Nutritional deficiencies are one of the many causes of or contributors to symptoms in patients with psychiatric disorders. In this article, we discuss the prevalence of iron deficiency and its link to poor mental health, and how proper treatment may improve psychiatric symptoms. We also offer suggestions for how and when to test for and treat iron deficiency in psychiatric patients.
A common condition
Iron deficiency is the most common mineral deficiency in the world. According to the World Health Organization (WHO), approximately 25% of the global population is anemic and nearly one-half of those cases are the result of iron deficiency.1 While the WHO has published guidelines defining iron deficiency as it relates to ferritin levels (<15 ug/L in adults and <12 ug/L in children), this estimate might be low.2,3 Mei et al2 found that hemoglobin and soluble transferrin receptors can be used to determine iron-deficient erythropoiesis, which indicates a physiological definition of iron deficiency. According to a study of children and nonpregnant women by Mei et al,2 children with ferritin levels <20 ug/L and women with ferritin levels <25 ug/L should be considered iron-deficient. If replicated, this study suggests the prevalence of iron deficiency is higher than currently estimated.2 Overall, an estimated 1.2 billion people worldwide have iron-deficiency anemia.4 Additionally, patients can be iron deficient without being anemic, a condition thought to be at least twice as common.4
Essential for brain function
Research shows the importance of iron to proper brain function.5 Iron deficiency in pregnant women is associated with significant neuropsychological impairments in neonates. Rodent studies have demonstrated the importance of iron and the effects of iron deficiency on the hippocampus, corpus striatum, and production of monoamines.5 Specifically, iron is a necessary cofactor in the enzymes tryptophan hydroxylase and tyrosine hydroxylase, which produce serotonin, dopamine, and norepinephrine. In rodent studies, monoamine deficits secondary to iron deficiency persist into adulthood even with iron supplementation, which highlights the importance of preventing iron deficiency during pregnancy and early life.5 While most research has focused on the impact of iron deficiency in infancy and early childhood, iron deficiency has an ongoing impact into adulthood, even if treated.6
Iron deficiency and psychiatric symptoms
Current research suggests an association between iron deficiency or low ferritin levels and psychiatric disorders, specifically depression, anxiety, and schizophrenia. In a web survey of 11,876 adults, Hidese et al7 found an association between a self-reported history of iron deficiency anemia and a self-reported history of depression. Another study of 528 municipal employees found an association between low serum ferritin concentrations and a high prevalence of depressive symptoms among men; no statistically significant association was detected in women.8 In an analysis of the Taiwan National Health Insurance Database from 2000 to 2012, Lee et al9 found a statistically significant increased risk of anxiety disorders, depression, sleep disorders, and psychotic disorders in patients with iron deficiency anemia after controlling for multiple confounders. Xu et al10 used quantitative susceptibility mapping to assess the iron status in certain regions of the brain of 30 patients with first-episode psychosis. They found lower levels of iron in the bilateral substantia nigra, left red nucleus, and left thalamus compared to healthy controls.10 Kim et al11 found an association between iron deficiency and more severe negative symptoms in 121 patients with first-episode psychosis, which supports the hypothesis that iron deficiency may alter dopamine transmission in the brain.
Iron deficiency has been associated with psychopathology across the lifespan. In a population-based study in Taiwan, Chen et al12 found an association between iron deficiency anemia and psychiatric disorders in children and adolescents, including mood disorders, autism spectrum disorder, attention-deficit/hyperactivity disorder, and developmental disorders. At the other end of the age spectrum, in a survey of 1,875 older adults in England, Stewart et al13 found an association between low ferritin levels (<45 ng/mL) and depressive symptoms after adjusting for demographic factors and overall health status.
In addition to specific psychiatric disorders and symptoms, iron deficiency is often associated with nonspecific symptoms such as fatigue.14 Fatigue is a symptom of numerous psychiatric disorders and is included in the DSM diagnostic criteria for major depressive disorder and generalized anxiety disorder.15
Iron supplementation might improve psychiatric symptoms
Some evidence suggests that using iron supplementation to treat iron deficiency can improve psychiatric symptoms. In a 2013 systematic literature review of 10 studies, Greig et al16 found a link between low iron status and poor cognition, poor mental health scores, and fatigue among women of childbearing age. In this review, 7 studies demonstrated improvement in cognition and 3 demonstrated improvement in mental health with iron supplementation.16 In a 2021 prospective study, 19 children and adolescents age 6 to 15 who had serum ferritin levels <30 ng/mL were treated with oral iron supplementation for 12 weeks.17 Participants showed significant improvements in sleep quality, depressive symptoms, and general mood as assessed via the Pittsburgh Sleep Quality Index, Center for Epidemiologic Studies Depression Scale, and Profile of Mood States (POMS) questionnaires, respectively.17 A randomized controlled trial of 219 female soldiers who were given iron supplementation or placebo for 8 weeks during basic combat training found that compared to placebo, iron supplementation led to improvements in mood as measured by the POMS questionnaire.18 Lastly, in a 2016 observational study of 412 adult psychiatric patients, Kassir19 found most patients (81%) had iron deficiency, defined as a transferrin saturation coefficient <30% or serum ferritin <100 ng/mL. Although these cutoffs are not considered standard and thus may have overrepresented the percentage of patients considered iron-deficient, more than one-half of patients considered iron-deficient in this study experienced a reduction or elimination of psychiatric symptoms following treatment with iron supplementation and/or psychotropic medications.19
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