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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.

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.

SUBMITTER: Hasan A

PROVIDER: S-EPMC7013159 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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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.

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

Contemporary clinical trials communications 20200128

<h4>Background</h4>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 ...[more]

PMID: 32072071

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Project description:Abstract Background Patients with schizophrenia often display three main types of symptoms: positive symptoms (e.g. auditory hallucinations or delusions), negative symptoms (e.g. blunted affect, lack or decline in speech, social withdrawal) and cognitive symptoms (e.g. impairment of working memory and declarative memory). Treatment of positive symptoms with available antipsychotics is well established, while therapy options for cognitive and negative symptoms are lacking. Neurobiological studies identified an enhanced NRG1-ERBB4 signaling as a risk pathway in schizophrenia. Spironolactone was found to function as an inhibitor of the ERBB4 receptor. In Nrg1 type III transgenic mice, spironolactone treatment led to an improvement of schizophrenia-like symptoms (Wehr et al. 2017). This is the first study to investigate an add-on spironolactone treatment in schizophrenia patients for the treatment of cognitive deficits. Methods This is a multicenter, randomized, double-blind, parallel (3-groups), longitudinal pilot study including 3 x 27 (81) patients with a clinically stable schizophrenia. Patients are randomized in three groups: one group receives add-on spironolactone 100 mg for three weeks (intervention I), one group receives add-on spironolactone 200 mg for three weeks (intervention II) and one group receives add-on placebo for three weeks (control group). The primary endpoint is the modification of the working memory in dependence to the intervention as investigated with the n-back task (0-, 1- and 2-back). Secondary endpoints include: modification of other cognitive functions (e.g. declarative memory and attention), psychopathology (e.g. PANSS and CDSS), overall level of functioning via GAF and severity of disease via CGI, changes in the number of patients in remission using the Andreasen Criteria, modifications of the inhibitory cortical function in the context of the prepuls paradigm with TMS, evaluating possible dose-differences, spironolactone effects on mRNA levels in peripheral blood lymphocytes (PBMC measures). Statistical analysis of the primary endpoint will be based on the intention-to-treat (ITT) population including all randomised patients using a mixed model ANOVA. Results The first patient was recruited in July 2015. Currently 45 patients are included in the trial. The overall tolerance of the medication was satisfactory with 48 reported AE (adverse events). In 3 cases, the causality of the medication was definite, in 4 cases probable and in 5 cases possible. The other cases were probably or definitely not related to the study medication. SAE (serious adverse events) were not reported. The current state of research will be discussed on the conference. Discussion This is the first study to describe the effects of an add-on treatment of spironolactone in patients with a clinically stable schizophrenia. Also, it is the first study with a direct target of a biochemically disturbed signaling pathway in schizophrenia patients with a possibly new treatment option in this severe disease. Funded by Stanley Foundation: (13T-004). EUDRACT: 2014-001968-35, WHO-Clinical-Trials: http://apps.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2014-001968-35-DE Reference: 1. Wehr, M.C., Hinrichs, W., Brzózka, M.M., Unterbarnscheidt, T., Herholt, A., Wintgens, J.P., Papiol, S., Soto-Bernardini, M.C., Kravchenko, M., Zhang, M., et al. (2017). Spironolactone is an antagonist of NRG1-ERBB4 signaling and schizophrenia-relevant endophenotypes in mice. EMBO Mol. Med.

Project description:NRG1 is a schizophrenia candidate gene and plays an important role in brain development and neural function. Schizophrenia is a complex disorder, with etiology likely due to epistasis.To examine epistasis between NRG1 and selected N-methyl-d-aspartate-glutamate pathway partners implicated in its effects, including ERBB4, AKT1, DLG4, NOS1, and NOS1AP.Schizophrenia case-control sample analyzed using machine learning algorithms and logistic regression with follow-up using neuroimaging on an independent sample of healthy controls.A referred sample of schizophrenic patients (n = 296) meeting DSM-IV criteria for schizophrenia spectrum disorder and a volunteer sample of controls for case-control comparison (n = 365) and a separate volunteer sample of controls for neuroimaging (n = 172).Epistatic association between single-nucleotide polymorphisms (SNPs) and case-control status; epistatic association between SNPs and the blood oxygen level-dependent physiological response during working memory measured by functional magnetic resonance imaging.We observed interaction between NRG1 5' and 3' SNPs rs4560751 and rs3802160 (likelihood ratio test P = .00020) and schizophrenia, which was validated using functional magnetic resonance imaging of working memory in healthy controls; carriers of risk-associated genotypes showed inefficient processing in the dorsolateral prefrontal cortex (P = .015, familywise error corrected). We observed epistasis between NRG1 (rs10503929; Thr286/289/294Met) and its receptor ERBB4 (rs1026882; likelihood ratio test P = .035); a 3-way interaction with these 2 SNPs and AKT1 (rs2494734) was also observed (odds ratio, 27.13; 95% confidence interval, 3.30-223.03; likelihood ratio test P = .042). These same 2- and 3-way interactions were further biologically validated via functional magnetic resonance imaging: healthy individuals carrying risk genotypes for NRG1 and ERBB4, or these 2 together with AKT1, were disproportionately less efficient in dorsolateral prefrontal cortex processing. Lower-level interactions were not observed between NRG1 /ERBB4 and AKT1 in association or neuroimaging, consistent with biological evidence that NRG1 × ERBB4 interaction modulates downstream AKT1 signaling.Our data suggest complex epistatic effects implicating an NRG1 molecular pathway in cognitive brain function and the pathogenesis of schizophrenia.

Dataset Information

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.

Publications

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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