First, it has been proposed75, 76, 77, 78, 79 that MDD is associated with reductions in tonic CREB activity, possibly secondary to reduced activity of neurotrophic factors (for example, brain-derived neurotrophic factor) and/or neurotransmitters (for example, adrenergic signaling from catecholamines). This evidence concerns the gene CREB1 and major depressive disorder.