Persistent tardive dyskinesia and neuroleptic effects on glucose tolerance

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29: IT-27

17

Elsevier

Persistent Glucose

Tardive Dyskinesia Tolerance

Sukdeb

Mukherjee,

Received 1989.

November

Steven

D. Roth,

29, 1988; revisrd

and Neuroleptic

Reuven

version received

Sandyk,

Effects

and David

on

B. Schnur

March 27. 1989: acc.epted Mal* IS,

Abstract. The relations of persistent tardive dyskinesia (TD) to glucose tolerance and family history of type 2 diabetes mellitus (FH-NIDDM) were examined in 22 schizophrenic patients. All patients underwent a standard oral glucose tolerance test (GTT) while receiving haloperidol, and I5 patients also underwent a GTT when drug free. Fasting blood glucose (FBS) was significantly higher in the TD group than in the non-TD group in the medicated condition, but not in the drug-free state. TD and non-TD groups did not differ significantly in postload glucose levels either in the drug-free or in the medicated condition. However, relative to the drug-free state, haloperidol-treated TD patients showed decreased glucose tolerance while non-TD patients showed increased glucose tolerance. Seven (32%) of the 22 patients had an FH-NIDDM. A positive FH-NIDDM was significantly associated with the presence of TD and with higher drug-free FBS. A possible role of melatonin in mediating the TD-augmenting effects of FHNIDDM and the neuroleptic-induced decrease in glucose tolerance has been proposed. Key Words. Tardive phrenia, neuroleptics,

dyskinesia, melatonin.

glucose

tolerance,

diabetes

mellitus,

schi7o-

A high prevalence of impaired glucose use has been reported in patients with a variety of neuropsychiatric disorders including schizophrenia, manic-depressive illness, Down’s syndrome, Huntington’s chorea, and senile dementia (Simon and Garvey, 195 1; Henneman et al., 1954; Baiter, 1961; Podolsky et al., 1972; Jeremiah et al., 1973; Brambilla et al., 1976; Lilliker, 1980; Wilkinson, 1981). We have recently proposed that tardive dyskinesia (TD) also is associated with impaired glucose

Sukdeb Mukherjee, M.D., is Chief, Department ofclinical Neuropsychiatry, New York State Psychiatric Institute, where Reuven Sandyk, M.D., M.Sc., is a Research Associate and David B. Schnur, M.D., is a Research Psychiatrist. Also, at the Columbia University College of Physicians & Surgeons of Columbia University, Dr. Mukherjee is Associate Professor of Clinical Psychiatry. Dr. Schnur is Assistant Clinical Professor of Psychiatry and, at the time the study was conducted, Steven D. Roth, M.D., was the Van Ameringen Investigator in Schizophrenia Research. Additionally, at the Special Treatment Unit, Creedmoor Psychiatric Center, New York, Dr. Mukherjee is the Research Director and the Director of the Movement Disorder Service, and Dr. Schnur is the Clinical Director. (Reprint requests to Dr. S. Mukherjee, New York State Psychiatric institute, 722 W. I68 St.. Box 72, New York, NY 10032. USA.) 0165-1781/X9/$03.50

@ 1989 Elsevier Scientific

Publishers Ireland

Ltd

18 metabolism (Mukherjee et al., 1985, 1986a). This view was based on our finding a high prevalence of diabetes mellitus (DM) in patients with TD, a high prevalence of DM in first-degree family members of patients with TD, and significantly higher fasting blood glucose in patients with TD than in patients without TD. Further, in a recent study, we found that experimentally induced hyperglycemia augments the development of neuroleptic-induced dyskinesia in the rat (Sandyk and Mukherjee, submitted for publication). It remains unclear whether impaired glucose metabolism in patients with TD represents a neuroleptic effect, or an independent pathological factor that contributes to the development of involuntary movements independent of the effects of neuroleptic treatment. There is evidence from the preneuroleptic era that a high prevalence of impaired glucose metabolism occurs in schizophrenic patients (Kooy, 1919; Lorenz, 1922; Meduna and Vaichulis, 1948; Simon and Garvey, 195 I; Henneman et al., 1954). Impaired glucose tolerance has also been reported following neuroleptic treatment (Charatan and Bartlett, 1955; Hiles, 1955; Korenyi and Lowenstein, 1968; Thonnard-Neuman, 1968). Virtually all of these studies were conducted before the development of standardized assessment procedures and diagnostic criteria in psychiatry, and before the significance of the distinction between type I DM (juvenile-onset or insulin-dependent DM) and type 2 DM (maturity-onset or non-insulin-dependent DM; NIDDM) was clearly established. It is not known whether decreased glucose tolerance, spontaneous or neurolepticinduced, in schizophrenic patients is related to a genetic predisposition for DM. There is evidence that genetic factors play a major role in the pathogenesis of NIDDM, although the mode of transmission remains unknown (O’Rahilly et al., 1987). Depending on age at time of ascertainment, concordance in monozygotic twins ranges from about 60% to almost 100% (Barnett et al., 1981; Newman et al., 1987), and the prevalence of abnormal glucose tolerance among the offspring of conjugal NIDDM parents has been reported to be as high as 62% (Viswanathan et al., 1988). It is noteworthy that impaired glucose tolerance in psychiatric patients has been reported to be associated with a high genetic risk for DM (Waitzkin, 1966; Thonnard-Neuman, 1968). We present below our findings from a preliminary study of the relations of persistent TD to a family history of NIDDM and glucose tolerance in schizophrenic patients. Since glucose tolerance normally decreases with aging (Marble et al., 1985), patients older than 45 years of age were not included in the study. Methods The sample comprised 22 chronic schiz.ophrenic inpatients (I4 male and 8 female) at the New York State Psychiatric Institute affiliated research unit at Creedmoor Psychiatric Center. A diagnosis of schizophrenia was established following independent semistructured interviews and review of clinical records by two research psychiatrists. and there was no instance of diagnostic disagreement. Patients with abnormal liver function or a medical illness requiring treatment and those with a history of substance abuse or head injury were excluded from the study. The patients had a mean age of 3 I I years (SD 5.7; range 20-45). a mean age at onset of illness of 18. I years (SD 3.8), a mean duration of illness of 13.0 years (SD 6.4). and a mean of I I .8 years (SD I .9) of formal education. There was no significant difference between the sexes

19 in any of these variables. The mean body weight was 157.4 tbs. (SD 22.0), with a trend toward males weighing more than females (p = 0.12). No patient was obese. Patients were examined for the presence of abnormal involuntary movements during baseline evaluations, and repeatedly thereafter during their stay on the research unit. All such ratings were done without knowledge of GTT findings. A diagnosis of persistent tardive dyskinesia (TD) was based on the criteria for Research Diagnostic Diagnosis of Tardive Dyskinesia (RDTD) (Schooler and Kane, 1982) by two psychiatrists following independent reviews of the abnormal involuntary movement ratings and medical records. Specifically, a diagnosis of persistent TD required the presence of abnormal involuntary movements of at least mild severity in two body areas, or moderate severity in one body area, that were present for at least 3 months. There was no case of interrater disagreement in the diagnosis of TD. Before the GTT, patients were maintained on an unrestricted diet containing at least 200 g of carbohydrate daily for 3 days. All patients were receiving a standard hospital diet, and none showed a change in body weight of more than IO Ibs. during the month before testing, Oral GTTs were performed in the morning after a l2- to l4-hour fasting period. Following-%lood sampling for baseline fasting blood glucose (FBS), patients ingested a commercially prepared solution containing 75 g of glucose. Venous blood for determination of glucose levels was obtained at 0.5, I, 2, and 3 hours following the glucose load. Oral GTT during the medicated state was performed in 22 patients while they were receiving steady doses of haloperidol for at least 4 weeks, with individual dosages varying from I5 to 40 mg daily. There was no difference in mean haloperidol dose between TD and non-TD patients. Fifteen of the patients had also undergone a GTT while drug free for at least IO days. No patient was in an acute exacerbation of psychosis during the GTT, and clinical state did not show more than a mild change on the Clinical Global Impression scale from drug-free to medicated conditions. On the average, body weight remained stable across these two conditions (r = 0.98), and no patient showed a body weight change greater than 10% of the baseline. Specifically, in these I5 patients mean body weight was 154.4 Ibs. (SD 19.7) during the medicated condition and 154. I Ibs. (SD 18.5) during the drug-free condition. Family history of type 2 DM was assessed by interviewing the parents as part of an ongoing investigation of major medical disorders in family members of schizophrenic and bipolar patients. Family members were classified as having NIDDM only if they had been diagnosed as such by their physician. Only biological parents and siblings were considered in this study. Additionally, to be classified as an FH-NIDDM case, it was required that none of the grandparents had been diagnosed to have NIDDM. The distributions of FBS and peak postload glucose levels did not significantly depart from normality in either the drug-free or the medicated state (skewness < 0.70). Pearson zero-order correlations were used to examine bivariate relations, and I tests were used for between-group comparisons. Two-tailed significance values were used throughout.

Results Persistent TD was diagnosed in 12 (55%) of the total sample of 22 patients, and in 8 (53%) of the I5 who underwent GTT during both haloperidol-treated (HAL) and drug-free conditions. The remaining patients did not meet RDTD criteria for TD. All non-TD patients, and IO of the 12 TD patients, had been examined while drug free for at least I week on at least one occasion. Thus, it can be assumed that there were no false-negative cases in the non-TD group. The TD and non-TD groups were not significantly different in their distributions of sex, or their means of age, duration of illness, or years of formal education. A family history of NIDDM was found in 7 (32%) of the 22 patients. In all cases, the affected family member was a parent (father 4, mother 3). There was no instance of both parents having NIDDM, and there was no family member identified as having

20

type 1 DM. Family history of NIDDM (FH-NIDDM) was not related to age, sex, body weight, duration of illness, or years of education in the patients. The results of the GTTs are summarized in Table I. Mean FBS was significantly higher in TD patients than in non-TD patients in the medicated (HAL) condition (t = 2.2, &= 20, p = 0.04) but not in the drug-free condition. Mean medicated FBS was higher also in the eight TD patients (92.9 mg/dl; SD 6.6) than in the seven non-TD patients (85.6 mg/dl; SD 6.7) when only the 15 who underwent GTTs in both drug-free and HAL conditions were considered (t = 2. I, c/j’= 13, p = 0.05). By contrast, a positive FH-NIDDM was associated with significantly higher FBS during the drug-free condition (t = 2.2, Q’= 13, p < 0.05), but not during the HAL condition (p = 0.15). It is noteworthy that no patient had a clearly abnormal FBS (> 6.6 mmol/l or 120 mg/dl) during either the drug-free condition or the HAL condition. Body weight was not correlated with FBS in either condition (r < 0.20; p > 0.30, for both comparisons). TD and non-TD patients did not differ significantly in postload glucose levels at any time point, during either the drug-free or the HAL condition. However, TD and non-TD patients differed significantly in postload peak glucose level (0.5 hours) in the HAL condition relative to that in the drug-free condition. A two-way analysis of variance (ANOVA) with diagnosis (TD vs. non-TD) as a between-subject factor and treatment condition (drug free vs. HAL) as a within-subject factor showed a significant Interaction effect of diagnosis X treatment condition on the 0.5-hour peak glucose level (F= 5.6; dJ’= 1, 13; p = 0.03) with no main effect of either diagnosis or treatment condition. Specifically, relative to the drug-free condition, HAL treatment was associated with decreased glucose tolerance in the TD group, and increased glucose tolerance in the non-TD group. A similar interaction was seen at each of the

Table 1. Patient characteristics and glucose tolerance test (GlT) findings in tardive dyskinesia (TD) and non-TD patients TD patients (n = 12)

Non-TD patients (n = 10)

Mean age (years)

31.8

6.6)

30.2 ( 4.9)

Mean duration

13.3

7.3)

12.8

( 5.4)

85.8

( 6.3)

of illness (years)

Blood glucose levels (mgidl) A. Medicated condition (n = 22) Fasting baseline 0.5 hour postload

91.6

6.0)

144.7

12.7)

121.9 (30.2)

1 hour postload

136.2

35.7)

119.8 (28.2)

2 hours postload

107.6 (16.5)

108.1 (23.5)

3 hours postload

74.6 (24.7)

83.6 (20.6)

B. Drug-free condition (n = 15)’ 89.0 ( 9.7)

89.0 (11.6)

0.5 hour postload

Fasting baseline

133.6 (33.3)

156.0 (27.6)

1 hour postload

132.9 (31.5)

145.4 (32.3)

2 hours postload

104.8 (22.2)

125.1 (36.1)

3 hours postload

76.6 (24.9)

90.6 (14.1)

Note. Figures in parentheses represent standard deviation of the means. 1. Drug-free GTT: 8 TD patients and 7 non-TD patients.

21 postload time periods, but these were not statistically significant. Body weight did not predict this effect at any time point (p > 0.20 for all comparisons). During the HAL condition, peak postload glucose level was > 180 mg/dl (IO mmol/l) in three patients, and all had TD. Six (86%) of the seven FH-NIDDM positive patients had persistent TD in contrast to six (40%) of the I5 FH-NIDDM negative patients (x2 = 4.0, p < 0.05). FH-NIDDM positive patients did not differ significantly from FH-NIDDM negative patients on any of the postload glucose levels or in body weight during either treatment condition. However, two of the three patients who showed peak postload glucose levels > IO mmol/l(l80 mg/dl) were FH-NIDDM and had TD. Discussion In this study, the presence of TD was associated with a higher FBS in the neuroleptic-treated condition. As in our earlier report (Mukherjee et al., 1985) this relation was observed even though no patient had an FBS that would be considered abnormal. However, drug free FBS did not differ significantly between the TD and non-TD groups, suggesting that differential neuroleptic effects on glucose use might be at issue. By contrast, FH-NIDDM was associated with a higher FBS during the drug-free condition, but not during the neuroleptic-treated condition. The temporal instability of FBS and the relatively small sample of patients require consideration of the possibility that these relations represent chance associations. However, the replicability of the findings across two independent investigations suggests that the findings may not be spurious and deserve careful consideration. These observed relations between TD and indices of glucose metabolism or FH-NIDDM could not be explained on the basis of malnutrition, obesity, or weight loss in our patients. TD and non-TD patients did not differ in peak postload glucose levels or in glucose levels during the postpeak recovery period, during either the medicated condition or the drug-free condition. However, the groups showed significantly different patterns when peak postload glucose levels during the medicated condition were compared to those during the drug-free condition. Specifically, a neurolepticinduced decrease in glucose tolerance was associated with the presence of TD, while a neuroleptic-induced increase in glucose tolerance was associated with the absence of TD. It appears that neuroleptics have variable effects on glucose tolerance in schizophrenic patients and that this variability may have implications for the pathophysiology of TD. Neither FH-NIDDM nor body weight predicted the direction of change in glucose tolerance from the drug-free to the medicated condition. Thonnard-Neuman (1968) had reported that a hyperglycemic response to neuroleptics was associated with both obesity and a family history of DM. He studied only female patients and used a categorical definition of hyperglycemia based on cutoff criteria for blood glucose levels, while we included both sexes and examined glucose levels as a continuous measure. Thus, our findings may not be directly comparable with his. It is indeed intriguing that relations between indices of glucose metabolism and a pathological condition (TD) were observed even though blood glucose levels, both fasting and postload, were largely within the normal range. There is evidence that

22 higher postload blood glucose levels within the normal range can have pathological significance (Tallarigo et al., 1986; Farmer et al., 1988). In a recent study of 9 17 nondiabetic pregnant women, a higher postload glucose level at about 32 weeks of gestation, although within the normal range, was found to be associated with an increased occurrence of fetal developmental complications (Farmer et al., 1988). Thus, the critical issue with respect to TD may be whether neuroleptics decrease or increase glucose tolerance, rather than whether or not they are associated with the development of “abnormal” glucose tolerance. Whether such decreased glucose tolerance is a result of decreased insulin production or insulin insensitivity needs to be examined. In a preliminary communication, we reported a high prevalence of FH-NIDDM in bipolar patients with TD (Mukherjee et al., 1985). In this study, we found that TD was associated with a FH-NIDDM also in schizophrenic patients. All but one of the seven patients who had a FH-NIDDM also had persistent TD. The prevalence of NIDDM in the general population is influenced by age and obesity and has been variably reported to range from 4% to 14% in the United States (Marble et al., 1985). We found 32% of our patients to have a parent with diagnosed NIDDM. While this is considerably in excess of expected prevalence rates, it is representative of the high prevalence of FH-NIDDM (3 1%) observed by us in a larger sample of schizophrenic patients (Mukherjee et al., 1989). FH-NIDDM and neuroleptic-induced decrease in glucose tolerance were not related, but both were associated with the presence of TD. How FH-NIDDM and neuroleptic-induced decrease in glucose tolerance might contribute to the development of TD is not known. In all likelihood, they facilitate the expression of TD through discrete mechanisms. Alternatively, as discussed below, both may facilitate the expression of TD through a common pathway. The neurobiological basis of TD is incompletely understood. The various hypotheses proposed to explain the pathogenesis of TD include, among others, striatal dopamine (DA) receptor supersensitivity following chronic blockade of DA receptors by neuroleptics (Klawans, 1973) increased noradrenergic activity (Jeste et al., 1982), decreased y-aminobutyric acid (GABA) functions (Gunne et al., 1984; Thaker et al., 1987), increased serotonergic functions (Korsgaard et al., 1985) and decreased serotonergic functions (Sandyk et al., 1987). It has also been proposed that pineal melatonin may act as a protective factor against the development of TD (Sandyk and Fisher, in press). A possible role of impaired glucose metabolism in the pathogenesis of TD does not necessarily conflict with any of the above views. Glucose has been reported to suppress the firing rate of striatal dopamine (DA) neurons in the rat (Sailer and Chiodo, 1980), and increased striatal dopamine receptor binding suggesting DA supersensitivity has been reported in alloxaninduced diabetic rats (Lozovsky et al., 1981). We found that alloxan-induced hyperglycemia may augment the development of neuroleptic-induced dyskinetic movements in the rat (Sandyk and Mukherjee, submitted for publication a). It is noteworthy that increased striatal DA and noradrenalin (NA) have both been found in a post-mortem study of diabetic patients (Lackovic et al., 1985). Thus, hyperglycemia possibly could facilitate the development of TD through involvement of monoaminergic systems.

23 Alternatively, the TD-augmenting effect of impaired glucose metabolism could be mediated via pineal melatonin functions that are related to peripheral glucose metabolism (Diaz and Blazquez, 1986). Experimentally induced diabetes in animals decreases pineal melatonin synthesis by inhibiting hydroxy-indole-O-methyltransferase (HIOMT), the final enzyme in the biosynthesis of melatonin (Champney et al., 1983; Pang et al., 1985). It is noteworthy that reduced melatonin has been reported in both plasma and cerebrospinal fluid of unmedicated schizophrenic patients (Ferrier et al., 1982a, 19826; Beckmann et al., 1984; Fanget et al., 1989). We found an increased incidence and severity of haloperidol-induced dyskinesia in pinealectomized rats, an effect that was partially reversed by exogenous melatonin (unpublished data). Further, alloxan-induced diabetes, which decreases pineal melatonin synthesis in the rat (Pang et al., 1985) can augment the development of neuroleptic-induced dyskinesias (Sandyk and Mukherjee, submitted for publication h). Haloperidol has been found to be highly concentrated in the rat pineal gland (Naylor and Olley, 1969) and neuroleptic treatment has been reported both to decrease melatonin synthesis by inhibiting HIOMT (Hartley et al., 1972) and to increase plasma melatonin concentration by inhibiting hepatic microsomal enzymes that catabolize melatonin (Ozaki et al., 1976). Increased melatonin has been found in neuroleptic-treated schizophrenic patients (Smith et al., 1977). Increased plasma melatonin levels could inhibit pineal melatonin synthesis either by feedback inhibition of HIOMT activity (Ozaki et al., 1976; Smith et al., 1979) or via increased blood glucose levels that could result from inhibition of pancreatic insulin production by melatonin (Csaba and Barath, 1971; Dhar et al., 1983). It is noteworthy that in humans aging is associated with an increased prevalence of both TD (Smith and Baldessarini, 1980) and impaired glucose tolerance (Marble et al., 1985) as well as with decreased production of melatonin (Iguchi et al., 1982; Sack et al., 1986; Nair et al., 1986) and pineal weight (and presumably pineal melatonin function) may be reduced in diabetic patients (Trentini et al., 1987). It has been reported that abnormal glucose metabolism in schizophrenic patients is corrected by administration of pineal extracts (Ahschule, 1975, cited in Horrobin, 1979). However, it is not established that this effect is mediated by melatonin. Patients with manic-depressive illness may also be at a high risk for developing TD (Kane et al., 1988; Mukherjee et al., 19866) and manic-depressive illness has been reported to be associated with both an increased prevalence of diabetes mellitus (Lilliker, 1980) and decreased pineal melatonin functions (Miles and Philbrick, 1988). We have previously reported a high prevalence of family history of NIDDM in bipolar patients with TD (Mukherjee et al., 1985) and have suggested that altered melatonin functions may have implications for TD in these patients (Sandyk and Mukherjee, submitted for publication b). While the effects of lithium on glucose tolerance have been studied, there has been no investigation of neuroleptic effects on glucose tolerance in patients with mood disorders, particularly in relation to TD or a family history of NIDDM in the patients. An intriguing possibility is that pineal melatonin functions are involved in the common neural pathway mediating the TD-augmenting effects of both FH-NIDDM and neuroleptic-induced decrease in glucose tolerance. Persistently high blood glucose levels, albeit in the normal range, that are not adequately contained by

24

regulatory feedback mechanisms could result in chronically decreased pineal melatonin synthesis. Decreased melatonin functions could, in turn, down-regulate both GABA-ergic and serotonergic systems (Anton-Tay et al., 1971; Datta and King, 1978; Aldegunde et al., 1985) and thereby contribute to an increased risk for the expression of TD. It has been suggested that melatonin acts as a “central inhibitory modulator” (Datta and King, 1978). Abnormal melatonin functions may be reflected in dysregulation of a variety of neurochemical systems, many of which have been implicated in the pathogenesis of TD. We do not propose a simple model that involves consideration of melatonin alone. The effects of melatonin on motor functions may involve complex interactions with opioid peptides (Sandyk and Mukherjee, in press), and other yet to be determined neurochemical systems. Further, abnormal glucose homeostasis may be associated with a variety of neuropsychiatric disorders other than schizophrenia, and the neural regulation of glucose homeostasis involves multiple brain functional systems, most notably those in the hypothalamus, amygdala, and pituitary gland. The pathophysiology of TD probably involves a dysregulation of complex interactions among various neurochemical and neuroendocrine systems, and any hypothesis that considers in isolation a single neural system is unlikely to explain satisfactorily the phenomenon of TD. Acknowledgments. This work was supported in part by NIMH from the van Ameringen Foundation, and by the New York State The authors thank Dr. Giovanni Caracci for his assessments movements in the patients, and the nursing staff of the Special assistance with the GTTs.

grant MH-41961, a grant Office of Mental Health. of abnormal involuntary Treatment Unit for their

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