Effect on Primary Sleep Disorders When Children With ADHD Are Administered Guanfacine Extended Release.

OBJECTIVE: To evaluate children with ADHD and sleep problems with polysomnography (PSG) after guanfacine extended-release (GXR) administration. METHOD: Double-blind, randomized, placebo-controlled study was terminated early due to treatment-emergent concerns after enrolling 29 children aged 6 to 12 years. After >4 weeks dose adjustment and >1 week dose stabilization, 11 children received GXR and 16 controls underwent analyses with PSG. RESULTS: Although GXR improved ADHD symptoms, the primary outcome variable, total sleep time, was shorter in contrast to placebo (-57.32, SD = 89.17 vs. +31.32, SD = 59.54 min, p = .005). Increased time awake after sleep onset per hour of sleep was the primary factor for the reduction. Although rapid eye movement (REM), non-REM, and N3/slow wave sleep times were reduced, these were proportional to the overall sleep reduction. Sedation was common with GXR (73% vs. 6%). CONCLUSION: Morning-administered GXR resulted in decreased sleep and may contribute to sedation.

Commentary: Objective aids for the assessment of ADHD - further clarification of what FDA approval for marketing means and why NEBA might help clinicians. A response to Arns et al. (2016).

Neuropsychiatric EEG-Based ADHD Assessment Aid (NEBA) is an EEG-based device designed to aid in the diagnostic process for ADHD by identifying individuals less likely to have ADHD by virtue of a lower theta/beta ratio. In using NEBA as an example, the Arns et al. commentary misstates the purpose of NEBA, which is to widen the differential rather than to make the diagnosis. Arns et al. caution about missing an ADHD diagnosis, but fail to mention the impact of overdiagnosis. If we are to advance our knowledge of the etiology and pathophysiology of ADHD, as well as develop tailored treatments and ultimately improve outcomes for ADHD, then biomarkers and objective assessment aids such as NEBA are needed to improve and refine diagnostic accuracy beyond symptom description and clinical history.

Integration of an EEG biomarker with a clinician's ADHD evaluation.

BACKGROUND: This study is the first to evaluate an assessment aid for attention-deficit/hyperactivity disorder (ADHD) according to both Class-I evidence standards of American Academy of Neurology and De Novo requirements of US Food and Drug Administration. The assessment aid involves a method to integrate an electroencephalographic (EEG) biomarker, theta/beta ratio (TBR), with a clinician's ADHD evaluation. The integration method is intended as a step to help improve certainty with criterion E (i.e., whether symptoms are better explained by another condition). METHODS: To evaluate the assessment aid, investigators conducted a prospective, triple-blinded, 13-site, clinical cohort study. Comprehensive clinical evaluation data were obtained from 275 children and adolescents presenting with attentional and behavioral concerns. A qualified clinician at each site performed differential diagnosis. EEG was collected by separate teams. The reference standard was consensus diagnosis by an independent, multidisciplinary team (psychiatrist, psychologist, and neurodevelopmental pediatrician), which is well-suited to evaluate criterion E in a complex clinical population. RESULTS: Of 209 patients meeting ADHD criteria per a site clinician's judgment, 93 were separately found by the multidisciplinary team to be less likely to meet criterion E, implying possible overdiagnosis by clinicians in 34% of the total clinical sample (93/275). Of those 93, 91% were also identified by EEG, showing a relatively lower TBR (85/93). Further, the integration method was in 97% agreement with the multidisciplinary team in the resolution of a clinician's uncertain cases (35/36). TBR showed statistical power specific to supporting certainty of criterion E per the multidisciplinary team (Cohen's d, 1.53). Patients with relatively lower TBR were more likely to have other conditions that could affect criterion E certainty (10 significant results; P ≤ 0.05). Integration of this information with a clinician's ADHD evaluation could help improve diagnostic accuracy from 61% to 88%. CONCLUSIONS: The EEG-based assessment aid may help improve accuracy of ADHD diagnosis by supporting greater criterion E certainty.

A randomized, double-blind, placebo-controlled study of modafinil film-coated tablets in children and adolescents with attention-deficit/hyperactivity disorder.

OBJECTIVE: To evaluate the efficacy and tolerability of modafinil in children and adolescents, ages 7 to 17, with attention-deficit/hyperactivity disorder (ADHD). METHOD: In this 9-week, double-blind, flexible-dose study, patients were randomized to once-daily modafinil (170-425 mg) or placebo. Assessments included ADHD Rating Scale-IV (ADHD-RS-IV) School and Home Versions and Clinical Global Impression of Improvement (CGI-I) scale. RESULTS: Two hundred patients were randomized. Modafinil produced significant reductions in ADHD-RS-IV total scores at school (n = 128; mean change +/- SD: -17.5 +/- 13.1 points) compared with placebo (n = 66; -9.7 +/- 10.3 points; p < .0001). Similarly, modafinil reduced ADHD-RS-IV total scores at home compared with placebo (-17.6 +/- 13.3 versus -7.5 +/- 11.8 points; p < .0001). Fifty-two percent of patients randomized to modafinil and 18% of those randomized to placebo met prestudy criteria for responder on the CGI-I (p < .0001). Randomization to modafinil was associated with significantly more insomnia, headache, decreased appetite, and weight loss than randomization to placebo, but discontinuation attributed to adverse events did not differ statistically between treatment groups (modafinil, 5%; placebo, 6%). CONCLUSION: Modafinil was well tolerated and reduced ADHD symptoms at school and home compared with placebo.

Aripiprazole in children and adolescents: clinical experience.

Despite few supportive data, aripiprazole was being administered to children and adolescents for management of mood instability, aggression, and psychosis. Using a retrospective review (n = 11) and prospective recruitment (n = 6), 17 children and adolescents received aripiprazole 5 to 20 mg/day. Only 4 of 16 bipolar and autistic subjects (25%) demonstrated reduced aggression without adverse events, and the symptoms of 2 of 4 psychotic subjects improved. Coadministration of sedative medications (particularly guanfacine or clonidine) and weight < 58 kg increased the risk of adverse events, such as increased lability and aggression. All three children < 8.6 years old, all four children < 34 kg, and all five children receiving alpha2-agonists developed adverse events prior to clinical efficacy. Age > 11 years, weight > 58 kg, and absence of sedative medications were associated with a 56% (five of nine) success rate. Until larger, prospective studies are completed, caution is advised when considering aripiprazole for smaller children and children receiving sedative medications.

Hypoalbuminemia with valproic acid administration.

Valproic acid and its derivatives are commonly administered antiepileptic drugs for children and adults. Five residents at a children's long-term care facility manifested hypoalbuminemia while being administered divalproex, although serum liver function test results and urinalysis results were normal. When the patients were free from valproic acid, the serum albumin levels increased into the normal range (17-30% higher than the serum albumin levels while patients were receiving valproic acid) despite the absence of any dietary changes. Comparing the serum albumin levels for eight residents who received divalproex (3.1 gm/dL +/- 0.4 gm/dL) with the serum albumin levels for 13 residents who were not receiving valproic acid or its derivatives (3.8 gm/dL +/- 0.2 gm/dL), the difference was significant (P < 0.001). This difference could not be accounted for by nutritional, environmental, laboratory, or urinary causes. In this study, divalproex administration was a contributing factor in the development of reversible hypoalbuminemia in this population of severely disabled, neurologically injured children and young adults. Further studies are required to determine the exact etiology and clinical significance of valproate-mediated hypoalbuminemia.

Modafinil in children with attention-deficit hyperactivity disorder.

Previous clinical evidence suggested that modafinil may improve clinical features of children with attention-deficit hyperactivity disorder. To test this hypothesis, a randomized, double-blind, placebo-controlled study design was used. Of 24 children initially randomized into the study, 11 control subjects and 11 treatment patients completed the study, with evaluation before medication and after 5 to 6 weeks. The average Test of Variables of Attention attention-deficit hyperactivity disorder z score improved by 2.53 S.D.s for the modafinil group compared with a decline of 1.02 for control patients (P < or = 0.02). Conners Rating Scales ADHD total t scores for the modafinil group improved from 76.6 to 68.2 compared with improvement from 77.7 to 76.0 for control subjects (P = 0.04). Ten of 11 treatment patients were reported as "significantly" improved, whereas eight of 11 control subjects were reported as manifesting "no" or "slight" improvement (P < 0.001). Adverse effects were few and manageable, with no anorexia. Modafinil may be a useful treatment for children with ADHD, particularly when anorexia limits use of stimulants.

Levetiracetam in autistic children: an open-label study.

The objectives of this study were to determine whether autistic children taking levetiracetam (1) showed improvement in the areas of aggression, impulsivity, hyperkinesis, and mood instability, and (2) showed a nootropic response. Ten white autistic boys ranging from 4 to 10 years were compared pretreatment and while taking levetiracetam for an average of 4.1 weeks. Inattention, hyperkinesis, and impulsivity were evaluated using the Achenbach Attention Problems scale, Conners DSM-IV Total scale, and the Conners Attention-Deficit Hyperactivity Disorder Index scale, all of which showed statistically significant improvements. Mood instability was measured with the Conners Global Index (CGI) Emotional Lability and CGI Total scales, both of which showed statistically significant improvements. Aggressive behavior, as measured with the Achenbach Aggression scale, showed statistically significant improvement only for subjects who were not recently weaned from medications that reduce aggression (e.g., risperidone, carbamazepine, desipramine). Levetiracetam may reduce hyperactivity, impulsivity, mood instability, and aggression in autistic children with these problems. No nootropic effect was observed.