Abstract
Below the toxic plasma level of nortriptyline (NT) an upper therapeutic limit has been postulated in patients with endogenous depression. If so the clinical significance is obvious and a double-blind, randomized study was performed in order to solve this problem. Two groups of patients were controlled at different plasma levels (< 150 ng/ml and > 180 ng/ml). The degree of depression was rated weekly. Only about one third (n=24) of the patients originally included, were carried through the full protocol, the most prominent reason for drop out beeing spontaneous remission during an initial placebo period. After 4 weeks of NT treatment the majority in the high level group was still depressed, but the difference barely significant (P=5.5%). However, a randomized reduction of the plasma level among the patients at the high level resulted in a significant correlation to remission. Evaluation of the total material after 6 weeks of NT treatment demonstrated a strong correlation of high plasma level to poor antidepressive effect of NT. No correlation could be obtained between side-effects, which were few, and plasma level. The non-proteinbound fraction in plasma was found to 7% (SD 1.83) by simultaneous determinations of NT in plasma and CSF in 13 patients. The variation in the proteinbinding was not likely to invalidate the over all results based on total NT determination. A therapeutic plasma range of 50–150 ng/ml is recommended.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Alexanderson, B., Borgå, O.: Interindividual differences in plasma protein binding of nortriptyline in man—A twin study. Europ. J. clin. Pharmacol. 4, 196–200 (1972)
Bennet, J. F.: Is there a superior antidepressant? In: Antidepressant drugs, S. Garattini and M. N. G. Dukes, eds. Excerpta Medica International Congress Series No. 122, pp. 375–393. Amsterdam 1967
Borgå, O., Azarnoff, D. L., Forshell, G. P., Sjöqvist, F.: Plasma protein binding of tricyclic antidepressant in man. Biochem. Pharmacol. 18, 2135–2143 (1969)
Bradley, J. V.: Distribution-free statistical tests. Englewood Cliffs: Prentice Hall 1968
Braithwaite, R. A., Goulding, R., Theano, G., Naily, J., Coppen, A.: Plasma concentration of amitriptyline and clinical response. Lancet 1972 I, 1297–1300
Burrows, G. D., Davies, B., Scoggins, B. A.: Plasma concentration of nortriptyline and clinical response in depressive illness. Lancet 1972 II, 619–623
Cronholm, B., Ottosson, J. O.-O.: Experimental studies of the therapeutic action of electroconvulsiv therapy in endogenous depression. The role of the electrical stimulation and of the seizure studied by variation of stimulus and modification by lidocaine of seizure discharge. In: Experimental studies of the mode of action of electroconvulsiv treatment, N.-O. Ottosson, ed. Acta psychiat. scand. 35, Suppl. 145, 69–97 (1960)
Cronholm, B., Schalling, D., åsberg, M.: Development of a rating scale for depressive illness. In: Psychological measurement. Modern problems in pharmacopsychiatry, P. Pichot, ed. Basel: Karger 1973
Freyhuss, U., Sjöqvist, F., Tuck, D.: Tyramine pressor effects in man before and during treatment with nortriptyline or ECT: Correlation between plasma level and effect of nortriptyline. Pharmacol. Clin. 2, 72–78 (1970)
Glassman, A. H., Hurwic, M. J., Perel, J. M.: Plasma binding of imipramine and clinical outcome. Amer. J. Psychiat 130, 1367–1369 (1973)
Glassman, A. H., Perel, J. M.: Plasma levels and tricyclic antidepressants. Clin. Pharmacol. Ther. 16, 198–200 (1974)
Gurney, C.: Diagnostic scales for affective disorders. Proceedings of the Fifth World Conference of Psychiatry, Mexico City, p. 330 (1971)
Gurney, C., Roth, M., Garside, R. F., Kerr, T. A., Schapira, A.: Studies in the classification of affective disorders. The relationship between anxiety state and depressive illness. Brit. J. Psychiat. 121, 162–166 (1972)
Hamilton, M.: In classification and prediction of outcome of depression. In: Symposia Medica Hoechst 8, J. Angst, ed., p. 195. Stuttgart-New York: Schattauer 1975
Haefely, W., Hürkmann, A., Thoenen, H.: Scheinbare paradoxe Beeinflussung von peripherer Noradrenalwirkungen durch einige Thymoleptica. Helv. physiol. pharmacol. Acta 22, 15–33 (1964)
Kragh-SØrensen, P., Hansen, C. E., åsberg, M.: Plasma-nortriptyline levels in endogenous depression. Lancet 1973 I, 113–115
Kragh-SØrensen, P., Hansen, C. E., Larsen, N.-E., NÆstoft, J., Hvidberg, E. F.: Long-term treatment of endogenous depression with nortriptyline with control of plasma levels. Psychol. Med. 4, 174–180 (1974)
Lader, M.: Plasma concentrations of tricyclic antidepressive drugs. Brit. J. clin. Pharmacol. 1, 281–283 (1974)
Modestin, J.: über die AbhÄngigkeit der klinischen Wirksamkeit des Dibenzepine (Noveril®) von seiner Plasmakonzentration. Pharmako-Psychiat. 6, 29–33 (1973)
MØller-Nielsen, J.: Does a true qualitative difference exist in the mode of action of neuroleptica on catecholamine neuron system? In: The neuroleptics modern problems of pharmacopsychiatry, Vol. 5, D. P. Bobon, P. A. J. Janssen, J. Bobon, eds., pp. 68–70. Basel: Karger 1970
Pletcher, A.: Akute Intoxikation mit Antidepressiva: Pharmakologische Grundlagen. Therapeut. Umsch. 2, 158–165 (1965)
Roth, M., Garside, R., Gurney, C.: Classification of depressive disorders. In: Classification and prediction of outcome of depression, pp. 3–26 (1974)
Sjöqvist, F.: A pharmacokinetic approach to the treatment of depression. Intern. Pharmacopsychiat. 6, 147–169 (1971)
Sjöqvist, F., Hammer, W., Borgå, O., Azarnoff, D. L.: Pharmacological significance of the plasma level of monomethylated tricyclic antidepressants. Excerpta Med. International Congress Series, No. 180. The present status of psychotropic drugs. Proceedings of the VI. International Congress of the C.I.N.P. (1968)
Walther, C. J. S.: Clinical significance of plasma imipramine levels. Proc. roy. Soc. Med. 64, 282–285 (1971)
åsberg, M.: Nortriptyline in the treatment of depression: Relationship between plasma levels and effects. Thesis, Karolinska Institute, Stockholm 1973
åsberg, M., Cronholm, B., Sjöqvist, F., Tuck, D.: Correlation of subjective side-effects with plasma concentrations of nortriptyline. Brit. med. J. 1970 IV, 18–21
åsberg, M., Cronholm, B., Sjöqvist, F., Tuck, D.: Relationship between plasma level and therapeutic effect of nortriptyline. Brit. med. J. 1971 III, 331–334
åsberg, M., Kragh-SØrensen, P., Mindham, R. H. S., Tuck, J. R.: International reliability and communicability of a rating scale for depression. Psychol. Med. 3, 458–465 (1973)
Author information
Authors and Affiliations
Additional information
Supported by Grants from The Danish State Medical Research Council.
Rights and permissions
About this article
Cite this article
Kragh-SØrensen, P., Eggert Hansen, C., Baastrup, P.C. et al. Self-inhibiting action of nortriptylin's antidepressive effect at high plasma levels. Psychopharmacologia 45, 305–312 (1976). https://doi.org/10.1007/BF00421145
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF00421145