Plasma levels of imipramine in depression. Environmental and genetic factors.

On the basis of tentative evidence obtained with 26 patients with unipolar affective illness, the variability in the response to imipramine is mostly due to interindividual differences in hydroxylating microsomal enzymes which are genetically controlled but whose activities are subject to modification by environmental factors such as overall pharmacological exposure and tobacco smoking. Additional significant pharmacodynamic variability (twofold) was found in the range of the volumes of distribution of imipramine in the patients. Clinical outcome was unequivocally related to plasma level. Unipolar nondelusional patients with levels less than 180 ng/ml had a low probability of recovery, while levels above 180 ng/ml were assoicated with a high probability of recovery. Unlike the findings of investigators working with nortriptyline, our data do not suggest an upper limit on plasma levels beyond which clinical response deteriorates. It appears that, on the basis of family studies, similar genetic characteristics are related to the ones controlling the pharmacodynamics will be the subject of further examination in our continuing studies.