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; 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; Zimmermann, Stephanie; Schneider‐Axmann, Thomas; Görlitz, Thomas; Karch, Susanne; Egert-Schwender, Silvia; Schossow, Beate; Rothe, Philipp; Falkai, Peter

doi:10.1016/j.conctc.2020.100537

Cited by 17 publications

(12 citation statements)

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“…In line with this hypothesis, olanzapine, risperidone, and haloperidol restored NRG1 and ErbB4 expression levels in mouse primary hippocampal neurons treated with an NMDA antagonist (Li et al 2016). These findings were contrary to the facts that patients with schizophrenia had high hippocampal NRG1 and ErbB4 levels (Petryshen et al 2005;Hahn et al 2006;Law et al 2006) and that blocking NRG1/ErbB4 signaling improves cognitive impairment in these patients (Hasan et al 2020). The degree of alterations in risk genes, the use of different antipsychotics, and different treatment durations may explain this inconsistency.…”

Section: Discussionmentioning

confidence: 81%

“…ErbB4 is the only receptor with a high affinity for NRG1 (Buonanno 2010). NRG1/ErbB4 signaling is strongly linked to working memory dysfunction, and several recent studies have investigated its relevance as a candidate therapeutic pathway for schizophrenia (Yamazaki and Sumikawa 2017;Chung et al 2018;Hasan et al 2020). The loss of ErbB4 signaling decreases the excitatory synaptic inputs to parvalbumin (PV) interneurons, reducing their activity and subsequently lowering activity-dependent PV expression and impairing working memory (Ting et al 2011;delPino et al 2013;Chung et al 2018).…”

Section: Introductionmentioning

confidence: 99%

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Role of the NRG1/ErbB4 and PI3K/AKT/mTOR signaling pathways in the anti-psychotic effects of aripiprazole and sertindole in ketamine-induced schizophrenia-like behaviors in rats

2022

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Schizophrenia is a common mental disorder affecting patients’ thoughts, behavior, and cognition. Recently, the NRG1/ErbB4 signaling pathway emerged as a candidate therapeutic target for schizophrenia. This study investigates the effects of aripiprazole and sertindole on the NRG1/ErbB4 and PI3K/AKT/mTOR signaling pathways in ketamine-induced schizophrenia in rats. Young male Wistar rats received ketamine (30 mg/kg, intraperitoneally) for 5 consecutive days and aripiprazole (3 mg/kg, orally) or sertindole (2.5 mg/kg, orally) for 14 days. The proposed pathway was investigated by injecting LY294002 (a selective PI3K inhibitor) (25 μg/kg, intrahippocampal injection) 30 min before the drugs. Twenty-four hours after the last injection, animals were subjected to behavioral tests: the open field test, sucrose preference test, novel object recognition task, and social interaction test. Both aripiprazole and sertindole significantly ameliorated ketamine-induced schizophrenic-like behavior, as expected, because of their previously demonstrated antipsychotic activity. Besides, both drugs alleviated ketamine-induced oxidative stress and neurotransmitter level changes in the hippocampus. They also increased the gamma-aminobutyric acid and glutamate levels and glutamate decarboxylase 67 and parvalbumin mRNA expression in the hippocampus. Moreover, aripiprazole and sertindole increased the NRG1 and ErbB4 mRNA expression levels and PI3K, p-Akt, and mTOR protein expression levels. Interestingly, pre-injecting LY294002 abolished all the effects of the drugs. This study reveals that the antipsychotic effects of aripiprazole and sertindole are partly due to oxidative stress reduction as well as NRG1/ErbB4 and PI3K/AKT/mTOR signaling pathways activation. The NRG1/ErbB4 and PI3K signaling pathways may offer a new therapeutic approach for treating schizophrenia in humans.

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Section: Discussionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Role of the NRG1/ErbB4 and PI3K/AKT/mTOR signaling pathways in the anti-psychotic effects of aripiprazole and sertindole in ketamine-induced schizophrenia-like behaviors in rats

2022

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“…For neuropsychiatric indications, SPL is given as daily dosage between 100 and 300 mg (Hasan et al., 2020; Hinkelmann et al., 2016; Wernze & Herdegen, 2014). The investigational medicinal product (IMP) was Aldactone ® 50 (Ch.B.…”

Section: Methodsmentioning

confidence: 99%

“…The brain spanning actions of MR render MR antagonists as attractive therapeutic drugs for neuropsychiatric disorders including dysfunctional stress regulation. Thus, it is not surprising that SPL has been investigated for its therapeutic potential in various neuropsychiatric disorders such as depression (Hinkelmann et al., 2016; Juruena et al., 2013; de Kloet et al., 2016), schizophrenia (Hasan et al., 2020; Wehr et al., 2017) or processing of stress responses (Schwabe, Höffken, et al., 2013; Schwabe, Tegenthoff, et al., 2013; Vogel et al., 2015, 2017). Furthermore and relevant for this study, MR has been shown to be involved in pain pathophysiology and MR antagonists including SPL reduce nociception and pain (Dong et al, 2012; Ibrahim et al., 2016; Li et al., 2018; Lilius et al., 2014; Tafelski et al., 2019).…”

Section: Introductionmentioning

confidence: 99%

“…In consequence, cerebral disturbances of the aldosterone-MR system trigger or reinforces neuropsychiatric disorders such as depression (Hinkelmann et al, 2016;de Kloet et al, 2016;Lin et al, 2019), stress-related behavioural adaptation (Juruena et al, 2009;Mifsud & Reul, 2018;Smythe et al, 1997;Vogel et al, 2015Vogel et al, , 2017 or schizophrenia (Hasan et al, 2020;Wehr et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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High‐dose spironolactone lacks effectiveness in treatment of fibromyalgia (RCT)

Böhm¹,

Westermann

Gleim

et al. 2021

European Journal of Pain

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Effects of add-on Celecoxib treatment on patients with schizophrenia spectrum disorders and inflammatory cytokine profile trial (TargetFlame): study design and methodology of a multicentre randomized, placebo-controlled trial

et al. 2022

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Neuroinflammation has been proposed to impact symptomatology in patients with schizophrenia spectrum disorders. While previous studies have shown equivocal effects of treatments with add-on anti-inflammatory drugs such as Aspirin, N-acetylcysteine and Celecoxib, none have used a subset of prospectively recruited patients exhibiting an inflammatory profile. The aim of the study is to evaluate the efficacy and safety as well as the cost-effectiveness of a treatment with 400 mg Celecoxib added to an ongoing antipsychotic treatment in patients with schizophrenia spectrum disorders exhibiting an inflammatory profile. The “Add-on Celecoxib treatment in patients with schizophrenia spectrum disorders and inflammatory cytokine profile trial (TargetFlame)” is a multicentre randomized, placebo-controlled phase III investigator-initiated clinical trial with the following two arms: patients exhibiting an inflammatory profile receiving either add-on Celecoxib 400 mg/day or add-on placebo. A total of 199 patients will be assessed for eligibility by measuring blood levels of three pro-inflammatory cytokines, and 109 patients with an inflammatory profile, i.e. inflamed, will be randomized, treated for 8 weeks and followed-up for additional four months. The primary endpoint will be changes in symptom severity as assessed by total Positive and Negative Syndrome Scale (PANSS) score changes from baseline to week 8. Secondary endpoints include various other measures of psychopathology and safety. Additional health economic analyses will be performed. TargetFlame is the first study aimed at evaluating the efficacy, safety and cost-effectiveness of the antiphlogistic agent Celecoxib in a subset of patients with schizophrenia spectrum disorders exhibiting an inflammatory profile. With TargetFlame, we intended to investigate a novel precision medicine approach towards anti-inflammatory antipsychotic treatment augmentation using drug repurposing. Clinical trial registration:http://www.drks.de/DRKS00029044 and https://trialsearch.who.int/Trial2.aspx?TrialID=DRKS00029044

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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

Cited by 17 publications

References 47 publications

Role of the NRG1/ErbB4 and PI3K/AKT/mTOR signaling pathways in the anti-psychotic effects of aripiprazole and sertindole in ketamine-induced schizophrenia-like behaviors in rats

Role of the NRG1/ErbB4 and PI3K/AKT/mTOR signaling pathways in the anti-psychotic effects of aripiprazole and sertindole in ketamine-induced schizophrenia-like behaviors in rats

High‐dose spironolactone lacks effectiveness in treatment of fibromyalgia (RCT)

Effects of add-on Celecoxib treatment on patients with schizophrenia spectrum disorders and inflammatory cytokine profile trial (TargetFlame): study design and methodology of a multicentre randomized, placebo-controlled trial

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