N-Acetylcysteine as a Mechanistic Adjunct to the Cheung Glutamatergic Regimen: Aligning an Oral Ketamine-Like Strategy with the Two-Stage Polygenic Model of Major Depressive Disorder

Major depressive disorder remains a stubborn clinical problem. A sizeable share of patients either fail to respond or respond only slowly to standard antidepressants that target monoamine systems. Over the past decade, interest has grown in glutamatergic pathways capable of producing faster antidepressant effects. Ketamine, for instance, appears to shift signalling away from NMDA-receptor-dominant transmission and toward AMPA-receptor-dominant transmission, setting off downstream processes that favour synaptic repair. Drawing on this line of work, Cheung (2025) put forward the Cheung Glutamatergic Regimen (CGR), an oral combination of four components: dextromethorphan (whose metabolism is slowed by a CYP2D6 inhibitor), piracetam acting as a positive allosteric modulator at AMPA receptors, and L-glutamine included both to supply glutamate precursor material and to buffer against excitotoxicity. The regimen was designed as a practical, affordable alternative that might approximate the plasticity cascade seen with ketamine, though its focus was largely on acute synaptic mechanisms in the adult brain. A separate but related body of genetic evidence has drawn attention to when, developmentally, risk for depression first takes shape. A re-analysis of large-scale genome-wide association study data put forward a two-stage polygenic model: in the first stage, spanning prenatal life through infancy, common genetic variants drive neuron-autonomous synaptic pruning that quietly weakens certain circuits; in the second stage, occurring later in development and into adulthood, deficits emerge in the regulation of synaptic plasticity alongside reduced oligodendrocyte-mediated metabolic support (Cheung, 2026). One implication of this framework is that treatments targeting only acute plasticity in adulthood may leave individuals vulnerable to relapse whenever stress mounts again. We propose that N-acetylcysteine (NAC), taken orally at doses between 600 and 2400 mg per day, could usefully be added to the CGR as a fifth component. NAC acts on the cystine-glutamate antiporter, and through this mechanism it may help regulate glutamate concentrations in the extracellular space in a way that complements what L-glutamine already provides. Work in animal models has further shown that NAC can support long-term potentiation, brain-derived neurotrophic factor signalling, and the health and function of oligodendrocytes when these cells are stressed by oxidation or inflammation. Such effects speak directly to the adult-phase vulnerabilities described in the two-stage polygenic model, and they may also partly compensate for circuit weaknesses left behind by earlier excessive pruning. From a safety standpoint, NAC does not interact in any clinically meaningful way with CYP2D6 substrates or inhibitors, and previous trials have found it to be well tolerated when given alongside existing antidepressant medications. This paper lays out the mechanistic reasoning behind the proposed augmentation, offers specific predictions that can be tested empirically — among them, greater symptom reduction compared with CGR alone, changes in electroencephalographic markers associated with plasticity, and shifts in myelin-sensitive neuroimaging — and outlines practical steps for putting the augmented regimen into use. Formal studies, both preclinical and clinical, are now needed to determine whether adding NAC meaningfully improves outcomes achieved with the Cheung Glutamatergic Regimen. Keywords: N-acetylcysteine, Cheung Glutamatergic Regimen, synaptic plasticity, oligodendrocytes, rapid-acting antidepressants, polygenic risk, major depressive disorder