The implication of concentration/response studies of tricyclic antidepressants for psychiatric research and practice

The action of a drug is mediated by the attainment of an appropriate concentration at an effector site. However, the mechanisms of action of TCA's are complex, with multiple effector sites mediating multiple actions. If a well-defined concentration/response relationship can be demonstrated for a given response, it follows that the responsible drug/effector site interaction is likely to be rapidly reversible. If the effective concentration range is narrow, this may help to identify the particular action responsible for a given response, or to test whether beneficial responses in different settings are mediated by a similar underlying mechanism. The clinical value of defining concentration/response relationships derives from the identification of thresholds of efficacy, and of the limits beyond which the risk of toxicity outweighs the probability of therapeutic gain. The question of what constitutes the 'concentration', and what is meant by 'response' are discussed. Concentration depends upon absorption, distribution, metabolism, concomitant drug administration and elimination. The relative merits of biological, chemical, radioimmuno- and radioreceptor-assays, and the various sources of error which can render measures of concentration inconclusive, are discussed. With regard to the study of the antidepressant response to TCA's the problems involve issues of diagnosis, of trial design, of dosage, of data analysis, as well as response assessment. Given the range of methodological difficulties which have often not been adequately controlled, it is all the more remarkable that broadly consistent concentration/response relationships have been defined for the TCA's.