CREB1 and major depressive disorder: However, it is important to highlight that cAMP Response Element Binding Protein (CREB) upregulates the BDNF gene and that antidepressant treatments currently used in clinical practice, which increase NA and/or 5-HT concentrations in the synaptic cleft, stimulate CREB expression, and BDNF is therefore closely related to the monoaminergic hypothesis of depression.