To the Editor: We read with interest the letter by Dr. Mackin and Mr. Gallagher in which they suggest interpreting the interactive effects of BDNF and serotonin in major depressive disorder in the context of HPA axis function. Preclinical studies (1) have suggested major functional interactions between knockout mice with genetically induced alterations in serotonin (5-HT) transporters and heterozygous BDNF knockout mice and have also shown that this leads to enhanced stress responses with altered HPA axis function. Notably, a decrease in BDNF concentrations does not appear sufficient to lower extracellular 5-HT; similarly, constitutional changes in extracellular 5-HT because of differences in 5-HT reuptake by 5-HT transporters do not affect BDNF protein levels. This adds to the importance of identifying additional parameters that may contribute to the interactive effects of 5-HT and BDNF in major depressive disorder. There is a wide range of evidence supporting the idea that glucocorticoids play a key role in acute and chronic stress responses. For example, stress and glucocorticoids impair hippocampal neurogenesis; furthermore, in addition to directly causing neuronal atrophy, stress and glucocorticoids also impair cellular resilience that together may lead to the well-established morphological alterations in major depressive disorder. Notably, BDNF and other neurotrophic factors are believed to counteract these effects (2). It has been previously demonstrated that in addition to glucocorticoids, BDNF is involved in the early response to acute stress (3). In our study, tryptophan depletion was used as a model to study the effects of acute stress in the context of reduced 5-HT function in major depressive disorder and healthy comparison subjects. Additional work is clearly necessary to delineate the causal relationships between altered 5-HT function, BDNF, and HPA axis function and the pathogenesis of major depressive disorder. Dysregulation of these cascades may be a key mechanism by which stress induces impairments of cellular plasticity. This highlights the interactive effects of different neurobiological systems in the pathogenesis of major depressive disorder, and all three of the referenced major neurobiological systems appear to be involved.