Do vitamins or minerals (apart from lithium) have mood-stabilizing effects?

Received Oct. 8, 2001; accepted Oct. 8, 2001. From the Department of Psychiatry, Harvard Medical School, Boston, and McLean Hospital, Belmont, Mass. Reprint requests to: Charles W. Popper, M.D., McLean Hospital, 115 Mill St., Belmont, MA 02478–1048 (e-mail: Charles_Popper@harvard.edu). N interfere with animal health, including aggressive and destructive behavior. When farm animals become “violent”—when pigs start biting each others’ ears and tails, when chickens attack chickens—farmers have learned that the aggressive behavior can be reduced by adding certain minerals and vitamins to their diet, without the need for veterinary intervention. In 1996, animal nutrition specialist David L. Hardy described this approach to Anthony F. Stephan, whose children had severe treatment-resistant bipolar disorder. Stephan then added similar nutrients to his children’s diet. On the nutritional supplements, both children stabilized clinically and have not needed psychiatric medication for the last 5 years. Hardy and Stephan began advising family members and friends about this nutrient supplement and have now worked with over 2500 psychiatric patients (D. L. Hardy, personal communication, 2001). They also began to collaborate with Bonnie J. Kaplan, Ph.D., a research psychologist at the University of Calgary in Alberta, Canada. In this issue, Kaplan and colleagues describe an open trial of the first 14 adults with bipolar disorder treated with this nutritional supplement, which consists of a broad range of minerals and vitamins, plus 3 amino acids and several antioxidants. Symptom reductions were clinically noted within 2 weeks and sustained over 6 months of observation. All outcome measures showed significant improvements (55% to 66% symptom reduction), and a strong effect size (> .80) was observed for ratings of depression as well as mania. Most patients could reduce their doses of psychiatric medications, and some patients became stable without any psychiatric medication. Only 2 patients started on new medications that might conceivably have contributed to their stabilization. Even allowing for the usual overestimation of effects in openlabel series, these preliminary findings raise interesting questions about nutrition-behavior interactions. In view of the 50 years of experience with lithium, the notion that minerals can treat bipolar disorder is unsurprising. However, the nutrient supplement studied by Kaplan and colleagues contains no lithium. Might other dietary nutrients have mood-stabilizer properties? Some may object that a clinical trial of a mixture of ingredients is inherently unscientific: How can one know which ingredient is the active one, whether a smaller number of ingredients will have the same clinical effect, or whether the same ingredients are active in different patients? These questions will become worth pursuing once it has been formally determined whether the mixture, handed down from animal husbandry as a single entity, works in humans. Kaplan’s open-label report justifies her now ongoing controlled study, whose outcome appropriately precedes pursuing questions of mechanism of action and parsimony. Even so, it is difficult to avoid speculating about possible mechanisms. Might minerals serve as catalysts for enzymes involved in neurotransmitter metabolism, change drug biotransformation, modify membrane receptors or channels, influence second or third messenger systems, or alter gene expression? Lithium, a single cation, has spawned a minor industry of investigations into mechanisms of action, and the possibilities if there were numerous interacting micronutrients (the collective term for minerals and vitamins) are staggering. Commentary