Relationship between plasma antidepressant concentrations and the therapeutic response

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Over the past 20 years there has been widespread interest in monitoring plasma antidepressant, particularly tricyclic, levels to optimize the response to treatment. One aspect of this research that is universally agreed upon concerns the extensive interindividual variability among patients, but it is still uncertain whether a knowledge of the plasma drug concentration is of clinical value.

For the tricyclic antidepressants (TCAs) the two major oxidative pathways that occur in the liver are desmethylation and hydroxylation, the latter pathway being the main rate-limiting step that governs the renal excretion of these drugs. First-pass metabolism, whereby the drug passes via the portal system directly to the liver, is much greater following oral rather than intravenous administration of such drugs. For the major TCAs, firstpass metabolism accounts for approximately 50% or more of the drug concentration which enters the portal circulation. Such extensive first-pass metabolism probably occurs with the newer antidepressants that also undergo oxidation and desmethylation in the liver. It seems possible that the presence of high concentrations of the therapeutically inactive hydroxylated metabolites of the TCAs in the brain could result in a reduction in the therapeutic activity of the parent compound. The presence of desmethylated metabolites of the tertiary antidepressants such as nor-chlorimipramine and desipramine undoubtedly contribute to the anti-depressant effects of the parent compound. Whereas the tertiary precursors show some selectivity for inhibiting the uptake of 5-hydroxytryptamine

(5-HT) into the nerve terminal, the desmethylated metabolites show selectivity as noradrenaline uptake inhibitors. Thus no TCA can be considered to be selective in inhibiting the uptake of either of these biogenic amines. In the case of TCA overdose, the normal oxidative pathways in the liver are probably saturated, which leads to a disproportionately high concentration of the desmethylated metabolite. The practical consequence of this finding is that toxic plasma concentrations of a TCA are very likely to occur if the dose of the drug is increased in those patients who fail to respond to normal therapeutic doses of the drug. Such a transition to toxic doses could occur suddenly.

There is good evidence that genetic differences in hepatic metabolism are responsible for the large interindividual variation in the metabolism of TCAs, including maprotiline and the monoamine oxidase inhibitors. Such genetic factors have been investigated using pharmacogenetic probes. Drugs such as antipyrine (phenazone) and debrisoquine have been investigated in patients treated with TCAs to see if the clearance of such drugs correlates with the metabolism of the antidepressants. It has been found that the clearance of antipyrine correlated well with the metabolism of the benzodiazepines but not with all of the TCAs. Those individuals who showed a deficient hydroxylation of debrisoquine also differed from the normal population in their metabolism of TCAs. However, at the present level of knowledge, it would appear that despite overall similarities in the metabolic pathways for most antidepressants, specific drugs are subject to specific metabolic processes that limit the application of pharmacokinetic phenotyping compounds such as debrisoquine. If the pharmacokinetic properties of an antidepressant in an individual patient need to be known, a test dose of the drug should be given. However, to date there is no convincing evidence that such information improves the frequency of the therapeutic response!

It may be concluded that, so far, a pharmacokinetic analysis of antidepressants is of limited clinical value because of:

1. Large interindividual variability in plasma concentrations which reflect genetically determined metabolic differences.

2. The effects of variables such as age, sex, race and drug interactions on the pharmacokinetics of the antidepressant.

3. The presence of therapeutically active metabolites that may contribute to the pharmacodynamic and toxic effects.

In contrast to the limited value of pharmacokinetics to the use of antidepressants, knowledge of the kinetics of lithium has been important in defining the therapeutic and toxic range in unipolar or bipolar manic patients. Prediction of the dose required by the individual patient by giving a single dose of the drug and measuring the erythrocyte/plasma lithium ratio has been shown to be useful, and non-compliance of a patient can be readily detected. The pharmacokinetic profiles of the various types of normal- and slow-release preparations now enable adjustment of the dosage to the needs of the individual patient. Such knowledge has also led to the clinical practice of maintaining the patient on the lowest plasma concentration of lithium for long periods of time, thereby prolonging the remission of both manic and depressive symptoms.

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