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PLATELET-SEROTONIN LEVEL IN CHILDREN WITH " MINIMAL BRAIN DYSFUNCTION "
1012
PLATELET-SEROTONIN LEVEL IN CHILDREN WITH " MINIMAL BRAIN DYSFUNCTION " SIR,-Ishould like to communicate some preliminary of a metabolic study of children with the syndrome findings of " minimal brain dysfunction ". I take the view that one subgroup of these children (variously diagnosed as " hyperactive ", " minimally brain damaged ", " minimally cerebrally dysfunctioned ") may suffer, not from anatomical damage to the brain, but from a genetically transmitted metabolic defect.! On the basis of this hypothesis it was predicted that children coming from families with multiple occurrences of the syndrome would show abnormalities in the metabolism of noradrenaline, dopamine, or serotonin. To test this hypothesis, two investigations were undertaken: (1) a study of the urinary metabolites of the above compounds,2 and (2) a study of the level of platelet-serotonin. Pletscher3 has hypothesised that the platelet may serve as a model for the central neuron in regard to uptake and release of serotonin. Accordingly, we decided to investigate serotonin levels in a group of children who had been " " diagnosed as hyperactive ", and minimally cerebrally and who dysfunctioned ", displayed no evidence of defect. neurological 14 patients were investigated, all between the ages of 5 and 13. Each of the children had been diagnosed, on the basis of parents’ and teachers’ reports, as having " minimal cerebral dysfunction". The defining signs were " hyperactivity ", excessive distractability and inability to focus attention, affective volatility, intractability, and negativism. All but one of the children (patient 3) were of normal
intelligence, but approximately half were reported as having learning disorders "-heterogeneously defined problems mainly referring to an inability to learn which seemed discrepant with the child’s intellectual abilities. None of the children had a history of neurological insult or any evidence of neurological damage. 7 of the children came from two families. Family " 8 " consisted of 4 sibs who had an emotionally unstable mother and a manic-depressive maternal grandmother. Family " 9 " consisted of 3 sibs whose father was a borderline paranoid schizophrenic, and whose mother described herself as having been excessively active and a poor student during her childhood. The children were placed on a hydroxyindole-poor diet (no fruit or fruit juices, nuts, or eggplant) for 3 days, and whole-blood total 5-hydroxyindoles were determined by the "
method of Undenfriend et a1.4 The measurements were at the C.R.C. Neurology Laboratory, Children’s Hospital of D.C. under the supervision of Dr. Mary Coleman. Dr. Coleman reports that with this method normal values for children in this laboratory are between 110 and 200 ng. per ml. The 14 children fell into three groups:
performed
1. 2. 3. 4.
Wender, P. H. Unpublished. Wender, P. H., Epstein, R., Kopin, I. Unpublished. Pletscher, A. Br. J. Pharmac. Chemother. 1968, 32, 1. Undenfriend, S., Weissbach, H., Brodie, B. B. Methods of Biochemical Analysis; vol. VI, p. 95. New York, 1958.
The patients fell into three groups : the first group of children have borderline 5-hydroxyindole values; the middle group have depressed levels which, Dr. Coleman reports, are consistently seen in patients reacting to admission to hospital or undergoing other temporary upsets; and the last group, a group of siblings who have notably abnormal values. These low values might be produced by several mechanisms. The source of platelet-serotonin is the gut. Serotonin is produced in the intestinal mucosa, released into the blood, actively transported against a concentration gradient into the platelet, where it is bound and subsequently released. Accordingly the depression of the platelet-serotonin might be the result of any of several mechanisms: deficient production or release, deficient uptake by the platelet, excessive uptake by other sites, deficient binding by the platelet (with excessive release), or any combination of these. It remains to be demonstrated whether the low 5-hydroxyindole values are a primary abnormality or merely one of several non-specific responses to stress (like increased steroid release). For example, it is known that noradrenaline competes with serotonin transport mechanisms and if noradrenaline compound is released in stressful periods, it would be expected to compete with serotonin and displace it from the platelet. The observation that many children apparently have transiently low values when admitted to hospital without manifesting minimal-cerebral-dysfunction behaviour abnormalities militates against the view that the moderately depressed values which we found are of primary xtiological
significance. Currently the " 9 family is being investigated to determine which, if any, of the hypothesised mechanisms account for the depressed 5-hydroxyindole values. "
Laboratory of Psychology, National Institute of Mental Health, Bethesda, Maryland
20014.
PAUL H. WENDER.
EFFECT OF LITHIUM ON CARBOHYDRATE METABOLISM use of lithium in the treatment of manicSIR,-The depressive disorders has drawn attention to the side-effects of this ion. One of these is weight-gain, which in some cases leads the patient to refuse to continue lithium treatment. We have investigated the influence of lithium on glycogen metabolism in rats, and have found that 500-1200 moles of lithium chloride, injected intraperitoneally, increases the glycogen content of both brain and diaphragm.l This is presumably due to a direct effect on the transport of glucose across the cell-membrane, since it has been shown that lithium also increases diaphragm-glycogen in vitro.2,3 The most interesting finding was, however, that lithium caused an almost complete disappearance of liver-glycogen.4 The decrease in liver-glycogen was significant half an hour after the injection, and after 2 hours only a minimal amount of glycogen remained. Even after 24 hours the liverglycogen was still substantially reduced. Parallel with these changes there was an initial increase in blood-glucose, followed by a return to normal values, or to below-normal values when larger doses of lithium were used. One possible explanation of these results is that lithium chloride might have stimulated glucagon secretion. This possibility was investigated and it was found that, after injection of lithium, the serum-glucagon was twice as high as in the control animals, when measured 90 minutes and 20 hours after injection. Along with the glucagon, 1. Plenge, P., Mellerup, E. T., Rafaelsen, O. J. Proceedings of the Second International Meeting of the International Society for Neurochemistry; p. 321. Milan, 1969. 2. Bhattacharya, G. Biochim. biophys. Acta, 1964, 93, 644. 3. 4.
Clausen, T. ibid. 1968, 150, 56. Plenge, P. Paper read at the Second Meeting of the Scandinavian Society for Biological Psychiatry, Skokloster, Sweden, May, 1968.
PLATELET-SEROTONIN LEVEL IN CHILDREN WITH " MINIMAL BRAIN DYSFUNCTION " SIR,-Ishould like to communicate some preliminary of a metabolic study of children with the syndrome findings of " minimal brain dysfunction ". I take the view that one subgroup of these children (variously diagnosed as " hyperactive ", " minimally brain damaged ", " minimally cerebrally dysfunctioned ") may suffer, not from anatomical damage to the brain, but from a genetically transmitted metabolic defect.! On the basis of this hypothesis it was predicted that children coming from families with multiple occurrences of the syndrome would show abnormalities in the metabolism of noradrenaline, dopamine, or serotonin. To test this hypothesis, two investigations were undertaken: (1) a study of the urinary metabolites of the above compounds,2 and (2) a study of the level of platelet-serotonin. Pletscher3 has hypothesised that the platelet may serve as a model for the central neuron in regard to uptake and release of serotonin. Accordingly, we decided to investigate serotonin levels in a group of children who had been " " diagnosed as hyperactive ", and minimally cerebrally and who dysfunctioned ", displayed no evidence of defect. neurological 14 patients were investigated, all between the ages of 5 and 13. Each of the children had been diagnosed, on the basis of parents’ and teachers’ reports, as having " minimal cerebral dysfunction". The defining signs were " hyperactivity ", excessive distractability and inability to focus attention, affective volatility, intractability, and negativism. All but one of the children (patient 3) were of normal
intelligence, but approximately half were reported as having learning disorders "-heterogeneously defined problems mainly referring to an inability to learn which seemed discrepant with the child’s intellectual abilities. None of the children had a history of neurological insult or any evidence of neurological damage. 7 of the children came from two families. Family " 8 " consisted of 4 sibs who had an emotionally unstable mother and a manic-depressive maternal grandmother. Family " 9 " consisted of 3 sibs whose father was a borderline paranoid schizophrenic, and whose mother described herself as having been excessively active and a poor student during her childhood. The children were placed on a hydroxyindole-poor diet (no fruit or fruit juices, nuts, or eggplant) for 3 days, and whole-blood total 5-hydroxyindoles were determined by the "
method of Undenfriend et a1.4 The measurements were at the C.R.C. Neurology Laboratory, Children’s Hospital of D.C. under the supervision of Dr. Mary Coleman. Dr. Coleman reports that with this method normal values for children in this laboratory are between 110 and 200 ng. per ml. The 14 children fell into three groups:
performed
1. 2. 3. 4.
Wender, P. H. Unpublished. Wender, P. H., Epstein, R., Kopin, I. Unpublished. Pletscher, A. Br. J. Pharmac. Chemother. 1968, 32, 1. Undenfriend, S., Weissbach, H., Brodie, B. B. Methods of Biochemical Analysis; vol. VI, p. 95. New York, 1958.
The patients fell into three groups : the first group of children have borderline 5-hydroxyindole values; the middle group have depressed levels which, Dr. Coleman reports, are consistently seen in patients reacting to admission to hospital or undergoing other temporary upsets; and the last group, a group of siblings who have notably abnormal values. These low values might be produced by several mechanisms. The source of platelet-serotonin is the gut. Serotonin is produced in the intestinal mucosa, released into the blood, actively transported against a concentration gradient into the platelet, where it is bound and subsequently released. Accordingly the depression of the platelet-serotonin might be the result of any of several mechanisms: deficient production or release, deficient uptake by the platelet, excessive uptake by other sites, deficient binding by the platelet (with excessive release), or any combination of these. It remains to be demonstrated whether the low 5-hydroxyindole values are a primary abnormality or merely one of several non-specific responses to stress (like increased steroid release). For example, it is known that noradrenaline competes with serotonin transport mechanisms and if noradrenaline compound is released in stressful periods, it would be expected to compete with serotonin and displace it from the platelet. The observation that many children apparently have transiently low values when admitted to hospital without manifesting minimal-cerebral-dysfunction behaviour abnormalities militates against the view that the moderately depressed values which we found are of primary xtiological
significance. Currently the " 9 family is being investigated to determine which, if any, of the hypothesised mechanisms account for the depressed 5-hydroxyindole values. "
Laboratory of Psychology, National Institute of Mental Health, Bethesda, Maryland
20014.
PAUL H. WENDER.
EFFECT OF LITHIUM ON CARBOHYDRATE METABOLISM use of lithium in the treatment of manicSIR,-The depressive disorders has drawn attention to the side-effects of this ion. One of these is weight-gain, which in some cases leads the patient to refuse to continue lithium treatment. We have investigated the influence of lithium on glycogen metabolism in rats, and have found that 500-1200 moles of lithium chloride, injected intraperitoneally, increases the glycogen content of both brain and diaphragm.l This is presumably due to a direct effect on the transport of glucose across the cell-membrane, since it has been shown that lithium also increases diaphragm-glycogen in vitro.2,3 The most interesting finding was, however, that lithium caused an almost complete disappearance of liver-glycogen.4 The decrease in liver-glycogen was significant half an hour after the injection, and after 2 hours only a minimal amount of glycogen remained. Even after 24 hours the liverglycogen was still substantially reduced. Parallel with these changes there was an initial increase in blood-glucose, followed by a return to normal values, or to below-normal values when larger doses of lithium were used. One possible explanation of these results is that lithium chloride might have stimulated glucagon secretion. This possibility was investigated and it was found that, after injection of lithium, the serum-glucagon was twice as high as in the control animals, when measured 90 minutes and 20 hours after injection. Along with the glucagon, 1. Plenge, P., Mellerup, E. T., Rafaelsen, O. J. Proceedings of the Second International Meeting of the International Society for Neurochemistry; p. 321. Milan, 1969. 2. Bhattacharya, G. Biochim. biophys. Acta, 1964, 93, 644. 3. 4.
Clausen, T. ibid. 1968, 150, 56. Plenge, P. Paper read at the Second Meeting of the Scandinavian Society for Biological Psychiatry, Skokloster, Sweden, May, 1968.