Cristian Patrick Zeni

Aripiprazole in children and adolescents with bipolar disorder comorbid with attention-deficit/hyperactivity disorder: a pilot randomized clinical trial.

OBJECTIVE To assess response to treatment with aripiprazole in children and adolescents with bipolar disorder comorbid with attention-deficit/hyperactivity disorder (ADHD). METHOD Children and adolescents were extensively assessed according to DSM-IV criteria for bipolar disorder comorbid with ADHD (n = 710). Those with this comorbidity who were acutely manic or in mixed states were randomly assigned in a 6-week double-blind, placebo-controlled trial to aripiprazole (n = 18) or placebo (n = 25). Primary outcome measures were assessed weekly and included the Young Mania Rating Scale; the Swanson, Nolan, and Pelham Scale-Version IV; and weight. Secondary outcome measures were the Clinical Global Impressions-Severity of Illness scale, the Child Mania Rating Scale-Parental Version (CMRS-P), the Childrens Depression Rating Scale-Revised, the Kutcher Adolescent Depression Scale, and adverse events. The trial was conducted at the Hospital de Clínicas de Porto Alegre, Rio Grande do Sul, Brazil, from January 2005 to November 2007. RESULTS The group receiving aripiprazole showed a significantly greater reduction in YMRS scores (P = .02, effect size [ES] = 0.80), CMRS-P scores (P = .02; ES = 0.54), and CGI-S scores (P = .04; ES = 0.28) from baseline to endpoint than the placebo group. In addition, higher rates of response (P = .02) and remission (P = .01) were found for the aripiprazole group. No significant between-group differences were found in weight, ADHD symptoms, and depressive symptoms. Adverse events significantly more frequent in the aripiprazole group were somnolence and sialorrhea. CONCLUSION Aripiprazole was effective in reducing manic symptoms and improving global functioning without promoting severe adverse events or weight gain. No significant treatment effect in ADHD symptoms was observed. Studies are needed to assess psychopharmacologic interventions for improving ADHD symptoms in juvenile bipolar disorder comorbid with ADHD. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00116259.

Methylphenidate Combined with Aripiprazole in Children and Adolescents with Bipolar Disorder and Attention-Deficit/Hyperactivity Disorder: A Randomized Crossover Trial

In clinical samples, juvenile bipolar disorder (JBPD) is frequently accompanied by co-morbid attention-deficit/hyperactivity disorder (ADHD). Clinical trials assessing combined psychopharmacological interventions in this population are scarce, and methylphenidate (MPH) may worsen manic symptoms. We conducted a randomized crossover trial with MPH and placebo (2 weeks each) combined with aripiprazole in children and adolescents (n = 16; 8-17 years old) with JBPD and ADHD who had a significant response in manic symptoms with aripiprazole but still presented clinically significant symptoms of ADHD. ADHD, manic, and depressive symptoms were assessed by means of standard scales. Fourteen out of the 16 subjects completed the trial. No significant differences between the effects of methylphenidate and placebo were detected in ADHD (F(1, 43.22) = 0.00; p = 0.97) or manic (F(1, 40.19) = 0.93; p = 0.34) symptoms. Significant improvement in depressive symptoms was observed in the MPH group (F(1,19.03) = 7.75; p = 0.01) according to a secondary self-reported outcome measure. One patient using aripiprazole and MPH discontinued the trial due to the onset of a severe mixed episode. No other significant adverse events were observed. Although MPH did not worsen manic symptoms, it was not more effective than placebo in improving ADHD symptoms in children and adolescents with JBPD co-morbid with ADHD stabilized with aripiprazole. Further investigations are warranted. This study is registered at www.clinicaltrials.gov under the identifier NCT00305370.

No significant association between response to methylphenidate and genes of the dopaminergic and serotonergic systems in a sample of Brazilian children with attention‐deficit/hyperactivity disorder

Few studies on pharmacogenetics of Attention‐Deficit/Hyperactivity Disorder (ADHD) have been conducted. Most of them evaluated dopaminergic genes resulting in positive and negative findings. We assessed effects of polymorphisms in candidate dopaminergic (DRD4, DAT1) and serotonergic genes (HTR1B, HTR2A, and 5‐HTT) on the response to treatment in 111 patients for whom methylphenidate (MPH) was prescribed. Outcome measures (Swanson, Nolan, and Pelham scale—version IV, Children Global Assessment Scale, Barkleys Stimulants Side Effects Rating Scale) were assessed at baseline and 1 month after the intervention. No significant association was detected between polymorphisms assessed and both response and side effects to MPH. Prospective multi‐site controlled studies with larger sample sizes are needed in order to disentangle the role of candidate genes in response to ADHD treatment.

A common haplotype at the dopamine transporter gene 5′ region is associated with attention‐deficit/hyperactivity disorder

The dopamine transporter (DAT) is the major site of methylphenidate action, which is one of the main drugs used to treat attention‐deficit/hyperactivity disorder (ADHD). Most association studies with ADHD focused in a VNTR at the 3′‐untranslated region of the gene (3′UTR) presenting conflicting results. However, the most common explanation to inconsistent results is variable linkage disequilibrium with an adjacent functional variant, just a few number of DAT1 studies have reported LD structure across the gene. In this study, we screened 16 polymorphisms across the DAT1 gene to understand LD structure in a Brazilian sample of families with ADHD probands and to verify if there were evidence for a biased transmission of alleles and haplotypes from parents to their 243 children with ADHD. In the DSM‐IV combined subtype, we observed a preferential transmission of the haplotype A/C/C/C/A derived from five SNPs (rs2550948, rs11564750, rs261759, rs2652511, rs2975223) in 5′ region (P corrected = 0.018) and no association with any allele/haplotype at the 3′ region of the gene, including the 3′ VNTR and the VNTR of intron 8. These results suggest a role for the promoter region in ADHD susceptibility and that allele heterogeneity should be highly considered in DAT1 gene association studies highlighting the importance of this gene in the genetics of the disorder.

Further evidence of the involvement of alpha-2A-adrenergic receptor gene (ADRA2A) in inattentive dimensional scores of attention-deficit/hyperactivity disorder

Further evidence of the involvement of alpha-2A-adrenergic receptor gene (ADRA2A) in inattentive dimensional scores of attention-deficit/hyperactivity disorder

Serotonin genes and attention deficit/hyperactivity disorder in a Brazilian sample : Preferential transmission of the HTR2A 452His allele to affected boys

Attention‐deficit hyperactivity disorder (ADHD) is one of the most common psychiatric disorders of childhood. The role of genetic factors in its etiology is strongly supported by family, adoption, and twin studies. Low serotonin activity has been associated in both animal and human studies with measures of impulsivity, aggression, and disinhibited behaviors, which make genes from the serotonin system reasonable candidates for ADHD susceptibility. In the present study, we investigated a polymorphism in the promoter region of the serotonin transporter (SLC6A4) and two polymorphisms (−1438 A > G and His452Tyr) in the serotonin 5‐HTR2A receptor gene using family based association analyses in a sample of 243 Brazilian ADHD children and adolescents and their parents. No linkage disequilibrium between the two HTR2A polymorphisms was detected in this sample (P = 0.76). Considering several evidences from animal models for sexual dimorphism in serotonin genes expression, analyses were performed separately for the whole sample and for male probands. No evidences for biased transmissions of both HTR2A −1438 A > G and SLC6A4 polymorphisms to ADHD youths were observed. Preferential transmission of the HTR2A His452 allele was observed only in families with affected boys (P = 0.04). Our results suggest that findings from ADHD association studies for serotonin genes might be understood in the context of a gender effect, which may help to explain conflicting results in these association studies.

Attention-deficit/hyperactivity disorder: advancing on pharmacogenomics

Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent psychiatric disorder. An impressive volume of literature documents both a strong participation of genetics in its etiology and a high rate of response to medication. However, few studies on the pharmacogenomics of ADHD have been conducted to date. This systematic review aims to present a critical discussion of findings from recent investigations. The majority of studies have focused on individual polymorphisms of the dopaminergic genes, with special emphasis on variants of the dopamine transporter gene (DAT1). Almost all studies have assessed the effects of genes in the response to methylphenidate (MPH). Some preliminary results suggest an association between homozygosity for the 10-repeat allele at DAT1 and poor response to MPH. However, other studies have reported contrasting findings. Very few investigations addressed the role of non-dopaminergic genes or gene-gene interactions in ADHD pharmacogenomics. Recent findings suggesting an association between response to MPH and an MspI polymorphism in the promoter region of the alpha2A-adrenoceptor gene (ADRA2A) are discussed. Pharmacogenomic studies of ADHD are in their infancy, and comparability between studies is difficult due to the use of different methodological approaches. As such, multi-site collaborative efforts to obtain larger samples with standardized methodology should be encouraged.

Association of a carboxylesterase 1 polymorphism with appetite reduction in children and adolescents with attention-deficit/hyperactivity disorder treated with methylphenidate

Carboxylesterase 1 is the enzyme involved in methylphenidate (MPH) metabolism. The aim of this study was to evaluate the association between a −75 T>G polymorphism and appetite reduction in children with attention-deficit/hyperactivity disorder (ADHD). A sample of 213 children with ADHD was investigated. The primary outcome was appetite reduction measured by the Barkley Stimulant Side Effect Rating Scale applied at baseline, at 1 and 3 months of treatment. MPH doses were augmented until no further clinical improvement or significant adverse events occurred. The G allele presented a trend for association with appetite reduction scores (P=0.05). A significant interaction between the G allele and treatment over time for appetite reduction scores was also observed (P=0.03). The G allele carriers presented a higher risk for appetite reduction worsening when compared with T allele homozygotes (odds ratio=3.47, P=0.01). The present results suggest an influence of carboxylesterase 1 −75 T>G polymorphism on the worsening of appetite reduction with MPH treatment in youths with ADHD.

An Open-Label Trial of Risperidone in Children and Adolescents with Severe Mood Dysregulation

OBJECTIVE The diagnosis and treatment of youth with severe nonepisodic irritability and hyperarousal, a syndrome defined as severe mood dysregulation (SMD), has been the focus of increasing concern and debate among clinicians and researchers. Our main objective was to assess the effectiveness of risperidone for youths with SMD. METHODS An 8-week open label trial with risperidone was conducted. We extensively assessed 97 subjects with semistructured and clinical interviews and enrolled 21 patients in the study. Risperidone was titrated from 0.5 to 3 mg/day in the first 2 weeks. Evaluations were performed at baseline and weeks 2, 4, 6, and 8. Clinical outcome measures were (1) Aberrant Behavior Checklist-Irritability Subscale, (2) Clinical Global Impressions, and (3) severity of co-morbid conditions. RESULTS We found a significant reduction of the Aberrant Behavior Checklist-Irritability scores during the trial after risperidone use (p < 0.001). The scores at week 2 (mean = 12.03; standard error [SE] = 2.94), week 4 (mean = 15.48; SE = 2.93), week 6 (mean = 12.29; SE = 2.86), and week 8 (mean = 11.28; SE = 3.06) were significantly reduced compared with the baseline mean score (mean = 25.89; SE = 2.76) (p < 0.001). We also found an improvement in attention-deficit/hyperactivity disorder, depression, and global functioning (p < 0.001). CONCLUSION Risperidone was effective in reducing irritability in SMD youth. To the best of our knowledge, this is the first psychopharmacological trial in this group of patients with positive results. Further randomized, controlled studies are needed.

Catechol-O-Methyltransferase Valine158Methionine Polymorphism Moderates Methylphenidate Effects on Oppositional Symptoms in Boys with Attention-Deficit/Hyperactivity Disorder

BACKGROUND The catechol-O-methyltransferase enzyme plays a key role in the function of prefrontal cortex, accounting for most of the degradation of dopamine. Previous studies have documented the improvement of oppositional symptoms in attention-deficit/hyperactivity disorder (ADHD) patients with methylphenidate (MPH) treatment. However, the effect of the COMT gene in the response to MPH on oppositional symptoms has not been investigated. METHODS A total of 251 children with ADHD fulfilled inclusion criteria to participate in the study. Dosages of short-acting MPH were augmented until no further clinical improvement was detected or until there were significant adverse events (MPH dose always > .3 mg/kg/day). The outcome measure was the parent-rated oppositional subscale of the Swanson, Nolan and Pelham Scale-Version IV (SNAP-IV). The scale was applied by child psychiatrists blinded to genotype at baseline and in the first and third months. The COMT valine158methionine polymorphism was genotyped by polymerase chain reaction based methods. RESULTS We detected significant improvement in SNAP-IV oppositional scores from baseline to the first and three months of treatment [n = 112; F(2,231) = 5.35, p = .005]. A significant effect of the presence of methionine allele in oppositional defiant disorder scores during treatment [F(1,148) = 5.02, p = .027] and a significant interaction between the methionine allele and treatment over time for the SNAP-IV oppositional scores during this period of treatment [F(2,229) = 6.40, p = .002] were both observed. CONCLUSIONS These results suggest an effect of the COMT genotype on the trajectory of oppositional defiant disorder symptoms improvement with MPH treatment in boys with ADHD.