Skip to main content Accessibility help

Abrupt Discontinuation of Tricyclic Antidepressant Drugs: Evidence for Noradrenergic Hyperactivity

  • Dennis S. Charney (a1), George R. Heninger (a1), David E. Sternberg (a1) and D. Harold Landis (a1)


The effect of abrupt discontinuation of amitriptyline, desipramine, or imipramine) on norepinephrine turnover and specific symptoms in seven depressed patients was examined. Turnover, as determined by plasma and urinary 3 methoxy-4-hydroxy-phenylethylene glycol (MHPG), was increased to a peak during the second week following discontinuation. There were no changes in blood pressure or heart rate. Two of the seven patients experienced clear increases in anxiety. The implications for the role of noradrenergic function is discussed.


Corresponding author



Hide All
Aghajanian, G. K. (1978) Tolerance of locus coeruleus neurons to morphine and suppression of withdrawal response by clonidine. Nature, 276, 186–8.
Andersen, H. & Kristiansen, E. S. (1959) Tofraniltreatment of endogenous depressions. Acta Psychiatrica Neurologica Scandinavica, 34, 387–97.
Blomberg, P. A., Kopin, I. J., Gorden, E. K., Mackey, S. P. & Ebert, M. H. (1980) Conversion of MHPG to vanillyl-mandelic acid. Archives of General Psychiatry, 37, 1095–7.
Brown, G. M., Stancer, H. C., Moldofsky, H., Harman, J., Murphy, J. T. & Gupta, R. N. (1978) Withdrawal from long-term high-dose desipramine therapy. Archives of General Psychiatry, 35, 1261–4.
Bunney, W. E., Wehr, T. R., Gillin, J. C., Post, R. M., Goodwin, F. K. & Van Kammen, D. P. (1977) The switch process in manic-depressive psychosis. Annals of Internal Medicine, 87, 319–35.
Cedarbaum, J. M. & Aghajanian, G. K. (1977) Catecholamine receptors on locus coeruleus neurons: pharmacological characterization. European Journal of Pharmacology, 44, 375–85.
Charney, D. S., Heninger, G. R., Sternberg, D. E. & Roth, R. H. (1981a) Plasma MHPG in depression: effects of acute and chronic desipramine treatment. Psychiatry Research, 5, 217–29.
Charney, D. S., Heninger, G. R., Sternberg, D. E., Redmond, D. E., Leckman, J. F., Maas, J. W. & Roth, R. H. (1981b) Presynaptic adrenergic receptor sensitivity in depression: the effect of chronic desipramine treatment. Archives of General Psychiatry, 38, 1334–40.
Charney, D. S., Menkes, D. B. & Heninger, G. R. (1981c) Receptor sensitivity and the mechanism of action of antidepressant treatment: implications for the etiology and theory of depression. Archives of General Psychiatry, 38, 1160–80.
Charney, D. S., Sternberg, D. E., Kleber, H. D., Heninger, G. R. & Redmond, D. E. (1981d) The clinical use of clonidine in abrupt withdrawal from methadone. Archives of General Psychiatry, 38, 1273–8.
Crawley, J. N., Laverty, R. N. & Roth, R. H. (1979) Clonidine reversal of increased norepinephrine metabolite levels during morphine withdrawal. European Journal of Pharmacology, 57, 247–55.
Crews, F. T. & Smith, C. B. (1978) Presynaptic alpha-receptor subsensitivity after long-term antidepressant treatment. Science, 202, 422–3.
Crews, F. T. & Smith, C. B. (1980) Potentiation of responses to adrenergic nerve stimulation in isolated rat atria during chronic tricyclic antidepressant administration. Journal of Pharmacology and Experimental Therapeutics, 215, 143–9.
Dekirmenjian, G. & Maas, J. W. (1974) 3-methoxy-4-hydroxyphenethyleneglycol in plasma. Clinica Chimica Acta, 52, 203–10.
de Montigny, C. & Aghajanian, G. K. (1978) Tricyclic antidepressants: Long-term treatment increases responsivity of rat forebrain neurons to serotonin. Science, 202, 1303–6.
Elsworth, J. D., Redmond, D. E. & Roth, R. H. (1982) Plasma and cerebrospinal fluid 3-methoxy-4-hydroxy-phenylethylene glycol (MHPG) as indices of brain norepinephrine metabolism in primates. Brain Research, (in press).
Garcia-Sevilla, J. A., Zis, A. P., Hollingsworth, P. A., Greden, J. F. & Smith, C. B. (1981a) Platelet alpha-2 adrenergic receptors in major depressive disorder: binding of tritiated clonidine before and after tricyclic antidepressant drug treatment. Archives of General Psychiatry, 36, 1327–33.
Garcia-Sevilla, J. A., Zis, A. P., Zelnik, R. & Smith, C. B. (1981b) Tricyclic drug treatment decreases alpha-2 adrenoceptors on human platelets membranes. European Journal of Pharmacology, 69, 121–3.
Gawin, F. H. & Markoff, R. A. (1981) Panic anxiety after abrupt discontinuation of amitriptyline. American Journal of Psychiatry, 138, 117–18.
Gloger, S., Grunhaus, L., Birmacher, B. & Troudart, T. (1981) Treatment of spontaneous panic attacks with chlorimipramine. American Journal of Psychiatry, 138, 1215–17.
Gold, M. S., Redmond, D. E. & Kleber, H. D. (1978) Clonidine blocks acute opiate withdrawal symptoms. Lancet, 2, 599602.
Gower, A. J. & Marriott, A. S. (1980) The inhibition of clonidine induced sedation in the mouse by antidepressant drugs. British Journal of Pharmacology, 69, 287.
Gualtieri, C. T. & Staye, J. (1979) Withdrawal symptoms after abrupt cessation of amitriptyline in an eight-year-old boy. American Journal of Psychiatry, 136, 457–8.
Heninger, G. R., French, N. H., Slavinsky, A. T., Davis, L. & Mueller, P. S. (1970) A short clinical rating scale for use by nursing personnel: II. Reliability, validity, and application. Archives of General Psychiatry, 23, 241–50.
Karoum, F., Mayer-Schwing, J., Potkin, S. G. & Wyatt, R. J. (1977) Presence of free sulfate, and glucuronide conjugated MHPG in human brain, cerebrospinal fluid, and plasma. Brain Research, 125, 333–9.
Klein, D. F., Zitrin, C. M. & Woerner, M. (1978) Antidepressants, anxiety, panic, and phobia. In Psychopharmacology: A Generation of Progress, (eds. Lipton, M. A., DiMascio, A. and Killam, D. F.). New York: Raven Press.
Kopin, I. J. (1978) Measuring turnover of neurotransmitters in human brains. In Psychopharmacology: A Generation of Progress, (eds. Lipton, M. A., DiMascio, A. and Killam, D. F.). New York: Raven Press.
Kramer, J. C., Klein, D. F. & Fink, M. (1961) Withdrawal symptoms following discontinuation of imipramine therapy. American Journal of Psychiatry, 118, 549–50.
Langer, S. Z., Briley, M. S. & Raisman, R. (1980) Regulation of neurotransmission through presynaptic receptors and other mechanisms: Possible clinical relevance and therapeutic potential. In Receptors for Neurotransmitters and Peptides, (eds. Pepau, G., Kuhan, M. J. and Enna, S. J.). New York: Raven Press.
Law, W., Petti, T. A. & Kazdin, A. E. (1981) Withdrawal symptoms after graduated cessation of imipramine in children. American Journal of Psychiatry, 138, 647–50.
Llorens, C., Martres, M. P., Baudry, M. & Schwartz, J. C. (1978) Hypersensitivity to noradrenaline in cortex after chronic morphine: Relevance to tolerance and dependence. Nature, 274, 603–5.
Maas, J. W., Hattox, S. E., Greene, N. M. & Landis, D. H. (1979) MHPG production by human brain in vivo. Science, 205, 1025–7.
Maas, J. W., Landis, H. & Dekirmenjian, G. (1976) The occurrence of free vs conjugated MHPG in nonhuman and human primate brain. Psychopharmacology Communication, 2, 403–10.
Mann, A. M. & MacPherson, A. S. (1959) Clinical experience with imipramine (G22355) in the treatment of depression. Canadian Psychiatric Association Journal, 4, 3847.
McMillen, B. A., Warnack, W., German, D. C. & Shore, P. A. (1980) Effects of chronic desipramine treatment on rat brain noradrenergic responses to alpha-adrenergic drugs. European Journal of Pharmacology, 61, 239–46.
Menkes, D. B., Aghajanian, G. K. & McCall, R. B. (1980) Chronic antidepressant treatment enhances alpha-adrenergic and serotonergic responses in the facial nucleus. Life Sciences, 27, 4555.
Mirin, S. M., Schatzberg, A. F. & Creasey, D. E. (1981) Hypomania and mania after withdrawal of tricyclic antidepressants. American Journal of Psychiatry, 138, 87–9.
Nagy, A. (1977) Blood and brain concentrations of imipramine, chlorimipramine, and their monomethylated metabolites after oral and intramuscular administration in rats. Journal of Pharmaceutical Pharmacology, 29, 104–7.
Nathanson, J. A. & Redmond, D. E. Jr. (1981) Morphine withdrawal causes supersensitivity of adrenergic receptor response. Life Sciences, 28, 1353–60.
Nyback, H. V., Walters, J. R., Aghajanian, G. K. & Roth, R. H. (1975) Tricyclic antidepressants: effects on the firing rate of brain noradrenergic neurons. European Journal of Pharmacology, 32, 302–12.
Petti, T. A. & Law, W. (1981) Abrupt cessation of high-dose imipramine in children. Journal of the American Medical Association, 246, 768–9.
Potter, W. Z., Calil, H. M., Extein, I., Muscettola, G. & Goodwin, F. K. (1981) Crossover study of zimelidine and desipramine: Evidence for amine specificity. Psychopharmacology Bulletin, 17, 26.
Redmond, D. E. & Huang, Y. H. (1979) New evidence for a locus coeruleus-noradrenergic connection with anxiety. Life Sciences, 25, 2149–62.
Santos, A. B. & McCurdy, L. (1980) Delirium after abrupt withdrawal for doxepine: case report. American Journal of Psychiatry, 137, 239–40.
Sathananthan, G. L. & Gershon, S. (1973) Imipramine withdrawal; an akathisia-like syndrome. American Journal of Psychiatry, 130, 1286–7.
Schildkraut, J. J., Winokur, A., Draskoczy, P. R. & Hensle, J. H. (1971) Changes in norepinephrine turnover during chronic administration of imipramine and protriptyline: A possible explanation for the delay of onset of clinical antidepressant effects. American Journal of Psychiatry, 127, 72–9.
Shatan, C. (1966) Withdrawal symptoms after abrupt termination of imipramine. Canadian Psychiatric Association Journal, 11 (Supplement), S1508.
Sheehan, D. V., Ballenger, J. & Jacobsen, G. (1980) Treatment of endogenous anxiety with phobic, hysterical, and hypochondriacal symptoms. Archives of General Psychiatry, 37, 51–9.
Siever, L. F., Cohen, R. M. & Murphy, D. L. (1981) Antidepressants and alpha-2 adrenergic autoreceptor desensitization. American Journal of Psychiatry, 138, 681–2.
Smith, C. B., Garcia-Sevilla, J. A. & Hollingsworth, P. J. (1981) Alpha-2 adrenoceptors in rat brain are decreased after long-term tricyclic antidepressant drug treatment. Brain Research, 210, 413–18.
Spitzer, R. L., Endicott, J. & Robins, E. (1977) Research Diagnostic Criteria (RDC) for a Selected Group of Functional Disorders, 3rd edition. New York: New York State Psychiatric Institute.
Sugrue, M. G. (1980a) Changes in rat brain monoamine turnover following chronic antidepressant administration. Life Sciences, 26, 423–33.
Sugrue, M. G. (1980b) Effects of acutely and chronically administered antidepressants on the clonidine-induced decrease in rat brain 3-methoxy-4-hydroxyphenethyleneglycol sulphate. Life Sciences, 28, 377–84.
Sulser, F., Vetulani, J. & Mobley, P. L. (1978) Mode of action of antidepressant drugs. Biochemical Pharmacology, 27, 257–61.
Svensson, T. H. & Usdin, T. (1978) Feedback inhibition of brain noradrenaline neurons by tricyclic antidepressants: alpha receptor mediation. Science, 202, 1089–91.
Svensson, T. H. & Usdin, T. (1979) Alpha-adrenoceptor mediated inhibition of brain noradrenergic neurons after acute and chronic treatment with tricyclic antidepressants. In Catecholamines: Basic and Clinical Frontiers, (eds. Usdin, E., Kopin, I. J. and Barchas, J.). Oxford: Pergamon Press.
Sypraki, C. & Fibiger, H. C. (1980) Functional evidence for subsensitivity of noradrenergic receptors after chronic desipramine treatment. Life Sciences, 27, 1963–7.
Tallman, J. F., Paul, S. M., Skolnick, P. & Gallager, D. W. (1980) Receptors for the age of anxiety: Pharmacology of the benzodiazepines. Science, 207, 274–81.
Tang, S. W., Helmeste, D. M. & Stancer, H. C. (1978) The effect of acute and chronic desipramine and amitriptyline treatment on rat brain total 3-methoxy-4-hydroxyphenylglycol. Naunyn-Schmiedeberg's Archives of Pharmacology, 305, 207–11.
Tang, S. W., Helmeste, D. M. & Stancer, H. C. (1979) Interaction of antidepressants with clonidine on rat brain total 3-methoxy-4-hydroxyphenylglycol. Canadian Journal of Physiology and Pharmacology, 57, 435–7.
Wolfe, B. B., Harden, T. K., Sporn, J. R. & Molinoff, P. B. (1978) Presynaptic modulation of beta adrenergic receptors in rat cerebral cortex after treatment with antidepressants. Journal of Pharmacology and Experimental Therapeutics, 207, 446–57.
Zitrin, C., Klein, D. F. & Woerner, M. G. (1978) Behavior therapy, supportive psychotherapy, imipramine, and phobias. Archives of General Psychiatry, 35, 307–16.
Zitrin, C., Klein, D. F. & Woerner, M. G. (1980) Treatment of agoraphobia with group exposure in vivo and imipramine. Archives of General Psychiatry, 37, 6372.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

The British Journal of Psychiatry
  • ISSN: 0007-1250
  • EISSN: 1472-1465
  • URL: /core/journals/the-british-journal-of-psychiatry
Please enter your name
Please enter a valid email address
Who would you like to send this to? *


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed

Abrupt Discontinuation of Tricyclic Antidepressant Drugs: Evidence for Noradrenergic Hyperactivity

  • Dennis S. Charney (a1), George R. Heninger (a1), David E. Sternberg (a1) and D. Harold Landis (a1)
Submit a response


No eLetters have been published for this article.


Reply to: Submit a response

Your details

Conflicting interests

Do you have any conflicting interests? *