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Pallidal dopamine receptors, neuroleptics and tardive dyskinesia
279
ABNORMAL INVOLUNTARY MOVEMENTS A GENERAL POPULATION SAMPLE OF MIDDLE-AGED MEN A. Nilsson*, L. Waller, L. Wilhelmsen Department GBtehorg,
of Psychiatry,
A. Rosengren,
Lillhagen
IN
A. Adlerberth,
Hospital,
University of
422 03 Hisings Backa, Sweden
Tardive dyskinesia (TD), a syndrome of involuntary, choreoathetoid movements occurring in patients exposed to neuroleptics, contributes to the burden of psychosocial problems associated with psychiatric illness. The etiology is unclear, but advanced age, female sex, mood disorder, and diabetes are implicated, and severity of TD is inversely related to essential fatty acid levels. Abnormal involuntary movements indistinguishable from TD are reported in 5 % of populations never exposed to neuroleptics, but these dyskinetic phenomena have generally been assessed without standardized methods in samples of elderly nursing home residents. The present study was aimed at exploration of spontaneous dyskinesia as a possible approach towards further understanding of TD. In a random sample of half of all men in Goteborg, Sweden, born in 1933 (n=l016), 76 % were investigated at age 50, whereby physical, laboratory, and psychosocial data were collected. A current follow-up at age 59 has been extended to include video-taped, standardized ratings of abnormal involuntary movements (AIMS) and extrapyramidal symptoms (Simpson & Angus). Data regarding prevalence of dyskinesia and its relation to medical history, alcohol consumption, cigarette smoking, and laboratory data, including blood levels of glucose and essential fatty acids in almost 600 men will be presented.
TARDIVE DYSKINESIA, AND VITAMIN E M. Peet, J. Laughame, R.E.B.
Watson,
LIPID PEROXIDATION
N. Rangarajan,
G.P.
Reynolds,
A.J. Cutts
Departments of Psychiatry Sheffield, Sheffield, UK
& Biomedical
Science,
University
of
Increased levels of lipid peroxidation products have been reported in the cerebrospinal fluid of patients treated with neuroleptics (Pall et al, 1987, Lancet 25962599). This is consistent with the hypothesis that free radical damage might be the cause of tardive dyskinesia (TD). Furthermore, vitamin E, a free radical scavenger, has been reported to improve symptoms of TD (Eohr et al, 1987, Lancet 1913-1914). Plasma was obtained from 14 neuroleptic treated chronic schizophrenic in-patients (1 lm, 3f, aged 44-70 years) who met diagnostic criteria for TD which was assessed according to the Abnormal Involuntary Movement Scale (AIMS). Patients were then treated with vitamin E 400 iu. three times daily for one month whereupon the AIMS was repeated and a further blood sample taken. The lipid peroxidation product malondialdehyde
(MDA) was measured by reaction with thiobarbituric acid (TBA). At baseline, there was a highly significant correlation between plasma MDA and the AIMS score (r=0.60: 0.02) and an even greater correction between iron-stimulation highly significant improvement in severity of TD and this improvement was maintained in the 11 patients followed up at seven to thirteen months, despite no further administration of vitamin E. There was no consistent change in plasma MDA related to treatment with vitamin E. Following vitamin E treatment, there was no longer any significant correlation between plasma MDA and severity of TD. The association between increased lipid peroxidation and severity of TD, together with the sustained ameliorating effect of TD of vitamin E, gives support to the hypothesis that lipid peroxidation by free radicals is of aetiological importance in TD.
PLASMA NEUROLEPTIC LEVELS IN PATIENTS WITH AND WITHOUT ACUTE DYSTONIC REACTIONS G.J. Remington*,
B. Pollock,
K. Reed, K. Coulter,
G. Voineskos Neuropsychopharmacology Psychiatry.
250 College
Research
Unit, Clarke Institute of
Street, Toronto.
Ont. MT
IR8, Canada
Acute dystonic reactions represent a serious side effect associated with neuroleptic treatment. While certain risk factors have been identified, the precise etiological mechanisms underlying dystonic reactions remain unclear. One possibility is that neuroleptic levels are higher in those individuals who develop acute dystonic reactions versus those who don’t. To test this hypothesis, plasma neuroleptic levels were collected in 41 acutely psychotic patients who were treated with parenteral haloperidol. From this group, 6 pairs matched for age, gender, and neuroleptic dose were identified: dystonia (N=6), and no dystonia (N=6). Plasma neuroleptic levels were drawn at baseline, and hours I, 3, 5, 8 and 24 following the initiation of treatment. Individual peak levels as high as 62 ng/ml were recorded during acute neuroleptic treatment. However, no significant differences in plasma levels were noted for the 2 groups. Although dystonic reactions often occur during the first day of treatment, the present findings indicate that these acute neuroleptic-induced dystonias cannot be explained by differences in the pattern of neuroleptic levels over the first 24 hours.
PALLIDAL DOPAMINE RECEPTORS, NEUROLEPTICS AND TARDIVE DYSKINESIA G.P. Reynolds, Department
J. Block,
of Biomedical
Shejjield SIO 2TN, UK
A.J. Cutts Science,
University of Sheffield,
The increased density of the neuroleptic-sensitive dopamine D2 receptors in brain tissue taken post mortem from patients with schizophrenia is well established. While it is now considered that previous drug treatment is primarily responsible for a resultant upregulation in D2 receptors, it may be that this response is related to the side effects induced by chronic treatment with antipsychotic drugs. In particular, it has been suggested that tardive dyskinesia is due to such a “supersensitivity” of dopamine receptors, although no direct evidence. in the form of an additional increase in striatal D2 receptors in schizophrenic patients with dyskinesias, has emerged. However it is the pallidum, rather than the striatum alone, that is important in the production of dyskinesias. A post mortem study of elderly. drug-free patients with tardive dyskinesia has demonstrated an increase in dopamine D2 receptors in the pallidum relative to the striatum in comparison to age-matched control subjects (Reynolds et al. (1992) J Neural Transm 87,225). We have also undertaken a post-mortem study of dopamine receptors in the pallidum in drug-treated schizophrenic patients to determine the response of these receptors to chronic drug treatment. Here too sit was found that D2 receptor density in the pallidum had increased above control values to an extent significantly greater than that found in the striatum (Reynolds and Cutts (1992) Schiz Res 6,137). We have followed these studies with an investigation of the effects of chronic administration of antipsychotic drugs on pallidum D2 receptors. While three weeks of haloperidol administered in drinking water induced increases of 67% in both pallida1 and striatal D2 receptor density, after six weeks administration the pallidum D2 receptors increased by 95%. significantly above the 63% increase found in the striatum. This study indicates differences in the response of D2 receptor density to antipsychotic drug treatment between striatal and pallidal tissues that, taken with the post mortem studies mentioned above, may be relevant to our understanding of the pathogenesis of tardive dyskinesia.
VITAMIN E IN THE TREATMENT OF TARDIVE DYSKINESIA: DOES IT REALLY WORK? C.L.
Shtiqui
Centre hospital& Robert-Giffard. 2601 chemin de la Canardit?re. Beauport, Que., Canada, GIJ 2G3 Free radicals are implicated in the development of tardive dyskinesia (TD) (Lohr et al, 1986; 1987; 1988; 1990; Lohr 1991). By increasing catecholamine turnover and metabolism, neuroleptics would increase production of cytotoxic free radicals. This neurodegenerative process would contribute to the development of TD
in predisposed individuals. Since 1987, 7 clinical trials, most of which were double-blind placebo-controlled, have assessed the short-term efficacy of vitamin E in TD (L&r et al, 1987; Elkashef et al, 1990; Schmidt et al, 1991; Shriqui et al, 1992; Egan et al, 1992; Alder et al, 1992; Spivak et al, 1992). 5 of these studies have reported a significant beneficial effect of vitamin E. The clinical use of vitamin E in TD was recommended in a recent textbook [Tanner CM. (1992) In: Textbook of Clinical Neuropharmacology and Therapeutics, 2nd Edition, Raven Press]. A critical review of the literature indicates the need to conduct a large scale multiple-dose prospective study of vitamin E in TD. In addition, the efficacy of atypical antioxidants such as selegiline, idebenone, and co-enzyme Q,O in TD patients deserves careful scrutiny.
POLYDIPSIA AND TARDIVE DYSKINESIA IN CHRONIC PSYCHIATRIC PATIENTS: RELATED DISORDER? Daniel Umbticht*, Lieberman
Bruce
Saltz,
Simcha
Pollack,
Jefferey
Hillside Hospital, Psychiatry Research, P.O. Bo,- 38, Glen Oaks, NY 11004, USA It has been hypothesized that dopamine supersensitivity, assumed to play a role in tardive dyskinesia, may also underlie the idiopathic polydipsia in chronic psychiatric patients a disorder in fluid regulation, often erroneously called “psychogenic polydipsia.” Patients who develop TD with neuroleptic maintenance treatment may therefore also be at greater risk for this abnormality. In a group of patients, followed in a prospective incidence study of TD, the values of serum sodium, BUN and specific urinary gravity of 6X patients who developed TD and had laboratory work done when TD was diagnosed were compared to the available corresponding values at entry into the parent study, when TD was absent. The number of patients with laboratory results below predefined cutoff values, suggestive of a disordered fluid regulation, and the mean group values of each laboratory parameter at both points in time were compared. No statistically significant differences in the number of patients with laboratory values suggestive of a disordered fluid regulation nor in the mean group values of serum sodium, BUN and specific urinary gravity were found. There was no evidence that patients who develop tardive dyskinesia also develop abnormalities in the water metabolism at the same time.
ABNORMAL INVOLUNTARY MOVEMENTS A GENERAL POPULATION SAMPLE OF MIDDLE-AGED MEN A. Nilsson*, L. Waller, L. Wilhelmsen Department GBtehorg,
of Psychiatry,
A. Rosengren,
Lillhagen
IN
A. Adlerberth,
Hospital,
University of
422 03 Hisings Backa, Sweden
Tardive dyskinesia (TD), a syndrome of involuntary, choreoathetoid movements occurring in patients exposed to neuroleptics, contributes to the burden of psychosocial problems associated with psychiatric illness. The etiology is unclear, but advanced age, female sex, mood disorder, and diabetes are implicated, and severity of TD is inversely related to essential fatty acid levels. Abnormal involuntary movements indistinguishable from TD are reported in 5 % of populations never exposed to neuroleptics, but these dyskinetic phenomena have generally been assessed without standardized methods in samples of elderly nursing home residents. The present study was aimed at exploration of spontaneous dyskinesia as a possible approach towards further understanding of TD. In a random sample of half of all men in Goteborg, Sweden, born in 1933 (n=l016), 76 % were investigated at age 50, whereby physical, laboratory, and psychosocial data were collected. A current follow-up at age 59 has been extended to include video-taped, standardized ratings of abnormal involuntary movements (AIMS) and extrapyramidal symptoms (Simpson & Angus). Data regarding prevalence of dyskinesia and its relation to medical history, alcohol consumption, cigarette smoking, and laboratory data, including blood levels of glucose and essential fatty acids in almost 600 men will be presented.
TARDIVE DYSKINESIA, AND VITAMIN E M. Peet, J. Laughame, R.E.B.
Watson,
LIPID PEROXIDATION
N. Rangarajan,
G.P.
Reynolds,
A.J. Cutts
Departments of Psychiatry Sheffield, Sheffield, UK
& Biomedical
Science,
University
of
Increased levels of lipid peroxidation products have been reported in the cerebrospinal fluid of patients treated with neuroleptics (Pall et al, 1987, Lancet 25962599). This is consistent with the hypothesis that free radical damage might be the cause of tardive dyskinesia (TD). Furthermore, vitamin E, a free radical scavenger, has been reported to improve symptoms of TD (Eohr et al, 1987, Lancet 1913-1914). Plasma was obtained from 14 neuroleptic treated chronic schizophrenic in-patients (1 lm, 3f, aged 44-70 years) who met diagnostic criteria for TD which was assessed according to the Abnormal Involuntary Movement Scale (AIMS). Patients were then treated with vitamin E 400 iu. three times daily for one month whereupon the AIMS was repeated and a further blood sample taken. The lipid peroxidation product malondialdehyde
(MDA) was measured by reaction with thiobarbituric acid (TBA). At baseline, there was a highly significant correlation between plasma MDA and the AIMS score (r=0.60: 0.02) and an even greater correction between iron-stimulation highly significant improvement in severity of TD and this improvement was maintained in the 11 patients followed up at seven to thirteen months, despite no further administration of vitamin E. There was no consistent change in plasma MDA related to treatment with vitamin E. Following vitamin E treatment, there was no longer any significant correlation between plasma MDA and severity of TD. The association between increased lipid peroxidation and severity of TD, together with the sustained ameliorating effect of TD of vitamin E, gives support to the hypothesis that lipid peroxidation by free radicals is of aetiological importance in TD.
PLASMA NEUROLEPTIC LEVELS IN PATIENTS WITH AND WITHOUT ACUTE DYSTONIC REACTIONS G.J. Remington*,
B. Pollock,
K. Reed, K. Coulter,
G. Voineskos Neuropsychopharmacology Psychiatry.
250 College
Research
Unit, Clarke Institute of
Street, Toronto.
Ont. MT
IR8, Canada
Acute dystonic reactions represent a serious side effect associated with neuroleptic treatment. While certain risk factors have been identified, the precise etiological mechanisms underlying dystonic reactions remain unclear. One possibility is that neuroleptic levels are higher in those individuals who develop acute dystonic reactions versus those who don’t. To test this hypothesis, plasma neuroleptic levels were collected in 41 acutely psychotic patients who were treated with parenteral haloperidol. From this group, 6 pairs matched for age, gender, and neuroleptic dose were identified: dystonia (N=6), and no dystonia (N=6). Plasma neuroleptic levels were drawn at baseline, and hours I, 3, 5, 8 and 24 following the initiation of treatment. Individual peak levels as high as 62 ng/ml were recorded during acute neuroleptic treatment. However, no significant differences in plasma levels were noted for the 2 groups. Although dystonic reactions often occur during the first day of treatment, the present findings indicate that these acute neuroleptic-induced dystonias cannot be explained by differences in the pattern of neuroleptic levels over the first 24 hours.
PALLIDAL DOPAMINE RECEPTORS, NEUROLEPTICS AND TARDIVE DYSKINESIA G.P. Reynolds, Department
J. Block,
of Biomedical
Shejjield SIO 2TN, UK
A.J. Cutts Science,
University of Sheffield,
The increased density of the neuroleptic-sensitive dopamine D2 receptors in brain tissue taken post mortem from patients with schizophrenia is well established. While it is now considered that previous drug treatment is primarily responsible for a resultant upregulation in D2 receptors, it may be that this response is related to the side effects induced by chronic treatment with antipsychotic drugs. In particular, it has been suggested that tardive dyskinesia is due to such a “supersensitivity” of dopamine receptors, although no direct evidence. in the form of an additional increase in striatal D2 receptors in schizophrenic patients with dyskinesias, has emerged. However it is the pallidum, rather than the striatum alone, that is important in the production of dyskinesias. A post mortem study of elderly. drug-free patients with tardive dyskinesia has demonstrated an increase in dopamine D2 receptors in the pallidum relative to the striatum in comparison to age-matched control subjects (Reynolds et al. (1992) J Neural Transm 87,225). We have also undertaken a post-mortem study of dopamine receptors in the pallidum in drug-treated schizophrenic patients to determine the response of these receptors to chronic drug treatment. Here too sit was found that D2 receptor density in the pallidum had increased above control values to an extent significantly greater than that found in the striatum (Reynolds and Cutts (1992) Schiz Res 6,137). We have followed these studies with an investigation of the effects of chronic administration of antipsychotic drugs on pallidum D2 receptors. While three weeks of haloperidol administered in drinking water induced increases of 67% in both pallida1 and striatal D2 receptor density, after six weeks administration the pallidum D2 receptors increased by 95%. significantly above the 63% increase found in the striatum. This study indicates differences in the response of D2 receptor density to antipsychotic drug treatment between striatal and pallidal tissues that, taken with the post mortem studies mentioned above, may be relevant to our understanding of the pathogenesis of tardive dyskinesia.
VITAMIN E IN THE TREATMENT OF TARDIVE DYSKINESIA: DOES IT REALLY WORK? C.L.
Shtiqui
Centre hospital& Robert-Giffard. 2601 chemin de la Canardit?re. Beauport, Que., Canada, GIJ 2G3 Free radicals are implicated in the development of tardive dyskinesia (TD) (Lohr et al, 1986; 1987; 1988; 1990; Lohr 1991). By increasing catecholamine turnover and metabolism, neuroleptics would increase production of cytotoxic free radicals. This neurodegenerative process would contribute to the development of TD
in predisposed individuals. Since 1987, 7 clinical trials, most of which were double-blind placebo-controlled, have assessed the short-term efficacy of vitamin E in TD (L&r et al, 1987; Elkashef et al, 1990; Schmidt et al, 1991; Shriqui et al, 1992; Egan et al, 1992; Alder et al, 1992; Spivak et al, 1992). 5 of these studies have reported a significant beneficial effect of vitamin E. The clinical use of vitamin E in TD was recommended in a recent textbook [Tanner CM. (1992) In: Textbook of Clinical Neuropharmacology and Therapeutics, 2nd Edition, Raven Press]. A critical review of the literature indicates the need to conduct a large scale multiple-dose prospective study of vitamin E in TD. In addition, the efficacy of atypical antioxidants such as selegiline, idebenone, and co-enzyme Q,O in TD patients deserves careful scrutiny.
POLYDIPSIA AND TARDIVE DYSKINESIA IN CHRONIC PSYCHIATRIC PATIENTS: RELATED DISORDER? Daniel Umbticht*, Lieberman
Bruce
Saltz,
Simcha
Pollack,
Jefferey
Hillside Hospital, Psychiatry Research, P.O. Bo,- 38, Glen Oaks, NY 11004, USA It has been hypothesized that dopamine supersensitivity, assumed to play a role in tardive dyskinesia, may also underlie the idiopathic polydipsia in chronic psychiatric patients a disorder in fluid regulation, often erroneously called “psychogenic polydipsia.” Patients who develop TD with neuroleptic maintenance treatment may therefore also be at greater risk for this abnormality. In a group of patients, followed in a prospective incidence study of TD, the values of serum sodium, BUN and specific urinary gravity of 6X patients who developed TD and had laboratory work done when TD was diagnosed were compared to the available corresponding values at entry into the parent study, when TD was absent. The number of patients with laboratory results below predefined cutoff values, suggestive of a disordered fluid regulation, and the mean group values of each laboratory parameter at both points in time were compared. No statistically significant differences in the number of patients with laboratory values suggestive of a disordered fluid regulation nor in the mean group values of serum sodium, BUN and specific urinary gravity were found. There was no evidence that patients who develop tardive dyskinesia also develop abnormalities in the water metabolism at the same time.