Skip to main content
SpringerLink
Log in

Metabolism of Tricyclic Antidepressants

  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

1. Despite the considerable advances in the treatments available for mood disorders over the past generation, tricyclic antidepressants (TCAs) remain an important option for the pharmacotherapy of depression.

2. The pharmacokinetics of TCAs are characterized by substantial presystemic first-pass metabolism, a large volume of distribution, extensive protein binding, and an elimination half-life averaging about 1 day (up to 3 days for protriptyline).

3. Clearance of tricyclics is dependent primarily on hepatic cytochrome P450 (CYP) oxidative enzymes. Although the activities of some P450 isoenzymes are largely under genetic control, they may be influenced by external factors, such as the concomitant use of other medications or substances. Patient variables, such as ethnicity and age, also affect TCA metabolism. The impact of gender and related reproductive issues is coming under increased scrutiny.

4. Metabolism of TCAs, especially their hydroxylation, results in the formation of active metabolites, which contribute to both the therapeutic and the adverse effects of these compounds.

5. Renal clearance of the polar metabolites of TCAs is reduced by normal aging, accounting for much of the increased risk of toxicity in older patients.

6. Knowledge of factors affecting the metabolism of TCAs can further the development and understanding of newer antidepressant medications.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  • Abernethy, D. R. (1997). Grapefruits and drugs: When is statistically significant clinically significant? (Editorial). J. Clin. Invest. 99:2297–2298.

    Google Scholar 

  • Abernethy, D. R., Greenblatt, D. J., and Shader, R. I. (1984). Imipramine disposition in users of oral contraceptive steroids. Clin. Pharmacol. Ther. 35:792–797.

    Google Scholar 

  • Altshuler, L. L., and Hendrick, V. C. (1996). Pregnancy and psychotropic medication: Changes in blood levels. J. Clin. Psychopharmacol. 16:78–80.

    Google Scholar 

  • Alvan, G., Borga, O., Lind, M., Palmer, L., and Siwers, B. (1977). Concentrations of parent drug and major metabolites in plasma. Eur. J. Clin. Pharmacol. 11:219–224.

    Google Scholar 

  • Amitai, Y., Erickson, T., Kennedy, E. J., Leikin, J. B., Hryhorczuk, D. O., Noble, J., Hanashiro, P. K., and Frischer, H. (1993). Tricyclic antidepressants in red cells and plasma: Correlation with impaired intraventricular conduction in acute overdose. Clin. Pharmacol. Ther. 54:219–227.

    Google Scholar 

  • Amsterdam, J. D., Brunswick, D. J., Potter, W. Z., Winokur, A., and Rickels, K. (1985). Desipramine and 2-hydroxydesipramine plasma levels in endogenous depressed patients: Lack of correlation with therapeutic response. Arch. Gen. Psychiatry 42:361–364.

    Google Scholar 

  • Anonymous (1995). Grapefruit juice interactions with drugs. Med. Lett. 37:73–74.

  • Anton, R. F., Jr., and Burch, E. A., Jr. (1990). Amoxapine versus amitriptyline combined with perphenazine in the treatment of psychotic depression. Am. J. Psychiatry 147:1203–1208.

    Google Scholar 

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

    Google Scholar 

  • Baker, B., Dorian, P., Sandor, P., Shapiro, C., Schell, C., Mitchell, J., and Irvine, J. (1997). Electrocardiographic effects of fluoxetine and doxepin in patients with major depressive disorder. J. Clin. Psychopharmacol. 17:15–21.

    Google Scholar 

  • Balant-Gorgia, A. E., Balant, L. P., Genet, C., Dayer, P., Aeschlimann, J. M., and Garrone, G. (1986). Importance of oxidative polymorphism and levomepromazine treatment on the steady-state blood concentrations of clomipramine and its major metabolites. Eur. J. Clin. Pharmacol. 31:449–455.

    Google Scholar 

  • Balant-Gorgia, A. E., Gex-Fabry, M., and Balant, L. P. (1991). Clinical pharmacokinetics of clomipramine. Clin. Pharmacokinet. 20:447–462.

    Google Scholar 

  • Bendtsen, L., Jensen, R., and Olesen, J. (1996). A non-selective (amitriptyline), but not a selective (citalopram), serotonin reuptake inhibitor is effective in the prophylactic treatment of chronic tension-type headache. J. Neurol. Neurosurg. Psychiatry 61:285–290.

    Google Scholar 

  • Ben Musa, A., and Smith, C. S. (1979). Neonatal effects of maternal clomipramine therapy. Arch. Dis. Child. 54:405.

    Google Scholar 

  • Bergstrom, R. F., Peyton, A. L., and Lemberger, L. (1992). Quantification and mechanism of the fluoxetine and tricyclic antidepressant interaction. Clin. Pharmacol. Ther. 51:239–248.

    Google Scholar 

  • Bertilsson, L., and Dahl, M.-L. (1996). Polymorphic drug oxidation: Relevance to the treatment of psychiatric disorders. CNS Drugs 5:200–223.

    Google Scholar 

  • Bertilsson, L., Nordin, C., Otani, K., Resul, B., Scheinin, M., Siwers, B., and Sjöqvist, F. (1986). Disposition of single oral doses of E-10-hydroxynortriptyline in healthly subjects, with some observations on pharmacodynamic effects. Clin. Pharmacol. Ther. 40:261–267.

    Google Scholar 

  • Bertilsson, L., Mellström, B., and Sjöqvist, F. (1979). Pronounced inhibition of noradrenaline uptake by 10-hydroxy-metabolites of nortriptyline. Life Sci. 25:1285–1292.

    Google Scholar 

  • Bertilsson, L., Åberg-Wistedt, A., Gustafsson, L. L., and Nordin, C. (1985). Extremely rapid hydroxylation of debrisoquine: A case report with implication for treatment with nortriptyline and other tricyclic antidepressants. Ther. Drug Monit. 7:478–480.

    Google Scholar 

  • Bertilsson, L., Dahl-Puustinen, M.-L., and Nordin, C. (1989). E-10-hydroxynortriptyline: Effects and disposition of a potential novel antidepressant. In Dahl, S. G., and Gram, L. F. (eds.), Clinical Pharmacology in Psychiatry, Springer-Verlag, Berlin, pp. 52–59.

    Google Scholar 

  • Bhagwat, S. V., Bhamre, S., Boyd, M. R., and Ravindranath, V. (1996). Cerebral metabolism of imipramine and a purified flavin-containing monooxygenase from human brain. Neuropsychopharmacology 15:133–142.

    Google Scholar 

  • Biederman, J., Baldessarini, R. J., Goldblatt, A., Lapey, K. A., Doyle, A., and Hesslein, P. S. (1993). A naturalistic study of 24-hour electrocardiographic recording and echocardiographic findings in children and adolescents treated with desipramine. J. Am. Acad. Child Adolesc. Psychiatry 32:805–813.

    Google Scholar 

  • Bluhm, R. E., Wilkinson, G. R., Shelton, R., and Branch, R. A. (1993). Genetically determined drug-metabolizing activity and desipramine-associated cardiotoxicity: A case report. Clin. Pharmacol. Ther. 53:89–95.

    Google Scholar 

  • Bock, J., Giller, E., Gray, S., and Jatlow, P. (1982). Steady-state plasma concentrations of cis-and trans-10-H amitriptyline metabolites. Clin. Pharmacol. Ther. 31:609–616.

    Google Scholar 

  • Bock, J. L., Nelson, J. C., Gray, S., and Jatlow, P. (1983). Desipramine hydroxylation: Variability and effect of antipsychotic drugs. Clin. Pharmacol. Ther. 33:322–328.

    Google Scholar 

  • Breyer-Pfaff, U., Giedke, H., Gaertner, H. J., and Nill, K. (1989). Validation of a therapeutic plasma level range in amitriptyline treatment of depression. J. Clin. Psychopharmacol. 9:116–121.

    Google Scholar 

  • Breyer-Pfaff, U., Pfandl, B., Nill, K., Nusser, E., Monney, C., Jonzier-Perey, M., Baettig, D., and Baumann, P. (1992). Enantioselective amitriptyline metabolism in patients phenotyped for two cytochrome P450 isozymes. Clin. Pharmacol. Ther. 52:350–358.

    Google Scholar 

  • Breyer-Pfaff, U., Entenmann, A., and Gaertner, H. J. (1995). Secretion of amitriptyline and metabolites into breast milk. Am. J. Psychiatry 152:812–813.

    Google Scholar 

  • Brixen-Rasmussen, L., Halgrener, J., and Jorgensen, A. (1982). Amitriptyline and nortriptyline excretion in human breast milk. Psychopharmacology 76:94–95.

    Google Scholar 

  • Brosen, K., Gram, L. F., Klysner, R., and Bech, P. (1986). Steady-state levels of imipramine and its metabolites: Significance of dose-dependent kinetics. Eur. J. Pharmacol. 30:43–49.

    Google Scholar 

  • Brown, C. S., Wells, B. G., Cold, J. A., Froemming, J. H., Self, T. H., and Jabbour, J. T. (1990). Possible influences of carbamazepine on plasma imipramine concentrations in children with attention deficit hyperactivity disorder. J. Clin. Psychopharmacol. 10:359–362.

    Google Scholar 

  • Browne, J. L., Perry, P. J., Taylor, J. W., Sieleni, B. A., and Kronfol, S. (1984). Nortriptyline capacity-limited metabolism: A case report. J. Clin. Psychopharmacol. 4:322–325.

    Google Scholar 

  • Buist, A., and Janson, H. (1995). Effect of exposure to dothiepin and northiaden in breast milk on child development. Br. J. Psychiatry 167:370–373.

    Google Scholar 

  • Caccia, S., and Garattini, S. (1992). Pharmacokinetic and pharmacodynamic significance of antidepressant drug metabolites. Pharmacol. Res. 26:317–329.

    Google Scholar 

  • Callahan, A. M., Fava, M., and Rosenbaum, J. F. (1993). Drug interaction in psychopharmacology. Psychiatr. Clin. North Am. 16:647–671.

    Google Scholar 

  • Calvo, B., García, M. J., Pedraz, J. L., Mariño, E. L., and Domínguez-Gil, A. (1985). Pharmacokinetics of amoxapine and its active metabolites. Int. J. Clin. Pharmacol. Ther. Toxicol. 23:180–185.

    Google Scholar 

  • Cassidy, S. L., and Henry, J. A. (1987). Fatal toxicity of antidepressant drugs in overdose. Br. Med. J. 295:1021–1024.

    Google Scholar 

  • Cooke, R. G., Warsh, J. J., Stancer, H. C., Reed, K. L., and Persad, E. (1984). The nonlinear kinetics of desipramine and 2-hydroxydesipramine in plasma. Clin. Pharmacol. Ther. 36:343–349.

    Google Scholar 

  • Cutler, N. R., Zavadil, A., Linnoila, M., Scheinin, M., Rudorfer, M. V., and Potter, W. Z. (1984). Effects of chronic desipramine on plasma norepinephrine concentrations and cardiovascular parameters in elderly depressed women: A preliminary report. Biol. Psychiatry 19:549–556.

    Google Scholar 

  • Dahl-Puustinen, M.-L., Perry, T. L., Dumont, E., von Bahr, C., Nordin, C., and Bertilsson, L. (1989a). Stereoselective disposition of racemic E-10-hydroxynortriptyline in human beings. Clin. Pharmacol. Ther. 45:650–656.

    Google Scholar 

  • Dahl-Puustinen, M.-L., Åberg-Wistedt, A., and Bertilsson, L. (1989b). Glucuronidation of amitriptyline in man in vivo. Toxicology 65:37–39.

    Google Scholar 

  • Daly, A. K., Brockmoller, J., Broly, F., Eichelbaum, M., Evans, W. E., Gonzalez, F. J., Huang, J. D., Idle, J.R., Ingelman-Sundberg, M., Ishizaki, T., Jacqz-Aigrain, E., Meyer, U. A., Nebert, D.W., Steen, V. M., Wolf, C. R., and Zanger, U. M. (1996). Nomenclature for human CYP2D6 alleles. Pharmacogenetics 6:193–201.

    Google Scholar 

  • Dawkins, K., and Potter, W. Z. (1991). Gender differences in pharmacokinetics and pharmacodynamics of psychotropics: Focus on women. Psychopharmacol. Bull. 27:417–426.

    Google Scholar 

  • Dawling, S., Lynn, K., Rosser, R., and Braithwaite, R. (1982). Nortriptyline metabolism in chronic renal failure: Metabolite elimination. Clin. Pharmacol. Ther. 32:322–329.

    Google Scholar 

  • Delgado, P. L., and Gelenberg, A. J. (1997). Decision making in the use of antidepressants, part II: Choosing a medication. Essent. Psychopharmacol. 1:313–330.

    Google Scholar 

  • Dessain, E. C., Schatzberg, A. F., Woods, B. T., and Cole, J. O. (1986). Maprotiline treatment in depression: A perspective on seizures. Arch. Gen. Psychiatry 43:86–90.

    Google Scholar 

  • De Vane, C. L. (1994). Pharmacogenetics and drug metabolism of newer antidepressant agents. J. Clin. Psychiatry 55 (Suppl. 12):38–45.

    Google Scholar 

  • De Vane, C. L., and Jusko, W. (1981). Plasma concentration monitoring of hydroxylated metabolites of imipramine and desipramine. Drug Intell. Clin. Pharm. 15:263–266.

    Google Scholar 

  • De Vane, C. L., Savett, M., and Jusko, W. J. (1981). Desipramine and 2-hydroxy-desipramine pharmacokinetics in normal volunteers. Eur. J. Clin. Pharmacol. 19:61–64.

    Google Scholar 

  • Donnelly, M., Zametkin, A. J., Rapoport, J. L., Ismond, D. R., Weingartner, H., Lane, E., Oliver, J., Linnoila, M., and Potter, W. Z. (1986). Treatment of childhood hyperactivity with desipramine: Plasma drug concentration, cardiovascular effects, plasma and urinary catecholamine levels, and clinical response. Clin. Pharmacol. Ther. 39:72–81.

    Google Scholar 

  • Ducharme, M. P., Provenzano, R., Dehoorne-Smith, M., and Edwards, D. J. (1993). Trough concentrations of cyclosporine in blood following administration with grapefruit juice. Br. J. Clin. Pharmacol. 36:457–459.

    Google Scholar 

  • Edelbroek, P. M., Zitman, F. G., Knoppert-van der Klein, E. A. M., van Putten, P. M., and de Wolff, F. A. (1987). Therapeutic drug monitoring of amitriptyline: Impact of age, smoking and contraceptives on drug and metabolite levels in bulimic women. Clin. Chim. Acta 165:177–187.

    Google Scholar 

  • Edgar, B., Bailey, D., Bergstrand, R., Johnsson, G., and Regårdh, C. G. (1992). Acute effects of drinking grapefruit juice on the pharmacokinetics and dynamics on felodipine—and its potential clinical relevance. Eur. J. Clin. Pharmacol. 42:313–317.

    Google Scholar 

  • Edwards, D. J., Bellevue, F. H., III, and Woster, P. M. (1996). Identification of 6′,7′-dihydroxybergamottin, a cytochrome P450 inhibitor, in grapefruit juice. Drug Metab. Dispos. 24:1287–1290.

    Google Scholar 

  • El-Fakahany, E., and Richelson, E. (1983). Antagonism by antidepressants of muscarinic acetylcholine receptors of human brain. Br. J. Pharmacol. 78:97–102.

    Google Scholar 

  • Fallon, B. A., and Liebowitz, M. R. (1999). Intravenous clomipramine for obsessive compulsive disorder. In Goodman, W. K., Rudorfer, M. V., and Maser, J. D. (eds.), Treatment Challenges in Obsessive-Compulsive Disorder, Lawrence Erlbaum Associates, Mahwah, NJ (in press).

    Google Scholar 

  • Fleischmann, R., Remmer, H., and Starz, U. (1986). Induction of cytochrome P-448 iso-enzymes and related glucuronyltransferases in the human liver by cigarette smoking. Eur. J. Clin. Pharmacol. 30:475–480.

    Google Scholar 

  • Fogelson, D. L. (1997). Fenfluramine and the cytochrome P450 system. Am. J. Psychiatry 154:436–437.

    Google Scholar 

  • Gelenberg, A. J., Cooper, D. S., Doller, J. C., and Maloof, F. (1979). Galactorrhea and hyperprolactinemia associated with amoxapine therapy: Report of a case. JAMA 242:1900–1901.

    Google Scholar 

  • Geller, B. (1991). Psychopharmacology of children and adolescents: Pharmacokinetics and relationships of plasma/serum levels to response. Psychopharmacol. Bull. 27:401–409.

    Google Scholar 

  • Geller, B., Cooper, T. B., Graham, D. L., Fetner, H. H., Marsteller, F. A., and Wells, J. M. (1992). Pharmacokinetically designed double-blind placebo-controlled study of nortriptyline in 6-to-12-year olds with major depressive disorder. J. Am. Acad. Child. Adolesc. Psychiatry 31:34–44.

    Google Scholar 

  • Gex-Fabry, M., Balant-Gorgia, A. E., Balant, L. P., and Garrone, G. (1990). Clomipramine metabolism: Model-based analysis of variability factors from drug monitoring data. Clin. Pharmacokinet. 19:241–255.

    Google Scholar 

  • Glassman, A. H., Roose, S. P., and Bigger, J. T., Jr. (1993). The safety of tricyclic antidepressants in cardiac patients: Risk-benefit reconsidered. JAMA 269:2673–2675.

    Google Scholar 

  • Golden, R. N., Gilmore, J. H., and Carson, S. W. (1991). Antidepressant challenge tests: The interface of pharmacokinetics and pharmacodynamics. Psychopharmacol. Bull. 27:611–617.

    Google Scholar 

  • Golden, R. N., Bebchuk, J. M., and Leatherman, M. E. (1995).Trazodone and other antidepressants. In Schatzberg, A.F., and Nemeroff, C. B. (eds.), The American Psychiatric Press Textbook of Psychopharmacology, American Psychiatric Press, Washington, DC, pp. 195–213.

    Google Scholar 

  • Gram, L. F., Bjerre, M., Kragh-Sørensen, P., Kvinesdal, B., Molin, J., and Pedersen, O. L. (1983). Imipramine metabolites in blood of patients during therapy and after overdose. Clin. Pharmacol. Ther. 33:335–342.

    Google Scholar 

  • Greenberg, H. E., England, M. J., and Bjornsson, T. D. (1997). Distribution of pharmacokinetic parameter values for various drug classes. Clin. Pharmacol. Ther. 61:220.

    Google Scholar 

  • Greenblatt, D. J., VonMoltke, L. L., and Shader, R. I. (1996). The importance of presystemic extraction in clinical psychopharmacology. J. Clin. Psychopharmacol. 16:417–419.

    Google Scholar 

  • Hammer, W., and Sjöqvist, F. (1967). Plasma levels of monomethylated tricyclic antidepressants during treatment with imipramine-like compounds. Life Sci. 6:1895–1903.

    Google Scholar 

  • Harvey, A. T., and Preskorn, S. H. (1996). Cytochrome P450 enzymes: Interpretation of their interactions with selective serotonin reuptake inhibitors. Part I. J. Clin. Psychopharmacol. 16:273–285.

    Google Scholar 

  • Hazell, P., O'Connell, D., and Heathcote, D. (1995). Efficacy of tricyclic drugs in treating child and adolescent depression: A meta-analysis. Br. Med. J. 310:897–901.

    Google Scholar 

  • Huang, C. C. (1986). Persistent tardive dyskinesia associated with amoxapine therapy. Am. J. Psychiatry 143:1069–1070.

    Google Scholar 

  • Jandhyala, B. S., Steenberg, M. L., Perel, J. M., Manian, A. A., and Buckley, J. (1977). Effects of several tricyclic antidepressants on the hemodynamics and myocardial contractility of anesthetized dogs. Eur. J. Pharmacol. 42:403–410.

    Google Scholar 

  • Jarvis, M. R. (1991). Clinical pharmacokinetics of tricyclic antidepressant overdose. Psychopharmacol. Bull. 27:541–550.

    Google Scholar 

  • Javaid, J. I., Perel, J. M., and Davis, J. M. (1979). Inhibition of biogenic amine uptake by imipramine, desipramine, 2 OH-imipramine and 2 OH-desipramine in rat brain. Life Sci. 24:21–28.

    Google Scholar 

  • Jefferson, J. W. (1995). Tamoxifen-associated reduction in tricyclic antidepressant levels in blood. J. Clin. Psychopharmacol. 15:223–224.

    Google Scholar 

  • Johansson, I., Lundqvist, E., Bertilsson, L., Dahl, M.-L., Sjöqvist, F., and Ingelman-Sundberg, M. (1993). Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquine. Proc. Natl. Acad. Sci. USA 90:11825–11829.

    Google Scholar 

  • Kantor, S. J. (1989). Transference and the beta adrenergic receptor: A case presentation. Psychiatry 52:107–115.

    Google Scholar 

  • Kemp, J., Ilett, K. F., and Booth, J. (1985). Excretion of doxepin and N-desmethyldoxepin in human milk. Br. J. Clin. Pharmacol. 20:479–484.

    Google Scholar 

  • Ketter, T. A., Flockhart, D. A., Post, R. M., Denicoff, K., Pazzaglia, P. J., Marangell, L. B., George, M. S., and Callahan, A. M. (1995). The emerging role of cytochrome P450 3A in psychopharmacology. J. Clin. Psychopharmacol. 15:387–398.

    Google Scholar 

  • Kitanaka, I., Ross, R. J., Cutler, N. R., Zavadil, A. P., and Potter, W. Z. (1982). Altered hydroxydesipramine concentrations in elderly depressed patients. Clin. Pharmacol. Ther. 31:51–55.

    Google Scholar 

  • Koyama, E., Tanaka, T., Chiba, K., Kawakatsu, S., Morinobu, S., Totsuka, S., and Ishizaki, T. (1996). Steady-state plasma concentrations of imipramine and desipramine in relation to S-mephenytoin 4′-hydroxylation status in Japanese depressive patients. J. Clin. Psychopharmacol. 16:286–293.

    Google Scholar 

  • Krähenbühl, S., Smith-Gamble, V., and Hoppel, C. L. (1996). Pharmacokinetic interaction between diltiazem and nortriptyline. Eur. J. Clin. Pharmacol. 49:417–419.

    Google Scholar 

  • Kutcher, S. P., Reid, K., Dubbin, J. D., and Shulman, K. I. (1986a). Electrocardiogram changes and therapeutic desipramine and 2-hydroxy-desipramine concentrations in elderly depressives. Br. J. Psychiatry 148:676–679.

    Google Scholar 

  • Kutcher, S. P., Shulman, K. I., and Reed, K. (1986b). Desipramine plasma concentration and therapeutic response in elderly depressives: A naturalistic pilot study. Can. J. Psychiatry 31:752–754.

    Google Scholar 

  • Lancaster, S. G., and Gonzalez, J. P. (1989a). Lofepramine: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness. Drugs 37:123–140.

    Google Scholar 

  • Lancaster, S. G., and Gonzalez, J. P. (1989b). Dothiepin: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness. Drugs 38:123–147.

    Google Scholar 

  • Lane, E. A. (1991). Renal function and the disposition of antidepressants and their metabolites. Psychopharmacol. Bull. 27:533–540.

    Google Scholar 

  • Lieberman, J. A., Cooper, T. B., Suckow, R. F., Steinberg, H., Borenstein, M., Brenner, R., and Kane, J. M. (1985). Tricyclic antidepressant and metabolite levels in chronic renal failure. Clin. Pharmacol. Ther. 37:301–307.

    Google Scholar 

  • Lin, K.-M., and Poland, R. E. (1995). Ethnicity, culture, and psychopharmacology. In Bloom, F. E., and Kupfer, D. J. (eds.), Psychopharmacology: The Fourth Generation of Progress, Raven Press, New York, pp. 1907–1917.

    Google Scholar 

  • Linnoila, M., Insel, T., Kilts, C., Potter, W. Z., and Murphy, D. L. (1982). Plasma steady-state concentrations of hydroxylated metabolites of clomipramine. Clin. Pharmacol. Ther. 32:208–211.

    Google Scholar 

  • Litovitz, T. L., and Troutman, W. G. (1983). Amoxapine overdose. JAMA 250:1069–1071.

    Google Scholar 

  • Lydiard, R. B., and Gelenberg, A. J. (1981). Amoxapine: An antidepressant with some neuroleptic properties? Pharmacotherapy 1:163–178.

    Google Scholar 

  • Malmgren, R., Åberg-Wistedt, A., and Bertilsson, L. (1987). Serotonin uptake inhibition during treatment of depression with nortriptyline caused by parent drug and not by 10-hydroxymetabolites. Psychopharmacology 92:169–172.

    Google Scholar 

  • Matheson, J., Pande, H., and Alersten, A. R. (1985). Respiratory depression caused by N-desmethyldoxepin in breast milk. Lancet 2:1124.

    Google Scholar 

  • McCue, R. E., Georgotas, A., Nagachandran, N., Basir, M. A., Go, E. A., Suckow, R. F., and Cooper, T. B. (1989). Plasma levels of nortriptyline and 10-hydroxynortriptyline and treatment-related electrocardiographic changes in the elderly depressed. J. Psychiatr. Res. 23:73–79.

    Google Scholar 

  • Mellström, B., Bertilsson, L., Säwe, J., Schulz, H.-U., and Sjöqvist, F. (1981). E-and Z-10-hydroxylation of nortriptyline: Relationship to polymorphic debrisoquine hydroxlylation. Clin. Pharmacol. Ther. 30:189–193.

    Google Scholar 

  • Mellström, B., Alvan, G., Bertilsson, L., Potter, W. Z., Säwe, J., and Sjöqvist, F. (1982). Nortriptyline formation after single oral and intramuscular doses of amitriptyline. Clin. Pharmacol. Ther. 32:664–667.

    Google Scholar 

  • Mellström, B., Säwe, J., Bertilsson, L., and Sjöqvist, F. (1986). Amitriptyline metabolism: Association with debrisoquine hydroxylation in nonsmokers. Clin. Pharmacol. Ther. 39:369–371.

    Google Scholar 

  • Musa, M. N. (1989). Nonlinear kinetics of trimipramine in depressed patients. J. Clin. Pharmacol. 29:746–747.

    Google Scholar 

  • Neilsen, K. K., and Gram, L. F. (1992). Steady-state plasma levels of clomipramine and its metabolites: Impact of sparteine/debrisoquine oxidation polymorphism. Eur. J. Pharmacol. 43:405–411.

    Google Scholar 

  • Nelson, J. C., Jatlow, P. I., and Bock, J. (1982). Major adverse reactions during desipramine treatment: Relationship to drug plasma concentrations, concomitant antipsychotic treatment and patient characteristics. Arch. Gen. Psychiatry 39:1055–1061.

    Google Scholar 

  • Nelson, J. C., Bock, J. L., and Jatlow, P. (1983). Clinical implications of 2-hydroxydesipramine plasma concentrations. Clin. Pharmacol. Ther. 33:183–189.

    Google Scholar 

  • Nelson, J. C., Atillasoy, E., Mazure, C., and Jatlow, P. I. (1988a). Hydroxydesipramine in the elderly. J. Clin. Psychopharmacol. 8:428–433.

    Google Scholar 

  • Nelson, J. C., Mazure, C., and Jatlow, P. I. (1988b). Antidepressant activity of 2-hydroxydesipramine. Clin. Pharmacol. Ther. 88:283–288.

    Google Scholar 

  • Nelson, J. C., Mazure, C., and Jatlow, P. I. (1989). Clinical implications of the pharmacokinetics of tricyclic antidepressant. In Dahl, S. G., and Gram, L. F. (eds.), Clinical Pharmacology in Psychiatry, Springer-Verlag, Berlin, pp. 219–227.

    Google Scholar 

  • Ng Ying Kin, N. M. K., Klitgaard, N., Nair, N. P. V., Amin, M., Kragh-Sørensen, P., and Schwartz, G. (1996). Clinical relevance of serum nortriptyline and 10-hydroxy-nortriptyline measurements in the depressed elderly: A multicenter pharmacokinetic and pharmacodynamic study. Neuropsychpharmacology 15:1–6.

    Google Scholar 

  • Nierenberg, A. A., and Cole, J. O. (1991). Antidepressant adverse drug reactions. J. Clin. Psychiatry. 52 (Suppl. 6):40–47.

    Google Scholar 

  • Nilvebrant, L., and Nordin, C. (1991). Affinity of nortriptyline and its E-10-hydroxy metabolite for muscarinic receptors. Pharmacol. Toxicol. 68:64–67.

    Google Scholar 

  • Nordin, C. (1993). CSF/plasma ratio of 10-hydroxynortriptyline is influenced by sex and body height. Psychopharmacology 113:222–224.

    Google Scholar 

  • Nordin, C., and Bertilsson, L. (1995). Active hydroxymetabolites of antidepressants: Emphasis on E-10-hydroxy-nortriptyline. Clin. Pharmacokinet. 28:26–40.

    Google Scholar 

  • Nordin, C., Bertilsson, L., and Siwers, B. (1985a). CSF and plasma levels of nortriptyline and its 10-hydroxy metabolite. Br. J. Pharmacol. 20:411–413.

    Google Scholar 

  • Nordin, C., Siwers, B., Benitez, J., and Bertilsson, L. (1985b). Plasma concentrations of nortiptyline and its 10-hydroxy metabolite in depressed patients—Relationship to the debrisoquine hydroxylation metabolic ratio. Br. J. Clin. Pharmacol. 19::832–835.

    Google Scholar 

  • Nordin, C., Bertilsson, L., Otani, K., and Widmark, A. (1987a). Little anticholinergic effect of E-10-hydroxynortriptyline compared with nortriptyline in healthy subjects. Clin. Pharmacol. Ther. 41:97–102.

    Google Scholar 

  • Nordin, C., Bertilsson, L., and Siwers, B. (1987b). Clinical and biochemical effects during treatment with nortriptyline: The role of 10-hydroxynortriptyline. Clin. Pharmacol. Ther. 42:10–19.

    Google Scholar 

  • Nordin, C., Bertilsson, L., Dahl-Puustinen, M.-L., Resul, B., Toresson, G., and Sjöqvist, F. (1991). Treatment of depression with E-10-hydroxynortriptyline—pilot study on biochemical effects and pharmacokinetics. Psychopharmacology 103:287–290.

    Google Scholar 

  • Nunez, R., and Perel, J. M. (1995). Comparative neurotransmitter reuptake and anticholinergic potencies of the 8-hydroxy metabolites of clomipramine. Psychopharmacol. Bull. 31:217–221.

    Google Scholar 

  • Oesterheld, J., and Kallepalli, B. R. (1997). Grapefruit juice and clomipramine: Shifting metabolic ratios. J. Clin. Psychopharmacol. 17:62–63.

    Google Scholar 

  • Perry, P. J., Browne, J. L., Prince, R. A., Alexander, B., and Tsuang, M. T. (1986). Effects of smoking on nortriptyline plasma concentrations in depressed patients. Ther. Drug. Monit. 8:279–284.

    Google Scholar 

  • Pi, E. H., Tran-Johnson, T. K., Walker, N. R., Cooper, T. B., Suckow, R. F., and Gray, G. E. (1989). Pharmacokinetics of desipramine in Asian and Caucasian volunteers. Psychopharmacol. Bull. 25:483–487.

    Google Scholar 

  • Pollock, B. G. (1994). Recent developments in drug metabolism of relevance to psychiatrists. Harv. Rev. Psychiatry. 2:204–213.

    Google Scholar 

  • Pollock, B. G. (1997). Gender differences in psychotropic drug metabolism. Psychopharmacol. Bull. 33:235–241.

    Google Scholar 

  • Pollock, B. G., and Perel, J. M. (1989). Hydroxy metabolites of tricyclic antidepressants: Evaluation of relative cardiotoxicity. In Dahl, S. G., and Gram, L. F. (eds.), Clinical Pharmacology in Psychiatry, Springer-Verlag, Berlin, pp. 232–236.

    Google Scholar 

  • Pollock, B. G., Everett, G., and Perel, J. M. (1992a). Comparative cardiotoxicity of nortriptyline and its isomeric 10-hydroxymetabolites. Neuropsychopharmacology 6:1–10.

    Google Scholar 

  • Pollock, B. G., Perel, J. M., Altieri, L., Kirshner, M., Yeager, A., and Reynolds, C.F. (1992b). Debrisoquine hydroxylation phenotyping in geriatric psychopharmacology. Psychopharmacol Bull 28:163–168.

    Google Scholar 

  • Pollock, B. G., Mulsant, B. H., Nebes, R., Kirshner, M. A., Begley, A. E., and Reynolds, C. F., III, (1997). Serum anticholinergicity in older patients treated with paroxetine or nortriptyline. Psychopharmacol. Bull. 33::479 (abstract).

    Google Scholar 

  • Potter, W. Z., and Calil, H. M. (1981). Metabolites of tricyclic antidepressants—Biological activity and clinical implications. In Usdin, E. (ed.), Clinical Pharmacology in Psychiatry, Elsevier North-Holland, New York, pp. 311–324.

    Google Scholar 

  • Potter, W. Z., and Manji, H. K. (1990). Antidepressants, metabolites, and apparent drug resistance. Clin. Neuropharmacol. 13 (Suppl 1):S45-S53.

    Google Scholar 

  • Potter, W. Z., Calil, H. M., Manian, A., Zavadil, A. P., and Goodwin, F. K. (1979). Hydroxylated metabolites of tricyclic antidepressants. Biol. Psychiatry 14:601–613.

    Google Scholar 

  • Potter, W. Z., Calil, H. M., Zavadil, A. P., Sutfin, T., Jusko, W. J., and Rapoport, J. (1980). Steadystate concentrations of hydroxylated metabolites of tricyclic antidepressants in patients: Relationship to clinical effect. Psychopharmacol. Bull. 16:32–34.

    Google Scholar 

  • Potter, W. Z., Calil, H. M., Sutfin, T., Zavadil, A. P., Jusko, W. J., and Rapoport, J., and Goodwin, F. K. (1982). Active metabolites of imipramine and desipramine in man. Clin. Pharmacol. Ther. 31:393–401.

    Google Scholar 

  • Potter, W. Z., Lane, E. A., and Rudorfer, M. V. (1983). Hydroxy metabolite concentrations: Role of renal clearance. In Gram, L. F., Usdin, E., Dahl, S. G., Kragh-Sørensen, P., Sjöqvist, F., and Morselli, P. L. (eds.), Clinical Pharmacology in Psychiatry: Bridging the Experimental-Therapeutic Gap, Macmillan Press, London, pp. 203–216.

    Google Scholar 

  • Potter, W. Z., Rudorfer, M. V., and Lane, E. A. (1984). Active metabolites of antidepressants: Pharmacodynamics and relevant pharmacokinetics. In Usdin, E., Bertilsson, L., and Sjögvist, F. (eds.), Frontiers in Biochemical and Pharmacological Research in Depression, Raven Press, New York, pp. 373–390.

    Google Scholar 

  • Potter, W. Z., Scheinin, M., Golden, R. N., Rudorfer, M. V., Cowdry, R. W., Calil, H. M., Ross, R. J., and Linnoila, M. (1985). Selective antidepressants and cerebrospinal fluid: Lack of specificity on norepinephrine and serotonin metabolites. Arch, Gen. Psychiatry 42:1171–1177.

    Google Scholar 

  • Potter, W. Z., Rudorfer, M. V., and Linnoila, M. (1988). New clinical studies support a role of norepinephrine in antidepressant action. In Barchas, J. D., and Bunney, W. E., Jr. (eds.), Perspectives in Psychopharmacology: A Collection of Papers in Honor of Earl Usdin. Alan R. Liss, New York, pp. 495–513.

    Google Scholar 

  • Potter, W. Z., Rudorfer, M. V., and Manji, H. K. (1991). The pharmacologic treatment of depression. N. Engl. J. Med. 325:633–642.

    Google Scholar 

  • Potter, W. Z., Manji, H. K., and Rudorfer, M. V. (1998). Tricyclics and tetracyclics. In Schatzberg, A. F., and Nemeroff, C. B. (eds.), The American Psychiatric Press Textbook of Psychopharmacology, American Psychiatric Press, Washington, DC, pp. 191–218.

    Google Scholar 

  • Preskorn, S. H. (1993). Pharmacokinetics of antidepressants: Why and how they are relevant to treatment. J. Clin. Psychiatry 54 (Suppl 9):14–34.

    Google Scholar 

  • Preskorn, S. H. (1996). Clinical Pharmacology of Selective Serotonin Reuptake Inhibitors, Professional Communications, Caddo, OK.

    Google Scholar 

  • Preskorn, S. H., and Fast, G. A. (1991). Therapeutic drug monitoring for antidepressants: Efficacy, safety, and cost effectiveness. J. Clin. Psychiatry 52 (Suppl 6):23–33.

    Google Scholar 

  • Preskorn, S., and Irwin, H. (1982). Toxicity of tricyclic antidepressants—Kinetics, mechanism, intervention: A review. J. Clin. Psychiatry 43:151–156.

    Google Scholar 

  • Preskorn, S. H., Bupp, S. J., Weller, E. B., and Weller, R. A. (1989). Plasma levels of imipramine and metabolites in 68 hospitalized children. J. Am. Acad. Child Adolesc. Psychiatry 28:373–375.

    Google Scholar 

  • Preskorn, S. H., Alderman, J., Chung, M., Harrison, W., Messig, M., and Harris, S. (1994). Pharmacokinetics of desipramine coadministered with sertraline or fluoxetine. J. Clin. Psychopharmacol. 14:90–98.

    Google Scholar 

  • Prince, J., and Wilens, T. E. (1996). Naturalistic study of the coadministration of psychostimulants and desipramine: Effects on serum desipramine levels. Child Adolesc. Psychopharmacol. News 1 (2):7.

    Google Scholar 

  • Richelson, E., and Nelson, A. L. (1984). Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro. J. Pharmacol. Toxicol. Methods 230:94–102.

    Google Scholar 

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

    Google Scholar 

  • Rudorfer, M. V. (1993a). Challenges in medication clinical trials. Psychopharmacol. Bull. 29:35–44.

    Google Scholar 

  • Rudorfer, M. V. (1993b). Pharmacokinetics of psychotropic drugs in special populations. J. Clin. Psychiatry 54 (Suppl 9):50–54.

    Google Scholar 

  • Rudorfer, M. V., and Potter, W. Z. (1989). Antidepressants: a comparative review of the clinical pharmacology and therapeutic use of the “newer” versus the “older” drugs. Drugs 37:713–738.

    Google Scholar 

  • Rudorfer, M. V., and Potter, W. Z. (1997). The role of metabolites of antidepressants in the treatment of depression. CNS Drugs 7:273–312.

    Google Scholar 

  • Rudorfer, M. V., and Young, R. C. (1980a). Desipramine: Cardiovascular effects and plasma levels. Am. J. Psychiatry 137:984–986.

    Google Scholar 

  • Rudorfer, M. V., and Young, R. C. (1980b). Anticholinergic effects and plasma desipramine levels. Clin. Pharmacol. Ther. 28:703–706.

    Google Scholar 

  • Rudorfer, M. V., and Potter, W. Z. (1987). Pharmacokinetics of antidepressants. In Meltzer, H.Y. (ed.), Psychopharmacology: The Third Generation of Progress. Raven Press, New York, pp. 1353–1363.

    Google Scholar 

  • Rudorfer, M. V., Golden, R. N., and Potter, W. Z. (1984a). Second-generation antidepressants. Psychiatr. Clin. North Am. 7:519–534.

    Google Scholar 

  • Rudorfer, M. V., Lane, E. A., Chang, W.-H., Zhang, M., and Potter, W. Z. (1984b). Desipramine pharmacokinetics in Chinese and Caucasian volunteers. Br. J. Clin. Pharmacol. 17:433–440.

    Google Scholar 

  • Rudorfer, M. V., Linnoila, M., and Potter, W. Z. (1987). Accidental antidepressants: Search for specific action. In Dahl, S. G., Gram, L. F., Paul, S. M., and Potter, W. Z. (eds.), Clinical Pharmacology in Psychiatry. IV. Selectivity in Psychotropic Drug Action—Promises or Problems? Springer-Verlag, Heidelberg, pp. 157–166.

    Google Scholar 

  • Rudorfer, M. V., Manji, H. K., and Potter, W. Z. (1994). Comparative tolerability profiles of the newer versus older antidepressants. Drug Saf. 10:18–46.

    Google Scholar 

  • Schimmell, M. S., Katz, E. Z., Shaag, Y., Pastuszak, A., and Koren, G. (1991). Toxic neonatal effects following maternal clomipramine therapy. Clin. Toxicol. 29:479–484.

    Google Scholar 

  • Schneider, L. S., Cooper, T. B., Severson, J. A., Zemplenyi, T., and Sloane, R.B. (1988). Electrocardiographic changes with nortriptyline and 10-hydroxynortriptyline in elderly depressed outpatients. J. Clin. Psychopharmacol. 8:402–408.

    Google Scholar 

  • Schneider, L. S., Cooper, T. B., Suckow, R. F., Lyness, S. A., Haugen, C., Palmer, R., and Sloane, R. B. (1990). Relationship of hydroxynortriptyline to nortriptyline concentration and creatinine clearance in depressed elderly outpatients. J. Clin. Psychopharmacol. 10:333–337.

    Google Scholar 

  • Shader, R. I., and Greenblatt, D. J. (1997). Fruit juices and pharmacology (Editorial). J. Clin. Psychopharmacol. 17:245–246.

    Google Scholar 

  • Shen, W. W. (1995). Cytochrome P450 monooxygenases and interactions of psychotropic drugs: A five-year update. Int. J. Psychiatry Med. 25:271–284.

    Google Scholar 

  • Shen, W. W. (1997). The metabolism of psychoactive drugs: A review of enzymatic biotransformation and inhibition. Biol. Psychiatry 41:814–826.

    Google Scholar 

  • Shen, W. W., and Lin, K.-M. (1991). Cytochrome P450 monooxygenases and interactions of psychotropic drugs. Int. J. Psychiatry Med. 21:47–56.

    Google Scholar 

  • Shimoda, K., Noguchi, T., Morita, S., Ozeki, Y., Shibasaki, M., Someya, T., and Takahashi, S. (1995a). Interindividual variations of desmethylation and hydroxylation of amitriptyline in a Japanese psychiatric population. J. Clin. Psychopharmacol. 15:175–181.

    Google Scholar 

  • Shimoda, K., Noguchi, T., Ozeki, Y., Morita, S., Shibasaki, M., and Someya, T., Takahashi, S. (1995b). Metabolism of clomipramine in a Japanese psychiatric population: Hydroxylation, desmethylation, and glucuronidation. Neurospychopharmacology 12:323–333.

    Google Scholar 

  • Shoaf, S. E., and Linnoila, M. (1991). Interaction of ethanol and smoking on the pharmacokinetics and pharmacodynamics of psychotropic medications. Psychopharmacol. Bull. 27:577–594.

    Google Scholar 

  • Sjöqvist, F. (1989). Pharmacogenetics of antidepressants. In Dahl, S. G., and Gram, L. F. (eds.), Clinical Pharmacology in Psychiatry, Springer-Verlag, Berlin, 1989, pp. 181–191.

    Google Scholar 

  • Skjelbo, E., Brosen, K., Hallas, J., and Gram, L. F. (1991). The mephenytoin oxidation polymorphism is partially responsible for the N-demethylation of imipramine. Clin. Pharmacol. Ther. 49:18–23.

    Google Scholar 

  • Snyder, S. H., and Yamamura, H. I. (1977). Antidepressants and the muscarinic acetylcholine receptor. Arch. Gen.Psychiatry 34:236–239.

    Google Scholar 

  • Soons, P. A., Vogels, B. A. P. M., Roosemalen, M. C. M., Schoemaker, H. C., Uchida, E., Edgar, B., Lundahl, J., Cohen, A. F., and Breimer, D. D. (1991). Grapefruit juice and cimetidine inhibit stereoselective metabolism of nitrendipine in humans. Clin. Pharmacol. Ther. 50:394–403.

    Google Scholar 

  • Spence, D. J. (1997). Drug interactions with grapefruit: Whose responsibility is it to warn the public? (Editorial). Clin. Pharmacol. Ther. 61:395–400.

    Google Scholar 

  • Spigset, O., Carleborg, L., Hedenmalm, K., and Dahlqvist, R. (1995). Effect of cigarette smoking on fluvoxamine pharmacokinetics in humans. Clin. Pharmacol. Ther. 58:399–403.

    Google Scholar 

  • Spina, E., and Perucca, E. (1994). Newer and older antidepressants: A comparative review of drug interactions. CNS Drugs 2:479–497.

    Google Scholar 

  • Spina, E., Pollicino, A. M., Avenoso, A., Campo, G. M., Perucca, E., and Caputi, A. P. (1993a). Effect of fluvoxamine on the pharmacokinetics of imipramine and desipramine in healthy subjects. Ther. Drug Monit. 15:243–246.

    Google Scholar 

  • Spina, E., Pollicino, A. M., Avenoso, A., Campo, G. M., and Caputi, A. P. (1993b). Fluvoxamineinduced alterations in plasma concentrations of imipramine and desipramine in depressed patients. Int. J. Clin. Pharmacol. Res. 13:167–171.

    Google Scholar 

  • Stewart, D. E. (1992). High-fiber diet and serum tricyclic antidepressant levels. J. Clin. Psychopharmacol. 12:438–440.

    Google Scholar 

  • Sutfin, T. A., DeVane, L. C., and Jusko, W. J. (1984). The analysis and disposition of imipramine and its metabolites in man. Psychopharmacology 82:310–317.

    Google Scholar 

  • Sutfin, T., Perini, G., Molnar, G., and Jusko, W. J. (1988). Multiple-dose pharmacokinetics of imipramine and its major active and conjugated metabolites in depressed patients. J. Clin. Psychopharmacol. 8:48–53.

    Google Scholar 

  • Taylor, N. E., and Schwartz, H. I. (1988). Neuroleptic malignant syndrome following amoxapine overdose. J. Nerv. Ment. Dis. 176:249–251.

    Google Scholar 

  • Träskman, L., Åsberg, M., Bertilsson, L., Cronholm, B., Mellström, B., Neckers, L. M., Sjöqvist, F., Thoren, P., and Tybring, G. (1979). Plasma levels of chlorimipramine and its demethyl metabolite during treatment of depression. Clin. Pharmacol. Ther. 26:600–610.

    Google Scholar 

  • Vitiello, B., and Jensen, P. S. (1995). Developmental perspectives in pediatric psychopharmacology. Psychopharmacol. Bull. 31:75–81.

    Google Scholar 

  • Wägner, A., Ekqvist, B., Bertilsson, L., and Sjöqvist, F. (1984). Weak binding of 10-hydroxymetabolites of nortriptyline to rat brain muscarinic acetylcholine receptors. Life Sci. 35:1379–1383.

    Google Scholar 

  • Watkins, P. B. (1990). Role of cytochromes P450 in drug metabolism and hepatotoxicity. Semin. Liver Dis. 10:235–250.

    Google Scholar 

  • Wilens, T. E., Biederman, J., Baldessarini, R. J., and Puopolo, P. R. (1992). Developmental changes in serum concentrations of desipramine and 2-hydroxydesipramine during treatment with desipramine. J. Am. Acad. Child Adolesc. Psychiatry 31:691–698.

    Google Scholar 

  • Wilens, T. E., Biederman, J., Baldessarini, R. J., Puopolo, P. R., and Flood, J. G. (1993). Electrocardiographic effects of desipramine and 2-hydroxydesipramine in children, adolescents, and adults treated with desipramine. J. Am. Acad. Child Adolesc. Psychiatry 32:798–804.

    Google Scholar 

  • Wilens, T. E., Biederman, J., and Spencer, T. J. (1997). Case study: Adverse effects of smoking marijuana while receiving tricyclic antidepressants. J. Am. Acad. Child Adolesc. Psychiatry 36:45–48.

    Google Scholar 

  • Wilkerson, R. D. (1978). Antiarrhythmic effects of tricyclic antidepressant drugs in ouabain-induced arrhythmias in the dog. J. Pharmacol. Exp. Ther. 206:666–674.

    Google Scholar 

  • Wisner, K. L., and Perel, J. M. (1991). Serum nortriptyline levels in nursing mothers and their infants. Am. J. Psychiatry 148:1234–1236.

    Google Scholar 

  • Wisner, K. L., Perel, J. M., and Wheeler, S. B. (1993). Tricyclic dose requirements across pregnancy. Am. J. Psychiatry. 150:1541–1542.

    Google Scholar 

  • Wisner, K. L., Perel, J. M., and Foglia, J. P. (1995). Serum clomipramine and metabolite levels in four nursing mother-infant pairs. J. Clin. Psychiatry 56:17–20.

    Google Scholar 

  • Wisner, K. L., Perel, J. M., Findling, R. L., and Hinnes, R. L. (1997). Nortriptyline and its hydroxymetabolites in breastfeeding mothers and newborns. Psychopharmacol. Bull. 33:249–251.

    Google Scholar 

  • Wong, S. L., Cavanaugh, J., Shi, H., Awni, W. M., and Granneman, R. (1996). Effects of divalproes sodium on amitriptyline and nortriptyline pharmacokinetics. Clin. Pharmacol. Ther. 60:48–53.

    Google Scholar 

  • Yonkers, K. A., Kando, J. C., Cole, J. O., and Blumentahl, S. (1992). Gender differences in pharmacokinetics and pharmacodynamics of psychotropic medication. Am. J. Psychiatry 149:587–595.

    Google Scholar 

  • Young, R. C. (1991). Hydroxylated metabolites of antidepressants. Psychopharmacol. Bull. 27:521–552.

    Google Scholar 

  • Young, R. C., Alexopoulos, G. S., Shamoian, C. A., Dhar, A. K., and Kutt, H. (1984a). Heart failure associated with high plasma 10-hydroxynortriptyline levels. Am. J. Psychiatry 141:432–433.

    Google Scholar 

  • Young, R. C., Alexopoulos, G. S., and Shamoian, C. A. (1984b). Plasma 10-hydroxynortriptyline in elderly depressed patients. Clin. Pharmacol. Ther. 35:540–544.

    Google Scholar 

  • Young, R. C., Alexopoulos, G. S., Kent, E., Shamoian, C. A., Dhar, A. K., and Kutt, H. (1985). Plasma 10-hydroxynortriptyline and ECG changes in elderly depressed patients. Am. J. Psychiatry 142:866–868.

    Google Scholar 

  • Young, R. C., Alexopoulos, G. S., Dhar, A. K., and Kutt, H. (1987). 10-hydroxynortriptyline and renal function in elderly depressives. Biol. Psychiatry 22:1283–1287.

    Google Scholar 

  • Young, R. C., Alexopoulos, G. S., Shindledecker, R., Dhar, A. K., and Kutt, H. (1988a). Plasma 10-hydroxynortriptyline and therapeutic response in geriatric depression. Neuropsychopharmacology 1:213–215.

    Google Scholar 

  • Young, R. C., Dhar, A. K., Kutt, H., Alexopoulos, G. S., and Shamoian, C. A. (1988b). Isomers of 10-hydroxynortriptyline in geriatric depression. Ther. Drug Monit. 10:164–167.

    Google Scholar 

  • Ziegler, V. E., and Biggs, J. T. (1977). Tricyclic plasma levels: Effect of age, race, sex, and smoking. JAMA 238:2167–2169.

    Google Scholar 

  • Ziegler, V. E., Fuller, T. A., and Biggs, J. T. (1976). Nortriptyline and 10-hydroxynortriptyline plasma concentrations. J. Pharm. Pharmacol. 28:849–850.

    Google Scholar 

  • Ziegler, V. E., Biggs, J. T., Wylie, L. T., Coryell, W. H., Hanifl, K. M., Hawf, D. J, and Rosen, S. H. (1978). Protriptyline kinetics. Clin. Pharmacol. Ther. 23:580–584.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Services and Intervention Research, National Institute of Mental Health, Bethesda, Maryland

    Matthew V. Rudorfer

  2. Lilly Research Laboratories, Indianapolis, Indiana

    William Z. Potter

Authors
  1. Matthew V. Rudorfer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William Z. Potter
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rudorfer, M.V., Potter, W.Z. Metabolism of Tricyclic Antidepressants. Cell Mol Neurobiol 19, 373–409 (1999). https://doi.org/10.1023/A:1006949816036

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1006949816036

Search

Navigation