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Clozapine, Chlorpromazine, and Placebo in Newly Hospitalized, Acutely Schizophrenic Patients: A Controlled, Double-Blind Comparison

Clozapine, Chlorpromazine, and Placebo in Newly Hospitalized, Acutely Schizophrenic Patients: A... Abstract • Clozapine is a unique compound belonging to a relatively new group of antipsychotic agents, the dibenzazepines. To our knowledge, the present study represents the first double-blind, controlled comparison recorded in the United States. The data suggest that clozapine in the present population of newly admitted, acutely psychotic schizophrenic individuals, and in the doses employed, was more effective in overall improvement response, discharge rate, and ameliorating discrete symptoms across the different objective rating scales used than was chlorpromazine (Thorazine) hydrochloride. Placebo was ineffective. Unlike chlorpromazine, no extrapyramidal reactions occurred in those patients ingesting clozapine. Clozapine was also beneficial in reversing abnormal involuntary motor movements. It is an excellent anxiolytic and hypnotic agent. Sedation, hypotension, and hypersalivation are among the more common side effects observed. References 1. Janssen PAJ, Neimegeers CJE, Schellekens KHL: Is it possible to predict the clinical effects of neuroleptic drugs (major tranquilizers) from aniaml data? Arzneim Forsch 15:104-117, 1965. 2. Carlsson A, Lindqvist M: Effect of chlorpromazine or haloperidol on formation of 3-methoxy-tyramine and normetanephrine in mouse brain . Acta Pharmacol 20:140-144, 1963.Crossref 3. Roos BE: Effect of certain tranquilizers on the level of homovanillic acid in the corpus striatum . J Pharm Pharmacol 17:820-821, 1965.Crossref 4. Anden NE, Roos BE, Werdinius B: Effects of chlorpromazine, haloperidol and reserpine on the level of phenolic acids in the rabbit corpus striatum . Life Sci 3:149-158, 1964.Crossref 5. Haase HJ: Uber Vorkommen und Deutung des psychomotorischen Parkinsonsyndrom bei Megaphen bzw . Largactil-Dauerbehandlung Nervenarzt 25:486-492, 1954. 6. Horn AS, Snyder SH: Chlorpromazine and dopamine: Conformational similarities that correlate with the antischizophrenic activity of phenothiazine drugs . Proc Natl Acad Sci USA 68:2325-2328, 1971.Crossref 7. Clement-Cormier YC, Kebabian JW, Petzold GL, et al: Dopaminesensitivity adenylate cyclase in mammalian brain: A possible site of action of antipsychotic drugs . Proc Nati Acad Sci USA 71:1113-1117, 1974.Crossref 8. Snyder SH, Greenberg D, Yamamura HI: Antischizophrenic drugs and brain cholinergic receptors . Arch Gen Psychiatry 31:58-61, 1974.Crossref 9. Haase HJ: Müglichkeiten und Grenzen der Psychopharmakotherapie mit Tranquilizern und Neuroleptika . Dtsch Med Wochenschr 88:505-514, 1963.Crossref 10. Haase HJ: Therapie mit Psychopharmaka und anderen psychotropen Medikamenten . Düsseldorf, Germany, Janssen GmbH, 1969. 11. Van Rossum JM, Janssen PAJ, Boissier JR, et al: Pharmacology . Mod Probl Pharmacopsychiatry 5:23-70, 1970. 12. Gross H, Langner E: Das Wirkungsprofil eines chemisch neuartigen Breitbandneuroleptikums der Dibenzodiazepingruppe . Wein Med Wochenschr 116:814-816, 1966. 13. DeMaio D: Preliminary clinical evaluation of a new neuroleptic agent HF-1854 , in: The Present Status of Psychotropic Drugs: Pharmacological and Clinical Aspects . Amsterdam, Exerpta Medica Foundation, 1969, pp 485-488. 14. Berzewski H, Helmchen H, Hippius H, et al: Das klinische Wirkungsspektrum eines neuen Dibenzodiazepinderivates W-108/HF-1854: 8-Chlor11-(4'-methyl)-piperazino-5-dibenzo [b,e] [1,4] diazepin . Arzneim Forsch 19:495-496, 1969. 15. Stille G, Ackerman H, Lauener H, et al: The pharmacological properties of a potent neuroleptic compound from the dibenzodiazepine group . Int J Neuropharmacol 4:375-383, 1971.Crossref 16. Stille G, Lauener H, Eichenberger E: The pharmacology of 8-chloro11-(4'-methyl)-piperazino)-5H-dibenzo [b,e] [1,4] diazepine (clozapine) . Farmaco [Prat] 26:603-625, 1971. 17. Ayd FJ: Clozapine: A unique new neuroleptic . Int Drug Ther Newsletter 9:5-12, 1974. 18. Matz R, Rick W, Oh D, et al: Clozapine: A potential antipsychotic agent without extrapyramidal manifestations . Cur Ther Res 7:687-695, 1974. 19. Shopsin B, Pearson E, Gershon Ṣ, et al: A controlled double-blind comparison between loxapine succinate and chlorpromazine in acute newly hospitalized schizophrenic patients . Curr Ther Res 14:739-748, 1972. 20. Clinical Investigators Manual, Clozapine. Hanover, NJ, Pharmaceutical Division Sandoz, Inc, 1976. 21. Angst J, Haenicke U, Padrutt A, et al: Ergebnisse eines Doppelblindversuches von HF-1854 (8-Chlor-11-(4 methyl-l-piperazinyl)-5H-dibeno (b,e) (1,4) diazepine) . Vergleich Levomepromazin Pharmakopsychiat 4:192-200, 1971.Crossref 22. Gross H, Langner E, Pfolz H: Clozapin in der Langzeittherapie der Chronischen Schizophrenie . Arzneim Forsch 24:987-989, 1970. 23. Fisher-Cornelssen K, Ferner U, Steiner H: Multifokale Psychopharmakaprufung . Arzneim Forsch 24:1006-1007, 1974. 24. Nidkanen P, Achte K, Jaskari M, et al: Results of a comparative double-blind study with clozapine and chlorpromazine in the treatment of schizophrenic patients . Eripainos Psychiatria Fennica , 1974, pp 307-313. 25. Gerlach J, Koppelhus P, Helweg E, et al: 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, 1974.Crossref 26. Gerlach J, Munkvad I: Clozapine and haloperidol: Clinical and biochemical aspects in the treatment of schizophrenia . Nor Psykiatr Tidsskr 28:463, 1974.Crossref 27. Gerlach J, Thorsen K, Fog R: Extrapyramidal reactions and amine metabolites in cerebrospinal fluid during haloperidol and clozapine treatment of schizophrenic patients . Psychopharmacologia 40:341-350, 1975.Crossref 28. Klein H, Aronson M, Shopsin B: Clozapine: Double-blind control trial in the treatment of acute schizophrenia . Psychopharmacol Bull 14:12-15, 1978. 29. Hippius H, Klein HE: Summary of the clinical aspects on treatment with clozapine (Leponex). Read before the Leponex Symposium, New York, Sept 30, 1974. 30. Blum AWW: Temperaturanstiege und Bluteiweis-veränderungen unter der Therapie mit Neuroleptika—unter besonderer Berücksichtigung des neuartigen Dibenzodiazepin-Derivates Clozapine (Wander) . Verlag Weiner Med Akad , 1972, pp 113-119. 31. Gram LF: Bone-marrow depression following treatment with clozapine (Leponex) . Vgeskr Laeg 138:1271-1273, 1976. 32. Griffith RW, Saameli K: Clozapine and agranulocytosis . Lancet 4:657, 1975.Crossref 33. Idanpaan-Heikkila J, Alhava E, Olkinuora M: Clozapine and agranulocytosis . Lancet 2:611, 1975.Crossref 34. Leucocytopenias and agranulocytosis during Leponex treatment , in Situation Report . Basel, Switzerland, Sandoz Ltd, 1976. 35. Stille G: Effect of single and repeated administration of clozapine on the metabolism of dopamine and noradrenaline in the brain of the rat . Eur J Pharmacol 27:180-190, 1974.Crossref 36. Miller RJ, Hiley CR: Antimuscarinic properties of neuroleptics and drug-induced parkinsonism . Nature 248:495-497, 1974.Crossref 37. Stadler H, Loyd KG, Bartholini G: Dopaminergic inhibition of striatal cholinergic neurons; Synergistic blocking action of γ-butyrolactone and neuroleptic drugs . Arch Pharmacol Exp Pathol 283:129-134, 1974.Crossref 38. Bartholini G, Haefeli W, Jalfre M, et al: Effects of clozapine on cerebral catecholaminergic neurone systems . Br J Pharmacol 46:736-740, 1972.Crossref 39. Sedvall G, Nybäck H: Effect of clozapine and some other antipsychotic agents on synthesis and turnover of dopamine formed from 14C-tyrosine in mouse brain . Israel U Med Sci J 9:24-30, 1973. 40. Eichenberger E, Sayers AC, White TG: Clozapine and the dopamine hypothesis of schizophrenia: A critical appraisal . Phermakopsychiatr Neuropsychopharmakol 8:115-121, 1975.Crossref 41. Gruen P, Sachar E, Langer G, et al: Prolactin response to neuroleptics in normals and schizophrenics . Arch Gen Psychiatry 35:1222-1227, 1978.Crossref 42. Ackenheil M, Matussek N, Hippius H, et al: Sulpiride and the dopamine hypothesis of schizophrenia. Read before the International Group for the Study of Affective Disorders, Munich, Germany, June 24, 1976. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of General Psychiatry American Medical Association

Clozapine, Chlorpromazine, and Placebo in Newly Hospitalized, Acutely Schizophrenic Patients: A Controlled, Double-Blind Comparison

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Publisher
American Medical Association
Copyright
Copyright © 1979 American Medical Association. All Rights Reserved.
ISSN
0003-990X
eISSN
1598-3636
DOI
10.1001/archpsyc.1979.01780060047005
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Abstract

Abstract • Clozapine is a unique compound belonging to a relatively new group of antipsychotic agents, the dibenzazepines. To our knowledge, the present study represents the first double-blind, controlled comparison recorded in the United States. The data suggest that clozapine in the present population of newly admitted, acutely psychotic schizophrenic individuals, and in the doses employed, was more effective in overall improvement response, discharge rate, and ameliorating discrete symptoms across the different objective rating scales used than was chlorpromazine (Thorazine) hydrochloride. Placebo was ineffective. Unlike chlorpromazine, no extrapyramidal reactions occurred in those patients ingesting clozapine. Clozapine was also beneficial in reversing abnormal involuntary motor movements. It is an excellent anxiolytic and hypnotic agent. Sedation, hypotension, and hypersalivation are among the more common side effects observed. References 1. Janssen PAJ, Neimegeers CJE, Schellekens KHL: Is it possible to predict the clinical effects of neuroleptic drugs (major tranquilizers) from aniaml data? Arzneim Forsch 15:104-117, 1965. 2. Carlsson A, Lindqvist M: Effect of chlorpromazine or haloperidol on formation of 3-methoxy-tyramine and normetanephrine in mouse brain . Acta Pharmacol 20:140-144, 1963.Crossref 3. Roos BE: Effect of certain tranquilizers on the level of homovanillic acid in the corpus striatum . J Pharm Pharmacol 17:820-821, 1965.Crossref 4. Anden NE, Roos BE, Werdinius B: Effects of chlorpromazine, haloperidol and reserpine on the level of phenolic acids in the rabbit corpus striatum . Life Sci 3:149-158, 1964.Crossref 5. Haase HJ: Uber Vorkommen und Deutung des psychomotorischen Parkinsonsyndrom bei Megaphen bzw . Largactil-Dauerbehandlung Nervenarzt 25:486-492, 1954. 6. Horn AS, Snyder SH: Chlorpromazine and dopamine: Conformational similarities that correlate with the antischizophrenic activity of phenothiazine drugs . Proc Natl Acad Sci USA 68:2325-2328, 1971.Crossref 7. Clement-Cormier YC, Kebabian JW, Petzold GL, et al: Dopaminesensitivity adenylate cyclase in mammalian brain: A possible site of action of antipsychotic drugs . Proc Nati Acad Sci USA 71:1113-1117, 1974.Crossref 8. Snyder SH, Greenberg D, Yamamura HI: Antischizophrenic drugs and brain cholinergic receptors . Arch Gen Psychiatry 31:58-61, 1974.Crossref 9. Haase HJ: Müglichkeiten und Grenzen der Psychopharmakotherapie mit Tranquilizern und Neuroleptika . Dtsch Med Wochenschr 88:505-514, 1963.Crossref 10. Haase HJ: Therapie mit Psychopharmaka und anderen psychotropen Medikamenten . Düsseldorf, Germany, Janssen GmbH, 1969. 11. Van Rossum JM, Janssen PAJ, Boissier JR, et al: Pharmacology . Mod Probl Pharmacopsychiatry 5:23-70, 1970. 12. Gross H, Langner E: Das Wirkungsprofil eines chemisch neuartigen Breitbandneuroleptikums der Dibenzodiazepingruppe . Wein Med Wochenschr 116:814-816, 1966. 13. DeMaio D: Preliminary clinical evaluation of a new neuroleptic agent HF-1854 , in: The Present Status of Psychotropic Drugs: Pharmacological and Clinical Aspects . Amsterdam, Exerpta Medica Foundation, 1969, pp 485-488. 14. Berzewski H, Helmchen H, Hippius H, et al: Das klinische Wirkungsspektrum eines neuen Dibenzodiazepinderivates W-108/HF-1854: 8-Chlor11-(4'-methyl)-piperazino-5-dibenzo [b,e] [1,4] diazepin . Arzneim Forsch 19:495-496, 1969. 15. Stille G, Ackerman H, Lauener H, et al: The pharmacological properties of a potent neuroleptic compound from the dibenzodiazepine group . Int J Neuropharmacol 4:375-383, 1971.Crossref 16. Stille G, Lauener H, Eichenberger E: The pharmacology of 8-chloro11-(4'-methyl)-piperazino)-5H-dibenzo [b,e] [1,4] diazepine (clozapine) . Farmaco [Prat] 26:603-625, 1971. 17. Ayd FJ: Clozapine: A unique new neuroleptic . Int Drug Ther Newsletter 9:5-12, 1974. 18. Matz R, Rick W, Oh D, et al: Clozapine: A potential antipsychotic agent without extrapyramidal manifestations . Cur Ther Res 7:687-695, 1974. 19. Shopsin B, Pearson E, Gershon Ṣ, et al: A controlled double-blind comparison between loxapine succinate and chlorpromazine in acute newly hospitalized schizophrenic patients . Curr Ther Res 14:739-748, 1972. 20. Clinical Investigators Manual, Clozapine. Hanover, NJ, Pharmaceutical Division Sandoz, Inc, 1976. 21. Angst J, Haenicke U, Padrutt A, et al: Ergebnisse eines Doppelblindversuches von HF-1854 (8-Chlor-11-(4 methyl-l-piperazinyl)-5H-dibeno (b,e) (1,4) diazepine) . Vergleich Levomepromazin Pharmakopsychiat 4:192-200, 1971.Crossref 22. Gross H, Langner E, Pfolz H: Clozapin in der Langzeittherapie der Chronischen Schizophrenie . Arzneim Forsch 24:987-989, 1970. 23. Fisher-Cornelssen K, Ferner U, Steiner H: Multifokale Psychopharmakaprufung . Arzneim Forsch 24:1006-1007, 1974. 24. Nidkanen P, Achte K, Jaskari M, et al: Results of a comparative double-blind study with clozapine and chlorpromazine in the treatment of schizophrenic patients . Eripainos Psychiatria Fennica , 1974, pp 307-313. 25. Gerlach J, Koppelhus P, Helweg E, et al: 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, 1974.Crossref 26. Gerlach J, Munkvad I: Clozapine and haloperidol: Clinical and biochemical aspects in the treatment of schizophrenia . Nor Psykiatr Tidsskr 28:463, 1974.Crossref 27. Gerlach J, Thorsen K, Fog R: Extrapyramidal reactions and amine metabolites in cerebrospinal fluid during haloperidol and clozapine treatment of schizophrenic patients . Psychopharmacologia 40:341-350, 1975.Crossref 28. Klein H, Aronson M, Shopsin B: Clozapine: Double-blind control trial in the treatment of acute schizophrenia . Psychopharmacol Bull 14:12-15, 1978. 29. Hippius H, Klein HE: Summary of the clinical aspects on treatment with clozapine (Leponex). Read before the Leponex Symposium, New York, Sept 30, 1974. 30. Blum AWW: Temperaturanstiege und Bluteiweis-veränderungen unter der Therapie mit Neuroleptika—unter besonderer Berücksichtigung des neuartigen Dibenzodiazepin-Derivates Clozapine (Wander) . Verlag Weiner Med Akad , 1972, pp 113-119. 31. Gram LF: Bone-marrow depression following treatment with clozapine (Leponex) . Vgeskr Laeg 138:1271-1273, 1976. 32. Griffith RW, Saameli K: Clozapine and agranulocytosis . Lancet 4:657, 1975.Crossref 33. Idanpaan-Heikkila J, Alhava E, Olkinuora M: Clozapine and agranulocytosis . Lancet 2:611, 1975.Crossref 34. Leucocytopenias and agranulocytosis during Leponex treatment , in Situation Report . Basel, Switzerland, Sandoz Ltd, 1976. 35. Stille G: Effect of single and repeated administration of clozapine on the metabolism of dopamine and noradrenaline in the brain of the rat . Eur J Pharmacol 27:180-190, 1974.Crossref 36. Miller RJ, Hiley CR: Antimuscarinic properties of neuroleptics and drug-induced parkinsonism . Nature 248:495-497, 1974.Crossref 37. Stadler H, Loyd KG, Bartholini G: Dopaminergic inhibition of striatal cholinergic neurons; Synergistic blocking action of γ-butyrolactone and neuroleptic drugs . Arch Pharmacol Exp Pathol 283:129-134, 1974.Crossref 38. Bartholini G, Haefeli W, Jalfre M, et al: Effects of clozapine on cerebral catecholaminergic neurone systems . Br J Pharmacol 46:736-740, 1972.Crossref 39. Sedvall G, Nybäck H: Effect of clozapine and some other antipsychotic agents on synthesis and turnover of dopamine formed from 14C-tyrosine in mouse brain . Israel U Med Sci J 9:24-30, 1973. 40. Eichenberger E, Sayers AC, White TG: Clozapine and the dopamine hypothesis of schizophrenia: A critical appraisal . Phermakopsychiatr Neuropsychopharmakol 8:115-121, 1975.Crossref 41. Gruen P, Sachar E, Langer G, et al: Prolactin response to neuroleptics in normals and schizophrenics . Arch Gen Psychiatry 35:1222-1227, 1978.Crossref 42. Ackenheil M, Matussek N, Hippius H, et al: Sulpiride and the dopamine hypothesis of schizophrenia. Read before the International Group for the Study of Affective Disorders, Munich, Germany, June 24, 1976.

Journal

Archives of General PsychiatryAmerican Medical Association

Published: Jun 1, 1979

References