Essential Trace Elements in Psychiatric Disorders: Mechanistic Pathways and Therapeutic Implications

Abstract

Essential trace elements—including zinc (Zn), iron (Fe), copper (Cu), selenium (Se), manganese (Mn), molybdenum (Mo), and cobalt (Co)—participate in neurotransmission, redox regulation, mitochondrial function, immune signaling, and neuroendocrine processes. Increasing evidence suggests that disturbances in trace-element homeostasis may be associated with several psychiatric disorders; however, the strength and consistency of the evidence remain heterogeneous. This narrative review integrates recent human clinical studies with relevant biochemical, mechanistic, and selected preclinical evidence concerning trace-element dysregulation and psychiatric outcomes. Among the elements examined, Zn and Se have the strongest interventional support. Meta-analyses of randomized controlled trials suggest that adjunctive Zn supplementation may reduce depressive symptom severity in some populations, whereas individual trials indicate possible symptomatic benefit in attention-deficit/hyperactivity disorder (ADHD). Findings for Se also suggest potential benefit, particularly in postpartum depression, although generalizability across populations remains uncertain. Observational studies have associated lower Fe indices with greater ADHD symptom burden, cognitive difficulties, and atypical neurodevelopment, while higher circulating Cu concentrations have been reported in major depressive disorder and autism spectrum disorder. Evidence concerning Mn, Mo, and Co remains limited and inconsistent and is derived mainly from small observational studies. Mechanisms involving oxidative stress, mitochondrial dysfunction, excitatory–inhibitory imbalance and altered monoaminergic signaling are biologically plausible but do not independently establish clinical causality. Overall, disturbances in essential trace-element homeostasis have been associated with mood disorders, neurodevelopmental conditions, and cognitive dysfunction. Nevertheless, substantial heterogeneity in study design, biomarker matrices and assays, sample characteristics, and control of confounding limits causal interpretation. Longitudinal and interventional studies using standardized methods are therefore needed to clarify temporal and causal relationships and to determine whether targeted micronutrient assessment or supplementation provides clinically meaningful benefit in psychiatric practice.