Examination of Org 26576, an AMPA receptor positive allosteric modulator, in patients diagnosed with major depressive disorder: an exploratory, randomized, double-blind, placebo-controlled trial

Abstract

Org 26576 acts by modulating ionotropic AMPA-type glutamate receptors to enhance glutamatergic neurotransmission. The aim of this Phase 1b study (N=54) was to explore safety, tolerability, pharmacokinetics, and pharmacodynamics of Org 26576 in depressed patients. Part I (N=24) evaluated the maximum tolerated dose (MTD) and optimal titration schedule in a multiple rising dose paradigm (range 100 mg BID to 600 mg BID); Part II (N=30) utilized a parallel groups design (100 mg BID, 400 mg BID, placebo) to examine all endpoints over a 28-day dosing period. Based on the number of moderate intensity adverse events reported at the 600 mg BID dose level, the MTD established in Part I was 450 mg BID. Symptomatic improvement as measured by the Montgomery-Asberg Depression Rating Scale was numerically greater in the Org 26576 groups than in the placebo group in both study parts. In Part II, the 400 mg BID dose was associated with improvements in executive functioning and speed of processing cognitive tests. Org 26576 was also associated with growth hormone increases and cortisol decreases at the end of treatment but did not influence prolactin or brain-derived neurotrophic factor. The quantitative electroencephalogram index Antidepressant Treatment Response at Week 1 was able to significantly predict symptomatic response at endpoint in the active treatment group, as was early improvement in social acuity. Overall, Org 26576 demonstrated good tolerability and pharmacokinetic properties in depressed patients, and pharmacodynamic endpoints suggested that it may show promise in future well-controlled, adequately powered proof of concept trials.

Antidepressant effects of ketamine and the roles of AMPA glutamate receptors and other mechanisms beyond NMDA receptor antagonism

“…In addition, the AMPAkine Org 26576 showed some (although not significant) efficacy, good tolerability and even cognitive enhancement in depressed patients in a small pilot phase 1b clinical trial, but further investigation of AMPAkines for depression is needed. 53 Therefore, conver gent evidence reveals that postsynaptic AMPA receptor acti vation and upregulation is emerging as a crucial factor in mediating ketamine's antidepressant effects 29 -findings that are particularly important at a time when the NMDA recep tor blockade hypothesis of ketamine's antidepressant actions is hotly debated.…”

Involvement of adrenoceptors, dopamine receptors and AMPA receptors in antidepressant-like action of 7-O-ethylfangchinoline in mice

“…In addition, it is well known that ketamine has a short systemic half-life and is extensively metabolized in the liver, which results in a high first-pass effect and thus makes the drug unsuitable for oral delivery. Interestingly, studies have demonstrated that AMPA receptor agonists may also produce antidepressant effects [40,41] . Thus, the development of promising novel agents that target the AMPA receptor is currently possible.…”

Using Our Understanding of Stress-Related Effects on Glutamate Neurotransmission to Guide the Development of Novel Treatment Strategies

“…However, this remains to be confirmed in more definite studies. As will be further discussed below, while blocking NMDARs has antidepressant action, therapies that instead boost AMPAR throughput may be associated with similar types of antidepressant-like therapeutic effects (Chappell et al 2007;Knapp et al 2002;Li et al 2001;Lindholm et al 2012;Nations et al 2012). Correspondingly stress-induced pyramidal cell atrophy can be reduced by blocking NMDAR activation, but not by blocking AMPA receptors (Magariños and McEwen 1995b).…”