Abstract
Several electrophysiological parameters, including the auditory evoked response component M50/M100 latencies and the phase synchrony of transient and steady-state gamma-band oscillations have been implicated as atypical (to various extents) in autism spectrum disorder (ASD). Furthermore, some hypotheses suggest that an underlying neurobiological mechanism for these observations might be atypical local circuit function indexed by atypical levels of inhibitory neurotransmitter, GABA. This study was a randomized, placebo-controlled, double-blind, escalating-dose, acute investigation conducted in 25 14–18 year-old adolescents with ASD. The study assessed the sensitivity of magnetoencephalography (MEG) and MEGAPRESS “GABA” magnetic resonance spectroscopy (MRS) to monitor dose-dependent acute effects, as well as seeking to define properties of the pre-drug “baseline” electrophysiological and GABA signatures that might predict responsiveness to the GABA-B agonist, arbaclofen (STX-209). Overall, GABA levels and gamma-band oscillatory activity showed no acute changes at either low (15 mg) or high (30 mg) dose. Evoked M50 response latency measures tended to shorten (normalize), but there was heterogeneity across the group in M50 latency response, with only a subset of participants (n = 6) showing significant M50 latency shortening, and only at the 15 mg dose. Findings thus suggest that MEG M50 latency measures show acute effects of arbaclofen administration in select individuals, perhaps reflecting effective target engagement. Whether these subjects have a greater trend towards clinical benefit remains to be established. Finally, findings also provide preliminary support for the use of objective electrophysiological measures upon which to base inclusion for optimal enrichment of populations to be included in full-scale clinical trials of arbaclofen.
Highlights
The drug arbaclofen (STX-209) is a promising candidate for pharmaceutical therapy for use in autism spectrum disorder (ASD; Veenstra-VanderWeele et al, 2017) and fragile X syndrome (Berry-Kravis et al, 2012, 2017; Henderson et al, 2012; Qin et al, 2015), unsuccessful clinical trial outcomes challenge the excitation/inhibition imbalance hypothesis of ASD (Rubenstein and Merzenich, 2003), that helped motivate the development of arbaclofen
MEG measures of auditory sensory processing appear responsive to a particular dose of the GABA-B agonist, STX-209 in a subset of adolescents with ASD
It is possible that this responsiveness indicates an observable marker of differential drug biological activity in some individuals vs. others
Summary
The drug arbaclofen (STX-209) is a promising candidate for pharmaceutical therapy for use in autism spectrum disorder (ASD; Veenstra-VanderWeele et al, 2017) and fragile X syndrome (Berry-Kravis et al, 2012, 2017; Henderson et al, 2012; Qin et al, 2015), unsuccessful clinical trial outcomes challenge the excitation/inhibition imbalance hypothesis of ASD (Rubenstein and Merzenich, 2003), that helped motivate the development of arbaclofen. Given between-individual differences in the neurobiology of ASD, broad inclusion criteria in clinical trials, as commonly employed, would diminish the ability to resolve positive change if the drug was only effective only in a subset of participants. To begin exploring the above, it is of interest to demonstrate, in an acute setting, whether a participant who is a potential candidate for inclusion in a clinical trial manifests evidence in support of pharmaceutical target engagement via a single ‘‘test’’ dose administration. With respect to changes in symptoms associated with a disorder, an acute readout is unlikely to be a behavioral measure (e.g., in ASD, changes in repetitive behaviors) as behavioral and symptom changes in ASD likely occur over an extended period of time (weeks to months). If only a subset of potential participants did exhibit an acute drug-related response, examination of this subgroup might identify candidates distinguished by demographic or other baseline characteristics
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