Some documentation is requested on steady-state levels of trimipramine.

Fråga: Some documentation is requested on steady-state levels of trimipramine.

Sammanfattning: In a study comparing trimipramine plasma levels in two dosage groups, 75 mg/day and 150 mg/day, mean steady-state plasma levels varied between 35 and 80 ng/ml in the low-dose group and 90 and 164 ng/ml in the high-dose group. No clear correlation was found between plasma levels and clinical efficacy, although patients at high plasma levels (above 124 ng/ml) had a tendency to do less well. It is not known whether the main metabolite, desmethyltrimipramine, has any pharmacological activity. It was suggested that plasma monitoring could be of value, not so much to predict clinical efficacy, but rather to maintain a therapeutic response once it has been achieved.

Svar: Trimipramine has a structural resemblance to both imipramine and levopromazine (1). It differs from imipramine in that the n-propyl side-chain is replaced by a 2-methylpropyl group, which introduces an asymmetrical carbon atom into the molecule. Trimipramine is therefore administered as a racemate. Whether this is clinically relevant is not clear, although L-trimipramine seems to show a higher affinity to dopamine, noradrenaline and serotonin receptors than D-trimipramine (1). It is unknown whether the main metabolite of trimipramine, desmethyltrimipramine, is pharmacologically active (2). Other metabolites are 2-hydroxytrimipramine and 2-hydroxy desmethyltrimipramine (3). The 2-hydroxylation of trimipramine has been suggested to be mediated by the cytochrome P450IID6 (related to the debrisoquine polymorphism) (1).

According to (2) there is no clear therapeutic window of trimipramine plasma levels, but levels between 20 and 100 ug/ml are commonly applied. In a 6-week-long double-blind study involving 34 endogenously depressed patients, plasma trimipramine levels of two dosage groups, 75 mg/day and 150 mg/day, were compared with regard to clinical efficacy (4). Steady-state levels were reached after 2-3 weeks of treatment. The mean plasma levels of trimipramine during these 6 weeks varied between 35 and 80 ng/ml in the 75 mg/day group and between 90 and 164 ng/ml in the 150 mg/day group. The mean levels of desmethyltrimipramine varied between 18 and 37 ng/ml in the 75 mg/day group and between 70 and 200 ng/ml in the 150 mg/day group. It has been suggested that this disproportionate increase in desmethyltrimipramine levels in the high-dose group could be due to the saturability of the enzyme that hydroxylates desmethyltrimipramine (5). This may perhaps affect the toxicity and therapeutic efficacy of the drug.

There was no clear correlation in this study between plasma levels and clinical response, neither in the low-dosage group, nor in the high-dosage group; patients in the low-dosage group who markedly improved had mean trimipramine plasma levels ranging between 11 and 90 ng/ml and patients who only moderately improved had mean levels between 21 and 129 ng/ml. In the high-dosage group patients who had much improved had levels between 28 and 129 ng/ml and patients who moderately improved had levels from 81 to 194 ng/ml. In a comment on this study (6) it was pointed out that patients with plasma levels in the upper 25 per cent range (above 124 ng/ml) did less well compared with patients below this point (although the difference was not statistically significant), and therefore 75 mg may be preferable to 150 mg. It was suggested that as plasma levels do not correlate well with clinical improvement, monitoring of plasma levels may be especially of value in maintaining a therapeutic response, once it has been achieved (4).