The metabolism of tricyclic antidepressants is catalysed by the cytochrome P- 450 family of isozymes. The tertiary amines amitriptyline, imipramine and chlorimipramine are all demethylated to active secondary amines. Desmethylimipramine and nortriptyline, on the other hand, are hydroxylated in aromatic and benzylic positions, respectively. The latter involves the formation of two isomers, E and Z, each of which occurs in the R and in the S form. These metabolic changes modify the effects of the drugs on monoaminergic neurons.