Plasma nortriptyline levels—relationship to clinical effects

Abstract

One of the baffling problems in the treatment of depression is the dilficulty of differential diagnosis as to type of depression. This may be one complicating factor in selecting the pharmacologic agent that will prove effective for the individual patient. Of the available tricyclic antidepressants, no clear‐cut and consistent differences in effect have been demonstrated olinically, despite the known mode of action: all inhibit reuptake of transmitter substance into monoaminergic neurons. This property is believed to be related to the antidepressant effect. One exception is iprindole, which does not inhibit monoamine uptake, but its antidepressant effects are claimed to be comparable to imipramine. In patients, in all of whom a diagnosis of endogenous depression had been made, the relationship between drug plasma levels and therapeutic effects was studied with nortriptyline (NT) as the therapeutic agent. The basic study design was as follows: after a washout period, with patients on placebo for 4 to 7 days, NT was given for 4 weeks. A single dosage level of 50 mg three fimes daily was found to ensure sulficient variability in plasma level. Ratings for side effects and severity of depression were performed at the end of the washout period and once weekly during active treatment, with NT concentrations in plasma done twice weekly. The incidence of “side etfect symptoms” was high during treatment, and strongly correlated with the severity of depression at base line, as well as on active treatment. However, the estimate of “true” side effects significantly correlated with the plasma level of NT during the first three weeks of treatment. A modified version of the Cronholm‐Ottosson rating scale was used to estimate severity of depression. The ratings on this scale strongly correlated with nurse ratings (r = 0.87), but were lower with the Beck self‐rating scale (r = 0.67). Low agreement between self‐ratings and psychiatrists' ratings supports the observation of others that self‐rating scales should not be relied on exolusively in severely depressed patients. The best classification between “responders” and “nonresponders” to NT was obtained at 175 ng NT per milliliter of plasma. Although the general tendency is for patients to do less well on high plasma levels, some seem to benefit from them, while others do not recover even on moderate levels. Variability in receptor sensitivity and heterogeneity within the depressive disorder may be an explanation. On any standard dosage, a certain number of patients will have plasma levels that are too low to be effective, and some will develop toxic levels even on very low dosages. Monitoring NT plasma levels may be a way to increase the efficacy of treatment in patients who do not respond to standard therapy and in patients with disturbing side etfects.