Dataset Information

Cognitive Effects of Stimulant, Guanfacine, and Combined Treatment in Child and Adolescent Attention-Deficit/Hyperactivity Disorder.

ABSTRACT: Psychostimulants are partially effective in reducing cognitive dysfunction associated with attention-deficit/hyperactivity disorder (ADHD). Cognitive effects of guanfacine, an alternative treatment, are poorly understood. Given its distinct action on ?2A receptors, guanfacine may have different or complementary effects relative to stimulants. This study tested stimulant and guanfacine monotherapies relative to combined treatment on cognitive functions important in ADHD.Children with ADHD (n = 182; aged 7-14 years) completed an 8-week, double blind, randomized, controlled trial with 3 arms: d-methylphenidate (DMPH), guanfacine (GUAN), or combination treatment with DMPH and GUAN (COMB). A nonclinical comparison group (n = 93) had baseline testing, and a subset was retested 8 weeks later (n = 38). Analyses examined treatment effects in 4 cognitive domains (working memory, response inhibition, reaction time, and reaction time variability) constructed from 20 variables.The ADHD group showed impaired working memory relative to the nonclinical comparison group (effect size = -0.53 SD unit). The treatments differed in effects on working memory but not other cognitive domains. Combination treatment improved working memory more than GUAN but was not significantly better than DMPH alone. Treatment did not fully normalize the initial deficit in ADHD relative to the comparison group.Combined treatment with DMPH and GUAN yielded greater improvements in working memory than placebo or GUAN alone, but the combined treatment was not superior to DMPH alone and did not extend to other cognitive domains. Although GUAN may be a useful add-on treatment to psychostimulants, additional strategies appear to be necessary to achieve normalization of cognitive function in ADHD.Single Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder; http://clinicaltrials.gov/; NCT00429273.

SUBMITTER: Bilder RM

PROVIDER: S-EPMC4964604 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Cognitive Effects of Stimulant, Guanfacine, and Combined Treatment in Child and Adolescent Attention-Deficit/Hyperactivity Disorder.

Bilder Robert M RM Loo Sandra K SK McGough James J JJ Whelan Fiona F Hellemann Gerhard G Sugar Catherine C Del'Homme Melissa M Sturm Alexandra A Cowen Jennifer J Hanada Grant G McCracken James T JT

Journal of the American Academy of Child and Adolescent Psychiatry 20160607 8

<h4>Objective</h4>Psychostimulants are partially effective in reducing cognitive dysfunction associated with attention-deficit/hyperactivity disorder (ADHD). Cognitive effects of guanfacine, an alternative treatment, are poorly understood. Given its distinct action on α2A receptors, guanfacine may have different or complementary effects relative to stimulants. This study tested stimulant and guanfacine monotherapies relative to combined treatment on cognitive functions important in ADHD.<h4>Meth ...[more]

PMID: 27453080

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Project description:ObjectiveBecause models of attention-deficit/hyperactivity disorder (ADHD) therapeutics emphasize benefits of both enhanced dopaminergic and noradrenergic signaling, strategies to enhance D1 and α2A agonism may yield enhanced clinical and cognitive responses. This study tested the hypothesis that combined effects of a dopamine and noradrenergic agonist, d-methylphenidate extended-release (DMPH) with guanfacine (GUAN), an α2A receptor agonist, would be clinically superior to either monotherapy and would have equal tolerability.MethodAn 8-week, double-blind, 3-arm, comparative trial randomized 7- to 14-year-olds with DSM-IV ADHD to GUAN (1-3 mg/day), DMPH (5-20 mg/day), or a combination (COMB) with fixed-flexible dosing. Outcome measures were the ADHD Rating Scale IV (ADHD-RS-IV) and the Clinical Global Impression-Improvement (CGI-I) scale. Data on adverse events and safety measures were obtained.ResultsA total of 207 participants were randomized and received drug. Analyses showed significant treatment group main effects for ADHD-RS-IV ADHD total (p = .0001) and inattentive symptoms (p = .0001). COMB demonstrated small but consistently greater reductions in ADHD-RS-IV Inattentive subscale scores versus monotherapies (DMPH: p = .05; f(2) = .02; and GUAN: p = .02; f(2) = .02), and was associated with a greater positive response rate by CGI-I (p = .01). No serious cardiovascular events occurred. Sedation, somnolence, lethargy, and fatigue were greater in both guanfacine groups. All treatments were well tolerated.ConclusionCOMB showed consistent evidence of clinical benefits over monotherapies, possibly reflecting advantages of greater combined dopaminergic and α2A agonism. Adverse events were generally mild to moderate, and COMB treatment showed no differences in safety or tolerability.Clinical trial registration informationSingle Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder (Project1); http://clinicaltrials.gov/; NCT00429273.

Project description:ObjectiveThe combination of d-methylphenidate and guanfacine (an α-2A agonist) has emerged as a potential alternative to either monotherapy in children with attention-deficit/hyperactivity disorder (ADHD), but it is unclear what predicts response to these treatments. This study is the first to investigate pretreatment clinical and electroencephalography (EEG) profiles as predictors of treatment outcome in children randomized to these different medications.MethodA total of 181 children with ADHD (aged 7-14 years; 123 boys) completed an 8-week randomized, double-blind, comparative study with d-methylphenidate, guanfacine, or combined treatments. Pretreatment assessments included ratings on ADHD, anxiety, and oppositional behavior. EEG activity from cortical sources localized within midfrontal and midoccipital regions was measured during a spatial working memory task with encoding, maintenance, and retrieval phases. Analyses tested whether pretreatment clinical and EEG measures predicted treatment-related change in ADHD severity.ResultsHigher pretreatment hyperactivity-impulsivity and oppositional symptoms and lower anxiety predicted greater ADHD improvements across all medication groups. Pretreatment event-related midfrontal beta power predicted treatment outcome with combined and monotherapy treatments, albeit in different directions. Weaker beta modulations predicted improvements with combined treatment, whereas stronger modulation during encoding and retrieval predicted improvements with d-methylphenidate and guanfacine, respectively. A multivariate model including EEG and clinical measures explained twice as much variance in ADHD improvement with guanfacine and combined treatment (R2= 0.34-0.41) as clinical measures alone (R2 = 0.14-.21).ConclusionWe identified treatment-specific and shared predictors of response to different pharmacotherapies in children with ADHD. If replicated, these findings would suggest that aggregating information from clinical and brain measures may aid personalized treatment decisions in ADHD.Clinical trial registration informationSingle Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder; https://clinicaltrials.gov; NCT00429273.

Project description:ObjectiveThe combination of d-methylphenidate and guanfacine (an α-2A adrenergic agonist) may be an effective alternative to either agent as monotherapy in children with attention-deficit/hyperactivity disorder (ADHD). This study investigated the neural mechanisms underlying medication effects using cortical source analysis of electroencephalography (EEG) data.MethodA total of 172 children with ADHD (aged 7-14; 118 boys) completed an 8-week randomized, double-blind, comparative study with 3 treatment arms: d-methylphenidate, guanfacine, or their combination. EEG modulations of brain oscillations at baseline and end point were measured during a spatial working memory task from cortical sources localized within the anterior cingulate (midfrontal) and primary visual cortex (midoccipital), based on previously reported ADHD and control differences. Linear mixed models examined treatment effects on EEG and performance measures.ResultsCombined treatment decreased midoccipital EEG power across most frequency bands and task phases. Several midoccipital EEG measures also showed significantly greater changes with combined treatment than with monotherapies. D-methylphenidate significantly increased midoccipital theta during retrieval, while guanfacine produced only trend-level reductions in midoccipital alpha during maintenance and retrieval. Task accuracy improved with combined treatment, was unchanged with d-methylphenidate, and worsened with guanfacine. Treatment-related changes in midoccipital power correlated with improvement in ADHD severity.ConclusionThese findings show that combined treatment ameliorates midoccipital neural activity associated with treatment-related behavioral improvements and previously implicated in visuo-attentional deficits in ADHD. Both monotherapies had limited effects on EEG measures, with guanfacine further showing detrimental effects on performance. The identified midoccipital EEG profile may aid future treatment monitoring for children with ADHD.Clinical trial registration informationSingle Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder (Project1); https://clinicaltrials.gov/; NCT00429273.Diversity & inclusion statementWe worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure sex and gender balance in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. We actively worked to promote sex and gender balance in our author group.

Project description:ObjectiveAlthough combination pharmacotherapy is common in child and adolescent psychiatry, there has been little research evaluating it. The value of adding risperidone to concurrent psychostimulant and parent training (PT) in behavior management for children with severe aggression was tested.MethodOne hundred sixty-eight children 6 to 12 years old (mean age 8.89 ± 2.01 years) with severe physical aggression were randomized to a 9-week trial of PT, stimulant (STIM), and placebo (Basic treatment; n = 84) or PT, STIM, and risperidone (Augmented treatment; n = 84). All had diagnoses of attention-deficit/hyperactivity disorder and oppositional-defiant disorder (n = 124) or conduct disorder (n = 44). Children received psychostimulant (usually Osmotic Release Oral System methylphenidate) for 3 weeks, titrated for optimal effect, while parents received PT. If there was room for improvement at the end of week 3, placebo or risperidone was added. Assessments included parent ratings on the Nisonger Child Behavior Rating Form (Disruptive-Total subscale was the primary outcome) and Antisocial Behavior Scale; blinded clinicians rated change on the Clinical Global Impressions scale.ResultsCompared with Basic treatment (PT + STIM [44.8 ± 14.6 mg/day] + placebo [1.88 mg/day ± 0.72]), Augmented treatment (PT + STIM [46.1 ± 16.8 mg/day] + risperidone [1.65 mg/day ± 0.75]) showed statistically significant improvement on the Nisonger Child Behavior Rating Form Disruptive-Total subscale (treatment-by-time interaction, p = .0016), the Nisonger Child Behavior Rating Form Social Competence subscale (p = .0049), and Antisocial Behavior Scale Reactive Aggression subscale (p = .01). Clinical Global Impressions scores were substantially improved for the 2 groups but did not discriminate between treatments (Clinical Global Impressions-Improvement score ≤2, 70% for Basic treatment versus 79% for Augmented treatment). Prolactin elevations and gastrointestinal upset occurred more with Augmented treatment; other adverse events differed modestly from Basic treatment; weight gain in the Augmented treatment group was minor.ConclusionsRisperidone provided moderate but variable improvement in aggressive and other seriously disruptive child behaviors when added to PT and optimized stimulant treatment. Clinical trial registration information-Treatment of Severe Childhood Aggression (The TOSCA Study), URL: http://clinicaltrials.gov, unique identifier: NCT00796302.

Project description:Attention-deficit hyperactivity disorder (ADHD) is a common psychiatric disorder in childhood, affecting 3-7% of school-age children in the US and imposing substantial economic burden. Stimulants are considered first-line pharmacological treatment and are the most prescribed treatment for ADHD. However, approximately 30% of children with ADHD do not have an optimal response to a single stimulant and may require adjunctive therapy.Our objective was to conduct a cost-effectiveness analysis (CEA) of adding a non-stimulant, guanfacine extended release (GXR), to stimulants versus maintaining existing stimulant monotherapy in the treatment of ADHD in children and adolescents with suboptimal response to stimulant monotherapy.A 1-year Markov model was developed to estimate costs and effectiveness from a US third-party payer perspective. Effectiveness was measured by the QALY. The model assumed that patients transitioned among four health states (normal, mild, moderate and severe), defined by the Clinical Global Impression-Severity (CGI-S) scale. Transition probabilities were estimated in an ordered logit model using patient-level data from a multicentre, 9-week, double-blind, placebo-controlled, dose-optimization study, where subjects (n?=?461) continued their stable morning stimulant and were randomized to GXR administered in the morning, GXR administered in the evening, or placebo. The model assumed that patients in moderate/severe health states after week 8 would discontinue ADHD treatment and remain in that state for the rest of the study period. Direct costs included drug wholesale acquisition costs and health state costs, all in $US, year 2010 values. Utility associated with each health state was obtained from the literature and disutilities associated with adverse events were applied for the first 4 weeks. One-way sensitivity analyses and probabilistic sensitivity analysis (PSA) were conducted by varying costs, utilities, adverse-event duration, and transition probabilities.Compared with maintaining existing stimulant monotherapy, adding GXR to existing stimulant monotherapy was associated with an incremental drug cost of $US1016 but a lower medical cost of $US124, resulting in a total incremental cost of $US892 at 1 year. The addition of GXR to stimulants led to an incremental QALY of 0.03 and an incremental cost-effectiveness ratio (ICER) of $US31,660/QALY. In one-way sensitivity analysis, ICER values ranged from $US19,723, when 100% of patients were assumed to be severe in their initial health state, to $US46,631, when the last observed states from the clinical trial were carried forward to the end of the 1-year analysis period. PSA demonstrated a 94.6% likelihood that the ICER falls below $US50,000/QALY.The impairment associated with residual ADHD symptoms after stimulant therapy is becoming increasingly recognized. This is the first analysis of the cost effectiveness of stimulants combined with an adjunctive medication. This study suggests that the adjunctive therapy of GXR with stimulants is a cost-effective treatment based on a willingness-to-pay threshold of $US50,000/QALY. This may address an unmet need among patients with suboptimal response to stimulant monotherapy.

Dataset Information

Cognitive Effects of Stimulant, Guanfacine, and Combined Treatment in Child and Adolescent Attention-Deficit/Hyperactivity Disorder.

Publications

Cognitive Effects of Stimulant, Guanfacine, and Combined Treatment in Child and Adolescent Attention-Deficit/Hyperactivity Disorder.

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