Treating Autism with Bumetanide By YehezkelBen‐Ari, ÉricLemonnier, NouchineHadjikhani, Cambridge scholars publishing. 2023. pp. 105

The first chapter provides an overview of neurons, synapses, neural networks, ionic currents and the central stages of brain development. The main section deals with the two principal chemical mediators in the brain, which are the neurotransmitters glutamate and gamma-aminobutyric acid (GABA). The glutamatergic neurons release glutamate that triggers excitatory currents, and the GABAergic neurons release GABA that translates into inhibitory currents. However, before birth, GABA plays an excitatory trophic role, due to the high chloride concentrations in the neurons. The chapter describes the two regulators of intracellular chloride levels, namely the NKCC1 chloride importer and the KCC2 exporter. The normal shift of GABA, from excitatory in the embryo to inhibitory after birth, is due to a switch from a high to low chloride content in the nerve cells. In addition, animal studies have demonstrated that the fall in chloride concentration around birth, which changes the glutamate:GABA ratio, is also mediated by oxytocin. Despite this, we do not know exactly when this switch occurs in humans. A molecule like bumetanide selectively blocks NKCC1, lowering the intracellular chloride concentration and reinforcing the inhibition of young neurons. The authors linked this scientific knowledge to reports from parents about the paradoxical effects that sedative medication may have had on their child when given before a medical investigation, such as MRI (magnetic resonance imaging). These excitatory, rather than inhibitory effects in children with autism, paved the way for studying treatment with the diuretic bumetanide. The chapter on what autism, and its related disorders are, explores a large range of aetiologies. It also looks at clinical presentations and the coexistence of other neurodevelopmental disorders in autism. There are some case presentations on children with autism, illustrated with clinical pictures and clinical improvements seen after treatment with the bumetanide. A special chapter is devoted to brain imaging of individuals with autism, especially studies of amygdala, a structure that is hypersensitive to eye contact. There is evidence to support that the amygdala is over activated in people with autism. The background to the imaging study was the authors' reflection on the cause of the common gaze avoidance in individuals with autism. Interesting results were obtained from a functional magnetic resonance imaging study by Hadjikhani et al in a paper published in 2018. This demonstrated that administering bumetanide normalised the level of amygdala activation during constrained eye contact with emotional face stimuli. In the final part of the book, the authors report their experiences of the implementation of their multi-centre treatment study. However, the final phase III study, which was carried out between 2019 and 2022, demonstrated no significant differences between children treated with bumetanide and a placebo. This was in contrast to many other phase II trials with bumetanide treatment. New studies are now underway that aim to identify which subpopulations of children with autism will respond to bumetanide. There are already published studies showing that excitatory and inhibitory sensitive electroencephalography measures can be a valuable tool to identify responders. The authors state that bumetanide will remain a significant treatment option if it is efficient enough to reduce the effects of autism in 25%–30% of children. So, the story has not ended. As Yehezkel Ben-Ari, one of the authors says, 'Discoveries are always made on side roads, not on highways'.