Polygenic Constraints on NAD⁺ Metabolism in Major Psychiatric Illness: Mechanistic Support for NMN Supplementation

Rapid-acting glutamatergic antidepressants such as ketamine and esketamine can produce striking short-term responses in treatment-resistant depression, but relapse is common and long-term durability remains limited. Cheung’s pruning-plasticity-aging framework proposes that persistent vulnerability arises from excessive developmental synaptic pruning, followed by failed adult plasticity and amplification by senescence-related processes. Within that framework, the senescence component has received less genetic attention than the others. To address that gap, a transdiagnostic S-PrediXcan analysis was conducted across eight NMN- and NAD+-related gene sets using Psychiatric Genomics Consortium summary statistics for major depressive disorder, bipolar disorder, obsessive-compulsive disorder, and schizophrenia. Across core NAD+ salvage, biosynthesis, and mitochondrial respiration pathways, the pattern was generally one of modest negative enrichment, although none of these signals survived permutation testing, with all permutation p values above .16. At the gene level, several recurrent signals stood out. NAMPT, the rate-limiting enzyme in NAD+ salvage, showed consistent downregulation, with a mean Z of -2.89. The nucleotidase NT5C showed an even stronger negative pattern, with a mean Z of -7.37. Negative signals were also evident for mitochondrial sirtuin SIRT4 and the immune-mitochondrial gene CD40. By contrast, the mitochondrial NAD+ transporters SLC25A17 and SLC25A51 showed positive Z-scores, which may reflect compensation. Taken together, these results suggest a genetically predicted salvage bottleneck that could accelerate NAD+ depletion during stress or aging, weaken mitochondrial function, and promote senescence-associated inflammation. On that basis, a “NAD+ Salvage Bottleneck-Senescence Amplifier” mechanism is proposed as one process that may reinforce the pruning-plasticity-aging triad. Exogenous NMN may be able to bypass this bottleneck, restore mitochondrial NAD+, and provide bioenergetic support for sustained synaptogenesis when added to the Cheung Glutamatergic Regimen. The findings do not provide definitive proof, but they do offer a modest and internally coherent genetic rationale for testing NMN augmentation in treatment-resistant depression and for pursuing biomarker-stratified pilot studies.