Normand Carrey

Effects of Methylphenidate and Behavior Modification on the Social and Academic Behavior of Children With Disruptive Behavior Disorders: The Moderating Role of Callous/Unemotional Traits

This study examined whether response to behavior modification with and without methylphenidate differed for children with attention-deficit/hyperactivity disorder (ADHD) and conduct problems (CP) depending on the presence of callous/unemotional (CU) traits. Participants were 37 children ages 7 to 12, including 19 with ADHD/CP-only and 18 with ADHD/CP-CU, referred to a university-based summer treatment program. Results showed that ADHD/CP-CU children had worse behavior in the behavior-therapy-only (BT-only) condition, especially on measures of CP, noncompliance, and rule violations, but these differences largely disappeared when medication was added to BT. Children with ADHD/CP-CU were also less likely to be normalized by treatment than were children with ADHD/CP-only. These findings, though tentative, suggest that children with ADHD/CP-CU may not show a sufficient positive response to BT alone and that the combination of medication and BT may be especially important for them.

Proton spectroscopy in medication-free pediatric attention-deficit/hyperactivity disorder

BACKGROUND The frontal-striatal pathway has been previously implicated in the neuropathology of attention-deficit/hyperactivity disorder (ADHD). Hence, we used proton magnetic resonance spectroscopy (1H-MRS) to examine metabolite levels in the prefrontal cortex of children with ADHD. METHODS Nine age- and gender-matched case-control pairs were examined, ages 7 to 16 years. A long-echo 1H-MRS scan was acquired from the right prefrontal cortex and left striatum in all subjects. Compounds that can be visualized with 1H-MRS include N-acetyl-aspartate (NAA), glutamate/glutamine/gamma-aminobutyric acid (Glx), creatine/phosphocreatine (Cr), and choline compounds (Cho). RESULTS Frontal-striatal glutamatergic resonances were elevated in the children with ADHD as compared to healthy control subjects. No differences were noted in NAA, Cho, or Cr metabolite ratios. CONCLUSIONS These findings suggest that frontal-striatal Glx resonances may be increased in children with ADHD in comparison with healthy control subjects.

Treatment response in CP/ADHD children with callous/unemotional traits.

The current study examines the role of callous/unemotional (CU) traits in response to treatment among children with conduct problems (CP) and attention-deficit/hyperactivity disorder (ADHD). Fifty-four children with CP/ADHD and 16 controls (age = 9.48, SD = 1.58) took part in a summer treatment and research program. Simple correlations showed that CU and CP were associated with a number of treatment outcome measures. When examined together in regression analyses, CU and CP were uniquely associated with three treatment outcomes each (CU—improvement in social skills and problem solving, negative behaviors in time-out; CP—time-outs per day, peer ratings, peer dislike). The implications for these findings with regard to treatment response in children with CP/ADHD with and without CU traits are explored.

Metabolite changes resulting from treatment in children with ADHD: a 1H-MRS study.

Previously the authors noted an increase in glutamatergic tone in children with attention deficit hyperactivity disorder compared with age- and gender-matched control subjects. In this study they examine the effect of treatment on metabolite concentrations. Fourteen children with attention deficit hyperactivity disorder were investigated medication free and after treatment, using proton magnetic resonance spectroscopy. In the prefrontal cortex and striatum, metabolite peaks of N-acetyl-aspartate, glutamate/glutamine/&ggr;-aminobutyric acid, creatine/phosphocreatine, and choline compounds were measured, and ratios of the peaks were calculated and compared before and after treatment. The glutamate/glutamine/&ggr;-aminobutyric acid-to-creatine/phosphocreatine ratio decreased significantly in the striatum. No other metabolites demonstrated any change in response to medication. These findings suggest that glutamate may be involved in treatment response in attention deficit hyperactivity disorder, especially in the striatum.

Glutamatergic Changes with Treatment in Attention Deficit Hyperactivity Disorder: A Preliminary Case Series

Magnetic resonance spectroscopy, a noninvasive neuroimaging method, is a technique with the potential to measure in vivo neurochemical changes to different medication treatments. Symptoms of attention deficit hyperactivity disorder (ADHD) improved in two children treated with methylphenidate and two children treated with atomoxetine, for whom pre- and posttreatment proton magnetic resonance spectroscopy examinations were obtained to assess the relation between the neurochemical profiles in the striatum and prefrontal cortex among symptom severity and response to treatment. In the striatum, a striking decrease in the glutamate/creatine ratio (mean change 56.1%) was observed between 14 and 18 weeks of therapy in all four children with ADHD. In the prefrontal cortex, however, changes in the glutamate/creatine ratio were noted only in subjects receiving atomoxetine, not in those receiving methylphenidate. These data suggest that in vivo magnetic resonance spectroscopy measurement has the potential to assess response to psychopharmacological treatment in children with ADHD.

Methylphenidate regulates Activity regulated cytoskeletal associated but not Brain-derived neurotrophic factor gene expression in the developing rat striatum

Methylphenidate (MPH) is a psychostimulant drug used to treat attention deficit hyperactivity disorder in children. To explore the central effects of chronic MPH, we investigated the expression of an effector immediate early gene, activity regulated cytoskeletal associated (arc), and the neurotrophin, brain-derived neurotrophic factor (bdnf) in the brain of immature and adult rats following repeated MPH. Prepubertal (postnatal day (PD) 25-38) and adult (PD 53-66) male rats were injected once daily for: a) 14 days with saline or MPH (2 or 10 mg/kg; s.c.) or b) 13 days with saline followed by a single dose of MPH (2 or 10 mg/kg; s.c.). To determine possible long-term effects of MPH, prepubertal rats were allowed a drug-free period of 4 weeks following the 14 days of treatment, and then were given a challenge dose of MPH. We demonstrated, for the first time, that an acute injection of MPH increased levels of activity-regulated cytoskeletal protein (ARC) and arc mRNA in the prepubertal rat striatum and cingulate/frontal cortex. This response was significantly attenuated by chronic MPH. The desensitization in arc expression observed in prepubertal rats persisted in the adult striatum following a later MPH challenge. In contrast to these data we observed little effect of MPH on bdnf expression. We also developed an effective, non-stressful technique to treat freely moving immature rats with oral MPH. Consistent with the results described above, we observed that oral MPH (7.5 and 10 mg/kg) also increased arc expression in the prepubertal rat striatum. However, unlike the effects of injected MPH, repeated oral MPH (7.5 mg/kg) did not alter the normal arc response. This result raises the important possibility that oral doses of MPH that reproduce clinically relevant blood levels of MPH may not down-regulate gene expression, at least in the short term (14 days). We confirmed, using mass spectrometry, that the oral doses of MPH used in our experiments yielded blood levels within the clinical range observed in children. The novel oral administration paradigm that we describe thus provides a clinically relevant animal model to further explore the effects of chronic drug exposure on central gene expression in the developing rat brain.

Cortical thickness in youth with major depressive disorder

BackgroundStudies in adults with major depressive disorder (MDD) have implicated dysregulation of frontal-limbic circuits in the symptomology of this disorder. We hypothesized that the middle frontal gyrus (MFG; a core portion of the dorsolateral prefrontal cortex or DLPFC) and the anterior cingulate (caudal), regions implicated in emotive and cognitive control, would display a reduced cortical thickness in youth with MDD as compared to healthy, non-depressed adolescents.MethodsSixteen healthy control adolescents (17.19 ± 1.87 years; 7 males, 9 females) and thirty MDD participants (16.89 ± 2.01 years; 9 males, 21 females) underwent magnetic resonance imaging (MRI). Cortical thickness analysis was carried out using FreeSurfer software.ResultsCounter to our hypothesis, we observed thicker right and left rostral MFG in MDD adolescents as compared to controls (p = 0.004 and p = 0.005, respectively). Furthermore, the left caudal anterior cingulate cortex was thicker in MDD subjects as compared to controls (p = 0.009). In MDD subjects, there was a significant inverse correlation between age and left MFG thickness (r = -0.45, p = 0.001).ConclusionsThese results have implications for the developmental trajectory of the frontal lobe in adolescent MDD. The MFG is implicated in the frontal-limbic circuits underlying executive functioning and their interaction with affective processing. Alterations in this region are likely involved with the symptoms of MDD. Limitations include a small sample size and cross sectional design.

Age-related distribution of c-fos expression in the striatum of CD-1 mice after acute methylphenidate administration

Ritalin (methylphenidate hydrochloride, MPH) is the drug of choice for the treatment of attention deficit hyperactivity disorder. Previous research has shown that MPH administration affects the adult brain in a manner different from the young brain. In the current study, we set out to determine the target brain regions of acutely administered MPH at different stages of development. On postnatal days 3, 7, 11, 24, and 45, mice were treated with a single injection (s.c.) of saline, 5 or 20 mg/kg of MPH, and sacrificed 1 h later. Localization of c-fos expression was determined by immunocytochemistry. Compared to saline treated controls, mice treated with the high dose of MPH (20 mg/kg) showed dense Fos-immunoreactivity (Fos-IR) in the striatum. In most cases the low dose of MPH (5 mg/kg) produced only weak c-fos expression that was nearly indistinguishable from saline-treated controls. At PND 3 and 7, Fos-IR was localized in patches in the striatum. This patchy distribution of c-fos positive cells began to decline by PND 11 and was absent in PND 45 mice, with Fos-IR showing a scattered distribution throughout the striatum. The results of this study indicate that MPH induces the expression of c-fos in the same brain regions as cocaine and amphetamine, and that this expression is distributed differentially according to the age of the mouse.

Update and Recommendations for the Use of Antipsychotics in Early-Onset Psychoses

A review was undertaken of studies evaluating the efficacy and tolerability of antipsychotic medications for the management of psychosis in children and adolescents. All identified published and unpublished studies from 1996 onward were included for review. The search located one randomized control trial, seven open-label trials, six retrospective chart reviews, and nine case reports. The studies assessed the use of haloperidol, clozapine, risperidone, olanzapine, and quetiapine in the management of psychosis in children and adolescents. Most studies reported reasonable treatment response; however, extrapyramidal side effects, sedation, and weight gain are concerning. This points to the need for appropriate baseline assessments prior to initiating treatment with these agents. Particular attention should be given to assessment of the extrapyramidal system as well as to baseline weight, lipid profile, and blood glucose. Further study is needed to refine the use of antipsychotic medications in children and adolescents in order to minimize adverse effects while conferring an optimum therapeutic response. The importance of instituting effective early treatment in youth with psychoses is an important goal that may serve to lessen the long-term morbidity of the illness.

Noradrenergic and Serotonergic Neuroendocrine Responses in Prepubertal, Peripubertal, and Postpubertal Rats Pretreated With Desipramine and Sertraline

OBJECTIVE To explore whether developmental status of neurotransmitter systems may affect response to antidepressant treatment. This study investigated whether younger animals, compared with mature animals, showed the same neuroendocrine response to challenge drug probes when pretreated with a serotonergic or noradrenergic antidepressant. METHOD Prepubertal, pubertal, and adult rats were pretreated with low- or high-dose sertraline or desipramine for 14 days. Animals were then challenged with a noradrenergic probe (clonidine for desipramine-treated animals) or a serotonergic probe (fenfluramine for sertraline-treated animals). The neurohormonal response of growth hormone to the clonidine challenge and prolactin to the fenfluramine challenge was then measured. RESULTS In animals challenged with fenfluramine, the postpubertal control group showed a significantly higher prolactin response to fenfluramine than postpubertal animals pretreated with low- or high-dose sertraline. No differences were found in the pubertal or prepubertal group. In animals challenged with clonidine, there was a significant age by treatment interaction effect for the prepubertal group pretreated with high doses of desipramine (less growth hormone secretion) but not for the peri- or postpubertal groups. CONCLUSIONS These data indicate neurodevelopmental factors may play a role in the functional physiology of neurotransmitter systems, which in turn may affect response to psychotropics.