The tricyclic and related antidepressants are strongly bound to plasma proteins and interindividual differences in the free (unbound) fraction of drug may be important. However, there are serious methodological problems with the determination of protein-binding and misleading results may sometimes be obtained so the use of more than one technique is recommended. Other plasma proteins apart from albumin may be involved in the binding process and may be influenced by the presence of other disease states. The observed 4-fold interindividual differences in the binding of these drugs represents an additional source of variability in drug response, but are relatively less important than the 20- to 30-fold interindividual differences in total drug plasma concentrations that are commonly observed.