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1.  Pharmacological interventions for adolescents and adults with ADHD: stimulant and nonstimulant medications and misuse of prescription stimulants 
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by symptoms of inattention, hyperactivity, and impulsivity that cause functional impairment. Recent research indicates that symptoms persist into adulthood in the majority of cases, with prevalence estimates of approximately 5% in the school age population and 2.5%–4% in the adult population. Although students with ADHD are at greater risk for academic underachievement and psychosocial problems, increasing numbers of students with ADHD are graduating from high school and pursuing higher education. Stimulant medications are considered the first line of pharmacotherapy for individuals with ADHD, including college students. Although preliminary evidence indicates that prescription stimulants are safe and effective for college students with ADHD when used as prescribed, very few controlled studies have been conducted concerning the efficacy of prescription stimulants with college students. In addition, misuse of prescription stimulants has become a serious problem on college campuses across the US and has been recently documented in other countries as well. The purpose of the present systematic review was to investigate the efficacy of prescription stimulants for adolescents and young adults with ADHD and the nonmedical use and misuse of prescription stimulants. Results revealed that both prostimulant and stimulant medications, including lisdexamfetamine dimesylate, methylphenidate, amphetamines, and mixed-amphetamine salts, are effective at reducing ADHD symptoms in adolescents and adults with ADHD. Findings also suggest that individuals with ADHD may have higher rates of stimulant misuse than individuals without the disorder, and characteristics such as sex, race, use of illicit drugs, and academic performance are associated with misuse of stimulant medications. Results also indicate that individuals both with and without ADHD are more likely to misuse short-acting agents than long-acting agents. These findings have implications for intervention, prevention, and future research.
PMCID: PMC4164338  PMID: 25228824
ADHD symptomatology; pharmacotherapy; nonmedical stimulant use; lisdexamfetamine; methylphenidate; amphetamine
2.  Illicit Use of Specific Prescription Stimulants Among College Students: Prevalence, Motives, and Routes of Administration 
Pharmacotherapy  2006;26(10):1501-1510.
To explore the illicit use of specific prescription stimulants among college students and add to our understanding of reasons (motives) and routes of administration associated with illicit use of these drugs.
A random sample of 4580 college students self-administered a Web-based survey. The survey contained a variety of items pertaining to the illicit use of prescription stimulants. An extensive list of prescription stimulants was provided, and students were asked to select all the specific prescription stimulants that they had used illicitly. Items were also included to assess the motives and routes of administration associated with illicit use of prescription stimulants.
Lifetime and past-year prevalence rates for illicit use of prescription stimulants were 8.3% (382 students) and 5.9% (269 students), respectively. Approximately three fourths (75.8%) of the 269 past-year illicit users of prescription stimulants reported using an amphetamine-dextroamphetamine combination agent (e.g., Adderall) in the past year, and approximately one fourth (24.5%) reported using methylphenidate (e.g., Ritalin, Concerta, Metadate, Methylin). Past-year illicit use of prescription stimulants was more than 3 times more likely among Caucasians (odds ratio [OR] 3.1, 95% confidence interval [CI] 1.5–6.6) and Hispanics (OR 3.8, 95% CI 1.6–9.3) compared with African-Americans, and more than twice as likely among Caucasians (OR 2.1, 95% CI 1.3–3.4) and Hispanics (OR 2.6, 95% CI 1.4–5.1) compared with Asians. The most commonly reported motives for illicit use were to help with concentration (65.2%), help study (59.8%), and increase alertness (47.5%). Other motives included getting high (31.0%) and experimentation (29.9%). Nearly every illicit user (95.3%) reported oral administration, and 38.1% reported snorting prescription stimulants.
Illicit use of amphetamine-dextroamphetamine is more prevalent than illicit use of methylphenidate formulations among college students.
PMCID: PMC1794223  PMID: 16999660
prescription stimulants; illicit use; college students; motives; amphetamines; methylphenidate; route of administration
3.  Minimizing Adverse Events While Maintaining Clinical Improvement in a Pediatric Attention-Deficit/Hyperactivity Disorder Crossover Trial with Dextroamphetamine and Methylphenidate 
Objective: The purpose of this study was to investigate whether the availability of both dextroamphetamine and methylphenidate provides an opportunity to minimize adverse events in a pediatric attention-deficit/hyperactivity disorder (ADHD) stimulant trial.
Methods: Thirty-six medication-naïve children 9–14 years of age, diagnosed with ADHD, were enrolled for 6 weeks in a crossover trial, with 2 weeks of methylphenidate, dextroamphetamine, and a placebo in a randomly assigned, counterbalanced sequence. Barkley's Side-Effect Rating Scale (SERS), rated by parents, was used to assess adverse events. SERS were available for 34 children, and data were analyzed both at the group and the single-subject level.
Results: The side-effect profiles of dextroamphetamine and methylphenidate appeared similar at the group level. Overall, insomnia and decreased appetite were the only adverse events associated with the stimulants as compared with placebo. No significant increase from placebo to stimulant conditions was detected on SERS items reflecting emotional symptoms. Furthermore, dextroamphetamine and methylphenidate did not differ from each other on any SERS item, except that dextroamphetamine was associated with higher severity of “insomnia” and a higher prevalence of “unusually happy.” Single-subject analyses showed that one or more adverse events were reported in 14 children (41%), and were evenly distributed between those with dextroamphetamine as the drug that showed the greatest reduction in their ADHD symptoms (“best drug”) and those with methylphenidate as their best drug. Among children in whom both stimulants were associated with a decrease in ADHD symptoms, a clinically valid difference between the two stimulants in total adverse events score was found in 7 (39%) of the 18 cases. In these children, the availability of both stimulants provided an opportunity to minimize adverse events, while maintaining a reduction in ADHD symptoms.
Conclusions: The availability of both dextroamphetamine and methylphenidate may contribute to minimize adverse events in a subsample of children in pediatric ADHD stimulant trials.
Clinical Trials Registry: The study was first registered in clinical trials September 28, 2010. Clinical Identifier: NCT01220440.
PMCID: PMC3993015  PMID: 24666268
4.  Misuse of Methamphetamine and Prescription stimulants among Youths and Young Adults in the Community 
Drug and alcohol dependence  2007;89(2-3):195-205.
Gender differences in the prevalence and characteristics of misuse of methamphetamine (meth) and prescription stimulants were examined in a representative U.S. sample of youths and young adults aged 16–25 (N = 24,409).
Stimulant misusers were categorized into three mutually exclusive subgroups: meth users only, meth and prescription stimulant users, and prescription stimulant users only (e.g., Benzedrine®, Ritalin®, or Dexedrine®). Multinominal logistic regression analyses identified the characteristics associated with misuse of meth and prescription stimulants.
About 1 in 10 youths reported any misuse of stimulants in their lifetime. Prescription stimulant misuse occurred earlier and was more frequent than meth misuse. About 47% of meth misusers also reported prescription stimulant misuse. Among misusers of meth and prescription stimulants, males were more likely than females to misuse methylphenidate (82% vs. 65%) but were less likely to misuse diet pills or amphetamines (37% vs. 49%). Multinominal logistic regression analyses indicated that all subgroups of lifetime stimulant misuse were associated with past year substance abuse. The characteristics of meth misusers differed slightly from prescription stimulants misusers.
Multidrug use is common among stimulant misusers. Parents should be informed about the risk of prescription stimulant misuse by their youths.
PMCID: PMC2063507  PMID: 17257780
Gender differences; Methamphetamine; Methylphenidate; Prescription stimulants; Substance use disorders
5.  Stigmatization in teachers towards adults with attention deficit hyperactivity disorder 
SpringerPlus  2014;3:26.
Attention deficit hyperactivity disorder (ADHD) is understood as a developmental disorder which shares common characteristics between childhood, adolescence and adulthood. However, ADHD is widely associated with misconceptions and misbeliefs which can lead to stigmatization. Teachers have an important role for the individual development as they accompany students for a long period of time. The aim of the present study was to explore stigmatizing attitudes in teachers towards adults with ADHD, thereby focusing on the developmental trajectory of the condition. Furthermore, it was aimed to identify factors contributing to prevention and intervention of stigmatization in ADHD.
Stigma responses of 170 teachers and 170 comparison participants were measured and compared with a recently developed tool for the assessment of stigmatization towards adults with ADHD. Furthermore, the contribution of knowledge about ADHD and the frequency of contact with adults with ADHD to stigmatization were explored.
Teachers showed significantly less stigmatizing attitudes than comparison participants in various dimensions, including Reliability and Social Functioning, Malingering and Misuse of Medication and the total scale. With regard to teachers, frequency of contact with adults with ADHD was not related to stigma. However, knowledge about the disorder was negatively correlated with stigma in teachers, indicating lower expressed stigma with increasing knowledge about adult ADHD.
Teachers demonstrated more sensitized attitudes towards stigma in adults with ADHD than comparison participants. Since the present results indicate that knowledge about ADHD increase the sensitivity towards the disorder, special education programs for the community may have the potential to reduce stigmatization towards adults with ADHD. Possibilities for intervention strategies of stigmatization in educational settings were discussed.
PMCID: PMC3895438  PMID: 24455470
Stigmatization; Adult ADHD; Education; Teachers; Prevention; Intervention
6.  Misuse of Prescribed Stimulant Medication for ADHD and Associated Patterns of Substance Use: Preliminary Analysis Among College Students 
Journal of Pharmacy Practice  2011;24(6):551-560.
To explore the prevalence and characteristics associated with college students who misuse their prescribed stimulants for attention-deficit hyperactivity disorder (ADHD) and examine diversion and substance use behaviors as a function of misuse.
Cohort of 55 past-year prescribed stimulant users was identified from a random sample (n = 1738) at a large Midwestern research university following the self-administration of a web-based survey. An index was created to assess misuse of prescribed stimulants (i.e., Misuse Index).
Of 55 college students who reported past-year use of prescribed stimulants for ADHD, 22 (40%) endorsed at least one item on the misuse index. The most frequently endorsed misuse items were used too much (36%), self-reported misuse (19%), and intentionally used with alcohol or other drugs (19%). Misusers of prescribed stimulant medication were more likely to report cigarette smoking (p = 0.022), binge drinking (p = 0.022), illicit use of cocaine (p = 0.032), and screen positive on the Drug Abuse Screening test (DAST-10) criteria (p = 0.002). The bivariate odds ratio for the DAST-10 findings was 8.4 (95% CI: 2.0–34.6). Diversion of prescribed stimulants was common (36%) and occurred more frequently among stimulant misusers (57%; p = 0.008).
There is a strong relationship between misuse of prescribed stimulants for ADHD and substance use behaviors, as well as other deleterious behaviors such as diversion. These findings suggest the need for close screening, assessment, and therapeutic monitoring of medication use in the college population.
PMCID: PMC3277944  PMID: 22095577
attention-deficit hyperactivity disorder; medication; stimulant; misuse; diversion; amphetamine
7.  High dose methylphenidate treatment in adult attention deficit hyperactivity disorder: a case report 
Stimulant medication improves hyperactivity, inattention, and impulsivity in both pediatric and adult populations with Attention Deficit Hyperactivity Disorder (ADHD). However, data regarding the optimal dosage in adults is still limited.
Case presentation
We report the case of a 38-year-old Caucasian patient who was diagnosed with Attention Deficit Hyperactivity Disorder when he was nine years old. He then received up to 10 mg methylphenidate (Ritalin®) and 20 mg sustained-release methylphenidate (Ritalin SR®) daily. When he was 13, his medication was changed to desipramine (Norpramin®), and both Ritalin® and Ritalin SR® were discontinued; and at age 18, when he developed obsessive-compulsive symptoms, his medication was changed to clomipramine (Anafranil®) 75 mg daily. Still suffering from inattention and hyperactivity, the patient began college when he was 19, but did not receive stimulant medication until three years later, when Ritalin® 60 mg daily was re-established. During the 14 months that followed, he began to use Ritalin® excessively, both orally and rectally, in dosages from 4800-6000 mg daily. Four years ago, he was referred to our outpatient service, where his Attention Deficit Hyperactivity Disorder was re-evaluated. At that point, the patient’s daily Ritalin® dosage was reduced to 200 mg daily orally, but he still experienced pronounced symptoms of, Attention Deficit Hyperactivity Disorder so this dosage was raised again. The patient’s plasma levels consistently remained between 60–187 nmol/l—within the recommended range—and signs of his obsessive-compulsive symptoms diminished with fluoxetine 40 mg daily. Finally, on a dosage of 378 mg extended-release methylphenidate (Concerta®), his symptoms of Attention Deficit Hyperactivity Disorder have improved dramatically and no further use of methylphenidate has been recorded during the 24 months preceding this report.
Symptoms of Attention Deficit Hyperactivity Disorder (ADHD) in this adult patient, who also manifested a co-occurring obsessive compulsive disorder, dramatically improved only after application of a higher-than-normal dose of methylphenidate. We therefore suggest that clinicians consider these findings in relation to their adherence to current therapeutic guidelines.
PMCID: PMC3407707  PMID: 22583957
8.  Long-acting methylphenidate formulations in the treatment of attention-deficit/hyperactivity disorder: a systematic review of head-to-head studies 
BMC Psychiatry  2013;13:237.
The stimulant methylphenidate (MPH) has been a mainstay of treatment for attention-deficit/hyperactivity disorder (ADHD) for many years. Owing to the short half-life and the issues associated with multiple daily dosing of immediate-release MPH formulations, a new generation of long-acting MPH formulations has emerged. Direct head-to-head studies of these long-acting MPH formulations are important to facilitate an evaluation of their comparative pharmacokinetics and efficacy; however, to date, relatively few head-to-head studies have been performed.
The objective of this systematic review was to compare the evidence available from head-to-head studies of long-acting MPH formulations and provide information that can guide treatment selection.
A systematic literature search was conducted in MEDLINE and PsycINFO in March 2012 using the MeSH terms: attention deficit disorder with hyperactivity/drug therapy; methylphenidate/therapeutic use and All Fields: Concerta; Ritalin LA; OROS and ADHD; Medikinet; Equasym XL and ADHD; long-acting methylphenidate; Diffucaps and ADHD; SODAS and methylphenidate. No filters were applied and no language, publication date or publication status limitations were imposed. Articles were selected if the title indicated a comparison of two or more long-acting MPH preparations in human subjects of any age; non-systematic review articles and unpublished data were not included.
Of 15,295 references returned in the literature search and screened by title, 34 articles were identified for inclusion: nine articles from pharmacokinetic studies (nine studies); nine articles from laboratory school studies (six studies); two articles from randomized controlled trials (two studies); three articles from switching studies (two studies) and three articles from one observational study.
Emerging head-to-head studies provide important data on the comparative efficacy of the formulations available. At a group level, efficacy across the day generally follows the pharmacokinetic profile of the MPH formulation. No formulation is clearly superior to another; careful consideration of patient needs and subtle differences between formulations is required to optimize treatment. For patients achieving suboptimal symptom control, switching long-acting MPH formulations may be beneficial. When switching formulations, it is usually appropriate to titrate the immediate-release component of the formulation; a limitation of current studies is a focus on total daily dose rather than equivalent immediate-release components. Further studies are necessary to provide guidance in clinical practice, particularly in the treatment of adults and pre-school children and the impact of comorbidities and symptom severity on treatment response.
PMCID: PMC3852277  PMID: 24074240
Methylphenidate; Attention-deficit/hyperactivity disorder; Comparison; Long-acting formulation; Pharmacokinetics; Review
9.  Nonmedical Use of Prescription ADHD Stimulants and Preexisting Patterns of Drug Abuse 
Journal of Addictive Diseases  2013;32(1):1-10.
Multidrug use is well documented among nonmedical users of prescription stimulants. We sought to provide insight into the drug use patterns of those reporting nonmedical use of prescription attention-deficit hyperactivity disorder (ADHD) stimulants in an attempt to discern whether such use is a first step in a pattern of drug-abusing behavior or, conversely, is a later development accompanied or preceded by a history of drug abuse. A cross-sectional, population-based survey of the U.S. civilian, non-institutionalized population aged 12 years and older was analyzed for lifetime nonmedical use of prescription ADHD stimulants, lifetime nonmedical use of another prescription drug, illicit drug use, and drug use initiation patterns. This included 443,041 respondents from the 2002–2009 National Survey on Drug Use and Health. Lifetime nonmedical use of prescription ADHD stimulants was reported by 3.4% of those aged 12 years and older. Of these, 95.3% also reported use of an illicit drug (i.e., marijuana, cocaine/crack, heroin, hallucinogens, inhalants) or nonmedical use of another prescription drug (i.e., tranquilizers, pain relievers, or sedatives), and such use preceded nonmedical use of prescription ADHD stimulants in 77.6% of cases. On average, 2.40 drugs were used prior to the first nonmedical use of prescription ADHD stimulants. These data suggest that nonmedical use of prescription ADHD stimulants is not commonly an initiating factor leading to the nonmedical use of other prescription medications or abuse of illicit drugs. Rather, nonmedical use of prescription ADHD stimulants appears to be adopted by individuals already engaged in broader patterns of drug abuse and misuse.
PMCID: PMC3630453  PMID: 23480243
Attention-deficit hyperactivity disorder; amphetamine; methylphenidate; psycho-stimulants; substance abuse and dependence
10.  Clinical Gains from Including Both Dextroamphetamine and Methylphenidate in Stimulant Trials 
The purpose of this study was to investigate clinical gains from including both dextroamphetamine and methylphenidate in stimulant trials.
Thirty-six medication-naïve children ages 9–14 years diagnosed with attention-deficit/hyperactivity disorder (ADHD) were enrolled for 6 weeks in a crossover trial, with 2 weeks of methylphenidate, dextroamphetamine, and placebo, in a randomly assigned, counterbalanced sequence. Outcome measures constituted a computer-based continuous performance test combined with a motion tracking system (Qb Test) and an ADHD questionnaire rated by parents and teachers.
Group analyses found significant treatment effects of similar size for the two stimulants on both outcome measures. Single-subject analyses revealed that each stimulant produced a favourable response in 26 children; however, an individual child frequently responded qualitatively or quantitatively differently to the two stimulants. By including both stimulants in the trial, the number of favorable responders increased from 26 (72%) to 33 (92%). In children with favorable responses of unequal strength to the two stimulants, a shift from inferior drug to best drug was associated with a 64% mean increase in the overall response strength score, as measured by the ADHD questionnaire.
The likelihood of a favorable response and optimal response strength is increased by including both stimulants in the stimulant trial.
The study was first registered in clinical trials 28 September 2010. Clinical Identifier: NCT01220440.
PMCID: PMC3842881  PMID: 23659360
11.  Attention-deficit hyperactivity disorder (ADHD) stimulant medications as cognitive enhancers 
Recent increases in attention deficit hyperactivity disorder (ADHD) diagnoses, and the escalation of stimulant prescriptions, has raised concern about diversion and abuse of stimulants, as well as the ethics of using these drugs as “cognitive enhancers.”Such concern appears misplaced in the face of substantial evidence that stimulant drugs do not improve the academic performance of ADHD-diagnosed students. Moreover, numerous studies have found little or no benefit of stimulants on neuropsychological tests of ADHD-diagnosed as well as normal, individuals. This paper examines the apparent paradox: why don't drugs that improve “attention,” produce better academic outcomes in ADHD-diagnosed students? We found that stimulant drugs significantly improved impairment of episodic memory in ADHD-diagnosed undergraduate students. Nevertheless, we also found consistent academic deficits between ADHD students and their non-ADHD counterparts, regardless of whether or not they used stimulant medications. We reviewed the current literature on the behavioral effects of stimulants, to try to find an explanation for these conflicting phenomena. Across a variety of behavioral tasks, stimulants have been shown to reduce emotional reactions to frustration, improve the ability to detect errors, and increase effortful behavior. However, all of these effects would presumably enhance academic performance. On the other hand, the drugs were also found to promote “risky behavior” and to increase susceptibility to environmental distraction. Such negative effects, including the use of drugs to promote wakefulness for last minute study, might explain the lack of academic benefit in the “real world,” despite their cognitive potential. Like many drugs, stimulants influence behavior in multiple ways, depending on the environmental contingencies. Depending on the circumstances, stimulants may, or may not, enhance cognition.
PMCID: PMC3666055  PMID: 23754970
attention-deficit hyperactivity disorder; cognitive enhancement; episodic memory; stimulants; amphetamine; methylphenidate
12.  Effectiveness of pharmaceutical therapy of ADHD (Attention-Deficit/Hyperactivity Disorder) in adults – health technology assessment 
Attention-Deficit/Hyperactivity Disorder (ADHD) is a mental disorder. Symptoms include hyperactivity, lack of attentiveness, and frivolousness. This disorder always begins in childhood, but can remain through adulthood. ADHD affects all areas of life and limits the quality of life due to its symptoms and the high rate of associated disorders that can develop.
An established form of therapy is using stimulant medications, most commonly, containing Methylphenidate as the active ingredient. However, in Germany this ingredient is not approved for adults suffering from ADHD. Therefore, many adults cannot obtain appropriate medication to treat this disorder.
The following report (Health Technology Assessment [HTA]) examines the effectiveness and cost-effectiveness of the medical treatment of ADHD in adults as well as the ethical, social and legal aspects thereof.
In August 2009, a systematic literature search is performed in all relevant scientific databases. The selected citations fulfill predetermined inclusion criteria. The data in the publications is then systematically extracted, reviewed and assessed. A manual search of citations is conducted as well.
Nineteen studies fulfill the inclusion criteria: nine randomised controlled studies (RCT), five meta-analyses, three economic studies and two studies relevant to the legal aspects of the HTA.
All RCT reveal that adult patients who receive medication containing a stimulant (Methylphenidate and Amphetamine) and Atomoxetine, see a reduction of ADHD symptoms compared to the placebo-treated patients. The drug response rate among the control group ranges from 7 to 42%; in the treatment group from 17 to 59.6%. The meta-analyses confirm the findings of the RCT.
In light of the control group, it can be ascertained that there are higher annual costs (both direct and indirect) for patients with ADHD. The average annual medical expenses for an adult with ADHD were 1,262 $ in 1998 and 1,673 $ in 2001 (the converted and inflation-adjusted rate for 2009: between 1,270 and 1,619 Euro).
The use of stimulants use may impair the patient’s ability to drive, travel or do sports. No relevant studies can be identified concerning the ethical, social and/or legal aspects of stimulant medication for ADHD patients.
Medical treatment, particularly including Methylphenidate and Atomoxetine, proves to have a positive effect. In order to attain an optimal drug response, dosing must be determined on an individual basis.
There is a need of high-quality studies that directly compare various agents – an aspect which is relevant to medical effectiveness of a therapy. No definite statement can be made about the cost-effectiveness of the medical treatment of ADHD in adults. More health economic studies are therefore required.
Apart from the unquestionable mental indication, it is already recommended by health economic reasons to establish the conditions for an adequate treatment with these medicaments also for adults.
PMCID: PMC3010888  PMID: 21289886
attention deficit disorder with hyperactivity; drug therapy; methylphenidate; adult; stimulants, historical; treatment outcome; costs and cost analysis; antidepressive agents; amphetamine; bupropion; review literature as topic; attention deficit disorder; attention deficit syndrom; hyperactivity syndrom; hyperkinetic disorder; psychic; psychic disorder; behaviour disorder; behavior disorder; minimal cerebral dysfunction; psycho-organic syndrome; striatal frontal dysfunction; comorbidity; fidgety; hyperactivty; overactivity; lack of concentration; concentration disorder; learning disability; unconcentrated; pharmacotherapy; drugs; medicaments; medicine; noradrenaline reuptake inhibitors; stimulant; stimulants; behavior therapy; behaviour therapy; behavior; behaviour; therapy; treatment; add-on therapy; care; needed care; quality of life; health economics; ethics; juridical; social; economics; efficiency; efficacy; efffectiveness; cost-effectiveness; costs; systematic review; HTA; Health Technology Assessment; ADHD; ADD; attention deficit hyperactivity disorder; medication therapy; pharmaceutical therapy; medical interventions; drug therapy; methylphenidate; atomoxetine; non-stimulants; ritalin; antidepressive agents; amphetamine; bupropion; adults; adulthood; review; cost analysis
13.  Influence of relative age on diagnosis and treatment of attention-deficit/hyperactivity disorder in children 
The annual cut-off date of birth for entry to school in British Columbia, Canada, is Dec. 31. Thus, children born in December are typically the youngest in their grade. We sought to determine the influence of relative age within a grade on the diagnosis and pharmacologic treatment of attention-deficit/hyperactivity disorder (ADHD) in children.
We conducted a cohort study involving 937 943 children in British Columbia who were 6–12 years of age at any time between Dec. 1, 1997, and Nov. 30, 2008. We calculated the absolute and relative risk of receiving a diagnosis of ADHD and of receiving a prescription for a medication used to treat ADHD (i.e., methylphenidate, dextroamphetamine, mixed amphetamine salts or atomoxetine) for children born in December compared with children born in January.
Boys who were born in December were 30% more likely (relative risk [RR] 1.30, 95% confidence interval [CI] 1.23–1.37) to receive a diagnosis of ADHD than boys born in January. Girls born in December were 70% more likely (RR 1.70, 95% CI 1.53–1.88) to receive a diagnosis of ADHD than girls born in January. Similarly, boys were 41% more likely (RR 1.41, 95% CI 1.33–1.50) and girls 77% more likely (RR 1.77, 95% CI 1.57–2.00) to be given a prescription for a medication to treat ADHD if they were born in December than if they were born in January.
The results of our analyses show a relative-age effect in the diagnosis and treatment of ADHD in children aged 6–12 years in British Columbia. These findings raise concerns about the potential harms of overdiagnosis and overprescribing. These harms include adverse effects on sleep, appetite and growth, in addition to increased risk of cardiovascular events.
PMCID: PMC3328520  PMID: 22392937
14.  Adderall Induced Acute Liver Injury: A Rare Case and Review of the Literature 
Adderall (dextroamphetamine/amphetamine) is a widely prescribed medicine for the treatment of attention-deficit/hyperactivity disorder (ADHD) and is considered safe with due precautions. Use of prescribed Adderall without intention to overdose as a cause of acute liver injury is extremely rare, and to our knowledge no cases have been reported in the English literature. Amphetamine is an ingredient of recreational drugs such as Ecstacy and is known to cause hepatotoxicity. We describe here the case of a 55-year-old woman who developed acute liver failure during the treatment of ADHD with Adderall. She presented to the emergency room with worsening abdominal pain, malaise, and jaundice requiring hospitalization. She had a past history of partial hepatic resection secondary to metastasis from colon cancer which was under remission at the time of presentation. She recovered after intensive monitoring and conservative management. Adderall should be used carefully in individuals with underlying liver conditions.
PMCID: PMC3706063  PMID: 23864967
15.  Addiction-Related Gene Regulation: Risks of Exposure to Cognitive Enhancers vs. Other Psychostimulants 
Progress in neurobiology  2012;100:60-80.
The psychostimulants methylphenidate (Ritalin, Concerta), amphetamine (Adderall), and modafinil (Provigil) are widely used in the treatment of medical conditions such as attention-deficit hyperactivity disorder and narcolepsy and, increasingly, as “cognitive enhancers” by healthy people. The long-term neuronal effects of these drugs, however, are poorly understood. A substantial amount of research over the past 2 decades has investigated the effects of psychostimulants such as cocaine and amphetamines on gene regulation in the brain because these molecular changes are considered critical for psychostimulant addiction. This work has determined in some detail the neurochemical and cellular mechanisms that mediate psychostimulant-induced gene regulation and has also identified the neuronal systems altered by these drugs. Among the most affected brain systems are corticostriatal circuits, which are part of cortico-basal ganglia-cortical loops that mediate motivated behavior. The neurotransmitters critical for such gene regulation are dopamine in interaction with glutamate, while other neurotransmitters (e.g., serotonin) play modulatory roles. This review presents (1) an overview of the main findings on cocaine- and amphetamine-induced gene regulation in corticostriatal circuits in an effort to provide a cellular framework for (2) an assessment of the molecular changes produced by methylphenidate, medical amphetamine (Adderall), and modafinil. The findings lead to the conclusion that protracted exposure to these cognitive enhancers can induce gene regulation effects in corticostriatal circuits that are qualitatively similar to those of cocaine and other amphetamines. These neuronal changes may contribute to the addiction liability of the psychostimulant cognitive enhancers.
PMCID: PMC3525776  PMID: 23085425
amphetamine; cocaine; cognitive enhancer; cortex; dopamine; gene regulation; methylphenidate; psychostimulant; striatum
16.  Prefrontal cortical and striatal transcriptional responses to the reinforcing effect of repeated methylphenidate treatment in the spontaneously hypertensive rat, animal model of attention-deficit/hyperactivity disorder (ADHD) 
Methylphenidate is the most commonly used stimulant drug for the treatment of attention-deficit/hyperactivity disorder (ADHD). Research has found that methylphenidate is a “reinforcer” and that individuals with ADHD also abuse this medication. Nevertheless, the molecular consequences of long-term recreational methylphenidate use or abuse in individuals with ADHD are not yet fully known.
Spontaneously hypertensive rats (SHR), the most validated and widely used ADHD animal model, were pretreated with methylphenidate (5 mg/kg, i.p.) during their adolescence (post-natal day [PND] 42–48) and tested for subsequent methylphenidate-induced conditioned place preference (CPP) and self-administration. Thereafter, the differentially expressed genes in the prefrontal cortex (PFC) and striatum of representative methylphenidate-treated SHRs, which showed CPP to and self-administration of methylphenidate, were analyzed.
Genome-wide transcriptome profiling analyses revealed 30 differentially expressed genes in the PFC, which include transcripts involved in apoptosis (e.g. S100a9, Angptl4, Nfkbia), transcription (Cebpb, Per3), and neuronal plasticity (Homer1, Jam2, Asap1). In contrast, 306 genes were differentially expressed in the striatum and among them, 252 were downregulated. The main functional categories overrepresented among the downregulated genes include those involved in cell adhesion (e.g. Pcdh10, Ctbbd1, Itgb6), positive regulation of apoptosis (Perp, Taf1, Api5), (Notch3, Nsbp1, Sik1), mitochondrion organization (Prps18c, Letm1, Uqcrc2), and ubiquitin-mediated proteolysis (Nedd4, Usp27x, Ube2d2).
Together, these changes indicate methylphenidate-induced neurotoxicity, altered synaptic and neuronal plasticity, energy metabolism and ubiquitin-dependent protein degradation in the brains of methylphenidate-treated SHRs, which showed methylphenidate CPP and self-administration. In addition, these findings may also reflect cognitive impairment associated with chronic methylphenidate use as demonstrated in preclinical studies. Future studies are warranted to determine the clinical significance of the present findings with regard to long-term recreational methylphenidate use or abuse in individuals with ADHD.
PMCID: PMC4077266  PMID: 24884696
Methylphenidate; ADHD; Gene expression; Addiction
17.  Potential Adverse Effects of Amphetamine Treatment on Brain and Behavior: A Review 
Molecular psychiatry  2008;14(2):123-142.
Amphetamine stimulants have been used medically since early in the twentieth century, but they have a high abuse potential and can be neurotoxic. Although they have long been used effectively to treat attention deficit hyperactivity disorder (ADHD) in children and adolescents, amphetamines are now being prescribed increasingly as maintenance therapy for ADHD and narcolepsy in adults, considerably extending the period of potential exposure. Effects of prolonged stimulant treatment have not been fully explored, and understanding such effects is a research priority 1. Because the pharmacokinetics of amphetamines differ between children and adults, reevaluation of the potential for adverse effects of chronic treatment of adults is essential.
Despite information on the effects of stimulants in laboratory animals, profound species differences in susceptibility to stimulant-induced neurotoxicity underscore the need for systematic studies of prolonged human exposure. Early amphetamine treatment has been linked to slowing in height and weight growth in some children. Because the number of prescriptions for amphetamines has increased several-fold over the past decade, an amphetamine-containing formulation is the most commonly prescribed stimulant in North America, and it is noteworthy that amphetamines are also the most abused prescription medications. Although early treatment does not increase risk for substance abuse, few studies have tracked the compliance and usage profiles of individuals who began amphetamine treatment as adults. Overall, there is concern about risk for slowed growth in young patients who are dosed continuously, and for substance abuse in patients first medicated in late adolescence or adulthood.
Although most adult patients also use amphetamines effectively and safely, occasional case reports indicate that prescription use can produce marked psychological adverse events, including stimulant-induced psychosis. Assessments of central toxicity and adverse psychological effects during late adulthood and senescence of adults who receive prolonged courses of amphetamine treatment are warranted. Finally, identification of the biological factors that confer risk and those that offer protection are also needed to better specify the parameters of safe, long-term, therapeutic administration of amphetamines to adults.
PMCID: PMC2670101  PMID: 18698321
amphetamine; methamphetamine; stimulant; ADHD; narcolepsy; drug abuse
18.  Methylphenidate increases cigarette smoking in participants with ADHD 
Psychopharmacology  2011;218(2):381-390.
Methylphenidate (Ritalin®) is commonly prescribed for behavioral problems associated with attention deficit/hyperactivity disorder (ADHD). The results of previous studies suggest that methylphenidate increases cigarette smoking in participants without psychiatric diagnoses. Whether methylphenidate increases cigarette smoking in participants diagnosed with ADHD is unknown.
In this within-subjects, repeated measures experiment, the acute effects of a range of doses of methylphenidate (10, 20, and 40 mg) and placebo were assessed in nine cigarette smokers who were not attempting to quit and met diagnostic criteria for ADHD but no other Axis I psychiatric disorders other than nicotine dependence.
Each dose of methylphenidate was tested once while placebo was tested twice. One hour after ingesting drug, participants were allowed to smoke ad libitum for 4 h. Measures of smoking included total cigarettes smoked, total puffs, and carbon monoxide levels. Snacks and decaffeinated drinks were available ad libitum; caloric intake during the 4-h smoking session was calculated.
Methylphenidate increased the total number of cigarettes smoked, total number of puffs, and carbon monoxide levels. Methylphenidate decreased the number of food items consumed and caloric intake.
The results of this experiment suggest that acutely administered methylphenidate increases cigarette smoking in participants with ADHD, which is concordant with findings from previous studies that tested healthy young adults. These data indicate that clinicians may need to consider non-stimulant options or counsel their patients before starting methylphenidate when managing ADHD-diagnosed individuals who smoke.
PMCID: PMC3189423  PMID: 21590284
Methylphenidate; Smoking; ADHD; Subjective effects; Humans
19.  A Post Hoc Comparison of the Effects of Lisdexamfetamine Dimesylate and Osmotic-Release Oral System Methylphenidate on Symptoms of Attention-Deficit Hyperactivity Disorder in Children and Adolescents 
CNS Drugs  2013;27(9):743-751.
There are limited head-to-head data comparing the efficacy of long-acting amfetamine- and methylphenidate-based psychostimulants as treatments for individuals with attention-deficit hyperactivity disorder (ADHD). This post hoc analysis provides the first parallel-group comparison of the effect of lisdexamfetamine dimesylate (lisdexamfetamine) and osmotic-release oral system methylphenidate (OROS-MPH) on symptoms of ADHD in children and adolescents.
Study Design
This was a post hoc analysis of a randomized, double-blind, parallel-group, dose-optimized, placebo-controlled, phase III study.
The phase III study was carried out in 48 centres across ten European countries.
The phase III study enrolled children and adolescents (aged 6–17 years) who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for a primary diagnosis of ADHD and who had a baseline ADHD Rating Scale IV (ADHD-RS-IV) total score of 28 or higher.
Eligible patients were randomized (1:1:1) to receive a once-daily, optimized dose of lisdexamfetamine (30, 50 or 70 mg/day), placebo or OROS-MPH (18, 36 or 54 mg/day) for 7 weeks.
Main Outcome Measures
In this post hoc analysis, efficacy was assessed using the ADHD-RS-IV and Clinical Global Impressions-Improvement (CGI-I) scale. Responders were defined as those achieving at least a 30 % reduction from baseline in ADHD-RS-IV total score and a CGI-I score of 1 (very much improved) or 2 (much improved). The proportion of patients achieving an ADHD-RS-IV total score less than or equal to the mean for their age (based on normative data) was also determined. Endpoint was the last on-treatment visit with a valid assessment. Safety assessments included treatment-emergent adverse events (TEAEs) and vital signs.
Of the 336 patients randomized, 332 were included in the safety population, 317 were included in the full analysis set and 196 completed the study. The mean (standard deviation) ADHD-RS-IV total score at baseline was 40.7 (7.31) for lisdexamfetamine, 41.0 (7.14) for placebo and 40.5 (6.72) for OROS-MPH. The least-squares (LS) mean change (standard error) in ADHD-RS-IV total score from baseline to endpoint was −24.3 (1.16) for lisdexamfetamine, −5.7 (1.13) for placebo and −18.7 (1.14) for OROS-MPH. The difference between lisdexamfetamine and OROS-MPH in LS mean change (95 % confidence interval [CI]) in ADHD-RS-IV total score from baseline to endpoint was statistically significant in favour of lisdexamfetamine (−5.6 [−8.4 to −2.7]; p < 0.001). The difference between lisdexamfetamine and OROS-MPH in the percentage of patients (95 % CI) with a CGI-I score of 1 or 2 at endpoint was 17.4 (5.0–29.8; p < 0.05; number needed to treat [NNT] 6), and the difference in the percentage of patients (95 % CI) achieving at least a 30 % reduction in ADHD-RS-IV total score and a CGI-I score of 1 or 2 was 18.3 (5.4–31.3; p < 0.05; NNT 6). The difference between lisdexamfetamine and OROS-MPH in the percentage of patients (95 % CI) with an ADHD-RS-IV total score less than or equal to the mean for their age at endpoint was 14.0 (0.6–27.4; p = 0.050). The overall frequency of TEAEs and the frequencies of decreased appetite, insomnia, decreased weight, nausea and anorexia TEAEs were greater in patients treated with lisdexamfetamine than in those treated with OROS-MPH, whereas headache and nasopharyngitis were more frequently reported in patients receiving OROS-MPH.
This post hoc analysis showed that, at the doses tested, patients treated with lisdexamfetamine showed statistically significantly greater improvement in symptoms of ADHD than those receiving OROS-MPH, as assessed using the ADHD-RS-IV and CGI-I. The safety profiles of lisdexamfetamine and OROS-MPH were consistent with the known effects of stimulant medications.
PMCID: PMC3751426  PMID: 23801529
20.  Meta-Analysis: Treatment of Attention-Deficit/Hyperactivity Disorder in Children With Comorbid Tic Disorders 
The Food and Drug Administration currently requires the package inserts of most psychostimulant medications to list the presence of a tic disorder as a contraindication to their use. Approximately half of children with Tourette’s syndrome experience comorbid attention-deficit/hyperactivity disorder (ADHD). We sought to determine the relative efficacy of different medications in treating ADHD and tic symptoms in children with both Tourette’s syndrome and ADHD.
We conducted a PubMed search to identify all double-blind, randomized, placebo-controlled trials examining the efficacy of medications in the treatment of ADHD in the children with comorbid tics. We used a random effects meta-analysis with standardized mean difference as our primary outcome to estimate the effect size of pharmaceutical agents in the treatment of ADHD symptoms and tics.
Our meta-analysis included nine studies involving 477 subjects. We assessed the efficacy of six medications—dextroamphetamine, methylphenidate, alpha-2 agonists (clonidine and guanfacine), desipramine, atomoxetine, and deprenyl. Methylphenidate, alpha-2 agonists, desipramine, and atomoxetine demonstrated efficacy in improving ADHD symptoms in children with comorbid tics. Alpha-2 agonists and atomoxetine significantly improved comorbid tic symptoms. Although there was evidence that supratherapeutic doses of dextroamphetamine worsens tics, there was no evidence that methylphenidate worsened tic severity in the short term.
Methylphenidate seems to offer the greatest and most immediate improvement of ADHD symptoms and does not seem to worsen tic symptoms. Alpha-2 agonists offer the best combined improvement in both tic and ADHD symptoms. Atomoxetine and desipramine offer additional evidence-based treatments of ADHD in children with comorbid tics. Supratherapeutic doses of dextroamphetamine should be avoided.
PMCID: PMC3943246  PMID: 19625978
tic disorders; attention-deficit/hyperactivity disorder; methylphenidate; α2 adrenergic agonists; meta-analysis
21.  Shopping Behavior for ADHD Drugs: Results of a Cohort Study in a Pharmacy Database 
Drugs in R&D  2014;14(3):205-211.
Attention-deficit hyperactivity disorder (ADHD) medications are subject to abuse, misuse, and diversion. Obtaining ADHD prescriptions from multiple prescribers or filled across multiple pharmacies, known as ‘doctor shopping’, may reflect such unsanctioned use. We sought to create a definition of shopping behavior that differentiated ADHD medications from medications with low risk of diversion, i.e. asthma medications, and describe the incidence, frequency, and demography of shopping behavior.
This was a retrospective cohort study in a pharmacy database—LRx—covering 65 % of US retail pharmacies. Subjects had ADHD or asthma medication dispensed between February 2011 and January 2012. We followed subjects for 18 months to assess the number with overlapping dispensings from different prescribers, and the number of prescribers and pharmacies involved in those dispensings.
We included 4,402,464 subjects who were dispensed ADHD medications, and 6,128,025 subjects who were dispensed asthma medications. Overlapping prescriptions from two or more prescribers dispensed by three or more pharmacies was four times more frequent in the ADHD cohort than in the asthma cohort. Using this definition, ADHD medication shopping behavior was more common among experienced users than naïve users, and was most common in subjects aged 10–39 years. Among subjects who shopped, 57.4 % shopped only once (accounting for 22.4 % of episodes), and 9.2 % shopped six or more times (accounting for 42.0 % of episodes). Shoppers more often received stimulant ADHD drugs than non-stimulants.
Overlapping prescriptions by different prescribers and filled at three or more pharmacies defines ADHD medication shopping. Shopping behavior is most common in adolescents and younger adults. A small proportion of shoppers is responsible for a large number of shopping episodes.
PMCID: PMC4153965  PMID: 25118848
22.  Shopping Behavior for ADHD Drugs: Results of a Cohort Study in a Pharmacy Database 
Drugs in R&D  2014;14(3):205-211.
Attention-deficit hyperactivity disorder (ADHD) medications are subject to abuse, misuse, and diversion. Obtaining ADHD prescriptions from multiple prescribers or filled across multiple pharmacies, known as ‘doctor shopping’, may reflect such unsanctioned use. We sought to create a definition of shopping behavior that differentiated ADHD medications from medications with low risk of diversion, i.e. asthma medications, and describe the incidence, frequency, and demography of shopping behavior.
This was a retrospective cohort study in a pharmacy database—LRx—covering 65 % of US retail pharmacies. Subjects had ADHD or asthma medication dispensed between February 2011 and January 2012. We followed subjects for 18 months to assess the number with overlapping dispensings from different prescribers, and the number of prescribers and pharmacies involved in those dispensings.
We included 4,402,464 subjects who were dispensed ADHD medications, and 6,128,025 subjects who were dispensed asthma medications. Overlapping prescriptions from two or more prescribers dispensed by three or more pharmacies was four times more frequent in the ADHD cohort than in the asthma cohort. Using this definition, ADHD medication shopping behavior was more common among experienced users than naïve users, and was most common in subjects aged 10–39 years. Among subjects who shopped, 57.4 % shopped only once (accounting for 22.4 % of episodes), and 9.2 % shopped six or more times (accounting for 42.0 % of episodes). Shoppers more often received stimulant ADHD drugs than non-stimulants.
Overlapping prescriptions by different prescribers and filled at three or more pharmacies defines ADHD medication shopping. Shopping behavior is most common in adolescents and younger adults. A small proportion of shoppers is responsible for a large number of shopping episodes.
PMCID: PMC4153965  PMID: 25118848
23.  Attention deficit/hyperactivity disorders with co-existing substance use disorder is characterized by early antisocial behaviour and poor cognitive skills 
BMC Psychiatry  2013;13:336.
Attention Deficit/Hyperactivity Disorder (ADHD) is associated with an increased risk of co-existing substance abuse. The Swedish legislation on compulsory healthcare can be applied to persons with severe substance abuse who can be treated involuntarily during a period of six months. This context enables a reliable clinical assessment of ADHD in individuals with severe substance use disorder (SUD).
In the context of compulsory care for individuals with severe SUD, male patients were assessed for ADHD, co-morbid psychiatric symptoms, psychosocial background, treatment history, and cognition. The data from the ADHD/SUD group (n = 60) was compared with data from (1) a group of individuals with severe substance abuse without known ADHD (SUD group, n = 120), as well as (2) a group with ADHD from an outpatient psychiatric clinic (ADHD/Psych group, n = 107).
Compared to the general SUD group in compulsory care, the ADHD/SUD group had already been significantly more often in compulsory care during childhood or adolescence, as well as imprisoned more often as adults. The most common preferred abused substance in the ADHD/SUD group was stimulant drugs, while alcohol and benzodiazepine abuse was more usual in the general SUD group. Compared to the ADHD/Psych group, the ADHD/SUD group reported more ADHD symptoms during childhood and performed poorer on all tests of general intellectual ability and executive functions.
The clinical characteristics of the ADHD/SUD group differed from those of both the SUD group and the ADHD/Psych group in several respects, indicating that ADHD in combination with SUD is a particularly disabling condition. The combination of severe substance abuse, poor general cognitive ability, severe psychosocial problems, including indications of antisocial behaviour, and other co-existing psychiatric conditions should be considered in treatment planning for adults with ADHD and SUD.
PMCID: PMC3878757  PMID: 24330331
ADHD; SUD; Co-morbidity; Compulsory care; Adults; Cognition
24.  Focus on Lisdexamfetamine: A Review of its use in Child and Adolescent Psychiatry 
To summarize and review published literature regarding lisdexamfetamine and its use in child and adolescent psychiatry.
A literature review was conducted using the PubMed search term: ‘lisdexamfetamine’ with limits: Human trials, English language, All Child (aged 0–18 years). Additional articles were identified from reference information and poster presentation data.
Lisdexamfetamine (Vyvanse®) is a prodrug formulation of dextroamphetamine used for the treatment of Attention Deficit/Hyperactivity Disorder (ADHD). Conversion of lisdexamfetamine to active dextroamphetamine occurs via hydrolytic enzymes located on erythrocytes, and leads to an onset of action within 1–2 hours post-dose, and duration of up to 13 hours. Administration of lisdexamfetamine via nasal or intravenous routes did not result in significant elevation of drug liking scores in known stimulant abusers, suggesting low potential for abuse. Lisdexamfetamine has been available in the United States since 2007, but was only recently approved by Health Canada for use in children 6 to 12 years of age. There are five randomized controlled trials with lisdexamfetamine in children and adolescents showing efficacy for treatment of ADHD. In addition, several open-label trials and case reports were identified. The adverse effect profile of lisdexamfetamine is similar to that observed with other long-acting amphetamine formulations.
Lisdexamfetamine is a novel long-acting stimulant formulation with efficacy for treatment of ADHD and low abuse potential due to its prodrug formulation.
PMCID: PMC2962544  PMID: 21037922
lisdexamfetamine; ADHD; amphetamine; stimulants; attention deficit; hyperactivity; substance abuse
25.  Impact of methylphenidate formulation on treatment patterns and hospitalizations: a retrospective analysis 
While stimulant therapy has been shown to be effective in the treatment of attention-deficit/hyperactivity disorder (ADHD), there is less information concerning differences between alternative stimulant medications. The purpose of this study is to examine how different formulations of methylphenidate (MPH) affect treatment patterns and hospitalizations.
From a large claims database we retrospectively identified individuals age 6 or older who were diagnosed with ADHD and who received either once daily, extended-release oral system methylphenidate (OROS® MPH) (e.g., Concerta®) or three-times daily immediate-release generic methylphenidate (TID MPH). There were 5,939 individuals included in the analysis – 4,785 who initiated therapy with OROS MPH and 1,154 who initiated therapy with TID MPH. We used Analyses of Covariance (ANCOVAs) to examine differences in treatment patterns between individuals who initiated therapy on OROS MPH and those who initiated therapy on TID MPH. We used logistic and negative binomial multivariate regressions to examine the probability of being hospitalized and the hospital length of stay.
Controlling for demographic characteristics, patient general health status, and comorbid diagnoses, significantly fewer individuals who initiated therapy with OROS MPH had a 15-day gap in therapy (85% vs. 97%, p < 0.0001 or a 30-day gap in therapy (77% vs. 95%, p < 0.0001) or switched to another ADHD medication (27% vs. 68%, p < 0.0001). Individuals who initiated therapy with OROS MPH stayed on therapy significantly longer (199 vs. 108 mean days, p < 0.0001) and more individuals received medication for 90% (24% vs. 5%, p < 0.0001), 80% (29% vs. 7%, p < 0.0001), or 75% (30% vs. 7%, p < 0.0001) of the days during the first year post initiation of therapy. Individuals who initiated therapy on OROS MPH were also significantly less likely to be hospitalized (odds ratio = 0.67, p = 0.0454) and stayed, on average, 0.69 fewer days in the hospital (p = 0.0035).
Results demonstrate that among individuals diagnosed with ADHD who receive either OROS MPH or TID MPH, the use of OROS MPH is associated with fewer gaps in medication, less switches in medication, and more days on intent-to-treat therapy. In addition, use of OROS MPH compared to TID MPH was associated with improved outcomes, as measured by the reduced use of hospitalizations.
PMCID: PMC1462992  PMID: 16606463

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