Into the Darkness: A Thiamine-Dependent Functional Reserve Hypothesis of Affective Decompensation

Severe neuropsychiatric decompensation is commonly organized into syndromic diagnoses that describe phenotype without necessarily identifying upstream physiology. This paper develops the hypothesis that normal cerebral function requires adequate thiamine-dependent metabolic capacity and that neurological and neuropsychiatric abnormality emerges when effective cerebral thiamine-dependent capacity becomes insufficient relative to prevailing demand. The hypothesis does not require every psychiatric presentation to arise through this mechanism or every affected person to express the same phenotype. The Dynamic-Reserve framework represents the relationship between effective capacity and demand as RT(t)=CT(t)−DT(t), with declining reserve predicted to produce increasing fragility, nonlinear perturbation sensitivity, and domain-specific dysfunction. The Pre-Darkness Descent describes progressive loss of functional margin before severe decompensation; the Darkness denotes the proposed severe low-reserve neuropsychiatric state. Activated and low-output phenotypes may arise along the same physiological trajectory. Borrowed Function extends the model to external substances, behaviors, activities, relationships, or other regulators that may become increasingly important because they temporarily supply function the organism is struggling to generate internally. Whole-blood TPP is interpreted according to a Compartment Rule: it characterizes the sampled blood compartment but cannot by itself establish cerebral thiamine availability, target engagement, or functional sufficiency. The accompanying Addendum develops a Perturbation Chain distinguishing administered dose, systemic exposure, cerebral exposure, target engagement, metabolic correction, and functional correction, and extends the framework to route and exposure profile, patient-state pharmacokinetic compression, route-dependent oral delivery, magnesium co-limitation, medication-state recalibration, and rechallenge. The central hypothesis is explicitly falsifiable: a genuine Darkness phenotype should not occur in a person whose relevant cerebral thiamine-dependent functional capacity is demonstrably adequate relative to demand. Prospective testing requires longitudinal characterization of physiology and phenotype, explicit assessment of target engagement, and reproducible state change across deterioration and restoration.