Sonuga-Barke EJS et al.

J Am Acad Child Adolesc Psychiatry 2007 Jun; 46:701-10.

Compared with boys, girls had better responses to MPH at 1.5 hours and an inferior response at 12 hours.

The sex of a patient typically does not enter into a clinician’s decision about the use of a medication. However, ADHD might be a condition in which sex matters: Compared with boys, girls are more likely to have the inattentive type of ADHD, coexisting anxiety, more active and efficient clearance of brain dopamine, and fewer dopamine receptors. To evaluate sex-specific responses to methylphenidate (MPH) among children with ADHD, investigators reanalyzed data from a randomized, placebo-controlled, crossover study in 184 children (age, 6–12 years) with the disorder (26% female; mean age, 9.5). The study compared two forms of once-daily MPH: Concerta, which provides 12-hour symptom coverage with 22% immediate release, and Metadate CD, which provides 8-hour symptom coverage with 30% immediate release. MPH dose did not differ for boys and girls.

The only characteristic that differed between sexes was that more girls had coexisting anxiety disorder. ADHD symptoms were assessed on a standardized scale by trained observers in a laboratory classroom on day 7 of treatment at 7 time points during the school day. After controlling for the sex difference in anxiety, girls had a statistically significant better response to both formulations of MPH at 1.5 hours and an inferior response at 12 hours, compared with boys.

Comment: Recognition of a sex difference in response to stimulants for children with ADHD is an important finding. By asking focused questions, pediatricians can assess behavior responses at specific times of day. Girls with ADHD who are treated with an extended-release form of MPH might require special attention for behavior management at the end of the day.

2. Characteristics of adults with attention deficit hyperactivity disorder plus substance use disorder: the role of psychiatric comorbidity.

Wilens TE, Kwon A, Tanguay S, Chase R, Moore H, Faraone SV, Biederman J.
Clinical Research Program in Pediatric Psychopharmacology, Massachusetts General Hospital, Boston, MA, USA.

Am J Addict. 2005 Jul-Sep; 14(4):319-27.
The objective of the study was to investigate the characteristics of adults with Attention Deficit Hyperactivity Disorder (ADHD) or substance use disorder (SUD), especially in the context of comorbid psychiatric disorders. Subjects were adults (n = 78) participating in a controlled family study of ADHD and SUD. Four groups were identified based on a diagnosis of ADHD or SUD: ADHD, SUD, ADHD + SUD, and neither ADHD nor SUD. All diagnoses were determined by structured clinical interview for DSM IV. Rates of psychiatric comorbidity were lowest in the controls, intermediate in the ADHD and SUD groups, and highest in the ADHD + SUD group. Relative to controls, the ADHD, SUD, and ADHD + SUD groups had higher rates of major depression (z = 1.98, p = 0.05), conduct disorder (z = 2.0, p = 0.04), antisocial personality disorder (z = 2.6, p = 0.009), agoraphobia (z = 2.5, p = 0.01) and social phobia (z = 2.7, p = 0.007). Higher rates of psychiatric comorbidity, especially mood and anxiety disorders, exist in subjects with SUD + ADHD relative to subjects with SUD, ADHD, or controls. Clinicians need to be attentive to other psychiatric disorders that may occur in the large group of adults with ADHD + SUD.

3. A Randomized, Double-Blind, Placebo- Controlled Study of Modafinil Film-Coated Tablets in Children and Adolescents with Attention-Deficit Hyperactivity Disorder

Greenhill LL, Biederman J, Boellner SW, et al

J American Acad Child Adolesc Psychiatry. 2006; 45:503-511

Previous research has supported the effectiveness of modafinil in treating children with ADHD. These investigators used a smaller and more easily swallowed tablet than the one now on the market. They enrolled 200 patients, 73% boys and mean age 9.9 years, 131 of whom received modafinil; the rest received placebo. The medication, given once each morning, ranged in dose from 170 mg to 425 mg. The primary outcome measurement was the ADHD-RS-IV administered to teachers (School Version) and parents (Home Version) by researchers blind to treatment condition. They monitored adverse effects by nonspecific inquiry and spontaneous report, and obtained baseline and follow-up blood count, EKG, chemistries, vital signs, height, and weight.
Mean treatment duration was 31.5 days for modafinil and 36.4 days for placebo. Discontinuation for adverse effects occurred in 5% of the modafinil group and 6% of the placebo group. The adverse effects that occurred significantly more often in the modafinil-treated patients included insomnia, headache, and decreased appetite. Decreased appetite resolved in 61% of cases during treatment, but the children taking modafinil lost a mean of 0.6 kg while the children on placebo gained a mean of 1.3 kg ( P < .0001).
The mean scores on the ADHD-DS-IV School Version of the modafinil group began improving compared with the placebo group after 1 week of treatment but reached significance at the end of week 5. The mean scores on the ADHD-DS-IV Home Version diverged after 1 week, and the difference was significant in that and each subsequent week until the ninth, when the study ended. The effect size was 0.63 for teacher ratings and 0.78 for parent ratings.

Viewpoint
This well-designed, short-term study of modafinil confirms its promise as a treatment for ADHD in children. Modafinil, now in use for treating hypersomnia in adults, shows efficacy in inattention and hyperactivity and is well tolerated. It does not, however, seem to be an alternative to stimulants that are devoid of their most troublesome side effects, including insomnia and appetite suppression, even with a once-daily morning dose. The long-term tolerability is an important question that a 1-year, open-label extension of this study, which is underway, will help answer.

4. Long-Acting Methylphenidate has an Effect on Aggressive Behavior in Children with Attention-Deficit/Hyperactivity Disorder.

J Child Adolesc Psychopharmacology. 2007 Aug; 17(4):421-32.

Sinzig J, Döpfner M, Lehmkuhl G; German Methylphenidate Study Group.
Department for Psychiatry and Psychotherapy of Children & Adolescents at the University of Cologne, Germany.

Introduction: Aggression is frequently observed in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). The aim of this study was to assess the efficacy with regard to oppositional and aggressive behavior of a new long-acting methylphenidate preparation (Medikinet retard (R)), MPH-MR), with equal portions of the immediate-release and the sustained-release active substance, and especially to look at correlations between either teacher or parent assessment of aggression and ADHD sub-symptomatology.

Methods: Eighty five children and adolescents (6-16 years) were investigated in a double-blind, randomized, clinical trial over 5 weeks under a treatment with MPH-MR using symptom checklists for ADHD, oppositional-defiant and conduct disorder according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). Results: A total of 64.9% of the children showed oppositional defiant disorder/conduct disorder (ODD/CD) symptoms. A statistically significant effect was found in the group treated with MPH (verum-group). On the basis of Cohen's criteria, high effects were found for aggressive symptoms in school (d = 1.0), but not in the afternoon (d = 0.4). There were also lower effect sizes for more severe aggressive symptoms. We found characteristic correlations between ODD/CD symptoms and the ADHD subscale hyperactivity/impulsivity compared to the subscale inattention.

Conclusions: Long-acting MPH is effective in the treatment of oppositional-defiant and aggressive behavior, especially concerning milder symptoms. The expected correlation between impulsivity and aggressiveness could be confirmed.

5. Do Formulation Differences Alter Abuse Liability of Methylphenidate?: A Placebo-Controlled, Randomized, Double-Blind, Crossover Study in Recreational Drug Users.

Parasrampuria DA, Schoedel KA, Schuller R, Silber SA, Ciccone PE, Gu J, Sellers EM.

J Clin Psychopharmacol. 2007 Oct; 27(5):459-467.

The primary objective of this study was to determine if the abuse liability of methylphenidate is governed by formulation differences that affect rates of drug delivery. In this double-blind, placebo-controlled, randomized, crossover study, subjects with a history of recreational drug use received single oral doses of placebo, 60 mg of immediate-release methylphenidate (IR) and 108 mg of extended-release methylphenidate (osmotic release oral system [OROS]). Over 24 hours after dosing, blood was collected to determine plasma concentrations of methylphenidate, and subjects completed subjective assessments of abuse liability (Addiction Research Center Inventory, Drug Rating Questionnaire-Subject, and Subjective Drug Value).The abuse-related subjective effects of IR and OROS methylphenidate were statistically significantly different from placebo, confirming the overall validity of the study. Although a higher dose of OROS methylphenidate was used compared with IR methylphenidate (108 mg vs 60 mg), subjective effects were consistently lower for OROS compared with IR methylphenidate (statistically significant for 3 of 6 measures of positive effects), particularly at early time points. In general, pharmacokinetic-pharmacodynamic parameters were correlated from a poor to modest degree, with greater correlations observed for IR methylphenidate. In addition, a post hoc "qualification" method was developed, which demonstrated that pharmacological qualification might improve the assessment of subjective effects. Although requiring epidemiological confirmation, the results suggest that OROS methylphenidate, with its characteristic slow ascending plasma concentration profile, may have lower abuse potential. This conclusion is reflected by lower subjective responses during early hours as compared with the IR formulation with its rapid drug delivery and accompanying greater subjective effects.