Monoamine oxidase activity in blood platelets from autistic children

In order to evaluate the possible abnormality in monoamine oxidase (MAO) activity in early infantile autism, blood platelet samples were obtained from 20 autistic children, aged 2--12 years. MAO activity, measured fluorometrically using serotonin as substrate, was 5.24 +/- 1.65 (Mean +/- Standard Deviation) nM/MG protein/hour in these autistic children. This value was not significantly different from either that in 30 age-matched normal children or that in 39 nonautistic children with various psychiatric and neurological disorders, although autistic children had higher platelet serotonin concentration than these nonautistic individuals.     

Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children

Serotonin content, serotonin uptake sites, and serotonin receptor binding measured in animal studies are all higher in the developing brain, compared with adult values, and decline before puberty. Furthermore, a disruption of synaptic connectivity in sensory cortical regions can result from experimental increase or decrease of brain serotonin before puberty. The purpose of the present study was to determine whether brain serotonin synthesis capacity is higher in children than in adults and whether there are differences in serotonin synthesis capacity between autistic and nonautistic children. Serotonin synthesis capacity was measured in autistic and nonautistic children at different ages, using alpha[11C]methyl-L-tryptophan and positron emission tomography. Global brain values for serotonin synthesis capacity (K complex) were obtained for autistic children (n = 30), their nonautistic siblings (n = 8), and epileptic children without autism (n = 16). K-complex values were plotted according to age and fitted to linear and five-parameter functions, to determine developmental changes and differences in serotonin synthesis between groups. For nonautistic children, serotonin synthesis capacity was more than 200% of adult values until the age of 5 years and then declined toward adult values. Serotonin synthesis capacity values declined at an earlier age in girls than in boys. In autistic children, serotonin synthesis capacity increased gradually between the ages of 2 years and 15 years to values 1.5 times adult normal values and showed no sex difference. Significant differences were detected between the autistic and epileptic groups and between the autistic and sibling groups for the change with age in the serotonin synthesis capacity. These data suggest that humans undergo a period of high brain serotonin synthesis capacity during childhood, and that this developmental process is disrupted in autistic children.     

Disorders of catecholamine metabolism in infantile autism. Comparative study of 22 autistic children

In a group of 22 autistic children aged 5 to 16 y., and a group of normal controls matched for age and sex, catecholamines metabolism has been investigated in plasma, platelets and urine. This investigation was part of a research project in which several biological parameters (including serotonin) were simultaneously explored in the same children. In the autistic group, epinephrine and norepinephrine and dopamine were significantly lower in isolated platelets, and no significant difference was found between the two groups for the urinary excretion of epinephrine, norepinephrine, dopamine, DOPAC and MHPG. Other differences between the two groups in the statistical correlations of several biochemical parameters (plasma norepinephrine and dopamine with platelet MAO activity, platelet norepinephrine with platelet dopamine, platelet dopamine, platelet dopamine with platelet serotonin) also suggest abnormalities of bioamine metabolism in the platelets of autistic children.     

Monoamine Oxidase Activity in Blood Platelets From Manic and Depressed Patients

To evaluate the possible abnormality in MAO activity in affective disorders, blood platelet samples were obtained from 80 patients with mania and depression. Blood-platelet MAO activity was measured by a newly developed assay procedures using serotonin as substrate. MAO activities in 121 normal adult subjects were in a range of 2.49-12.05 nM/mg protein/hour, with the mean values of 4.91 ±1.72 (±S.D.) for men and 6.88±1.99 for women. (p<0.001) MAO activities in the manic and depressed patients were in a range of 0.65–13.40 nM/mg protein/hour, and both manic and depressed patients showed the mean value very similar to that in the normal subjects. Bipolar depressed patients did not exhibited lower MAO activity in the blood platelets than other clinical subtypes of depressive illness, including unipolar, involutional, neurotic and chronic characterological, and first-episode depressions. No significant differences were established between these five subcategories of depression, while significant higher values were evident in female than male patients (p<0.001). No correlation was found between the MAO activity and serotonin levels in the blood platelets either in the normal subjects or in the depressed patients.     

Metabolism of serotonin in autism in children

In this controlled study of 22 autistic children and 22 normal controls matched for age and sex, the frequency of hyperserotonemia in infantile autism was confirmed. Platelet serotonin was elevated in patients. Comparative to controls, serotonin was also high in urine of autistic patients, while, on the contrary there was no difference for the urinary excretion of 5-HIAA. No difference was observed either for serotonin uptake and efflux or for MAO activity, in isolated platelets. The elevation of plasma free tryptophan - significant only with the Kolmogorov Smirnov test - suggests that 5-HT biosynthesis might be enhanced. In the group of patient reported in this study, disorders of serotonin metabolism are associated with disturbances of platelet catecholamines, and also with elevated immunoglobulins and enhanced cellular immunity reactions.     

Reassessment of elevated serotonin levels in blood platelets in early infantile autism

Blood platelet serotonin content was measured in 30 children with early infantile autism, as defined by Kanner, 30 age-matched normal subjects, and 45 children with various neurological and psychiatric disorders. Serotonin content in the autistic group was 980±357 ng/mg platelet protein (mean±standard deviation), a value significantly higher than that for normal children, 807±202 ng/mg (p <.025). Autistic children under school age had higher platelet serotonin concentrations than other older autistic individuals. There was little correlation between age and serotonin levels in the normal children. Elevated serotonin was also seen in some of the non-autistic pathological group, who were disturbed and hyperactive. Elevated serotonin levels are not necessarily a specific biochemical finding for autistic children, but seem to be due to their behavioral distinction.     

Measurement of Platelet Monoamine Oxidase Using Three Different Substrates in Patients with Alcoholism and Schizophrenia

Abstract: The platelet monoamine oxidase (MAO) activities in alcoholism and schizophrenia were investigated by means of the simultaneous determination, using β-phenyl-ethylamine, tryptamine and serotonin as substrates. No significant difference was found between the MAO levels in the alcoholic and schizophrenic groups, when tryptamine was used as a substrate, but both groups showed lower values than the controls. On the other hand, β-phenylethylamine, a specific substrate for MAO B used as a substrate, showed no significant difference between the alcoholic and control groups in the activities. These two groups showed higher values in MAO activity than the schizophrenic group, whereas when MAO activity was estimated using serotonin, platelet enzyme was found to be inhibited significantly in alcoholism, and the level of activities in the schizophrenics was similar to that of the controls. Moreover, the β-phenylethylamine inhibition curve obtained serotonin as the substrate in the pooled platelets of 50 normal human subjects, and the MAO activity could not be inhibited by higher concentrations than the Km value of serotonin. These findings suggested that there might be two interacting catabolic sites having different substrate affinities in blood platelet MAO. Thus, it could be speculated that serotonergic catabolic sites of MAO in the platelets are disturbed in the alcoholics, while β-phenylethylaminergic catabolic sites of platelet MAO are inherently vulnerable in schizophrenia.     

Review of fenfluramine in the treatment of the developmental disabilities

Fenfluramine, a serotonin reducing agent, has been the subject of intense research effort in recent years. A variety of biochemical studies summarized suggest that some autistic children and many nonautistic severely retarded individuals have elevated blood serotonin concentrations. The research on fenfluramine's clinical efficacy is thoroughly reviewed from a methodological perspective. All studies assessing the drug's effects on blood serotonin have observed reductions in whole blood serotonin to about 50% of baseline concentrations. Although there were early reports of drug enhancement of IQ, there is no good evidence that this is the case. However, there are data to suggest that fenfluramine may enhance social relatedness, reduce stereotypic behavior, lessen overactivity, and improve attention span in some autistic children, although these results do not appear consistently across studies. The animal literature on the neurotoxicity of fenfluramine is reviewed, and a number of limitations in this research are identified that raise questions about its relevance to the pharmacotherapy of children.     

Brief report: Differences in sex ratios in autism as a function of measured intelligence

Results from analyses of sex ratios as a function of IQ are presented for 623 autistic children (487 males, 136 females) and 506 nonautistic, communication-handicapped and behavior-disordered children (374 males, 132 females). Proportionately more autistic females were found to have IQs of 34 or below than above 34. However, a linear trend of an increasing number of males with increasing intelligence was found only for nonautistic subjects. The relevance of these findings to genetic factors and the heterogeneity of autism is discussed.     

Altered serotonin synthesis in the dentatothalamocortical pathway in autistic boys

Based on reports of increased platelet serotonin in 30 to 50% of autistic subjects, abnormal serotonergic neurotransmission may be important in the pathogenesis of autism. However, serotonin metabolite measurements in cerebrospinal fluid of autistic subjects have failed to demonstrate consistent abnormalities. Using α-[¹¹C]methyl-L ?tryptophan as a tracer for serotonin synthesis with positron emission tomography, we now report unilateral alterations of serotonin synthesis in the dentatothalamocortical pathway in autistic boys. Asymmetries of serotonin synthesis were found in frontal cortex, thalamus, and dentate nucleus of the cerebellum in all 7 boys, but not in the 1 autistic girl studied. Decreased serotonin synthesis was found in the left frontal cortex and thalamus in 5 of the 7 boys and in the right frontal cortex and thalamus in the 2 remaining autistic boys. In all 7 cases, elevated serotonin synthesis in the contralateral dentate nucleus was observed. Statistically significant differences between autistic boys and their nonautistic siblings (n = 5) were obtained when comparing asymmetry indices for frontal cortex, thalamus, and dentate nucleus combined as well as individually for frontal cortex and thalamus. These serotonergic abnormalities in a brain pathway, important for language production and sensory integration, may represent one mechanism underlying the pathophysiology of autism.     

Minerals in the hair and nutrient intake of autistic children

The concentrations of calcium, magnesium, zinc, copper, lead, and cadmium were determined in scalp hair samples from a group of 12 autistic children and a group of 12 nonautistic control children. The only statistically significant difference between median concentrations of minerals in the hair from the two groups was a 62% decrease in the concentration of cadmium in the hair of autistic children. This decrease was probably not physiologically significant. The nutrient intake of autistic children as a group was found to be adequate and typical of well-fed American children. It was concluded that the children in neither the autistic nor the nonautistic control group showed evidence of toxicity or deficiency of the minerals or nutrients studied, but because of food idiosyncracies nutrient intake should be monitored.     

Correlation of platelet MAO activity with introversion: A study on a German rural population

Platelet monoamine oxidase (MAO) activity and personality characteristics were correlated in a sample of 52 men (37 ± SD 13 years) and 54 women (37 ± SD 15 years) from a rural community. Personality characteristics were measured by using the Freiburger Persönlichkeitsinventar (FPI-A). In the males, weak but significant linear correlations (Pearson product-moment and Spearman rank correlations) were found between platelet MAO activity (p-tyramine and benzylamine as substrates) and the extraversion/introversion dimension. In the females, however, there were no consistent significant correlations between MAO activity and FPI test scores. Comparing the top and bottom 25% of the platelet MAO distribution resulted in a significant difference for the second order factor extraversion in the group of men but not in the group of women. The significant correlation between MAO and introversion could not be attributed to cigarette smoking, food consumption, alcohol, or drugs. In accord with previous biochemical-behavior research, it is suggested that reduced platelet MAO activity may, to some extent, reflect an impulsive personality type.     

Uptake and efflux of serotonin from platelets of autistic and nonautistic children

This study examined, in vitro, the uptake and efflux of serotonin by platelets from autistic children, nonautistic hospitalized comparison cases, and normal children. The autistic patients were carefully selected according to previously established diagnostic criteria. The hospitalized comparison children were utilized to assess possible environmental and dietary influences upon the results. Uptake methods were similar to those used by previous investigators. Two efflux procedures were utilized to explore the possibility that methodological factors accounted for previously reported differences between autistic and comparison groups. The results failed to indicate statistically significant differences in uptake or efflux between the autistic and the hospitalized comparison groups or the normals. Methodologic considerations which could possibly account for the failure to confirm previous findings are discussed in detail.     

Social class distribution of fathers of children enrolled in the Iowa Autism program

The social class distribution of fathers with autistic children attending a locally well-known and state-supported modern autism program was examined and was compared to the social class distributions observed in a nonautistic, mentally retarded population, in children with other psychiatric disorders, and in the general population from which the present autistic sample was drawn. No significant differences were found among the groups. The findings supported the view that if studies are not biased by certain selection factors outside the autistic child's clinical picture and diagnosis, and if services become better known and readily available, then no differences in social class distribution between autistic and nonautistic groups occur. The results suggest that social class is not an important factor in the origin of autistic syndrome.     

Biochemical changes during clomipramine treatment of childhood obsessive-compulsive disorder

Peripheral measures of serotonergic and noradrenergic function were obtained in 29 obsessive-compulsive adolescents and 31 age- and sex-matched controls, as well as in a subsample of 22 patients after five weeks of treatment with clomipramine hydrochloride (134 +/- 33 mg/d) (mean +/- SD) given in a double-blind placebo-controlled trial. Drug-free obsessive-compulsive subjects did not differ from controls on measures of platelet serotonin and monoamine oxidase (MAO) activity, nor on plasma epinephrine or norepinephrine concentrations at rest and after a standard orthostatic challenge procedure. Compared with placebo, treatment with clomipramine was clinically effective and produced a marked decrease in platelet serotonin concentration, a trend toward a reduction in platelet MAO activity, and a rise in standing plasma norepinephrine. Clinical improvement during drug therapy was closely correlated with pretreatment platelet serotonin concentration and MAO activity, as well as with the decrease in both measures during clomipramine administration. This suggests that the effects of clomipramine on serotonin uptake may be essential to the antiobsessional action observed.     

Clinical correlates of tricyclic antidepressant-mediated inhibition of platelet monoamine oxidase

Previous reports suggest that tricyclic antidepressants inhibit platelet monoamine oxidase (MAO) activity in vitro and in vivo. This study was undertaken to examine the relationship between tricyclic-mediated inhibition of platelet MAO and resolution of clinical signs and symptoms which are commonly associated with the depressive syndrome. The results indicate that the sedative-hypnotic effects of the tricyclics closely correlate with the magnitude of platelet MAO inhibition. It appears that these effects may be mediated through alterations in the metabolism of serotonin and/or the phenylethylamines.     

Monoamine Oxidase Activity in Blood Platelets in Alcoholism

A newly developed assay for monoamine oxidase (MAO) activity in blood platelets was applied in 50 alcoholic patients. The assay is the direct measurement of serotonin oxidation by MAO employing a double microcolumn technique on Sephadex G-10 and Amberlite CG-50 for separating 5–HIAA formed, which is measured fluori-metrically. Rebound of MAO activity levels after withdrawal of alcohol was observed to be more pronounced in the patients with delirium tremens than those who exhibited no outstanding abstinent symptomatology. MAO activity levels measured in the 1st week of alcohol withdrawal were 3.49±1.15 (Mean±S.D.) nmol/mg protein/hour in the alcoholic patients with delirium tremens, a value significantly lower than that in the subjects without (p<0.01) and that in the male normal subjects (p<0.001). Four weeks after withdrawal of alcohol, the reduced MAO activity levels in the alcoholic population were restored to normal levels. These data demonstrate that physical dependency for alcohol occurred evidently in the alcoholic patients examined. Delirium tremens and other psychotic symptoms in alcoholism may be manifested as impaired serotonin metabolism in the brain, which may be due to MAO inhibition caused by excessive alcohol intake.     

Psychobiology of borderline personality traits related to subtypes of eating disorders: a study of platelet MAO activity

Increased and decreased levers of platelet monoamine oxidase (MAO) activity have been reported in patients with eating disorders, indicating abnormalities of the serotonin turnover. However, whether these findings are related to eating disorders or are rather reflecting the pathophysiology of borderline personality traits in these patients is still unknown. Platelet MAO activity and comorbid personality disorders were investigated in 72 patients with different subtypes of eating disorders (ED) and in a group of 28 healthy controls. ED patients comprised the following subtypes: 25 anorexia nervosa (AN) restrictive, 14 AN binge eating-purging (AN b-p), 3 anorexia nervosa not otherwise specified (AN NOS) and 30 bulimia nervosa (BN). Personality disorders and traits were assessed with the Structured Interview for Personality Disorders (SCID-II), the Zanarini Rating Scale for Borderline Personality Disorder, and the Barrat Impulsiveness Scale. Platelet MAO activity was significantly lower in ED patients with comorbid borderline personality disorder (BPD) than in ED without Borderline personality disorder (BDP). Platelet MAO activity was significantly and inversely correlated with the number and severity of BPD clinical features. In the subsample of patients with binge eating-purging symptoms (AN b-p, AN NOS and BN), platelet MAO activity was significantly lower in binge-purge patients with comorbid BPD than in binge-purge patients without BPD. The whole group of eating disorders had a significantly reduced lever of platelet MAO activity compared with the control group. The results suggest that low platelet MAO activity might characterize eating disorders with comorbid borderline personality traits, reflecting greater serotonin dysfunction in these patients. The role of decreased platelet MAO as an endophenotype with specific clinical manifestations should be explored in future studies.     

Reduction of blood platelet monoamine oxidase activity in schizophrenic patients on phenothiazines.

A newly developed assay for monoamine oxidase (MAO) activity in blood platelets (serotonin used as substrate) was applied for the measurement of the enzyme activity in 76 schizophrenic patients. No significant reduction was found in the blood platelet MAO activity in a group of 33 untreated schizophrenic patients, as compared to that in the normal controls. Male patients revealed to have lower enzyme activity than females in the schizophrenic group, as we described previously in the normal subjects. Treatment with phenothiazines caused significant reduction of blood platelet MAO activity, while platelet serotonin content and platelet count appeared to be not affected by the drug treatment. The authors suggest that blood platelet MAO activity may be related to hormonal factors but not to psychiatric diagnosis of schizophrenia or constitution liable to schizophrenic illnesses.     

Laboratory predictions of infantile autism based on 5-hydroxytryptamine efflux from blood platelets and their correlation with the rimland E-2 score

Experiments were conducted to determine the possibility of predicting a diagnosis of autism on the basis of an abnormally high release of¹⁴C-5-hydroxy-tryptamine from 5-HT loaded blood platelets of children. Such increased 5-HT release was previously reported by the authors for blood platelets of children diagnosed as autistic according to the Rimland E-2 score. The platelets of 10 psychotic children (including a number of subjects diagnosed as autistic by the E-2 score) were examined without knowledge of the diagnosis, in order to determine whether the biochemical results correlated with the E-2 score. On the basis of experimental data it was possible to predict that six children were autistic and four were nonautistic psychotics. According to the E-2 score, seven children were autistic and three nonautistic psychotics. The authors conclude that there is a correlation between a diagnosis of infantile autism by the E-2 score and enhanced release of radioactive 5-HT from 5-HT-loaded blood plateletsin vitro.This research was supported in part by National Institutes of Health Grant RR 00 284 and National Institute of Mental Health Grant HD 08429.