A randomised, double-blind, placebo-controlled trial of tropisetron in patients with schizophrenia

Abstract

BackgroundCognitive deficits in schizophrenia are associated with psychosocial deficits that are primarily responsible for the poor long-term outcome of this disease. Auditory sensory gating P50 deficits are correlated with neuropsychological deficits in attention, one of the principal cognitive disturbances in schizophrenia. Our studies suggest that the α7 nicotinic acetylcholine receptor (α7 nAChR) agonist tropisetron might be a potential therapeutic drug for cognitive deficits in schizophrenia. Therefore, it is of particular interest to investigate the effects of tropisetron on the cognitive deficits in patients with schizophrenia.MethodsA randomised, placebo-controlled trial of tropisetron in patients with schizophrenia was performed. A total of 40 patients with chronic schizophrenia who had taken risperidone (2 to 6 mg/day) were enrolled. Subjects were randomly assigned to a fixed titration of tropisetron (n = 20, 10 mg/day) or placebo (n = 20) in an 8-week double-blind trial. Auditory sensory gating P50 deficits and Quality of Life Scale (QLS), Cambridge Neuropsychological Test Automated Battery (CANTAB), and Positive and Negative Syndrome Scale (PANSS) scores were measured.ResultsIn all, 33 patients completed the trial. Tropisetron was well tolerated. Administration of tropisetron, but not placebo, significantly improved auditory sensory gating P50 deficits in non-smoking patients with schizophrenia. The score on the rapid visual information processing (sustained visual attention) task of CANTAB was significantly improved by tropisetron treatment. Total and subscale scores of PANSS were not changed by this trial. QLS scores in the all patients, but not non-smoking patients, were significantly improved by tropisetron trial.ConclusionsThis first randomised, double-blind, placebo-controlled trial supports the safety and efficacy of adjunctive tropisetron for treatment of cognitive deficits in schizophrenia.

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

“…The logical next steps for proof-of-concept were obtained in early clinical studies using a7 nAChR agonists (Olincy et al, 2006;Tregellas et al, 2011;Barbier et al, 2015;Preskorn et al, 2014). Although a more detailed discussion of these clinical trials is presented in section III, it is important to note that studies of the 5-HT 3 receptor antagonist tropisetron, which also acts as an agonist at a7 nAChRs, caused a normalization of the P50 response in schizophrenic patients (Shiina et al, 2010;Zhang et al, 2012).…”

“…Tropisetron, an a7 nAChR agonist/5-HT 3 receptor antagonist (K i = 6.9 nM for a7 nAChRs and K i = 5.3 nM for 5-HT 3 receptors), which is primarily used as an antiemetic, was reported to improve sustained attention and to significantly improve sensory gating in a randomized, double-blind, placebo-controlled study in schizophrenia (Shiina et al, 2010). More recently, FORUM reported an improvement in cognitive deficits with encenicline, another a7 nAChR agonist/5-HT 3 receptor antagonist using the CogState test battery, with trends for improvement on the MCCB composite score, as well as improvement in the SANS in a Phase 2, double-blind, placebo-controlled clinical trial in schizophrenia that included smokers and nonsmokers .…”

Nicotinic Acetylcholine Receptor Alterations in Autism Spectrum Disorders – Biomarkers and Therapeutic Targets

“…Auditory sensory gating P50 deficits are correlated with neuropsychological deficits in attention, one of the principal cognitive disturbances in schizophrenia. In a clinical trial with 33 schizophrenic patients administration of tropisetron, without placebo, significantly improved auditory sensory gating P50 deficits in non-smoking patients with schizophrenia (Shiina et al, 2010). In mice, the early postnatal period represents a critical time window essential for brain development.…”

Tropisetron and its targets in Alzheimer’s disease

“…In addition to its 5-HT 3 receptor antagonism properties, tropisetron is also a partial agonist at the a7 nAChR. Tropisetron (5 --20 mg/day) is reportedly effective in the treatment of auditory sensory gating P50 deficits, cognitive impairment, and negative symptoms in patients with schizophrenia [8][9][10][11], indicating that tropisetron would be a potential therapeutic drug for schizophrenia [3,12].…”