- Email: [email protected]
Inhibition of complex I activity by neuroleptics parallels extrapyramidal toxicity
151
VII.B. Extrapyramidal symptoms VII.B. 1 AN INVESTIGATION INTO EXTRAPYRAMIDAL SIDE EFFECTS INDUCED BY NEUROLEPTICS AND THEIR RELATIONSHIP TO CREATINE PHOSPHOKINASE M. Atkins, M. Camprubi, J. Evans, S.G. Ball and M. Riccio
Academic Psychiatry, Charing Cross & WestminsterMedical School Mental Health Unit, Chelsea & WestminsterHospital, London SWIO 9NG, U.K. Aim. To assess the relationship between the severity of muscular symptoms induced by neuroleptics and serum creatine phosphokinase concentration (CPK). Method. 35 subjects were recruited and rated on 3 separate occasions for the severity of their extrapyramidal side effects (EPS), using standardised rating scales with concurrent CPK levels being estimated. Results. No association was found between CPK levels and severity of EPS. Conclusion. The recent speculation about a spectrum concept of neuroleptic malignant syndrome (NMS) and debate about the importance of CPK in the diagnosis of NMS inspired this prospective study. Although the study has not shown a positive relationship between CPK levels and EPS published case reports suggesting an association between these factors cannot be ignored and a larger study may be indicated. The case is however made for more caution to be exercised in the use of CPK as a clinical indicator in the rechallenging of patients who have suffered from an episode of NMS in view of published evidence cited for the asymptomatic rise of CPK and other factors which cause a rise in this enzyme.
VII.B. 2 TIME TO ONSET OF EXTRAPYRAMIDAL SYMPTOMS IN FIRST EPISODE OF PSYCHOSIS H. Lee, M. Chakos, J.M.J. Alvir and J.A. Lieberman
Hillside Hospital a Division of Long Islandjewish Hospital Glen Oaks, New York, N Y llO04, US.A. Introduction. Most previous studies have reported incidences of extrapyramidal symptoms (EPS) in chronic schizophrenics. This study examined a cohort of first episode psychotic patients and their time to develop EPS on neuroleptic treatment. Methods. 118 patients who had an RDC diagnosis of schizophrenia (n=83), schizoaffective disorder-manic (n=9) and
schizoaffective disorder-depressed (n =26) were entered. Mean age of onset of symptoms was 22.1(6.9) years, patients had had minimal total life time antipsychotic exposure and were drug free on study entry. Time to development of parkinsonism, dystonia, and akathisia during acute antipsychotic treatment was calculated using survival analysis. Results. At 10 weeks 26% (95% confidence interval (CI)= 18, 34) had developed parkinsonism, 36% (95% CI=27, 44) dystonia, and 19% (95% CI = 12, 26) akathisia. The incidence of parkinsonism and dystonia had plateaued by 10 weeks, while the incidence of akathisia continued to rise to plateau at 25% (95% CI=17, 33) by 22 weeks of treatment. Biochemical correlates (plasma HVA and drug level) with incidence of EPS in first and subsequent episodes will also be presented. Conclusions. EPS response in first episode psychotic patients differs from chronically ill patients and needs to be examined separately.
VII.B. 3 INHIBITION OF COMPLEX I ACTIVITY NEUROLEPTICS PARALLELS EXTRAPYRAMIDAL TOXICITY
BY
I.C. Maurer, S. Zierz 1 and H.-J. M611er 2
Dept of Neurology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany 1Dept of Neurology, University of Halle, Halle, Germany 2Dept of Psychiatry, Universityof Munich, Munich, Germany Drug-induced parkinsonism is a major limiting side effect of neuroleptics. Since idiopathic parkinsonism is associated with defects of mitochondrial respiratory chain complex I, we determined whether neuroleptics inhibit complex I of the respiratory chain and wether this inhibition is related to the incidence of side effects induced by different neuroleptics. We measured spectrophotometrically the activities of complexes I and Ill, complexes II and III, succinate dehydrogenase, complex IV (cytochrome c oxidase), and of citrate synthase in human brain tissue after the addition of various concentrations of the classical neuroleptics haloperidol and chlorpromazine and the atypical neuroleptics risperidone, zotepine, and clozapine. Activity of complex I was progressively inhibited by all neuroleptics. Half-maximal inhibition (ICso) was 0.1 mM for haloperidol, 0.4mM for chlorpromazine, and 0,5mM for risperidone and zotepine. Clozapine had no effect on enzyme activity at concentrations up to 0.5 mM (IC5o=2.5 mM). The extent of inhibition paralleled the incidence of extrapyramidal side effects induced by neuroleptics. Complex II was not significantly inhibited at concentrations up to 1.0 mM. The data support the hypothesis that neuroleptic-induced extrapyramidal side effects may be due to oxidative damage of the mitochondrial respiratory chain.
VII.B. Extrapyramidal symptoms VII.B. 1 AN INVESTIGATION INTO EXTRAPYRAMIDAL SIDE EFFECTS INDUCED BY NEUROLEPTICS AND THEIR RELATIONSHIP TO CREATINE PHOSPHOKINASE M. Atkins, M. Camprubi, J. Evans, S.G. Ball and M. Riccio
Academic Psychiatry, Charing Cross & WestminsterMedical School Mental Health Unit, Chelsea & WestminsterHospital, London SWIO 9NG, U.K. Aim. To assess the relationship between the severity of muscular symptoms induced by neuroleptics and serum creatine phosphokinase concentration (CPK). Method. 35 subjects were recruited and rated on 3 separate occasions for the severity of their extrapyramidal side effects (EPS), using standardised rating scales with concurrent CPK levels being estimated. Results. No association was found between CPK levels and severity of EPS. Conclusion. The recent speculation about a spectrum concept of neuroleptic malignant syndrome (NMS) and debate about the importance of CPK in the diagnosis of NMS inspired this prospective study. Although the study has not shown a positive relationship between CPK levels and EPS published case reports suggesting an association between these factors cannot be ignored and a larger study may be indicated. The case is however made for more caution to be exercised in the use of CPK as a clinical indicator in the rechallenging of patients who have suffered from an episode of NMS in view of published evidence cited for the asymptomatic rise of CPK and other factors which cause a rise in this enzyme.
VII.B. 2 TIME TO ONSET OF EXTRAPYRAMIDAL SYMPTOMS IN FIRST EPISODE OF PSYCHOSIS H. Lee, M. Chakos, J.M.J. Alvir and J.A. Lieberman
Hillside Hospital a Division of Long Islandjewish Hospital Glen Oaks, New York, N Y llO04, US.A. Introduction. Most previous studies have reported incidences of extrapyramidal symptoms (EPS) in chronic schizophrenics. This study examined a cohort of first episode psychotic patients and their time to develop EPS on neuroleptic treatment. Methods. 118 patients who had an RDC diagnosis of schizophrenia (n=83), schizoaffective disorder-manic (n=9) and
schizoaffective disorder-depressed (n =26) were entered. Mean age of onset of symptoms was 22.1(6.9) years, patients had had minimal total life time antipsychotic exposure and were drug free on study entry. Time to development of parkinsonism, dystonia, and akathisia during acute antipsychotic treatment was calculated using survival analysis. Results. At 10 weeks 26% (95% confidence interval (CI)= 18, 34) had developed parkinsonism, 36% (95% CI=27, 44) dystonia, and 19% (95% CI = 12, 26) akathisia. The incidence of parkinsonism and dystonia had plateaued by 10 weeks, while the incidence of akathisia continued to rise to plateau at 25% (95% CI=17, 33) by 22 weeks of treatment. Biochemical correlates (plasma HVA and drug level) with incidence of EPS in first and subsequent episodes will also be presented. Conclusions. EPS response in first episode psychotic patients differs from chronically ill patients and needs to be examined separately.
VII.B. 3 INHIBITION OF COMPLEX I ACTIVITY NEUROLEPTICS PARALLELS EXTRAPYRAMIDAL TOXICITY
BY
I.C. Maurer, S. Zierz 1 and H.-J. M611er 2
Dept of Neurology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany 1Dept of Neurology, University of Halle, Halle, Germany 2Dept of Psychiatry, Universityof Munich, Munich, Germany Drug-induced parkinsonism is a major limiting side effect of neuroleptics. Since idiopathic parkinsonism is associated with defects of mitochondrial respiratory chain complex I, we determined whether neuroleptics inhibit complex I of the respiratory chain and wether this inhibition is related to the incidence of side effects induced by different neuroleptics. We measured spectrophotometrically the activities of complexes I and Ill, complexes II and III, succinate dehydrogenase, complex IV (cytochrome c oxidase), and of citrate synthase in human brain tissue after the addition of various concentrations of the classical neuroleptics haloperidol and chlorpromazine and the atypical neuroleptics risperidone, zotepine, and clozapine. Activity of complex I was progressively inhibited by all neuroleptics. Half-maximal inhibition (ICso) was 0.1 mM for haloperidol, 0.4mM for chlorpromazine, and 0,5mM for risperidone and zotepine. Clozapine had no effect on enzyme activity at concentrations up to 0.5 mM (IC5o=2.5 mM). The extent of inhibition paralleled the incidence of extrapyramidal side effects induced by neuroleptics. Complex II was not significantly inhibited at concentrations up to 1.0 mM. The data support the hypothesis that neuroleptic-induced extrapyramidal side effects may be due to oxidative damage of the mitochondrial respiratory chain.