Debrisoquin and S-mephenytoin hydroxylation phenotypes were determined in 72 Spanish psychiatric patients treated with neuroleptic or antidepressant agents. One patient (1.4%) was classified as a poor metabolizer of S-mephenytoin. Between both neuroleptic- and antidepressant-treated patients, the distribution of the debrisoquin metabolic ratio was shifted toward higher values compared with 54 drug-free healthy subjects. Forty percent of patients treated with neuroleptics and 5% of patients treated with antidepressants were classified as poor metabolizers of debrisoquin. CYP2D6 genotype analysis in 36 neuroleptic-treated patients confirmed that the high metabolic ratios were attributable to inhibition of CYP2D6 and not to overrepresentation of subjects with poor metabolizer genotypes. In 48 selected Spanish drug-free subjects, CYP2D6 genotype predicted the phenotype with 95% accuracy. Neuroleptics and antidepressants interfere at therapeutic doses with phenotyping for CYP2D6 but not for S-mephenytoin hydroxylation capacity. In psychotropic-treated patients, genotyping provides a valuable tool for prediction of the CYP2D6 phenotype.