The antidepressants listed in Table 19.1 are generally well absorbed after oral administration. Steady-state plasma concentrations of TCAs show great individual variation but correlate with therapeutic effect. Measurement of plasma concentration can be useful especially where there is apparent failure of response (though it is often not available).

Antidepressants in general are inactivated principally by metabolism by hepatic cytochrome P450 enzymes (see p. 112). Of the many isoenzymes identified, the most important in antidepressant metabolism are Cytochrome P450 (CYP) 2D6 (Table 19.2a) and CYP 3A4 (Table 19.2b). Other important P450 enzymes are CYP 1A2 (inhibited by the SSRI fluvoxamine, induced by cigarette smoking, substrates include caffeine and the atypical antipsychotics clozapine and olanzapine) and the CYP 2C group (inhibition by fluvoxamine and fluoxetine, involved in breakdown of moclobemide). Sometimes several CYP enzymes are capable of mediating the same metabolic step. For example at least six isoenzymes, including CYP 2D6, 3A4 and 2C9 can mediate the desmethylation of the SSRI sertraline to its major metabolite.

Several of these drugs produce active metabolites which prolong their action (e.g. fluoxetine is

TABLE 19.2A Psychotropic (and selected other) drugs known to be CYP 2D6 substrates and inhibitors

CYP 2D4 inhibitors

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