Influence of stimulant and non-stimulant drug treatment on driving performance in patients with attention deficit hyperactivity disorder: A systematic review

Adults with Attention Deficit Hyperactivity Disorder (ADHD), especially teenagers and young adults, show important car driving impairments, including risky driving, accidents, fines and suspension of driver׳s license. We systematically reviewed the efficacy of stimulant and non-stimulant drugs on driving performance of ADHD patients. We searched several databases for randomized controlled trials (RCTs) published through March, 2013. Fifteen RCTs (the majority with crossover design) evaluated methylphenidate (MPH) immediate-release (MPH-IR), MPH osmotic-controlled oral system (MPH-OROS), MPH transdermal system (MTS), extended-release mixed amphetamine salts (MAS-XR); atomoxetine (ATX) and lisdexamfetamine (LDX). Methods varied widely; including simulators and/or cars and different courses and scenarios. Various outcomes of driving performance, including a ‘composite’ or ‘overall’ driving score were considered. In general, stimulants improved driving performance in ADHD patients (either in RCTs conducted in simulators and/or cars). MPH-OROS improved driving performance compared with MAS-XR, placebo, or no-drug conditions. Although MPH-OROS and MPH-IR produced similar improvements during the day, MPH-IR lost its efficacy in the evening. MAS-XR also improved driving performance, but worsened driving performance in the evening. MTS (one study) showed a positive effect, but drug compliance varied widely across patients. LDX had positive effect on driving (two studies with the same sample). Studies with ATX report conflicting results. Improvement was more consistent in teenagers and young adults. In general, treatment with psychostimulants or ATX in therapeutic dosages had no negative impact on driving performance of ADHD patients. To conclude, treatment with stimulants in therapeutic doses improves driving performance in ADHD patients, especially teenagers and young adults.     

Methylphenidate HCL for the treatment of ADHD in children and adolescents

Introduction: Since Ritalin (methylphenidate immediate-release or MPH IR) was first marketed in 1955, it has been a mainstay of treatment for Attention-Deficit/Hyperactivity Disorder (ADHD).

Areas covered: The postulated mechanism of action, adverse events and efficacy of MPH are examined. MPH formulations that are currently on the market in the United States and those that will soon be available are considered. Various products are examined by comparing onset of effect and duration of action.

Expert opinion: MPH has a well-known efficacy and safety profile. The development of extended-release (MPH-ER) was a significant advance in ADHD treatment. Recent products offer convenience in terms of dosing and timing of drug administration to improve symptom control, but efficacy is similar among all MPH-ER products. One formulation may be more appropriate for an individual patient, but no product offers significant advantages over all others. Since MPH is only effective in about 80% of patients, identifying factors that predict drug response is an active area of research. Although MPH is not effective for every patient, until there is a better understanding of the genetic contributions and nuances of functioning of central nervous system pathways, MPH will be a first choice for the treatment of ADHD.     

Methylphenidate and cocaine: a placebo-controlled drug interaction study

Up to thirty percent of cocaine addicted individuals may meet diagnostic criteria for Attention-Deficit/Hyperactivity Disorder (ADHD). Methylphenidate (MPH) is a highly effective and commonly used treatment for ADHD but, like cocaine, is a cardiovascular and central nervous system stimulant with the potential to cause toxicity at high doses. The present study was undertaken to investigate the likelihood of a toxic reaction in individuals who use cocaine while concurrently taking MPH. Seven non-treatment seeking cocaine-dependent individuals completed this placebo-controlled, crossover study with two factors: Medication (placebo, 60 mg MPH, 90 mg MPH) and Infusion (saline, 20 mg cocaine, 40 mg cocaine). Physiological measures included vital signs, adverse events, and electrocardiogram. Subjective response was measured with visual analog scale (VAS) ratings of craving and drug effect. Cocaine pharmacokinetic parameters were calculated for each participant at each drug combination, using a non-compartmental model. MPH was well tolerated, did not have a clinically significant impact on cocaine's physiological effects, and decreased some of the positive subjective effects of cocaine. MPH did not significantly alter the pharmacokinetics of cocaine. The study results suggest that MPH at the doses studied can likely be used safely in an outpatient setting with active cocaine users.     

Carboxylesterase 1 gene polymorphism and methylphenidate response in ADHD

Methylphenidate (MPH) is the most frequently prescribed drug in the treatment of attention deficit hyperactivity disorder (ADHD). Several pharmacogenetic studies suggested that catecholamine candidate genes influence individual MPH-responses, but these results are mostly contradictory. Genetic analyses of MPH metabolizing carboxylesterase 1 enzyme (CES1) have not been carried out, whereas, meta-analysis of CYP2D6 genetic variants has been already indicated significant pharmacogenetic differences in atomoxetine treatment. Here we present an association analysis of the CES1 Gly143Glu functional polymorphism in a Hungarian ADHD group (n = 173). The genotype frequencies were similar to that of the general population (5.8% vs 4.1% of Gly/Glu heterozygote). Pharmacogenetic analysis was conducted among 122 ADHD children treated with MPH. Neither the categorical analysis comparing 90 responders vs 32 non-responders, nor the dimensional analysis of Inattention and Hyperactivity–Impulsivity score reduction showed a significant main genotype effect. However, analyzing the daily dose, we observed an association with the rare 143Glu-variant: 5 patients in the responder group carrying the Glu-allele required lower doses of MPH for symptom reduction (0.410 ± 0.127 vs 0.572 ± 0.153 mg/kg, t(1,88) = 2.33, p = 0.022). This result warrants for further investigations of the CES1 gene in larger ADHD samples.     

Consumption of methylphenidate and atomoxetine in the private healthcare sector in South Africa: a longitudinal study

International Journal of Clinical Pharmacy - Background Globally Attention-Deficit/Hyperactivity Disorder (ADHD) has been in the spotlight. Despite some controversies, treatment of ADHD remains the...     

A postmarketing clinical experience study of Metadate CD

OBJECTIVE: The objective of the study was to investigate the effectiveness and safety of Metadate CD (methylphenidate HCl, USP) Extended Release Capsules in the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD), in actual clinical practice. METHOD: This was a multicenter, open-label, postmarketing study. Eligible patients were aged 6-17 with a diagnosis of ADHD and receiving either no treatment or maintenance treatment with another approved methylphenidate (MPH) product. Metadate CD was administered once daily for 3 weeks, titrated against reported and observed symptoms. Clinical Global Impression (CGI) scores at Week 3 were used for the primary efficacy evaluation. Patient treatment satisfaction was determined by questionnaire at the final evaluation visit. Safety was assessed through adverse event reporting, laboratory tests and vital sign measurements. RESULTS: Overall, of the 308 patients in the Intent-To-Treat population, the majority (65%) demonstrated a positive response to Metadate CD (defined as CGI Global Improvement rating of very much or much improved). In addition, patients previously treated with immediate-release or extended-release tablet formulations of MPH were successfully converted to Metadate CD at a comparable dose. Most patients (87%) were very satisfied or moderately satisfied with study treatment, and among previously treated patients, 71% rated Metadate CD as much better or better than their previous MPH treatment. Adverse events were consistent with current FDA-approved product labeling for Metadate CD. CONCLUSIONS: Metadate CD is effective and well-tolerated in actual clinical use for ADHD.     

Dopamine Transporter (SLC6A3) Genotype Impacts Neurophysiological Correlates of Cognitive Response Control in an Adult Sample of Patients with ADHD

Studies provide ample evidence for a dysfunction in dopaminergic neurotransmission in Attention-Deficit/Hyperactivity Disorder (ADHD). In that respect, a common variable number of tandem repeats (VNTR) polymorphism in the 3′ untranslated region (UTR) of the dopamine transporter gene (SLC6A3) has been repeatedly associated with the disorder. Here, we examined the influence of the common 9- and 10-repeat alleles of SLC6A3 on prefrontal brain functioning and cognitive response control in a large sample of adult ADHD patients (n=161) and healthy controls (n=109). To this end, we inspected a neurophysiological marker of cognitive response control (NoGo anteriorization, NGA) elicited by means of a Go-NoGo task (continuous performance test, CPT). Within the group of ADHD patients, nine-repeat allele carriers showed significantly reduced NGA, whereas no influence of SLC6A3 genotype was observed in the control group. In contrast to previous association studies of children, the nine-repeat—not the 10-repeat—allele was associated with functional impairments in our sample of adult ADHD patients. Our findings confirm a significant effect of the SLC6A3 genotype on the neurophysiological correlates of cognitive response control in ADHD, and indicate that still to-be-identified age-related factors are important variables modulating the effect of genetic factors on endophenotypes.     

A Postmarketing Clinical Experience Study of Metadate® CD

Summary

Objective:The objective of the study was to investigate the effectiveness and safety of Metadate® CD (methylphenidate HCl, USP) Extended Release Capsules in the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD), in actual clinical practice.

Method:This was a multicenter, open-label, postmarketing study. Eligible patients were aged 6-17 with a diagnosis of ADHD and receiving either no treatment or maintenance treatment with another approved methylphenidate (MPH) product. Metadate® CD was administered once daily for 3 weeks, titrated against reported and observed symptoms. Clinical Global Impression (CGI) scores at Week 3 were used for the primary efficacy evaluation. Patient treatment satisfaction was determined by questionnaire at the final evaluation visit. Safety was assessed through adverse event reporting, laboratory tests and vital sign measurements.

Results: Overall, of the 308 patients in the Intent-To-Treat population, the majority (65%) demonstrated a positive response to Metadate® CD (defined as CGI Global Improvement rating of very much or much improved). In addition, patients previously treated with immediate-release or extended-release tablet formulations of MPH were successfully converted to Metadate® CD at a comparable dose. Most patients (87%) were very satisfied or moderately satisfied with study treatment, and among previously treated patients, 71% rated Metadate® CD as much better or better than their previous MPH treatment. Adverse events were consistent with current FDA-approved product labeling for Metadate® CD.

Conclusions: Metadate® CD is effective and well-tolerated in actual clinical use for ADHD.     

Meta-analysis of the efficacy of methylphenidate for treating adult attention-deficit/hyperactivity disorder

This article reviews the efficacy of methylphenidate (MPH) for adult attention-deficit/hyperactivity disorder (ADHD). A literature search identified double-blind placebo-controlled MPH treatment studies of ADHD adults. Meta-analysis estimated the pooled effect size for MPH treatment and tested for publication bias. Meta-analysis regression assessed the influence of study design features on medication effects. Six trials met criteria and were included in this meta-analysis. These studies included a total of 140 MPH-treated ADHD adults and 113 placebo-treated ADHD adults. The mean effect size of 0.9 was statistically significant and there was no evidence of publication bias. Larger MPH effect sizes were associated with physician ratings of outcome and use of higher doses. When treatment is optimized to high doses, the effect size for MPH in adults was 1.3. We found strong support for the assertion that MPH is efficacious for treating adult ADHD. Because the degree of efficacy of MPH in treating ADHD adults is similar to what has been reported from meta-analyses of the child and adolescent literature, our work provides further assurance to clinicians that the diagnosis of ADHD can be validly applied in adulthood.     

Shaman Woman,Mainline Lady: Women's Writings on the Drug Experience

Abstract

The addictive nature of nicotine appears to depend on a number of psychobiological factors. This study explores the psychoactive effects of nicotine in relationship to the particular dysphoric aspects of Attention Deficit Disorder as a coincident factor in nicotine dependence and resistance to treatment. The psychological and behavioral effects of nicotine directly correspond to reduction in symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD) and the neurochemical effects of nicotine are qualitatively similar to stimulant medications used to treat ADHD. Aspects of the treatment of nicotine or other addictions in such comorbid situations are discussed in the context of self-medication.     

Assessing the abuse potential of methylphenidate in nonhuman and human subjects: a review

Methylphenidate (MPH) is widely used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children, adolescents, and adults. Methylphenidate is clearly effective for the treatment of ADHD, but there is controversy as to whether it has significant abuse potential like other psychostimulants (e.g., D-amphetamine and cocaine). In general, the drug is believed to be abused at rates much lower than those for other stimulants. The present review examines studies that investigated the behavioral pharmacological profile of methylphenidate and discusses how results from these studies address its abuse liability. Using MEDLINE search terms methylphenidate, drug discrimination, reinforcement, self-administration, subjective effects, subject-rated effects, abuse potential, and abuse liability, along with a review of the references from identified articles, 60 studies were located in which the reinforcing, discriminative-stimulus, or subjective effects of methylphenidate were directly assessed in nonhumans or humans. Forty-eight (80.0%) of the studies reviewed indicate that methylphenidate either functions in a manner similar to D-amphetamine or cocaine (e.g., functions as a reinforcer, substitutes fully in drug discrimination experiments), or produces a pattern of subjective effects suggestive of abuse potential. The results are discussed as they pertain to factors that may account for the apparent discrepancy in abuse rates between methylphenidate and other stimulants, including characterization of actual abuse rates, defining abuse and misuse, pharmacokinetic factors, and validity of abuse liability assays.     

Dopaminergic and Noradrenergic Contributions to Functionality in ADHD: The Role of Methylphenidate

Attention Deficit Hyperactivity Disorder (ADHD) is a childhood psychiatric condition characterized by severe impulsiveness, inattention and overactivity. Methylphenidate (MPH), a psychostimulant affecting both the dopaminergic and the noradrenergic systems, is one of the most frequently prescribed treatments for ADHD. Despite the widespread use of MPH and its proven effectiveness, its precise neurochemical mechanisms of action are under debate. For the most part, MPH’s influence on subcortical dopamine neurotransmission is thought to play a crucial role in its behavioral and cognitive effects. In their hypothesis of biphasic MPH action, Seeman and Madras [42, 43] suggest that therapeutic doses of MPH elevate tonic dopamine while inhibiting phasic transmitter release in subcortical structures, leading to reduced postsynaptic receptor stimulation and psychomotor activation in response to salient stimuli. Volkow and colleagues [56] suggest that by amplifying a weak striatal dopamine signal, MPH increases the perception of a stimulus or task as salient. The enhanced interest for the task is thought to increase attention and improve performance. Recent animal studies have however shown that when administered at doses producing clinically relevant drug plasma levels and enhancing cognitive function, MPH preferentially activates dopamine and noradrenaline efflux within the prefrontal cortex relative to the subcortical structures [5]. Overall, we suggest that the delineated theories of MPH therapeutic action should not be discussed as exclusive. Studies are outlined that allow integrating the different findings and models.     

OROS methylphenidate hydrochloride for adult patients with attention deficit/hyperactivity disorder

INTRODUCTION: Attention deficit/hyperactivity disorder (ADHD) is estimated to affect 4-5% of adults. Impairment across multiple domains of daily living can be mild to serious. OROS methylphenidate (MPH) was evaluated in two large adult clinical trials, and in 2008 it was approved in the USA to treat ADHD in adults aged up to 65 years. AREAS COVERED: Products approved for adult ADHD; chemistry, pharmacodynamics, pharmacokinetics, metabolism, efficacy, safety, tolerability, abuse liability, regulatory affairs, and relative merits and limitations associated with OROS MPH; and complexities associated with diagnosis and treatment of ADHD are discussed in this review. The reader will gain an introduction to the epidemiology, features and special issues regarding clinical management of ADHD in adults. Key features and development of OROS MPH are presented, and unique characteristics of the delivery system and their implications for clinical use of the drug are discussed. EXPERT OPINION: The OROS system delivers MPH in a highly consistent manner using osmotic pressure at a controlled rate over a 12-h duration of effect. Compared with immediate-release MPH, it provides a smoother pharmacokinetic curve, and it may show greater patient compliance, fewer missed doses and reduced abuse liability.     

A New Approach to Substance Abuse Treatment: Adolescents and Adults With ADHD

Adolescents and young adults with Attention Deficit Hyperactivity Disorder (ADHD) are not only at risk for drug and alcohol dependence, but are also difficult to maintain in a chemical dependency facility due to disruptive behaviors. Such patients may be “hyperaroused,” a term coined by the field of occupational therapy, but oppositional behaviors hide their physical and emotional overreactivity. Thirty years ago, occupational therapist Dr. Jean Ayres developed Sensory Integration (SI) techniques that are traditionally used with children under 12 years of age who are diagnosed with learning disabilities, autism, and ADHD. Many of the chemically dependent adolescent and young adult patients with ADHD who are in treatment display characteristics similar to those of children traditionally targeted for this therapy. Techniques used by occupational therapists trained in SI were adapted to treat hyperarousal and overreactivity to the environment in chemically dependent adolescents and young adults, in order to maintain them in the treatment environment until they were ready to graduate. The techniques were successful in maintaining and educating patients about ADHD and chemical dependency.     

Patterns of inattentive and hyperactive symptomatology in cocaine-addicted and non-cocaine-addicted smokers diagnosed with adult attention deficit hyperactivity disorder

Despite a robust relationship between Attention Deficit Hyperactivity Disorder (ADHD) and cigarette smoking, as well as increased prevalence of other substance use disorders in these individuals, little is known about the particular patterns of ADHD symptomatology associated with different forms of drug abuse. The present study com- pared ADHD adults with and without cocaine dependence (COCDEP) on severity of ADHD symptomatology. Groups did not differ in smoking rate or degree of nicotine dependence. COCDEP ADHD smokers reported significantly more childhood and adult hyperactive/impulsive symptoms, and a higher number of symptoms overall, during adulthood, even after controlling for group differences in age and sex. Our finding of a more severe adult ADHD symptom profile among ADHD smokers with cocaine dependence, accounted for by elevated hyperactive/impulsive but not inattentive features, suggests that cocaine use in smokers with ADHD may be driven by excesses in hyperactivity. These findings have important implications for research, since similarities and differences in patterns and severity of ADHD symptomatology may shed light on drug-specific mechanisms. Our results may also point to improved approaches for treatment of substance abuse based on attention to patterns of ADHD symptomatology specific to different drugs.     

ADHD and Marijuana-Use Expectancies in Young Adulthood

Objective: This study examined mean level differences in marijuana expectancies and the differential associations between expectancies and marijuana use for individuals with and without a history of Attention-Deficit/Hyperactivity Disorder (ADHD). Background: Substance-use expectancies are a widely studied risk factor for alcohol and other drug use. The relations between marijuana-use expectancies and self-reported marijuana use have not been examined in young adults with ADHD, a population shown to be at risk for marijuana use. Method: Participants were 306 (190 ADHD and 116 non-ADHD) young adults (M age = 20.06, SD = 2.03) from the Pittsburgh ADHD Longitudinal Study (PALS) who provided data about marijuana use and marijuana-use expectancies. Results: Individuals in the ADHD group reported lower levels of social enhancement, tension reduction, and cognitive and behavioral-impairment expectancies compared to individuals in the non-ADHD group. Positive and negative marijuana-use expectancies were associated with marijuana use frequency in the whole sample and statistically significant ADHD group by expectancy interactions were found. Sexual-enhancement expectancies were more strongly associated with marijuana use frequency among individuals with ADHD histories while cognitive behavioral-impairment expectancies were more strongly associated with marijuana use frequency among individuals without ADHD. Conclusions: Marijuana-use expectancies may be acquired, and operate differently, for individuals with and without ADHD histories. Although future research is needed to test this speculation, these differences may be associated with ADHD-related difficulties in higher order cognitive processes that affect the encoding and utilization of expectations regarding marijuana's effects.     

Characterization of anxiety-related responses in male rats following prolonged exposure to therapeutic doses of oral methylphenidate

Increases in the rates of attention-deficit/hyperactivity disorder (ADHD) diagnosis and the prescribed use of methylphenidate (MPH) in recent years have raised concerns over the potential effects of early MPH exposure on brain structure and function in adulthood. Animal studies have shown that long-term MPH exposure can modify anxiety-related behaviors and related neural circuitry in adulthood. The present study employed a battery of behavioral tests and repeated testing to assess the long-term effects of MPH exposure on anxious responding. Male Wistar rats beginning on post-natal day 27 were exposed to 4 or 7 weeks of twice daily MPH administration at doses of 2, 3, or 5 mg/kg. MPH was administered orally and on weekdays only in order to approximate drug treatment in clinical populations. Behavioral testing began 18 days following the last drug administration. Our results indicate that prolonged oral MPH treatment at therapeutic doses has little or no enduring effects on anxious behaviors. However, a comparison of MPH groups that received treatment for 4 or 7 weeks suggests that the two treatment periods influenced anxious behaviors in observably different manners in adulthood; namely, a more prolonged period of exposure produced less anxiety relative to the shorter period of MPH exposure as indicated by behaviors in the light–dark transition, elevated plus-maze, and fear conditioning tests. These findings were interpreted as evidence of the importance of considering length of drug exposure in pre-clinical studies aimed at investigating the effects of MPH exposure in ADHD populations.     

Predictors of treatment response in adolescents with comorbid substance use disorder and attention-deficit/hyperactivity disorder

Attention-Deficit/Hyperactivity Disorder (ADHD) frequently co-occurs with substance use disorder (SUD) and is associated with poor substance-use treatment outcomes. A trial evaluating osmotic-release oral system methylphenidate (OROS-MPH) for adolescents with ADHD and SUD, concurrently receiving behavioral therapy, revealed inconsistent medication effects on ADHD or SUD. Clinical care for this population would be advanced by knowledge of treatment outcome predictors. Data from the randomized placebo-controlled trial (n = 299) were analyzed. Significant treatment predictors included: 1) Substance use severity, associated with poorer ADHD and SUD outcomes, 2) ADHD severity, associated with better ADHD and SUD outcomes, 3) comorbid conduct disorder, associated with poorer ADHD outcomes, and 4) court-mandated status, associated with better SUD outcomes but poorer treatment completion. An interaction effect showed that OROS-MPH improved SUD outcomes in adolescents with comorbid conduct disorder compared to placebo. While severe SUD may require more intensive psychosocial treatment, OROS-MPH may improve substance treatment outcomes in adolescents with co-morbid attention and conduct problems.     

Patterns of Inattentive and Hyperactive Symptomatology in Cocaine-Addicted and Non-Cocaine-Addicted Smokers Diagnosed with Adult Attention Deficit Hyperactivity Disorder

Abstract

Despite a robust relationship between Attention Deficit Hyperactivity Disorder (ADHD) and cigarette smoking, as well as increased prevalence of other substance use disorders in these individuals, little is known about the particular patterns of ADHD symptomatology associated with different forms of drug abuse. The present study compared ADHD adults with and without cocaine dependence (COCDEP) on severity of ADHD symptomatology. Groups did not differ in smoking rate or degree of nicotine dependence. COCDEP ADHD smokers reported significantly more childhood and adult hyperactive/impulsive symptoms, and a higher number of symptoms overall, during adulthood, even after controlling for group differences in age and sex. Our finding of a more severe adult ADHD symptom profile among ADHD smokers with cocaine dependence, accounted for by elevated hyperactive/impulsive but not inattentive features, suggests that cocaine use in smokers with ADHD may be driven by excesses in hyperactivity. These findings have important implications for research, since similarities and differences in patterns and severity of ADHD symptomatology may shed light on drug-specific mechanisms. Our results may also point to improved approaches for treatment of substance abuse based on attention to patterns of ADHD symptomatology specific to different drugs.