TSQ ESI MS/MS and ion trap ESI MS(2) cleave protonated molecules. MS(2) at m/z 332 of zotepine cleaved m/z 245 (10%), m/z 287 (5%) and m/z 315 (100%) fragment ions at protonated positions. MS(2) at m/z 356 of tiaramide cleaved m/z 338 (18%), 313 (10%), 226 (100%), 198 (78%) and 131 (60%) fragment ions at protonated positions. The ESI ion trap MS produced new internal protonated molecules in an ion trap, such as m/z 113 and m/z 88 from m/z 131 protonated piperazinonium, and m/z 245 protonated 8-chloro dibenzo[b,f]thiepin. ESI ion trap (MS)(n) (n>or=3) cleaved new internal protonated molecules. It also causes carbocation cleavage, alpha cleavage, onium cleavage and McLafferty cleavage. We can easily elucidate the structure of metabolites from the difference in m/z of corresponding fragments between unchanged compound and its metabolite. Reactive oxygen diradicals involved in cytochrome P-450 cycles react with electron rich groups and reactive C-H bonds of zotepine and tiaramide to produce metabolites of 2-hydroxyzotepine, 3-hydroxyzotepine, norzotepine, zotepine-N-oxide, zotepine-S-oxide, Tiaramide carboxylic acid, dehydroxyethyltiaramide and tiaramide-N-oxide. The strategy for structure elucidation of drug metabolites was established on the basis of the reactivity of unchanged drug with reactive oxygen diradicals involved in cytochrome P-450 cycles and theory associated with protonated molecules and (MS)(n) fragmentation of drug metabolites.