Lack of the effect of bumetanide, a selective NKCC1 inhibitor, in patients with schizophrenia: A double-blind randomized trial.

T HE EXCITATORY FUNCTION of GABA has been reported to contribute to the pathogenesis of some neuropsychological disorders, for example autism and epilepsy. The switch in GABA function, from inhibitory to excitatory, has been attributed to the alteration of cation-chloride cotransporters involved in the regulation of intercellular chloride concentration, chloride-intruder NKCC1 and chlorideextruder KCC2. A recent post-mortem study revealed that the NKCC1/KCC2 expression ratio is reduced in hippocampal formation of schizophrenic patients, which notably indicates that GABA may be excitatory in this region. In accordance, it has been suggested that hippocampal overactivity may underlie dopaminergic system dysregulation in cortical and subcortical regions. Bumetanide, a selective NKCC1 inhibitor, works as a potent agent for restoring the inhibitory function of GABA. Recently, the therapeutic effect of bumetanide in some neurological disorders, such as autism and epilepsy, has been shown. Thus, we designed a study to investigate the effect of bumetanide on patients with schizophrenia. The present study was registered in the official clinical trial registration system of the Iranian Health Ministry with registration number IRCT2014012616374N1. All of the procedures and treatments were approved by the local ethics committee of the University of Social Welfare and Rehabilitation Sciences with ethical number USWR. REC.1392.47. Twenty-six patients with schizophrenia were enrolled in this study. In summary, the diagnosis of schizophrenia, at any subtype, according to the DSM-IV, was the mainstay of patients’ enrollment and patients were excluded: (i) if they had a total score of <65 on the Positive and Negative Syndrome Scale (PANSS); (ii) if they had a documented fluctuation in symptoms; or (iii) if they had concurrent history of significant psychiatric disorder (except schizophrenia) or any other significant organ disorders. All patients and their families provided written consent. The experimental group (n = 14) received bumetanide tablet orally 1 mg twice daily while the control group (n = 12) received placebo in the same way. All patients were allowed to continue their routine antipsychotic drugs during the study. Duration of treatment was 2 months. For each group, the PANSS total score, PANSS subscores (Positive, Negative, and Cognitive), and the Brief Psychiatric Rating Scale (BPRS) total score were determined at the beginning, 1 and 2 months after treatment, and 1 month after a drug-free washout period (Table 1). Results of two-way repeated-measure analysis of variance revealed that in schizophrenic patients, treatment with bumetanide or placebo had no significant effect on: PANSS total score, F(1, 24) = 1.47, P = 0.236; PANSS Positive subscore, F(1, 24) = 0.012, P = 0.913; PANSS Negative subscore, F(1, 24) = 1.492, P = 0.234; or PANSS Cognitive subscore, F(1, 24) = 1.33, P = 0.259. Also, the effect of interaction of time and treatment on PANSS score was not significantly different, F(3, 72) = 0.098, P = 0.961. In addition, our results