Augmenting the Cheung Glutamatergic Regimen with a Senescence-Modulator Arm: Mechanistic Rationale for NMN, Intermittent Senolytics, and N-Acetylcysteine in Treatment-Resistant Depression

Major depressive disorder remains a major source of disability, and treatment resistance continues to limit the long-term effectiveness of standard antidepressant care. Ketamine-class therapies have changed the acute treatment landscape by producing rapid improvement in some patients, but their use is constrained by cost, supervision requirements, limited access, and high relapse rates after initial response. These limitations have increased interest in oral, mechanism-based alternatives. One such proposal is the Cheung Glutamatergic Regimen, which combines low-dose dextromethorphan, a CYP2D6 inhibitor, and piracetam, with glutamine or N-acetylcysteine added in some cases. Early naturalistic reports suggest that this regimen may produce rapid improvement in refractory depressive and obsessive-compulsive symptoms and may even allow some patients to transition from esketamine treatment (Cheung, 2025).Cheung’s broader etiological model of major depressive disorder argues that the disorder is rooted in excessive developmental synaptic pruning, followed later by impaired adult plasticity and reduced cognitive reserve, with cellular senescence acting as a further amplifier of vulnerability (Cheung, 2026a, 2026b, 2026d). In a March 2026 preprint, Cheung explicitly proposed that the glutamatergic regimen should be explored together with N-acetylcysteine and aging-focused modulators to address this pruning-plasticity-aging triad (Cheung, 2026d). The present hypothesis follows directly from that suggestion and outlines a minimal senescence-modulator arm consisting of nicotinamide mononucleotide for NAD+ restoration and mitochondrial support, intermittent senolytics such as fisetin or dasatinib plus quercetin to reduce senescence-associated secretory phenotype burden, and ongoing N-acetylcysteine to support redox balance and glutamate homeostasis.Mechanistically, this adjunctive arm could provide the metabolic support needed for sustained mTOR- and BDNF-linked synaptogenesis, reduce glial-immune noise that interferes with plasticity consolidation, and stabilize glutamatergic signaling during the remodeling window. These proposed actions fit closely with the glial-immune and peripheral-metabolic pathways highlighted in Cheung’s transcriptomic and computational work. If early testing supports the idea, this combination could improve the durability of remission, reduce residual fatigue and cognitive symptoms, and potentially offer modest protection against accelerated brain aging. At present, however, the proposal remains hypothetical. Open-label pilot studies followed by stratified randomized trials will be needed to evaluate feasibility, target engagement, safety, and clinical value within Cheung’s evolving framework. Keywords: depression; synaptic pruning; cellular senescence; NMN; senolytics; glutamatergic regimen; treatment-resistant depression