To the Editor: We read with interest the article by Alexander Neumeister, M.D., and colleagues (1). The neurobiology of brain-derived neurotrophic factor (BDNF) is complex and influenced by a number of different hormonal systems, including the hypothalamic-pituitary-adrenal (HPA) axis, which is known to be dysfunctional in patients with severe mood disorders. Stress-responsive corticosteroids, which are the end products of the HPA axis, have been shown to have important effects on the expression of BDNF in preclinical studies (2). We have also recently shown an interaction between cortisol and serum levels of BDNF in patients with bipolar depression and schizophrenia (3). Furthermore, tryptophan depletion has been shown to lower cortisol levels in patients with mood disorders (4) as well as in healthy comparison subjects (5). Of interest, sham tryptophan depletion has also been reported to cause a significant decrease of plasma cortisol (4). Changes in cortisol levels may, therefore, account for the increases in BDNF following sham depletion observed by Dr. Neumeister and colleagues.