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Metoclopramide-associated tardive dyskinesia in hemodialysis patients with diabetes mellitus
Metoclopramide-Associated Tardive Dyskinesia Hemodialysis Patients with Diabetes Mellitus
in
Two Case Reports Daniel D. Sewell, M.D., Blain H. Yoshinobu, Pharm.D., Michael P. Caligiuri, Ph.D., and Dilip V. Jeste, M.D.
Abstract: Metoclopramide, a drug used almost exclusively for medical indications, is a dopamine (D-2) receptor blocker and has been reported to cause extrapyramidal side effects. We present two case reports of hemodialysis patients who were treated with metoclopramide for diabetic gastroparesis. Within 12 months of beginning treatment, both patients developed persistent tardive dyskinesia. These cases highlight the fact that some patients who benefit from metoclopramide may also have a relatively high risk of developing persistent tardive dyskinesia. The consultation-liaison psychiatrist can play an important role in the education of the medical staff regarding metoclopramideinduced tardive dyskinesia.
Introduction The association between the development of tardive dyskinesia (TD) and exposure to the traditional antipsychotics is now widely recognized [l]. Among the factors that combine to make TD a very serious problem are 1) its tendency to persist in a large proportion of patients even after neuroleptics have been discontinued [2], 2) the lack of any wellestablished, effective treatment [3], and 3) the increasing number of patients with TD who are ini-
From the Universitv of California, San Diego and the San Diego VA Medical Cenier (DDS, MPC, DVJ); and the San Diego VA Medical Center (BHY). San Diego. California. This work was presented in pari at the annual meeting of the American Association for Geriatric Psychiatry in February 1992, in San Francisco, California. Address reprint requests to: Daniel D. Sewell, M.D., Psychiatry Service (V-116A), San Diego VA Medical Center, 3350 La Jolla Village Drive, San Diego, CA 92161.
416 ISSN 0163-8343/92/$5.00
tiating malpractice suits against clinicians and hospitals [2]. For some time, TD has been viewed as an iatrogenie disorder almost exclusively restricted to the field of neuropsychiatry. Although the published literature, which we have reviewed elsewhere [4], has contained a few case reports of TD associated with metoclopramide (MCI’) given for medical indications [5-lo], few of these cases were detected prospectively and therefore the exact chronology of exposure to MCI’ and the subsequent development of TD was generally not possible to determine. IMS America, a principal source of information used in drug marketing and sales management, estimates that 5,162,OOO prescriptions for MCI’ were dispensed in the United States during 1990. The proportion of MCI’ prescriptions written by physicians in various specialty areas was as follows: family practice (28%); internal medicine (26.8%), general practice (10.8%), gastroenterology (7.6%), and other specialties (26.8%). Just as psychiatrists were initially slow to recognize and diagnose TD during the period following the first description of TD, physicians outside of the psychiatric field may be somewhat less likely to recognize TD, especially when it is mild. Consultation-liaison psychiatrists are well-suited to educate nonpsychiatrist physicians about TD and to assist in the detection of MCI’-associated TD. We present two new case reports of patients who developed persistent TD after approximately 1 year of treatment with MCI’. We followed the patients prospectively from before they had signs of TD until months after the diagnosis of TD was General Hospital Psychiatry 14, 416-419, 1992 0 1992 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010
Metoclopramide-Associated
made. Standard criteria for diagnosing TD [ll] as well as rating scales such as the Abnormal Involuntary Movement Scale (AIMS) [12], and Simpson Angus’ scale for parkinsonism [13] were employed.
Case Reports Case 1 Mr. A was a 60-year-old black man who retired at age 40 because of heart disease. He had no history of psychiatric illness or of treatment with neuroleptics or other psychotropic drugs. He had a long history of hypertension and insulin-dependent diabetes mellitus complicated by retinopathy, neuropathy, and nephropathy. Four months prior to his first visit with us, Mr. A was placed on hemodialysis. He was later diagnosed with diabetic gastroparesis and was started on MCI’ 10 mg with meals. He obtained a good response from MCI’. At the time of his first visit, one of the authors (D.S.) examined Mr. A as part of a study of MCP-induced side effects, and found that the patient exhibited no dyskinesia but had a moderate loss of facial expression, mild bilateral rigidity, mild parkinsonian gait and posture, and moderate bradykinesia but no tremor. Over the next 5 months the dose of MCI’ was increased to 30 mg daily and then to 45 mg daily. A month later, he was evaluated again by D.S. Mr. A exhibited questionable choreoathetoid movements of lips, perioral area, and jaw, along with a mild loss of facial expression, minimal rigidity, mild parkinsonian gait and posture, and mild bradykinesia. At this time, Mr. A did not meet the Schooler and Kane [ll] criteria for TD. Six months later, Mr. A displayed moderately severe choreoathetoid movements of his lips, perioral area, and jaw; mild loss of facial expression; mild rigidity; minimal parkinsonian gait and posture; and minimal bradykinesia. Conditions in the differential diagnosis of TD, such as hyperthyroidism, were ruled out by physical (including neurological) examination and appropriate laboratory tests (e.g., thyroid function tests), and TD was diagnosed. After consultation with his internist, Mr. A agreed to discontinue treatment with MCP. At the time of his last visit, his TD signs had remained unchanged for 18 months.
Case 2 Mr. B was a 42-year-old black man who obtained a medical retirement at age 41 due to severe respiratory failure, secondary to interstitial pneumonitis and cardiomyopathy. He also had a 7-year history of hypertension and insulin-deaendent diabetes mellitus; there was no history of psychiatric disorders or treatI
ment with neuroleptics. One month prior to his first visit with us, he was hospitalized and started on hemodialysis.
He was later diagnosed as having diabetic
Tardive Dyskinesia
gastroparesis and treated with MCI’ 10 mg intravenous push bolus (IVPB) every 6 hours. Mr. B responded well to MCI’. At his first visit, D.S. examined Mr. B and found that he exhibited no dyskinesia but had mild parkinsonism with a loss of facial expression, bilateral rigidity, parkinsonian gait and posture, bradykinesia, but no tremor. One week later, his treatment was changed from IVPB to oral MCI’ 30 mg daily, and 3 months later, to 40 mg daily. One year after beginning treatment with MCI’, he was evaluated again by D.S. He exhibited moderately severe choreoathetoid movements of the tongue, along with a moderate loss of facial expression, mild bilateral rigidity, minimal parkinsonian gait and posture, and moderate bradykinesia. Conditions in the differential diagnosis of TD were again ruled out by careful physical examination and appropriate laboratory tests, and TD was diagnosed. After consultation with his internist, Mr. B decided to continue treatment with MCI’. He was last seen 3 months later and his TD appeared unchanged as did his overall medical condition.
Discussion Although the pharmacology of MCI’ is complex and not yet completely understood, it has been shown that MCI’ is a dopamine receptor blocker which may act as an antipsychotic when doses in the 500-1000 mg range are used [14]. It has also been shown that MCP crosses the blood-brain barrier and enters the Central Nervous System in animals, with high concentrations in the area postrema, which contains the chemoreceptor trigger zones [15]. MCI’ has been reported to cause various extrapyramidal side effects (EKE), however, the reported frequency of these side effects varies widely [11,16,17]. Our case reports provide support for the reported causal relationship between MCI’ exposure and the development of TD [4,5]. In addition, our cases highlight several potential risk factors for TD. First of all, both of the patients were noted to have parkinsonism shortly after beginning treatment with MCI’. Saltz et al. [18] recently reported that patients with parkinsonian signs (secondary to neuroleptic therapy as well as secondary to other causes) developed TD at a faster rate. Secondly, both of our patients had diabetes mellitus which has been suggested to be a risk factor for TD [19]. Lastly, they both had renal disease and were on hemodialysis. Interestingly, hemodialysis does not appear to remove MCI’ from the body, and MCI’ clearance subsequent to dialysis is un417
D. D. Sewell et al.
altered [20,21]. The elimination half-life of MCP has been reported to be 2.6-5 hours in healthy individuals but approximately 14 hours in patients with moderate to severe renal impairment [22]. Although MCI’ is not extensively bound to plasma protein [23], in normal healthy individuals, the proportion of MCI’ that does bind to protein (approximately 30%) is primarily bound to plasma albumin [24]. In patients with renal disease, plasma albumin concentration is reduced. According to Lehman et al. [21], MCI’ clearance may depend upon renal catabolism. Patients with advanced renal failure have little renal mass and, therefore, would have greatly reduced renal catabolism of MCI’, leading to a prolonged half-life of MCI’ in these patients. This may be responsible for the heightened risk of MCI’-induced persistent TD in patients with renal failure. Given the possibility that MCP-associated TD may be persistent and given that there are currently no well-established, effective treatments for TD, consultation-liaison psychiatrists should maintain a high degree of vigilance for TD when consulting on a patient whose medication regimen includes MCP. This vigilance is especially important when evaluating elderly patients with parkinsonian features, diabetes mellitus, or renal impairment. The psychiatrist should recommend using starting doses of MCP that are one-half to one-quarter of those given to healthy, young adults. Patients may be taught to take MCP approximately 30-60 minutes before a meal or before sleep in order to achieve maximum benefit while using the smallest possible dose. Lastly, a substitute for MCI’ may be suggested, such as ondansetron hydrochloride (Zofran), a new antiemetic agent whose mechanism of action is believed to be antagonism of serotonin (rather than dopamine) receptors in the chemoreceptor trigger zone and the GI tract [25]. This work was supported, in part, by NlMH Grant #IROlMH45131 and by the Department of Veterans Affairs. We also wa?lt to thank IMS America for prozpiding us with information about metoclopramide prescriptions.
References 1. Jeste DV, Wyatt RJ: Changing epidemiology of tardive dyskinesia-an overview. Am J Psychiatry 138:297-309, 1981 2. Kane JM, Jeste DV, Barnes TRE, et al: Tardive Dyskinesia: A Task Force Report of the American Psychiatric Association. Washington, DC, American Psychiatric Association, 1992
418
3. Jeste DV, Lohr JB, Clark K, Wyatt RJ: Pharmacologic treatment of tardive dyskinesia in the 1980s. J Clin Psychopharmacol8(4 Suppl):38S-48S, 1988 4. Sewell DD, Jeste DV: Metoclopramide-associated tardive dyskinesia: An analysis of 67 cases. Arch Fam Med (in press) 5. Lazzara RR, Stoudemire A, Manning D, Prewitt KC: Metoclopramide-induced tardive dyskinesia: A case report. Gen Hosp Psychiatry 8:107-109, 1986 6. Miller LG, Jankovic J: Metoclopramide-induced movement disorders: clinical findings with a review of the literature. Arch Intern Med 149:2486-2492, 1989 7. Samie MR, Dannenhoffer MA, Rozek S: Lifethreatening tardive dyskinesia caused by metoclopramide. Mov Disord 2:125-129, 1987 8. Bateman DN, Rawlins MD, Simpson JM: Extrapyramidal reactions with metoclopramide. Br Med J 291: 930-932, 1985 9. Grimes JD, Hassan MN, Preston DN: Adverse neurologic effects of metoclopramide. Can Med J 126:2325, 1982 10. Orme ML, Tallis RC: Metoclopramide and tardive dyskinesia in the elderly. Br Med J 289:397-398,1984 11. Schooler NR, Kane JM: Research diagnoses for tardive dyskinesia. Arch Gen Psychiatry 39:488-489, 1982 12. National Institute of Mental Health Psychopharmacology Research Branch: Abnormal Involuntary Movement Scale. ECDEU Intercom 4:3-6, 1975 13. Simpson GM, Angus JWS: A rating scale for extrapyramidal side effects. Acta Psychiatr Stand [Suppl] 212:11-19, 1970 14. Stanley M, Lautin A, Rotrosen J, Gershon S, Kleinberg D: Metoclopramide: Antipsychotic efficacy of a drug lacking potency in receptor models. Psychopharmacology 71:219-225, 1980 15. McEvoy GK: AHFS Drug Information. Bethesda, MD, American Society of Hospital Pharmacists, 1991, p 1767 16. Borenstein PP, Bles G: Effets cliniques et electroencephalo-graphiques du metoclopramide en psychiatrie. Therapie 20:975-995, 1965 17. Borda IT: Drug treatment of gastrointestinal disorders. In Swift CG (ed), Clinical Pharmacology in the Elderly. New York, Marcel Dekker, 1987, pp 529579 18. Saltz BL, Woerner MG, Kane JM, et al: Prospective study of tardive dyskinesia incidence in the elderly. JAMA 266:2402-2406, 1991 19. Ganzini L, Heintz RT, Hoffman WF, Casey DE: The prevalence of tardive dyskinesia in neuroleptictreated diabetics. Arch Gen Psychiatry 48:259-263, 1991 20. Wright MR, Axelson JE, Rurak, et al: Effects of haemodialysis on metoclopramide kinetics in patients with severe renal failure. Br J Clin Pharmacol26:474477, 1988 21. Lehman CR, Heironimus JD, Collins CB, et al: Metoclopramide kinetics in patients with impaired renal function and clearance by hemodialysis. Clin Pharmacol Ther 37:284-289, 1985 22. Harrington RA, Hamilton CW, Brogden RN, et al:
Metoclopramide-Associated
Metoclopramide: An updated review of its pharmacologic properties and clinical use. Drug Evaluations 25:451-494, 1983 23. Physicians’ Desk Reference, 46th ed. New Jersey, Medical Economics Company, 1991, p 1870 24. Webb D, Buss DC, Fifield R, Bateman DN, Routledge
Tardive Dyskinesia
PA: The plasma protein binding of metoclopramide in health and renal disease. Br J Clin Pharmacol 21:334-336, 1986 25. Chaffee BJ, Tankanow RM: Ondansetron-The first of a new class of antiemetic agents. Clin Pharmacol 10:430-446, 1991
419
in
Two Case Reports Daniel D. Sewell, M.D., Blain H. Yoshinobu, Pharm.D., Michael P. Caligiuri, Ph.D., and Dilip V. Jeste, M.D.
Abstract: Metoclopramide, a drug used almost exclusively for medical indications, is a dopamine (D-2) receptor blocker and has been reported to cause extrapyramidal side effects. We present two case reports of hemodialysis patients who were treated with metoclopramide for diabetic gastroparesis. Within 12 months of beginning treatment, both patients developed persistent tardive dyskinesia. These cases highlight the fact that some patients who benefit from metoclopramide may also have a relatively high risk of developing persistent tardive dyskinesia. The consultation-liaison psychiatrist can play an important role in the education of the medical staff regarding metoclopramideinduced tardive dyskinesia.
Introduction The association between the development of tardive dyskinesia (TD) and exposure to the traditional antipsychotics is now widely recognized [l]. Among the factors that combine to make TD a very serious problem are 1) its tendency to persist in a large proportion of patients even after neuroleptics have been discontinued [2], 2) the lack of any wellestablished, effective treatment [3], and 3) the increasing number of patients with TD who are ini-
From the Universitv of California, San Diego and the San Diego VA Medical Cenier (DDS, MPC, DVJ); and the San Diego VA Medical Center (BHY). San Diego. California. This work was presented in pari at the annual meeting of the American Association for Geriatric Psychiatry in February 1992, in San Francisco, California. Address reprint requests to: Daniel D. Sewell, M.D., Psychiatry Service (V-116A), San Diego VA Medical Center, 3350 La Jolla Village Drive, San Diego, CA 92161.
416 ISSN 0163-8343/92/$5.00
tiating malpractice suits against clinicians and hospitals [2]. For some time, TD has been viewed as an iatrogenie disorder almost exclusively restricted to the field of neuropsychiatry. Although the published literature, which we have reviewed elsewhere [4], has contained a few case reports of TD associated with metoclopramide (MCI’) given for medical indications [5-lo], few of these cases were detected prospectively and therefore the exact chronology of exposure to MCI’ and the subsequent development of TD was generally not possible to determine. IMS America, a principal source of information used in drug marketing and sales management, estimates that 5,162,OOO prescriptions for MCI’ were dispensed in the United States during 1990. The proportion of MCI’ prescriptions written by physicians in various specialty areas was as follows: family practice (28%); internal medicine (26.8%), general practice (10.8%), gastroenterology (7.6%), and other specialties (26.8%). Just as psychiatrists were initially slow to recognize and diagnose TD during the period following the first description of TD, physicians outside of the psychiatric field may be somewhat less likely to recognize TD, especially when it is mild. Consultation-liaison psychiatrists are well-suited to educate nonpsychiatrist physicians about TD and to assist in the detection of MCI’-associated TD. We present two new case reports of patients who developed persistent TD after approximately 1 year of treatment with MCI’. We followed the patients prospectively from before they had signs of TD until months after the diagnosis of TD was General Hospital Psychiatry 14, 416-419, 1992 0 1992 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010
Metoclopramide-Associated
made. Standard criteria for diagnosing TD [ll] as well as rating scales such as the Abnormal Involuntary Movement Scale (AIMS) [12], and Simpson Angus’ scale for parkinsonism [13] were employed.
Case Reports Case 1 Mr. A was a 60-year-old black man who retired at age 40 because of heart disease. He had no history of psychiatric illness or of treatment with neuroleptics or other psychotropic drugs. He had a long history of hypertension and insulin-dependent diabetes mellitus complicated by retinopathy, neuropathy, and nephropathy. Four months prior to his first visit with us, Mr. A was placed on hemodialysis. He was later diagnosed with diabetic gastroparesis and was started on MCI’ 10 mg with meals. He obtained a good response from MCI’. At the time of his first visit, one of the authors (D.S.) examined Mr. A as part of a study of MCP-induced side effects, and found that the patient exhibited no dyskinesia but had a moderate loss of facial expression, mild bilateral rigidity, mild parkinsonian gait and posture, and moderate bradykinesia but no tremor. Over the next 5 months the dose of MCI’ was increased to 30 mg daily and then to 45 mg daily. A month later, he was evaluated again by D.S. Mr. A exhibited questionable choreoathetoid movements of lips, perioral area, and jaw, along with a mild loss of facial expression, minimal rigidity, mild parkinsonian gait and posture, and mild bradykinesia. At this time, Mr. A did not meet the Schooler and Kane [ll] criteria for TD. Six months later, Mr. A displayed moderately severe choreoathetoid movements of his lips, perioral area, and jaw; mild loss of facial expression; mild rigidity; minimal parkinsonian gait and posture; and minimal bradykinesia. Conditions in the differential diagnosis of TD, such as hyperthyroidism, were ruled out by physical (including neurological) examination and appropriate laboratory tests (e.g., thyroid function tests), and TD was diagnosed. After consultation with his internist, Mr. A agreed to discontinue treatment with MCP. At the time of his last visit, his TD signs had remained unchanged for 18 months.
Case 2 Mr. B was a 42-year-old black man who obtained a medical retirement at age 41 due to severe respiratory failure, secondary to interstitial pneumonitis and cardiomyopathy. He also had a 7-year history of hypertension and insulin-deaendent diabetes mellitus; there was no history of psychiatric disorders or treatI
ment with neuroleptics. One month prior to his first visit with us, he was hospitalized and started on hemodialysis.
He was later diagnosed as having diabetic
Tardive Dyskinesia
gastroparesis and treated with MCI’ 10 mg intravenous push bolus (IVPB) every 6 hours. Mr. B responded well to MCI’. At his first visit, D.S. examined Mr. B and found that he exhibited no dyskinesia but had mild parkinsonism with a loss of facial expression, bilateral rigidity, parkinsonian gait and posture, bradykinesia, but no tremor. One week later, his treatment was changed from IVPB to oral MCI’ 30 mg daily, and 3 months later, to 40 mg daily. One year after beginning treatment with MCI’, he was evaluated again by D.S. He exhibited moderately severe choreoathetoid movements of the tongue, along with a moderate loss of facial expression, mild bilateral rigidity, minimal parkinsonian gait and posture, and moderate bradykinesia. Conditions in the differential diagnosis of TD were again ruled out by careful physical examination and appropriate laboratory tests, and TD was diagnosed. After consultation with his internist, Mr. B decided to continue treatment with MCI’. He was last seen 3 months later and his TD appeared unchanged as did his overall medical condition.
Discussion Although the pharmacology of MCI’ is complex and not yet completely understood, it has been shown that MCI’ is a dopamine receptor blocker which may act as an antipsychotic when doses in the 500-1000 mg range are used [14]. It has also been shown that MCP crosses the blood-brain barrier and enters the Central Nervous System in animals, with high concentrations in the area postrema, which contains the chemoreceptor trigger zones [15]. MCI’ has been reported to cause various extrapyramidal side effects (EKE), however, the reported frequency of these side effects varies widely [11,16,17]. Our case reports provide support for the reported causal relationship between MCI’ exposure and the development of TD [4,5]. In addition, our cases highlight several potential risk factors for TD. First of all, both of the patients were noted to have parkinsonism shortly after beginning treatment with MCI’. Saltz et al. [18] recently reported that patients with parkinsonian signs (secondary to neuroleptic therapy as well as secondary to other causes) developed TD at a faster rate. Secondly, both of our patients had diabetes mellitus which has been suggested to be a risk factor for TD [19]. Lastly, they both had renal disease and were on hemodialysis. Interestingly, hemodialysis does not appear to remove MCI’ from the body, and MCI’ clearance subsequent to dialysis is un417
D. D. Sewell et al.
altered [20,21]. The elimination half-life of MCP has been reported to be 2.6-5 hours in healthy individuals but approximately 14 hours in patients with moderate to severe renal impairment [22]. Although MCI’ is not extensively bound to plasma protein [23], in normal healthy individuals, the proportion of MCI’ that does bind to protein (approximately 30%) is primarily bound to plasma albumin [24]. In patients with renal disease, plasma albumin concentration is reduced. According to Lehman et al. [21], MCI’ clearance may depend upon renal catabolism. Patients with advanced renal failure have little renal mass and, therefore, would have greatly reduced renal catabolism of MCI’, leading to a prolonged half-life of MCI’ in these patients. This may be responsible for the heightened risk of MCI’-induced persistent TD in patients with renal failure. Given the possibility that MCP-associated TD may be persistent and given that there are currently no well-established, effective treatments for TD, consultation-liaison psychiatrists should maintain a high degree of vigilance for TD when consulting on a patient whose medication regimen includes MCP. This vigilance is especially important when evaluating elderly patients with parkinsonian features, diabetes mellitus, or renal impairment. The psychiatrist should recommend using starting doses of MCP that are one-half to one-quarter of those given to healthy, young adults. Patients may be taught to take MCP approximately 30-60 minutes before a meal or before sleep in order to achieve maximum benefit while using the smallest possible dose. Lastly, a substitute for MCI’ may be suggested, such as ondansetron hydrochloride (Zofran), a new antiemetic agent whose mechanism of action is believed to be antagonism of serotonin (rather than dopamine) receptors in the chemoreceptor trigger zone and the GI tract [25]. This work was supported, in part, by NlMH Grant #IROlMH45131 and by the Department of Veterans Affairs. We also wa?lt to thank IMS America for prozpiding us with information about metoclopramide prescriptions.
References 1. Jeste DV, Wyatt RJ: Changing epidemiology of tardive dyskinesia-an overview. Am J Psychiatry 138:297-309, 1981 2. Kane JM, Jeste DV, Barnes TRE, et al: Tardive Dyskinesia: A Task Force Report of the American Psychiatric Association. Washington, DC, American Psychiatric Association, 1992
418
3. Jeste DV, Lohr JB, Clark K, Wyatt RJ: Pharmacologic treatment of tardive dyskinesia in the 1980s. J Clin Psychopharmacol8(4 Suppl):38S-48S, 1988 4. Sewell DD, Jeste DV: Metoclopramide-associated tardive dyskinesia: An analysis of 67 cases. Arch Fam Med (in press) 5. Lazzara RR, Stoudemire A, Manning D, Prewitt KC: Metoclopramide-induced tardive dyskinesia: A case report. Gen Hosp Psychiatry 8:107-109, 1986 6. Miller LG, Jankovic J: Metoclopramide-induced movement disorders: clinical findings with a review of the literature. Arch Intern Med 149:2486-2492, 1989 7. Samie MR, Dannenhoffer MA, Rozek S: Lifethreatening tardive dyskinesia caused by metoclopramide. Mov Disord 2:125-129, 1987 8. Bateman DN, Rawlins MD, Simpson JM: Extrapyramidal reactions with metoclopramide. Br Med J 291: 930-932, 1985 9. Grimes JD, Hassan MN, Preston DN: Adverse neurologic effects of metoclopramide. Can Med J 126:2325, 1982 10. Orme ML, Tallis RC: Metoclopramide and tardive dyskinesia in the elderly. Br Med J 289:397-398,1984 11. Schooler NR, Kane JM: Research diagnoses for tardive dyskinesia. Arch Gen Psychiatry 39:488-489, 1982 12. National Institute of Mental Health Psychopharmacology Research Branch: Abnormal Involuntary Movement Scale. ECDEU Intercom 4:3-6, 1975 13. Simpson GM, Angus JWS: A rating scale for extrapyramidal side effects. Acta Psychiatr Stand [Suppl] 212:11-19, 1970 14. Stanley M, Lautin A, Rotrosen J, Gershon S, Kleinberg D: Metoclopramide: Antipsychotic efficacy of a drug lacking potency in receptor models. Psychopharmacology 71:219-225, 1980 15. McEvoy GK: AHFS Drug Information. Bethesda, MD, American Society of Hospital Pharmacists, 1991, p 1767 16. Borenstein PP, Bles G: Effets cliniques et electroencephalo-graphiques du metoclopramide en psychiatrie. Therapie 20:975-995, 1965 17. Borda IT: Drug treatment of gastrointestinal disorders. In Swift CG (ed), Clinical Pharmacology in the Elderly. New York, Marcel Dekker, 1987, pp 529579 18. Saltz BL, Woerner MG, Kane JM, et al: Prospective study of tardive dyskinesia incidence in the elderly. JAMA 266:2402-2406, 1991 19. Ganzini L, Heintz RT, Hoffman WF, Casey DE: The prevalence of tardive dyskinesia in neuroleptictreated diabetics. Arch Gen Psychiatry 48:259-263, 1991 20. Wright MR, Axelson JE, Rurak, et al: Effects of haemodialysis on metoclopramide kinetics in patients with severe renal failure. Br J Clin Pharmacol26:474477, 1988 21. Lehman CR, Heironimus JD, Collins CB, et al: Metoclopramide kinetics in patients with impaired renal function and clearance by hemodialysis. Clin Pharmacol Ther 37:284-289, 1985 22. Harrington RA, Hamilton CW, Brogden RN, et al:
Metoclopramide-Associated
Metoclopramide: An updated review of its pharmacologic properties and clinical use. Drug Evaluations 25:451-494, 1983 23. Physicians’ Desk Reference, 46th ed. New Jersey, Medical Economics Company, 1991, p 1870 24. Webb D, Buss DC, Fifield R, Bateman DN, Routledge
Tardive Dyskinesia
PA: The plasma protein binding of metoclopramide in health and renal disease. Br J Clin Pharmacol 21:334-336, 1986 25. Chaffee BJ, Tankanow RM: Ondansetron-The first of a new class of antiemetic agents. Clin Pharmacol 10:430-446, 1991
419