Abstract :The pharmacological manipulation of interaction of the intracellular signalling pathways mediated by Ca2+ and cAMP (Ca2+/cAMP interaction) may provide new insights for the pharmacotherapy of psychiatric disorders, dramatically impacting clinical pharmacology and translational medicine. Disorders mainly resulting by reduction of serotonin and catecholamine release in central nervous system could be directly impacted by the manipulation of the Ca2+/cAMP interaction, such as depression. Since 1975, several clinical studies have reported that administration of L-type Ca2+ channel blockers (CCBs) produces reduction in vascular resistance and arterial pressure in hypertensive patients, associated with an increase in plasma noradrenaline levels and tachycardia characterized by sympathetic hyperactivity. During almost four decades these enigmatic phenomena remained unclear. In 2013, we discovered that this paradoxical sympathetic hyperactivity produced by CCBs is due to its interference on the Ca2+/cAMP interaction. Then, the pharmacological manipulation of this interaction could be a more efficient therapeutic strategy for increasing serotoninergic and monoaminergic neurotransmission in depression.