Psychopharmacology

, Volume 124, Issue 1–2, pp 176–187

Relapse following clozapine withdrawal: effect of neuroleptic drugs and cyproheptadine

  • H. Y. Meltzer
  • M. A. Lee
  • R. Ranjan
  • E. A. Mason
  • P. A. Cola
Original Investigation
  • 85 Downloads

Abstract

The objective of this study was to report the effect of the slow withdrawal of clozapine from 19 patients withneuroleptic-responsive schizophrenia at the end of a 2-year clinical trial of clozapine and to compare this with the results of naturalistic discontinuation of clozapine treatment in 64neuroleptic-resistant schizophrenic patients. Nineteen neuroleptic-responsive schizophrenic patients who received clozapine were withdrawn from clozapine by tapering it over 3-week period with and without the addition of a typical neuroleptic. Fifteen of the 19 neuroleptic-responsive patients experienced the return of psychotic symptoms during or after the clozapine taper, which were most severe in the ten patients in whom the withdrawal of clozapine was carried out without prior addition of neuroleptic treatment. Addition of a neuroleptic prior to clozapine withdrawal prevented the emergence of positive symptoms during clozapine withdrawal in each of eight patients. Nevertheless, psychotic symptoms emerged, usually within a week after discontinuing clozapine, in six of the eight patients. Neuroleptic treatment, with or without an anticholingergic drug, was much less effective in treating positive symptoms in these patients immediately after the clozapine withdrawal than it had been 2 years previously. Cyproheptadine, a non-selective serotonin receptor antagonist, augmented the antipsychotic effect of neuroleptics in each of four patients who relapsed following withdrawal from clozapine and relieved extrapyramidal symptoms in a fifth patient. The frequency of relapse following withdrawal of clozapine in 64 neuroleptic-resistant patients was significantly lower (25/64, 39.1%) than in the neuroleptic-responsive patients.

Key words

Clozapine Schizophrenia Serotonin Dopamine Psychosis 

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References

  1. Alphs LD, Lee HS (1991) Comparison of withdrawal of typical and atypical antipsychotic drugs: a case study. J Clin Psychiatry 52:346–348Google Scholar
  2. Bacher NM, Sanzone MM, Kamp B (1994) Cyproheptadine in treatment-resistant chronic schizophrenics with prior negative response to fluoxetine. J Clin Psychopharmacol 14:424–425Google Scholar
  3. Borison RL, Diamond BI, Sinha D, Gupta RP, Ajboye PA (1988) Clozapine withdrawal rebound psychosis. Psychopharmacol Bull 24:260–263Google Scholar
  4. Breier A, Buchanan RW, Kirkpatrick B, Davis OR, Irish D, Summerfelt A, Carpenter WT Jr (1994) Effects of clozapine on positive and negative symptoms in outpatients with schizophrenia. Am J Psychiatry 151:20–26Google Scholar
  5. Buckland PR, O'Donovan MC, McGriffin P (1992) Changes in dopamine D1, D2, and D3 receptor mRNA levels in rat brain following antipsychotic treatment. Psychopharmacology 106:479–483Google Scholar
  6. Buckland PR, O'Donovan MC, McGriffin P (1993) Clozapine and sulpiride up-regulate dopamine D3 receptormRNA levels. Neuropharmacology 32:901–907Google Scholar
  7. Chouinard G, Jones B, Remington G, Bloom D, Addington D, MacEwan GW, Labelle A, Beauclair L, Arnott W (1993) A Canadian multicenter placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clin Psychopharmacol 13:25–40Google Scholar
  8. Davis KL, Rosenberg GS (1979) Is there a limbic system equivalent of tardive dyskinesia? Biol Psychiatry 14:699–703Google Scholar
  9. Diamond BI, Borison RL (1986) Basic and clinical studies of neuroleptic-induced supersensitivity psychosis and dyskinesia. Psychopharmacol Bull 26:900–905Google Scholar
  10. Dickson R, Williams R, Dalby JT (1994) Dystonic reaction and relapse with clozapine discontinuation and risperidone initiation. Can J Psychiatry 39:184Google Scholar
  11. Ekblom B, Haggstrom JE (1974) Clozapine (Leponex) compared with chlorpromazine: a double-blind evaluation of pharmacological and clinical properties. Curr Ther Res 16:945–957Google Scholar
  12. Ekblom B, Eriksson K, Lindström LH (1984) Supersensitivity psychosis in schizophrenic patients after sudden clozapine withdrawal. Psychopharmacology 83:293–294Google Scholar
  13. Eklund K (1987) Supersensitivity and clozapine withdrawal. Psychopharmacology 91:135Google Scholar
  14. Endicott J, Spitzer RL (1978) A diagnostic interview: the Schedule for Affective Disorders and Schizophrenia. Arch Gen Psychiatry 35:837–844Google Scholar
  15. Fink H, Morgenstern R, Oelssner W (1979) Psychotomimetics potentiate locomotor hyperactivity induced by dopaminergic drugs. Pharmacol Biochem Behav 11:479–482Google Scholar
  16. Fischer-Cornelssen KA, Ferner UJ, Steiner H (1974) Multifokale Psychopharmaka-prufung (“Multihospital Trial”). Arzneimittelforschung 24:1706–1724Google Scholar
  17. Garrison JC (1990) Histamine, bradykinesia, 5-hydroxytryptamine, and their antagonists. In Gelenberg AJ, Doller JC (1979) Clozapine versus chlorpromazine for the treatment of schizophrenia: preliminary results from a double-blind study. J Clin Psychiatry 40:238–240Google Scholar
  18. Gerlach J, Koppelhus P, Helweg E, Manrad A (1974) Clozapine and haloperidol in a single-blind cross-over trial. Therapeutic and biochemical aspects in the treatment of schizophrenia. Acta Psychiatr Scand 50:410–424Google Scholar
  19. Gilbert PL, Harris WJ, McAdams LA, Jeste DA (1995) Neuroleptic withdrawal in schizophrenic patients: a review of the literature. Arch Gen Psychiatry 52:173–188Google Scholar
  20. Glovinsky D, Kirch DG, Wyatt RJ (1992) Early antipsychotic response to resumption of neuroleptics in drug-free chronic schizophrenic patients. Biol Psychiatry 31:968–970Google Scholar
  21. Halperin R, Guerin JJ Jr, Davis KL (1989) Regional differences in the induction of behavioral supersensitivity by prolonged treatment with atypical neuroleptics. Psychopharmacology 98:386–391Google Scholar
  22. Hasegawa M, Gutierrez-Esteinou R, Way L, Meltzer HY (1993) Relationship between clinical efficacy and clozapine plasma concentrations in schizophrenia: effect of smoking. J ClinPsychopharmacol 13:383–390Google Scholar
  23. Heinrichs DW, Hanlon TE, Carpenter WT (1984) The quality of life scale: an instrument for rating the schizophrenic deficit syndrome. Schizophr Bull 10[3]:388–398Google Scholar
  24. Hogarty G, Ulrich R, Mussare F, Aristigueta N (1976) Drug discrimination among long-term successfully maintained schizophrenic outpatients. Dis Nerv Syst 37:494–500Google Scholar
  25. Ichikawa J, Meltzer HY (1991) Differential effects of repeated treatment with haloperidol and clozapine on dopamine release and metabolism in the striatum and the nucleus accumbens. J Pharmacol Exp Ther 256:348–357Google Scholar
  26. Ichikawa J, Meltzer HY (1995) DOI, a 5-HT2C/2A receptor agonist, potentiates amphetamine-induced dopamine release in rat striatum. Brain Res (in press)Google Scholar
  27. Ichikawa J, Meltzer HY (1992) Amperozide, a novel antipsychotic drug, inhibits the ability ofd-amphetamine to increase dopamine release in vitro in rat striatum and nucleus accumbens. J Neurochem 58:2285–2291Google Scholar
  28. Idzikowski C, Cowen PJ, Mutt D, Mills FJ (1987) The effects of chronic ritanserin treatment on sleep and the neuroendocrine response toL-tryptophan. Psychopharmacology 93:416–420Google Scholar
  29. Idzikowski C, Mills FJ, James RJ (1991) A dose-response study examining the effects of ritanserin on human slow wave sleep. Br J Clin Pharmacol 31:193–196Google Scholar
  30. Kane J, Honigfeld G, Singer J, Meltzer HY, Clozaril Collaborative Study Group (1988) Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine. Arch Gen Psychiatry 45:789–796Google Scholar
  31. Krupp P, Barnes P (1989) Leponex®-associated granulocytopenia: a review of the situation. Psychopharmacology (Suppl) 99:S118-S121Google Scholar
  32. Kuoppamäki M, Seppälä T, Syvälahti E, Hietala J (1993) Chronic clozapine treatment decreases 5-hydroxytryptamine1C receptor density in the rat choroid plexus: comparison with haloperidol. J Pharmacol Exp Ther 264:1262–1267Google Scholar
  33. Lee MA, Thompson P, Meltzer HY (1994) Effects of clozapine on cognitive function in schizophrenia. J Clin Psychiatry 55[Suppl B]:82–87Google Scholar
  34. Lee HS, Song DH, Kim JH, Lee YM, Han ES, Yoo KJ (1995) Cyproheptadine augmentation of haloperidol in chronic schizophrenic patients: a double-blind placebo-controlled study. Int Clin Psychopharmacol 10:67–72Google Scholar
  35. Linszen DH, Dinegemans PM, Lenoir ME, Nugter MA, Scholte WF, Van der Does AJW (1994) Relapse criteria in schizophrenic disorders: difference perspectives. Psychiatry Res 54:273–281Google Scholar
  36. Llorca DM, Wolf MA, Laneon C, Bougerol T (1993) Efficcaté compareé de la bromocriptine, de la carbamazépine et de la cyproheptadine, schizophrènes chroniques résistants. Encephale 19:565–571Google Scholar
  37. Luchins DJ, Freed WJ, Wyatt RJ (1980) The role of cholinergic supersensitivity in the medical symptoms associated with withdrawal of antipsychotic drugs. Am J Psychiatry 137:1395–1398Google Scholar
  38. Matsubara S, Meltzer HY (1989) Effect of typical and atypical antipsychotic drugs on 5-HT2 receptor density in rat cerebral cortex. Life Sci 45:1397–1406Google Scholar
  39. Meltzer HY (1991) The mechanism of action of novel antipsychotic drugs. Schizophr Bull 17:263–287Google Scholar
  40. Meltzer HY (1992a) Dimensions of outcome with clozapine. Br J Psychiatry 160 [Suppl 17]:46–53Google Scholar
  41. Meltzer HY (1992b) Treatment of the neuroleptic non-responsive schizophrenic patients. Schizophr Bull 18:515–542Google Scholar
  42. Miller DD, Flaum M, Arndt S, Fleming F, Andreasan NC (1994) Effect of antipsychotic withdrawal on negative symptoms in schizophrenia. Neuropsychopharmacology 11:11–20Google Scholar
  43. Miller RJ, Hiley CR (1974) Antimuscarinic properties of neuroleptics and drug-induced parkinsonism. Nature 248:596–597Google Scholar
  44. Nash JF, Meltzer HY, Gudelsky GA (1990) Effect of 3,4-methylenedioxymethamphetamine on 3,4-di-hydroxyphenylalanine in the striatum and nucleus accumulation in the striatum and nucleus accumbens. J Neurochem 54:1062–1067Google Scholar
  45. Neylan TC, Van Kammen DP, Kelley ME, Peters JL (1992) Sleep in schizophrenic patients on and off haloperidol therapy: clinically stable versus relapsed patients. Arch Gen Psychiatry 49:643–649Google Scholar
  46. Overall JE, Gorham D (1962) The Brief Psychiatric Rating Scale. Psychol Rep 10:149–165Google Scholar
  47. Parsa MA, Al-Lanhram Y, Ramirez LF, Meltzer HY (1993) Prolonged psychotic relapse after abrupt clozapine withdrawal. J Clin Psychopharmacol 13:154–155Google Scholar
  48. Perényi A, Kunsz E, Bagdy G (1985) Early relapse after sudden withdrawal or dose reduction of clozapine. Psychopharmacology 86:244Google Scholar
  49. Perry PJ, Miller DD, Arndt S, Cadoret RJ (1991) Clozapine and norclozapine plasma concentrations and clinical response of treatment-refractory schizophrenic patients. Am J Psychiatry 148:231–235Google Scholar
  50. Prien RF, Cole J, Belkin N (1968) Relapse in chronic schizophrenics following abrupt withdrawal of tranquilizing medication. Br J Psychiatry 115:679–686Google Scholar
  51. Rupniak NMJ, Kilpatrick G, Hall MD, Jenner P, Marsden CD (1984) Differential alterations in striatal dopamine receptor sensitivity induced by repeated administration of clinically equivalent doses of haloperidol, sulpiride or clozapine in rats. Psychopharmacology 84:512–519Google Scholar
  52. Schremmer C, Morgenstern R, Fink H, Oh T (1990) Atypical neurlopetics suppress dopaminergic behavioral supersensitivity. Psychopharmacology 100:399–403Google Scholar
  53. Sharpley AL, Solomon RA, Fernando AI, da Roza Davis JM, Cown PJ (1990) Dose-related effects of selective 5-HT2 receptor antagonists on slow wave sleep in humans. Psychopharmacology 101:568–569Google Scholar
  54. Shiovitz TM, Welke TL, Tigel PD, Anand R, Hartman RD, Sramek JJ, Kurtz NM, Cutler NR (1995) Cholinergic rebound and rapid onset psychosis following abrupt clozapine with-drawal. Schizophr Bull (in press)Google Scholar
  55. Shopsin B, Klein H, Aaronson M, Collora M (1979) Clozapine, chlorpromazine and placebo in newly hospitalized, acutely schizophrenic patients. Arch Gen Psychiatry 36:657–664Google Scholar
  56. Shore D, Matthew S, Cott J, Lieberman JA (1995) Clinical implications of clozapine discontinuation: report of an NIMH workshop. Schizophr Bull 21:333–338Google Scholar
  57. Silver H, Blacker M, Weller MP, Lerer B (1989) Treatment of chronic schizophrenia with cyproheptadine. Biol Psychiatry 25:502–504Google Scholar
  58. Silver H, Blacker M, Weller MP, Lerer B (1991) Treatment of chronic schizophrenia with cyproheptadine: a double-blind placebo controlled study. Biol Psychiatry 30:523–525Google Scholar
  59. Solomon RA, Sharpley AL, Cowen PJ (1984) Increased slow wave sleep with 5-HT2 receptor antagonists; detection by ambulatory EEG recording and automatic sleep stage analysis. J Psychopharmacol 3:125–129Google Scholar
  60. Sorensen SM, Kehne JH, Fadayel GM, Humphreys TM, Kettler HJ, Sullivan CK, Taylor VL, Schmidt CJ (1993) Characterization of the 5-HT2 receptor antagonist MDL 100907 as a putative atypical antipsychotic behavioral, electrophysiological and neurochemical studies. J Pharmacol Exp Ther 266:684–691Google Scholar
  61. Specchio LM, Puca FM, Genco S, Candeliere G, Galeone D, Dammacco F (1976) Effectti della ciproheptadine sul sonno dellumo normale. Boll Soc Ital Biol Sper 52:1789–1793Google Scholar
  62. Stutzmann JM, Eon B, Roux M, Lucas M, Blanchard JC, Laduron RM (1990) RP 62203, a 5-HT2 antagonist, enhances slow wave sleep in rats. 17th Congress of Collegium Internationale Neuropharmacologicum, Kyoto, Japan, Abstract 1394Google Scholar
  63. Van Rizen H (1972) Different central effects of the 5-HT antagonists mianserin and cyproheptadine. Arch Int Pharmacodyn 198:256–269Google Scholar
  64. Vencovsky E, Peterova E, Baudis P (1975) Comparison of therapeutic effect of clozapine and chlorpromazine. Ceskoslovenska Psychiatric 71:21–26Google Scholar
  65. Wilmot CA, Szczepanick AM (1989) Effects of acute and chronic treatments with clozapine and haloperidol on serotonin (5-HT) and dopamine (D2) receptors in the rat brain. Brain Res 487:288–298Google Scholar
  66. Yamamoto BK, Pehek EA, Meltzer HY (1994) Brain region effects of clozapine on amino acid and monoamine transmission. J Clin Psychiatry 55 [Suppl B]:8–14Google Scholar
  67. Zapletálek M, Preiningerova O, Hanus H (1980) Does clozapine cause dependence? (German) Agressologie 21[A]:19–22Google Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • H. Y. Meltzer
    • 1
  • M. A. Lee
    • 1
  • R. Ranjan
    • 1
  • E. A. Mason
    • 1
  • P. A. Cola
    • 1
  1. 1.Laboratory of Biological Psychiatry, Department of PsychiatryUniversity Hospitals of ClevelandClevelandUSA

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