Predictors of relapse or maintenance of response in pediatric and adult patients with attention-deficit/hyperactivity disorder following discontinuation of long-term treatment with atomoxetine

We identified relapse/maintenance-of-response (MOR) predictors following discontinuation of long-term atomoxetine treatment in pediatric and adult patients with attention-deficit/hyperactivity disorder (ADHD) and assessed correlations between ADHD symptoms and quality of life (QoL). Post hoc analyses of data from two randomized, double-blind, placebo-controlled, phase 3 withdrawal studies in patients with ADHD meeting predefined response criteria before randomization. Study 1: patients (N = 163; 6–15 years) received atomoxetine (1.2–1.8 mg/kg/day) for 1 year, followed by randomization to atomoxetine (n = 81) or placebo (n = 82) for 6 months. Study 2: patients (N = 524; 18–50 years) received atomoxetine (80–100 mg/day) for ~6 months, followed by randomization to atomoxetine (n = 266) or placebo (n = 258) for ~6 months. Placebo patients were used for the analyses. Relapse: ≥50% worsening of prerandomization improvement in ADHD symptoms and ≥2 level severity increase on the Clinical Global Impression-Severity (CGI-S) scale at 2 consecutive visits; MOR: retaining ≥75% of prerandomization symptom improvement and CGI-S ≤ 2 at all visits (study 1); retaining ≥70% of prerandomization symptom improvement and CGI-S ≤ 3 at all visits (study 2). In adults, statistically significantly (P ≤ .05) increased likelihood of relapse was associated with prerandomization presence of Conners’ Adult Attention-Deficit/Hyperactivity Disorder Rating Scale-Investigator-Rated:Screening Version (CAARS-Inv:SV) items “difficulty awaiting turn” and “careless mistakes.” In pediatric patients, less MOR was associated with prerandomization presence of ADHD Rating Scale-IV-Parent Version Investigator-Rated item “does not listen”; in adults, less MOR was associated with prerandomization presence of CAARS-Inv:SV items “loses things” and “difficulty awaiting turn.” Changes in patients’ QoL after withdrawal from atomoxetine moderately correlated with changes in ADHD symptoms in pediatric patients and mildly in adults.     

Prognostic factors of improvement in health-related quality of life in atomoxetine-treated children and adolescents with attention-deficit/hyperactivity disorder,based on a pooled analysis

The objective of this study is to identify prognostic factors of treatment response to atomoxetine in improvement of health-related quality of life (HR-QoL), measured by the Child Health and Illness Profile-Child Edition Parent Report Form (CHIP-CE PRF) Achievement and Risk Avoidance domains, in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Pooled data from 3 placebo-controlled trials and separate data from 3 open-label trials of atomoxetine in children and adolescents with ADHD were analyzed using logistic regression methods. Based on baseline impairment in the Achievement and/or Risk Avoidance domains (CHIP-CE PRF < 40 points), 2 subsamples of subjects were included. Treatment outcome was categorized as <5 points or ≥5 points increase in the CHIP-CE PRF Achievement and Risk Avoidance domains. Data of 190 and 183 subjects from the pooled sample, and 422 and 355 subjects from the open-label trials were included in the analysis of Achievement and Risk Avoidance domains. Baseline CHIP-CE subdomain scores proved to be the most robust prognostic factors for treatment outcome in both domains, based on data from the pooled sample of double-blind studies and from the individual open-label studies (odds ratios [OR] 0.74–1.56, p < 0.05; OR < 1, indicating a worse baseline score associated with worse odds of responding). Initial treatment response (≥25 % reduction in ADHD Rating Scale scores in the first 4–6 weeks) was another robust prognostic factor, based on data from the open-label studies (OR 2.99–6.19, p < 0.05). Baseline impairment in HR-QoL and initial treatment response can be early prognostic factors of atomoxetine treatment outcome in HR-QoL in children and adolescents with ADHD.     

Potential Contribution of Monoamine Oxidase A Gene Variants in ADHD and Behavioral Co-Morbidities: Scenario in Eastern Indian Probands

Attention deficit hyperactivity disorder (ADHD) is the most frequently diagnosed behavioral disorder in children with a high frequency of co-morbid conditions like conduct disorder (CD) and oppositional defiant disorder (ODD). These traits are controlled by neurotransmitters like dopamine, serotonin and norepinephrine. Monoamine oxidase A (MAOA), a mitochondrial enzyme involved in the degradation of amines, has been reported to be associated with aggression, impulsivity, depression, and mood changes. We hypothesized that MAOA can have a potential role in ADHD associated CD/ODD and analyzed 24 markers in a group of Indo-Caucasoid subjects. ADHD probands and controls (N = 150 each) matched for ethnicity and gender were recruited following the Diagnostic and Statistical Manual for Mental Disorders-IV. Appropriate scales were used for measuring CD and ODD traits. Markers were genotyped by PCR-based methods and data obtained analyzed using the Cocaphase program under UNPHASED. Only eight markers were found to be polymorphic. rs6323 “G” allele showed higher frequencies in ADHD (P = 0.0023), ADHD + CD (P = 0.03) and ADHD + ODD (P = 0.01) as compared to controls. Haplotype analysis revealed statistically significant difference for three haplotypes in ADHD cases (P < 0.02). Statistically significant differences were also noticed for haplotypes in ADHD + CD and ADHD + ODD cases (P < 0.01). LD analysis showed significant variation in different groups. Multidimensionality reduction analysis showed independent as well as interactive effects of markers. Genotypes showed correlation with behavioral problems in ADHD and ADHD + CD. We interpret that MAOA gene variants may contribute to the etiology of ADHD as well as associated co-morbid CD and ODD in this ethnic group.     

Atomoxetine treatment for children and adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD): a comprehensive meta-analysis of outcomes on parent-rated core symptomatology

Attention-Deficit/Hyperactivity Disorder (ADHD) impacts a significant number of children and adolescents and often leads to deleterious functional impairment. Psychostimulant medication has historically been the first line of pharmacological intervention, though recent years have seen greater attention paid to non-stimulant alternatives. The objective of the present study was to conduct the most comprehensive meta-analysis to date evaluating the efficacy of atomoxetine in reducing core symptomatology of ADHD according to parent report. Selection criteria were applied, and studies were located by searching electronic databases, review of reference sections, and contact with expert researchers; article searching began on 10/01/2013, and the final search was conducted on 09/01/2014. A total of 42 studies met inclusion criteria—33 with control groups and 9 without—for a total sample of 8398 individuals. For those receiving atomoxetine, the summary pre–post (e.g., standardized mean gain) effect size estimate was 1.37 (95% CI [1.24, 1.51], p < .001); atomoxetine was found to statistically significantly outperform control conditions overall (Z = 4.07, p < .001), though results differed by the type of control group; for instance, when comparing atomoxetine to alternative medications as controls, significant differences were no longer present. The non-stimulant atomoxetine led to significant improvement in core ADHD symptomatology and should be considered as a viable pharmacological treatment option for ADHD.     

Reduced platelet monoamine oxidase type B activity and lymphocyte muscarinic receptor binding in unmedicated children with attention deficit hyperactivity disorder

Several lines of evidence support the role of monoaminergic and cholinergic dysregulation in attention deficit hyperactivity disorder (ADHD) and the concept that peripheral blood neurotransmission indices may represent valuable surrogate CNS markers. We determined platelet MAO-B activity (p-MAO-B) and lymphocyte muscarinic cholinergic receptor binding (l-MR) in 44 unmedicated ADHD children (aged 9.1?±?2.87 years) and in 26 age-matched controls for comparison. Lower levels of p-MAO-B (~35%) and l-MR (~55%) in ADHD were observed compared with controls. Differences were gender-dependent: p-MAO-B was reduced in males only (5.20?±?2.99 vs 8.46?±?5.1 nmol mg^?1 protein h^?1 in ADHD and controls, respectively) and l-MR in females only (ADHD vs control: 6.63?±?1.75 and 15.30?±?8.35?fmol 10^?6 cells). The clinical significance was corroborated by the correlation between these markers and severity of specific symptoms: lower p-MAO-B associated with increased inattention scores (Conners’ teacher-rating scale); lower l-MR associated with increased score for oppositional-defiant disorder (ODD) (SNAP-IV); and trend towards correlation between increased inattention (SNAP-IV) and lower l-MR.     

Is emotion recognition the only problem in ADHD? effects of pharmacotherapy on face and emotion recognition in children with ADHD

The objectives of this study were to evaluate both face and emotion recognition, to detect differences among attention deficit and hyperactivity disorder (ADHD) subgroups, to identify effects of the gender and to assess the effects of methylphenidate and atomoxetine treatment on both face and emotion recognition in patients with ADHD. The study sample consisted of 41 male, 29 female patients, 8–15 years of age, who were diagnosed as having combined type ADHD (N = 26), hyperactive/impulsive type ADHD (N = 21) or inattentive type ADHD (N = 23) but had not previously used any medication for ADHD and 35 male, 25 female healthy individuals. Long-acting methylphenidate (OROS-MPH) was prescribed to 38 patients, whereas atomoxetine was prescribed to 32 patients. The reading the mind in the eyes test (RMET) and Benton face recognition test (BFRT) were applied to all participants before and after treatment. The patients with ADHD had a significantly lower number of correct answers in child and adolescent RMET and in BFRT than the healthy controls. Among the ADHD subtypes, the hyperactive/impulsive subtype had a lower number of correct answers in the RMET than the inattentive subtypes, and the hyperactive/impulsive subtype had a lower number of correct answers in short and long form of BFRT than the combined and inattentive subtypes. Male and female patients with ADHD did not differ significantly with respect to the number of correct answers on the RMET and BFRT. The patients showed significant improvement in RMET and BFRT after treatment with OROS-MPH or atomoxetine. Patients with ADHD have difficulties in face recognition as well as emotion recognition. Both OROS-MPH and atomoxetine affect emotion recognition. However, further studies on the face and emotion recognition are needed in ADHD.     

Atomoxetine response in the inattentive and combined subtypes of attention deficit hyperactivity disorder: a retrospective chart review

The DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, 1994, American Psychiatric Association) describes attention deficit hyperactivity disorder (ADHD) as a heterogeneous disorder; providing diagnostic criteria for three subtypes: hyperactive/impulsive (ADHD/HI), inattentive (ADHD/I), and combined type (ADHD/C). Differences among the subtypes are well defined, but there may be also differences in terms of treatment responses. The aim of this study is to assess the responses of ADHD/I and ADHD/C to atomoxetine treatment. The medical records of the January–June 2012 term, first time referrals to outpatient clinic, were reviewed, and 37 ADHD diagnosed primary school age children (18 ADHD/I, 19 ADHD/C) that were treated with atomoxetine were determined. Thirty-five of them who completed 8 weeks of treatment duration were recruited for the study. The children with an ADHD medication use history in 2 months time prior to onset of treatment and/or the children receiving additional psychopharmacologic treatment to atomoxetine were excluded. Baseline and eighth week assessment, records were evaluated. Efficacy assessments included Turgay DSM-IV ADHD Screening and Rating Scale parent and teacher forms (T-DSM-IV) and Clinical Global Impression Scale-Severity and Improvement subscales. Safety assessments included laboratory and body weight assessments, ECG, heart rate, and blood pressure evaluations (baseline and eighth week) along a scale filled by the parents at the eighth week to review side effects. Atomoxetine was found to be effective in both ADHD/I and ADHD/C groups. Atomoxetine also decreased the opposition defiance subscale scores of T-DSM-IV (both parent and teacher forms), whereas it was not found to make statistically significant difference in the conduct disorder subscale scores. Mean difference in 8-week time in T-DSM-IV hyperactivity subscale and total scores of parent and teacher forms; inattention subscale scores of only parent forms and the CGI- severity subscale scores; differed significantly among the ADHD/I and ADHD/C groups; that ADHD/C types responded better to medication. Results of this study revealed that atomoxetine is effective both in ADHD/I and ADHD/C subtypes. ADHD/C types may be responding better to atomoxetine treatment than the ADHD/I subtypes.     

Possible involvement of PPARγ-associated eNOS signaling activation in rosuvastatin-mediated prevention of nicotine-induced experimental vascular endothelial abnormalities

Nicotine exposure via cigarette smoking and tobacco chewing is associated with vascular complications. The present study investigated the effect of rosuvastatin in nicotine (2 mg/kg/day, i.p., 4 weeks)-induced vascular endothelial dysfunction (VED) in rats. The development of VED was assessed by employing isolated aortic ring preparation and estimating aortic and serum nitrite/nitrate concentration. Further, scanning electron microscopy and hematoxylin-eosin staining of thoracic aorta were performed to assess the vascular endothelial integrity. Moreover, oxidative stress was assessed by estimating aortic superoxide anion generation and serum thiobarbituric acid-reactive substances. The nicotine administration produced VED by markedly reducing acetylcholine-induced endothelium-dependent relaxation, impairing the integrity of vascular endothelium, decreasing aortic and serum nitrite/nitrate concentration, increasing oxidative stress, and inducing lipid alteration. However, treatment with rosuvastatin (10 mg/kg/day, i.p., 4 weeks) markedly attenuated nicotine-induced vascular endothelial abnormalities, oxidative stress, and lipid alteration. Interestingly, the co-administration of peroxisome proliferator-activated receptor γ (PPARγ) antagonist, GW9662 (1 mg/kg/day, i.p., 2 weeks) submaximally, significantly prevented rosuvastatin-induced improvement in vascular endothelial integrity, endothelium-dependent relaxation, and nitrite/nitrate concentration in rats administered nicotine. However, GW9662 co-administration did not affect rosuvastatin-associated vascular anti-oxidant and lipid-lowering effects. The incubation of aortic ring, isolated from rosuvastatin-treated nicotine-administered rats, with L-NAME (100 μM), an inhibitor of nitric oxide synthase (NOS), significantly attenuated rosuvastatin-induced improvement in acetylcholine-induced endothelium-dependent relaxation. Rosuvastatin prevents nicotine-induced vascular endothelial abnormalities by activating PPARγ and endothelial NOS signaling pathways. Moreover, the PPARγ-independent anti-oxidant and lipid-lowering effects of rosuvastatin might additionally play a role in the improvement of vascular endothelial function.     

Assessment of effects of atomoxetine in adult patients with ADHD: consistency among three geographic regions in a response maintenance study

A previous study (Upadhyaya et al. in Eur J Psychiatry 2013b; 27:185–205) reported that adults with attention-deficit/hyperactivity disorder (ADHD) demonstrated maintenance of response for up to 25 weeks after initially responding to atomoxetine treatment. In the present report, the consistency of treatment effect across three geographic regions (Europe, United States/Canada [US/Can], and Latin America [Latin Am]) was explored. Data were analyzed from a phase 3, multicenter, randomized, double-blind, maintenance-of-response (randomized withdrawal) trial of atomoxetine versus placebo in adults with ADHD. Patients were randomized to atomoxetine (N = 266) or placebo (N = 258) for 25 weeks. Consistency assessments included the interaction test, pairwise t tests, noninferiority, and the criteria from Basic Principles on Global Clinical Trials (Ministry of Health, Labour and Welfare of Japan 2007). Atomoxetine-treated patients maintained the improved ADHD symptoms relative to placebo-treated patients on the Conners’ Adult ADHD Rating Scale Investigator-Rated: Screening Version 18-Item (CAARS-Inv:SV) total score in all three regions (atomoxetine–placebo mean difference = ?4.55, ?3.18, and ?0.07 for Europe, US/Can, and Latin Am, respectively). For the Latin Am region, the mean change in total score (0.41) was notably smaller for the placebo group than for Europe (5.87) and US/Can (4.39). Similar results were observed for the CAARS-Inv:SV hyperactivity/impulsivity and inattention subscale scores. Overall, patients maintained the response with atomoxetine treatment compared to placebo; however, the magnitude of treatment effect differed among the regions studied, being numerically higher in the EU and US/Can than Latin Am. Trial registration http://www.clinicaltrials.gov/(NCT00700427).     

Minor differences in ADHD-related difficulties between boys and girls treated with atomoxetine for attention-deficit/hyperactivity disorder

Atomoxetine may improve ADHD-related difficulties and hence the quality of life (QoL) in children and adolescents. Perception of these difficulties may differ with the rater perspective (patient, parent, physician) or patients' sex. The objective of this study was to investigate QoL as reflected by perceived ADHD-related difficulties perceived from these three perspectives and compare boys and girls. Patients aged 6-17 with ADHD were treated with atomoxetine (target dose 0.5-1.2 mg/kg/day) in two studies. In both studies, ADHD-related difficulties were assessed after 8 and 24 weeks using the Global Impression of Perceived Difficulties (GIPD) instrument, which can be taken to reflect the patient's QoL from the three perspectives. Data from the two studies were combined and analyzed together in order to compare boys and girls. Four hundred and twenty-one patients were treated with atomoxetine, 338 boys and 83 girls. Three hundred and fifty-five patients completed the 8-week study period. QoL, as reflected by perceived ADHD-related difficulties (measured with GIPD), improved over time. Mean GIPD total scores showed a similar course over time for all rater groups, although the patients rated the degree of difficulties significantly lower than parents and physicians. The sexes did not differ significantly in mean GIPD total scores. The GIPD scores over time suggest that patients' QoL, as reflected by perceived ADHD-related difficulties, improved with time on atomoxetine. However, improvement did not differ significantly between boys and girls. Trial Registration: ClinicalTrials.gov Identifiers NCT00191516 and NCT00191737.     

Factors predicting treatment adherence in patients with adult attention-deficit/hyperactivity disorder: a preliminary study

This study aimed to elicit patient- and treatment-related factors that can potentially predict treatment adherence in adult ADHD. Subjects who were over 18 and received a diagnosis of ADHD were included in the study. Chart review data of 102 subjects regarding demographics, medications, comorbidities, concomitant medications and domains of functional impairment were collected, and predictors were assessed using a binominal logistical regression model. One hundred and two patients (78.4 % male) with a mean age of 28.8 (SD = 9.8, range = 18–55) years were enrolled in the study. Childhood diagnosis of ADHD, agents used for treatment (MPH or atomoxetine), individual domains of dysfunction and use of additional psychotropic drugs were not found to be related to treatment adherence. Patients with a university education and those referred for family history of ADHD were more likely to adhere to treatment (p = 0.05 and 0.03, respectively). On the other hand, reasons for referral other than ADHD were significantly more frequently related to non-adherence (p = 0.02). Treatment noncompliance remains a significant problem despite therapeutic effects of medications. Identification of predictors of non-adherence can lead to heightened awareness of special populations at risk. We have found that prior awareness on ADHD (via past history/media/friends) leading to self/clinician referral to rule out ADHD and pervasiveness of symptoms across functional domains led to better compliance in our sample. Future research with prospective design utilizing objective tools for adherence is required.     

Self-esteem in adolescent patients with attention-deficit/hyperactivity disorder during open-label atomoxetine treatment: psychometric evaluation of the Rosenberg Self-Esteem Scale and clinical findings

To report on (1) psychometric properties of the Rosenberg Self-Esteem Scale (SES) studied in adolescents with ADHD, (2) correlations of SES with ADHD scale scores, and (3) change in patient-reported self-esteem with atomoxetine treatment. ADHD patients (12–17 years), treated in an open-label study for 24 weeks. Secondary analyses on ADHD symptoms (assessed with ADHD-RS, CGI, GIPD scales) and self-esteem (SES) were performed. One hundred and fifty-nine patients were treated. A dichotomous structure of the SES could be confirmed. Reliability and internal consistency were moderate to excellent. Highest coefficients were found for the correlation between SES and GIPD scores. Self-esteem significantly increased over time, accompanied by an improvement of ADHD symptoms and related perceived difficulties. The Rosenberg SES was shown to be internally consistent, reliable, and sensitive to treatment-related changes of self-esteem. According to these findings, self-esteem may be an important individual patient outcome beyond the core symptoms of ADHD.     

Effect of restricted feeding and realimentation periods on compensatory growth performance and physiological characteristics of pigs

An experiment with 94 growing pigs was conducted to determine the effect of a feed restriction of 25% on performance, carcass quality, organ weight, blood hormone levels and some biochemical parameters. The experiment consisted of four periods of 21 days each. In the different periods animals (initial BW about 31 kg) were fed ad libitum (A) or restrictively (R), resulting at day 84 in Groups AAAA, AARA, RAAA and RARA. During Period I, the daily gain of restrictively fed pigs (Group R) was about 22% lower than from Group A (p < 0.01). During realimentation, compensatory growth was observed in Period II for Group RA, and in Period IV for Group RARA. No compensatory growth was observed for Group AARA, which was fed restrictively in Period III only (day 43 to 63). For the whole experiment (day 1 to 84), BW gain and feed conversion amounted to 830 g/d and 3.03 kg/kg, 798 g/d and 2.99 kg/kg, 813 g/d and 2.86 kg/kg, and 800 g/d and 2.78 kg/kg for Groups AAAA, AARA, RAAA and RARA, respectively. The decrease of liver and kidney weights as a result of restricted feeding was not significant and after three weeks of realimentation these differences almost disappeared. At day 3 after realimentation of restrictively fed pigs (Group RA) the growth hormone level was significantly increased, but at day 14 of realimentation this level turned out to be lower (p < 0.01) than in pigs fed ad libitum (Group AA). This was considered as a further indication of compensatory growth.     

Decreased binding capacity (B max) of muscarinic acetylcholine receptors in fibroblasts from boys with attention-deficit/hyperactivity disorder (ADHD)

Monoaminergic dysregulation is implicated in attention-deficit/hyperactivity disorder (ADHD), and methylphenidate and amphetamines are the most frequently prescribed pharmacological agents for treating ADHD. However, it has recently been proposed that the core symptoms of the disorder might be due to an imbalance between monoaminergic and cholinergic systems. In this study, we used fibroblast cell homogenates from boys with and without ADHD as an extraneural cell model to examine the cholinergic receptor density, that is, muscarinic acetylcholine receptors (mAChRs). We found that the binding capacity (B _max) of [³H] Quinuclidinyl benzilate (³H-QNB) to mAChRs was decreased by almost 50 % in the children with ADHD (mean = 30.6 fmol/mg protein, SD = 25.6) in comparison with controls [mean = 63.1 fmol/mg protein, SD = 20.5, p ≤ 0.01 (Student’s unpaired t test)]. The decreased B _max indicates a reduced cholinergic receptor density, which might constitute a biomarker for ADHD. However, these preliminary findings need to be replicated in larger ADHD and comparison cohorts.     

Atomoxetine-Induced Increases in Monoamine Release in the Prefrontal Cortex are Similar in Spontaneously Hypertensive Rats and Wistar-Kyoto Rats

Spontaneously hypertensive rats (SHRs) are used as a model for attention-deficit/hyperactivity disorder (ADHD), since SHRs are hyperactive and show defective sustained attention in behavioral tasks. The psychostimulants amphetamine and methylphenidate and the selective norepinephrine reuptake inhibitor atomoxetine are used as ADHD medications. The effects of high K⁺ stimulation or psychostimulants on brain norepinephrine or dopamine release in SHRs have been previously studied both in vitro and in vivo, but the effects of atomoxetine on these neurotransmitters have not. The present study examined the effects of administration of atomoxetine on extracellular norepinephrine, dopamine, and serotonin levels in the prefrontal cortex of juvenile SHRs and Wistar-Kyoto (WKY) rats. Baseline levels of prefrontal norepinephrine, dopamine, and serotonin were similar in SHRs and WKY rats. Systemic administration of atomoxetine (3 mg/kg) induced similar increases in prefrontal norepinephrine and dopamine, but not serotonin, levels in both strains. Furthermore, there was no difference in high K⁺-induced increases in extracellular norepinephrine, dopamine, and serotonin levels in the prefrontal cortex between SHRs and WKY rats. These findings indicate that monoamine systems in the prefrontal cortex are similar between SHRs and WKY rats.     

Testosterone Levels in Athletes at Rest and Exhaustion: Effects of Calcium Supplementation

The effects of 4 weeks of calcium supplementation on free- and total testosterone levels were established in active and sedentary adult males at rest and exhaustion. Thirty healthy male athletes were equally divided into three study groups, as follows: Group 1—non-exercising subjects receiving 35 mg calcium/kg body weight; Group 2—subjects receiving 35 mg calcium/kg body weight undergoing training routines for 90 min/day, 5 days a week and Group 3—subjects undergoing training routines for 90 min/day, 5 days a week. The testosterone levels were determined before and after supplementation, at rest and following a hard training routine. The plasma free- and total testosterone levels increased at exhaustion before and after supplementation relative to resting values (p?<?0.05). This was also true when active subjects were compared to inactive subjects (p?<?0.05). Our results show that training results in increased testosterone levels in athletes and that the increase is greater if accompanied by calcium supplementation, which may be useful for increasing overall athletic performance.     

Evidence of association between SNAP25 gene and attention deficit hyperactivity disorder in a Latin American sample

Attention deficit hyperactivity disorder (ADHD) is one of the most highly heritable behavioral disorders in childhood, with heritability estimates between 60 and 90 %. Family, twin and adoption studies have indicated a strong genetic component in the susceptibility to ADHD. The synaptosomal-associated protein of molecular weight 25 kDa (SNAP25) is a plasma membrane protein known to be involved in synaptic and neural plasticity. Animal model studies have shown that SNAP25 gene is responsible for hyperkinetic behavior in the coloboma mouse. In recent studies, several authors reported an association between SNAP25 and ADHD. In this study, we used a case–control approach to analyze the possible association of two polymorphisms of SNAP25 for possible association with ADHD in a sample of 73 cases and 152 controls in a Colombian children population. Polymorphisms are located in 3′ untranslated region of SNAP25, positions T1065G and T1069C. We found a significant association with the GT haplotype (rs3746554|rs1051312) of SNAP25 (p = 0.001). Evidence of association was also found for the G/G genotype of rs3746554 (p = 0.002) and C/C genotype of rs1051312 (p = 0.009). This is the first study in a Latin American population. Similar to other studies, we found evidence of the association of SNAP25 and ADHD.     

Oxytocin plasma concentrations in children and adolescents with autism spectrum disorder: correlation with autistic symptomatology

Findings from research in animal models and humans have shown a clear role for the neuropeptide oxytocin (OT) on complex social behaviors. This is also true in the context of autism spectrum disorder (ASD). Previous studies on peripheral OT concentrations in children and young adults have reported conflicting results with the initial studies presenting mainly decreased OT plasma levels in ASD compared to healthy controls. Our study therefore aimed to further investigate changes in peripheral OT concentrations as a potential surrogate for the effects observed in the central nervous system (CNS) in ASD. OT plasma concentrations were assessed in 19 male children and adolescents with ASD, all with an IQ > 70 (age 10.7 ± 3.8 years), 17 healthy male children (age 13.6 ± 2.1 years) and 19 young male patients with attention deficit hyperactivity disorder (ADHD) as a clinical control group (age 10.4 ± 1.9 years) using a validated radioimmunoassay. Analysis of covariance revealed significant group differences in OT plasma concentrations (F(2, 48) = 9.574, p < 0.001, η ² = 0.285; plasma concentrations ASD 19.61 ± 7.12 pg/ml, ADHD 8.05 ± 5.49 pg/ml, healthy controls 14.43 ± 9.64 pg/ml). Post hoc analyses showed significantly higher concentrations in children with ASD compared to ADHD (p < 0.001). After Bonferroni correction, there was no significant difference in ASD in comparison with healthy controls (p = 0.132). A significant strong correlation between plasma OT and autistic symptomatology, assessed by the Autism Diagnostic Observation Schedule, was observed in the ASD group (p = 0.013, r = 0.603). Patients with ADHD differed from healthy control children by significantly decreased OT concentrations (p = 0.014). No significant influences of the covariates age, IQ, medication and comorbidity could be seen. Our preliminary results point to a correlation of OT plasma concentrations with autistic symptom load in children with ASD and a modulation of the OT system also in the etiologically and phenotypically overlapping disorder ADHD. Further studies in humans and animal models are warranted to clarify the complex association of the OT system with social impairments as well as stress-related and depressive behavior and whether peripheral findings reflect primary changes of OT synthesis and/or release in relevant areas of the CNS.     

A non-interventional study of extended-release methylphenidate in the routine treatment of adolescents with ADHD: effectiveness, safety and adherence to treatment

This multi-centre, open-label, non-interventional study evaluates effectiveness, safety and adherence to treatment of a specific extended-release methylphenidate with a 50 % immediate and a 50 % extended-release component (Medikinet^® retard) in the clinical routine treatment of 381 adolescents with ADHD and a mean age of 14.0 ± 1.9 years. ADHD and associated psychiatric symptoms, medication status and dosage frequency, treatment adherence and adverse events were assessed at baseline and after a median treatment length with Medikinet^® retard of 70 days. Primary outcome criterion was the change of ADHD symptom severity from baseline to endpoint according to the ADHD–KGE (German: ADHS–Klinische Gesamteinschätzung) change score. At baseline, 4.2 % of the patients were treatment naïve, 92.7 % had previously received different methylphenidate formulations and 3.1 % had received atomoxetine or amphetamine. During the study, patients received a mean daily dose of 35.7 ± 15.1 mg Medikinet^® retard. At endpoint, in 78 % of patients, the total ADHD symptom severity was reduced, in 20.4 %, it remained unchanged and in 1.6 %, it was worsened. The mean ADHD–KGE total ADHD symptom score was reduced from 1.8 ± 0.7 (moderate) at baseline to 0.8 ± 0.5 (mild; p < 0.001) at endpoint; the mean ADHD–KGE total-associated symptom score was reduced from 1.9 ± 0.7 (moderate) at baseline to 1.0 ± 0.6 (mild; p < 0.0001) at endpoint. After the medication switch from previous methylphenidate formulation to Medikinet^® retard, multiple dosing with ≥3 daily medication intakes was reduced from 12.9 % at baseline to 3.1 % at endpoint (p < 0.001). Adherence to treatment was improved in 37 % of patients. Most frequent adverse events were loss of appetite and gastrointestinal problems. The findings suggest that pharmacologically treated adolescents with ADHD and insufficient symptom reduction and/or treatment adherence benefit from switching to Medikinet^® retard and that it is well tolerated when given in clinical routine care.     

Effect of Atomoxetine on Hyperactivity in an Animal Model of Attention-Deficit/Hyperactivity Disorder (ADHD)

Background

Hyperactivity related behaviors as well as inattention and impulsivity are regarded as the nuclear symptoms of attention-deficit/hyperactivity disorder (ADHD).

Purpose

To investigate the therapeutic effects of atomoxetine on the motor activity in relation to the expression of the dopamine (DA) D2 receptor based on the hypothesis that DA system hypofunction causes ADHD symptoms, which would correlate with extensive D2 receptor overproduction and a lack of DA synthesis in specific brain regions: prefrontal cortex (PFC), striatum, and hypothalamus.

Methods

Young male spontaneously hypertensive rats (SHR), animal models of ADHD, were randomly divided into four groups according to the daily dosage of atomoxetine and treated for 21 consecutive days. The animals were assessed using an open-field test, and the DA D2 receptor expression was examined.

Results

The motor activity improved continuously in the group treated with atomoxetine at a dose of 1 mg/Kg/day than in the groups treated with atomoxetine at a dose of 0.25 mg/Kg/day or 0.5 mg/Kg/day. With respect to DA D₂ receptor immunohistochemistry, we observed significantly increased DA D₂ receptor expression in the PFC, striatum, and hypothalamus of the SHRs as compared to the WKY rats. Treatment with atomoxetine significantly decreased DA D₂ expression in the PFC, striatum, and hypothalamus of the SHRs, in a dose-dependent manner.

Conclusion

Hyperactivity in young SHRs can be improved by treatment with atomoxetine via the DA D2 pathway.