Toward Precision Psychiatry in Major Depressive Disorder: A Symptom-Level Bioenergetic-Plasticity Model Linking Mitochondrial Function, NAD⁺ Metabolism, and Treatment Response

Major depressive disorder remains a major source of disability worldwide, yet many patients do not recover fully with existing treatments. Some experience only partial improvement, while others receive little meaningful benefit. One reason for this limited success is that major depressive disorder is highly heterogeneous, both clinically and biologically, but current diagnostic systems often treat it as a single condition. Recent work has therefore shifted attention toward symptom-level and dimensional approaches, in which individual depressive symptoms are viewed as potentially informative biological signals rather than interchangeable features of one syndrome.This manuscript synthesizes seven 2026 preprints by Cheung that used multi-tissue transcriptome-wide association studies and competitive gene-set analyses to examine symptom-structured genome-wide association data in major depressive disorder. Across these studies, individual symptoms showed distinct patterns of enrichment in mitochondrial, NAD⁺, synaptic plasticity, pruning, and senescence-related pathways. The same body of work also reported symptom-specific genetic proximity to bipolar disorder, obsessive-compulsive disorder, and schizophrenia, as well as associations between predicted gene expression and antidepressant treatment outcomes.Integrating these findings with established literature, this paper proposes a multi-layered bioenergetic-plasticity framework for major depressive disorder. The framework argues that depressive symptoms may emerge when the brain’s need for adaptive synaptic and circuit remodeling exceeds available cellular energy, NAD⁺-dependent repair capacity, or appropriately timed stress-response programs. Different symptom profiles may therefore reflect different vulnerabilities within a shared system linking developmental synaptic architecture, adult mitochondrial and NAD⁺ function, peripheral metabolic signaling, senescence biology, and treatment response. The model generates testable hypotheses concerning fatigue as a bioenergetic endotype, directional appetite and sleep symptoms, energy-plasticity coupling, adaptive versus maladaptive senescence programs, and symptom-stratified treatment response. These hypotheses may help guide biologically informed biomarkers, symptom-stratified trials, and more precise approaches to treating major depressive disorder.