The P-450 enzymatic complex (CYP) is one of the main enzymatic systems used by the organism to metabolize different substances, including 90% of drugs of common clinical use. Drugs can act on the CYP as substrates or as modifiers of its activity, either as inhibitors or as enzymatic inducers. Antidepressant drugs, including tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRI), are widely metabolized by CYP. In addition, SSRI are potent inhibitors of different isoenzymes of this family. This fact allows to establish interesting differences relating the safety profile of these agents. In this review we analyze in detail, and comparatively, the effects of the different classes of antidepressants on CYP. Knowledge of these effects is of great relevance for an optimum clinical practice, allowing us to know the basis of some interactions, providing guidance for the use of correct dosage in different groups of patients and to explain some cases of unexpected toxicity or lack of therapeutic effect.