might eventually lead to the development of more effective therapeutics.
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              Cognition in schizophrenia: core psychological and neural mechanisms.

              Deanna Barch, Alan Ceaser (2012)
              The challenge in understanding cognitive impairment in schizophrenia is that people with this illness have deficits in an array of domains. Here, we briefly review evidence regarding the pattern of deficits within three domains: context processing, working memory and episodic memory. We suggest that there may be a common mechanism driving deficits in these domains - an impairment in the ability to actively represent goal information in working memory to guide behavior, a function we refer to as proactive control. We suggest that such deficits in proactive control reflect impairments in dorsolateral prefrontal cortex, its interactions with other brain regions, such as parietal cortex, thalamus and striatum, and the influence of neurotransmitter systems, such as dopamine, GABA and glutamate. Copyright © 2011 Elsevier Ltd. All rights reserved.
              Article 0 comments Cited 182 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Alkomiet Hasan
                Journal
                Journal ID (nlm-ta): Contemp Clin Trials Commun
                Journal ID (iso-abbrev): Contemp Clin Trials Commun
                Title: Contemporary Clinical Trials Communications
                Publisher: Elsevier
                ISSN (Electronic): 2451-8654
                Publication date PMC-release: 28 January 2020
                Publication date Collection: March 2020
                Publication date (Electronic): 28 January 2020
                Volume: 17
                Electronic Location Identifier: 100537
                Affiliations
                [a ]Department of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians University München, Germany
                [b ]Department of Psychiatry, Psychotherapy and Psychosomatics of the University Augsburg, Bezirkskrankenhaus Augsburg, University of Augsburg, Augsburg, Germany
                [c ]Department of Psychiatry and Psychotherapy, Technical University of Munich, Munich, Faculty of Medicine, Klinikum Rechts der Isar, Germany
                [d ]Department of Psychiatry and Psychotherapy, University of Regensburg, Germany
                [e ]Münchner Studienzentrum, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany
                [f ]Department of Forensic Psychiatry and Psychotherapy, Ulm University, Ulm, Germany
                Author notes
                [∗ ]Corresponding author. Department of Psychiatry & Psychotherapy, Klinikum der Universität München, Ludwig-Maximilians University Munich, Nußbaumstraße 7, D-80336, Munich, Germany. alkomiet.hasan@ 123456med.uni-muenchen.de
                [1]

                both authors contributed equally.

                Article
                Publisher ID: S2451-8654(20)30021-1 Publisher ID: 100537
                DOI: 10.1016/j.conctc.2020.100537
                PMC ID: 7013159
                PubMed ID: 32072071
                SO-VID: 885c2346-e2cb-44f5-822e-94fbbdc38be3
                Copyright © © 2020 The Author(s)
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 1 September 2019
                Date revision received : 18 January 2020
                Date accepted : 26 January 2020
                Categories
                Subject: Article

                Keywords: schizophrenia,cognitive impairment,spironolactone,nrg1-erbb4,drug repositioning,drug repurposing
                Data availability:
                Keywords: schizophrenia, cognitive impairment, spironolactone, nrg1-erbb4, drug repositioning, drug repurposing

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