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Antidepressive effect of amitriptyline treatment with plasma drug levels controlled within three different ranges

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Abstract

Seventy-four depressed patients were treated with amitriptyline for 4–6 weeks. Their doses were individually adjusted to maintain the sum of the plasma levels of amitriptyline (AT) and nortriptyline (NT) within one of three different ranges, randomly allocated. Allowance was made for individual plasma binding of the drugs. In the 50 patients between 25 and 65 years of age, the antidepressive response at low plasma drug levels was somewhat poorer than at medium or high levels, which were equally effective. In this age group an association was found between outcome and the individual rate of AT metabolism, expressed as “reciprocal clearance” (RC), the steady-state plasma concentration of AT plus NT divided by the daily AT dose. Good antidepressive outcome was associated with high RC. The implications of these findings for patient treatment and for the interpretation of other studies are discussed. The 18 patients between 65 and 80 years of age showed no significant differences between the effectiveness of treatment at different plasma drug levels, and no significant associations between outcome and RC.

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References

  • Alexanderson B (1973) Prediction of steady-state plasma levels of nortriptyline from single oral dose kinetics: a study in twins. Eur J Clin Pharmacol 6:44–53

    Google Scholar 

  • Alexanderson B, Evans DAP, Sjöqvist F (1969) Steady-state plasma levels of nortriptyline in twins: influence of genetic factors and drug therapy. Br Med J 4:764–768

    Google Scholar 

  • APA Task force on the use of laboratory tests in psychiatry (1985) Tricyclic antidepressants — blood measurements and clinical outcome: an APA task force report. Am J Psychiatry 142:155–162

    Google Scholar 

  • Åsberg M, Cronholm B, Sjöqvist F, Tuck D (1971) Relationship between plasma level and therapeutic effect of nortriptyline. Br Med J 3:331–334

    Google Scholar 

  • Braithwaite RA, Goulding R, Theano G, Bailey J, Coppen A (1972) Plasma concentration of amitriptyline and clinical response. Lancet I:1297–1300

    Google Scholar 

  • Braithwaite RA, Nakra BRS, Gaind R (1974) Steady-state plasma concentrations during single and multiple dosage schedules of amitriptyline. Psychol Med 4:338–341

    Google Scholar 

  • Breyer-Pfaff U, Gaertner HJ, Giedke H (1982a) Plasma levels, psychophysiological variables, and clinical response to amitriptyline. Psychiatr Res 6:223–234

    Google Scholar 

  • Breyer-Pfaff U, Gaertner HJ, Kreuter F, Scharek G, Brinkschulte M, Wiatr R (1982b) Antidepressive effect and pharmacokinetics of amitriptyline with consideration of unbound drug and 10-hydroxynortriptyline plasma levels. Psychopharmacology 76:240–244

    Google Scholar 

  • Burch JE, Hullin RP (1981) Amitriptyline pharmacokinetics. A crossover study with single doses of amitriptyline and nortriptyline. Psychopharmacology 74:35–42

    Google Scholar 

  • Burch JE, Raddats MA, Thompson SG (1979) Reliable routine method for the determination of plasma amitriptyline and nortriptyline by gas chromatography. J Chromatogr 162:351–366

    Google Scholar 

  • Burch JE, Roberts SG, Raddats MA (1981) Binding of amitriptyline and nortriptyline in plasma determined from their equilibrium distributions between red cells and plasma and between red cells and buffer solution. Psychopharmacology 75:262–272

    Google Scholar 

  • Burch JE, Roberts SG, Raddats MA (1984) Amitriptyline and its basic metabolites determined in plasma by gas chromatography. J Chromatogr 308:165–179

    Google Scholar 

  • Click MA, Zisook S (1982) Amoxapine and amitriptyline: serum levels and clinical response in patients with primary unipolar depression. J Clin Psychiatry 43:369–371

    Google Scholar 

  • Coppen A, Ghose K, Montgomery S, Rama Rao VA, Bailey J, Christiansen J, Mikkleson PL, van Praag HM, van de Poel F, Minsker EJ, Kozulja VG, Matussek N, Kungkunz G, Jørgensen A (1978) Amitriptyline plasma-concentration and clinical effect. Lancet I:63–66

    Google Scholar 

  • Corona GL, Fenoglio L, Pinelli P, Zerbi F (1977) Amitriptyline nortriptyline plasma levels and therapeutic response in depressed women. Pharmakopsychiatr NeuroPsychopharmakol 10:299–308

    Google Scholar 

  • Corona GL, Pinelli P, Zerbi F, Fenoglio L, Santagostino G, Frattini P, Cucchi ML (1980a) Amitriptyline nortriptyline plasma levels and clincial response in women with affective disorders. Pharmakopsychiatr NeuroPsychopharmakol 13:102–110

    Google Scholar 

  • Corona GL, Zerbi F, Pinelli P, Fenoglio L, Frattini P, Cucchi ML, Santagostino G (1980b) Amitriptyline and nortriptyline plasma levels monitoring: perspective in clinical practice. Commun Psychopharmacol 4:309–316

    Google Scholar 

  • De Maio D, Drago F, Nielsen P, Ascalone V, Cisternino M (1980) Plasma concentrations of amitriptyline during single nightly and thrice daily administration. Arzneimittelforschung Drug Res 30:335–337

    Google Scholar 

  • Edelbroek PM, Zitman FG, Schreuder JN, Rooymans HGM, de Wolff FA (1984) Amitriptyline metabolism in relation to anti-depressive effect. Clin Pharmacol Ther 35:467–473

    Google Scholar 

  • Feighner JP, Robins E, Guze SB, Woodruff RA, Winokur G, Munoz R (1972) Diagnostic criteria for use in psychiatric research. Arch Gen Psychiatry 26:57–63

    Google Scholar 

  • Garland WA, Min BH, Birkett DJ (1978) The kinetics of amitriptyline following single oral dose administration to man. Res Commun Chem Pathol Pharmacol 22:475–484

    Google Scholar 

  • Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62

    CAS  PubMed  Google Scholar 

  • Johnstone EC, Bourne RC, Crow TJ, Frith CD, Gamble S, Lofthouse R, Owen F, Owens DGC, Robinson J, Stevens M (1981) The relationships between clinical response, psychophysiological variables and plasma levels of amitriptyline and diazepam in neurotic outpatients. Psychopharmacology 72:233–240

    Google Scholar 

  • Jørgensen A, Staehr P (1976) On the biological half-life of amitriptyline. J Pharm Pharmacol 28:62–64

    Google Scholar 

  • Jungkunz G, Kuss H-J (1978) Amitriptyline and its demethylation rate. Lancet II:1263–1264

    Google Scholar 

  • Jungkunz G, Kuss H-J (1980) On the relationship of nortriptyline: amitriptyline ratio to clinical improvement of amitriptyline treated depressive patients. Pharmacopsychiatr NeuroPsychopharmakol 13:111–116

    Google Scholar 

  • Kearns NP, Cruickshank CA, McGuigan KJ, Riley SA, Shaw SP, Snaith RP (1982) A comparison of depression rating scales. Br J Psychiatry 141:45–49

    Google Scholar 

  • Kocsis JH, Hanin I, Bowden C, Brunswick D (1986) Imipramine and amitriptyline plasma concentrations and clinical response in major depression. Br J Psychiatry 148:52–57

    Google Scholar 

  • Kupfer DJ, Hanin I, Spiker D, Grau T, Coble P (1977) Amitriptyline plasma levels and clinical response in primary depression. Clin Pharmacol Ther 22:904–911

    Google Scholar 

  • Kupfer DJ, Hanin I, Spiker D, Neil J, Coble P, Grau T, Nevar C (1978) Amitriptyline plasma levels and clinical response in primary depression II. Commun Psychopharmacol 2:441–450

    Google Scholar 

  • Lüsberg P, Mose H, Amdisen A, Jørgensen A, Høpfner Petersen HE (1978) A clinical trial comparing sustained release amitriptyline (Saroten Retard) and conventional amitriptyline tablets (Saroten) in endogenously depressed patients with simultaneous determination of serum levels of amitriptyline and nortriptyline. Acta Psychiatr Scand 57:426–435

    Google Scholar 

  • Mendlewicz J, Linkowski P, Rees JA (1980) A double-blind comparison of dothiepin and amitriptyline in patients with primary affective disorder: serum levels and clinical response. Br J Psychiatry 136:154–160

    Google Scholar 

  • Montgomery SA (1980) Measurement of serum drug levels in the assessment of antidepressants. Br J Clin Pharmacol 10:411–416

    Google Scholar 

  • Montgomery SA, Åsberg M (1979) A new depression scale designed to be sensitive to change. Br J Psychiatry 134:382–389

    CAS  PubMed  Google Scholar 

  • Montgomery SA, McAuley R, Rani SJ, Montgomery DR, Braithwaite R, Dawling S (1979) Amitriptyline plasma concentration and clinical response. Br Med J 1:230–231 and 1711

    Google Scholar 

  • Montgomery SA, McAuley R, Montgomery DB, Dawling S, Braithwaite RA (1980) Pharmacokinetics and efficacy of maprotiline and amitriptyline in endogenous depression: A double-blind controlled trial. Clin Ther 3:292–310

    Google Scholar 

  • Montgomery SA, McAuley R, Rani SJ, Roy D, Montgomery DB (1981a) A double blind comparison of zimelidine and amitriptyline in endogenous depression. Acta Psychiatr Scand [Suppl] 290:314–327

    Google Scholar 

  • Montgomery SA, Rani SJ, McAuley R, Roy D, Montgomery DB (1981b) The antidepressant efficacy of zimelidine and maprotiline. Acta Psychiatr Scand [Suppl] 290:219–224

    Google Scholar 

  • Quednow B, Walther H, Genz A, Kühne G-E (1981) Amitriptyline levels and clinical effects. Aggressologie 22:15–18

    Google Scholar 

  • Rickels K, Weise C, Case G, Hucker H (1983) Tricyclic plasma levels in outpatients treated with amitriptyline. Psychopharmacology 80:14–18

    Google Scholar 

  • Robinson DS, Cooper TB, Ravaris CL, Ives JO, Nies A, Bartlett D, Lamborn KR (1979) Plasma tricyclic drug levels in amitriptyline-treated depressed patients. Psychopharmacology 63:223–231

    Google Scholar 

  • Robinson DS, Cooper TB, Howard D, Corcella J, Albright D (1985) Amitriptyline and hydroxylated metabolite plasma levels in depressed outpatients. J Clin Psychopharmacol 5:83–88

    Google Scholar 

  • Rollins DE, Alván G, Bertilsson L, Gillette JR, Mellström B, Sjöqvist F, Träskman L (1980) Interindividual differences in amitriptyline demethylation. Clin Pharmacol Ther 28:121–129

    Google Scholar 

  • Rowan PR, Paykel ES, Marks V, Mould G, Bhat A (1984) Serum levels and response to amitriptyline in depressed outpatients. Neuropsychobiology 12:9–15

    Google Scholar 

  • Snaith RP, Bridge GWK, Hamilton M (1976) The Leeds scale for the self-assessment of anxiety and depression. Br J Psychiatry 128:156–165

    Google Scholar 

  • Snaith RP, Harrop FM, Newby DA, Teale C (1986) Grade scores of the Montgomery-Åsberg depression and the clinical anxiety scales. Br J Psychiatry 148:599–601

    Google Scholar 

  • Thomson J, Rankin H, Ashcroft EW, Yates CM, McQueen JK, Cummings SW (1982) The treatment of depression in general practice: a comparison of l-tryptophan, amitriptyline, and a combination of l-tryptophan and amitriptyline with placebo. Psychol Med 12:741–751

    Google Scholar 

  • Vandel S, Vandel B, Sandoz M, Allers G, Bechtel P, Volmat R (1978) Clinical response and plasma concentration of amitriptyline and its metabolite nortriptyline. Eur J Clin Pharmacol 14:185–190

    Google Scholar 

  • Ziegler VE, Co BT, Taylor JR, Clayton PJ, Biggs JT (1976) Amitriptyline plasma levels and therapeutic response. Clin Pharmacol Ther 19:795–801

    Google Scholar 

  • Ziegler VE, Clayton PJ, Biggs JT (1977a) A comparison study of amitriptyline and nortriptyline with plasma levels. Arch Gen Psychiatry 34:607–612

    Google Scholar 

  • Ziegler VE, Meyer DA, Rosen SH, Knesevich JW, Biggs JT (1977b) Amitriptyline dosage schedule, sampling time and tricyclic plasma levels. Br J Psychiatry 131:168–171

    Google Scholar 

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Authors and Affiliations

  1. Department of Biochemistry, University of Leeds, LS2 9JT, Leeds, West Yorkshire, UK

    J. E. Burch & R. P. Hullin

  2. Department of Psychiatry, University of Leeds, LS2 9JT, Leeds, West Yorkshire, UK

    O. Ahmed & R. H. S. Mindham

Authors
  1. J. E. Burch
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  2. O. Ahmed
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  3. R. P. Hullin
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  4. R. H. S. Mindham
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Burch, J.E., Ahmed, O., Hullin, R.P. et al. Antidepressive effect of amitriptyline treatment with plasma drug levels controlled within three different ranges. Psychopharmacology 94, 197–205 (1988). https://doi.org/10.1007/BF00176845

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  • DOI: https://doi.org/10.1007/BF00176845

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