During the last decade, much attention has been given to the role of signal transduction pathways in affective disorders. This review describes the possible role of the cAMP signaling in such disorders. 

 Among the components of cAMP signaling, this review focuses on the cAMP‐dependent phosphorylation system. We analyzed the basic components of the cAMP‐dependent phosphorylation system and the preclinical evidence supporting their involvement in the biochemical action of antidepressants and mood stabilizers. The clinical data available until now, concerning the possible link between the cAMP‐dependent phosphorylation system and the pathophysiology of affective disorders, are also reviewed. 

 The studies herein presented demonstrated that the levels and the activity of cAMP‐dependent protein kinase are altered by antidepressants and mood stabilizers. Furthermore, these medications are able to modify the phosphorylation state, as well as the levels of some of the cAMP‐dependent protein kinase substrates. More recently, clinical studies have reported abnormalities in the cAMP‐dependent phosphorylation system in both peripheral cells and the postmortem brain of patients with affective disorders. 

 Overall, these studies support an involvement of cAMP signaling in affective disorders. The precise knowledge of the findings has the potential to improve the understanding of pharmacotherapy and to provide directions for the development of novel biochemical and genetic research strategies on the pathogenesis of affective disorders.