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.
Highlights
IntroductionIntroduction According to the GlobalBurden of Diseases, Injuries, and Risk Factors study in 20171 depressive disorders such as major depressive disorder (MDD) are amongst the leading causes for years lived with disability (YLD) worldwide
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O’Donnell et al Translational Psychiatry (2021)11:325 acid (GABA) interneuron function that enhances glutamate function and increases α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid receptor (AMPAR)mediated signaling[7]. This leads to a release of brainderived neurotrophic factor (BDNF) and stimulation of mammalian target of rapamycin signaling, which are both hypothesized to play a role in the pathophysiology of depressive disorders[7]
Summary
Introduction According to the GlobalBurden of Diseases, Injuries, and Risk Factors study in 20171 depressive disorders such as major depressive disorder (MDD) are amongst the leading causes for years lived with disability (YLD) worldwide. In 2000 it was demonstrated that subanesthetic doses of ketamine, an N-methyl-D-aspartate-receptor (NMDAR) antagonist, had antidepressant effects in patients with depression[4]. The mechanisms by which ketamine exerts its antidepressant effects are not yet fully understood, it has been demonstrated that NMDAR blockade leads to a selective reduction in γ-aminobutyric. O’Donnell et al Translational Psychiatry (2021)11:325 acid (GABA) interneuron function that enhances glutamate function and increases α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid receptor (AMPAR)mediated signaling[7]. This leads to a release of brainderived neurotrophic factor (BDNF) and stimulation of mammalian target of rapamycin (mTOR) signaling, which are both hypothesized to play a role in the pathophysiology of depressive disorders[7]. It is hypothesized that direct AMPA receptor potentiation might lead to similar antidepressant efficacy as ketamine, without causing the psychotomimetic side effects commonly observed after ketamine administration[9]
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