Methylphenidate off-label use and safety
© Trenque et al.; licensee Springer. 2014
Received: 10 February 2014
Accepted: 25 May 2014
Published: 7 June 2014
Methylphenidate is a piperidine derivative structurally and pharmacologically similar to amphetamine. Methylphenidate is indicated for Attention Deficit Hyperactivity Disorder (ADHD) in children aged 6 years of age and over when remedial measures alone prove insufficient. In adults, its indication, except in narcolepsy, is not defined. Methylphenidate received regulatory approval almost sixty years ago with a first registration in Switzerland in October 1954.
To evaluate the off-label use of methylphenidate and its characteristics from a database of spontaneous reports.
This study analysed data from the French Pharmacovigilance Database of adverse drug reactions spontaneously reported by health professionals from 1985 to December 2011. Off-label use was evaluated according to age.
In the French Pharmacovigilance database, 181 cases of adverse drug reactions were reported with methylphenidate. Neuropsychiatric effects were the most frequent adverse event reported (41%) followed by cardiovascular and cutaneous side effects (14%). 143 reports concerned children (113 boys, 30 girls, mean age 10.6 ± 3.3 years) of which 46 (30%) were off-label uses. There were 38 adults (20 men, 18 women), of which 32 (88%) off-label use. In adults, methylphenidate was prescribed for depression, and this practice was associated with serious adverse events of drug dependence, overdose and suicide attempt. Overall, off-label use was detected in 43% (78/181) of all cases reported.
More than 40% of the patients with drug reactions received methylphenidate for off-label indications. Additional long-term exposures and independent clinical studies are necessary to establish the long-term profile safety of methylphenidate.
Methylphenidate hydrochloride [(dl-threo-methyl-2-phenyl-2-(2-piperidyl) acetate] is a central nervous system stimulant derived from piperidine that is structurally similar to amphetamine, and acts as a norepinephrine - dopamine reuptake inhibitor. It increases dopaminergic neurotransmission, particularly at the striatal and frontal levels, by inhibiting presynaptic dopamine transporters. By blocking reuptake of noradrenaline and dopamine at the level of the presynaptic neuron, it increases the release of these monoamines at the level of the synaptic cleft. The effect of methyphenidate is mediated by blocking the Dopamine Transporter (DAT), which increases the synaptic concentration of dopamine (Volkow et al.2002), known to be a key neuromodulating agent. The ultimate result is increased attention, motor function and memory. Despite the extensive literature investigating methylphenidate, its mode of action and its effects, the exact mechanism of its therapeutic action remains unclear.
Methylphenidate is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD), one of the most common psychiatric disorders diagnosed in children (Scahill and Schwab-Stone2000). It was first registered under the brand name Ritalin® in Switzerland almost sixty years ago.
In France, it is available in both immediate release (Ritaline® 10 mg), and sustained release forms (Ritaline LP®, Quasym® and Concerta®). The immediate release form is also indicated for adults with narcolepsy. For all forms of methylphenidate, it is recommended not to exceed 60 mg per day. Methylphenidate is indicated as a part of a comprehensive treatment programme for ADHD in children aged 6 years and over, when remedial measures alone prove insufficient. Treatment must be under the supervision of a specialist in childhood behavioural disorders, and the diagnosis should be made according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (American Psychiatric Association2000) criteria or the International Classification of Diseases release 10 (ICD10). A comprehensive treatment programme typically includes psychological, educational, and social measures.
In France, methylphenidate is listed as a narcotic and has restrictive conditions of prescription and dispensing. The initial prescription must be signed by a hospital neurologist, psychiatrist or paediatrician on a specific form for scheduled drugs, and prescription duration is limited to twenty-eight days. The prescription can be renewed by any other physician for a maximum of one year, but the dose and quantity prescribed by the initial hospital-based physician cannot be changed. Moreover, pharmacies are only allowed to dispense methylphenidate on presentation of the two prescriptions, namely the initial hospital prescription and the renewal prescription. A contract of care is established between the pharmacist, the practitioner, and the patient. The names of the three individuals are listed on the renewal prescription, and the diagnosis must be re-evaluated each year by the specialist.
Despite the limited indications, and the stringent conditions of its prescription and dispensing, off-label use of methylphenidate exists. The guidelines of the European Medicines Agency define off-label use as “medicinal product intentionally used for a medical purpose not in accordance with the authorised product information” (European Medicines Agency2012). In this context, we aimed to evaluate the off-label use of methylphenidate, and describe the features of off-label use from a database of spontaneous reports for methylphenidate in France.
This study used data from the French National Pharmacovigilance Database of all Adverse Drug Reactions (ADRs) spontaneously reported with commercially approved drugs in France. This database was established in 1985 to register all ADRs spontaneously reported by health professionals to the French Pharmacovigilance System, but not those reported to manufacturers. The national database includes data from 31 regional pharmacovigilance centres. Reports are reviewed by medically qualified personnel in the regional centres before being entered into the national database. ADRs are coded according to the Medical Dictionary for Regulatory Activities (MedDRA®, version 12.1) (Brown and Sexson1988).
Seriousness of the reaction is also recorded in the Pharmacovigilance database: ADRs are considered serious when they result in death, are life-threatening, require patient hospitalisation or prolongation of existing hospitalisation, or any reaction that results in persistent or significant disability or incapacity, congenital anomaly or birth defect. All other ADRs are considered non-serious (European Medicines Agency2012).
all patients below six years of age treated with methylphenidate were considered as off-label use,
all adults (18 years and above) treated with methylphenidate for indications other than narcolepsy were considered as off-label use,
for narcolepsy, only the immediate-release form (Ritaline®) is approved for use in adults.
intentional drug misuse
For each case reported, we recorded the patient’s characteristics (age, gender, and underlying disease), prescription data (dose, dosage, indication) and the characteristics of the ADR (clinical symptoms, seriousness, mean onset delay, course, outcome). The data in the French Pharmacovigilance Database are anonymous. The study got the approval of the Institutional Review Board of the University Hospitals of Reims.
From 1 January 1985 to 31 December 2011, in the French National Pharmacovigilance database, 181 spontaneous reports were collected citing methylphenidate as the culprit drug. Among these, 78 (43%) were considered to be off-label uses of the drug.
Overall, 143 children were involved (113 boys, 30 girls), mean age 10 years, of which 46 (32%) were off-label use. In children, when used in accordance with its indications, serious adverse effects represented 31.3% of all spontaneous ADRs, and 43% of the spontaneous reports in the context of off-label use.
For patients aged <6 years, the main indications for prescribing methylphenidate were ADHD, autism and psychomotor activity. In the 6–18 year age group, the off-label indications for methylphenidate prescription were: behavioural disorders (38%), narcolepsy (Concerta®) (13%), instability (19%), autism (13%) and intellectual disability (8.8%).
Off-label uses of the drug, with presence of a contraindication, were observed in 9 cases (i.e. 20% of off-label use in children) (child aged <6 years, n = 6; prior history of epilepsy, n = 3).
In adults, the main indications for prescription of methylphenidate were: ADHD (n = 5), representing 13% of spontaneous reports in adults; narcolepsy-hypersomnia (n = 5, 13%); depression (n = 2, 5%) and Parkinson’s disease (n = 2, 5%).
Neuropsychiatric effects were the most frequent event reported, followed by cardiovascular and cutaneous side effects, both reported in 13.3% of cases.
Muscular effects were reported in 7.2%, and misuse represented 5.5% of ADRs. Lesions, intoxication and procedural complications represented 4.4% of cases; intestinal, hepatobiliary and haematological effects in 3%; urological, dental or ear-nose-throat effects, as well as biological modifications were rare (<1%).
In our study, we investigated prescriptions of methylphenidate outside of the described product characteristics, using data from the French National Pharmacovigilance Database. Despite very restrictive conditions for its prescription in France, over 40% of the spontaneous ADRs with methylphenidate could be considered as off-label use (age <6 years, or prescription in adults outside of the only approved indication, namely narcolepsy). The ADRs observed were more often classed as serious when the use was off-label.
In our study, we chose to take into account only the criteria based on age and indication, as this information is generally always recorded in pharmacovigilance databases. Thus, it is likely that the high rate of off-label use observed is actually an under-estimation of the true rate.
Possible sources for identifying off-label prescriptions are manifold, but unfortunately, not well structured. First among these sources are the pharmacovigilance databases, but other sources are also available, such as hospital databases, sales information or marketing studies, and data on reimbursement of medications through the social security system. The data from our study were taken only from the French National Pharmacovigilance Database. Spontaneous reporting systems are associated with under-reporting. The tendency of physicians to under-report is heightened by the fear of revealing an off-label (unapproved) use of the drug (Inman1996).
The motives for prescription of methylphenidate in adults varied widely in this study, with prescription for ADHD representing only 1/6 of all reports. The use of methylphenidate in adults is not codified, and there are currently almost 300 studies ongoing with this drug (http://clinicaltrials.gov, accessed 23/08/2013).
Among psychiatric drugs, off-label use is reportedly as high as 31% (Radley et al.2006).
Identifying off-label use is difficult, as this is not a specific item in databases that record ADRs. In addition, off-label use is legal in many countries, including the USA, and thus, in such cases, there would be no particular justification for noting whether use was on- or off-label. In France, off-label use is wholly under the responsibility of the prescriber. Off-label prescribing is not uncommon, and one third of chemotherapies used to fight cancer are reportedly prescribed “off-label” (Conti et al.2013). Similarly, in the United States, one report estimated that over 20% of prescriptions were to treat diseases or conditions in non-FDA approved indications (Radley et al.2006). In theory, the pharmaceutical industry cannot encourage or promote off-label use of its products. However, in December 2012, an American circuit court considered that in accordance with the first Amendment to the Constitution of the United States of America, every individual has the right to freedom of speech, and off-label marketing was considered to fall into this category (off-label Drug Marketing is “Free Speech” Court Rules - ABC News Retrieved 10 December 2012).
Methylphenidate is approved for the treatment of ADHD. However, the diagnosis of ADHD is controversial due to the existence of two different classification systems, namely the International Classification of Mental and Behavioural Disorders 10th revision (ICD10), and the Diagnosis and Statistical Manual Mental Disorders 4th edition (DSM-IV), used as the reference in the labelling. The ICD10 is published by the World Health Organization to track morbidity and mortality statistics for all diseases. The DSM-IV is developed by American physicians and used as a classification for mental disorders.
These two classifications differ considerably in the diagnostic criteria used to qualify ADHD, with reported agreement of only 68% (Andrews et al.1999). For the diagnosis of ADHD, the ICD10 classification is more restrictive in four ways. Firstly, it requires that symptoms appear before the age of 6 years. Second, it prohibits the diagnosis when the patient has anxiety, mood disorders, or schizophrenia, which is a restriction not imposed by the DSM-IV classification. Third, the ICD10 diagnosis requires that the inattention be directly observed by the clinician. Finally, the DSM-IV allows clinicians to make a diagnosis of ADHD even if the child fails to manifest all the required symptoms, whereas the ICD10 classification does not. Lahey et al. (2006) reported that only 26% of children with a diagnosis of ADHD according to the DSM-IV system actually met the ICD10 criteria, and Lee et al. (2008) reported an even lower rate, at only 11%. Accordingly, studies based on the DSM-IV indicate prevalence rates of ADHD between 5% and 12%, compared with ICD10 rates between 0.5% and 5% (Skounti et al.2007). Therefore, it is clear that off-label use is difficult to define and identify. Accordingly, we chose age limit as a criterion to define off-label use, as this parameter is independent of the different classification systems.
To date, the new, updated DSM-V classification (American Psychiatric Association2013) has not yet been integrated into the regulatory indications for the use of methylphenidate. This new classification widens the diagnostic criteria for ADHD as compared to the previous version, by requiring only that symptoms appear before the age of 12 years, instead of 6 years. The patient must present signs of inattention and/or hyperactivity. Each item is characterised by 9 criteria, of which 6 must be present in children and only 5 in adults (>17 years) in order for the diagnosis to be made. In practical terms therefore, the population potentially meeting these new criteria is considerably widened, and if these new criteria are integrated into the prescription indications for methylphenidate, then off-label use will become exceedingly difficult to detect. Such a wide potential target population for methylphenidate use is cause for concern. Off-label use of the drug in the adult population will not be resolved by uptake of the new definition into the labelling and product characteristics. Indeed, our study shows that there is considerable use of methylphenidate in indications other than ADHD.
Despite being on the market for almost 60 years, the tolerance of methylphenidate has never been studied in detail. One study from the UK Medicines and Healthcare products Regulatory Agency, which collects suspected drug reactions in patients aged <17 years, reported that, excluding vaccines, methylphenidate was the medication most commonly associated with adverse reactions in children (Hawcutt et al.2012). The long term safety of methylphenidate use is poorly documented. For example, the long term implications of continuous treatment from childhood to adulthood in terms of height, or long term changes in the brain are unknown. The cardiotoxicity of methylphenidate, in terms of tachycardia, hypertension, or potential valvulopathy, remains debated in the literature. Indeed, methylphenidate has been shown in vitro to bind to the 5-hydroxytryptamine (HT) receptor 2B (Markowitz et al.2006), and activation of these receptors has previously been shown to be involved in the development of valvular heart disease (Andrejak and Tribouilloy2013; Huang et al.2009). While binding affinity has been demonstrated, the pharmacological effects (notably agonist or antagonist activity) must be elucidated. This potentially harmful effect warrants close surveillance. Preliminary findings suggest that methylphenidate exerts binding activity as an agonist of 5HT receptor 1A (Markowitz et al.2009).
Pulmonary hypertension has also previously been alleged to result from treatment with CNS stimulant drugs. In 1972, Lewman (1972) published a case report of death occurring in a patient aged 30 years, who was a drug addict taking barbiturates, amphetamines, LSD and marijuana for 7 years. Under methadone treatment, the patient injected methylphenidate intravenously (Ritaline®), at a rate of 5 tablets per day for 7 months. The patient developed pulmonary hypertension and subsequently died, and significant pulmonary granulomatosis was observed at autopsy. More recently, Karaman et al. (2010) similarly reported pulmonary hypertension occurring in a patient aged 15 years, with clinical signs appearing only four days after initiation of methylphenidate therapy. Classically, methylphenidate is classed among the drugs likely to induce cardiomyopathies (Figueredo2011; Henderson and Fischer1995), with numerous reports published in the literature (Dadfarmay and Dixon2009; Fischer and Baner1977; Nymark et al.2008; Tollofsrud and Hoel2006).
A recent report by Schelleman et al. (2012) found a 1.8-fold increase in the risk of sudden death or ventricular arrhythmia, and a 1.7-fold increase in the risk of all-cause death in almost 44,000 new users of methylphenidate. However, the indications for treatment were not reported, and patients were only followed for 60 days. In a retrospective cohort of >800,000 adults aged 25 to 64 years, Habel et al. (2011) failed to find any increase in cardiovascular risk in users of ADHD medications (methylphenidate, amphetamine and atomoxetine) as compared to matched non-user controls. However, a meta-analysis by Mick et al. (2013) reported a statistically significant increased risk of high (>90 bmp) resting heart rate in adult ADHD patients treated with CNS stimulants, and these findings have been confirmed in recent studies (Vitiello et al.2012; Ginsberg and Lindefors2012). In paediatric populations, several reports have failed to observe any increased risk of cardiovascular events with methylphenidate in children and youths treated for ADHD (Schelleman et al.2011; Winterstein et al.2012; Olfson et al.2012).
Results are globally quite reassuring, despite individual reports of negative effects in adults (Schelleman et al.2012; Gould et al.2009). In addition, 3 cases of heart failure in young adults have recently been reported (Wikstrom et al.2012). Methodological biases are present in many of the studies reported heretofore, including short follow-up, high rate of patients lost to follow-up, lack of observational data from real-life practice (Molina et al.2009; Wilens et al.2003; Fredriksen et al.2013).
Fredriksen et al. (2013) performed a meta-analysis of long-term studies (8 studies in total) with follow-up of minimum 6 months, and maximum 1 year. The most recent study, by Ginsberg and Lindefors (2012) was performed in 30 prison inmates with follow-up of 52 weeks. This study confirmed an increase in systolic and diastolic blood pressure under treatment (systolic blood pressure +21 mmHg and diastolic blood pressure +11 mmHg).
The lack of pharmacoepidemiological data on the effects of long-term administration of methylphenidate, in terms of cardiovascular or cerebrovascular risk, impact on growth, risk of cancer, or other risks, is an issue that has often been raised in recent years.
The risk of sudden death in children and adolescents is very low, underlining the need for studies to encompass very large sample sizes.
A case–control study performed by Gould et al. (2009) on mortality data from 1985–1996 in the USA among children aged 7 to 19 years of age, showed an association between the use of psychostimulants and sudden death in children and adolescents, with a relative risk of 7. However, the methodology of this study has come in for some criticism.
Data from the WHO for the period 1999–2003 report the occurrence of 25 sudden deaths under psychostimulants, of which 8 were with methylphenidate (7 children, 1 adult) (Wilens et al.2006).
On 1 November 2011, the FDA published a statement for the general public emphasizing the absence of any relation between the use of psychostimulant drugs for the treatment of ADHD, and the appearance of adverse cardiovascular effects. A study by Cooper et al. (2011) that included 1,200,438 children and young adults aged 2 to 24 years undergoing treatment, corresponding to a follow-up of 2,579,104 person-years, reported a rate of 3.1 serious cardiovascular events per 100,000 patient-years. The authors concluded that there was no evidence that the use of ADHD drugs was associated with an increased risk of serious cardiovascular events. The methods and conclusions of this study are at odds with those of the study by Gould et al. (2009) showing an association between use of psychostimulants and risk of sudden death in children and adolescents, hence the call from the FDA to adhere strictly to prescription recommendations.
Through its amphetamine-like properties, methylphenidate also exerts anorexigenic effects. In the UK pharmacovigilance database, anorexia is the most frequently reported side effect in children treated for ADHD, representing 34% of all reports (Tobaiqy et al.2011). These findings confirm reports from the WHO’s Vigibase database indicating that in the 2–11 year age group, ADHD drugs account for 14% of reports, with anorexia cited most often (Star et al.2011). Non-medical use of methylphenidate in this context should be monitored, as it is possible that some subjects take it to induce weight loss. The amphetamine-like effect is primarily expressed as increased aggression, which is the most frequently reported adverse effect in the 12–17 year age group (Star et al.2011; Harty et al.2009).
Methylphenidate has also been shown to have teratogenic effects in animal studies, with reported anomalies of the skeleton, including spina bifida in rabbits, and behavioural disorders in the progeniture of mice treated during pregnancy with 4 times the maximum recommended dose for humans (Chapin1997; McFadyen-Leussis et al.2004). Methylphenidate administration in a rodent model of ADHD showed that treatment in adolescent rats enhanced cocaine self-administration during adulthood (Somkuwar et al.2013). The effects of methylphenidate on the reproductive system are unclear. One study in an animal model found a reduction in testosterone levels in male mice, associated with a reduction in the number of Leydig cells (Fazelipour et al.2012). In the absence of robust assessments of the teratogenic potential of methylphenidate, prescription its prescription in pregnant women should be contraindicated.
Although ADHD has been recognised as a distinct pathological entity in children since the 19th century, it was only described in adults in the 1970s (Wood et al.1976), providing the impetus for wider methylphenidate use in adults.
The definition of adult ADHD is the subject of some controversy, with various studies have attempted to describe the persistence of ADHD symptoms in adolescence and adulthood (Barkley et al.2002; Kessler et al.2005a,[b],2006). Several authors purport that adults can present ADHD (Davidson2008; Faraone et al.2004; Newcorn et al.2007; Spencer et al.1994,1995) and the diagnosis is associated with a prior history of ADHD in childhood. The diagnosis is based on the same DSM-IV criteria that are applied in children (Biederman et al.2006; Faraone and Biederman2005), thus rendering diagnosis difficult. Various diagnostic scores are under study for the specific diagnosis of adult ADHD, such as the Copeland Symptom Cheklist for Adult Attention Deficit Disorders, Wechsler Adult Intelligence Scale, ADHD Self-report Scale-version 1.1 (ASRS-v1.1), Current Symptoms Scale, Wender Utah Rating Scale (WUTS), Brown Attention-Deficit Disorder Rating Scale for Adults (Davidson2008), as well as neuropsychological tests focusing on attention and learning (Fargason and Ford1994). The myriad scales available for the diagnosis of ADHD in adults reflect the difficulty physicians encounter in this context (Riccio et al.2005). It should be noted that, to date, methylphenidate is not approved for the treatment of ADHD in adult populations in France or elsewhere.
Despite restricted conditions for the prescription of methylphenidate in France, we observed a progressive increase in the number of spontaneous reports of ADRs, with a high proportion of off-label use, in a national pharmacovigilance database. In half the reports where the use was considered to be off-label, the ADR was classed as serious. The widespread use of methylphenidate in adults is a cause for concern. The diagnosis of adult ADHD remains imprecise, and methylphenidate is not indicated in this context at the present time. The profile of side effects appears to differ between adult and paediatric populations, with greater risk of misuse, increased doses, probable cardiovascular effects and disinhibition in adult users. The use of methylphenidate in women aged >18 years incurs a risk of exposition during pregnancy, with potential teratogenic effects. In view of the numerous questions that remain unanswered regarding tolerance of this drug in the long term, its use should be strictly reserved to the approved indications, with evaluation of the risk-benefit ratio on a case-by-case basis. Closely monitoring of methylphenidate prescription practices by the regulatory health authorities is warranted.
Despite being on the market for several decades, the tolerance and mechanisms of action of methylphenidate are still under study. Additional long-term exposures and independent clinical studies are necessary to establish the long-term profile safety of methylphenidate.
The authors would like to thank all 31 regional centres of the French Pharmacovigilance System and to Fiona Ecarnot for translation and editorial assistance.
The manuscript does not contain clinical studies or patient data.
- American Psychiatric Association: Diagnostic and statistical manual of mental disorders, 4th edition, text revision: DSM-IV-TR. American Psychiatric Association, Washington, DC; 2000.View ArticleGoogle Scholar
- American Psychiatric Association: Diagnostic and statistical manual of mental disorders DSM-V. 5th edition. American Psychiatric Association, Washington; 2013.Google Scholar
- Andrejak M, Tribouilloy C: Drug-induced valvular heart disease: an update. Arch Cardiovasc Dis 2013, 106: 333-339. 10.1016/j.acvd.2013.02.003View ArticleGoogle Scholar
- Andrews G, Slade T, Peters L: Classification in psychiatry: ICD-10 versus DSM-IV. Br J Psychiatry 1999, 174: 3-5. 10.1192/bjp.174.1.3View ArticleGoogle Scholar
- Barkley RA, Fischer M, Smallish L, Fletcher K: The persistence of attention-deficit/hyperactivity disorder into young adulthood as a function of reporting source and definition of disorder. J Abnorm Psychol 2002, 111: 279-289.View ArticleGoogle Scholar
- Biederman J, Mick E, Surman C, Doyle R, Hammerness P, Harpold T, Dunkel S, Dougherty M, Aleardi M, Spencer T: A randomized, placebo-controlled trial of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry 2006, 59: 829-835. 10.1016/j.biopsych.2005.09.011View ArticleGoogle Scholar
- Brown RT, Sexson SB: A controlled trial of methylphenidate in black adolescents. Attentional, behavioral, and physiological effects. Clin Pediatr (Phila) 1988, 27: 74-81. 10.1177/000992288802700204View ArticleGoogle Scholar
- Chapin R: Methylphenidate hydrochloride. Environ Health Perspect 1997, 105(1):319-320.Google Scholar
- Conti RM, Bernstein AC, Villaflor VM, Schilsky RL, Rosenthal MB, Bach PB: Prevalence of off-label use and spending in 2010 among patent-protected chemotherapies in a population-based cohort of medical oncologists. J Clin Oncol 2013, 31: 1134-1139. 10.1200/JCO.2012.42.7252View ArticleGoogle Scholar
- Cooper WO, Habel LA, Sox CM, Chan KA, Arbogast PG, Cheetham TC, Murray KT, Quinn VP, Stein CM, Callahan ST, Fireman BH, Fish FA, Kirshner HS, O'Duffy A, Connell FA, Ray WA: ADHD drugs and serious cardiovascular events in children and young adults. N Engl J Med 2011, 365: 1896-1904. 10.1056/NEJMoa1110212View ArticleGoogle Scholar
- Dadfarmay S, Dixon J: A case of acute cardiomyopathy and pericarditis associated with methylphenidate. Cardiovasc Toxicol 2009, 9: 49-52. 10.1007/s12012-009-9033-7View ArticleGoogle Scholar
- Davidson MA: ADHD in adults: a review of the literature. J Atten Disord 2008, 11: 628-641.View ArticleGoogle Scholar
- European Medicines Agency: Guideline on good pharmacovigilance practices (GVP). Module V - risk management systems. 2012. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=search.jsp%26q=GVP+module+V%26btnG=Search%26mid=Google Scholar
- Faraone SV, Biederman J: What is the prevalence of adult ADHD? Results of a population screen of 966 adults. J Atten Disord 2005, 9: 384-391. 10.1177/1087054705281478View ArticleGoogle Scholar
- Faraone SV, Spencer T, Aleardi M, Pagano C, Biederman J: Meta-analysis of the efficacy of methylphenidate for treating adult attention-deficit/hyperactivity disorder - Abstract. J Clin Psychopharmacol 2004, 24: 24-29. 10.1097/01.jcp.0000108984.11879.95View ArticleGoogle Scholar
- Fargason RE, Ford CV: Attention deficit hyperactivity disorder in adults: diagnosis, treatment, and prognosis. South Med J 1994, 87: 302-309. 10.1097/00007611-199403000-00002View ArticleGoogle Scholar
- Fazelipour S, Hadipour Jahromy M, Tootian Z, Kiaei SB, Sheibani MT, Talaee N: The effect of chronic administration of methylphenidate on morphometric parameters of testes and fertility in male mice. J Reprod Infertil 2012, 13: 232-236.Google Scholar
- Figueredo VM: Chemical cardiomyopathies: the negative effects of medications and nonprescribed drugs on the heart. Am J Med 2011, 124: 480-488. 10.1016/j.amjmed.2010.11.031View ArticleGoogle Scholar
- Fischer VW, Baner H: Cardiomyopathic findings associated with methylphenidate. JAMA 1977, 238: 1497. 10.1001/jama.1977.03280150067014View ArticleGoogle Scholar
- Frauger E, Pauly V, Natali F, Pradel V, Reggio P, Coudert H, Thirion X, Micallef J: Patterns of methylphenidate use and assessment of its abuse and diversion in two French administrative areas using a proxy of deviant behaviour determined from a reimbursement database: main trends from 2005 to 2008. CNS Drugs 2011, 25: 415-424. 10.2165/11587640-000000000-00000View ArticleGoogle Scholar
- Fredriksen M, Halmoy A, Faraone SV, Haavik J: Long-term efficacy and safety of treatment with stimulants and atomoxetine in adult ADHD: a review of controlled and naturalistic studies. Eur Neuropsychopharmacol 2013, 23: 508-527. 10.1016/j.euroneuro.2012.07.016View ArticleGoogle Scholar
- Ginsberg Y, Lindefors N: Methylphenidate treatment of adult male prison inmates with attention-deficit hyperactivity disorder: randomised double-blind placebo-controlled trial with open-label extension. Br J Psychiatry 2012, 200: 68-73. 10.1192/bjp.bp.111.092940View ArticleGoogle Scholar
- Gould MS, Walsh BT, Munfakh JL, Kleinman M, Duan N, Olfson M, Greenhill L, Cooper T: Sudden death and use of stimulant medications in youths. Am J Psychiatry 2009, 166: 992-1001. 10.1176/appi.ajp.2009.09040472View ArticleGoogle Scholar
- Habel LA, Cooper WO, Sox CM, Chan KA, Fireman BH, Arbogast PG, Cheetham TC, Quinn VP, Dublin S, Boudreau DM, Andrade SE, Pawloski PA, Raebel MA, Smith DH, Achacoso N, Uratsu C, Go AS, Sidney S, Nguyen-Huynh MN, Ray WA, Selby JV: ADHD medications and risk of serious cardiovascular events in young and middle-aged adults. JAMA 2011, 306: 2673-2683. 10.1001/jama.2011.1830View ArticleGoogle Scholar
- Harty SC, Miller CJ, Newcorn JH, Halperin JM: Adolescents with childhood ADHD and comorbid disruptive behavior disorders: aggression, anger, and hostility. Child Psychiatry Hum Dev 2009, 40: 85-97. 10.1007/s10578-008-0110-0View ArticleGoogle Scholar
- Hawcutt DB, Mainie P, Riordan A, Smyth RL, Pirmohamed M: Reported paediatric adverse drug reactions in the UK 2000–2009. Br J Clin Pharmacol 2012, 73: 437-446. 10.1111/j.1365-2125.2011.04113.xView ArticleGoogle Scholar
- Henderson TA, Fischer VW: Effects of methylphenidate (Ritalin) on mammalian myocardial ultrastructure. Am J Cardiovasc Pathol 1995, 5: 68-78.Google Scholar
- Huang XP, Setola V, Yadav PN, Allen JA, Rogan SC, Hanson BJ, Revankar C, Robers M, Doucette C, Roth BL: Parallel functional activity profiling reveals valvulopathogens are potent 5-hydroxytryptamine(2B) receptor agonists: implications for drug safety assessment. Mol Pharmacol 2009, 76: 710-722. 10.1124/mol.109.058057View ArticleGoogle Scholar
- Inman WH: Attitudes to adverse drug reaction reporting. Br J Clin Pharmacol 1996, 41: 434-435.Google Scholar
- Karaman MG, Atalay F, Tufan AE, Erdogan A: Pulmonary arterial hypertension in an adolescent treated with methylphenidate. J Child Adolesc Psychopharmacol 2010, 20: 229-231. 10.1089/cap.2009.0095View ArticleGoogle Scholar
- Kessler RC, Adler L, Ames M, Barkley RA, Birnbaum H, Greenberg P, Johnston JA, Spencer T, Ustün TB: The prevalence and effects of adult attention deficit/hyperactivity disorder on work performance in a nationally representative sample of workers. J Occup Environ Med 2005, 47: 565-572. 10.1097/01.jom.0000166863.33541.39View ArticleGoogle Scholar
- Kessler RC, Adler LA, Barkley R, Biederman J, Conners CK, Faraone SV, Greenhill LL, Jaeger S, Secnik K, Spencer T, Ustün TB, Zaslavsky AM: Patterns and predictors of attention-deficit/hyperactivity disorder persistence into adulthood: results from the national comorbidity survey replication. Biol Psychiatry 2005, 57: 1442-1451. 10.1016/j.biopsych.2005.04.001View ArticleGoogle Scholar
- Kessler RC, Adler L, Barkley R, Biederman J, Conners CK, Demler O, Faraone SV, Greenhill LL, Howes MJ, Secnik K, Spencer T, Ustun TB, Walters EE, Zaslavsky AM: The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry 2006, 163: 716-723. 10.1176/appi.ajp.163.4.716View ArticleGoogle Scholar
- Knellwolf AL, Deligne J, Chiarotti F, Auleley GR, Palmieri S, Boisgard CB, Panei P, Autret-Leca E: Prevalence and patterns of methylphenidate use in French children and adolescents. Eur J Clin Pharmacol 2008, 64: 311-317. 10.1007/s00228-007-0401-6View ArticleGoogle Scholar
- Lahey BB, Pelham WE, Chronis A, Massetti G, Kipp H, Ehrhardt A, Lee SS: Predictive validity of ICD-10 hyperkinetic disorder relative to DSM-IV attention-deficit/hyperactivity disorder among younger children. J Child Psychol Psychiatry 2006, 47: 472-479. 10.1111/j.1469-7610.2005.01590.xView ArticleGoogle Scholar
- Lee SI, Schachar RJ, Chen SX, Ornstein TJ, Charach A, Barr C, Ickowicz A: Predictive validity of DSM-IV and ICD-10 criteria for ADHD and hyperkinetic disorder. J Child Psychol Psychiatry 2008, 49: 70-78. 10.1111/j.1469-7610.2007.01784.xView ArticleGoogle Scholar
- Lewman LV: Fatal pulmonary hypertension from intravenous injection of methylphenidate (Ritalin) tablets. Hum Pathol 1972, 3: 67-70. 10.1016/S0046-8177(72)80054-6View ArticleGoogle Scholar
- Markowitz JS, DeVane CL, Pestreich LK, Patrick KS, Muniz R: A comprehensive in vitro screening of d-, l-, and dl-threo-methylphenidate: an exploratory study. J Child Adolesc Psychopharmacol 2006, 16: 687-698. 10.1089/cap.2006.16.687View ArticleGoogle Scholar
- Markowitz JS, DeVane CL, Ramamoorthy S, Zhu HJ: The psychostimulant d-threo-(R, R)-methylphenidate binds as an agonist to the 5HT(1A) receptor. Pharmazie 2009, 64: 123-125.Google Scholar
- McFadyen-Leussis MP, Lewis SP, Bond TLY, Carrey N, Brown RE: Prenatal exposure to methylphenidate hydrochloride decreases anxiety and increases exploration in mice. Pharmacol Biochem Behav 2004, 77: 491-500. 10.1016/j.pbb.2003.12.011View ArticleGoogle Scholar
- Mick E, McManus DD, Goldberg RJ: Meta-analysis of increased heart rate and blood pressure associated with CNS stimulant treatment of ADHD in adults. Eur Neuropsychopharmacol 2013, 23: 534-541. 10.1016/j.euroneuro.2012.06.011View ArticleGoogle Scholar
- Molina BSG, Hinshaw SP, Swanson JM, Arnold LE, Vitiello B, Jensen PS, Epstein JN, Hoza B, Hechtman L, Abikoff HB, Elliott GR, Greenhill LL, Newcorn JH, Wells KC, Wigal T, Gibbons RD, Hur K, Houck PR, MTA Cooperative Group: The MTA at 8 years: prospective follow-up of children treated for combined-type ADHD in a multisite study. J Am Acad Child Adolesc Psychiatry 2009, 48: 484-500. 10.1097/CHI.0b013e31819c23d0View ArticleGoogle Scholar
- Newcorn JH, Weiss M, Stein MA: The complexity of ADHD: diagnosis and treatment of the adult patient with comorbidities (Abstract). CNS Spectr 2007, 12: 1-14.Google Scholar
- Nymark TB, Hovland A, Bjornstad H, Nielsen EW: A young man with acute dilated cardiomyopathy associated with methylphenidate. Vasc Health Risk Manag 2008, 4: 477-479.Google Scholar
- Olfson M, Huang C, Gerhard T, Winterstein AG, Crystal S, Allison PD, Marcus SC: Stimulants and cardiovascular events in youth with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2012, 51: 147-156. 10.1016/j.jaac.2011.11.008View ArticleGoogle Scholar
- Radley DC, Finkelstein SN, Stafford RS: Off-label prescribing among office-based physicians. Arch Intern Med 2006, 166: 1021-1026. 10.1001/archinte.166.9.1021View ArticleGoogle Scholar
- Riccio CA, Wolfe M, Davis B, Romine C, George C, Lee D: Attention deficit hyperactivity disorder: manifestation in adulthood. Arch Clin Neuropsychol 2005, 20: 249-269. 10.1016/j.acn.2004.07.005View ArticleGoogle Scholar
- Scahill L, Schwab-Stone M: Epidemiology of ADHD in school-age children. Child Adolesc Psychiatr Clin N Am 2000, 9: 541-555.Google Scholar
- Schelleman H, Bilker WB, Strom BL, Kimmel SE, Newcomb C, Guevara JP, Daniel GW, Cziraky MJ, Hennessy S: Cardiovascular events and death in children exposed and unexposed to ADHD agents. Pediatrics 2011, 127: 1102-1110. 10.1542/peds.2010-3371View ArticleGoogle Scholar
- Schelleman H, Bilker WB, Kimmel SE, Daniel GW, Newcomb C, Guevara JP, Cziraky MJ, Strom BL, Hennessy S: Methylphenidate and risk of serious cardiovascular events in adults. Am J Psychiatry 2012, 169: 178-185.View ArticleGoogle Scholar
- Skounti M, Philalithis A, Galanakis E: Variations in prevalence of attention deficit hyperactivity disorder worldwide. Eur J Pediatr 2007, 166: 117-123.View ArticleGoogle Scholar
- Somkuwar SS, Darna M, Kantak KM, Dwoskin LP: Adolescence methylphenidate treatment in a rodent model of attention deficit/hyperactivity disorder: dopamine transporter function and cellular distribution in adulthood. Biochem Pharmacol 2013, 86: 309-316. 10.1016/j.bcp.2013.04.013View ArticleGoogle Scholar
- Spencer T, Biederman J, Wilens T, Faraone SV: Is attention-deficit hyperactivity disorder in adults a valid disorder? Harv Rev Psychiatry 1994, 1: 326-335. 10.3109/10673229409017099View ArticleGoogle Scholar
- Spencer T, Wilens T, Biederman J, Faraone SV, Ablon JS, Lapey K: A double-blind, crossover comparison of methylphenidate and placebo in adults with childhood-onset attention-deficit hyperactivity disorder. Arch Gen Psychiatry 1995, 52: 434-443. 10.1001/archpsyc.1995.03950180020004View ArticleGoogle Scholar
- Star K, Noren GN, Nordin K, Edwards IR: Suspected adverse drug reactions reported for children worldwide: an exploratory study using VigiBase. Drug Saf 2011, 34: 415-428. 10.2165/11587540-000000000-00000View ArticleGoogle Scholar
- Tobaiqy M, Stewart D, Helms PJ, Williams J, Crum J, Steer C, McLay J: Parental reporting of adverse drug reactions associated with attention-deficit hyperactivity disorder (ADHD) medications in children attending specialist paediatric clinics in the UK. Drug Saf 2011, 34: 211-219. 10.2165/11586050-000000000-00000View ArticleGoogle Scholar
- Tollofsrud C, Hoel T: A young man with acute dilated cardiomyopathy. Tidsskr Nor Laegeforen 2006, 126: 1338-1339.Google Scholar
- Vitiello B, Elliott GR, Swanson JM, Arnold LE, Hechtman L, Abikoff H, Molina BS, Wells K, Wigal T, Jensen PS, Greenhill LL, Kaltman JR, Severe JB, Odbert C, Hur K, Gibbons R: Blood pressure and heart rate over 10 years in the multimodal treatment study of children with ADHD. Am J Psychiatry 2012, 169: 167-177.View ArticleGoogle Scholar
- Volkow ND, Fowler JS, Wang GJ, Ding YS, Gatley SJ: Role of dopamine in the therapeutic and reinforcing effects of methylphenidate in humans: results from imaging studies. Eur Neuropsychopharmacol 2002, 12: 557-566. 10.1016/S0924-977X(02)00104-9View ArticleGoogle Scholar
- Wikstrom G, Kvidal P, Hagstrom E: Life-threatening heart failure caused by ADHD medication. Five case reports described. Lakartidningen 2012, 109: 2016-2018.Google Scholar
- Wilens TE, Faraone SV, Biederman J, Gunawardene S: Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? A meta-analytic review of the literature. Pediatrics 2003, 111: 179-185. 10.1542/peds.111.1.179View ArticleGoogle Scholar
- Wilens TE, Prince JB, Spencer TJ, Biederman J: Stimulants and sudden death: what is a physician to do? Pediatrics 2006, 118: 1215-1219. 10.1542/peds.2006-0942View ArticleGoogle Scholar
- Wilens TE, Adler LA, Adams J, Sgambati S, Rotrosen J, Sawtelle R, Utzinger L, Fusillo S: Misuse and diversion of stimulants prescribed for ADHD: a systematic review of the literature. J Am Acad Child Adolesc Psychiatry 2008, 47: 21-31. 10.1097/chi.0b013e31815a56f1View ArticleGoogle Scholar
- Winterstein AG, Gerhard T, Kubilis P, Saidi A, Linden S, Crystal S, Zito J, Shuster JJ, Olfson M: Cardiovascular safety of central nervous system stimulants in children and adolescents: population based cohort study. BMJ 2012, 345: e4627. 10.1136/bmj.e4627View ArticleGoogle Scholar
- Wood DR, Reimherr FW, Wender PH, Johnson GE: Diagnosis and treatment of minimal brain dysfunction in adults: a preliminary report. Arch Gen Psychiatry 1976, 33: 1453-1460. 10.1001/archpsyc.1976.01770120057005View ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.