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Rates of cerebral glucose metabolism after neuroleptic withdrawal in schizophrenic patients
Schizophrenia H
BIOL PSYCHIATRY 1990;27:41A- 179A
97A
124 DOPAMINERGIC EFFECTS OF LSD IN AN ANIMAL MODEL OF
SENSORIMOTOR-GATING DEFICITS IN SCHIZOPHRENIA Mark A. Geyer, Ph.D., David L. Braff, M.D. Department of Psychiatry, University of California-San Diel,o School of Medicine, La Jolla, CA 92093. Although primarily a serotonin (5-HT) agonist, lysergic acid diethylamide (LSD) also has dopamine (DA)agonist activity. The relative importance of 5-HT and DA systems in the behavioral effects of LSD is unclear. We investigated the effects of LSD on prepulse inhibition of acoustic startle, a form. of sensorimotor gating that is sensitive to disruption by the DA agonists apomorphine, quinp'~role, and amphetamine. These DA effects mimic the loss of sensorimotor gating exhibited by schizophrenic patients in parallel tests of prepulse inhibition. Rats were subjected to 120 dB acoustic pulses, some of which were preceded at a 100 msec interval by a weak 75 dB prepulse stimulus. After saline, the prepulse reduced whole-body startle responses elicited by the pulse by approximately 50%. LSD (50, 100, or 200 p,g/kg body weight) significantly decreased the amount of prepulse inhibition. A subsequent study replicated the effect of 200 ~g/kg LSD and demonstrated that it could be blocked by the DA antagonist haloperidol (0. l mg/kg) but not by a dose of the S-HT-2 antagonist ritanserin (2.0 mg/kg), which is sufficient to block behavioral effects of 5-HT agonists. These results suggest that high doses ~f LSD disrupt sensorimotor gating by agonist actions at DA receptors.
125 VENTRICULAR TO BRAIN RATIO AND BLINK RATE
CHANGES PREDICT CLINICAL RESPONSE TO ACUTE AMPHETAMINE CHALLENGE IN SCHIZOPHRENIA Llewellyn B. Bigelow, M.D., Terry E. Goldberg, Ph.D. (by invitation), David G. Daniel, M.D., Ph.D. (by invitation), Joel E. Kleinman, M.D., Daniel R. Weinberger, M.D. Clinical Brain Disorders Branch, National lnsthute of Mental Health Neuroscience Center, Washington, D.C. 20032. As part of a larger investigation of the effects of dopamine agonist administration in chronic schizophrenia, we have administered to 21 patients a single oral dose of 0.25 mg/kg body weight amphetamine using a double-blind, placebo-controlled design. All patients were receiving concomitant haloperidol. Six of these patients were judged by blind videotape ratings as showing clinical improvement with active amphetamine. Compared with nonresponders, those who improved had a greater ventricular to brain ratio (p < 0.02) and greater increase in blink rate on amphetamine treatment (p < 0.01). Cognitive testing did not reveal any amphetamine effect on memory or attention, but there was improved performance on some parameters of the Wisconsin Card Sort task. These results suggest that a pharmacological subclassification might be possible and support the hypothesis that some deficit symptoms are reversible with amphetamine.
126 RATES OF CEREBRAL GLUCOSE METABOLISM AFTER
NEUROLEPTIC wrI'HDRAWAL IN SCHIZOPHRENIC PATIENTS N.G. Cascella, H.H. Holcomb, L.B. Dixon, G.K. Thaker, R. Dannals, H. Wagner, C.A. Tamminga Maryland Psychiatric Research Center, Baltimore, MD 21228. Previous studies, using positron emission tomography and tSF-2-deoxyglucose technique, have shown that neuroleptics increase the regional cerebral metabolic rate of glucose (rCMRglu) utilization in the basal ganglia of schizophrenic patients and induce metabolic normalization of brain areas involved in performing
98A
BIOL PSYCHIATRY 1990;27:41A- 179A
Schizophrenia II
a continuous auditory task. The goal of the present study is to assess the localization and time course of changes in rCMRglu upon neuroleptic withdrawal in schizophrenic patients. Sixteen chronic schizophrenic patients were scanned three tiradesdufirig the study: on haloperidol (20-30 mg at HS x 4-b weeks), at 57 days after abrupt haloperidol cessation, and at 30-35 days after haloperidol withdrawal. Preliminary findings analyzed from 4 of the 16 patients studied, show that haloperidol increases rCMRglu in almost all brain regions sampled. Some regions (i.e., hippocampus, caudate, thalamus) showed what appears to be a "rebound" decrease at 5 days after drug withdrawal, with rCMRglu slightly lo~'verthan those at 30-35 days after ha!operidol cessation. A few areas (i.e., cingulate cortex) showed no "rebound" but a continued reduction in rCMRglu between 5 and 30 days after haloperidol discontinuation. The significance of the final findings will be discussed with respect to the involvement of specific brain areas in the antipsychotic activity of haloperidol. Furthermore, possible correlations between clinical and metabolic parameters will be presented.
127 LOW-DOSE BROMOCRIPTINE IN TREATMENT OF
SCHIZOPHRENIA AND TARDIVE DYSKINESIA Lauren B. Marangell, M.D., Stanley R. Kay, Ph.D., Jean-Pierre Lindenmayer, M.D. Department of Psychiatry, Albert Einstein College of Medicine/Montefiore Medical Center and Schizophrenia Research Program, Bronx Psychiatric Center, Bronx, New York 10461. Dopamine (DA) agonists can be used in low doses to preferentially stimulate presynaptic autoreceptors, thereby decreasing DA synthesis and release. Clinical application of this principle to treat conditions such as schizophrenia and tardive dyskinesia (TD) has been hindered by uncertainty as to which doses in humans will lead to relatively selective attenuation of DA activity. Furthermore, the disparity in previous research findings may be due to a preponderance of neuroleptic-free patients as well as differing study paradigms. To further address these issues, we conducted a 6 week single-blind, randomized crossover study of 2.5 rag/day adjuvant bromocriptine in 7 neuroleptic-treated, chronic schizophrenic patients with TD. Psychopathology as measured by the Positive and Negative Syndrome Scale (PANSS) showed selective improvements, particularly on thought disorder (p < 0.01) and activation (p < 0.05). Improvement in TD as measured by the Abnormal Involuntary Movement Scale (AIMS) was significantly greater under bromocriptine as compared with the control condition (p < 0.01). The data suggest that the bromocriptine in doses of 2.5 r,g, day when added to standard neuroleptic treatment may ameliorate selected psychopathological symptoms, especially positive features, and TD in patients with both chronic schizophrenia and TD.
128 TtIE PREVALENCE OF TARDIVE DYSKINESIA (TD) IS INCREASED IN NEUROLEPTIC-TREATED DIABETICS Linda Ganzini, M.D., Ronald Heintz, M.D., Daniel E. Casey, M.D., William Hoffman, M.D. Department of Psychiatry, Ve(eransAffairs Medical Center, Portland, Oregon 97207. Each of 38 neuroleptic-treated diabetics (ND) were matched to a neuroleptic-treated nondiabetic control (NC) on 5 parameters: age, gender, psychiatric diagnosis, neuroleptic (NL) dose, and time on NL treatment. All were on stable doses of NLs. A rater, blind to all diagnoses and medications, assessed each subject for TD, P~:insonism, and cognitive deficits with the Abnormal Involuntary Movement Scale (AIMS), Sct Hans Dyskinesia Scale (SHDS), Sct Hans Parkinsonism Scale (SHPS), and the Mini-Mental State Exam (MMSE). 1~e group was predominantly older (mean age 62.7 years), treated long term with NLs (mean 18. I years) and treated with low to moderate doses of NLs (mean 303 chlorpromazine eq/day). Of the ND group, 79% met Schooler-Kane criteria for TD as compared wkh 53% of the NC group (p = 0.02). Mean AIMS score for ND was 7.6 as compared with 5.2 for NC (p = 0.004), mean SI-IDS summed score,
BIOL PSYCHIATRY 1990;27:41A- 179A
97A
124 DOPAMINERGIC EFFECTS OF LSD IN AN ANIMAL MODEL OF
SENSORIMOTOR-GATING DEFICITS IN SCHIZOPHRENIA Mark A. Geyer, Ph.D., David L. Braff, M.D. Department of Psychiatry, University of California-San Diel,o School of Medicine, La Jolla, CA 92093. Although primarily a serotonin (5-HT) agonist, lysergic acid diethylamide (LSD) also has dopamine (DA)agonist activity. The relative importance of 5-HT and DA systems in the behavioral effects of LSD is unclear. We investigated the effects of LSD on prepulse inhibition of acoustic startle, a form. of sensorimotor gating that is sensitive to disruption by the DA agonists apomorphine, quinp'~role, and amphetamine. These DA effects mimic the loss of sensorimotor gating exhibited by schizophrenic patients in parallel tests of prepulse inhibition. Rats were subjected to 120 dB acoustic pulses, some of which were preceded at a 100 msec interval by a weak 75 dB prepulse stimulus. After saline, the prepulse reduced whole-body startle responses elicited by the pulse by approximately 50%. LSD (50, 100, or 200 p,g/kg body weight) significantly decreased the amount of prepulse inhibition. A subsequent study replicated the effect of 200 ~g/kg LSD and demonstrated that it could be blocked by the DA antagonist haloperidol (0. l mg/kg) but not by a dose of the S-HT-2 antagonist ritanserin (2.0 mg/kg), which is sufficient to block behavioral effects of 5-HT agonists. These results suggest that high doses ~f LSD disrupt sensorimotor gating by agonist actions at DA receptors.
125 VENTRICULAR TO BRAIN RATIO AND BLINK RATE
CHANGES PREDICT CLINICAL RESPONSE TO ACUTE AMPHETAMINE CHALLENGE IN SCHIZOPHRENIA Llewellyn B. Bigelow, M.D., Terry E. Goldberg, Ph.D. (by invitation), David G. Daniel, M.D., Ph.D. (by invitation), Joel E. Kleinman, M.D., Daniel R. Weinberger, M.D. Clinical Brain Disorders Branch, National lnsthute of Mental Health Neuroscience Center, Washington, D.C. 20032. As part of a larger investigation of the effects of dopamine agonist administration in chronic schizophrenia, we have administered to 21 patients a single oral dose of 0.25 mg/kg body weight amphetamine using a double-blind, placebo-controlled design. All patients were receiving concomitant haloperidol. Six of these patients were judged by blind videotape ratings as showing clinical improvement with active amphetamine. Compared with nonresponders, those who improved had a greater ventricular to brain ratio (p < 0.02) and greater increase in blink rate on amphetamine treatment (p < 0.01). Cognitive testing did not reveal any amphetamine effect on memory or attention, but there was improved performance on some parameters of the Wisconsin Card Sort task. These results suggest that a pharmacological subclassification might be possible and support the hypothesis that some deficit symptoms are reversible with amphetamine.
126 RATES OF CEREBRAL GLUCOSE METABOLISM AFTER
NEUROLEPTIC wrI'HDRAWAL IN SCHIZOPHRENIC PATIENTS N.G. Cascella, H.H. Holcomb, L.B. Dixon, G.K. Thaker, R. Dannals, H. Wagner, C.A. Tamminga Maryland Psychiatric Research Center, Baltimore, MD 21228. Previous studies, using positron emission tomography and tSF-2-deoxyglucose technique, have shown that neuroleptics increase the regional cerebral metabolic rate of glucose (rCMRglu) utilization in the basal ganglia of schizophrenic patients and induce metabolic normalization of brain areas involved in performing
98A
BIOL PSYCHIATRY 1990;27:41A- 179A
Schizophrenia II
a continuous auditory task. The goal of the present study is to assess the localization and time course of changes in rCMRglu upon neuroleptic withdrawal in schizophrenic patients. Sixteen chronic schizophrenic patients were scanned three tiradesdufirig the study: on haloperidol (20-30 mg at HS x 4-b weeks), at 57 days after abrupt haloperidol cessation, and at 30-35 days after haloperidol withdrawal. Preliminary findings analyzed from 4 of the 16 patients studied, show that haloperidol increases rCMRglu in almost all brain regions sampled. Some regions (i.e., hippocampus, caudate, thalamus) showed what appears to be a "rebound" decrease at 5 days after drug withdrawal, with rCMRglu slightly lo~'verthan those at 30-35 days after ha!operidol cessation. A few areas (i.e., cingulate cortex) showed no "rebound" but a continued reduction in rCMRglu between 5 and 30 days after haloperidol discontinuation. The significance of the final findings will be discussed with respect to the involvement of specific brain areas in the antipsychotic activity of haloperidol. Furthermore, possible correlations between clinical and metabolic parameters will be presented.
127 LOW-DOSE BROMOCRIPTINE IN TREATMENT OF
SCHIZOPHRENIA AND TARDIVE DYSKINESIA Lauren B. Marangell, M.D., Stanley R. Kay, Ph.D., Jean-Pierre Lindenmayer, M.D. Department of Psychiatry, Albert Einstein College of Medicine/Montefiore Medical Center and Schizophrenia Research Program, Bronx Psychiatric Center, Bronx, New York 10461. Dopamine (DA) agonists can be used in low doses to preferentially stimulate presynaptic autoreceptors, thereby decreasing DA synthesis and release. Clinical application of this principle to treat conditions such as schizophrenia and tardive dyskinesia (TD) has been hindered by uncertainty as to which doses in humans will lead to relatively selective attenuation of DA activity. Furthermore, the disparity in previous research findings may be due to a preponderance of neuroleptic-free patients as well as differing study paradigms. To further address these issues, we conducted a 6 week single-blind, randomized crossover study of 2.5 rag/day adjuvant bromocriptine in 7 neuroleptic-treated, chronic schizophrenic patients with TD. Psychopathology as measured by the Positive and Negative Syndrome Scale (PANSS) showed selective improvements, particularly on thought disorder (p < 0.01) and activation (p < 0.05). Improvement in TD as measured by the Abnormal Involuntary Movement Scale (AIMS) was significantly greater under bromocriptine as compared with the control condition (p < 0.01). The data suggest that the bromocriptine in doses of 2.5 r,g, day when added to standard neuroleptic treatment may ameliorate selected psychopathological symptoms, especially positive features, and TD in patients with both chronic schizophrenia and TD.
128 TtIE PREVALENCE OF TARDIVE DYSKINESIA (TD) IS INCREASED IN NEUROLEPTIC-TREATED DIABETICS Linda Ganzini, M.D., Ronald Heintz, M.D., Daniel E. Casey, M.D., William Hoffman, M.D. Department of Psychiatry, Ve(eransAffairs Medical Center, Portland, Oregon 97207. Each of 38 neuroleptic-treated diabetics (ND) were matched to a neuroleptic-treated nondiabetic control (NC) on 5 parameters: age, gender, psychiatric diagnosis, neuroleptic (NL) dose, and time on NL treatment. All were on stable doses of NLs. A rater, blind to all diagnoses and medications, assessed each subject for TD, P~:insonism, and cognitive deficits with the Abnormal Involuntary Movement Scale (AIMS), Sct Hans Dyskinesia Scale (SHDS), Sct Hans Parkinsonism Scale (SHPS), and the Mini-Mental State Exam (MMSE). 1~e group was predominantly older (mean age 62.7 years), treated long term with NLs (mean 18. I years) and treated with low to moderate doses of NLs (mean 303 chlorpromazine eq/day). Of the ND group, 79% met Schooler-Kane criteria for TD as compared wkh 53% of the NC group (p = 0.02). Mean AIMS score for ND was 7.6 as compared with 5.2 for NC (p = 0.004), mean SI-IDS summed score,