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Disturbances of one-carbon metabolism in schizophrenia
175
P Poster Presentations
I P-15-23I
Disturbances of One-Carbon Metabolism in Schizophrenia
B. Regland. e.G. Gottfries, B. Grenfeldt. University ofGoreborg, lnstitute of Clinical Neuroscience. Dept of Psychiatry and Neurochemistry, Molndal , Sweden Transfer of methyl groups to various acceptors in the brain is a vital process for the central nervous system, influencing e.g. monoamine metabolism and membrane functions. Since the 1960s remarkably consistent reports of negative clinical effects of methionine in schizophrenic patients have frustrated the hopes tied to the ' transmethylation hypothesis' of this disorder. However. recent data from a number of different sources suggest a basic disorder of transmethyl ation mechanisms in a proportion of schizophrenics. Results of earlier kinetic studies. showing decreased activity of the enzymes methionine-adenosyl transferase (MAT) and serine hydroxy-methyl transferase in erythrocytes from schizophrenics, have been corroborated regarding MAT in erythrocytes. A multivariate analysis of brain tissue from schizophrenics showed decreased levels of 3-methoxytyramine in the caudate of a paranoid subgroup, suggesting a decreased level of COMT activity which is also dependent of one-carbon metabolism. Kinetic studies on the rate of transfer of the radiotagged methyl group of methionine to C02 in the breath have shown that the rate was three times as slow in schizophrenics as in controls. In a controlled study of 20 patients with schizophrenia 9 showed a significant increase in blood homocysteine levels. indicating that methylation deficiency is implicated in the pathogenesis of schizophrenia. Investigations of cerebrospinal fluid are in progress.
IP-15-24!lmpaired LTP of Recurrent Inhibition OntoCA 1 Hippocampal Pyramidal Cells as a Cellular Basis of Schizophrenia R Grunze, D. Rainnie, E. Hearn, E. Barkai, M. Hasselrno, R. McCarley, R. Greene. Harvard Medic al School & VAMC. Department of Psychiatry. Brock/on MA 02401
Modulation of recurrent inhibition is critical not only for the normal function of highly excitable regions of the brain, especially the limbic system. but may also be important in prevention of excitotoxic damage. Post-mortem data indicate reduced numbers of GABAergic intemeurons while MRI data show marked volume reductions. especially limbic gray matter, in schizophrenics suggesting a possible role of excitotoxic damage in this disorder. In our study, extracellular and intracellular recordings from in vitro brain slices of rat hippocampi showed that recurrent inhibition onto CA I neurons is enhanced by NM DA- mediated long term 32 extracellular recordings and 29 potentiation (LTP; 15 ± 2%. n ± 3% in 4 intracellular recordings ). This LTP was completely blocked by the NMDA antagonists APV. MK-80J. phencyclidine (PCP) and the endogenous substance N-Acetyl-L-a spartyl-L-glutamic acid (NAAG). As NAAG is reported to be elevated in the limbic region of schizophrenics [I]. blocking the LTP of recurrent inhibition by low concentrations of NAAG may lead to an overall increase of neuronal network excitability, causing initially psychotic symptoms and in the long term cell loss by the excitotoxic effect of NMDA antagonists. These findings may also explain the increased behavioral excitability in rats seen on exposure to PCP. whose effects in man mimic positive schizophrenic symptoms. Realistic biophysica l simulation of reduced recurrent inhibition in hippocampal circuitry shows that this leads to "overgeneralization" of learned patterns. quite analogous to the overgeneralization of associations (reduced gradient) seen clinically in schizophrenia.
=
[ I] Tsai G. Passani L, Slushe r B, Ca rter R. Kleinman 1. Coy le J, Arch ives Gen . Psychiatry (l995), in press
I P-15-25!
Changes of Plasma Prolactin, ACTH, Cortisol & Clinical Symptoms After ECTin Schizophrenia RW Woo, WJ . Lim, l .W Kim, S.Y. Nam. Department of Psychiatry, Ewha Woman s University Hospital , Seoul, Korea
The purpose of this study was to observe the changes in the level of prolactin, ACTH, cortisol, and clinical symptoms after ECT at schizophrenic patients and to find out the correlations between the effect of ECT on
hypothalamic-pituitary axis and clinical symptoms. Subjects were 15 inpatients who met DSM IV diagnostic criteria for schizophrenia, and ECT was applied to them. Plasma levels of prolactin, ACTH and cortisol 15 minutes before(preECT)and after(postECT) the 1st and 8th ECT were measured by RIA. Clinical symptoms were assessed by Brief Psychiatric Rating Scale. The results are as follows : I. After the 8th ECT, BPRS scores, especially thinking disturbances and withdrawal/retardation were significantly decreased as compared with those of the 1st ECT(p < 0.0 I). 2. Plasma levels of postECT prolactin. ACTH and cortisol were significantly higher than preECT levels of the 1st and 8th ECT. 3. Plasma levels of preECT prolactin at 8th ECT were significantly lower than the baseline levels(p < 0.05) and the response rate of prolactin(postECT -preECf) was significantly decreased on the 8th ECT as compared with the 1st ECT(p < 0.05). In conclusion, repeated ECT were related to increased activity of dopaminergic receptor, which can explain the effect ofECT on the improvement of negative symptoms in chronic schzophrenia.
I P-16-1 I Hydrocortisone-Induced Corticotropin Responses during the Menstrual Cycle F. Burnett, J.R Thakore, T.G. Dinan. Dept of Psycho! Med, St Bartholomew's Hospital, London, UK
Intravenous infusion of hydrocortisone in healthy volunteers results in a rapid decrease in plasma corticotropin (ACfH) levels, indicating the existence of a rate sensitive feedback mechanism within the hypothalamic-pituitary-adrenal axis. Cortisol is believed to reduce serum ACTH by acting on adrenocorticoid receptors. As sex steroids have a profound influence on the activity of glucocorticoid and mineralocorticoid receptors, we decided to characterise the effects of menstrual cycle status on fast feedback mechanisms in healthy females. Eight volunteers were tested during two menstrual cycles. Subjects were cannulated in both arms and allowed to rest for 30 min. Baseline samples of estradiol. progesterone. luteinizing hormone. cortisol and ACTH were drawn prior to the administration of hydrocortisone. At 900 hr hydrocortisone (20 mg) or placebo. was infused over a I hr period. Plasma levels of cortisol and ACTH were taken at + 15. +30, +45, +60. +90 and +120 min from the other arm. Fast feedback mechanisms, as indicated by hydrocortisoneinduced ACTH release, varied significantly throughout the menstrual cycle.
I
P-16-2 1 Effects of Metyrapone Treatment Upon Hormonal Secretion and Sleep
H. Jahn, K. Wiedemann, A. Steiger. Department of Psychiatry, Max Planck Institute ofPsychiatry, Clinical Institute, Munich, Germany Steroid hormones specifically modulate sleep EEG and the sleepassociated hormonal secretion mainly through nuclear receptors: the mineralocorticoid and the glucocorticoid receptor. Glucocorticoid receptor antagonists induce a profound deterioration of the nocturnal sleep pattern with frequent awakenings and a reduction of slow wave sleep (SWS) and REM sleep. the morning rise of plasma ACTH and cortisol is enhanced. To complementarily characterize a reduced glucocorticoid receptor occupation by depletion of endogenous cortisol, we administered metyrapone to 8 healthy volunteers. Metyrapone is known to inhibit the l l-,B-hydroxylase enzyme and therefore to reduce the synthesis and secretion of cortisol by the adrenals. In randomized order, the healthy controls received 2 dosages of metyrapone (4.5 and 6 g) in compar ison to placebo the day before sleep EEG recordings. The cortisol secretion from 22:00 to 07:00 h remained largely unchanged, whereas the ACTH secretion in (he morning (04:00- 07:00 h) was significantly enhanced by the higher dosage (AVC values: 932 ± 320 vs. 175 ± 20, P < 0.05; contrasts in MANOVAl. Both dosages induced a significant reduction of SWS sleep, but had no effect upon REM sleep. Our results indicate that also blockade of thc cortisol synthesis induces pronounced effects on hormonal secretion and sleep EEG. presumably by an enhanced release of corticotropine-releasing hormone and the consecutive ACTH surge to compensate for the reduction in cortisol plasma levels.
P Poster Presentations
I P-15-23I
Disturbances of One-Carbon Metabolism in Schizophrenia
B. Regland. e.G. Gottfries, B. Grenfeldt. University ofGoreborg, lnstitute of Clinical Neuroscience. Dept of Psychiatry and Neurochemistry, Molndal , Sweden Transfer of methyl groups to various acceptors in the brain is a vital process for the central nervous system, influencing e.g. monoamine metabolism and membrane functions. Since the 1960s remarkably consistent reports of negative clinical effects of methionine in schizophrenic patients have frustrated the hopes tied to the ' transmethylation hypothesis' of this disorder. However. recent data from a number of different sources suggest a basic disorder of transmethyl ation mechanisms in a proportion of schizophrenics. Results of earlier kinetic studies. showing decreased activity of the enzymes methionine-adenosyl transferase (MAT) and serine hydroxy-methyl transferase in erythrocytes from schizophrenics, have been corroborated regarding MAT in erythrocytes. A multivariate analysis of brain tissue from schizophrenics showed decreased levels of 3-methoxytyramine in the caudate of a paranoid subgroup, suggesting a decreased level of COMT activity which is also dependent of one-carbon metabolism. Kinetic studies on the rate of transfer of the radiotagged methyl group of methionine to C02 in the breath have shown that the rate was three times as slow in schizophrenics as in controls. In a controlled study of 20 patients with schizophrenia 9 showed a significant increase in blood homocysteine levels. indicating that methylation deficiency is implicated in the pathogenesis of schizophrenia. Investigations of cerebrospinal fluid are in progress.
IP-15-24!lmpaired LTP of Recurrent Inhibition OntoCA 1 Hippocampal Pyramidal Cells as a Cellular Basis of Schizophrenia R Grunze, D. Rainnie, E. Hearn, E. Barkai, M. Hasselrno, R. McCarley, R. Greene. Harvard Medic al School & VAMC. Department of Psychiatry. Brock/on MA 02401
Modulation of recurrent inhibition is critical not only for the normal function of highly excitable regions of the brain, especially the limbic system. but may also be important in prevention of excitotoxic damage. Post-mortem data indicate reduced numbers of GABAergic intemeurons while MRI data show marked volume reductions. especially limbic gray matter, in schizophrenics suggesting a possible role of excitotoxic damage in this disorder. In our study, extracellular and intracellular recordings from in vitro brain slices of rat hippocampi showed that recurrent inhibition onto CA I neurons is enhanced by NM DA- mediated long term 32 extracellular recordings and 29 potentiation (LTP; 15 ± 2%. n ± 3% in 4 intracellular recordings ). This LTP was completely blocked by the NMDA antagonists APV. MK-80J. phencyclidine (PCP) and the endogenous substance N-Acetyl-L-a spartyl-L-glutamic acid (NAAG). As NAAG is reported to be elevated in the limbic region of schizophrenics [I]. blocking the LTP of recurrent inhibition by low concentrations of NAAG may lead to an overall increase of neuronal network excitability, causing initially psychotic symptoms and in the long term cell loss by the excitotoxic effect of NMDA antagonists. These findings may also explain the increased behavioral excitability in rats seen on exposure to PCP. whose effects in man mimic positive schizophrenic symptoms. Realistic biophysica l simulation of reduced recurrent inhibition in hippocampal circuitry shows that this leads to "overgeneralization" of learned patterns. quite analogous to the overgeneralization of associations (reduced gradient) seen clinically in schizophrenia.
=
[ I] Tsai G. Passani L, Slushe r B, Ca rter R. Kleinman 1. Coy le J, Arch ives Gen . Psychiatry (l995), in press
I P-15-25!
Changes of Plasma Prolactin, ACTH, Cortisol & Clinical Symptoms After ECTin Schizophrenia RW Woo, WJ . Lim, l .W Kim, S.Y. Nam. Department of Psychiatry, Ewha Woman s University Hospital , Seoul, Korea
The purpose of this study was to observe the changes in the level of prolactin, ACTH, cortisol, and clinical symptoms after ECT at schizophrenic patients and to find out the correlations between the effect of ECT on
hypothalamic-pituitary axis and clinical symptoms. Subjects were 15 inpatients who met DSM IV diagnostic criteria for schizophrenia, and ECT was applied to them. Plasma levels of prolactin, ACTH and cortisol 15 minutes before(preECT)and after(postECT) the 1st and 8th ECT were measured by RIA. Clinical symptoms were assessed by Brief Psychiatric Rating Scale. The results are as follows : I. After the 8th ECT, BPRS scores, especially thinking disturbances and withdrawal/retardation were significantly decreased as compared with those of the 1st ECT(p < 0.0 I). 2. Plasma levels of postECT prolactin. ACTH and cortisol were significantly higher than preECT levels of the 1st and 8th ECT. 3. Plasma levels of preECT prolactin at 8th ECT were significantly lower than the baseline levels(p < 0.05) and the response rate of prolactin(postECT -preECf) was significantly decreased on the 8th ECT as compared with the 1st ECT(p < 0.05). In conclusion, repeated ECT were related to increased activity of dopaminergic receptor, which can explain the effect ofECT on the improvement of negative symptoms in chronic schzophrenia.
I P-16-1 I Hydrocortisone-Induced Corticotropin Responses during the Menstrual Cycle F. Burnett, J.R Thakore, T.G. Dinan. Dept of Psycho! Med, St Bartholomew's Hospital, London, UK
Intravenous infusion of hydrocortisone in healthy volunteers results in a rapid decrease in plasma corticotropin (ACfH) levels, indicating the existence of a rate sensitive feedback mechanism within the hypothalamic-pituitary-adrenal axis. Cortisol is believed to reduce serum ACTH by acting on adrenocorticoid receptors. As sex steroids have a profound influence on the activity of glucocorticoid and mineralocorticoid receptors, we decided to characterise the effects of menstrual cycle status on fast feedback mechanisms in healthy females. Eight volunteers were tested during two menstrual cycles. Subjects were cannulated in both arms and allowed to rest for 30 min. Baseline samples of estradiol. progesterone. luteinizing hormone. cortisol and ACTH were drawn prior to the administration of hydrocortisone. At 900 hr hydrocortisone (20 mg) or placebo. was infused over a I hr period. Plasma levels of cortisol and ACTH were taken at + 15. +30, +45, +60. +90 and +120 min from the other arm. Fast feedback mechanisms, as indicated by hydrocortisoneinduced ACTH release, varied significantly throughout the menstrual cycle.
I
P-16-2 1 Effects of Metyrapone Treatment Upon Hormonal Secretion and Sleep
H. Jahn, K. Wiedemann, A. Steiger. Department of Psychiatry, Max Planck Institute ofPsychiatry, Clinical Institute, Munich, Germany Steroid hormones specifically modulate sleep EEG and the sleepassociated hormonal secretion mainly through nuclear receptors: the mineralocorticoid and the glucocorticoid receptor. Glucocorticoid receptor antagonists induce a profound deterioration of the nocturnal sleep pattern with frequent awakenings and a reduction of slow wave sleep (SWS) and REM sleep. the morning rise of plasma ACTH and cortisol is enhanced. To complementarily characterize a reduced glucocorticoid receptor occupation by depletion of endogenous cortisol, we administered metyrapone to 8 healthy volunteers. Metyrapone is known to inhibit the l l-,B-hydroxylase enzyme and therefore to reduce the synthesis and secretion of cortisol by the adrenals. In randomized order, the healthy controls received 2 dosages of metyrapone (4.5 and 6 g) in compar ison to placebo the day before sleep EEG recordings. The cortisol secretion from 22:00 to 07:00 h remained largely unchanged, whereas the ACTH secretion in (he morning (04:00- 07:00 h) was significantly enhanced by the higher dosage (AVC values: 932 ± 320 vs. 175 ± 20, P < 0.05; contrasts in MANOVAl. Both dosages induced a significant reduction of SWS sleep, but had no effect upon REM sleep. Our results indicate that also blockade of thc cortisol synthesis induces pronounced effects on hormonal secretion and sleep EEG. presumably by an enhanced release of corticotropine-releasing hormone and the consecutive ACTH surge to compensate for the reduction in cortisol plasma levels.