Drug assays in neuropsychiatry

The measurement and interpretation of plasma concentrations of drugs are beset by numerous problems and, up to the present time, these have militated against their routine use in neuropsychiatry. In other areas of medicine, however, drug assays have proved to be of clinical importance, and experience here has allowed the establishment of a number of principles. Measurements of plasma steady state concentrations of anticonvulsants, for example, have led to their use in the following areas: in establishing non-compliance (especially with out-patients); for detecting abnormalities of absorption; in the differentiation of some toxic signs from those of primary brain disorder; in evaluating excessive metabolism due to liver microsomal enzyme induction from previous or concurrent treatment with other drugs, especially in non-responders; and, finally, in the evaluation of patients suspected of complex drug interactions. Measurement of plasma non-steady state concentration following single dosage has occasionally been mooted as being of predictive value in relation to therapeutic response. Unfortunately, the situation is less clear with respect to drugs currently used in neuropsychiatry for a number of reasons. First, less precise information is available concerning the pharmacokinetics in man, due to the high volume of distribution of lipophylic drugs and in many instances the very high degree of plasma protein binding. Secondly, the existence of numerous metabolites, the concentrations of which vary widely and some of which are pharmacologically active, leads to a poor correlation between drug pharmacokinetics and pharmacodynamics. To this may be added the fact that many drugs used in neuropsychiatry are rapidly absorbed, leading to wide fluctuations in plasma levels, which in itself leads to difficulties in interpretation. Thirdly, a problem exists in the laboratory concerned with the accurate measurement of the very low levels of drugs encountered and the associated metabolites. Finally, considerable difficulties arise over precise clinical evaluation of response in patients with mediumto long-term disorders, the natural history of which is characterized by a fluctuating course and in which even precise diagnosis of a homologous group of disorders is frequently difficult. It is perhaps not surprising, therefore, that it has proved difficult to establish therapeutic ranges; moreover, different ranges will be applicable, dependent upon whether one is interested in the management of the acute phase of illness, prophylaxis against relapse, or the identification of specific features of toxicity. By analogy with other groups of drugs, considerable individual variation, possibly genetically determined, is likely to be encountered, and different therapeutic ranges (as well as dosage) will be required for children and for the elderly. Factors such as diet and fasting which are associated with varying levels of free fatty acids in plasma will affect protein binding of drugs and where this is high, as is frequently the case with drugs used in neuropsychiatry, only small changes in binding will have large effects on the free fraction. Both pregnancy and disease states associated with alterations in plasma proteins give rise to similar problems.