Predictors of Therapeutic Effects in Amitriptyline Treatment

Objective: To analyze the spectrum of relationships between clinical effects of amitriptyline (At) treatment after 2 and 4 weeks (wks) and plasma levels of At, nortriptyline (Nt), At+Nt, demethylation rate of At, treatment modalities, age, and gender.

Methods: Patients with major depression (ICD 10: F31-F33) and a HAMD-21 total score of 15-41 received At on a dosage schedule chosen by the doctor for at least 4 wks. Plasma drug levels were assessed at baseline and at wks 2 and 4.

Results: Of the 58 patients enrolled in the study, 47 (15males, 32 females) were eligible for statistical analysis. An early response by wk 2 (decrease in HAMD-21 score of at least 50 % from baseline) was observed in 34.0 % of patients, and after 4 wks, the response rate was 63.8 % (males 86.6 %, females 53.1 %). There was a low, negative, and significant correlation between percent reduction in HAMD and steady state At concentration only at wk 2 (n = 47 r_Sp. = -0.306 p < 0.05). However, the correlation was dependent on the degree of At demethylation and treatment modalities.

 A ratio of Nt/At >1 was observed in 23 patients; of these, 11 (47.8 %) were non-responders by wk 4. A low rate of demethylation (Nt/At ≤ 1) in 24 patients was associated with a lower frequency of non-response (6/24 = 25.0 %). In the latter subgroup, the 2-wk At plasma concentration varied between 20 and 240 ng/ml, and all patients with ≤ 110 ng At /ml were responders by wk 4. On the other hand, in the Nt/At >1 group, the non-responders were distributed in the whole range of observed At plasma concentrations (20-150 ng/ml).

Only in patients with Nt/At ≤ 1 and constant doses from wk 1 to wk 4 (n = 14) was a strong, linear, and negative correlation between percent reduction in HAMD and plasma At, Nt, or At+Nt concentrations found for the 2-wk data (r_Sp. = -0.754, -0.716, and -0.732, respectively), but not after 4 wks.

Conclusions: The frequently assumed dependence of clinical effects on plasma drug levels is not a simple function. There most likely exist different patterns of relationships with partially unknown backgrounds. The ratio Nt/At may become a discriminating variable in future studies on the nature of plasma level-therapeutic effect relationship in At treatment of major depression.

References

• 1 Åsberg M, Cronholm B, Sjoqvist F, Tuck D. Relationship between plasma level and therapeutic effect of nortriptyline.  Br Med J. 1971;  3 331-334
• 2 Baumann P, Jonzier-Perey M, Koeb L, Le P -K, Tinguely D, Schöpf J. Amitriptyline pharmacokinetics and clinical response: I. Free and total plasma amitriptyline and nortriptyline.  Int Clin Psychopharmacol. 1986;  1 89-101
• 3 Breyer-Pfaff U, Gaertner H -J, Kreuter F, Scharek G, Brinkschulte M, Wiatr R. Antidepressive effect and pharmacokinetics of amitriptyline with consideration of unbound drug and 10-hydroxynortriptyline plasma levels.  Psychopharmacol. 1982;  76 240-244
• 4 Chen S, Chou W -H, Blouin R A, Mao Z, Humphries L L, Meek C, Neill J R, Martin W L, Hays L R, Wedlund P J. The cytochrom P450 2D6 (CYP2D6) enzyme polymorphism: screening costs and influence on clinical outcomes in psychiatry.  Clin Pharmacol Therapeut. 1996;  60 522-534
• 5 Catalano M. Functionally gene-linked polymorphic regions and genetically controlled neurotransmitters metabolism.  Eur Neuropsychopharmacol. 2001;  11 431-440
• 6 Corona G L, Fenoglia L, Pinelli P, Zerbi F. Amitriptyline and nortriptyline plasma levels and therapeutic response in depressed women.  Pharmakopsychiatry. 1977;  10 299-308
• 7 De Oliveira I R, Do Prado-Lima P AS, Samuel-Lajeunesse B. Monitoring of tricyclic antidepressant plasma levels and clinical response: a review of the literature. Part 1.  Psychat Psychobiol. 1989;  4 43-60
• 8 Franke L, Schewe H- J, Uebelhack R, Müller-Oerlinghausen B. High platelet-5HT uptake activity is associated with a rapid response in depressed patients treated with amitriptyline.  European Neuropsychopharmacology. 2001;  12(3) S242
• 9 Glassman A H, Schildkraut J J, Orsulak P J, Cooper T B, Kupfer D J, Shader R I. et al . Tricyclic antidepressants - blood level measurements and clinical outcome: An APA task force report.  Am J Psychiatr. 1985;  142 155-162
• 10 Glotzbach R K, Preskorn S H. Brain concentrations of tricyclic antidepresants: single dose kinetics and relationship to plasma concentrations in chronically dosed rats.  Psychopharmacology. 1982;  78 25-27
• 11 Jungkunz G, Kuss H. On the relationship of nortriptyline: amitriptyline ratio to clinical improvement of amitriptyline treated depressive patients.  Pharmakopsychiatry. 1980;  13 111-116
• 12 Katz M M, Koslow S H, Maas J W, Frazer A, Kocsis J, Secunda S, Bowden C H, Casper R. Identifying the specific clinical actions of amitriptyline: interrelationships of behaviour, affect and plasma levels in depression.  Psychol Med. 1991;  21 599-611
• 13 Kocsis J -H, Hanin I, Bowden C, Brunswick D. Imipramine and amitriptyline plasma concentrations and clinical response in major depression.  Br J Psychiat. 1986;  148 52-57
• 14 Möller H -J, Glaser K, Leverkus F, Göbel C. Double-blind, multicenter comparative study of setraline versus amitriptyline in outpatients with major depression.  Pharmacopsychiatry. 2000;  33 206-212
• 15 Müller-Oerlinghausen B. Plasmaspiegelbestimmung von Antidepressiva.  Psychopharmakotherapie. 1995;  2 125-126
• 16 Perry P J, Zeilmann C, Arndt S. Tricyclic antidepressant concentrations in plasma: an estimate of their sensitivity and specificity as a predictor of response.  J Clin Psychopharmacol. 1994;  14 230-240
• 17 Rickels K, Weise C h, Case G, Hucker H. Tricyclic plasma levels in depressed outpatients treated with amitriptyline.  Psychopharmacology. 1983;  80 14-18
• 18 Shimoda K, Yasuda S, Morita S, Shibasaki M, Someya T, Bertilsson L, Takahashi S. Significance of monitoring plasma levels of amitriptyline, and its hydroxylated and desmethylated metabolites in prediction of the clinical outcome of depressive state.  Psychiat Clin Neurosci. 1997;  51 35-41
• 19 Shen W . The metabolism of psychoactive drugs: a review of enzymatic biotransformation and inhibition.  Biol Psychiatry. 1997;  41 814-826
• 20 Steimer W, Müller B, Leucht S t, Kissling W. Pharmacogenetics: a new diagnostic tool in the management of antidepressive drug therapy.  Clin Chim Acta. 2001;  308 33-41
• 21 Ulrich S, Northoff G, Wurthmann C, Partscht G, Pester U, Herscu H, Meyer F P. Serum levels of amitriptyline and therapeutic effect in non-delusional moderately to severely depressed in-patients: a therapeutic window relationship.  Pharmacopsychiatry. 2001;  34 33-40

1 Supported by the German Research Foundation (DFG Ue38/2-1 and Mu477/9-1).