Atualização de Junho de 2008

1. Assessment of Pharmacokinetics and Pharmacodynamic Effects Related to Abuse Potential of a Unique Oral Osmotic-Controlled Extended-Release Methylphenidate Formulation in Humans.

Parasrampuria DA, Schoedel KA, Schuller R, Gu J, Ciccone P, Silber SA, Sellers EM.
J Clin Pharmacol. 2007 Oct 25;

This was a double-blind, placebo-controlled, randomized, 5-period crossover study in 49 healthy subjects with a history of light (occasional) recreational stimulant use, to evaluate the abuse-related subjective effects of oral osmotic-controlled extended-release methylphenidate with comparable doses of immediate-release methylphenidate. Healthy subjects with a history of light recreational stimulant use were enrolled in the study if they demonstrated a positive response to a 20-mg dose of d-amphetamine and a negative placebo response. Enrolled subjects received single doses of placebo, 54 and 108 mg osmotic-controlled extended-release methylphenidate, and 50 and 90 mg immediate-release methylphenidate. For each treatment, pharmacokinetics, pharmacodynamics, and safety were assessed for 24 hours. Subjective data were collected through standard questionnaires and visual analog scales for positive, stimulant, negative, and other effects. Immediate-release and osmotic-controlled extended-release methylphenidate produced expected plasma concentration-time profiles of d-methylphenidate. Both doses of immediate-release methylphenidate (50 and 90 mg) produced statistically significantly higher subjective effects (eg, positive, stimulant) with respect to placebo for all measures. The higher osmotic-controlled extended-release methylphenidate dose of 108 mg also produced statistically significant differences from placebo for most measures. However, the most commonly prescribed therapeutic dose of osmotic-controlled extended-release methylphenidate (54 mg) did not produce significant differences from placebo for most measures. In addition, for comparable dose levels, osmotic-controlled extended-release methylphenidate produced lower positive and stimulant subjective effects than immediate-release methylphenidate, and low-dose immediate-release methylphenidate (50 mg) produced greater subjective effects than high-dose osmotic-controlled extended-release methylphenidate, with many effects demonstrating statistically significant differences. These data support the hypothesis that a formulation can modulate abuse potential by controlling the rate and extent of drug delivery.

2. A Case of Disulfiram-Methylphenidate Interaction: Implications for Treatment

Hervé Caci, M.D., Ph.D.and Franck Baylé, M.D.

Am J Psychiatry 164:1759, November 2007

Low dopamine-beta-hydroxylase activity has been associated with disorders such as attention deficit disorder/attention deficit hyperactivity disorder (ADHD) as well as psychotic symptoms. One underlying mechanism that may be attributable to disulfiram would be its action in blocking dopamine-beta-hydroxylase. We report the case of a possible drug-drug interaction with disulfiram and methylphenidate for the treatment of alcohol abuse and ADHD.

A 33-year-old man was hospitalized for a convulsive episode in an intensive care unit. He was diagnosed with alcohol abuse and was noted to have a past history of alcohol and other substance abuse since the age of 15. After 1 month, he was transferred to another clinical unit where he received a diagnosis of attention deficit disorder. During this stay, he was prescribed disulfiram (400 mg/day), without any noticeable adverse effect. The patient was later discharged, and after returning home he began treatment for the first time with OROS-methylphenidate (36 mg daily). After receiving his first dose of methylphenidate, he rapidly experienced a psychotic-like episode that lasted throughout the morning until the end of the afternoon. He denied any alcohol intake and described the experience as similar to acute cocaine intoxication with visual hallucinations. He discontinued methylphenidate, continued to receive disulfiram and vitamins, and recovered fully.

Two months later, in an outpatient follow-up visit, the patient’s diagnosis of attention deficit disorder was confirmed as the predominantly inattentive subtype according to DSM-IV criteria. His score on the screening portion of the Adult ADHD Symptoms Rating Scale was 5 (out of a maximum of 6). His score on the 25-item Wender Utah Rating Scale was 59, strongly in favor of significant inattentive/hyperactive symptoms in childhood. There was no clinical evidence of psychosis, anxiety, or depression. Three months following this assessment, the patient discontinued receiving disulfiram. He was then prescribed OROS-methylphenidate (36 mg/day). No adverse effect was reported in the weeks thereafter, and the dosage was increased to 54 mg/day over the following 3 months, without adverse effect or recurrence of the psychotic experience.

Our case raises suspicion for a possible drug-drug interaction as indicated by a score of 4 on the Drug Interaction Probability Scale, although it is possible that there were other contributing metabolic factors that might have been identified through serum chemistries at the time of the initial reaction. Since the alcohol-aversive effect of disulfiram persists up to 2 weeks after discontinuation of the drug, a significant washout period should be observed before starting methylphenidate. Alternatively, a nondopaminergic psychostimulant might be preferred for the treatment of attention deficit disorder/ADHD when concomitant disulfiram is mandatory.

3. Does Early Pharmacotherapy for ADHD Protect Against Risk of Later Depression?

Maria Bishop

54th Annual Meeting of the American Academy of Child & Adolescent Psychiatry (AACAP) - November 1, 2007

Pharmacotherapy for attention-deficit hyperactivity disorder (ADHD) does not increase the risk of major depressive disorder (MDD) in children, and, in fact, may reduce the risk of later comorbid MDD.

While animal studies have suggested a link between MDD and early exposure to stimulants, in this trial a link was found between delayed ADHD pharmacotherapy and higher risk of eventual MDD in youths with ADHD, noted lead author W. Burleson Daviss, MD, Associate Professor, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States.

Youths with ADHD have rates of MDD that are 5.5 times higher than the rate in the general population, although ADHD usually occurs several years before the onset of MDD.

In their retrospective, case-control study, Dr. Daviss and colleagues utilised data from consecutive research evaluations of adolescents 11 to 18 years old with ADHD who were participating in an observational study.

Two groups were categorised and compared in univariate analysis: youths with histories of a major depressive episode (never depressed) and youths with no history of MDD or minor depressive episodes (history of MDD).

The two groups had similar ages of onset and current symptoms of ADHD. However, the history of MDD group had significantly later fist pharmacotherapy for ADHD (P =.002). Allowing other significant predictors to enter a backward stepwise Cox Regression analysis, the time-dependent variable ADHD pharmacotherapy emerged as the only significant predictor of MDD after ADHD onset (P =.037).

Early externalizing and early anxiety disorders did not show a trend toward prediction of MDD.

Although it did not remain a variable in a separate stepwise regression analysis, female gender showed a trend toward being a significant predictor of MDD (P =.07). Females also showed a greater delay, however, in receiving ADHD pharmacotherapy.

Dr. Davis concluded that, "These results will require replication in an independent sample of ADHD youths -- ideally using prospective rather than retrospective observations."

He added that further studies might explore the link between delayed pharmacotherapy and comorbid MDD (e.g., family psychopathology, poor parenting, environment).

4. Agreement between parent and child report of quality of life in children with attention-deficit/hyperactivity disorder.

Klassen AF, Miller A, Fine S.
Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.

Child Care Health Dev. 2006 Jul; 32(4):397-406.

BACKGROUND: There is little information in the research literature of agreement between parent and child in reports of child quality of life (QOL) for a sample of children diagnosed with attention-deficit/hyperactivity disorder (ADHD). The aim of our study was to determine whether parent and child concordance is greater for physical domains of QOL than for psychosocial domains; whether parents rate their child's QOL better or poorer than their child's ratings; and whether concordance is related to demographic, socioeconomic or clinical factors.

METHODS: The study was a questionnaire survey of children aged 10-17 referred to the ADHD clinic and diagnosed with ADHD in the province of British Columbia (Canada) between November 2001 and October 2002 and their parent. RESULTS: Fifty-eight children diagnosed with ADHD and their parents completed our study questionnaire. The main outcome measure was the Child Health Questionnaire, which permitted comparisons on eight QOL domains and one single item. Intraclass correlation coefficients were moderate for five domains (range from 0.40 to 0.51), and good for three domains (range from 0.60 to 0.75). Children rated their QOL significantly better than their parents in four areas and poorer in one. Standardized Response Means indicated clinically important differences in mean scores for Behaviour and Self-esteem. Compared with population norms, across most domains, children with ADHD reported comparable health. Discrepancies between parent-child ratings were related to the presence of a comorbid oppositional/defiant disorder, a psychosocial stressor and increased ADHD symptoms.

CONCLUSIONS: Although self-report is an important means of eliciting QOL data, in children with ADHD, given the discrepancies in this study between parent and child report, measuring both perspectives seems appropriate.

5. High-dose methylphenidate treatment of attention deficit hyperactivity disorder in a preschooler.

Lipkin PH, Butz AM, Cozen MA.
Department of Pediatrics, The Kennedy Krieger Institute, Johns Hopkins University School of Medicine, 707 North Broadway, Baltimore, MD 21205, USA. l

J Child Adolesc Psychopharmacol. 2003 Spring; 13(1):103-6.

Although attention deficit hyperactivity disorder is thought to be present in preschoolers, there are no clear guidelines for dosing stimulant medications in this population. This is a case of a 4-year-old boy who was given 108 mg/day extended-release methylphenidate (OROS) MPH) (6.1 mg/kg/day) by his caregiver with notable behavioral improvement. However, weight loss incurred due to the anorexic side effect of the medication led the clinician to decrease his dose to 72 mg/day OROS MPH (3.7 mg/kg/day). The case highlights that some young children with attention deficit hyperactivity disorder treated with MPH may require higher doses than would be predicted by weight-based dosing. An increased frequency of side effects associated with high doses of MPH necessitates that the clinician balance the positive behavioral response of the medication with adverse side effects in determining ideal dose.