Dataset Information

Adjunctive divalproex versus placebo for children with ADHD and aggression refractory to stimulant monotherapy.

ABSTRACT:

Objective

The purpose of the present study was to evaluate the efficacy of divalproex for reducing aggressive behavior among children 6 to 13 years old with attention deficit hyperactivity disorder (ADHD) and a disruptive disorder whose chronic aggression was underresponsive to a prospective psychostimulant trial.

Method

Children received open stimulant treatment during a lead-in phase that averaged 5 weeks. Agent and dose were assessed weekly and modified to optimize response. Children whose aggressive behavior persisted at the conclusion of the lead-in phase were randomly assigned to receive double-blind, flexibly dosed divalproex or a placebo adjunctive to stimulant for 8 weeks. Families received weekly behavioral therapy throughout the trial. The primary outcome measure was the proportion of children whose aggressive behavior remitted, defined by post-trial ratings of negligible or absent aggression.

Result

A significantly higher proportion of children randomly assigned to divalproex met remission criteria (eight out of 14 [57%]) than those randomly assigned to placebo (two out of 13 [15%]). Divalproex was generally well tolerated.

Conclusions

Among children with ADHD whose chronic aggressive behavior is refractory to optimized stimulant treatment, the addition of divalproex increases the likelihood that aggression will remit. A larger trial is necessary to specify with greater precision the magnitude of benefit for adjuvant divalproex.

SUBMITTER: Blader JC

PROVIDER: S-EPMC2940237 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The objective of this study was to examine factors that are associated with aggression that is responsive versus refractory to individualized optimization of stimulant monotherapy among children with attention-deficit/hyperactivity disorder (ADHD).Children who were aged 6 to 13 years and had ADHD, either oppositional defiant disorder or conduct disorder, significant aggressive behavior, and a history of insufficient response to stimulants completed an open stimulant monotherapy optimization protocol. Stimulant titration with weekly assessments of behavior and tolerability identified an optimal regimen for each child. Families also received behavioral therapy. Parents completed the Retrospective-Modified Overt Aggression Scale (R-MOAS) at each visit. Children were classified as having stimulant-refractory aggression on the basis of R-MOAS ratings and clinician judgment. Differences that pertained to treatment, demographic, and psychopathology between groups with stimulant monotherapy-responsive and -refractory aggression were evaluated.Aggression among 32 (49.3%) of 65 children was reduced sufficiently after stimulant dosage adjustment and behavioral therapy to preclude adjunctive medication. Those who responded to stimulant monotherapy were more likely to benefit from the protocol's methylphenidate preparation (once-daily, triphasic release), showed a trend for lower average dosages, and received fewer behavioral therapy sessions than did children with stimulant-refractory aggression. Boys, especially those with higher ratings of baseline aggression and of depressive and manic symptoms, more often exhibited stimulant-refractory aggression.Among children whose aggressive behavior develops in the context of ADHD and of oppositional defiant disorder or conduct disorder, and who had insufficient response to previous stimulant treatment in routine clinical care, systematic, well-monitored titration of stimulant monotherapy often culminates in reduced aggression that averts the need for additional agents.

Project description:ObjectiveStimulant medications are the most prevalent first-line pharmacotherapy for attention-deficit/hyperactivity disorder, but children with aggressive behavior often receive multiagent treatment. There is sparse evidence for the benefits of adjunctive medications when stimulant monotherapy provides inadequate benefit for aggressive behavior, yet the adverse effects of common adjuncts are well established. This study compared the efficacy in reducing aggressive behavior of risperidone (RISP), divalproex sodium (DVPX), and placebo (PBO) added to stimulant medication among childrenwhose symptoms persisted after individually optimized stimulant treatment.MethodThis trial enrolled 6- to 12-year-old with attention-deficit/hyperactivity disorder, a disruptive disorder, significant aggressive behavior, and prior stimulant treatment. Open, systematically titrated stimulant treatment identified patients with inadequate reductions in aggressive behavior, who were then randomly assigned to receive adjunctive RISP, DVPX, or PBO under double-blinded conditions for 8 weeks. Family-based behavioral treatment was offered throughout the trial. The primary outcome was the parent-completed Retrospective Modified Overt Aggression Scale.ResultsParticipants included 175 children (mean [SD] age 9.48 [2.04] years, 19% female). Of participants, 151 completed the stimulant optimization phase, with aggression remitting among 96 (63%), and 45 were randomly assigned to adjunctive treatment groups. The adjunctive RISP group showed greater reductions in aggression ratings than the PBO group (least squares means difference [ΔLSM], -2.33; 95% CI, -3.83 to -0.82; effect size [ES], -1.32), as did the DVPX group (ΔLSM, -1.60; 95% CI, -3.18 to -0.03; ES, -0.91). Mean standardized body mass index scores increased more among RISP-treated participants than participants receiving PBO (ΔLSM, 1.54; 95% CI, 0.68 to 2.40; ES, 0.58).ConclusionHigh response rate during the trial's open stimulant optimization phase suggests that rigorous titration of stimulant medication and concurrent behavioral therapy may avert the need for additional medications. Among nonremitters, RISP and DVPX were efficacious adjunctive treatments, although RISP was associated with weight gain.Clinical trial registration informationEffectiveness of Combined Medication Treatment for Aggression in Children With Attention Deficit With Hyperactivity Disorder (The SPICY Study); https://www.clinicaltrials.gov; NCT00794625.

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.

Project description:BackgroundEvaluation of broad-spectrum micronutrient (vitamins and minerals) treatment for childhood ADHD has been limited to open-label studies that highlight beneficial effects across many aspects of psychological functioning.MethodThis is the first fully blinded randomized controlled trial of medication-free children (n = 93) with ADHD (7-12 years) assigned to either micronutrients (n = 47) or placebo (n = 46) in a 1:1 ratio, for 10 weeks. All children received standardized ADHD assessments. Data were collected from clinicians, parents, participants and teachers across a range of measures assessing ADHD symptoms, general functioning and impairment, mood, aggression and emotional regulation.ResultsIntent-to-treat analyses showed significant between-group differences favouring micronutrient treatment on the Clinical Global Impression-Improvement (ES = 0.46), with 47% of those on micronutrients identified as 'much' to 'very much' improved versus 28% on placebo. No group differences were identified on clinician, parent and teacher ratings of overall ADHD symptoms (ES ranged 0.03-0.17). However, according to clinicians, 32% of those on micronutrients versus 9% of those on placebo showed a clinically meaningful improvement on inattentive (OR = 4.9; 95% CI: 1.5-16.3), but no group differences on improvement in hyperactive-impulsive symptoms (OR = 1.0; 95% CI: 0.4-2.5). Based on clinician, parent and teacher report, those on micronutrients showed greater improvements in emotional regulation, aggression and general functioning compared to placebo (ES ranged 0.35-0.66). There were two dropouts per group, no group differences in adverse events and no serious adverse events identified. Blinding was successful with guessing no better than chance.ConclusionsMicronutrients improved overall function, reduced impairment and improved inattention, emotional regulation and aggression, but not hyperactive/impulsive symptoms, in this sample of children with ADHD. Although direct benefit for core ADHD symptoms was modest, with mixed findings across raters, the low rate of adverse effects and the benefits reported across multiple areas of functioning indicate micronutrients may be a favourable option for some children, particularly those with both ADHD and emotional dysregulation. Trial registered with the Australian New Zealand Clinical Trials Registry ACTRN12613000896774.