No Tryptophan, Tyrosine and Phenylalanine Abnormalities in Children with Attention-Deficit/Hyperactivity Disorder.

BACKGROUND: The aim of the current study was to explore the role of aromatic amino acids (AAAs) in blood in relation to attention-deficit/hyperactivity disorder (ADHD). Given their impact on the synthesis of serotonin and dopamine, decreased concentrations of the AAAs tryptophan, tyrosine and phenylalanine in blood may contribute to the expression of ADHD symptoms. Decreased AAA blood concentrations, in turn, may be related to lowered dietary protein intake or to abnormal AAA catabolism, as evidenced by increased urinary AAA concentrations. METHODS: Eighty-three children with ADHD (75% males) and 72 typically developing (TD) children (51% males), aged 6 to 13 years, participated in the study. AAA concentrations were assessed in blood spots and an 18-hour urinary sample. A nutritional diary was filled out by parents to calculate dietary protein intake. Parent and teacher questionnaires assessed symptoms of ADHD, oppositional defiant disorder, conduct disorder, and autism spectrum disorder. RESULTS: Children with ADHD showed normal AAA concentrations in blood spots and urine, as well as normal protein intake compared to controls. No associations between AAA concentrations and symptoms of ADHD or comorbid psychiatric disorders were found. CONCLUSIONS: This study is the first to explore AAA metabolism in children with ADHD using a well-defined and relatively large sample. We found that AAA deficiencies are not related to ADHD. The results do not support treatment with AAA supplements in children with ADHD. Future studies regarding the cause of serotonin and dopamine alterations in ADHD should focus on other explanations, such as effects of altered transport of AAAs.

A randomized, controlled, crossover trial of fish oil treatment for impulsive aggression in children and adolescents with disruptive behavior disorders.

OBJECTIVE: Epidemiological research links aggression to low serum concentrations of omega-3 fatty acids, such as those found in fish oil. However, no studies have specifically examined whether fish oil supplementation can reduce the frequency and severity of impulsive aggression in children with disruptive behavior disorders. METHODS: Children presenting with impulsive aggression and meeting research criteria for diagnosis of disruptive behavior disorders were randomized to receive either: 1) Fish oil capsules (4 g daily) for 6 weeks followed by placebo (identical-looking capsules) for 6 weeks; or 2) placebo for 6 weeks, followed by fish oil for 6 weeks, in a double-blind, crossover design. Primary outcomes were the Children's Aggression Scale and the Modified Overt Aggression Scale. Secondary outcomes included emotional and behavioral functioning (Strengths and Difficulties Questionnaire [SDQ]), hyperactivity symptoms (Attention-Deficit/Hyperactivity Disorder [ADHD] Rating Scale), family functioning (Family Assessment Device), and cognitive functioning (Stop Signal Task, Trail-Making Task, and Eriksen Flanker Task). Serum concentrations of omega-3 and omega-6 fatty acids were measured at baseline, and at 6 and 12 weeks. RESULTS: Twenty-one children participated (81% male; mean age 10.3±2.2 years; range 7-14). Fish oil treatment increased serum concentrations of eicosapentanoic acid (F=14.76, p<0.05) and total omega-3s (F=20.56, p<0.05), but did not influence primary ratings of aggression. In fact, a trend suggested that fish oil worsened a secondary measure of aggression (SDQ Conduct Subscale, F=4.34, p=0.06). Fish oil treatment was associated with an improvement in one rating of hyperactivity (SDQ Hyperactivity Subscale, F=2.22, p<0.05), but did not influence any other outcome measures. CONCLUSIONS: These findings suggest that fish oil treatment does not improve aggression in children with disruptive behavior disorders.

Impact of maternal depression across the first 6 years of life on the child's mental health, social engagement, and empathy: The moderating role of oxytocin.

OBJECTIVE: Maternal depression across the postbirth period has long-term negative consequences for infant development. Little is known of the neurobiological underpinnings, but they could involve oxytocin, a neuropeptide that is dysfunctional in depression and is implicated in birth and parenting. METHOD: The authors recruited a community cohort of women with high or low depression scores 2 days after childbirth and measured depression again at 6 and 9 months. When the child was 6, the authors evaluated the families of 46 chronically depressed mothers and 103 mothers reporting no depression since childbirth. The child was assessed for psychiatric diagnoses, social engagement, and empathy. Mother, father, and child were tested for salivary oxytocin level and variation in the rs2254298 single nucleotide polymorphism on the OXTR gene. RESULTS: Of the children of the chronically depressed mothers, 61% displayed axis I disorders, mainly anxiety and oppositional defiant disorder, compared with 15% of the children of nondepressed mothers. In the depressed mothers' families, salivary oxytocin was lower in mothers, fathers, and children, and the children had lower empathy and social engagement levels. The rs2254298 GG homozygous genotype was overrepresented in depressed mothers and their families, and it correlated with lower salivary oxytocin. Presence of a single rs2254298 A allele (GA or AA genotype) in depressed mothers markedly decreased risk of child psychopathology. CONCLUSIONS: The negative effect of chronic maternal depression on child social outcomes was related to genetic and peripheral biomarkers of the oxytocin system. This suggests a potential for oxytocin-based interventions.

Antipsychotic-induced hyperprolactinemia and testosterone levels in boys.

AIMS: This cross-sectional study investigates the effect of antipsychotic (AP)-induced hyperprolactinemia on testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), inhibin B, and puberty in boys with mainly autism spectrum disorders (ASD). METHOD: One hundred and four physically healthy 10- to 19-year-old boys with ASD or disruptive behavior disorder (DBD) were recruited between October 2006 and November 2009. Fifty-six adolescents had been treated with AP for >16 months; 48 had never been exposed to AP. Morning non-fasting levels of serum prolactin, testosterone, LH, FSH and inhibin B were obtained and Tanner pubertal stage was determined. Patients with hyperprolactinemia (n = 28) were compared to those without hyperprolactinemia (n = 76) using non-parametric or parametric tests, as appropriate. RESULTS: Patients with AP-induced hyperprolactinemia had significantly lower testosterone levels with adjustment for age (p = 0.035) compared to patients without hyperprolactinemia and without AP treatment. The difference was not significant within the AP-treated group, and the level of testosterone was within the reference range compared to age- and gender-matched normative data. There was no between-group difference for LH, FSH, inhibin B or Tanner stages. CONCLUSION: AP-induced hyperprolactinemia is related to significantly lower testosterone levels in pubertal boys with ASD and DBD.

Influence of treatment for disruptive behavior disorders on adrenal and gonadal hormones in youth.

The study examined whether psychosocial intervention for children diagnosed with a disruptive behavior disorder (DBD; n = 84) changed concentrations of cortisol and testosterone across a 3-year follow-up when compared to a matched, nonclinical, healthy comparison (HC; n = 69) group. Boys and girls (6-11 years) with a DBD were randomly assigned to one of two arms of a multimethod intervention. Hierarchical linear modeling revealed that children undergoing psychosocial intervention for a DBD experienced a significant decline in diurnal cortisol change over time (p < .05) when compared to the HC condition. Boys with a DBD diagnosis had significantly lower mean cortisol concentrations prior to treatment (p < .05) and showed a significantly steeper increase in mean cortisol over time (p < .05) when compared to HC boys. Treatment effects for diurnal cortisol change were replicated in the boys-only analysis. No treatment effects were noted for testosterone in either analysis.

Effects of zinc supplementation on parent and teacher behaviour rating scores in low socioeconomic level Turkish primary school children.

OBJECTIVE: To determine the effect of zinc supplementation on behaviour in low-income school aged children. DESIGN: Double-blind randomized, placebo controlled trial. SETTING: Low-income district primary school in Turkey. PARTICIPANTS: Third grade students in the school. Among 252 students, 226 participated and 218 completed the study. INTERVENTION: Children in each class were randomized either to the study group to receive 15 mg/day elemental zinc syrup or to placebo group to receive the syrup without zinc for 10 weeks. MAIN OUTCOME MEASURES: The change in Conner's Rating Scales for Teachers and Parents scores after supplementation. RESULTS: The mean Conner's Rating Scale for Parents scores on attention deficit, hyperactivity, oppositional behaviour and conduct disorder decreased significantly in the study and placebo groups after supplementation (p < 0.01). The prevalence of children with clinically significant parent ratings on attention deficit (p = 0.01) and hyperactivity (p = 0.004) decreased in the study group while prevalence of oppositional behaviour (p = 0.007) decreased in the placebo group. In children of mothers with low education all mean Parents' scores decreased significantly (p < 0.01) in the study group while only hyperactivity scores decreased in the placebo group (p < 0.01). In this subgroup the prevalence of children with clinically significant scores for attention deficit, hyperactivity and oppositional behaviour decreased only in the study group (p < 0.05). There was no change in mean Teachers' scores. CONCLUSION: In our study zinc supplementation decreased the prevalence of children with clinically significant scores for attention deficit and hyperactivity. The affect on behaviour was more evident in the children of low educated mothers.

Ghrelin and leptin response to oral glucose challenge among antipsychotic drug-treated children.

We investigated ghrelin, leptin, glucose, and insulin response to an oral glucose tolerance test among children receiving antipsychotics. Hormone concentrations were assayed at fasting, 30, 60, and 120 minutes. The sample was composed of 9 obese (defined as at or above the 95th percentile for age) and 10 overweight/normal children (defined as less than the 95th percentile in weight) based on National Institutes of Health criteria. Ages of the obese (10.7 +/- 3.4 years) and the overweight/normal (13.1 +/- 1.6 years) did not differ. Leptin was significantly higher among the obese group and did not change consequent to glucose. Ghrelin did not differ between the groups, and when the values were combined, ghrelin decreased at 30 minutes and approached fasting concentrations at 120 minutes. To further explore our data, we constituted separate groups based upon z score changes. When weight gain defined as an increase in z score (X = 0.4), the nongainers showed leptin concentrations to decrease over time. Findings encourage further oral glucose tolerance test studies to explain the leptin response to weight gain seen among children receiving antipsychotic medication.

Divalproex sodium reduces overall aggression in youth at high risk for bipolar disorder.

INTRODUCTION: The psychopharmacology of aggression in youth is relatively unexplored, even though such maladaptive aggression manifests across many different diagnoses. METHODS: This study was a 12-week, open-label trial with divalproex sodium (DVPX) in 24 bipolar offspring 6-18 years of age (mean age = 11.3 years; 17 boys) with mixed diagnoses of major depression, cyclothymia, attention-deficit/hyperactivity disorder (ADHD), and oppositional defiant disorder (ODD). The Overt Aggression Scale (OAS) was used to measure aggression in 4-week intervals. We measured serum gamma-butyric acid (GABA) and glutamate levels at baseline and week 12. RESULTS: Seventy-one percent of evaluable subjects were considered responders to DVPX treatment by the OAS. There was a significant correlation between the Young Mania Rating Scale (YMRS) and OAS scores at week 0 (p = 0.036) and week 12 (p = 0.025). Serum DVPX level did not correlate with treatment response. CONCLUSIONS: These youths who are at high risk for bipolar disorder experienced an overall decrease in aggressive behavior in response to DVPX. Age or gender did not predict a positive response to DVPX. This study is the first report of treatment efficacy of a mood stabilizer for aggression in youth at high risk for bipolar disorder.

Low basal salivary cortisol is associated with teacher-reported symptoms of conduct disorder.

Cortisol has been implicated in psychobiological explanations of antisocial behavior. This study measured basal salivary cortisol in a sample of 25 children (age range 6 to 12 years) selected to vary in levels of antisocial behavior. Regression analyses were used to predict cortisol concentrations from parent- and teacher-reported symptoms. Parent-reported symptoms did not predict basal cortisol. Teacher-reported conduct disorder (CD) symptoms explained 38% of the variance in the cortisol concentrations, with high symptom severity associated with low cortisol. When a distinction was made between aggressive and non-aggressive CD symptoms, aggressive CD symptoms were more clearly related to low cortisol than non-aggressive CD symptoms. In contrast to previous research, no evidence was found for a mediating role of anxiety symptoms in the relationship between CD and cortisol. The results support biologically based models of antisocial behavior in children that involve reduced autonomic activity.

Cortisol and treatment effect in children with disruptive behavior disorders: a preliminary study.

OBJECTIVE: Basal cortisol and cortisol stress responsivity are valuable biological characteristics of children with disruptive behavior disorder (DBD). In this study, the predictive value of cortisol to outcome of intervention was investigated. METHOD: Basal cortisol levels and cortisol levels under stress were studied in 22 children with DBD before the start of a psychotherapeutic treatment. The disruptive behavior of the child was assessed before treatment and after cessation (9 months later). RESULTS: Children with DBD with relatively high and low basal cortisol levels differed in the severity of problem behavior at pretreatment, with the low basal cortisol group having more severe problems. During stress, children with DBD showed either increasing or decreasing cortisol values. Although these cortisol responsivity groups were similar in the severity of behavioral problems at pretreatment, the behavioral problems of the group with high cortisol stress responsivity were significantly lower after the intervention than the behavioral problems of the group with low cortisol stress responsivity. CONCLUSIONS: In children with DBD, the basal cortisol level was related to the severity of behavioral problems at pretreatment but not to the severity of behavioral problems after treatment. The cortisol response pattern during stress was related to treatment outcome.

Growth and sexual maturation during long-term treatment with risperidone.

OBJECTIVE: This study assessed the impact of risperidone on growth and sexual maturation. METHOD: The pooled database of five studies included 700 children ages 5-15 years with disruptive behavior disorders. All evaluable patients had received risperidone for 11 or 12 months. Those evaluable for growth also had baseline and 11- or 12-month height measurements (N=350); girls >/=9 years and boys >/=10 years who were evaluable for sexual maturation also had baseline and 11- or 12-month Tanner staging (N=222). RESULTS: Risperidone-treated children had a mean increase in height 1.2 cm greater than the reference population, and they experienced no delay in progression through Tanner staging. Transient increases in prolactin did not correlate with growth or sexual maturation. CONCLUSIONS: In this retrospective analysis, there was no evidence of statistically or clinically significant growth failure or delay in pubertal onset or progression in children treated for up to 1 year with risperidone.

EFA supplementation in children with inattention, hyperactivity, and other disruptive behaviors.

This pilot study evaluated the effects of supplementation with PUFA on blood FA composition and behavior in children with Attention-Deficit/Hyperactivity Disorder (AD/HD)-like symptoms also reporting thirst and skin problems. Fifty children were randomized to treatment groups receiving either a PUFA supplement providing a daily dose of 480 mg DHA, 80 mg EPA, 40 mg arachidonic acid (AA), 96 mg GLA, and 24 mg alpha-tocopheryl acetate, or an olive oil placebo for 4 mon of double-blind parallel treatment. Supplementation with the PUFA led to a substantial increase in the proportions of EPA, DHA, and alpha-tocopherol in the plasma phospholipids and red blood cell (RBC) total lipids, but an increase was noted in the plasma phospholipid proportions of 18:3n-3 with olive oil as well. Significant improvements in multiple outcomes (as rated by parents) were noted in both groups, but a clear benefit from PUFA supplementation for all behaviors characteristic of AD/HD was not observed. For most outcomes, improvement of the PUFA group was consistently nominally better than that of the olive oil group; but the treatment difference was significant, by secondary intent-to-treat analysis, on only 2 out of 16 outcome measures: conduct problems rated by parents (-42.7 vs. -9.9%, n = 47, P = 0.05), and attention symptoms rated by teachers (-14.8 vs. +3.4%, n = 47, P = 0.03). PUFA supplementation led to a greater number of participants showing improvement in oppositional defiant behavior from a clinical to a nonclinical range compared with olive oil supplementation (8 out of 12 vs. 3 out of 11, n = 33, P = 0.02). Also, significant correlations were observed when comparing the magnitude of change between increasing proportions of EPA in the RBC and decreasing disruptive behavior as assessed by the Abbreviated Symptom Questionnaire (ASQ) for parents (r = -0.38, n = 31, P < 0.05), and for EPA and DHA in the RBC and the teachers' Disruptive Behavior Disorders (DBD) Rating Scale for Attention (r = -0.49, n = 24, P < 0.05). Interestingly, significant correlations were observed between the magnitude of increase in alpha-tocopherol concentrations in the RBC and a decrease in scores for all four subscales of the teachers' DBD (Hyperactivity, r = -0.45; Attention, r= -0.60; Conduct, r = -0.41; Oppositional/Defiant Disorder, r = -0.54; n = 24, P < 0.05) as well as the ASQ for teachers (r = -0.51, n = 24, P < 0.05). Thus, the results of this pilot study suggest the need for further research with both n-3 FA and vitamin E in children with behavioral disorders.

Alterations in stress cortisol reactivity in depressed preschoolers relative to psychiatric and no-disorder comparison groups.

BACKGROUND: Despite the robust and widely replicated finding of elevated hypothalamic-pituitary-adrenal (HPA) axis reactivity in depressed adults, studies of depressed children have yielded ambiguous findings. Animal models of early depression and studies of children experiencing early psychosocial deprivation have suggested that alterations in HPA axis reactivity are evident in early "depressive-like" conditions. The current study is, to our knowledge, the first investigation of HPA axis reactivity in very young children with a clinical depressive syndrome for which content validity has been established. METHODS: Depressed, psychiatric, and no-disorder comparison children aged 3 through 5.6 years were studied for HPA axis reactivity in response to experimental psychosocial stressors. The children were diagnosed using a developmentally appropriate, structured psychiatric interview. Salivary cortisol was obtained at 3 time points during a laboratory assessment before and after stressors involving separation from the parent and frustrating tasks. RESULTS: Repeated measures of multivariate analysis of variance revealed a significant interaction between the diagnostic group and 2 cortisol percent change scores. Depressed preschoolers displayed a pattern of increasing cortisol levels throughout the assessment in response to both separation and frustration stressors. In contrast, both comparison groups showed decreasing cortisol levels in response to the separation stressor. All groups displayed increasing cortisol levels in response to frustrating tasks. Preschoolers with a presumptive melancholic depressive subtype displayed these alterations at a greater magnitude relative to comparison groups. CONCLUSIONS: To our knowledge, these findings are the first to demonstrate altered HPA axis reactivity in depressed preschoolers. These alterations are consistent with those described in depressed adults and in animal models of early depression. These findings provide evidence for possible continuity of HPA axis alterations in depressive disorders across the lifespan and are discussed in the context of prior studies of HPA axis reactivity in clinically depressed children and adolescents, suggesting that younger age and inpatient status are features associated with altered HPA axis reactivity.

Increased adrenal androgen functioning in children with oppositional defiant disorder: a comparison with psychiatric and normal controls.

OBJECTIVE: To examine the relationship between adrenal androgens and aggression in children with oppositional and antisocial behavior and to compare their levels with those of psychiatric and normal controls. METHOD: Dehydroepiandrosterone sulfate (DHEAS) was measured in 24 children with oppositional defiant disorder (ODD), 42 psychiatric controls (including 20 children with attention-deficit/hyperactivity disorder [ADHD]), and 30 normal controls. The children's parents filled out the Child Behavior Checklist (CBCL). RESULTS: Children with ODD had higher DHEAS levels than either the psychiatric control or normal control groups; DHEAS levels of the latter groups did not differ. Moreover, it was possible to classify children as having either ODD or ADHD on the basis of their DHEAS levels, whereas this was not the case on the basis of the CBCL data. CONCLUSIONS: The results indicate that adrenal androgen functioning is specifically elevated in children with ODD. It is speculated that the mechanism could be a shift in balance of ACTH-beta-endorphin functioning in the hypothalamic-pituitary-adrenal axis due to early stress or genetic factors.

Plasma monoamine metabolites and aggression: two studies of normal and oppositional defiant disorder children.

In two studies the relationship between plasma monoamine metabolites and different parameters of aggression were examined in children suffering from severe aggression and antisocial behavior. No prior studies have related measures of serotonergic function to experimentally elicited aggression and only a few included healthy comparison groups. Plasma 5-HIAA, HVA and MHPG were measured in 15 boys with a oppositional defiant disorder (ODD) and 25 normal controls (NC) (study 1), and 22 ODD and 25 NC children (study 2). On a separate occasion each subject had the opportunity to behave aggressively towards an opponent. 5-HIAA and HVA were significantly lower in the ODD than NC group and both parameters were significantly inversely correlated with aggression and delinquency. These findings were replicated in the second study: The results of the study support a role for serotonergic functioning in persistent antisocial and aggressive behavior in young children.

Peripheral serotonin measures in prepubertal psychiatric inpatients and normal children: associations with suicidal behavior and its risk factors.

BACKGROUND: This study reports relationships between suicidal behavior and its risk factors in prepubertal children and whole blood and platelet serotonin-related measures. METHODS: Seventy-five prepubertal psychiatric inpatients including 23 (30.7%) nonsuicidal, 32 (42.7%) with suicidal ideation, and 20 (26.6%) with a suicide attempt were compared to 35 normal prepubertal controls with regard to platelet serotonin content, serotonin-amplified platelet aggregation, and whole blood tryptophan. RESULTS: Mean whole blood tryptophan content was significantly lower among inpatient children with a recent suicide attempt than among normal controls or inpatients with suicidal ideation (F = 3.94, df = 3.54, p < or = .01). Inpatient children with a mood disorder had significantly higher platelet serotonin content than inpatients without a mood disorder (F = 3.86, df = 2.80, p < or = .03). Racial/ethnic differences were also observed for inpatients and normal controls, with whites having significantly lower levels of platelet serotonin (expressed as ng/mL blood or ng/10(9) platelets) than blacks or Latinos. Blacks had significantly higher levels of whole blood tryptophan than other racial/ethnic groups. CONCLUSIONS: The results suggest that whole blood tryptophan and platelet serotonin content should be studied for their predictive validity as risk factors for suicidal behavior in youth while controlling for racial/ethnic differences.