Treatment of Depression — Pharmacokinetic and Pharmacogenetic Considerations

  • Gunnar Alván
  • Folke Sjöqvist


In spite of rapid progress in neurobiology, the brain remains the least explored organ in clinical pharmacology and its responses to drugs are notoriously difficult to assess in a reproducible way. In the mid-′60s, we began to study the mechanisms behind interindividual differences in response to tricyclic antidepressant drugs (TCA) using a pharmacokinetic research strategy. This paper summarizes some of the results obtained and the methodological problems encountered in this work.


Depressed Patient Plasma Protein Binding Metabolic Ratio Endogenous Depression Monoamine Metabolite 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    M. Åsberg, B. Cronholm, F. Sjöqvist and D. Tuck, Relationship between plasma level of nortriptyline and therapeutic effect, Br. Med. J. 3: 331 – 334 (1971).PubMedCrossRefGoogle Scholar
  2. 2.
    W.Z. Potter, L. Bertilsson and F. Sjöqvist, Clinical pharmacokinetics of psychotropic drugs–Fundamentals and practical aspects, in: “Handbook of Biological Psychiatry,” H.M. van Praag, M.H. Lader, O.J. Rafaelsen and E.J. Sachar, eds., Marcel Dekker Inc., New York (1980).Google Scholar
  3. 3.
    W. Hammer, C.M. Idestrom and F. Sjöqvist, Chemical control of antidepressant drug therapy, in: “Proceedings of the First International Symposium on Antidepressant Drugs,” S. Garattini and M.N.G. Dukes, eds., Excerpta Med. Congr. Ser., Vol. 122, Milan (1967), pp. 301–310.Google Scholar
  4. 4.
    W. Hammer and F. Sjöqvist, Plasma levels of monomethylated tricyclic antidepressants during treatment with imipramine- like compounds, Life Sci. 6: 1895 – 1903 (1967).PubMedCrossRefGoogle Scholar
  5. 5.
    O. Borgå L. Palmér, A. Linnarsson and B. Holmstedt, Quantitative determination of nortriptyline and desmethylnortriptyline in human plasma by combined gas chromatography-mass spectrometry, Anal. Letters 4: 837 – 849 (1971).Google Scholar
  6. 6.
    B. Alexanderson and F. Sjöqvist, Pharmacokinetic and genetic studies of nortriptyline and desmethylimipramine in man: The predictability of therapeutic plasma levels from single dose plasma concentration data, in: “Pharmacology and the Future of Man,” Proc. 5th Int. Congr. Pharmacology (Vol. 3), Karger, Basel (1973), pp. 150 – 162.Google Scholar
  7. 7.
    J.P. Moody, A.C. Tait and A. Todrick, Plasma levels of imipramine and desmethylimipramine during therapy, Br. J. Psychiatry 113: 183 – 193 (1967).PubMedCrossRefGoogle Scholar
  8. 8.
    B. Alexanderson, D.A. Price Evans and F. Sjöqvist, Steady- state plasma levels of nortriptyline in twins: Influence of genetic factors and drug therapy, Br. Med. J. 2: 764–768 (1969).CrossRefGoogle Scholar
  9. 9.
    M. Åsberg, D. Price Evans and F. Sjöqvist, Genetic control of nortriptyline kinetics in man–A study of the relatives of propositi with high plasma concentrations, Br. J. Med. Genet. 8: 129–135 (1971).CrossRefGoogle Scholar
  10. 10.
    B. Alexanderson, Prediction of steady-state plasma levels of nortriptyline from single oral dose kinetics: A study in twins, Eur. J. Clin. Pharmacol. 6: 44–53 (1973).PubMedCrossRefGoogle Scholar
  11. 11.
    B. Alexanderson, O. Borgå and G. Alván, The availability of orally administered nortriptyline, Eur. J. Clin. Pharmacol. 5: 181–185 (1973).CrossRefGoogle Scholar
  12. 12.
    C. von Bahr, O. Borgå, E. Fellenius and M. Rowland, Kinetics of nortriptyline (NT) in rats in vivo and in the isolated perfused liver: Demonstration of a “first-pass disappearance” of NT in the liver, Pharmacology 9: 177–186 (1973).CrossRefGoogle Scholar
  13. 13.
    L.F. Gram and K. Fredrickson-Overø First-pass metabolism of nortriptyline in man, Clin. Pharmacol. Ther. 18: 305–314 (1975).PubMedGoogle Scholar
  14. 14.
    L.F. Gram and J. Christiansen, First-pass metabolism of imipramine in man, Clin. Pharmacol. Ther. 17: 555–563 (1975).PubMedGoogle Scholar
  15. 15.
    G. Alván, O. Borgå, M. Lind, L. Palmér and B. Siwers, First- pass hydroxylation of nortriptyline: Concentrations of parent drug and major metabolites in plasma, Eur. J. Clin. Pharmacol. 11: 219–224 (1977).PubMedCrossRefGoogle Scholar
  16. 16.
    B. Alexanderson and F. Sjöqvist, Individual differences in the pharmacokinetics of monomethylated tricyclic antidepressants: Role of genetic and environmental factors and clinical importance, Ann. N.Y. Acad. Sci. 179: 739–751 (1971).PubMedCrossRefGoogle Scholar
  17. 17.
    O. BorgS, D.L. Azarnoff, G. Plym-Forshell and F. Sjöqvist, Plasma protein binding of tricyclic antidepressants in man, Biochem. Pharmacol. 18: 2135–2143 (1969).PubMedCrossRefGoogle Scholar
  18. 18.
    F. Sjöqvist, L. Bertilsson and M. Åsberg, Frontiers in therapeutic drug monitoring-tricyclic antidepressants, in: “Frontiers in Therapeutic Drug Monitoring,” G. Tognoni and W. Jusko, eds., Raven Press, (1980). Also published in Therapeutic Drug Monitoring, (1980).Google Scholar
  19. 19.
    K. Piafsky and O. Borgå, Plasma protein binding of basic drugs. II. Importance of α1-acid glycoprotein for interindividual variation, Clin. Pharmacol. Ther. 22: 545–549 (1977).PubMedGoogle Scholar
  20. 20.
    K. Piafsky, O. Borgå, I. Odar-Cederlöf, C. Johansson and F. Sjöqvist, Increased plasma protein binding of propranolol and chlorpromazine mediated by disease-induced elevations of plasma α1-acid glycoprotein, N. Engl. J. Med. 229: 1435–1439 (1978).CrossRefGoogle Scholar
  21. 21.
    D. Fremstad, K. Bergerud and J.F.W. Haffner, Increased plasma binding of quinidine after surgery: A preliminary report, Eur. J. Clin. Pharmacol. 10: 441–444 (1976).PubMedCrossRefGoogle Scholar
  22. 22.
    P. Kragh-Sørensen, C. Eggert-Hansen, P.C. Baastrup and E.F. Hvidberg, Self-inhibiting action of nortriptyline’s effect at high plasma levels, Psychopharmacology 45: 305–312 (1976).CrossRefGoogle Scholar
  23. 23.
    R. Braithwaite, S. Montgomery and S. Dawling, Nortriptyline in depressed patients with high plasma levels, Clin. Pharmacol. Ther. 23: 303–314 (1978).PubMedGoogle Scholar
  24. 24.
    V.E. Ziegler, P.J. Clayton, J.R. Taylor, B.T. Co and J.T. Biggs, Nortriptyline plasma levels and therapeutic response, Clin. Pharmacol. Ther. 20: 458–463 (1976).PubMedGoogle Scholar
  25. 25.
    A.H. Glassman, J.M. Perel, M. Shostak, S.J. Kantor and J.L. Fleiss, Clinical implications of imipramine levels for depressive illness, Arch. Gen. Psychiatry 34: 197–204 (1977).PubMedGoogle Scholar
  26. 26.
    . B. Alexanderson, On interindividual variability in plasma levels of nortriptyline and desmethylimipramine in man: A pharmacokinetic and genetic study, MD thesis, Linkoping, (1972).Google Scholar
  27. 27.
    A. Mahgoub, J.R. Idle, L.G. Dring, R. Lancaster and R.L. Smith, Polymorphic hydroxylation of debrisoquine in man, Lancet, 11: 584–586 (1977).CrossRefGoogle Scholar
  28. 28.
    . B. Mellström, L. Bertilsson, J. Sawe, H.-U-. Schulz and F. Sjöqvist, E- and Z-10-hydroxylation of nortriptyline in man–relationship to polymorphic hydroxylation of debrisoquine, Clin. Pharmacol. Ther. 30: 190–193 (1981).CrossRefGoogle Scholar
  29. 29.
    L. Bertilsson, B. Mellström, F. Sjöqvist, B. Mårtensson and M. Åsberg, Slow hydroxylation of nortriptyline and concomitant poor debrisoquine hydroxylation: Clinical implications, Lancet, 1: 560–561 (1981).PubMedCrossRefGoogle Scholar
  30. 30.
    C. von Bahr, H. Glaumann, B. Mellström and F. Sjöqvist,In vitro assessment of hepatic drug metabolism in man–a clinical pharmacological perspective, Trends in Pharmacological Sciences 3: 487–490 (1982).CrossRefGoogle Scholar
  31. 31.
    L. Bertilsson, Quantitative mass fragmentography–A valuable tool in clinical psychopharmacology, in: “Clinical Pharmacology in Psychiatry,” J. Davies and E. Usdin, eds., Elsevier, North Holland, New York (1980).Google Scholar
  32. 32.
    .L. Bertilsson, M. Åsberg, O. Lantto, G.-P. Scalia-Tomba, L. Traskman and G. Tybring, Gradients of monoamine metabolites and Cortisol in cerebrospinal fluid of psychiatric patients and healthy controls, Psych. Res. 6: 77–83 (1982).CrossRefGoogle Scholar
  33. 33.
    M. Åsberg, L. Bertilsson, E. Ryding, D. Schalling, P. Thoren and T. Traskman-Bendz, Monoamine metabolites in cerebrospinal fluid in relation to depressive illness, suicidal behaviour and personality, Proc. 12th CINP Congress, in: “Recent Advances in Neuropsycho-Pharmacology, Advances in the Bio- Sciences” (Vol. 31), B. Angrist, G.D. Burrows, M. Lader, O. Lingjaerde, G. Sedvall and D. Wheatley, eds., Pergamon Press, Oxford and New York (1981).Google Scholar
  34. 34.
    M. Åsberg, L. Bertilsson, D. Tuck, B. Cronholm and F. Sjöqvist, Indoleamine metabolites in the cerebrospinal fluid of depressed patients before and during treatment with nortriptyline, Clin. Pharmacol. Ther. 14: 277–286 (1973).PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1984

Authors and Affiliations

  • Gunnar Alván
    • 1
  • Folke Sjöqvist
    • 1
  1. 1.Department of Clinical Pharmacology Karolinska InstituteHuddinge University HospitalHuddingeSweden

Personalised recommendations