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Clozapine-related tardive dyskinesia
H CASEREPORT Clozapine-Related Tardive Dyskinesia Mahendra Day6
Introduction Classical antipsychotic medications may cause extrapyramidal syndromes (EPS), as compared to the atypical antipsychotic agent, clozapine, which has a low incidence of EPS. Present here are cases of tardive dyskinesia (TD) associated with clozapine. ! was informed (personal communication, Dr. Krassner, May 1993) by Sandoz, the makers of the Clozaril brand of clozapine, that, "there have been no confirmed cases of tardive dyskinesia associated with Clozaril," and that there have been several reports on, "successful reversal of neuroleptic-induced tardive dyskinesia in patients switched to Clozaril." This was indeed confirmed by my literature review. Small et al (1987) treated 38 chronically psychotic patients, 19 of whom had TD, with clozapine. They report improvement in the abnormal movements in all the TD patients, and that, '*no patient showed worsening of abnormal movements." Lieberman et al (1991), in their review of eight studies on the effect of clozapine on TD, and their own study of use of clozapine on 30 patients with TD, found that although 43% of the patients showed improvement in TD, "others showed no change." This is the first report on clozapine associated TD.
Case 1 Mr. A is a 3 I-year-old single man with a 15-year history of paranoid schizophrenia. He has had seven inpatient psychiatric hospitalizations for psychotic regression. His latest hospitalization extended for over 10 years. Over the years, he had received adequate trials on six different classical antipsychotic agents, with poor results. He was started on clozapine 2 years ago. At that time, he was f,'l therapeutic doses of chlorpromazine, lithium, and carbamazepine for his unremitting psychosis, and benztropine for parkinsonian side effects. He was started on clozapine as the other medications only partially controlled his physical and verbal as-
From the Georgia Mental Health Institute, Atlanta, GA, Address reprint requests to Mahendra Dav~ Unit Medical Director, Georgia Mental Health Institute. 1256 Briarcliff Road, NE, Atlanta, GA 30306, Received August3.1993; revised December 2, 1993.
© 1994 Seciety of Biological Psychiatry
gressivity, with continued auditory, visual, and olfactory hallucinations, persecutory delusions, delusions of being controlled by computers, delusions of reference, thought broadcasting, thought withdrawal, asociality, withdrawal, amotivation, marked lack of interests, and menacing demeanor. His carbamazepine was discontinued within I week of starting clozapine; and chlorpromazine, lithium, and benztropine were discominued in the next 7 weeks. He was discharged in n remitted state, free of psychosis, and with a pleasant, outgoing manner, to a community residence after he had been on clozapine for 2 years. His discharge dose of cloznpine was 600 rag. He was also on ranitidine (Zantac) 150 ms/day for hiatal hernia-related stomach upset, and on docusate sodium (Colaoe) for clozapine-induced constipation during his last I year of hospitalization. A detailed neurological examination [which included electroencephalogram (EEG), and computed tomography (CT) scan and magnetic resonance imaging (MRI) of brain] done by a neurologist, I year prior to his discharge, was normal except for mildly nonspocific slowing on the EEG. The routine Abnormal Involuntary Movement Scale (AIMS) testing became abnormal after he had been on clozapine for 20 months, when he showed "foot squirming" at grade I, and side-to-side tongue movements on activation at grade 2. ! repeated the AIMS test a week after this abnormal finding, and found similar results again. Mr, A does not have a family history of Huntington's disease or dystonia. The previous 5 AIMS testings, done at approximately 8 months' interval, were available to me. These did not show presence of TD. Case 2 Ms. B is a 37-year-old single woman, who has suffered from paranoid schizophrenia for the last 12 years. She was started on clozapine ! I months ago, as she had responded poorly to 2 classical antipsychotic agents. She had mild TD. with an AIMS score of 2-3 when clozapine was started. Since then, her TD has worsened to AIMS score of 7, with prominent bucco-lingual movements, which are apparent even as she talks. Ms. B's mother, who also has schizophrenia, has severe neuroleptic induced TD. Currently she is on 700 ms/day of clozapine. Ms. B's schizophrenia has improved to the level that she is no longer aggressive, has fewer 00(O-3223/94/$07.00
Case Report
hallucinations, has improved insight into her delusions, and improved concentration and motivation, so that she can now participate in work programs.
Discussion It is well known that TD may have a remitting and reversible course in younger people, and it may first become manifest either when a patient is on a neuroleptic agent, or when the neuroleptic agent is being decreased or discontinued. It is possible that Ms. B's TD may have worsened because she was taken off the classical neuroleptics, and she may be one of the 50% of the TD cases whose
toOLPSYCHIATRY 1994;35:886--887
887
TD does not improve on clozapine. The point to note is that, unlike other literature reports of ciozapine treatment of patients who have TD, Ms. B's TD continued to worsen in spite of being on clozapine. Mr. A's mild TD appears to be related to clozapine use as his TD did not appear until well into the second year of clozapine treatment. Besides, he had two normal AIMS test results at the 8-month interval, prior to the positive AIMS finding when he was not on any other antipsychotic agent except clozapine. It is possible that Mr. A may have had some subclinical brain lesion as shown by the EEG abnormality, and this may have made him somehow susceptible to develop TD on clozapine.
References Lieberman JA, Saltz BL, Johns CA, Pollack S, Borenstein M, Kane J (I 99 I): The effects of clozapine on tardive dyskinesia. Br J Psychiatry i 58:503-510. Small JG, Milstein V, Marhenke JD, Hall DD, Kellams JJ (1987):
Treatment outcome with clozapine in tardive dyskinesia, neuroleptic sensitivity, and treatment-resistant psychosis. J Clin
Psychiat~. 48:263-267.
Introduction Classical antipsychotic medications may cause extrapyramidal syndromes (EPS), as compared to the atypical antipsychotic agent, clozapine, which has a low incidence of EPS. Present here are cases of tardive dyskinesia (TD) associated with clozapine. ! was informed (personal communication, Dr. Krassner, May 1993) by Sandoz, the makers of the Clozaril brand of clozapine, that, "there have been no confirmed cases of tardive dyskinesia associated with Clozaril," and that there have been several reports on, "successful reversal of neuroleptic-induced tardive dyskinesia in patients switched to Clozaril." This was indeed confirmed by my literature review. Small et al (1987) treated 38 chronically psychotic patients, 19 of whom had TD, with clozapine. They report improvement in the abnormal movements in all the TD patients, and that, '*no patient showed worsening of abnormal movements." Lieberman et al (1991), in their review of eight studies on the effect of clozapine on TD, and their own study of use of clozapine on 30 patients with TD, found that although 43% of the patients showed improvement in TD, "others showed no change." This is the first report on clozapine associated TD.
Case 1 Mr. A is a 3 I-year-old single man with a 15-year history of paranoid schizophrenia. He has had seven inpatient psychiatric hospitalizations for psychotic regression. His latest hospitalization extended for over 10 years. Over the years, he had received adequate trials on six different classical antipsychotic agents, with poor results. He was started on clozapine 2 years ago. At that time, he was f,'l therapeutic doses of chlorpromazine, lithium, and carbamazepine for his unremitting psychosis, and benztropine for parkinsonian side effects. He was started on clozapine as the other medications only partially controlled his physical and verbal as-
From the Georgia Mental Health Institute, Atlanta, GA, Address reprint requests to Mahendra Dav~ Unit Medical Director, Georgia Mental Health Institute. 1256 Briarcliff Road, NE, Atlanta, GA 30306, Received August3.1993; revised December 2, 1993.
© 1994 Seciety of Biological Psychiatry
gressivity, with continued auditory, visual, and olfactory hallucinations, persecutory delusions, delusions of being controlled by computers, delusions of reference, thought broadcasting, thought withdrawal, asociality, withdrawal, amotivation, marked lack of interests, and menacing demeanor. His carbamazepine was discontinued within I week of starting clozapine; and chlorpromazine, lithium, and benztropine were discominued in the next 7 weeks. He was discharged in n remitted state, free of psychosis, and with a pleasant, outgoing manner, to a community residence after he had been on clozapine for 2 years. His discharge dose of cloznpine was 600 rag. He was also on ranitidine (Zantac) 150 ms/day for hiatal hernia-related stomach upset, and on docusate sodium (Colaoe) for clozapine-induced constipation during his last I year of hospitalization. A detailed neurological examination [which included electroencephalogram (EEG), and computed tomography (CT) scan and magnetic resonance imaging (MRI) of brain] done by a neurologist, I year prior to his discharge, was normal except for mildly nonspocific slowing on the EEG. The routine Abnormal Involuntary Movement Scale (AIMS) testing became abnormal after he had been on clozapine for 20 months, when he showed "foot squirming" at grade I, and side-to-side tongue movements on activation at grade 2. ! repeated the AIMS test a week after this abnormal finding, and found similar results again. Mr, A does not have a family history of Huntington's disease or dystonia. The previous 5 AIMS testings, done at approximately 8 months' interval, were available to me. These did not show presence of TD. Case 2 Ms. B is a 37-year-old single woman, who has suffered from paranoid schizophrenia for the last 12 years. She was started on clozapine ! I months ago, as she had responded poorly to 2 classical antipsychotic agents. She had mild TD. with an AIMS score of 2-3 when clozapine was started. Since then, her TD has worsened to AIMS score of 7, with prominent bucco-lingual movements, which are apparent even as she talks. Ms. B's mother, who also has schizophrenia, has severe neuroleptic induced TD. Currently she is on 700 ms/day of clozapine. Ms. B's schizophrenia has improved to the level that she is no longer aggressive, has fewer 00(O-3223/94/$07.00
Case Report
hallucinations, has improved insight into her delusions, and improved concentration and motivation, so that she can now participate in work programs.
Discussion It is well known that TD may have a remitting and reversible course in younger people, and it may first become manifest either when a patient is on a neuroleptic agent, or when the neuroleptic agent is being decreased or discontinued. It is possible that Ms. B's TD may have worsened because she was taken off the classical neuroleptics, and she may be one of the 50% of the TD cases whose
toOLPSYCHIATRY 1994;35:886--887
887
TD does not improve on clozapine. The point to note is that, unlike other literature reports of ciozapine treatment of patients who have TD, Ms. B's TD continued to worsen in spite of being on clozapine. Mr. A's mild TD appears to be related to clozapine use as his TD did not appear until well into the second year of clozapine treatment. Besides, he had two normal AIMS test results at the 8-month interval, prior to the positive AIMS finding when he was not on any other antipsychotic agent except clozapine. It is possible that Mr. A may have had some subclinical brain lesion as shown by the EEG abnormality, and this may have made him somehow susceptible to develop TD on clozapine.
References Lieberman JA, Saltz BL, Johns CA, Pollack S, Borenstein M, Kane J (I 99 I): The effects of clozapine on tardive dyskinesia. Br J Psychiatry i 58:503-510. Small JG, Milstein V, Marhenke JD, Hall DD, Kellams JJ (1987):
Treatment outcome with clozapine in tardive dyskinesia, neuroleptic sensitivity, and treatment-resistant psychosis. J Clin
Psychiat~. 48:263-267.