By increasing intracellular levels of cAMP, PDE4-selective inhibitors activate cAMP-dependent protein kinase (PKA) and thereby increase its activity at numerous substrates, most importantly at the cyclic nucleotide response element binding protein (CREB), implicated in numerous functions, notably learning and memory (see [19–21] for reviews) and depression [22]. Here, CREB1 is linked to depressive disorder.