Treating the Base, Not the Top: A Friction-Theoretic Hypothesis for Cofactor-Support Below the Diagnostic Threshold

A Hypothesis & Theory synthesis on one-carbon metabolism, the MTHFR C677T polymorphism, and depression, and on targeted (high-risk) prevention and screening. It builds on the established gene–cofactor and screening literature (Bjelland et al. 2003; Gilbody et al. 2007; Tiemeier et al. 2002; Rose 1985; Dobrow et al. 2018) and proposes one pre-registrable prediction: that measured baseline cofactor status moderates the transition from sub-threshold to manifest mood disorder among risk-variant carriers. It is a perspective and an invitation to test that prediction against the existing literature. v4 (August 2026). This version credits the prior literature the sub-threshold argument builds on: treating below a diagnostic threshold is positioned as an established, non-novel strategy whose precedents point both ways (the subclinical-hypothyroidism trials that found no benefit, and the strongly-recommended iron repletion for restless-legs syndrome), and the high-risk-prevention and screening traditions are credited; the paper's own contribution is narrowed to the substrate-route framing and the gene-by-cofactor manifestation prediction, with a pre-specified joint status-plus-consequence criterion as its operational instantiation. Friction Theory's positioning is clarified: it is described as a mechanism-level framework standing on the sequential-sampling, information-cost, and resource-rational-analysis traditions, with the nesting of Behavioural Friction Theory within it stated as a working hypothesis rather than an established entailment. Companion-paper citations now point to their published records. Editorial pass. Earlier versions remain in the version history.