In the last several years it has become apparent that identical oral doses of a tricyclic antidepressant can, in different individuals, result in radically different blood levels. This phenomenon which is the result of drug-drug interactions and individual genetic characteristics has major clinical implications. The plasma level resulting from a standard oral dose can be markedly increased or decreased by the concomitant administration of numerous usually used medications. This is a significant and commonly unrecognized problem and compounds the genetic metabolic variability inherent in these drugs.

In this review imipramine hydrochloride is used as a model for the tricyclic antidepressants in general. Its metabolism and pharmacodynamics are examined with specific emphasis on their relationship to the marked individual variability seen in this class of drugs and the relationship of this variability to clinical effectiveness.