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Presynaptic inhibitory alpha-adrenergic receptors are involved in regulating the release of norepinephrine (NE) through a negative feedback mechanism mediated by NE. Increased alpha2-adrenergic receptor activity suggests decrease NE release and activity, while decreased alpha2-adrenergic activity suggests increase NE release and activity. A large body of evidence suggests the involvement of a disturbance in NE activity in the pathophysiology of attention deficit hyperactivity disorder (ADHD) in childhood. Platelet alpha2-adrenergic receptor binding was compared in 23 boys aged 7-12 with the diagnosis of ADHD and 11 normal controls. The ADHD boys tended to have lower levels of alpha2-binding than controls. The administration of d-amphetamine in a double-blind placebo-controlled crossover design did not have any effect on alpha2-receptor binding in ADHD boys. Nonresponders to d-amphetamine had the lowest alpha2-receptor binding compared to responders and controls. These findings suggest a normal alpha2-adrenergic activity in ADHD boys responders to d-amphetamine and a possible increase in NE release in ADHD boys nonresponders to d-amphetamine due to decreased alpha2-adrenergic receptors.

It is becoming increasingly recognized that one third to one half of children diagnosed as having attention deficit/hyperactivity disorder (ADHD) continue to exhibit symptoms of the disorder into adulthood. The nature of the clinical picture is not well understood by a substantial number of clinicians. The purpose of this study is to report on the demographic and clinical profile of 56 adults, age 19 to 65 years (48 men, eight women) who present with adult ADHD and meet DSM-III-R criteria for the disorder. Patients underwent a diagnostic work-up consisting of medical and psychiatric evaluation, a structured interview Schedule for Affective Disorders and Schizophrenia-Lifetime Version [SADS-L]), the Symptoms Checklist Revised (SCL-9OR), Conners Attention Deficit Disorder With Hyperactivity (ADDH) scale, structured interview of ADDH, the Global Assessment of Functioning Scale (GAF), and, when available, information from parents was obtained. Ninety-one percent of our sample met the Utah Criteria for adult ADHD. The majority of the sample had additional DSM-III-R diagnoses and only seven had ADHD diagnosis alone. Fifty-three percent of the sample met the criteria for generalized anxiety disorder, 34% alcohol abuse or dependence, 30% drug abuse, 25% dysthymic disorder, and 25% cyclothymic disorder. These findings were similar to those reported in the literature.

The authors examined platelet alpha 2-adrenergic receptor binding to 3H-yohimbine and several personality variables in 58 adult males in a campus community. Subjects with high receptor Bmax levels exhibited personality traits of less social inhibition and more sensation seeking and thrill seeking behavior, were more playful and autonomous, and came from healthier, more intact families. The results also suggested that high affinity states of platelet alpha 2-adrenergic receptors (low Kd) correlate with traits suggestive of stability, i.e., Autonomy, Dominance, Nurturance, Order, Succorance, and General Sensation Seeking Scale of Zuckerman, while low affinity states (high Kd) of platelet alpha 2-receptors correlate with psychopathological traits of Dependence, Exhibitionism, and Paranoia.

The psychostimulants d-amphetamine and methylphenidate are thought to be the most effective treatment in children, adolescents, and adults with attention deficit-hyperactivity disorder (ADHD) because they potentiate both dopamine (DA) and norepinephrine (NE) at the synaptic cleft. These medications are not free from side effects and controversy. Newer effective and safe treatments are needed. S-Adenosyl-L-methionine (SAM), the active form of methionine, acts as a methyl donor and is involved in many metabolic pathways. It has beta adrenergic and DA receptor agonist activity. We have been using oral SAM in a sample of well-diagnosed adults with ADHD, residual state (RS) in a 4-week open trial to establish SAM effectiveness and safety and in a 9-week, double-blind, placebo-controlled crossover trial. Preliminary data from the open trial reveal that 75 percent (6 out of 8 male) patients improve on it. The 2 who did not improve had not improved on methylphenidate trial. Improvement ranged from moderate to marked, with minimal and transient side effects that did not interfere with functioning.

The authors measured the urinary metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG) and homovanillic acid (HVA) in 21 hyperactive boys and 12 matched healthy boys. The hyperactive boys excreted lower amounts of MHPG than control boys. Hyperactive drug responders excreted lower amounts of HVA than control boys and hyperactive nonresponders. Drug responders with normal MHPG excreted low amounts of HVA and those with normal HVA excreted low amounts of MHPG. d-Amphetamine decreased MHPG in all drug responders and HVA in drug responders with normal HVA levels, although it tended to increase HVA in those with low HVA levels. The authors discuss their data in terms of the possible involvement of norepinephrine and dopamine in the etiology of hyperactivity in children.

The rapidly increasing research interest in childhood depression indicates that it has become a recognized disorder. The authors review the literature on depression in children, focusing on epidemiology, various diagnostic criteria, classification schemes, assessment instruments, and intervention studies that have been applied to childhood depression. Given that there are many etiological factors, it will be important to study the disorder from various conceptual frameworks, including biochemical, genetic learned helplessness, life stresses, cognitive distortion, behavioral reinforcement, and sociological models.

The authors studied the excretion of 3-methoxy-4-hydroxyphenyl glycol (MHPG), normetanephrine (NM), metanephrine, and homovanillic acid in 7 hyperactive and 12 control children. MHPG was lower but NM was significantly higher in hyperactive children than in controls. Administration of d-amphetamine for 2 weeks depressed the levels of MHPG, NM, and metanephrine. The authors suggest a decreased central norepinephrine activity, which may be secondary to the interruption of norepinephrine fibers in the medial forebrain bundle.

The authors examined the relationship between the activity of platelet monoamine oxidase (MAO) and a variety of psychoeducational measures, as well as the scores on the Matching Familiar Figures Test (MFF), a psychological test of reflection-impulsivity, in 21 normal children (12 boys, 9 girls) who were admitted to a clinical research center and placed on a low monoamine diet. The children were divided into three equal groups (n = 7) based on their values of platelet MAO. There were no significant differences among the three groups in the psychoeducational measures. However, the high and low MAO groups made significantly more errors and had shorter latency periods on the MFF than the middle MAO group. These findings suggest that normal children with platelet MAO activity values in the high and low ends of the MAO distribution are more impulsive than the children with platelet MAO values in the middle range on the MFF Test of Impulsivity. The findings further suggest that there is no relationship between platelet MAO levels and intellectual abilities or scholastic achievement in normal children.

We studied the effect of several clinically important variables on the characteristics of alpha 2-adrenergic receptors in human platelet membranes. The number and affinity of the receptor binding sites were determined from radioligand binding experiments, with [3H]yohimbine being the radioligand of choice. Platelets from female subjects had a cyclic variation in the number of alpha 2-adrenergic receptors that coincided with their menstrual cycles. The number of alpha 2-receptors was highest at the onset of menses and dropped to 74% to 79% of that value during the middle of the cycle. In concurrent experiments we did not observe comparable cyclic changes in receptor binding sites in platelets from male subjects. There was no age-dependent alteration in receptor number in a sample of 39 subjects ranging in age from 8 to 80 yr, but the number of alpha 2-receptors in platelets from male and female subjects differed. We also tested the possibility of a circadian rhythm in alpha 2-receptor number but found no cyclic changes as a function of time of day. There was no alteration in alpha 2-adrenergic receptor binding in the platelets from five subjects with Parkinson's disease. Finally, there was no change in receptor affinity as a function of any of the variables tested. These data should apply to the design of further studies on the clinical importance of platelet alpha 2-adrenergic receptors.

Platelet monoamine oxidase (MAO) activity was studied in 22 boys diagnosed as having attention deficit disorder with hyperactivity and 12 healthy control boys admitted to a clinical research center and placed on a diet low in monoamines. The hyperactive boys had lower platelet MAO activity than controls, and MAO activity was related to performance on the Matching Familiar Figures Test (MFF) and the Continuous Performance Test (CPT), which yield scores sensitive to impulsivity and inattention. Furthermore, it was negatively related, in hyperactive boys only, to two tests of reading and spelling achievement. Administration of d-amphetamine and placebo in a double-blind crossover design did not significantly raise MAO levels above baseline and was minimally related to improved performance on the MFF and CPT.

The authors studied 18 adults (8 men and 10 women) in an open trial of nomifensine maleate for the treatment of attention deficit disorder (ADD). All patients met DSM-III criteria and the Utah criteria for ADD, residual type (RT). Medication effect was measured at week 1 and week 4 of treatment using the Structured Interview for ADD-H Symptoms. Data from week 4 showed that all eight men and seven of the women responded well to nomifensine, showing a significant decrease in ADD with hyperactivity symptoms. Side effects were minimal, consisting of drowsiness, dry mouth, headache, and nausea. One responder (5%) was taken off the medicine after developing an allergic reaction. Results showed that short-term use of nomifensine was relatively free from side effects and was remarkably effective in the treatment of ADD-RT. The authors discussed the implications of the use of nomifensine and related drugs in the treatment of ADD-RT.

The authors examined the effect of diets with low and high monoamine content on the 24-hour urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) and creatinine in eight healthy preadolescent boys. The subjects were admitted to a clinical research center and were placed on a diet low in monoamines--the vanillylmandelic acid (VMA)-exclusion diet--for 5 consecutive days. They were switched on the 6th day to a diet rich in monoamines, and urine specimens were collected for 4 more consecutive days. There were no differences in MHPG or creatinine excretion between the urine taken on the low and high monoamine diet days.

The authors examined the excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) and homovanillic acid (HVA) in nine hyperactive and nine control boys admitted to a clinical research center. The hyperactives excreted lower 24 hr MHPG and HVA levels than controls. d-Amphetamine 0.5 mg/kg body weight daily for 2 weeks decreased MHPG and increased HVA. These data replicate the authors' previous findings on MHPG and HVA and on the effect of d-amphetamine in hyperactive children. The data suggest the involvement of norepinephrine and dopamine in the etiology of hyperactivity. It further suggests d-amphetamine may achieve its clinical effects in hyperactivity by inhibiting NE and potentiating DA activity.

The present study evaluated the biochemical measures of urinary homovanillic acid (HVA) and 3-methoxy-4-hydroxy-phenylglycol (MHPG) in relation to functioning on selected psychoeducational tests in a group of boys with attention deficit disorder and hyperactivity. The Wechsler Intelligence Scale for Children-Revised (WISC-R), the Wide Range Achievement Test (WRAT), and the Peabody Picture Vocabulary Test were administered to 28 hyperactive and 23 control subjects. The findings suggest subtle differences in psychoeducational test performance in relation to specific levels of homovanillic acid and MHPG.

The authors examined platelet MAO activity in 8 hyperactive and 18 control children who were admitted to a clinical research center and placed on a low monoamine diet. After 5 days, their blood was analyzed; the hyperactive children were discharged on day 7, placed on d-amphetamine for 2 weeks, and readmitted for repeat blood analysis. The hyperactive children initially had significantly lower levels of platelet MAO than the controls. After the hyperactive children were treated with d-amphetamine for 2 weeks, their platelet MAO levels were comparable to those of the control children. The authors suggest an association between low platelet MAO activity and a behavioral state of overactivity, short attention span, and impulsivity.

The 24-hour urinary catecholamine metabolites 3-methoxy-4-hydroxyphenylglycol, normetanephrine, and metanephrine were measured in 23 hyperactive boys and 13 matched healthy controls. The hyperactive children excreted lower MHPG and higher NM (low MHPG/NM ratio) amounts than in controls. The administration of d-amphetamine in the dose of 0.5 mg/kg body weight divided over two doses daily for two weeks decreased MHPG excretion in the hyperactive children. When the hyperactive children group was divided into drug responders and nonresponders according to their pre- and post-treatment scores on the Conners Teacher Questionnaire, d-amphetamine administration decreased MHPG excretion in the responders and did not change it in the nonresponders. Percent decrease in MHPG excretion correlated significantly with percent change in the hyperactivity factor of the questionnaire on the Spearman Rank Order Correlation Coefficient. Pretreatment urinary metabolites did not differentiate the responders from nonresponders. It is suggested that a relationship between CNS norepinephrine metabolism and hyperactivity exists and that d-amphetamine may achieve its therapeutic action in hyperactive children by altering CNS NE metabolism.

A review of the clinical profile of congenital sensory neuropathy with anhydrosis is presented. It is stressed that major diagnostic criteria of this recessively inherited condition should be limited to insensitivity to pain with normal tactile perception, anhydrosis, recurrent unexplained fever, self-mutilation, mental retardation, hypotonia, histologically normal sweat glands and variable autonomic abnormality. A case conforming to this description is reported and compared with 13 published cases. Special investigations of the autonomic nervous system through measurement of urinary catecholamine metabolites and psychophysiologic variables were conducted on this patient. Based on the analysis of 5 X 24-hour urine, values of metabolites of dopamine and epinephrine were normal. Metabolites of norepinephrine, such as 3-methoxy-4-hydroxy phenylglycol and normetanephrine, however, were significantly low when compared with those of four controls, suggesting decreased peripheral and central norepinephrine activity. Polygraph recording and evaluation of some orienting response components revealed no obvious signs of autonomic perturbation and, specifically, no phasic electrodermal activity. These two findings (biochemical and electrodermal) strongly suggest an autonomic imbalance, specifically component, both central and peripheral. It is suggested that autonomic disorder is an integral part of the syndrome and may be demonstrated by special investigations.

The authors examined platelet MAO activity and several personality variables in 58 non-clinic-referred healthy adult males. The psychological tests administered consisted of the Minnesota Multiphasic Personality Inventory, the Personality Research Form-E, and the Zuckerman Sensation Seeking Scale. The findings replicated previous findings in the literature.

The authors studied the excretion of 3-methoxy-4-hydroxyphenlyglycol (MHPG) in 15 hyperactive boys and 13 controls. They further examined soft neurologic signs and clinical drug response to d-amphetamine administration for two weeks in the hyperactive boys. MHPG excretion was significantly lower in the hyperactive boys than in the controls. d-Amphetamine decreased MHPG excretion significantly in the drug responders only. Pretreatment MHPG excretion did not predict clinical drug response. The responders had more soft neurologic signs than the nonresponders. Furthermore, soft neurologic signs were not related to pretreatment MHPG levels.

We studied the relationship between the excretion of 3-methoxy-4-hydroxyphenylglycol, the main metabolite of central nervous system norepinephrine, and homovanillic acid, the main metabolite of dopamine, in 16 hyperactive boys and ten controls who were admitted to a clinical research center. We further examined the effect of d-amphetamine (0.5 mg/kg body weight daily for two weeks) on that relationship. The correlation coefficients r between MHPG and HVA excretion were significantly negative in hyperactive boys and significantly positive in controls when the relational effects of age, body surface, and 24-hour urinary creatinine with MHPG and HVA excretion were removed. Furthermore, the correlation coefficient r in hyperactive boys and in responders at baseline differed significantly from the correlation coefficients in post-treatment and in controls. The post-treatment correlation coefficient in hyperactive boys and responders did not differ from that in controls. We suggest an altered relationship between DA and NE activity in hyperactive children. Meaningful interpretation of the data should await the availability of more information on the amount of contribution of central NE and DA metabolism to urinary MHPG and HVA in both hyperactive and normal children.