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The effects of anticholinergic withdrawal on tardive dyskinesia and parkinsonian tremor
176A
BIOL PSYCHIATRY 1991;29:43A- 185A
M o v e m e n t Disorders
doses of O. 12. and 18 rag, and a single IV dose of 5 g,g/hr for 8 hr, with a 2-day washout between each successive dose. The maximum plasma concentration (Cn~), mean T,,~ values, and mean AUC values of the various doses are presented. Mean plasma half-life was 3.8 hr. Bioavaiiabilities were low (---5%) and very. similar for the three tab!et formulations tested. Disposition was independent of dose over the dose range studied. The role of this selective D., agonist in PD is discussed.
292 COGNITIVE IMPAIRMENT 1N SCHIZOPHRENIA: RELATIONS TO TARDIVE DYSKINESIA AND NEUROLEPTIC-INDUCED PARKINSONISM Sukdeb Mukherjee, M.D., Paolo Decina, M.D., PierLuigi Scapicchio, M.D., Giovanni Caracci, M.D. New York State Psychiatric Institute, New York, NY 10032. Studies in schizophrenic patients consistently have found the presence of tardive dyskinesia (TD) to be associated with greater cognitive deficits, with some evidence that this relation may be specific to omfaciolingual dyskinesia. By contrast, there has been le~ emphasis on examining the relation of neurolepticinduced parkinsonism (NIP) to cognitive deficits That dementia often occurs in patients with Parkinson's disease raises the possibility that NIP also may be associated with greater cognitive deficits. Using a tenitem batter),' (Waddington et al, Am J Psy,chiatry 143: ! 162, 1986) we examined in 75 elderly schizophrenic patients cognitive functioning (lower scores reflected greater impairment), and the relations of cognitive deficit to orofaciolingual dyskinesia, limb-axial dyskinesia, NIP (rigidity-br~dykinesia score), affective blunting, age, sex, and drug treatment variables. Initial univariate tests showed cognitive impah'ment to be related to greater severity of both parkinsonism and affective blunting, but not to any of the other variables. A stepwise regression was then performed (F to enter = 3). Affective flattening entered the equation first, and was followed respectively by rigidity-bradykinesia, limb-axial dyskinesia, and orofaciolingual dyskinesia. Together these variables accounted for 37% of the variance in cognitive scores. None of the dr+g treatment variables contrib,ated to the equation. A simultaneous regression showed that NIP predicted cognitive impairment even after controlling for the variance due to the other variables, including drug treatment variables. The findings are presented in detail, and their implications ior an understanding of cognitive deficits associated with movement disorders in schizophrenic patients are discussed.
293 THE EFFECTS OF ANTICHOLINERGIC WITHDRAWAL ON TARDiVE DYSKiNESiA AND PARKINSONIAN TREMOR James B. I .n~,,, ' ' M.D. , Michael P. Caligiuri, Ph.D. Gary L. Ellenor, Pharm.D. Department of P~:chiatr3,, University of California, San Diego, CA 92093. The effects of anticholinergic medications on patients with tardive dyskinesia are unclear. There is evidence in the literature to suggest that anticholinergic withdrawal may exacerbate or improve the dyskinesia. Also, in patients treated chronically with both neuroleptic and anticholinergic medication, anticholinergic withdrawal may not necessarily result in a worsening of parkinsoni~. We decided to assess the effects of anticholinergic withdrawal on patients with TD who had been chronically treated with neuroleptic and anticholinergic medication. We selected patients with asymmetrical TD in which there was minimal of no dyskinesia on the one hand, but mild to moderate dyskinesia on the other hand. Using force- transducers, we quantified dyskinesia in the dyskinetic hand, and we quantified parkinsonian tremor in both hands. Following anticholinergic withdrawal, we found a significant decrease in dyskinesia (t = 6.3, p < 0.01), but a significant increase in tremor (t = 2.49, p < 0.05) in the nondyskinetic hand. Tremor in the dyskinetic hand was relatively unchanged. These res~dts support the contention that anticholinergic medications worsen TD, but can reduce parkiasonian tremor even after long periods of neuroleptic exposure. The finding of no char,ge in t:-.emor in the dyskinetic hand implies that the existence of dyskine~ia may suppress the tremor-
Movement Disorders
BtOl. PSVCmA~Y i991:29:43A- |85A
177A
inducing effects of anticholinergic withdrawal. This possible interaction between dyskines~a and tremor during anticholinergic withdrav,'al may account for some of ~.heconflicting findings prev~ouaty r e d e d in which clinical rating scales were used. These findings demonstrate the utili~, of quanutafive procedures m elucidating the effects ot pharmacological interventions on neuroleptic-induced mo~emem disorders.
294 TARDIVE DYSKINESIA AND PLASMA CHOLINESTERASE ISOZYME LEVELS IN SCHIZOPHRENIC PATIENTS Ravinder Reddy, M.D., Sukdeb Mukherjee, M.D., Sahebarao P. Mahadik, Ph.D., Anna Korenovsky, M.S. New York State P~vchiatric h~titute, New York, NY 10032. We have previously repot'tea th,~ chronic schizophrenic patients shot' abnormally high blood leveh of a specific cholinesterase isozyme ~ChE3). and that this appear~ not be a function of medtcation stares CMahadik et al, Biol Psychiatry 25:173A, 1989). Although ChE3 sho~s predominantly " ~ e ' cho[inesterase activity, the implications of the abnormal levels of this isozyme tbr an understanding of ~ e disease process of schizophrenia or its complications remain unclear. In this study we examined the relations of b l ~ ChE3 levels as a function of persistent tardive dyskinesia (I'D) i_n 35 medicated chronic schizopNenic patients (mean age 33.8 +_ 5.9 years). On the average blood ChE3 level was significantly ~gher in the 35 patients than in 25 age- and sex-matched normal controls (p < 0,01), and significantly higher m 14 TD patients than in 21 patients without "I'D (p < 0.05). Nei:her gender nor age was related to TD. A "I'D × sex ANOVA showed a main effect of TD (p < 0.05), but no main effect of sex and no TD x sex interactiou on ChE3 levels. Twenty-one patients were examined also when drug-free for at least 10 years, h these patients, a TD x sex ANOVA showed significant main effects of both TD (p = 0.0| ~ and sex (p < 0.005), with a trend toward a TD x sex interaction (p = 0.07). These data suggest that ~rther investigatiens of plasma ChE3 levels may provide an avenue for exploring pathophysiological mechanisms in neuropsychiatric disorders. The theoretical implicatior, s of the findings are discus~d, with particular reference to the issue of whether blood ChE3 levels reflect central cholinergic tone, or the deregulation of some other metatml'~c system.
295 EFFECT OF TARDIVE DYSKINESIA ON "-fk~E
ANTEROPOSTERIOR GRADIENT OF CEREBRAL BLOOD FLOW IN SCHIZOPHRENIC PATIENTS Sukdeb Mukherjee, M.D., isak Prohovnik, Ph.D., 'Harold A. Sackeim, Ph.D., David B. Schnur, M.D. New York State Psychiatric ln~.titute, New York, NY 10032. That, in comparison with normal control subjects, schizophrenic patients show a decreased anteroposterior (AP) gradient of cerebral blood flow (CBF) has been found in some studies, but not in others. The reasons for the discrepant findings remain unclear. On theoretical grounds, we predicted that patients with tardive dyskinesia (TD) would show higher AP gradients than. patients without "I'D. Using the 133Xe inhalation method, we measured resting CBF in 23 chronic schizophrenic patients, both while they were on a stable dose of halopeddol and when they were drug free for at least 2 weeks, artd in 23 age- ~ O sex-matched normal controls. The mean age of patients was 33.8 years (SD = 5.3), and there was no difference in age between the 12 women and 11 men, or between 9 patients with "I'D and 14 patie_n_ts without TD. Tb_e AP gradient was defined in two ways: APl--mean of flow values at the 5 frontal detectors divided by mean of flow values at the remaining 11 detectors; and AP2--mean of flow values at the 7 frontal and central detectors divided by the mean of flow values at :he remaining 9 detectors. Consistently across medicated and drug free conditions, both AP1 and AP2 were significantl3, higher in TD patients than in non-TD patients. During the drug-free state, API and AP2 were sign~fic. ~tly lower in non-TD pafien~ (1.04 and ! .07, respective! 3') than in normal controls (1.11 an~i 1.13, respectively), but these differences were atten-
BIOL PSYCHIATRY 1991;29:43A- 185A
M o v e m e n t Disorders
doses of O. 12. and 18 rag, and a single IV dose of 5 g,g/hr for 8 hr, with a 2-day washout between each successive dose. The maximum plasma concentration (Cn~), mean T,,~ values, and mean AUC values of the various doses are presented. Mean plasma half-life was 3.8 hr. Bioavaiiabilities were low (---5%) and very. similar for the three tab!et formulations tested. Disposition was independent of dose over the dose range studied. The role of this selective D., agonist in PD is discussed.
292 COGNITIVE IMPAIRMENT 1N SCHIZOPHRENIA: RELATIONS TO TARDIVE DYSKINESIA AND NEUROLEPTIC-INDUCED PARKINSONISM Sukdeb Mukherjee, M.D., Paolo Decina, M.D., PierLuigi Scapicchio, M.D., Giovanni Caracci, M.D. New York State Psychiatric Institute, New York, NY 10032. Studies in schizophrenic patients consistently have found the presence of tardive dyskinesia (TD) to be associated with greater cognitive deficits, with some evidence that this relation may be specific to omfaciolingual dyskinesia. By contrast, there has been le~ emphasis on examining the relation of neurolepticinduced parkinsonism (NIP) to cognitive deficits That dementia often occurs in patients with Parkinson's disease raises the possibility that NIP also may be associated with greater cognitive deficits. Using a tenitem batter),' (Waddington et al, Am J Psy,chiatry 143: ! 162, 1986) we examined in 75 elderly schizophrenic patients cognitive functioning (lower scores reflected greater impairment), and the relations of cognitive deficit to orofaciolingual dyskinesia, limb-axial dyskinesia, NIP (rigidity-br~dykinesia score), affective blunting, age, sex, and drug treatment variables. Initial univariate tests showed cognitive impah'ment to be related to greater severity of both parkinsonism and affective blunting, but not to any of the other variables. A stepwise regression was then performed (F to enter = 3). Affective flattening entered the equation first, and was followed respectively by rigidity-bradykinesia, limb-axial dyskinesia, and orofaciolingual dyskinesia. Together these variables accounted for 37% of the variance in cognitive scores. None of the dr+g treatment variables contrib,ated to the equation. A simultaneous regression showed that NIP predicted cognitive impairment even after controlling for the variance due to the other variables, including drug treatment variables. The findings are presented in detail, and their implications ior an understanding of cognitive deficits associated with movement disorders in schizophrenic patients are discussed.
293 THE EFFECTS OF ANTICHOLINERGIC WITHDRAWAL ON TARDiVE DYSKiNESiA AND PARKINSONIAN TREMOR James B. I .n~,,, ' ' M.D. , Michael P. Caligiuri, Ph.D. Gary L. Ellenor, Pharm.D. Department of P~:chiatr3,, University of California, San Diego, CA 92093. The effects of anticholinergic medications on patients with tardive dyskinesia are unclear. There is evidence in the literature to suggest that anticholinergic withdrawal may exacerbate or improve the dyskinesia. Also, in patients treated chronically with both neuroleptic and anticholinergic medication, anticholinergic withdrawal may not necessarily result in a worsening of parkinsoni~. We decided to assess the effects of anticholinergic withdrawal on patients with TD who had been chronically treated with neuroleptic and anticholinergic medication. We selected patients with asymmetrical TD in which there was minimal of no dyskinesia on the one hand, but mild to moderate dyskinesia on the other hand. Using force- transducers, we quantified dyskinesia in the dyskinetic hand, and we quantified parkinsonian tremor in both hands. Following anticholinergic withdrawal, we found a significant decrease in dyskinesia (t = 6.3, p < 0.01), but a significant increase in tremor (t = 2.49, p < 0.05) in the nondyskinetic hand. Tremor in the dyskinetic hand was relatively unchanged. These res~dts support the contention that anticholinergic medications worsen TD, but can reduce parkiasonian tremor even after long periods of neuroleptic exposure. The finding of no char,ge in t:-.emor in the dyskinetic hand implies that the existence of dyskine~ia may suppress the tremor-
Movement Disorders
BtOl. PSVCmA~Y i991:29:43A- |85A
177A
inducing effects of anticholinergic withdrawal. This possible interaction between dyskines~a and tremor during anticholinergic withdrav,'al may account for some of ~.heconflicting findings prev~ouaty r e d e d in which clinical rating scales were used. These findings demonstrate the utili~, of quanutafive procedures m elucidating the effects ot pharmacological interventions on neuroleptic-induced mo~emem disorders.
294 TARDIVE DYSKINESIA AND PLASMA CHOLINESTERASE ISOZYME LEVELS IN SCHIZOPHRENIC PATIENTS Ravinder Reddy, M.D., Sukdeb Mukherjee, M.D., Sahebarao P. Mahadik, Ph.D., Anna Korenovsky, M.S. New York State P~vchiatric h~titute, New York, NY 10032. We have previously repot'tea th,~ chronic schizophrenic patients shot' abnormally high blood leveh of a specific cholinesterase isozyme ~ChE3). and that this appear~ not be a function of medtcation stares CMahadik et al, Biol Psychiatry 25:173A, 1989). Although ChE3 sho~s predominantly " ~ e ' cho[inesterase activity, the implications of the abnormal levels of this isozyme tbr an understanding of ~ e disease process of schizophrenia or its complications remain unclear. In this study we examined the relations of b l ~ ChE3 levels as a function of persistent tardive dyskinesia (I'D) i_n 35 medicated chronic schizopNenic patients (mean age 33.8 +_ 5.9 years). On the average blood ChE3 level was significantly ~gher in the 35 patients than in 25 age- and sex-matched normal controls (p < 0,01), and significantly higher m 14 TD patients than in 21 patients without "I'D (p < 0.05). Nei:her gender nor age was related to TD. A "I'D × sex ANOVA showed a main effect of TD (p < 0.05), but no main effect of sex and no TD x sex interactiou on ChE3 levels. Twenty-one patients were examined also when drug-free for at least 10 years, h these patients, a TD x sex ANOVA showed significant main effects of both TD (p = 0.0| ~ and sex (p < 0.005), with a trend toward a TD x sex interaction (p = 0.07). These data suggest that ~rther investigatiens of plasma ChE3 levels may provide an avenue for exploring pathophysiological mechanisms in neuropsychiatric disorders. The theoretical implicatior, s of the findings are discus~d, with particular reference to the issue of whether blood ChE3 levels reflect central cholinergic tone, or the deregulation of some other metatml'~c system.
295 EFFECT OF TARDIVE DYSKINESIA ON "-fk~E
ANTEROPOSTERIOR GRADIENT OF CEREBRAL BLOOD FLOW IN SCHIZOPHRENIC PATIENTS Sukdeb Mukherjee, M.D., isak Prohovnik, Ph.D., 'Harold A. Sackeim, Ph.D., David B. Schnur, M.D. New York State Psychiatric ln~.titute, New York, NY 10032. That, in comparison with normal control subjects, schizophrenic patients show a decreased anteroposterior (AP) gradient of cerebral blood flow (CBF) has been found in some studies, but not in others. The reasons for the discrepant findings remain unclear. On theoretical grounds, we predicted that patients with tardive dyskinesia (TD) would show higher AP gradients than. patients without "I'D. Using the 133Xe inhalation method, we measured resting CBF in 23 chronic schizophrenic patients, both while they were on a stable dose of halopeddol and when they were drug free for at least 2 weeks, artd in 23 age- ~ O sex-matched normal controls. The mean age of patients was 33.8 years (SD = 5.3), and there was no difference in age between the 12 women and 11 men, or between 9 patients with "I'D and 14 patie_n_ts without TD. Tb_e AP gradient was defined in two ways: APl--mean of flow values at the 5 frontal detectors divided by mean of flow values at the remaining 11 detectors; and AP2--mean of flow values at the 7 frontal and central detectors divided by the mean of flow values at :he remaining 9 detectors. Consistently across medicated and drug free conditions, both AP1 and AP2 were significantl3, higher in TD patients than in non-TD patients. During the drug-free state, API and AP2 were sign~fic. ~tly lower in non-TD pafien~ (1.04 and ! .07, respective! 3') than in normal controls (1.11 an~i 1.13, respectively), but these differences were atten-