Transcranial magnetic stimulation as a translational biomarker for AMPA receptor modulation

Abstract

TAK-653 is a novel α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-positive allosteric modulator being developed as a potential therapeutic for major depressive disorder (MDD). Currently, there are no translational biomarkers that evaluate physiological responses to the activation of glutamatergic brain circuits available. Here, we tested whether noninvasive neurostimulation, specifically single-pulse or paired-pulse motor cortex transcranial magnetic stimulation (spTMS and ppTMS, respectively), coupled with measures of evoked motor response captures the pharmacodynamic effects of TAK-653 in rats and healthy humans. In the rat study, five escalating TAK-653 doses (0.1–50 mg/kg) or vehicle were administered to 31 adult male rats, while measures of cortical excitability were obtained by spTMS coupled with mechanomyography. Twenty additional rats were used to measure brain and plasma TAK-653 concentrations. The human study was conducted in 24 healthy volunteers (23 males, 1 female) to assess the impact on cortical excitability of 0.5 and 6 mg TAK-653 compared with placebo, measured by spTMS and ppTMS coupled with electromyography in a double-blind crossover design. Plasma TAK-653 levels were also measured. TAK-653 increased both the mechanomyographic response to spTMS in rats and the amplitude of motor-evoked potentials in humans at doses yielding similar plasma concentrations. TAK-653 did not affect resting motor threshold or paired-pulse responses in humans. This is the first report of a translational functional biomarker for AMPA receptor potentiation and indicates that TMS may be a useful translational platform to assess the pharmacodynamic profile of glutamate receptor modulators.

Central nervous system effects of TAK-653, an investigational alpha-amino-3-hydroxy-5-methyl-4-isoxazole receptor (AMPAR) positive allosteric modulator in healthy volunteers

“…TAK-653 dose levels of 0.5 mg and 6 mg were selected as the lower dose was expected to have minimum to no effects based on the preclinical data and the higher dose to fall into the pharmacological active range. 22 Both dose levels were well tolerated in the previous healthy volunteer study. 11 Twenty-four healthy volunteers were included in this study.…”

“…As reported in our previous publication, mean (SD) TAK-653 plasma levels for the 0.5 mg dose were 0.99 (0.94) ng/ml at 0.5 hours post-dose and 4.19 (0.83) ng/ml at 2.5 hours post-dose. 22 Plasma levels for the 6 mg dose were 2.57 (3.29) ng/ml at 0.5 hours post-dose and 45.99 (8.84) ng/ml at 2.5 hours post-dose. 22 Functional pharmacodynamic NeuroCart assessments All NeuroCart parameters were normally distributed, except body sway measurements, which were log-normal distributed and therefore natural log transformation was applied for their analysis.…”

“…22 Plasma levels for the 6 mg dose were 2.57 (3.29) ng/ml at 0.5 hours post-dose and 45.99 (8.84) ng/ml at 2.5 hours post-dose. 22 Functional pharmacodynamic NeuroCart assessments All NeuroCart parameters were normally distributed, except body sway measurements, which were log-normal distributed and therefore natural log transformation was applied for their analysis. For interpretation back transformation was applied.…”

“…The study was a randomised, double-blind, placebo-controlled, three-period crossover study (Figure 1). A fourth, open-label period was conducted with ketamine for assay sensitivity, but the TMS and NeuroCart results were equivocal for reasons discussed previously, 22 and will not be discussed here. During the three-period crossover phase, each treatment period was one day in duration and separated by a wash-out period of 10 to 15 days.…”

“…22 It was observed that TAK-653 increased the amplitude of motor evoked potentials, indicative of increased AMPA receptor-mediated cortical excitability. 22 In the current paper, the NeuroCart data will be presented.…”