Role of NOS3 DNA variants in externalizing behavioral problems observed in childhood leukemia survivors.

OBJECTIVE: Neuropsychological problems occurrence varies among childhood cancer survivors, and associated risk factors have not been fully deciphered. We wanted to study the role of genetic variants in behavioral problems in this population. STUDY DESIGN: Behavioral problems in pediatric acute lymphoblastic leukemia patients (n=138) were investigated longitudinally, using the Child Behavior Checklist questionnaire and multilevel statistical modeling. Thirty-four candidate polymorphisms, related to anticancer drug effects, were investigated. RESULTS: NOS3 gene functional polymorphisms showed significant association: patients homozygous for the minor allele at investigated loci showed decreased externalizing behavioral problems scores over time (t tests: T-786C n=69, P=0.003; G894T n=71, P=0.065). The effect was even more pronounced for individuals that are homozygous for the -786C844T haplotype (t test, n=69, P<0.001) and results were supported by multilevel modeling analyses (P<0.001). No such association was observed for internalizing behavioral problems. CONCLUSION: NOS3 variants modulate externalizing problems individual trajectories, likely in relationship with glucocorticoid exposure.

Autism severity is associated with child and maternal MAOA genotypes.

Autism severity is associated with child and maternal MAOA genotypes. We replicated and extended a previously reported association between autism severity and a functional polymorphism in the monoamine oxidase A (MAOA) promoter region, MAOA-uVNTR, in a sample of 119 males, aged 2-13 years, with autism spectrum disorder from simplex families. We demonstrated that (i) boys with the low activity 3-repeat MAOA allele had more severe sensory behaviors, arousal regulation problems, and aggression, and worse social communication skills than males with the high activity allele; and (ii) problems with aggression, as well as with fears and rituals, were modified by the mothers' genotype. Boys with the 4-repeat high activity allele who had homozygous 4-repeat mothers showed increased severity of these behaviors relative to those born to heterozygous mothers. These findings indicate the importance of considering maternal genotype in examining associations of MAOA and other genes with behavior in male offspring.

Drug-metabolizing enzyme genotypes and aggressive behavior treatment response in hospitalized pediatric psychiatric patients.

OBJECTIVE: The aim of this study was to examine the association between the CYP2D6 and CYP2C19 genotype-predicted combined phenotypes and short-term measures of psychotropic efficacy and toxicity. METHODS: A rater-blinded, retrospective genotype association design examined a cohort of hospitalized pediatric psychiatric patients genotyped for CYP2D6 and CYP2C19 as part of clinical care. These combined genotypes were used to predict a combined phenotype. The primary efficacy outcome measure was the behavior intervention score (BIS), a function of the number of recorded timeouts/seclusions, therapeutic holds, and physical restraints. Drug tolerability was defined as the total number of recorded adverse drug reactions. RESULTS: Primary analysis was performed on 279 pediatric patients taking CYP2D6- or CYP2C19- dependent psychotropics. Combined phenotype was associated with BIS (p = 0.01) and number of adverse drug reactions (p = 0.03). Combined poor metabolizers treated with psychotropics had the lowest BIS (highest efficacy) and the highest number of adverse drug reactions. Combined ultrarapid metabolizers had the highest BIS (lowest efficacy) and the lowest number of adverse drug reactions. CONCLUSION: Common variants in CYP2D6 and CYP2C19 are associated with the short-term efficacy and tolerability of psychotropic medications in hospitalized pediatric patients.

High activity of monoamine oxidase A is associated with externalizing behaviour in maltreated and nonmaltreated adoptees.

Individual differences in a functional polymorphism of the promoter of the Monoamine oxidase A (MAO-A) gene might partly explain the increased vulnerability of maltreated children for externalizing behaviour. A sample of 239 internationally adopted boys was studied. Adoptive parents provided the information about abuse and neglect before the adoption and rated externalizing behaviour of their adopted children, using the Child Behaviour Checklist. MAO-A alleles were classified in high and low activity. We found that individuals with high MAO-A activity had more externalizing behaviour than those with low MAO-A activity. No modifying effect of MAO-A on the relationship between early maltreatment on externalizing behaviour was observed. Our results suggest that in severely maltreated children, high MAO-A activity may not protect against the effects of maltreatment but may convey an increased risk for externalizing behaviour.

Antisocial process screening device: validation on a Russian sample of juvenile delinquents with the emphasis on the role of personality and parental rearing.

The objectives of the present study were 1) to validate the Antisocial Process Screening Device (APSD) in a sample of Russian juvenile delinquents; 2) to examine subgroups of delinquents with higher versus lower levels of childhood problem behaviors with respect to the APSD subscales, personality traits, and parental rearing; and 3) to attempt to replicate the previous finding that the APSD subscale measuring callous/unemotional traits can differentiate subgroups of delinquents with different precursors for problem behaviors (predominantly biological versus predominantly social). A group of 250 Russian juvenile inmates (mean age=16.4) was examined by means of the APSD completed by the staff at the correctional institution. The inmates completed several self-reports assessing their current and childhood behavior problems, personality traits and experienced parental rearing practices. A factor structure of the APSD was obtained that is similar, albeit not identical, to that from the original studies by Frick and colleagues [Frick, P.J., O'Brien, B.S., Wootton, J.M., McBurnett, K., (1994). Psychopathy and conduct problems in children. Journal of Abnormal Psychology, 103, 700-707]; [Frick, P.J., Barry, C.T., Bodin, S.D., (1999). Applying the concept of psychopathy to children: Implications for the Assessment of antisocial youth. In Gacono, C.B. (Ed), The clinical and forensic assessment of psychopathy: A practitioners guide. Hillsdale, NJ: Erlbaum]; [Frick, P.J., Lilienfeld, S.O., Ellis, M., Loney, B., Silverthorn, P., (1999). The association between anxiety and psychopathy dimensions in children. Journal of Abnormal Child Psychology, 27, 383-392]; callous unemotional traits in the present sample were expressed in manipulative behavior. Results further disclosed higher levels of antisocial and aggressive activities, higher levels of personality attributes such as narcissism and novelty seeking, as well as lower cooperativeness, and negatively perceived parental rearing in a subgroup with higher (versus lower) number of childhood symptoms of conduct disorder and oppositional disorder. The juvenile delinquents with higher levels as compared to lower levels of callous unemotional traits also perceived their parents as using more negative rearing strategies. The findings are discussed in terms of interactional processes between personality of the juvenile delinquents and parental rearing in the development of antisocial behavior.

MAOA, maltreatment, and gene-environment interaction predicting children's mental health: new evidence and a meta-analysis.

Previous research on adults has shown that a functional polymorphism in the promoter region of the monoamine oxidase A (MAOA) gene moderates the impact of childhood maltreatment on risk for developing antisocial behavior. Thus far, attempts to replicate this finding have been mixed. The current study (i) presents new data investigating this finding in a sample of 975 seven-year-old boys, and (ii) evaluates the extant data by conducting a meta-analysis of published findings. We replicated the original finding by showing that the MAOA polymorphism moderates the development of psychopathology after exposure to physical abuse, we extended the finding to childhood closer in time to the maltreatment experience, and we ruled-out the possibility of a spurious finding by accounting for passive and evocative gene-environment correlation. Moreover, meta-analysis demonstrated that across studies, the association between maltreatment and mental health problems is significantly stronger in the group of males with the genotype conferring low vs high MAOA activity. These findings provide the strongest evidence to date suggesting that the MAOA gene influences vulnerability to environmental stress, and that this biological process can be initiated early in life.

Altered antioxidant enzyme activities in children with a serious adverse experience related to valproic acid therapy.

Specific oxidative metabolites of valproic acid (VPA) have been associated with the clinically defined toxicity of the drug. To investigate the role of enzymatic detoxification in clinical toxicity, we compared activities of five antioxidant enzymes in 15 patients with a serious adverse experience (SAE) related to VPA therapy, to enzyme activities measured in 35 patients with good clinical tolerance of VPA, and 50 healthy, age-matched subjects. These enzymes included glutathione peroxidase (GSH-Px), glutathione reductase (GSSG-R), glutathione transferase, superoxide dismutase, and catalase in erythrocytes; and GSH-Px in plasma. We also determined levels of Se, Cu, and Zn, trace elemental cofactors for these enzymes, in plasma from each individual. In patients with a VPA-associated SAE, GSH-Px was significantly depressed and GSSG-R was significantly elevated relative to values for the other groups. Selenium and zinc concentrations were lower in SAE patients than in controls. These findings may indicate a role for selenium dependent antioxidant activity in individual susceptibility to an SAE related to VPA therapy.

Serum dopamine beta hydroxylase and maltreatment in psychiatrically hospitalized boys.

Fifty boys, hospitalized on a school-age and an adolescent unit in an intermediate length psychiatric hospital, were studied while off psychoactive medication to determine how serum dopamine beta hydroxylase (DBH) activity varies with different childhood maltreatment experiences. Childhood maltreatment was categorized according to onset (before 36 months old, between 36-72 months old and over 72 months old). Childhood maltreatment groups were compared with a group of psychiatrically hospitalized boys who had neither been abused nor neglected. Boys who were younger than 72 months at age of onset of maltreatment had significantly lower DBH activity than those who had experienced maltreatment later in childhood and those who had not been subjected to abuse or neglect. This difference appeared attributable to the DBH activity of school age (but not adolescent) boys who had been abused/neglected before 72 months. Boys with a principal diagnosis of conduct disorder solitary aggressive type had lower DBH activity than boys without this diagnosis regardless of whether or not they had been maltreated. Low serum DBH may be a biological sequela of maltreatment early in life that correlates with the development of conduct disorder solitary aggressive type in boys.

Dopamine-beta-hydroxylase in behaviorally disturbed youth. Relationship between teacher and parent ratings.

A series of neurotransmitters, metabolites, and enzymes considered relevant to emotional and behavioral disorders was studied in blood samples obtained from boys admitted to a residential setting because of disruptive or unmanageable behavior in their home environments. The youth were categorized into mainly prepubertal (under 12.0 years) and pubertal/post pubertal (12.0 years and over) groups. Behavior ratings of the younger group completed by parents revealed significant inverse correlations between several behavioral factors and dopamine-beta-hydroxylase (DBH) activity levels, notably in the aggressive behavior and antisocial domains. Teacher ratings completed after about 1 month of living in the residential setting also showed numerous significant, but positive, correlations between several behavior factors and DBH activity levels. Furthermore, teacher and parent ratings themselves often were significantly and inversely correlated. The findings related to DBH activity levels were strongest in the younger group of boys. The results are discussed in terms of the possibility that low DBH activity in boys reflects a vulnerability towards behavioral disorder, which in certain environments becomes manifested by conduct problems and antisocial behavior.

Biodevelopmental aspects of conduct disorder in boys.

The association between biochemical parameters and conduct disorder (CD) was studied in 22 boys admitted to a residential center. Three-methoxy-4-hydroxyphenylglycol (MHPG) levels were significantly higher in prepubertal CD youth than in pubertal/post pubertal CD youth. Homovanillic acid (HVA) levels were significantly lower in CD youth under age 12.0 years than in non CD youth under age 12.0 years. The implications of these biodevelopmental findings in the study of CD are discussed.

Elevated platelet MAO is related to impulsivity in disruptive behavior disorders.

Platelet monoamine oxidase (MAO) activity was measured in 32 drug-free prepubertal boys with externalizing symptoms of disruptive behavior disorders and 47 boys with no DSM-III-R diagnoses, and correlated to questionnaire and laboratory performance measures of impulsivity. A subgroup of boys with high MAO activity exhibited significantly poorer performance (i.e., more impulsivity) than a subgroup of low MAO activity on laboratory tasks requiring response inhibition. High MAO patients were more impulsive than high MAO controls on some performance tasks and elevated platelet MAO was unrelated to personality questionnaire measures of impulsivity or to patient status. These data suggest that biological markers such as MAO activity may correlate better with performance than clinical questionnaire measures. Abnormally high platelet MAO activity may not be sufficient to produce externalizing symptoms in children, perhaps interacting with an underlying behavioral dimension of impulsivity.

DBH, MHPG, and MAO in children with depressive, anxiety, and conduct disorders: relationship to diagnosis and symptom ratings.

Plasma 3-methoxy-4-hydroxyphenylglycol (MHPG), plasma dopamine-beta-hydroxylase (DBH) activity, and platelet monoamine oxidase (MAO) were obtained in 42 boys (7-14 years old) consecutively evaluated at a community mental health clinic. The boys were diagnosed according to DSM-III criteria by a child psychiatrist using a semistructured interview with the parent and child. The Revised Behavior Problem Checklist (RBPC) and the Revised Children's Manifest Anxiety Scale (RCMAS) were consecutively obtained on the last 24 subjects. No relationship of any of the plasma measures was found with respect to the DSM-III diagnoses. Plasma MHPG was positively correlated with the parent's rating of the child's anxiety on the Anxiety-Withdrawal factor of the RBPC. Plasma MHPG as well as platelet MAO activity, correlated positively with the child's self-rating of anxiety on the RCMAS. Children classified by the RBPC as having high conduct symptoms and low anxiety symptoms had significantly lower plasma MHPG than those subjects with low conduct problems and high anxiety. Platelet MAO activity was found to be negatively correlated to the child's score on the Lie Scale of the RCMAS.

Biochemical differences in children with conduct disorder socialized and undersocialized.

The authors compared plasma dopamine beta-hydroxylase (DBH), platelet monoamine oxidase (MAO), whole blood serotonin, and RBC catechol O-methyltransferase (COMT) in 25 children with conduct disorder and 20 control children. They found that children diagnosed as having conduct disorder undersocialized had significantly lower DBH activity than children diagnosed as having conduct disorder socialized and the control group. The children with conduct disorder socialized had significantly higher COMT activity than the other two groups. When children with a diagnosis of conduct disorder plus a diagnosis of attention deficit disorder were compared with the control group, no significant biochemical differences were found because of the mixing of the two diagnoses.

Catechol-O-methyltransferase activity in psychotic children.

Catechol-O-Methyltransferase (COMT) activity was studied in three groups of institutionalized children: (1) a group of schizophrenic children; (2) a heterogeneous group of chronic psychotic children characterized by severe symptomatology and onset before 5 years of age; (3) a group of acting-out but nonpsychotic children. Erythrocyte COMT activity was found to be significantly lower among the schizophrenic subjects in contrast to the greater activity in both the other groups--the nonpsychotic and chronic psychotic children. The difference in COMT activity between psychotic groups appeared to be related to diagnosis and age of onset of disorder. Generality of findings is limited by the small sample size (N = 42) and by the difficulties inherent in the diagnosis of severe mental disorder in children. However, this preliminary study suggests that enzymatic activity may be associated with the development of schizophrenia in children.