Drug Safety

, Volume 10, Issue 2, pp 103–114 | Cite as

Withdrawal Phenomena Associated with Antidepressant and Antipsychotic Agents

  • Steven C. Dilsaver


The withdrawal of heterocyclic antidepressants and antipsychotic agents can produce nausea, emesis, anorexia, diarrhoea, rhinorrhoea, diaphoresis, myalgias, paraesthesias, anxiety, agitation, restlessness and insomnia. The withdrawal of monoamine oxidase (MAO) inhibitors may result in severe anxiety, agitation, pressured speech, sleeplessness or drowsiness, hallucinations, cognitive impairment, delirium, suicidality and delusions of persecution. The withdrawal of antipsychotic agents may give rise to symptoms preceding the onset of psychosis. These potential harbingers of relapse include anxiety, agitation, restlessness and insomnia. The withdrawal phenomena reviewed are usually prevented by gradually reducing the total daily dosage of the pertinent drug. Antimuscarinic agents often alleviate the distress produced by the withdrawal of tricyclic antidepressants and antipsychotic agents. MAO inhibitor withdrawal syndromes may constitute medical emergencies. The prevention of the evolution of a MAO inhibitor withdrawal-precipitated syndrome is a high priority.


Imipramine Desipramine Withdrawal Symptom Antipsychotic Agent Phenelzine 
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  1. Aghajanian GK, Vandermaelen C. Alpha2-adrenoceptor-mediated hyperpolarization of locus coeruleus neurons. Intracellular studies in vivo. Science 215: 1394–1396, 1982PubMedCrossRefGoogle Scholar
  2. Andersen H, Kristiansen ES. Trofranil-treatment of endogenous depressions. Acta Psychiatrica Scandinavica 34: 387–397, 1959PubMedCrossRefGoogle Scholar
  3. Baldessarini RJ. Drugs and the treatment of psychiatric disorders. In Goodman & Gilman (Eds) The pharmacological basis of therapeutics, 7th ed., pp. 423–426, MacMillan, New York, 1980Google Scholar
  4. Bategay R. Drug dependence as a criterion for differentiation of psychotropic drugs. Comprehensive Psychiatry 7: 501–509, 1966CrossRefGoogle Scholar
  5. Bialos D, Giller E, Jatlow P, Docherty J, Harkness L. Recurrence of depression after discontinuation of amitriptyline. American Journal of Psychiatry 139: 325–329, 1982PubMedGoogle Scholar
  6. Blackwell R, Stefopoulos A, Enders P, Kuzma R, Adolphe A. Anticholinergic activity of two tricyclic antidepressants. American Journal of Psychiatry 135: 722–724, 1978PubMedGoogle Scholar
  7. Boisvert D, Chouinard G. Rebound cardiac arrhythmia after withdrawal from imipramine: a case report. American Journal of Psychiatry 138: 985–986, 1981PubMedGoogle Scholar
  8. Brown GM, Stancer HC, Moldofsky H, Harman J, Murphy JT, et al. Withdrawal from long-term, high-dose desipramine therapy: clinical and biological changes. Archives of General Psychiatry 35: 1261–1264, 1978PubMedCrossRefGoogle Scholar
  9. Checcherini-Nelli A, Bardellini L, Cur A, Guazzalli M, Maggini C, et al. Antidepressant withdrawal phenomena: prospective findings. American Journal of Psychiatry 150: 165, 1993Google Scholar
  10. Chiodo LA, Antelman SM. Electroconvulsive shock: progressive dopamine autoreceptor subsensitivity independent of repeated treatment. Science 210: 799, 1980aPubMedCrossRefGoogle Scholar
  11. Chiodo LA, Antelman SM. Repeated tricyclics induce progressive dopamine autoreceptor subsensitivity independent of daily drug treatment. Nature 287: 451–454, 1980bPubMedCrossRefGoogle Scholar
  12. Clow A, Theodoru A, Jenner P, Marsden CD. Cerebral dopamine function in rats following withdrawal from one year of continuous neuroleptic administration. European Journal of Pharmacology 563: 145–157, 1980CrossRefGoogle Scholar
  13. Cohen RM, Campbell IC, Dauphin M, Tallman JF, Murphy DL. Changes in alpha and beta receptor densities in rat brain as a result of treatment with monoamine oxidase inhibitor antidepressants. Neuropharmacology 21: 293–298, 1982PubMedCrossRefGoogle Scholar
  14. Dilsaver SC. Cholinergic mechanisms in affective disorders. Further directions for investigation. Acta Psychiatrica Scandinavica 74: 312–334, 1986aPubMedCrossRefGoogle Scholar
  15. Dilsaver SC. Cholinergic mechanisms in depression. Brain Research Reviews 11: 285–316, 1986bCrossRefGoogle Scholar
  16. Dilsaver SC. Pharmacologic induction of cholinergic system upregulation and supersensitivity in affective disorders research. Journal of Clinical Psychopharmacology 7: 56–72, 1986cGoogle Scholar
  17. Dilsaver SC. The pathophysiologies of substance abuse and affective disorders: an integrative model? Journal of Clinical Psychopharmacology 7: 1–10, 1987PubMedCrossRefGoogle Scholar
  18. Dilsaver SC. Antimuscarinic agents as substances of abuse: a review. Journal of Clinical Psychopharmacology 8: 14–22, 1988PubMedGoogle Scholar
  19. Dilsaver SC, Alessi NE. Antipsychotic withdrawal symptoms: phenomenology and pathophysiology. Acta Psychiatrica Scandinavica 77: 241–246, 1988PubMedCrossRefGoogle Scholar
  20. Dilsaver SC, Davidson RK. Cholinergic properties of desipramine and amoxapine assessment using a thermoregulation paradigm. Progress in Neuro-Psychopharmacology and Biological Psychiatry 11: 581–599, 1987PubMedCrossRefGoogle Scholar
  21. Dilsaver SC, Feinberg M. Antidepressant withdrawal: cholinergic rebound. Presented at the 135th annual meeting of the American Psychiatric Association, Toronto, Canada, 1982Google Scholar
  22. Dilsaver SC, Greden JF. Antidepressant withdrawal syndromes: evidence for supersensitivity of the cholinergic system as an etiologic factor. Journal of Clinical Psychopharmacology 3: 330, 1983PubMedCrossRefGoogle Scholar
  23. Dilsaver SC, Greden JF. Antidepressant withdrawal phenomena. Biological Psychiatry 19: 237–256, 1984aPubMedCrossRefGoogle Scholar
  24. Dilsaver SC, Greden JF. Antidepressant withdrawal-induced activation (hypomania and mania): mechanism and theoretical significance. Brain Research Reviews 7: 29–48, 1984bCrossRefGoogle Scholar
  25. Dilsaver SC, Feinberg M, Greden JF. Antidepressant withdrawal symptoms treated with anticholinergic agents. American Journal of Psychiatry 140: 249–251, 1983aPubMedGoogle Scholar
  26. Dilsaver SC, Kronfol Z, Greden JF, Sackellares JC. Antidepressant withdrawal syndromes: evidence supporting the cholinergic overdrive hypothesis. Journal of Clinical Psychopharmacology 3: 157–164, 1983bPubMedGoogle Scholar
  27. Dilsaver SC, Greden JF, Snyder RM. Antidepressant withdrawal syndromes: phenomenology and pathophysiology. International Clinical Psychopharmacology 2: 1–19, 1987aPubMedCrossRefGoogle Scholar
  28. Dilsaver SC, Majchrzak MJ, Alessi NE. Chronic treatment with amitriptyline produces supersensitivity to nicotine. Biological Psychiatry 23: 169–175, 1988PubMedCrossRefGoogle Scholar
  29. Dilsaver SC, Snyder RM, Alessi NE. Amitriptyline supersensitizes a central cholinergic mechanism. Biological Psychiatry 22: 495–507, 1987bPubMedCrossRefGoogle Scholar
  30. Frankel DA, Raskin DE. Psychosis following phenelzine discontinuation. Journal of Clinical Psychopharmacology 5: 360, 1985Google Scholar
  31. Gallant DM, Edwards CG, Bishop MP, Galbraith GC. Withdrawal symptoms after abrupt cessation of antipsychotic compounds: clinical confirmation in chronic schizophrenics. American Journal of Psychiatry 121: 491–493, 1964PubMedGoogle Scholar
  32. Gawin FH, Markoff RA. Panic anxiety after abrupt discontinuation of amitriptyline. American Journal of Psychiatry 138: 117–118, 1981PubMedGoogle Scholar
  33. Goodman LS, Gilman A (Eds). The pharmacological basis of therapeutics, pp. 161, MacMillan, New York, 1975Google Scholar
  34. Greenberg LM, Roth S. Differential effects of abrupt versus gradual withdrawal of chlorpromazine in hospitalized chronic schizophrenic patients. American Journal of Psychiatry 1966: 221–226, 1966Google Scholar
  35. Grover PM, Young SJ, Wilson CJ. Self-inhibition of dopaminergic neurons: Disruption by ±-α-methyl-p-tyrosine pretreatment or diencephalic lesions. Neuropharmacology 15: 755–762, 1976CrossRefGoogle Scholar
  36. Gualtieri CT, Staye J. Withdrawal symptoms after abrupt cessation of amitriptyline in an eight-year-old boy. American Journal of Psychiatry 136: 457–458, 1979PubMedGoogle Scholar
  37. Haden P. Gastrointestinal disturbances associated with withdrawal of ataractic drugs. Canadian Medical Association Journal 91: 975, 1964Google Scholar
  38. Halle MH, Del Medico VJ, Dilsaver SC. Symptoms of major depression: an acute effect of withdrawing antidepressants. Acta Psychiatric Scandinavica 83: 238, 1991CrossRefGoogle Scholar
  39. Halle MT, Dilsaver SC. Tranylcypromine withdrawal phenomena. Journal of Psychiatry and Neuroscience, in press, 1994Google Scholar
  40. Hartmann PM. Mania or hypomania after withdrawal from antidepressants. Journal of Family Practice 30: 471–472, 1990PubMedGoogle Scholar
  41. Hornykiewicz D. Neurochemical pathology and pharmacology of brain dopamine: rational basis for the current drug treatment of parkinsonism. In Plum (Ed.) Recent advances in neurology, vol. 6, Contemporary Neurology Series, Davis, Philadelphia, 1970Google Scholar
  42. Jellinek T, Gardos G, Cole J. Adverse effects of antiparkinsonism drug withdrawal. American Journal of Psychiatry 138: 1567–1571, 1981PubMedGoogle Scholar
  43. Kehr W, Caisson A, Lindquist M, Magnusson T, Atack C. Evidence for a receptor mediated feedback control of striatal tyrosine hydroxylase. Journal of Pharmacology 24: 744–747, 1972CrossRefGoogle Scholar
  44. Kraft TB. Ernstige abstinentieverschijnselen na het gebruik van clomipramine. Nederlands Tijdschrift voor Geneeskunde 121: 1293, 1977PubMedGoogle Scholar
  45. Kramer JC, Klein DF, Fink M. Withdrawal symptoms following discontinuation of imipramine therapy. American Journal of Psychiatry 118: 549–550, 1961PubMedGoogle Scholar
  46. Kuhn R. On the treatment of depressive states of an iminodibenzl derivative (G22355). Nederlandsch Trjdschrift Voor Geneeskunde 87: 1135, 1957Google Scholar
  47. Kupfer DJ, Frank E, Perel JM, Comes C, Mallinger AG, et al. Five year outcome for maintenance therapies in recurrent depression. Archives of General Psychiatry 49: 769–773, 1992PubMedCrossRefGoogle Scholar
  48. Lacoursiere RB, Spohn HE, Thompson K. Medical effects of abrupt neuroleptic withdrawal. Comprehensive Psychiatry 17: 285–294, 1976PubMedCrossRefGoogle Scholar
  49. Langer SZ. Presynaptic regulation of the release of catecholamines. Pharmacology Reviews 32: 337–362, 1982Google Scholar
  50. Law W, Petti TA, Kazdin A. Withdrawal symptoms after graduated cessation of imipramine in children. American Journal of Psychiatry 138: 647–650, 1981PubMedGoogle Scholar
  51. Le Gassicke J, Ashcroft GW, Eccleston D, Evans JI, Oswald I, et al. The clinical state, sleep, and amine metabolism of a tranylcypromine (‘parnate’) addict. British Journal of Psychiatry 3: 357–364, 1965CrossRefGoogle Scholar
  52. Lee T, Leemen P. Correlation of antipsychotic drug potency and neuroleptic receptor inhibition in post-mortem human brains. Society of Neuroscience 5: 653, 1979Google Scholar
  53. Lieberman J. Cholinergic rebound in neuroleptic withdrawal syndromes. Psychosomatics 22: 253–254, 1981PubMedGoogle Scholar
  54. Liskin B, Roose SP, Walsh BT, Jackson WK. Acute psychosis following phenelzine discontinuation. Journal of Clinical Psycho-pharmacology 5: 46–47, 1985Google Scholar
  55. Mann AM, MacPherson AS. Clinical experience with imipramine (G22355) in the treatment of depression. Canadian Psychiatric Association Journal 4: 38–47, 1959PubMedGoogle Scholar
  56. Martres MP, Costentin J, Baudry M, Marcais H, Protais P, et al. Long-term changes in the sensitivity of pre- and postsynaptic dopamine receptors in mouse striatum evidenced by behavioral and biochemical studies. Brain Research 136: 319–337, 1977PubMedCrossRefGoogle Scholar
  57. Miller RJ, Hilly CR. Antimuscarinic properties of neuroleptics and drug induced parkinsonism. Nature 248: 596–597, 1974PubMedCrossRefGoogle Scholar
  58. Mirin SM, Schatzberg AF, Creasey DE. Hypomania and mania after withdrawal of tricyclic antidepressants. American Journal of Psychiatry 138: 87–89, 1981PubMedGoogle Scholar
  59. Nelson JC, Schottenfield RS, Condrad ED. Hypomania after desipramine withdrawal. American Journal of Psychiatry 140: 624–625, 1983PubMedGoogle Scholar
  60. Nielsen EB, Lyon M. Behavioral alterations during prolonged low continuous amphetamine administration in a monkey family group (cerophithecus aetipos). Biological Psychiatry 17: 423–435, 1982PubMedGoogle Scholar
  61. Petersen RC, Richelson E. Anticholinergic activity of imipramine and some analogues at muscarinic receptors of culture mouse neuroblastoma cells. Psychopharmacology 76: 26–28, 1982PubMedCrossRefGoogle Scholar
  62. Rehavi M, Ramot O, Yavetz B, Sokolovsky M. Amitriptyline: long-term treatment elevates α-adrenergic and muscarinic receptor binding in mouse brain. Brain Research 194: 443–453, 1980PubMedCrossRefGoogle Scholar
  63. Ridley RM, Baker HF, Owen F, Cross AJ, Crow TJ. Behavioral and biochemical effects of chronic treatment with amphetamine in the Vervet monkey. Neuropharmacology 22: 551–554, 1983PubMedCrossRefGoogle Scholar
  64. Roth RH, Walters JR, Murrin LC, Morgenroth III VH. Dopamine neurons: role of impulse flow and pre-synaptic receptors in the regulation of tyrosine hydroxylase. In Usdin & Bunney (Eds) Pre-and postsynaptic receptors, pp. 5–40, Marcel Dekker, New York, 1975Google Scholar
  65. Roth SD. More on psychosis following phenelzine discontinuation. Journal of Clinical Psychopharmacology 5: 360–361, 1985CrossRefGoogle Scholar
  66. Sathananthan GL, Gershon S. Imipramine withdrawal: an akathisialike syndrome. American Journal of Psychiatry 130: 1286–1287, 1973PubMedGoogle Scholar
  67. Sato M. An experimental study on onset and relapse mechanisms in the chronic methamphetamine psychoses. Psychiatry Neurology Japan 81: 21–32, 1979Google Scholar
  68. Shatan C. Withdrawal symptoms after abrupt termination of imipramine. Canadian Psychiatry Association Journal 11 (suppl.): s150–S158, 1966Google Scholar
  69. Shein K, Smith SE. Structure-activity relationships for anticholinoceptor action of tricyclic antidepressants. British Journal of Psychiatry 62: 567–571, 1978Google Scholar
  70. Shuster L, Yu G, Bates A. Sensitization to cocaine stimulation in mice. Psychopharmacology 52: 185–190, 1977PubMedCrossRefGoogle Scholar
  71. Siever LJ, Uhde TW, Murphy PL. Possible subsensitization of alpha2 adrenergic receptors by chronic monoamine oxidase inhibitor treatment in psychiatric patients. Psychiatry Research 6: 293–302, 1982PubMedCrossRefGoogle Scholar
  72. Simpson, GM, Amin M, Konz E. Withdrawal effects of phenothiazines. Comprehensive Psychiatry 6: 347–351, 1965PubMedCrossRefGoogle Scholar
  73. Snyder S, Greensbergs D, Yamamura HI. Antischizophrenic drugs and brain cholinergic receptors. Archives of General Psychiatry 31: 58–61, 1974PubMedCrossRefGoogle Scholar
  74. Snyder SH, Yamamura HI. Antidepressants and muscarinic acetylcholine receptors. Archives of General Psychiatry 34: 236–239, 1977PubMedCrossRefGoogle Scholar
  75. Starke K. Presynaptic receptors. Annual Review of Pharmacology and Toxicology 21: 7–20, 1981PubMedCrossRefGoogle Scholar
  76. Szabadi P, Basner P, Bradshaw CM. The peripheral anticholinergic activity of tricyclic antidepressants: comparison of amitriptyline and desipramine in human volunteers. British Journal of Psychiatry 137: 433–439, 1980PubMedCrossRefGoogle Scholar
  77. Tollefson GD, Senogles SE, Frey WH, Tuason VB, Nicol SE. A comparison of peripheral and central human muscarinic cholinergic receptor affinities for psychotropic drugs. Biological Psychiatry 17: 555–567, 1982PubMedGoogle Scholar
  78. van Sweden B. Rebound antidepressant cardiac arrhythmia. Biological Psychiatry 24: 363–364, 1988PubMedCrossRefGoogle Scholar
  79. Walsh BT, Stewart JW, Wright L, Harrison N, Roose SP, et al. Treatment of bulimia with monoamine oxidase inhibitors. American Journal of Psychiatry 139: 1629–1630, 1982PubMedGoogle Scholar
  80. Webster PAC. Withdrawal symptoms in neonates associated with maternal antidepressant therapy. Lancet 2: 318–319, 1973PubMedCrossRefGoogle Scholar
  81. Weiner WJ, Goertz CG, Nausidea PA, Klawans HL. Amphetamine induced hypersensitivity in guinea pigs. Neurology 29: 1054–1057, 1979PubMedCrossRefGoogle Scholar
  82. Wheller SC, Roth RH. Tolerance to fluphenazine and supersensitivity to apomorphine in central dopaminergic systems after chronic fluphenazine decanoate treatment. Archives of Pharmacology 312: 151–159, 1980CrossRefGoogle Scholar
  83. Wold PN. A long-term evaluation of chlorpromazine in six chronic schizophrenic patients. Journal of Nervous and Mental Diseases 130: 151–154, 1980Google Scholar
  84. Zivkovic B. The involvement of dopamine postsynaptic and autoreceptors in the regulation of dopamine synthesis. In Langer & Starke (Eds) Presynaptic receptors, pp. 249–253, Pergamon Press, Oxford, 1979Google Scholar

Copyright information

© Adis International Limited 1994

Authors and Affiliations

  • Steven C. Dilsaver
    • 1
  1. 1.The University of Texas School of Medicine at Houston, and Harris County Psychiatric CenterHoustonUSA

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