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Brain diseases including Alzheimer's and Parkinson's involve the cellular 'unfolded protein' (UPR) stress response. Psychiatric illnesses such as depressive disorders are thought to involve brain stress-response pathways. The XBP1 gene encodes a key transcription factor in the UPR stress response and therefore could be involved in the pathophysiology of depressive disorders. A functional polymorphism (-116C--&gt;G) in the XBP1 promoter was linked in some studies to bipolar disorder. Among 132 adults (mean age 39 yr) who presented with a major depressive episode, this polymorphism was found to be associated with a worse course during 1-yr prospective follow-up. In a subgroup (n=22), the polymorphism was associated with higher plasma levels of the stress hormone cortisol. The results suggest that hypothalamic-pituitary-adrenocortical and cellular stress pathways involving the XBP1 gene may be involved in the pathophysiology of major depressive disorder. These relationships merit further study.

Association of X-box binding protein 1 ( XBP1) genotype with morning cortisol and 1-year clinical course after a major depressive episode