Effects of Tricyclic Antidepressants on Norepinephrine Metabolism: Basic and Clinical Studies

  • Joseph J. Schildkraut
  • Paul R. Draskoczy
  • Elliot S. Gershon
  • Peter Reich
  • Edwin L. Grab
Part of the Advances in Behavioral Biology book series (ABBI, volume 1)


The tricyclic antidepressants have been well established as clinically effective treatments for certain types of depressions, and these drugs have provided important tools for investigating those neurochemical changes that may be associated with alterations in affective state in man (Schildkraut 1970). Some years ago, in clinical studies of depressed patients, we observed a decrease in the urinary excretion of 3-methoxy-4-hydroxymandelic acid (VMA), the major deaminated O-methylated metabolite of norepinephrine during treatment with imipramine (a tricyclic antidepressant) as well as with phenelzine (a monoamine oxidase inhibitor) (Table 1) (Schildkraut et al. 1964; Schildkraut, Gordon, and Durell 1965). In these studies with imipramine, we showed that the decrease in VMA excretion was a pharmacological effect of the drug per se and not a secondary concomitant of the alteration in clinical state (Table 2) (Schildkraut, Gordon, and Durell 1965). On the basis of these findings, which have been confirmed by other investigators (Haskovec and Rysanek 1967; Maas, Fawcett, and Dekirmenjian 1968b and personal communication), we suggested that tricyclic antidepressants like monoamine oxidase inhibitors may decrease the deamination of norepinephrine. Subsequently, Glowinski, Axelrod, and Iversen (1966) showed that desmethylimipramine decreased the deamination of intraventricularly administered tritiated norepinephrine in rat brain, and we found a similar decrease in the deamination of intracisternally administered tritiated norepinephrine and a concurrent increase in levels of tritiated normetanephrine in rat brain after administration of various other tricyclic antidepressants (Table 3) (Schildkraut et al. 1967; Schildkraut, Dodge, and Logue 1969).


Depressed Patient Biogenic Amine Intracisternal Injection Norepinephrine Synthesis MHPG Level 
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  1. Bunney, W. E,, Jr., and Davis, J. M. 1965. Norepinephrine in depressive reactions, Arch. Gen. Psychiat. 13:483.PubMedCrossRefGoogle Scholar
  2. Bunney, W. E., Jr.; Davis, J. M.; Weil-Malherbe, H.; and Smith, E.R.B, 1967, Biochemical changes in psychotic depression. Arch. Gen. Psychiat. 16:448.PubMedCrossRefGoogle Scholar
  3. Carlsson, A.; Corrodi, H.; Fuxe, K.; and Hökfelt, T. 1969a. Effect of antidepressant drugs on the depletion of intraneuronal brain 5-hydroxytryptamine stores caused by 4-methy1-alpha-ethyl-meta-tyra-mine. Europ. J. Pharmacol. 5:357.CrossRefGoogle Scholar
  4. Carlsson, A.; Corrodi, H.; Fuxe, K.; and Hökfelt, T. 1969b. Effects of some antidepressant drugs on the depletion of intraneuronal brain catecholamine stores caused by 4-alpha-dimethy1-meta-tyra-mine, Europ. J. Pharmacol. 5:367.CrossRefGoogle Scholar
  5. Glowinski, J., and Axelrod, J. 1964. Inhibition of uptake of tri-tiated noradrenaline in intact rat brain by imipramine and related compounds. Nature 204:1318.PubMedCrossRefGoogle Scholar
  6. Glowinski, J.; Axelrod, J.; and Iversen, L. L. 1966. Regional studies of catecholamines in rat brain IV. Effects of drugs on the disposition and metabolism of H3-norepinephrine and H3-dopamine, J. Pharmacol. Exp. Ther. 153:30.PubMedGoogle Scholar
  7. Greenspan, K.; Schildkraut, J. J.; Gordon, E. K.; Baer, L.; Aronoff, M. S.; and Durell, J. 1970. Catecholamine metabolism in affective disorders III. MHPG and other catecholamine metabolites in patients treated with lithium carbonate. J. Psychiat. Res. 7:171.PubMedCrossRefGoogle Scholar
  8. Haskovec, L., and Rysanek, K. 1967. Excretion of 3-methoxy-4-hy-droxy-mandelic acid and 5-hydroxyindoleacetic acid in depressed patients treated with imipramine. J. Psychiat. Res. 5:213.CrossRefGoogle Scholar
  9. Himwich, H.E., and Alpers, H. S. 1970. Psychopharmacology. Ann. Rev. Pharmacol. 10:313.PubMedCrossRefGoogle Scholar
  10. Karki, N. T. 1956. The urinary excretion of noradrenaline and adrenaline in different age groups, its diurnal variation and the effect of muscular work on it. Acta Physiol. Scand. 39: suppl. 132.Google Scholar
  11. Maas, J. W.; Fawcett, J.; and Dekirmenjian, H. 1968a. 3-Methoxy-4-hydroxyphenyl glycol (MHPG) excretion in depressed states: A pilot study. Arch. Gen. Psychiat. 19:129.PubMedCrossRefGoogle Scholar
  12. Maas, J. W.; Fawcett, J.; and Dekirmenjian, H. 1968b. Catecholamine metabolism and the depressive states. Presented at the annual meeting of American Psychiatric Association, Boston.Google Scholar
  13. Maas, J. W.; Fawcett, J.; and Dekirmenjian, H. Personal communication.Google Scholar
  14. Maas, J. W., and Landis, D. H. 1968. In vivo studies of the metabolism of norepinephrine in the central nervous system. J. Pharma-col. Exp. Ther. 163:147.Google Scholar
  15. Mannarino, E.; Kirshner, N.; and Nashold, B. S., Jr. 1963. The metabolism of (C-14) noradrenaline by cat brain in vivo. J. Neurochem. 10:373.CrossRefGoogle Scholar
  16. Nelson, G. N.; Masuda, M.; and Holmes, T. H. 1966. Correlations of behavior and catecholamine metabolite excretion. Psychosom. Med. 28:216.PubMedGoogle Scholar
  17. Prange, A. J., Jr.; McCurdy, L. R.; and Cochrane, C. M. 1967. The systolic blood pressure response of depressed patients to infused norepinephrine. J. Psychiat. Res. 5:1.PubMedCrossRefGoogle Scholar
  18. Prange, A. J., Jr.; Wilson, I. C.; Knox, A. E.; McClane, T. K.; Breese, G. R.; Martin, B. R.; Alltop, L. B.; and Lipton, M. A. 1971. Thyroid-imipramine interaction: Clinical results and basic mechanism. This volume.Google Scholar
  19. Sachar, E. J.; Mason, J. W.; Kolmer, H. A.; and Artiss, K. L. 1963. Psychoendocrine aspects of acute schizophrenic reactions. Psycho-som. Med. 25:510.Google Scholar
  20. Schanberg, S. M.; Breese, G. R.; Schildkraut, J. J.; Gordon, E. K.; and Kopin, I. J. 1968a. 3-Methoxy-4-hydroxyphenylglycol sulfate in brain and cerebrospinal fluid. Biochem. Pharmacol. 17:2006.PubMedCrossRefGoogle Scholar
  21. Schanberg, S. M.; Schildkraut, J. J.; Breese, G. R.; and Kopin, I. J. 1968b. Metabolism of normetanephrine-H3 in rat brain-Identification of conjugated 3-methoxy-4-hydroxyphenylglycol as the major metabolite. Biochem. Pharmacol. 17:247.PubMedCrossRefGoogle Scholar
  22. Schildkraut, J. J. 1965. The catecholamine hypothesis of affective disorders: A review of supporting evidence. Amer. J. Psychiat. 122:509.PubMedGoogle Scholar
  23. Schildkraut, J. J. 1970. Neuropsychopharmacology and the Affective Disorders. Boston: Little, Brown.Google Scholar
  24. Schildkraut, J. J.; Davis, J. M.; and Klerman, G. L. 1968. Biochemistry of depressions. In Psychopharmacology. A Review of Progress. D. H. Efron et al. (eds.). Washington, D. C.: U, S. Govt. Printing Office, p. 625.Google Scholar
  25. Schildkraut, J. J.; Dodge, G. A.; and Logue, M. A. 1969. Effects of tricyclic antidepressants on the uptake and metabolism of in-tracisternally administered norepinephrine-H3 in rat brain. J. Psychiat. Res. 7:29.PubMedCrossRefGoogle Scholar
  26. Schildkraut, J. J.; Draskoczy, P. R.; Gershon, E.; Reich, P.; and Grab, E. L. Catecholamine metabolism in affective disorders IV: Preliminary studies of norepinephrine metabolism in depressed patients treated with amitriptyline. J. Psychiat. Res. in press.Google Scholar
  27. Schildkraut, J. J.; Gordon, E. K.; and Durell, J. 1965. Catecholamine metabolism in affective disorders I: Normetanephrine and VMA excretion in depressed patients treated with imipramine. J. Psy-chiat. Res. 3:213.CrossRefGoogle Scholar
  28. Schildkraut, J. J.; Green, R.; Gordon, E. K.; and Durell, J. 1966. Normetanephrine excretion and affective state in depressed patients treated with imipramine. Amer. J. Psychiat. 123:690.PubMedGoogle Scholar
  29. Schildkraut, J. J.; and Kety, S. S. 1967. Biogenic amines and emotion. Science 156:21.PubMedCrossRefGoogle Scholar
  30. Schildkraut, J. J.; Klerman, G. L.; Hammond, R.; and Friend, D. G. 1964. Excretion of 3-methoxy-4-hydroxymandelic acid (VMA) in depressed patients treated with antidepressant drugs. J. Psychiat. Res. 2:257.CrossRefGoogle Scholar
  31. Schildkraut, J. J.; Schanberg, S. M.; Breese, G. R.; and Kopin, I. J. 1967. Norepinephrine metabolism and drugs used in the affective disorders: A possible mechanism of action. Amer. J. Psychiat. 124:600.PubMedGoogle Scholar
  32. Schildkraut, J. J.; Winokur, A.; and Applegate, W. 1970. Norepinephrine turnover and metabolism in rat brain after longterm administration of imipramine. Science 168:867.PubMedCrossRefGoogle Scholar
  33. Schildkraut, J. J.; Winokur, A.; Draskoczy, P. R.; and Hensle, J. H. 1971. Changes in norepinephrine turnover in rat brain during chronic administration of imipramine and protriptyline: A possible explanation for the delay in onset of clinical antidepressant effects. Amer. J. Psychiat. 127:1032.PubMedGoogle Scholar
  34. Schubert, J.; Nybäck, H.; and Sedvall, G. 1970. Effect of antidepressant drugs on accumulation and disappearance of monoamines formed in vivo from labeled precursors in mouse brain. J. Pharm. Pharmacol. 22:136.PubMedCrossRefGoogle Scholar
  35. Stille, G. 1968. Pharmacological investigation of antidepressant compounds. Pharmakopsychiatrie Ncuropsychopharmakologie 1:92.Google Scholar
  36. Weiner, N. 1970. Regulation of norepinephrine biosynthesis. Ann. Rev. Pharmacol. 10:273.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1971

Authors and Affiliations

  • Joseph J. Schildkraut
    • 1
    • 2
  • Paul R. Draskoczy
    • 1
    • 2
  • Elliot S. Gershon
    • 1
    • 2
  • Peter Reich
    • 1
    • 2
  • Edwin L. Grab
    • 1
    • 2
  1. 1.Massachusetts Mental Health CenterBostonUSA
  2. 2.Harvard Medical SchoolBostonUSA

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