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Lack of Behavioral Supersensitivity to d-Amphetamine After Pimozide Withdrawal: A Trial With Schizophrenic Patients

Lack of Behavioral Supersensitivity to d-Amphetamine After Pimozide Withdrawal: A Trial With... Abstract • The dopamine hypothesis of schizophrenia claims that increased dopamine activity underlies psychotic behavior. This hypothesis gets major support from the reported d-amphetamine-induced worsening of psychosis, because amphetamine increases dopamine activity in the brain. Dopamine receptor supersensitivity has been shown to be present in animals during the postneuroleptic period. In this study the postulated relationships between psychotic decompensation as observed after d-amphetamine infusion and the dopamine receptor supersensitivity expected to be present during the neuroleptic withdrawal period were examined. Twenty milligrams of d-amphetamine administered intravenously did not cause a stronger psychotogenic effect in 12 schizophrenic patients. One week after discontinuation of pimozide treatment, the d-amphetamine-induced change as indicated by the Brief Psychiatric Rating Scale (BPRS) paranoid disturbance cluster score, was not significantly different from the response to a similar infusion during the drug-free state. Unexpectedly, the increase in the BPRS mannerisms and posturing item and in the pulse rate response to d-amphetamine were decreased. These results raise questions about the role of dopamine in d-amphetamine effects and suggest postneuroleptic dopamine receptor subsensitivity. They challenge a simple dopamine hypothesis of schizophrenia. References 1. Burt D, Creese I, Snyder SH: Antischizophrenic drugs: Chronic treatment elevates dopamine receptor binding in brain . Science 196:326-328, 1977.Crossref 2. Pert A, Rosenblatt JE, Sivit C, et al: Long-term treatment with lithium prevents the development of dopamine receptor supersensitivity . Science 201:171-173, 1978.Crossref 3. Tarsy D, Baldessarini RJ: Behavioral supersensitivity to apomorphine following chronic treatment with drugs which interfere with the synaptic function of catecholamines . Neuropharmacology 13:927-940, 1974.Crossref 4. Gianutsos G, Moore KE: Dopaminergic supersensitivity in striatum and olfactory tubercle following chronic administration of haloperidol or clozapine . Life Sci 20:1585-1592, 1977.Crossref 5. Klawans HL, Rubovitz H: An experimental model of tardive dyskinesia . J Neural Transm 33:235-246, 1974.Crossref 6. Siggins GR, Hoffer BJ, Ungerstedt U: Electrophysiological evidence for involvement of cyclic adenosine monophosphate in dopamine responses of caudate neurons . Life Sci 15:779-784, 1974.Crossref 7. Gallager DW, Pert A, Bunney WE Jr: Haloperidol-induced presynaptic dopamine supersensitivity is blocked by chronic lithium . Nature 273:309--312, 1978.Crossref 8. Iversen LL: Dopamine receptors in the brain . Science 188:1084-1089, 1974.Crossref 9. Carlsson A: Antipsychotic drugs, neurotransmitters and schizophrenia . Am J Psychiatry 135:164-173, 1978. 10. Snyder SH: The dopamine hypothesis of schizophrenia: Focus on the dopamine receptor . Am J Psychiatry 133:197-202, 1976. 11. Meltzer HY, Stahl SM: The dopamine hypothesis of schizophrenia: A review . Schizophrenia Bull 2:19-76, 1976.Crossref 12. Van Kammen DP: The dopamine hypothesis revisited . Psychoneuroendocrinology 4:37-46, 1979.Crossref 13. Docherty JP, Siris SG, van Kammen DP, et al: Phenothiazine prophylaxis of schizophrenic relapse. Read before the annual meeting of the American Psychiatric Association, 1977. 14. Janowsky DA, Davis JM: Methylphenidate, dextroamphetamine, and levamphetamine . Arch Gen Psychiatry 33:304-308, 1976.Crossref 15. Van Kammen DP, Bunney WE Jr, Docherty JP, et al: Amphetamineinduced catecholamine activation in schizophrenia and depression: Behavioral and physiological effects . Adv Biochem Psychopharmacol 16:655-659, 1977. 16. Kornetsky E: Hyporesponsivity of chronic schizophrenic patients to dextroamphetamine . Arch Gen Psychiatry 33:1425-1428, 1976.Crossref 17. Bischoff A: Über eine therapeutische Verwendung der sogenannten "Weck-Amine" in der Behandlung Schizophrener Erregungszustände . Psychiatr Neurol 121:329-344, 1951.Crossref 18. Hope JM, Callaway E, Sands SL: Intravenous pervitin and the psychopathology of schizophrenia . Dis Nerv Syst 12:67-72, 1951. 19. Pennes HH: Clinical reactions of schizophrenics to sodium amytal, pervitin hydrochloride, mescaline sulphate and d-lysergic acid diethylamide (LSD 25) . J Nerv Ment Dis 119:95-112, 1954.Crossref 20. Kiloh LG, Neilson M, Andrews G: Response of depressed patients to methyl-amphetamine . Br J Psychiatry 125:496-499, 1974.Crossref 21. Pinder RM, Brogden RN, Sawyer PR, et al: Pimozide: A review of its pharmacological properties and therapeutic uses in psychiatry . Drugs 12:1-40, 1976.Crossref 22. Spitzer RL, Endicott J, Robins E: Research Diagnostic Criteria . New York, Biometric Research Unit, New York State Department of Mental Hygiene, New York State Psychiatric Institute, 1975. 23. Carpenter WT, Strauss JS, Bartko JS: Flexible system for the diagnosis of schizophrenia: Report from the WHO International Pilot Study of Schizophrenia . Science 182:1275-1278, 1973.Crossref 24. Bunney WE Jr, Hamburg DA: Methods for reliable longitudinal observation of behavior . Arch Gen Psychiatry 9:280-294, 1963.Crossref 25. Overall JE, Gorham DR: The Brief Psychiatric Rating Scale . Psychol Rep 10:799-812, 1962.Crossref 26. Overall JE, Hollister LE, Pichot P: Major psychiatric disorders: A four-dimensional model . Arch Gen Psychiatry 16:146-151, 1967.Crossref 27. Van Kammen DP, Marder SR, Murphy DL, et al: MAO activity, CSF amine metabolites and drug-free improvement in schizophrenia . Am J Psychiatry 135:567-569, 1978. 28. Marder SR, van Kammen DP, Docherty JP, et al: Predicting drugfree improvement in schizophrenic psychosis . Arch Gen Psychiatry 36:1080-1085, 1979.Crossref 29. Clow A, Jenner P, Theodoron A, et al: Striatal dopamine receptors become supersensitive while rats are given trifluoperizine for six months . Nature 278:59-60, 1979.Crossref 30. Wechsler LR, Savaki HE, Sokoloff L: Effects of d- and l-amphetamine on local cerebral glucose utilization in the conscious rat . J Neurochem 22:15-22, 1979.Crossref 31. Kebabian F: Multiple classes of dopamine receptors in mammalian central nervous system: The involvement of dopamine sensitive adenylyl cyclase . Life Sci 23:479-484, 1978.Crossref 32. Creese I, Usdin T, Snyder SH: Guanine nucleotides distinguish between two dopamine receptors . Nature 278:577-578, 1979.Crossref 33. Moore KE, Thornburg JE: Drug-induced dopaminergic supersensitivity , in Calne DB, Chase TH, Barbeau A (eds): Dopaminergic Mechanisms , vol 9. Advances in Neurology, New York, Raven Press, 1975, pp 93-104. 34. Siris SG, van Kammen DP, DeFraites EG, et al: Serum prolactin and antipsychotic responses to pimozide in schizophrenia . Psychopharmacol Bull 14:11-14, 1978. 35. Seeman P, Lee T, Chan-Wong M, et al: Antipsychotic drug doses and neuroleptic/dopamine receptors . Nature 261:717-718, 1976.Crossref 36. Creese I, Burt DR, Snyder SH: Dopamine receptor binding predicts clinical potential and pharmacological potencies of antischizophrenic drugs . Science 192:481-483, 1976.Crossref 37. Alpert M, Friedhoff AJ: Clinical trials of dopamine receptor sensitivity modification , in Usdin E, Kopin IJ, Barchas J (eds): Catecholamines: Basic and Clinical Frontiers . New York, Pergamon Press, 1979, vol 2, pp 1590-1592. 38. Angrist BM, Sathananthan GS, Gershon S: Behavioral effects of l-dopa in schizophrenic patients . Psychopharmacologia 31:1-12, 1973.Crossref 39. Gerlach J, Lühdorf K: The effect of 1-dopa on young patients with simple schizophrenia, treated with neuroleptic drugs: A double-blind crossover trial with madopar and placebo . Psychopharmacologia 44:105-110, 1975.Crossref 40. Crow TJ, Johnstone EC, McClelland HA: The coincidence of schizophrenia and Parkinsonism: Some neurochemical implications . Psychol Med 6:227-233, 1976.Crossref 41. DeFraites EG, Davis KL, Berger PA: Coexisting tardive dyskinesia and Parkinsonism: A case report . Biol Psychiatry 12:267-272, 1977. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of General Psychiatry American Medical Association

Lack of Behavioral Supersensitivity to d-Amphetamine After Pimozide Withdrawal: A Trial With Schizophrenic Patients

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Publisher
American Medical Association
Copyright
Copyright © 1980 American Medical Association. All Rights Reserved.
ISSN
0003-990X
eISSN
1598-3636
DOI
10.1001/archpsyc.1980.01780160057006
Publisher site
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Abstract

Abstract • The dopamine hypothesis of schizophrenia claims that increased dopamine activity underlies psychotic behavior. This hypothesis gets major support from the reported d-amphetamine-induced worsening of psychosis, because amphetamine increases dopamine activity in the brain. Dopamine receptor supersensitivity has been shown to be present in animals during the postneuroleptic period. In this study the postulated relationships between psychotic decompensation as observed after d-amphetamine infusion and the dopamine receptor supersensitivity expected to be present during the neuroleptic withdrawal period were examined. Twenty milligrams of d-amphetamine administered intravenously did not cause a stronger psychotogenic effect in 12 schizophrenic patients. One week after discontinuation of pimozide treatment, the d-amphetamine-induced change as indicated by the Brief Psychiatric Rating Scale (BPRS) paranoid disturbance cluster score, was not significantly different from the response to a similar infusion during the drug-free state. Unexpectedly, the increase in the BPRS mannerisms and posturing item and in the pulse rate response to d-amphetamine were decreased. These results raise questions about the role of dopamine in d-amphetamine effects and suggest postneuroleptic dopamine receptor subsensitivity. They challenge a simple dopamine hypothesis of schizophrenia. References 1. Burt D, Creese I, Snyder SH: Antischizophrenic drugs: Chronic treatment elevates dopamine receptor binding in brain . Science 196:326-328, 1977.Crossref 2. Pert A, Rosenblatt JE, Sivit C, et al: Long-term treatment with lithium prevents the development of dopamine receptor supersensitivity . Science 201:171-173, 1978.Crossref 3. Tarsy D, Baldessarini RJ: Behavioral supersensitivity to apomorphine following chronic treatment with drugs which interfere with the synaptic function of catecholamines . Neuropharmacology 13:927-940, 1974.Crossref 4. Gianutsos G, Moore KE: Dopaminergic supersensitivity in striatum and olfactory tubercle following chronic administration of haloperidol or clozapine . Life Sci 20:1585-1592, 1977.Crossref 5. Klawans HL, Rubovitz H: An experimental model of tardive dyskinesia . J Neural Transm 33:235-246, 1974.Crossref 6. Siggins GR, Hoffer BJ, Ungerstedt U: Electrophysiological evidence for involvement of cyclic adenosine monophosphate in dopamine responses of caudate neurons . Life Sci 15:779-784, 1974.Crossref 7. Gallager DW, Pert A, Bunney WE Jr: Haloperidol-induced presynaptic dopamine supersensitivity is blocked by chronic lithium . Nature 273:309--312, 1978.Crossref 8. Iversen LL: Dopamine receptors in the brain . Science 188:1084-1089, 1974.Crossref 9. Carlsson A: Antipsychotic drugs, neurotransmitters and schizophrenia . Am J Psychiatry 135:164-173, 1978. 10. Snyder SH: The dopamine hypothesis of schizophrenia: Focus on the dopamine receptor . Am J Psychiatry 133:197-202, 1976. 11. Meltzer HY, Stahl SM: The dopamine hypothesis of schizophrenia: A review . Schizophrenia Bull 2:19-76, 1976.Crossref 12. Van Kammen DP: The dopamine hypothesis revisited . Psychoneuroendocrinology 4:37-46, 1979.Crossref 13. Docherty JP, Siris SG, van Kammen DP, et al: Phenothiazine prophylaxis of schizophrenic relapse. Read before the annual meeting of the American Psychiatric Association, 1977. 14. Janowsky DA, Davis JM: Methylphenidate, dextroamphetamine, and levamphetamine . Arch Gen Psychiatry 33:304-308, 1976.Crossref 15. Van Kammen DP, Bunney WE Jr, Docherty JP, et al: Amphetamineinduced catecholamine activation in schizophrenia and depression: Behavioral and physiological effects . Adv Biochem Psychopharmacol 16:655-659, 1977. 16. Kornetsky E: Hyporesponsivity of chronic schizophrenic patients to dextroamphetamine . Arch Gen Psychiatry 33:1425-1428, 1976.Crossref 17. Bischoff A: Über eine therapeutische Verwendung der sogenannten "Weck-Amine" in der Behandlung Schizophrener Erregungszustände . Psychiatr Neurol 121:329-344, 1951.Crossref 18. Hope JM, Callaway E, Sands SL: Intravenous pervitin and the psychopathology of schizophrenia . Dis Nerv Syst 12:67-72, 1951. 19. Pennes HH: Clinical reactions of schizophrenics to sodium amytal, pervitin hydrochloride, mescaline sulphate and d-lysergic acid diethylamide (LSD 25) . J Nerv Ment Dis 119:95-112, 1954.Crossref 20. Kiloh LG, Neilson M, Andrews G: Response of depressed patients to methyl-amphetamine . Br J Psychiatry 125:496-499, 1974.Crossref 21. Pinder RM, Brogden RN, Sawyer PR, et al: Pimozide: A review of its pharmacological properties and therapeutic uses in psychiatry . Drugs 12:1-40, 1976.Crossref 22. Spitzer RL, Endicott J, Robins E: Research Diagnostic Criteria . New York, Biometric Research Unit, New York State Department of Mental Hygiene, New York State Psychiatric Institute, 1975. 23. Carpenter WT, Strauss JS, Bartko JS: Flexible system for the diagnosis of schizophrenia: Report from the WHO International Pilot Study of Schizophrenia . Science 182:1275-1278, 1973.Crossref 24. Bunney WE Jr, Hamburg DA: Methods for reliable longitudinal observation of behavior . Arch Gen Psychiatry 9:280-294, 1963.Crossref 25. Overall JE, Gorham DR: The Brief Psychiatric Rating Scale . Psychol Rep 10:799-812, 1962.Crossref 26. Overall JE, Hollister LE, Pichot P: Major psychiatric disorders: A four-dimensional model . Arch Gen Psychiatry 16:146-151, 1967.Crossref 27. Van Kammen DP, Marder SR, Murphy DL, et al: MAO activity, CSF amine metabolites and drug-free improvement in schizophrenia . Am J Psychiatry 135:567-569, 1978. 28. Marder SR, van Kammen DP, Docherty JP, et al: Predicting drugfree improvement in schizophrenic psychosis . Arch Gen Psychiatry 36:1080-1085, 1979.Crossref 29. Clow A, Jenner P, Theodoron A, et al: Striatal dopamine receptors become supersensitive while rats are given trifluoperizine for six months . Nature 278:59-60, 1979.Crossref 30. Wechsler LR, Savaki HE, Sokoloff L: Effects of d- and l-amphetamine on local cerebral glucose utilization in the conscious rat . J Neurochem 22:15-22, 1979.Crossref 31. Kebabian F: Multiple classes of dopamine receptors in mammalian central nervous system: The involvement of dopamine sensitive adenylyl cyclase . Life Sci 23:479-484, 1978.Crossref 32. Creese I, Usdin T, Snyder SH: Guanine nucleotides distinguish between two dopamine receptors . Nature 278:577-578, 1979.Crossref 33. Moore KE, Thornburg JE: Drug-induced dopaminergic supersensitivity , in Calne DB, Chase TH, Barbeau A (eds): Dopaminergic Mechanisms , vol 9. Advances in Neurology, New York, Raven Press, 1975, pp 93-104. 34. Siris SG, van Kammen DP, DeFraites EG, et al: Serum prolactin and antipsychotic responses to pimozide in schizophrenia . Psychopharmacol Bull 14:11-14, 1978. 35. Seeman P, Lee T, Chan-Wong M, et al: Antipsychotic drug doses and neuroleptic/dopamine receptors . Nature 261:717-718, 1976.Crossref 36. Creese I, Burt DR, Snyder SH: Dopamine receptor binding predicts clinical potential and pharmacological potencies of antischizophrenic drugs . Science 192:481-483, 1976.Crossref 37. Alpert M, Friedhoff AJ: Clinical trials of dopamine receptor sensitivity modification , in Usdin E, Kopin IJ, Barchas J (eds): Catecholamines: Basic and Clinical Frontiers . New York, Pergamon Press, 1979, vol 2, pp 1590-1592. 38. Angrist BM, Sathananthan GS, Gershon S: Behavioral effects of l-dopa in schizophrenic patients . Psychopharmacologia 31:1-12, 1973.Crossref 39. Gerlach J, Lühdorf K: The effect of 1-dopa on young patients with simple schizophrenia, treated with neuroleptic drugs: A double-blind crossover trial with madopar and placebo . Psychopharmacologia 44:105-110, 1975.Crossref 40. Crow TJ, Johnstone EC, McClelland HA: The coincidence of schizophrenia and Parkinsonism: Some neurochemical implications . Psychol Med 6:227-233, 1976.Crossref 41. DeFraites EG, Davis KL, Berger PA: Coexisting tardive dyskinesia and Parkinsonism: A case report . Biol Psychiatry 12:267-272, 1977.

Journal

Archives of General PsychiatryAmerican Medical Association

Published: Mar 1, 1980

References

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