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Relapse following clozapine withdrawal: effect of neuroleptic drugs and cyproheptadine

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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 Nineteen neuroleptic-responsive schizophrenic patients who received clozapine were withdrawn from clozapine by tapering it over 3-week period with and without the addition of a typical neuroleptic.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.

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References

  • Alphs LD, Lee HS (1991) Comparison of withdrawal of typical and atypical antipsychotic drugs: a case study. J Clin Psychiatry 52:346–348

    Google Scholar 

  • Bacher NM, Sanzone MM, Kamp B (1994) Cyproheptadine in treatment-resistant chronic schizophrenics with prior negative response to fluoxetine. J Clin Psychopharmacol 14:424–425

    Google Scholar 

  • Borison RL, Diamond BI, Sinha D, Gupta RP, Ajboye PA (1988) Clozapine withdrawal rebound psychosis. Psychopharmacol Bull 24:260–263

    Google Scholar 

  • 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 151:20–26

    Google Scholar 

  • 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 106:479–483

    Google Scholar 

  • Buckland PR, O'Donovan MC, McGriffin P (1993) Clozapine and sulpiride up-regulate dopamine D3 receptormRNA levels. Neuropharmacology 32:901–907

    Google Scholar 

  • 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 13:25–40

    Google Scholar 

  • Davis KL, Rosenberg GS (1979) Is there a limbic system equivalent of tardive dyskinesia? Biol Psychiatry 14:699–703

    Google Scholar 

  • Diamond BI, Borison RL (1986) Basic and clinical studies of neuroleptic-induced supersensitivity psychosis and dyskinesia. Psychopharmacol Bull 26:900–905

    Google Scholar 

  • Dickson R, Williams R, Dalby JT (1994) Dystonic reaction and relapse with clozapine discontinuation and risperidone initiation. Can J Psychiatry 39:184

    Google Scholar 

  • Ekblom B, Haggstrom JE (1974) Clozapine (Leponex) compared with chlorpromazine: a double-blind evaluation of pharmacological and clinical properties. Curr Ther Res 16:945–957

    Google Scholar 

  • Ekblom B, Eriksson K, Lindström LH (1984) Supersensitivity psychosis in schizophrenic patients after sudden clozapine withdrawal. Psychopharmacology 83:293–294

    Google Scholar 

  • Eklund K (1987) Supersensitivity and clozapine withdrawal. Psychopharmacology 91:135

    Google Scholar 

  • Endicott J, Spitzer RL (1978) A diagnostic interview: the Schedule for Affective Disorders and Schizophrenia. Arch Gen Psychiatry 35:837–844

    Google Scholar 

  • Fink H, Morgenstern R, Oelssner W (1979) Psychotomimetics potentiate locomotor hyperactivity induced by dopaminergic drugs. Pharmacol Biochem Behav 11:479–482

    Google Scholar 

  • Fischer-Cornelssen KA, Ferner UJ, Steiner H (1974) Multifokale Psychopharmaka-prufung (“Multihospital Trial”). Arzneimittelforschung 24:1706–1724

    Google Scholar 

  • 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 40:238–240

    Google Scholar 

  • 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 50:410–424

    Google Scholar 

  • Gilbert PL, Harris WJ, McAdams LA, Jeste DA (1995) Neuroleptic withdrawal in schizophrenic patients: a review of the literature. Arch Gen Psychiatry 52:173–188

    Google Scholar 

  • Glovinsky D, Kirch DG, Wyatt RJ (1992) Early antipsychotic response to resumption of neuroleptics in drug-free chronic schizophrenic patients. Biol Psychiatry 31:968–970

    Google Scholar 

  • Halperin R, Guerin JJ Jr, Davis KL (1989) Regional differences in the induction of behavioral supersensitivity by prolonged treatment with atypical neuroleptics. Psychopharmacology 98:386–391

    Google Scholar 

  • 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 13:383–390

    Google Scholar 

  • Heinrichs DW, Hanlon TE, Carpenter WT (1984) The quality of life scale: an instrument for rating the schizophrenic deficit syndrome. Schizophr Bull 10[3]:388–398

    Google Scholar 

  • Hogarty G, Ulrich R, Mussare F, Aristigueta N (1976) Drug discrimination among long-term successfully maintained schizophrenic outpatients. Dis Nerv Syst 37:494–500

    Google Scholar 

  • 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 256:348–357

    Google Scholar 

  • Ichikawa J, Meltzer HY (1995) DOI, a 5-HT2C/2A receptor agonist, potentiates amphetamine-induced dopamine release in rat striatum. Brain Res (in press)

  • 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 58:2285–2291

    Google Scholar 

  • Idzikowski C, Cowen PJ, Mutt D, Mills FJ (1987) The effects of chronic ritanserin treatment on sleep and the neuroendocrine response toL-tryptophan. Psychopharmacology 93:416–420

    Google Scholar 

  • 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 31:193–196

    Google Scholar 

  • 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 45:789–796

    Google Scholar 

  • Krupp P, Barnes P (1989) Leponex®-associated granulocytopenia: a review of the situation. Psychopharmacology (Suppl) 99:S118-S121

    Google Scholar 

  • 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 264:1262–1267

    Google Scholar 

  • Lee MA, Thompson P, Meltzer HY (1994) Effects of clozapine on cognitive function in schizophrenia. J Clin Psychiatry 55[Suppl B]:82–87

    Google Scholar 

  • 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 10:67–72

    Google Scholar 

  • Linszen DH, Dinegemans PM, Lenoir ME, Nugter MA, Scholte WF, Van der Does AJW (1994) Relapse criteria in schizophrenic disorders: difference perspectives. Psychiatry Res 54:273–281

    Google Scholar 

  • 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 19:565–571

    Google Scholar 

  • 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 137:1395–1398

    Google Scholar 

  • Matsubara S, Meltzer HY (1989) Effect of typical and atypical antipsychotic drugs on 5-HT2 receptor density in rat cerebral cortex. Life Sci 45:1397–1406

    Google Scholar 

  • Meltzer HY (1991) The mechanism of action of novel antipsychotic drugs. Schizophr Bull 17:263–287

    Google Scholar 

  • Meltzer HY (1992a) Dimensions of outcome with clozapine. Br J Psychiatry 160 [Suppl 17]:46–53

    Google Scholar 

  • Meltzer HY (1992b) Treatment of the neuroleptic non-responsive schizophrenic patients. Schizophr Bull 18:515–542

    Google Scholar 

  • Miller DD, Flaum M, Arndt S, Fleming F, Andreasan NC (1994) Effect of antipsychotic withdrawal on negative symptoms in schizophrenia. Neuropsychopharmacology 11:11–20

    Google Scholar 

  • Miller RJ, Hiley CR (1974) Antimuscarinic properties of neuroleptics and drug-induced parkinsonism. Nature 248:596–597

    Google Scholar 

  • 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 54:1062–1067

    Google Scholar 

  • 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 49:643–649

    Google Scholar 

  • Overall JE, Gorham D (1962) The Brief Psychiatric Rating Scale. Psychol Rep 10:149–165

    Google Scholar 

  • Parsa MA, Al-Lanhram Y, Ramirez LF, Meltzer HY (1993) Prolonged psychotic relapse after abrupt clozapine withdrawal. J Clin Psychopharmacol 13:154–155

    Google Scholar 

  • Perényi A, Kunsz E, Bagdy G (1985) Early relapse after sudden withdrawal or dose reduction of clozapine. Psychopharmacology 86:244

    Google Scholar 

  • 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 148:231–235

    Google Scholar 

  • Prien RF, Cole J, Belkin N (1968) Relapse in chronic schizophrenics following abrupt withdrawal of tranquilizing medication. Br J Psychiatry 115:679–686

    Google Scholar 

  • 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 84:512–519

    Google Scholar 

  • Schremmer C, Morgenstern R, Fink H, Oh T (1990) Atypical neurlopetics suppress dopaminergic behavioral supersensitivity. Psychopharmacology 100:399–403

    Google Scholar 

  • 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 101:568–569

    Google Scholar 

  • 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)

  • Shopsin B, Klein H, Aaronson M, Collora M (1979) Clozapine, chlorpromazine and placebo in newly hospitalized, acutely schizophrenic patients. Arch Gen Psychiatry 36:657–664

    Google Scholar 

  • Shore D, Matthew S, Cott J, Lieberman JA (1995) Clinical implications of clozapine discontinuation: report of an NIMH workshop. Schizophr Bull 21:333–338

    Google Scholar 

  • Silver H, Blacker M, Weller MP, Lerer B (1989) Treatment of chronic schizophrenia with cyproheptadine. Biol Psychiatry 25:502–504

    Google Scholar 

  • Silver H, Blacker M, Weller MP, Lerer B (1991) Treatment of chronic schizophrenia with cyproheptadine: a double-blind placebo controlled study. Biol Psychiatry 30:523–525

    Google Scholar 

  • 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 3:125–129

    Google Scholar 

  • 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 266:684–691

    Google Scholar 

  • 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 52:1789–1793

    Google Scholar 

  • 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 1394

  • Van Rizen H (1972) Different central effects of the 5-HT antagonists mianserin and cyproheptadine. Arch Int Pharmacodyn 198:256–269

    Google Scholar 

  • Vencovsky E, Peterova E, Baudis P (1975) Comparison of therapeutic effect of clozapine and chlorpromazine. Ceskoslovenska Psychiatric 71:21–26

    Google Scholar 

  • 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 487:288–298

    Google Scholar 

  • Yamamoto BK, Pehek EA, Meltzer HY (1994) Brain region effects of clozapine on amino acid and monoamine transmission. J Clin Psychiatry 55 [Suppl B]:8–14

    Google Scholar 

  • Zapletálek M, Preiningerova O, Hanus H (1980) Does clozapine cause dependence? (German) Agressologie 21[A]:19–22

    Google Scholar 

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Authors and Affiliations

  1. Laboratory of Biological Psychiatry, Department of Psychiatry, University Hospitals of Cleveland, Hanna Pavilion, Room B-68, 11100 Euclid Avenue, 44106-5078, Cleveland, OH, USA

    H. Y. Meltzer, M. A. Lee, R. Ranjan, E. A. Mason & P. A. Cola

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Meltzer, H.Y., Lee, M.A., Ranjan, R. et al. Relapse following clozapine withdrawal: effect of neuroleptic drugs and cyproheptadine. Psychopharmacology 124, 176–187 (1996). https://doi.org/10.1007/BF02245619

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