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Dopamine turnover in schizophrenia before and after haloperidol withdrawal: CSF, plasma and urine studies
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patients have higher rates of dexamethasone-suppression-test (DST) nonsuppression than the general population. The nonsuppression rates in neuroleptic-free patients ranged from 18% to 50% [1], and after 3-4 weeks of neuroleptic treatment a significant number of the nonsuppressors normalized their response to DST. DST resistance among nonhuman primates is associated with a selective decrease of glucocorticoid receptors in hippocampus [3]. A study analyzed the stress response associated to lumbar puncture and showed that schizophrenic patients did not have the normal response of increased levels of GH, cortisol and ACTH [2]. We present the development of a semiquantitative RT-PCR-EIA (reverse transcriptionpolymerase chain reaction-enzyme immunoassay) for the detection of glucocorticoid receptor mRNA in human hippocampus and peripheral blood mononuclear cells (PBMC). This essay will be used for evaluation of glucocorticoid receptor mRNA expression in schizophrenia. 1. Tandon et al. (1991) Biological Psychiatry 29: 953-964. 2. Breier et al. (1988) Psychiatry Research 25: 187-194. 3. Brooke et al. (1994) Neuroendocrinology 60: 134-140.
MEASUREMENT OF HIPPOCAMPAL GLUCOCORTICOID RECEPTORS IN SUICIDE E. Szigethy, M.T. Lowy, C.A. Stockmeier, J. Overholser, H.Y. Meltzer Abnormal hypothalamic-pituitary-adrenal (HPA) axis activation has been implicated in the pathophysiology of suicide. Numerous studies have supported the hypothesis that the hippocampus serves as a regulatory center for glucocorticoid secretion in rodent, primate, and human brains. In particular, hippocampal glucocorticoid receptors (GR) have been shown to be involved in the negative feedback regulation of the HPA axis. The goal of the present study is two-fold: (1) To characterize GR in postmortem human hippocampus using Western blots and immunohistochemistry; and (2) Using these techniques, to compare the density of hippocampal GR in suicides and matched controls. These latter findings will be correlated with psychological autopsy results to determine the role of variables such as diagnoses of depression and schizophrenia in regulation of hippocampal GR. Given preliminary findings, it is predicted that suicide, especially by violent means, will be associated with diminished number of hippocampal GR. Such a decrease would provide impetus for the development of psychopharmacological agents which could increase the number of hippocampal GR and suppress the activity of the HPA axis. Supported by grants from the American Suicide Foundation, MH45488 and MH41684.
DOPAMINE TURNOVER IN SCHIZOPHRENIA BEFORE AND AFTER HALOPERIDOL WITHDRAWAL: CSF, PLASMA AND URINE STUDIES M a r k Beuger*, Daniel P. van Kammen, Jeffrey K. Yao, Mary E. Kelley
University of Pittsburgh School of Medicine, 3811 O'Hara St., Pittsburgh, PA 15213, USA Background: CSF and plasma homovanillic acid (HVA) levels and urinary production of HVA have been studied following antipsychotic drug withdrawal, but rarely in the same patients. We designed a haloperidol withdrawal study to examine the effects of medication and clinical state, and the interaction between the two, on CSF and plasma HVA levels and urinary clearance of HVA in schizophrenic patients. Method: CSF and plasma HVA samples were obtained in 72 healthy schizophrenic (DSM-III-R) males (age: 36+7.4 years), before and after haloperidol withdrawal, either after six weeks of placebo or when they met relapse criteria, whichever came first. We collected 3 times 24 h urine samples for HVA in 34 of the 72 subjects. Results: CSF HVA decreased significantly after drug withdrawal. Plasma HVA increased significantly after withdrawal in relapsing patients, but not in non-relapsers, indicating a relapse x medication effect. Urinary HVA production decreased after withdrawal in both groups as did HVA clearance. Conclusions: Haloperidol withdrawal decreased dopamine turnover and increased removal of HVA from the CSF. The higher plasma levels of HVA in drug-free relapsed patients may be caused by the combined haloperidol withdrawal effect on HVA removal from the CSF and decreased urinary clearance, in addition to increased peripheral autonomic arousal associated with relapse.
PREDICTING HALOPERIDOL TREATMENT RESPONSE IN CHRONIC SCHIZOPHRENIA Daniel P. van Kammen*, Mary E. Kelley, Jeffrey K. Yao, M a r k W. Gilbertson, John A. Gurklis, Takei Inosaka, Jeffrey L. Peters
University of Pittsburgh School of Medicine, 3811 O'Hara St., Pittsburgh, PA 15213, USA Objective: To identify patient characteristics that predict remission and amount of clinical improvement with haloperidol in chronic schizophrenic (DSM Ill-R) patients prior to treatment. Methods: 35 acutely relapsed schizophrenic patients were entered into a double-blind haloperidol treatment protocol for six weeks. Pre-treatment measures were assessed for predictions of both remission status (dichotomous) and for correlations with change in psychopathology (continuous). Results: Later age of onset and higher plasma HVA values
patients have higher rates of dexamethasone-suppression-test (DST) nonsuppression than the general population. The nonsuppression rates in neuroleptic-free patients ranged from 18% to 50% [1], and after 3-4 weeks of neuroleptic treatment a significant number of the nonsuppressors normalized their response to DST. DST resistance among nonhuman primates is associated with a selective decrease of glucocorticoid receptors in hippocampus [3]. A study analyzed the stress response associated to lumbar puncture and showed that schizophrenic patients did not have the normal response of increased levels of GH, cortisol and ACTH [2]. We present the development of a semiquantitative RT-PCR-EIA (reverse transcriptionpolymerase chain reaction-enzyme immunoassay) for the detection of glucocorticoid receptor mRNA in human hippocampus and peripheral blood mononuclear cells (PBMC). This essay will be used for evaluation of glucocorticoid receptor mRNA expression in schizophrenia. 1. Tandon et al. (1991) Biological Psychiatry 29: 953-964. 2. Breier et al. (1988) Psychiatry Research 25: 187-194. 3. Brooke et al. (1994) Neuroendocrinology 60: 134-140.
MEASUREMENT OF HIPPOCAMPAL GLUCOCORTICOID RECEPTORS IN SUICIDE E. Szigethy, M.T. Lowy, C.A. Stockmeier, J. Overholser, H.Y. Meltzer Abnormal hypothalamic-pituitary-adrenal (HPA) axis activation has been implicated in the pathophysiology of suicide. Numerous studies have supported the hypothesis that the hippocampus serves as a regulatory center for glucocorticoid secretion in rodent, primate, and human brains. In particular, hippocampal glucocorticoid receptors (GR) have been shown to be involved in the negative feedback regulation of the HPA axis. The goal of the present study is two-fold: (1) To characterize GR in postmortem human hippocampus using Western blots and immunohistochemistry; and (2) Using these techniques, to compare the density of hippocampal GR in suicides and matched controls. These latter findings will be correlated with psychological autopsy results to determine the role of variables such as diagnoses of depression and schizophrenia in regulation of hippocampal GR. Given preliminary findings, it is predicted that suicide, especially by violent means, will be associated with diminished number of hippocampal GR. Such a decrease would provide impetus for the development of psychopharmacological agents which could increase the number of hippocampal GR and suppress the activity of the HPA axis. Supported by grants from the American Suicide Foundation, MH45488 and MH41684.
DOPAMINE TURNOVER IN SCHIZOPHRENIA BEFORE AND AFTER HALOPERIDOL WITHDRAWAL: CSF, PLASMA AND URINE STUDIES M a r k Beuger*, Daniel P. van Kammen, Jeffrey K. Yao, Mary E. Kelley
University of Pittsburgh School of Medicine, 3811 O'Hara St., Pittsburgh, PA 15213, USA Background: CSF and plasma homovanillic acid (HVA) levels and urinary production of HVA have been studied following antipsychotic drug withdrawal, but rarely in the same patients. We designed a haloperidol withdrawal study to examine the effects of medication and clinical state, and the interaction between the two, on CSF and plasma HVA levels and urinary clearance of HVA in schizophrenic patients. Method: CSF and plasma HVA samples were obtained in 72 healthy schizophrenic (DSM-III-R) males (age: 36+7.4 years), before and after haloperidol withdrawal, either after six weeks of placebo or when they met relapse criteria, whichever came first. We collected 3 times 24 h urine samples for HVA in 34 of the 72 subjects. Results: CSF HVA decreased significantly after drug withdrawal. Plasma HVA increased significantly after withdrawal in relapsing patients, but not in non-relapsers, indicating a relapse x medication effect. Urinary HVA production decreased after withdrawal in both groups as did HVA clearance. Conclusions: Haloperidol withdrawal decreased dopamine turnover and increased removal of HVA from the CSF. The higher plasma levels of HVA in drug-free relapsed patients may be caused by the combined haloperidol withdrawal effect on HVA removal from the CSF and decreased urinary clearance, in addition to increased peripheral autonomic arousal associated with relapse.
PREDICTING HALOPERIDOL TREATMENT RESPONSE IN CHRONIC SCHIZOPHRENIA Daniel P. van Kammen*, Mary E. Kelley, Jeffrey K. Yao, M a r k W. Gilbertson, John A. Gurklis, Takei Inosaka, Jeffrey L. Peters
University of Pittsburgh School of Medicine, 3811 O'Hara St., Pittsburgh, PA 15213, USA Objective: To identify patient characteristics that predict remission and amount of clinical improvement with haloperidol in chronic schizophrenic (DSM Ill-R) patients prior to treatment. Methods: 35 acutely relapsed schizophrenic patients were entered into a double-blind haloperidol treatment protocol for six weeks. Pre-treatment measures were assessed for predictions of both remission status (dichotomous) and for correlations with change in psychopathology (continuous). Results: Later age of onset and higher plasma HVA values