Non-stimulant Attention-deficit/hyperactivity Disorder Research Articles

EPA-0666 – Long-term maintenance of efficacy of extended-release guanfacine hydrochloride (GXR) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD): double-blind, placebo-controlled, multicentre, phase 3 randomized withdrawal study

GXR, a selective α2A-adrenergic agonist, is a non-stimulant ADHD treatment approved in the USA for children and adolescents, and in Canada for children. To evaluate long-term maintenance of efficacy of GXR in children and adolescents with ADHD who respond to an initial open-label, short-term trial. To determine if there is a higher rate of treatment failure for placebo vs GXR during the double-blind randomised-withdrawal phase (RWP) (NCT01081145). Patients (6–17 years) meeting DSM-IV-TR criteria for ADHD, baseline ADHD Rating Scale-IV (ADHD-RS-IV) ≥32 and Clinical Global Impressions-Severity (CGI-S) ratings ≥4 were enrolled. Following 7-week dose optimization and 6-week maintenance periods on open-label GXR (1–7 mg/day), eligible patients entered a 26-week, double-blind, RWP with GXR or placebo. The primary endpoint was rate of treatment failure (≥50% increase in ADHD-RS-IV total score and ≥2-point increase in CGI-S at two consecutive visits, compared to the RWP baseline). The key secondary endpoint was time-to-treatment failure. Safety assessments included treatment-emergent adverse events (TEAEs), electrocardiograms and vital signs. Of 528 patients enrolled, 316 (60.0%) entered the RWP. At study end, 49.3% (GXR) and 64.9% (placebo) (95%CI; −26.6, −4.5, p<0.01) of patients had relapsed (Figure). Time-to-treatment failure was 56 days (placebo) versus 218 days (GXR), p=0.003. During the RWP, the most common GXR TEAEs (≥5% patients) were headache, somnolence and nasopharyngitis. GXR demonstrated long-term maintenance of efficacy versus placebo in children and adolescents with ADHD.

Abstract 9368: Long QT Syndrome and Therapy for Attention Deficit/Hyperactivity Disorder

Objective: This study was designed to investigate the clinical course of patients with long QT syndrome (LQTS) who are treated for attention deficit/hyperactivity disorder (ADHD) with medications. Background: Current literature on the effect of ADHD treatment on the clinical outcome of LQTS patients is limited. We hypothesized that LQTS patients on ADHD pharmacotherapy, which has known adrenergic side effects, would be at increased risk for cardiac events. Methods: Patients in this study were from the Rochester-based LQTS Registry. LQTS patients being treated with stimulant or non-stimulant ADHD medications (n=48) were compared to a 2:1 age-, gender-, and QTc-duration matched LQTS control group not exposed to ADHD medications (n=96). Kaplan-Meier and Cox proportional hazards regression analyses were used to evaluate risk of cardiac events (syncope, aborted cardiac arrest, and sudden cardiac death) in LQTS patients treated with ADHD medications compared to those who were not. Results: During a mean follow-up of 7.9 ±5.4 years of follow-up after initiation of ADHD medication at a mean age 10.7 ±7.3 years, there was a 62% cumulative probability of cardiac events in the ADHD treatment group compared to 28% in the matched LQTS control group (p&lt;0.001 [Figure]). Time-dependent use of stimulant and non-stimulant ADHD medication was associated with an increased risk for cardiac events dominated by syncope (HR=3.07; 95% CI 1.09-8.64; p=0.03) in the multivariate Cox model adjusted for time-dependent β-blocker use and prior cardiac events. Subgroup gender analyses showed that time-dependent ADHD medication was associated with an increased risk in male LQTS patients (HR=6.80, p=0.04). Conclusion: LQTS patients treated with ADHD medications have an increased risk for cardiac events during follow-up, and this risk is augmented in males.

Impulsive action and impulsive choice are mediated by distinct neuropharmacological substrates in rat

Impulsivity is a heterogeneous construct according to clinical and preclinical behavioural measures and there is some preliminary evidence indicating distinct neurobiological substrates underlying the sub-components of impulsivity. Two preclinical assays, the five-choice serial reaction time task (5-CSRTT) and the delayed discounting task (DDT), are hypothesized to provide measures of impulsive action (premature responding) and impulsive choice (percent choice for delayed reward), respectively. In the present studies, we show that the norepinephrine reuptake inhibitor atomoxetine attenuated premature responding in the 5-CSRTT, but was ineffective in the DDT. The mixed dopamine/norepinephrine reuptake inhibitor methylphenidate exhibited an opposite profile of effects. In addition, blockade of 5-HT2A/C receptors via ketanserin decreased premature responding but had no effects on percent choice for delayed reward; blockade of 5-HT2C receptors via SB 242084 had opposite effects. Follow-up studies provided some limited evidence of additive effects of 5-HT2A/C receptor blockade on the effects of atomoxetine on impulsive action. These studies demonstrate dissociable profiles of stimulant vs. non-stimulant attention deficit hyperactivity disorder medications and 5-HT subtype-selective ligands, in the 5-CSRTT and DDT assays. Thus, the present findings support the sub-categorization of impulsivity and suggest that 5-HT receptor subtype-selective antagonists may provide therapeutic targets for disorders characterized by different forms of impulsivity.

P02-235 Reasons for choice of medication - baseline data of the outpatient ADHD treatment study “comply”

Aims:Patient-related factors and physicians’ attitudes leading to the decision which particular treatment is prescribed for attention-deficit/hyperactivity disorder (ADHD) have not been investigated in detail. We assessed the reasons for choice of medication and the socioeconomic status of treatment-naïve ADHD patients when initiated on ADHD medication.Method:Multicenter, prospective, 6-month observational study in children and adolescents with ADHD (ICD-10 or DSM-IV). Demographic, disease, and socioeconomic characteristics, and ADHD-related symptoms (ADHD-RS, CGI-S, GIPD) were captured at baseline, and compared between two medication groups (non-stimulant vs. stimulant). Physicians’ reasons for choice of medication were recorded. Correlations between those reasons were explored by Pearson"s correlation coefficient, Cohen"s Kappa, and cluster analyses.Results:Overall, 504 patients, mean age 9.6 years (range 6-17), 27.4% female, were included. Non-stimulant medication was prescribed in 50.0% and stimulant in 49.0% of patients (1% received both). In the non-stimulant group, patients were significantly older (0.6 years), had significantly more problems with regard to their psychosocial situation, and had more concomitant psychiatric disorders. There were no significant differences in questionnaire scores. Physicians’ reasons for prescribing medication differed for non-stimulant vs. stimulant treatment: duration of action (73.4%/28.7%), beneficial for compliance (60.3%/40.1%), and patient/parent decision (33.7%/26.3%) were reasons in favor of non-stimulant treatment; good efficacy (93.1%/73.0%), good tolerability (66.4%/44.1%), and well-priced (38.1%/2.8%) in favor of stimulant treatment.Conclusion:Patients initiating stimulant or non-stimulant ADHD treatment differed significantly on some points according to their baseline characteristics. Physicians’ reasons for choice of medication clearly differed between the two medication groups.