The role of CREB and other transcription factors in the pharmacotherapy and etiology of depression

Psychiatric diseases are genetically complex and consequently, altered programs of gene expression have been hypothesized as the molecular basis of psychopathology. Since transcription factors represent the final communicative link between receptor activation and the orchestration of programs of gene expression, they are prime targets for studies on both the pharmacotherapy and the etiology of depression. The cyclic AMP response element binding protein (CREB) and the glucocorticoid receptor (GR) are altered by chronic treatment with antidepressants. Since it is phosphorylated CREB (pCREB) that determines its transcriptional activity, it is pertinent that some antidepressants have been shown to reduce pCREB in brain in vivo and in tissue culture in vitro. Moreover, pCREB is down-regulated in human fibroblasts from patients with major depression and in postmortem brain of suicide victims with a history of depression. With regard to GR, its mRNA, immunoreactivity, density and cytoplasmic-nuclear translocation are increased by antidepressants. While transcription factor mediated programs of gene expression relevant to either the pharmacotherapy or the etiology of depression are still largely elusive, studies utilizing modern technologies such as differential display and cDNA microarrays promise to lead eventually to the identification of structure and function of psychopathologically relevant target genes.