Gerald L. Brown

Aggression in humans correlates with cerebrospinal fluid amine metabolites

Cerebrospinal fluid of the major central metabolites of serotonin (5HT), norepinephrine (NE), and dopamine (DA)--5-hydroxyindoleacetic acid (5HIAA), 3-methoxy-4-hydroxy=phenylglycol (MHPG), and homovanillic acid (HVA), respectively--were studied in a group of 26 age-similar military men with no history of major psychiatric illness, but with various personality disorders and difficulties adjusting to military life. Independently scored history of aggressive behavior showed a significant negative correlation with 5HIAA (r = -0.78) and a significant positive correlation with MHPG (r = 0.64).

D2 dopamine receptor genotype and cerebrospinal fluid homovanillic acid, 5-hydroxyindoleacetic acid and 3-methoxy-4-hydroxyphenylglycol in alcoholics in Finland and the United States

If a genetic association between the D2 dopamine receptor genotype and alcoholism is mediated by altered dopamine function, then a stronger association might be found in alcoholics who are deviant in indices of dopamine function and by comparing alcoholics to nonalcoholics matched for ethnic origin. Therefore, we evaluated the D2/TaqI polymorphism in 29 impulsive violent alcoholic Finns, 17 nonimpulsive violent alcoholic Finns and 36 Finnish controls free of mental disorders, alcoholism and substance abuse. In 37 of the alcoholics, we measured cerebrospinal fluid (CSF) homovanillic acid (HVA), 5‐hydroxyindoleacetic acid (5‐HIAA) and 3‐methoxy‐4‐hydroxyphenylglycol. There was no relationship between D2/Taq 1 genotype and concentrations of these monoamine metabolites in this group, which exhibits lower CSF HVA and 5‐HIAA as compared to controls. There was also no genotypic difference between Finnish alcoholics and nonalcoholic controls. The lack of relationship between D2/Taq1 genotype and HVA concentration was replicated in 24 Caucasian alcoholics in the United States.

Cerebrospinal fluid correlates of suicide attempts and aggression.

Human suicidal and aggressive behaviors have been studied extensively from sociopsychological perspectives. A stimulus for recent biochemical studies has been an interest in the relationship between suicide and aggression, a clinical relationship hypothesized by Freud.’ The studies of Asberg et aL2” and Brown et aL4s5 have stimulated considerable further work on the suicidelaggression /impulsivity reiationship from the point of view of central nervous system (CNS) biochemistry.

Plasma levels of d-amphetamine in hyperactive children

Amphetamine has been clearly documented to be an efficacious treatment for hyperactive children. The pharmacokinetics of amphetamine have been studied in adults, but not in children. Sixteen male children who scored >2 SD from norms on Factors I and IV of Connerss Teacher Rating Scale and who were not excluded for reasons to do with medical or psychiatric conditions, intelligence, or age, had a plasma d-amphetamine apparent elimination half-life of 6.8±0.5 h. Peak plasma level occurred between 3 and 4 h (62.7±3.8 and 65.9±3.6 ng/ml, respectively). Six of these children had a repeat study and there were no significant differences within subject in apparent elimination half-lives and attained peak blood levels. The variation in plasma levels was greater during absorption than during elimination. Both behavioral and motor activity resonses as analyzed by differences between amphetamine and placebo days (by paired t-tests) indicate significant responses between hours 1–4; however, these responses do not correlate with plasma amphetamine levels; they occur during the absorption phase. The decreased response to later similar plasma levels of d-amphetamine may be related to depletion of catecholamine stores, to replacement by a ‘false neurotransmitter’ metabolite of amphetamine, or to alteration in receptor sensitivity.

Behavior and Motor Activity Response in Hyperactive Children and Plasma Amphetamine Levels Following a Sustained Release Preparation

Abstract Amphetamine has been clearly documented to be an efficacious treatment for hyperactive children. Recently, pharmacokinetics of elixir, tablet, and sustained-release preparations have been studied in hyperactive children. Sustained release has been thought to provide a prolonged clinical response. In this study, nine hyperactive children, selected by specific exclusion-inclusion criteria, were administered single oral doses of sustained-release d-amphetamine and placebo; plasma levels, behavioral response, and motor activity were observed in double-blind design. The results, as with the earlier studies, indicate that significant clinical response is not observed beyond 4 hours and that responses occur only during the absorption phase and are not correlated with specific plasma levels of d-amphetamine.

Phenylethylamine Excretion in Attention Deficit Disorder

Urinary excretion of phenylethylamine (PEA), an endogenous amine similar to amphetamine in both molecular structure and pharmacological properties, was measured with gas-chromatography-mass-fragmentography in two separate studies of hyperactive male subjects between the ages of 6 and 12 years and age-matched controls. All hyperactive children were medication free for a minimum of 2 weeks before the urine collection and met DSM-III criteria for Attention Deficit Disorder with Hyperactivity. In both studies, PEA excretion per 24 hours was significantly lower than age-matched controls. PEA excretion expressed as milligrams per gram of creatinine excretion also tended to be lower for hyperactive children, but did not reach significance.

Neurologic Status in Hyperactive, Enuretic, Encopretic, and Normal Boys

Abstract The neurological status of 30 hyperactive, 40 enuretic, and 22 normal boys was investigated using the physical and neurological examination for soft signs (PANESS), a structured 44-item neurological exam with a 4-point scale for each item. There was a strong negative correlation between age and the PANESS score, indicating that the examination is also a kind of developmental scale. Age-adjusted mean PANESS score of hyperactive children was significantly higher than both the normal and enuretic groups, but there was no significant difference between the latter two groups in PANESS scores adjusted for age. PANESS scores correlated significantly with other measures of higher central nervous system function such as IQ, number of errors on the Bender test, and abnormal electroencephalograms (available in the hyperactive boys). Reliability of the examination as a whole by two independent raters was significant. Use of the PANESS in this study demonstrated a lag in neurodevelopmental maturity not necessarily specific to diagnostic category.

Urinary catecholamines and amphetamine excretion in hyperactive and normal boys.

Urinary catecholamines and metabolites and urinary amphetamine excretion were examined for hyperactive and normal boys following a single dose of dextroamphetamine (0.5 mg/kg) and placebo. Hyperactive children showed a significantly faster rate of excretion of amphetamine which could not be accounted for by previous exposure to drug or by signs of neurological involvement. Urinary norepinephrine (NE) was significantly higher for hyperactive than for normal children, but NE excretion did not correlate with motor activity or any measures of arousal. The single dose of amphetamine produced a significant rise in urinary epinephrine excretion (EP) for the normal children but not for the hyperactive group, supporting the notion of a more sluggish catecholamine response to stimulants for hyperkinetic children.

Aggression in Hyperactive Boys: Response to d-Amphetamine

Ten hyperactive boys were studied in a double-blind, placebo-counterbalanced trial of d -amphetamine. On the basis of reports citing the aggression-reducing effect of low doses of d -amphetamine in animals and adults, it was predicted that the study groups aggressive behavior and aggressive/impulsive attitudes and fantasies would be lower in the d -amphetamine phase than in the placebo phase of the study. Findings in the predicted direction were significant in three of the five measures used. The strongest effect occurred in playroom observation of overt aggressive behavior.

The hyperactive child syndrome: Peripheral sympathetic nervous system function and the effect of d-amphetamine

We evaluated sympathetic nervous system function in medication-free hyperactive children by measuring plasma levels of norepinephrine (NE) and dopamine-beta-hydroxylase and then comparing the effects of two therapeutics doses of d-amphetamine to placebo in these patients. The medication-free hyperactive patients and controls had similar plasma NE levels and blood pressures while recumbent, and a similar increase in NE on standing, but the patients had a larger pressor response on standing. In the hyperactive patients d-amphetamine significantly increased blood pressure, pulse rate, and NE levels. The change in NE levels correlated with the change in amphetamine levels. The medication-free patients, when more anxious, had higher plasma NE levels.