Relationship of Plasma Concentration to Clinical Action Plasma Concentration and Response

Marked interindividual variability of tricyclic plasma concentrations was described by Hammer and Sjoqvist in 1967. This finding suggested that drug level monitoring might ensure that therapeutic blood levels are achieved and might help to avoid toxic levels. In carefully selected inpatients with endogenous or melancholic major depression, treatment with adequate levels of imipramine or desipramine resulted in robust response rates of about 85% (Glassman et al. 1977; Nelson et al. 1982). For several years, the relationship of tricyclic blood levels to response and the utility of monitoring blood levels were the focus of considerable attention and debate.

A task force of the American Psychiatric Association (1985) that reviewed these studies concluded that relationships between plasma level and response had been demonstrated for imipramine, desipramine, and nortriptyline (see Table 12-2). For imipramine, drug levels above 200 ng/mL were more effective than lower levels (Glassman et al. 1977; Reisby et al. 1977). For desipramine, levels above 125 ng/mL were more effective (Nelson et al. 1982). For both desipramine and imipramine, blood levels in excess of 300 ng/mL were more likely to be associated with serious side effects. Effective plasma concentrations were also established for nortriptyline, but the relationship appeared to be curvilinear. For this drug, plasma levels between 50 ng/mL and 150 ng/mL were more effective than lower or higher levels (Asberg et al. 1971; Kragh-Sorenson et al. 1973, 1976).

For amitriptyline, it has been more difficult to establish a therapeutic relationship between plasma levels and response (American Psychiatric Association 1985). In part, this difficulty may be related to the fact that during amitriptyline administration, three active compounds are present (amitriptyline, nortriptyline, and hydroxynortriptyline), and it is unclear if their effects are additive or if there is a more complicated relationship (Breyer-Pfaff et al. 1982). During amitriptyline administration, responders usually have total amitriptyline and nortriptyline levels in the neighborhood of 150-250 ng/mL (Kupfer et al. 1977), but there is not good agreement between studies. For clomipramine, blood levels of 150-300 ng/mL (total of clomipramine and desmethylclomipramine) have been suggested for antidepressant effectiveness. Higher levels are usually employed in the treatment of OCD. The data relating blood levels and response are limited for the other tricyclic and tetracyclic compounds.

The therapeutic utility of blood level monitoring has been the subject of controversy. Blood level-response relationships have been demonstrated in melancholic inpatients. But similar relationships have proven difficult to demonstrate in depressed outpatients. In outpatients, drug-placebo differences are often small, and the effect of drug treatment is harder to detect. Depressed outpatients may be more heterogeneous and include individuals who are not responsive to any drug treatment. Finally, many studies are not designed to detect blood level-response relationships. Fixed dosing is required, and the plasma concentrations achieved must fall above and below the suspected threshold. If all patients achieve adequate drug concentrations, no relationship with response will be found. It is logical to conclude that blood level relationships determined in severely depressed inpatients might be used as a guide for treatment of outpatients, but this assumption has not been empirically validated.

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