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Background: Although attention-deficit hyperactivity disorder (ADHD) is often comorbid with schizophrenia spectrum and other psychotic disorders (SZSPD), concerns about an increased risk of psychotic events have limited its treatment with either psychostimulants or atomoxetine., Aims: To examine whether the risk of hospital admission for psychosis in people with SZSPD was increased during the year following the introduction of such medications compared with the year before., Method: This was a retrospective cohort study using Quebec (Canada) administrative health registries, including all Quebec residents with a public prescription drug insurance plan and a diagnosis of psychotic disorder, defined by relevant ICD-9 or ICD-10 codes, who initiated either methylphenidate, amphetamines or atomoxetine, between January 2010 and December 2016, in combination with antipsychotic medication. The primary outcome was time to hospital admission for psychosis within 1 year of initiation. State sequence analysis was also used to visualise admission trajectories for psychosis in the year following initiation of these medications, compared with the previous year., Results: Out of 2219 individuals, 1589 (71.6%) initiated methylphenidate, 339 (15.3%) amphetamines and 291 (13.1%) atomoxetine during the study period. After adjustment, the risk of hospital admission for psychosis was decreased during the 12 months following the introduction of these medications when used in combination with antipsychotics (adjusted HR = 0.36, 95% CI 0.24-0.54; P < 0.0001)., Conclusions: These findings suggest that, in a real-world setting, when used concurrently with antipsychotic medication, methylphenidate, amphetamines and atomoxetine may be safer than generally believed in individuals with psychotic disorders.

Objective: Examining the joint effect of two functional variants in two dopamine-related genes ( DRD3 and COMT ) on ADHD-relevant behaviors under three experimental conditions (EC)., Method: 362 children with ADHD were assessed by parents and teachers during a week of baseline evaluation, followed by 1 week of MPH and placebo, administered in a double-blind crossover design., Results: Statistically significant 3-way ( DRD3 -by- COMT -by-EC; p = .004) and 2-way interactions ( COMT by EC; p = .002) were observed on Conners'-Teachers scores. Children with the COMT Met/Met genotype had lower scores at baseline and on placebo compared to the other genotype groups. Furthermore, stratifying the children according to their COMT genotypes helped to detect statistically significant and biologically meaningful effects of DRD3 genotype., Conclusions: These findings suggest that COMT and DRD3 genetic variants may together play a role in ADHD symptomatology and response to treatment through gene-gene interaction.

Background: COMT had been considered a promising candidate gene in pharmacogenetic studies in ADHD; yet the findings from these studies have been inconsistent. Part of these inconsistencies could be related to epigenetic mechanisms (including DNA methylation). Here we investigated the role of genetic variants of the COMT gene on the methylation levels of CpG sites in the same gene and explored the effect of methylation on methylphenidate (MPH) and placebo (PBO) response in children with ADHD., Methods: Two hundred and thirty children with ADHD (6-12 years) participated in a randomized, double-blind, placebo-controlled crossover trial with MPH. Univariate analysis was performed to examine the associations between genotypes in the COMT gene and DNA methylation in the same genetic loci. Association between the DNA methylation of 11 CpG sites and PBO/MPH responses were then assessed using spearman's correlation analysis in 212 children. Multiple linear regression analyses were performed to test the interaction between these factors while accounting for sex., Results: Associations were observed between specific genetic variants and methylation level of cg20709110. Homozygous genotypes of GG (rs6269), CC (rs4633), GG (rs4818), Val/Val (rs4680) and the haplotype (ACCVal/GCGVal) were significantly associated with higher level of methylation. This CpG showed a significant correlation with placebo response (r = -0.15, P = 0.045) according to the teachers' evaluation, and a close-to significance correlation with response to MPH according to parents' evaluation (r = -0.134, p = 0.051). Regression analysis showed that in the model including rs4818, sex and DNA methylation of cg20709110 contributed significantly to treatment response., Conclusions: These preliminary results could provide evidence for the effect of genetic variations on methylation level and the involvement of the epigenetic variation of COMT loci in modulating the response to treatment in ADHD., Trial Registration: clinicaltrials.gov, number NCT00483106., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: This study aims at characterizing the extent of correlation of treatment response (TR) obtained in various observation settings (home, school, clinic) by different observers (parents, teachers, clinicians)., Methods: Children with attention deficit hyperactivity disorder (ADHD) underwent a 2-week double-blind, randomized, cross-over clinical trial with methylphenidate and placebo, and various measures were obtained during the 2 weeks. Interrelationships of TR were examined using Pearson's correlation coefficients., Results: The study included 526 children (420 male, 106 female) with ADHD. TR between different observers shows a variable correlation between parents and teachers. No correlation is seen between parents/teacher evaluation of TR and laboratory-based measures (Continuous Performance Task; Restricted Academic Situation Scale)., Conclusion: The results firmly support the need to synthesize information from many sources in evaluating TR in ADHD.

This exploratory study aims to determine whether the change in systolic blood pressure (sBP) after acute methylphenidate (MPH) administration (ΔBP MPH ) is associated with the neurocognitive response to MPH in the Conners Continuous Performance Test (CPT) in 513 children with ADHD (aged 6 to 12 years old). We noted that higher increases in sBP were associated with larger improvement in CPT performance with MPH. In the univariate regression model, the ΔBP MPH accounted for an additional 2% of the variance in the change in CPT-Overall Index (OI) after controlling for covariates (p < .001). Linear regression analysis also indicated that ΔBP MPH significantly contributed to predict a change in omission errors, reaction time, and reaction time variability (p < .001, p < .01, p = .001, respectively), but not in commission errors or detectability index (d`). Participants with a clinically meaningful sBP increase of at least 5 mmHg (n = 191) improved by 4.8 points on the CPT-OI score (p < .001), compared to an improvement of only 0.6 points for participants whose sBP declined by at least 5 mmHg (n = 121). In conclusion, larger sBP increases after MPH administration were associated with greater enhancement in CPT performance. These results could be useful in informing MPH dosing in clinical practice., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: Dopamine plays an important role in modulating attention and motor behaviours, dimensions altered in attention deficit/hyperactivity disorder (ADHD). Numerous association studies have linked dopamine receptor 4 ( DRD4 ) to increased risk of ADHD. This study investigated the effect of DRD4 exon 3 polymorphism on child behaviours in response to treatment with methylphenidate. Methods: A total of 374 children diagnosed with ADHD (ages 6-12 years) were evaluated under three experimental conditions: baseline, placebo and MPH (0.5 mg/kg/day). This was a 2-week prospective within-subject, placebo-controlled, crossover trial. The Conners' Global Index for parents and for teachers was used to evaluate the behaviours of the children. One-way repeated measures analysis of variance was used to test the effect of the interaction between DRD4 genotype and experimental conditions. Results: A significant interaction between DRD4 genotype and treatment was detected when the child's behaviour was evaluated by the parents ( P  = 0.035, effect size of 0.014), driven by a better treatment response in children homozygous for long 7-repeat allele. Conclusions: According to the parent assessment, children homozygous for the long 7-repeat allele were more responsive to experimental condition. This is the largest pharmacogenetic investigation of the effect of DRD4 exon 3 polymorphism in childhood ADHD. Trial Registration: clinicaltrials.gov, identifier NCT00483106.

Methylphenidate (MPH), commonly known as Ritalin, is the most widely prescribed drug worldwide to treat patients with attention deficit disorders. Although MPH is thought to modulate catecholamine neurotransmission in the brain, it remains unclear how these neurochemical effects influence neuronal activity and lead to attentional enhancements. Studies in rodents overwhelmingly point to the lateral prefrontal cortex (LPFC) as a main site of action of MPH. To understand the mechanism of action of MPH in a primate brain, we recorded the responses of neuronal populations using chronic multielectrode arrays implanted in the caudal LPFC of two macaque monkeys while the animals performed an attention task ( N = 2811 neuronal recordings). Over different recording sessions ( N = 55), we orally administered either various doses of MPH or a placebo to the animals. Behavioral analyses revealed positive effects of MPH on task performance at specific doses. However, analyses of individual neurons activity, noise correlations, and neuronal ensemble activity using machine learning algorithms revealed no effects of MPH. Our results suggest that the positive behavioral effects of MPH observed in primates (including humans) may not be mediated by changes in the activity of caudal LPFC neurons. MPH may enhance cognitive performance by modulating neuronal activity in other regions of the attentional network in the primate brain.

This study aims to quantify placebo response (PR) in children with attention deficit hyperactivity disorder (ADHD) as assessed by parents and teachers and to explore some of its determinants. Five hundred and forty children with ADHD (ages 6-12) were recruited to a randomized, double-blind, placebo-controlled crossover trial with methylphenidate. The main outcome variable was Conners' Global Index (CGI), based on assessment of behaviour by parents (CGI-P) and teacher (CGI-T). PR was calculated as the difference between CGI-P/T scores at baseline and placebo week. There was a highly significant PR as assessed by the parents' and teachers' (p < 0.001). The magnitude of PR as assessed by parents was greater (10.57 points) compared to that assessed by teachers (3.93 points). The determinants of PR were different between parents and teachers. For parents, income, marital status, education, maternal smoking during pregnancy, and prior psychostimulant exposure (PPE) showed a significant effect on PR. For teachers, only ethnicity and PPE had an effect. The pattern of PR revealed two distinct profiles that may shed some light on the mechanisms involved in PR. PR in children with ADHD varies depending on the setting of the observations and the evaluator. Several psychosocial factors have been identified as modulators of PR. This is relevant for the design and interpretation of clinical trials and for clinical practice., (Copyright © 2017 John Wiley & Sons, Ltd.)

Psychotic disorders (PDs) and attention-deficit hyperactivity disorder (ADHD) are frequently comorbid. Clinicians are often reticent to treat ADHD in patients with psychosis, fearing that psychostimulants will worsen psychotic symptoms. Advances in neurobiology have challenged the simplistic dichotomy where PD is considered a disorder of high dopamine (DA), treated by DA antagonists, and ADHD a disorder of low DA, treated by DA agonists. In our paper, we review the literature on comorbid ADHD and psychosis. Treating ADHD with psychostimulants may be considered in patients with PD who have been stabilized with antipsychotics (APs). Not treating ADHD may have consequences because ADHD may predispose patients to drug abuse, which further increases the risk of PD. Nevertheless, more systematic studies are needed as there remains some uncertainty on the combined use of APs and psychostimulants in comorbid PD and ADHD.

Objective: Examine the short-term (acute) effects of methylphenidate (MPH) on math performance in children with attention-deficit hyperactivity disorder (ADHD) and what factors predict improvement in math performance., Method: One hundred ninety-eight children with ADHD participated in a double-blind, placebo-controlled, randomized crossover MPH trial. Math response to MPH was determined through administration of math problems adjusted to their academic level during the Restricted Academic Situation Scale (RASS). Student t tests were conducted to assess change in math performance with psychostimulants. Correlation between change on the RASS and change on the math performance was also examined. Linear regression was performed to determine predictor variables., Results: Children with ADHD improved significantly in their math with MPH (P < 0.001). The degree of improvement on the RASS (which evaluates motor activity and orientation to task) and on math performance on MPH was highly correlated. A child's age at baseline and Wechsler Individual Achievement Test (WIAT)-Numerical Operations standard scores at baseline accounted for 15% of variances for acute math improvement., Conclusions: MPH improves acute math performance in children with ADHD. Younger children with lower math scores (as assessed by the WIAT) improved most on math scores when given psychostimulants., Clinical Trial Registration Number: NCT00483106.

Eye movements are sensitive indicators of pharmacological effects on sensorimotor and cognitive processing. Methylphenidate (MPH) is one of the most prescribed medications in psychiatry. It is increasingly used as a cognitive enhancer by healthy individuals. However, little is known of its effect on healthy cognition. Here we used oculomotor tests to evaluate the effects of MPH on basic oculomotor and executive functions. Twenty-nine males were given 20mg of MPH orally in a double-blind placebo-controlled crossover design. Participants performed visually-guided saccades, sinusoidal smooth pursuit, predictive saccades and antisaccades one hour post-capsule administration. Heart rate and blood pressure were assessed prior to capsule administration, and again before and after task performance. Visually-guided saccade latency decreased with MPH (p<0.004). Smooth pursuit gain increased on MPH (p<0.001) and number of saccades during pursuit decreased (p<0.001). Proportion of predictive saccades increased on MPH (p<0.004), specifically in conditions with predictable timing. Peak velocity of predictive saccades increased with MPH (p<0.01). Antisaccade errors and latency were unaffected. Physiological variables were also unaffected. The effects on visually-guided saccade latency and peak velocity are consistent with MPH effects on dopamine in basal ganglia. The improvements in predictive saccade conditions and smooth pursuit suggest effects on timing functions.

Background: Animal models of ADHD suggest that the paradoxical calming effect of methylphenidate on motor activity could be mediated through its action on serotonin transmission. In this study, we have investigated the relationship between the 5-HTTLPR polymorphism in the serotonin transporter gene (SLC6A4) and the response of ADHD relevant behaviors with methylphenidate treatment., Methods: Patients between ages 6-12 (n = 157) were assessed with regard to their behavioral response to methylphenidate (0.5 mg/kg/day) using a 2-week prospective within-subject, placebo-controlled (crossover) trial. The children were then genotyped with regard to the triallelic 5-HTTLPR polymorphism in the SLC6A4 gene., Main Outcome Measure: Conners' Global Index for parents (CGI-Parents) and teachers (CGI-Teachers) at baseline and at the end of each week of treatment with placebo and methylphenidate. For both outcome measurements, we used a mixed model analysis of variance to determine gene, treatment and gene x treatment interaction effects., Results: Mixed model analysis of variance revealed a gene x treatment interaction for CGI-Parents but not for CGI-Teachers. Children homozygous for the lower expressing alleles (s+lG = s') responded well to placebo and did not derive additional improvement with methylphenidate compared to children carrying a higher expressing allele (lA). No genotype main effects on either CGI-Parents or CGI-teachers were observed., Conclusions: A double blind placebo-controlled design was used to assess the behavioral effects of methylphenidate in relation to the triallelic 5-HTTLPR polymorphism of the SLC6A4 gene in children with ADHD. This polymorphism appears to modulate the behavioral response to methylphenidate in children with ADHD as assessed in the home environment by parents. Further investigation is needed to assess the clinical implications of this finding., Trial Registration: ClinicalTrials.gov NCT00483106.

Rat studies have shown that pups subjected to suboptimal rearing conditions exhibited permanently dysregulated dopamine activity and altered behavioral responses to dopamine stimulation. In humans, heightened stress-induced mesoaccumbens dopamine release in adults reporting low maternal care experience has been shown. We explored the relationship between quality of parental care and behavioral responsivity to reward and 20 mg of the dopamine agonist methylphenidate (MPH). Forty-three male university students accomplished a monetarily rewarded card-sorting task in a placebo controlled between-subjects study design. In participants scoring above the cut-off score for high parental care as assessed by the Parental Bonding Inventory, MPH decreased performance accuracy in the reward condition of the task. Contrarily, reward-induced performance accuracy of low care participants was enhanced with MPH. Activity measures in response to reward and MPH were uninfluenced by parental care. This is the first human study to reveal that the behavioral MPH response interacts with early life parental care experience.

The dopamine transporter locus (DAT1) has been studied as a risk factor for attention-deficit/hyperactivity disorder (ADHD) and in pharmacogenetic studies of stimulant response. Several prospective studies have reported an association between the homozygous 9 repeat allele of the DAT1 3' untranslated region (UTR) variable number tandem repeat (VNTR) (DAT1 3') and decreased efficacy of methylphenidate (MPH). We hypothesized that children with the 9/9 genotype would display higher rates of specific stimulant side effects. Data on adverse events and DAT1 3' genotypes were combined from two, double-blind, placebo-controlled, crossover studies of MPH conducted in child psychiatric outpatient clinics in Montreal and Washington, D.C. There were 177 participants, 5-16 years old (mean age = 8.99, standard deviation [SD] = 2), with ADHD. Parents completed the Stimulant Side Effect Scale (SERS) after a week of placebo and a week of MPH treatment. Principal components analysis of the SERS resulted in three factors: Emotionality, Somatic Complaints, and Over-focused. Children with the 9/9 genotype displayed higher scores on the Emotionality factor during placebo than children with the 9/10 and the 10/10 genotype, and their Emotionality scores increased further during MPH treatment (F[2,151] = 3.24, p < 0.05). Children with the 10/10 genotype displayed a significant increase in Somatic Complaint factor scores during MPH treatment relative to the other genotype groups (F[2,150] = 3.4, p < 0.05). These data provide suggestive evidence that DAT1 variants are differentially associated with specific stimulant side effects. Children with the 9/10 genotype displayed less severe stimulant side-effect ratings than either of the homozygous groups, who each displayed increased susceptibility to different types of adverse events. Preliminary evidence suggests that pharmacogenetic analysis using DAT1 variants shows promise for identifying individuals at increased or decreased risk for poor tolerability.

The purpose of this study was to compare the fundamental movement skills of 22 children with attention-deficit hyperactivity disorder (ADHD), from 6 to 12 years of age, to gender- and age-matched peers without ADHD and assess the effects of stimulant medication on the movement skill performance of the children with ADHD. Repeated measures analyses revealed significant skill differences between children with and without ADHD (p

Study Objective: To examine whether the level of sleep efficiency of children diagnosed with ADHD moderates their performance on the Continuous Performance Test (CPT) while receiving a placebo and while receiving methylphenidate (MPH)., Design: Nightly sleep actigraphic assessment during a double-blind, placebo-controlled, crossover clinical study (1 week of 0.5 mg/kg MPH; 1 week of placebo) were obtained on 37 children between 6 and 12 years of age with a DSM-IV diagnosis of ADHD. Subjects were divided into 2 groups based on the mean sleep efficiency score during the placebo condition, with subjects above and below the mean placed in the Poor Sleep Group (PSG) and Good Sleep Group (GSG), respectively., Setting: Vigilance testing was conducted in the laboratory; sleep was assessed in the home., Measurements: Sleep was monitored using actigraphy for 2 weeks. In addition, parents were asked to complete nightly sleep logs and a sleep questionnaire. The Conners' Continuous Performance Test (CPT) was used to assess vigilance., Results: Significant interaction of Sleep Group with Medication was found on 1 CPT factor., Conclusions: The findings of the present study support the hypothesis that sleep moderates performance on CPT in children with ADHD while receiving placebo or MPH.

We sought to test the hypothesis that the variable number of tandem repeat (VNTR) polymorphism in the 3'-untranslated region (3'-UTR) of the SLC6A3 gene modulates behavior in children with ADHD and/or behavioral response to methylphenidate (MPH). One hundred and fifty-nine children with AHDH (6-12 years) were assessed with regard to the Conners' Global Index for parents (CGI-Parents) and teachers (CGI-Teachers) and the response of these behaviors to MPH (0.5 mg/kg/day) using a 2-week prospective within-subject (crossover) trial. Based on CGI-Parents, the profile of behavioral response to MPH as compared to placebo was not parallel in the three groups of children separated according to their genotype in the 3'-UTR VNTR polymorphism of SLC6A3, as indicated by a significant (p=0.017) genotype by treatment two-way interaction. Individuals having the 9/10 and 10/10 genotypes displayed a significant positive response to MPH as opposed to those homozygous for the 9-repeat allele. No genotype or genotype by treatment interaction was observed for CGI-Teachers. These findings support a role for the DAT gene 3'-UTR VNTR polymorphism in modulating the response of some behavioral dimensions to MPH in children with ADHD. They also suggest the presence of genetic heterogeneity that could be indexed by the quality of behavioral response to MPH.

Objective: To compare the pattern of familial aggregation of psychopathology in children who are good responders (GR) to methylphenidate (MPH) versus those who are poor responders (PR)., Method: A total of 118 clinically referred children ages 6 to 12 years, diagnosed with ADHD participated in a double-blind, placebo-controlled, randomized 2-week crossover trial of MPH from 1999 to 2004. A low dose of 0.5 mg/kg of body weight of MPH divided in two equal doses was used. Family history was obtained by interviewing at least one key historian relative of each subject using Family Interview for Genetic Studies. Information was collected on 342 first-degree and 1,151 second-degree relatives of children with attention-deficit/hyperactivity disorder., Results: Forty-four subjects showed mild or no improvement (PR) and 74 showed moderate or very much improvement (GR) on MPH over placebo. First-degree relatives of GR subjects were at significantly higher risk of attention-deficit/hyperactivity disorder than the relatives of PR subjects (p<.05). Second-degree relatives of the GR were at significantly higher risk of antisocial personality disorder compared to the relatives of PR subjects (p<.05)., Conclusions: The significantly higher presence of attention-deficit/hyperactivity disorder in the first-degree relatives and of antisocial personality disorder in the second-degree relatives of GR children suggests that this group may, at least partially, be distinct from the PR group on the basis of genetic determinants.

Objective: To determine whether children with attention-deficit hyperactivity disorder (ADHD) and learning disabilities respond differently to methylphenidate (MPH) compared with children with ADHD only., Methods: We conducted a prospective, double-blind, placebo-controlled, randomized, 2-week crossover trial of MPH, during which response to MPH was assessed. Learning ability was appraised using the Wide Range Achievement Test, Revised (WRAT-R), for English-speaking students and the Test de rendement pour francophones for French-speaking students. The study was conducted at the Douglas Hospital, a McGill University-affiliated teaching hospital in Montréal. Ninety-five children, aged 6-12 years, who met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), criteria for ADHD participated in the study, which ran from 2001 to 2004. The outcome measure used was the Consensus Clinical Response, an indicator of the degree of clinical improvement shown when taking MPH., Results: The proportion of children with learning disabilities who responded to MPH (55%) was significantly smaller (chi(2)1 = 4.5, p = 0.034) than the proportion of children without learning disabilities who responded adequately to MPH (75%). This difference was mainly because of children with mathematics disability being particularly unresponsive to MPH (chi(2)1 = 4.5, p = 0.034). Children with reading disability did not show this pattern of poor response (chi(2)1 = 1.0, p = 0.33)., Conclusion: Children with ADHD and comorbid learning disability tended to respond more poorly to MPH. In particular, children with disability in mathematics responded less to MPH than those without disability in mathematics. Additional therapy may be indicated for this group of patients.

Objective: Sleep disturbances appear as a comorbid condition in children with attention-deficit/hyperactivity disorder. The aim of this study was to investigate the relationship of activity levels during sleep and therapeutic response to methylphenidate (MPH)., Method: Nightly sleep actigraphic recordings during a double-blind, placebo-controlled, crossover clinical study (1-week of 0.5 mg/kg MPH; 1-week of placebo) were obtained on 44 children, 6 to 12 years old, diagnosed with attention-deficit/hyperactivity disorder (DSM-IV)., Results: Significant (p <.005) differences between the conditions were found in several software-computed parameters: sleep onset latency (MPH, 39.3 minutes; placebo, 28.2 minutes), sleep efficiency (MPH, 78.0%; placebo, 80.4%), total sleep time (MPH, 7 hours; 57 minutes; placebo, 8 hours, 16 minutes). No significant differences on any of these measures were found among the 26 subjects who showed a moderate or large global improvement on MPH over placebo compared with 18 subjects who showed mild or no clinical improvement., Conclusions: MPH, given twice daily, induces a slight but significant sleep disturbance. Motor activity levels during sleep did not differentiate children who responded to MPH from those who did not respond. This suggests that responders to MPH treatment do not experience greater sleep disturbances than nonresponders, at least at the dose studied.