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Tardive dyskinesia and cytochrome P450 2D6 genotyping in schizophrenia
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XIX. Movement Disorders B.233. NEURODEVELOPMENTAL ORIGINS OF TARDIVE DYSKINESIA SIGNS IN YOUNGER SCHIZOPHRENIA PATIENTS B. Ismail, E. C a n t o r - G r a a e , T.F. McNeil
Department of Epidemiology/ Community Medicine, Lund University, University Hospital, S-205 02 Malm6, Sweden The question of whether signs of tardive dyskinesia (TF) related to schizophrenia have a neurodevelopmental background was investigated in 60 relatively young schizophrenia patients and 21 of their non-ill siblings (mean age 38 years in both groups). TD signs were studied in relationship to selected risk factors in the patients and in relation to neurological abnormality and signs of Parkinsonism in both patients and their siblings, TD signs in patients were significantly related to male gender, a history of obstetric complications, shorter neuroleptic exposure and shorter illness duration. Patient TD signs were associated with 'hard' neurological signs (independent of involuntary movements) but not with 'soft signs' or primitive reflexes. Patient TD signs were positively related to signs of Parkinsonism. TD signs were found in 29% of the siblings, and tended to be associated with their neurological abnormality. TD signs tended not to co-occur in the patient and sibling in the same family. TD signs in younger schizophrenia patients may have neurodevelopmental antecedents, and represent part of a larger panorama of neurological abnormality in schizophrenia.
B.234. CLOZAPINE EFFICACY IN TARDIVE D Y S K I N E S I A - 3 YEARS' FOLLOW-UP D.P. Bassitt*, M.R. Louz5
*Institute of Psychiatry, Medical Scool, University of Sao Paulo, Rua Itacolomi, 333 cjl06 CEP 01239-020, Sao Paulo, Brazil, e-mail: dbassit@amcham,com.br Tardive dyskinesia (TD) is a long term severe complication of antipsychotic treatment, with mean prevalence of 24% 1. In an open trial seven patients with schizophrenia and severe TD were given clozapine for 6 months 2 and after they were followed for additional 3 years. TD's severity was evaluated with Abnormal Involuntary Movement Scale and Extrapyramidal Symptoms Rating Scale and schizophrenic psychopathology with Positive and Negative Symptoms Rating Scale. Clozapine's mean dose at the end of 3 years was 400 mg/day. After 6 months a mean reduction of 52% was observed in ESRS scores for TD and in the end of 3 years mean scores were 83% lower than baseline's scores and 63% lower than 6 months' scores. There was also a further reduction of mean scores for dystonic movements between 6 months and 3 years (32%) and for parkinsonism's scores. Psychopathology also
improved in this period; there was a further mean reduction of 16%0 in PANSS scores. Improvement in psychopathology was independent of tardive dyskinesia improvement. Clozapine is an alternative in the treatment of schizophrenic patients with severe TD, improving psychopathology and tardive dyskinesia in a lasting and progressive way. Improvement of tardive dyskinesia with clozapine can be substantial even after a prolonged period, suggesting that maybe clozapine allows TD to remit rather than having a suppressive effect.
References 1. Yassa R, Jeste D.V., Gender differences in tardive dyskinesia: a critical review of the literature. Schizophr Bull, 18: 701715, 1992. 2. Bassitt D.P., Louz~ Neto M.R., Clozapine efficacy in tardive dyskinesia in schizophrenic patients. Eur Arch Psychiatry Clin Neurosci, 248, 209-211, 1998a.
B.235. TARDIVE DYSKINESIA AND CYTOCHROME P450 2D6 GENOTYPING IN SCHIZOPHRENIA *L.C.W. Lam, G.S. Ungvari, M. Garcia, S.L. Kwong, Helen F.K. C h i u
*Dept. of Psychiatry, the Chinese University of Hong Kong, Shatin, NT, Hong Kong, PRC Tardive dyskinesia (TD) is one of the most important side effects from longterm anti-psychotic administration. Despite awareness on its potential detrimental effects, the pathogenesis is still not well documented. Current literature on pharmacogenetics may throw light on its mechanism. Debrisoquine 4-hydrolase (CYP2D6) is found to be responsible for the metabolism of most anti-psychotic medications, genetic polymorphisms may be causative to the individual differences in drug metabolism. Although mutations for poor metabolism in Chinese population are rare, significant proportion has specific polymorphisms of CYP2D6 characterized by slower but not absence of 2D6 activity. It is possible that mutation of the above allele would be a factor related to increase risk of tardive dyskineia. 95 patients with DSM-IV diagnosis of schizophrenia were assessed for the presence of CYP2D6 C/T188 mutation using allele-specific PCR amplification followed by digestion with HphI. 52 patients had homozygous mutation, 43 had wild type or heterozygous alleles. There were no significant difference in AIMS scores between the homozygous and other group. Other factors known to affect TD like age and duration of illness were not significantly different. If only moderate to severe TD was considered as significant (AIMS scores greater than 6), 32.7% of the mutated group had significant TD, while only 18.6% of the heterozygous and wild type group had significant TD (P>0.05). In this preliminary study, although not reaching statistical significance, it appears that there is a trend for higher prevalence of significant TD in patients with homozygous mutation. Larger sample size will be needed to consolidate the possible association between CYP 2D6 polymorphism and TD.
XIX. Movement Disorders B.233. NEURODEVELOPMENTAL ORIGINS OF TARDIVE DYSKINESIA SIGNS IN YOUNGER SCHIZOPHRENIA PATIENTS B. Ismail, E. C a n t o r - G r a a e , T.F. McNeil
Department of Epidemiology/ Community Medicine, Lund University, University Hospital, S-205 02 Malm6, Sweden The question of whether signs of tardive dyskinesia (TF) related to schizophrenia have a neurodevelopmental background was investigated in 60 relatively young schizophrenia patients and 21 of their non-ill siblings (mean age 38 years in both groups). TD signs were studied in relationship to selected risk factors in the patients and in relation to neurological abnormality and signs of Parkinsonism in both patients and their siblings, TD signs in patients were significantly related to male gender, a history of obstetric complications, shorter neuroleptic exposure and shorter illness duration. Patient TD signs were associated with 'hard' neurological signs (independent of involuntary movements) but not with 'soft signs' or primitive reflexes. Patient TD signs were positively related to signs of Parkinsonism. TD signs were found in 29% of the siblings, and tended to be associated with their neurological abnormality. TD signs tended not to co-occur in the patient and sibling in the same family. TD signs in younger schizophrenia patients may have neurodevelopmental antecedents, and represent part of a larger panorama of neurological abnormality in schizophrenia.
B.234. CLOZAPINE EFFICACY IN TARDIVE D Y S K I N E S I A - 3 YEARS' FOLLOW-UP D.P. Bassitt*, M.R. Louz5
*Institute of Psychiatry, Medical Scool, University of Sao Paulo, Rua Itacolomi, 333 cjl06 CEP 01239-020, Sao Paulo, Brazil, e-mail: dbassit@amcham,com.br Tardive dyskinesia (TD) is a long term severe complication of antipsychotic treatment, with mean prevalence of 24% 1. In an open trial seven patients with schizophrenia and severe TD were given clozapine for 6 months 2 and after they were followed for additional 3 years. TD's severity was evaluated with Abnormal Involuntary Movement Scale and Extrapyramidal Symptoms Rating Scale and schizophrenic psychopathology with Positive and Negative Symptoms Rating Scale. Clozapine's mean dose at the end of 3 years was 400 mg/day. After 6 months a mean reduction of 52% was observed in ESRS scores for TD and in the end of 3 years mean scores were 83% lower than baseline's scores and 63% lower than 6 months' scores. There was also a further reduction of mean scores for dystonic movements between 6 months and 3 years (32%) and for parkinsonism's scores. Psychopathology also
improved in this period; there was a further mean reduction of 16%0 in PANSS scores. Improvement in psychopathology was independent of tardive dyskinesia improvement. Clozapine is an alternative in the treatment of schizophrenic patients with severe TD, improving psychopathology and tardive dyskinesia in a lasting and progressive way. Improvement of tardive dyskinesia with clozapine can be substantial even after a prolonged period, suggesting that maybe clozapine allows TD to remit rather than having a suppressive effect.
References 1. Yassa R, Jeste D.V., Gender differences in tardive dyskinesia: a critical review of the literature. Schizophr Bull, 18: 701715, 1992. 2. Bassitt D.P., Louz~ Neto M.R., Clozapine efficacy in tardive dyskinesia in schizophrenic patients. Eur Arch Psychiatry Clin Neurosci, 248, 209-211, 1998a.
B.235. TARDIVE DYSKINESIA AND CYTOCHROME P450 2D6 GENOTYPING IN SCHIZOPHRENIA *L.C.W. Lam, G.S. Ungvari, M. Garcia, S.L. Kwong, Helen F.K. C h i u
*Dept. of Psychiatry, the Chinese University of Hong Kong, Shatin, NT, Hong Kong, PRC Tardive dyskinesia (TD) is one of the most important side effects from longterm anti-psychotic administration. Despite awareness on its potential detrimental effects, the pathogenesis is still not well documented. Current literature on pharmacogenetics may throw light on its mechanism. Debrisoquine 4-hydrolase (CYP2D6) is found to be responsible for the metabolism of most anti-psychotic medications, genetic polymorphisms may be causative to the individual differences in drug metabolism. Although mutations for poor metabolism in Chinese population are rare, significant proportion has specific polymorphisms of CYP2D6 characterized by slower but not absence of 2D6 activity. It is possible that mutation of the above allele would be a factor related to increase risk of tardive dyskineia. 95 patients with DSM-IV diagnosis of schizophrenia were assessed for the presence of CYP2D6 C/T188 mutation using allele-specific PCR amplification followed by digestion with HphI. 52 patients had homozygous mutation, 43 had wild type or heterozygous alleles. There were no significant difference in AIMS scores between the homozygous and other group. Other factors known to affect TD like age and duration of illness were not significantly different. If only moderate to severe TD was considered as significant (AIMS scores greater than 6), 32.7% of the mutated group had significant TD, while only 18.6% of the heterozygous and wild type group had significant TD (P>0.05). In this preliminary study, although not reaching statistical significance, it appears that there is a trend for higher prevalence of significant TD in patients with homozygous mutation. Larger sample size will be needed to consolidate the possible association between CYP 2D6 polymorphism and TD.