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.
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.
attention-deficit hyperactivity disorder; cognitive enhancement; episodic memory; stimulants; amphetamine; methylphenidate
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.
attention-deficit hyperactivity disorder; medication; stimulant; misuse; diversion; amphetamine
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.
Nonmedical use of prescription stimulant medication such as methylphenidate (MPH) has increased among college students over the past several years. Common motivations for use include enhancements in cognition and subjective arousal. As it is unclear whether stimulant medication exerts the same effect on healthy individuals as for those with ADHD, it is possible that many reported effects of prescription stimulants by healthy individuals may stem from placebo effects, which may be an important mechanism underlying initiation and maintenance of nonmedical use. This study examined whether placebo effects influence reports of subjective mood and cognitive performance among college students who endorsed several risk factors for prescription stimulant misuse (i.e., low GPA, fraternity/sorority involvement, binge drinking, cannabis use). Ninety-six subjects (60% male) completed a battery of cognitive tests and questionnaires assessing present mood state on two occasions. Forty-seven participants were randomized to an experimental condition and orally ingested what they believed to be MPH, though actually placebo, on one visit and received no medication on the other visit. The control group received no medication on either visit. During the administration visit, experimental participants reported feeling significantly more high and stimulated compared to the non-administration visit and to the control subjects. However, cognitive enhancement differences were not generally seen between visits or groups. This research demonstrates that placebo effects for prescription stimulants do influence subjective mood and may be implicated in nonmedical stimulant use. This knowledge may be useful in challenging prescription stimulant-related expectancies to decrease the prevalence of use among college students.
prescription stimulants; placebo effects; expectancy effects; cognition; college students
Attention-deficit/hyperactivity disorder (ADD/ADHD) has been emerging as a world-wide psychiatric disorder. There appears to be an increasing rate of stimulant drug abuse, specifically methylphenidate (MPH) which is the most common treatment for ADHD, among individuals who do not meet the criteria for ADHD and particularly for cognitive enhancement among university students. However, the long term effects of exposure to MPH are unknown. Thus, in light of a developmental approach in humans, we aimed to test the effects of adolescence exposure to enriched environment (EE) followed by MPH administration during early adulthood, on reactions to stress in adulthood. Specifically, at approximate adolescence [post natal days (PND) 30–60] rats were reared in EE and were treated with MPH during early adulthood (PND 60–90). Adult (PND 90–92) rats were exposed to mild stress and starting at PND 110, the behavioral and endocrine effects of the combined drug and environmental conditions were assessed. Following adolescence EE, long term exposure to MPH led to decreased locomotor activity and increased sucrose preference. EE had a beneficial effect on PPI (attentive abilities), which was impaired by long term exposure to MPH. Finally, the interaction between EE and, exposure to MPH led to long-term elevated corticosterone and testosterone levels. In view of the marked increase in MPH consumption over the past decade, vigilance is crucial in order to prevent potential drug abuse and its long term detrimental consequences.
Amphetamine-like psychostimulant drugs have been used for decades to treat a variety of clinical conditions. Methylphenidate (MPH) - RitalinR, a compound that blocks reuptake of synaptically released norepinephrine (NE) and dopamine (DA) in the brain, has been used for more than 30 years in low dose, long-term regimens to treat attention deficit-hyperactive disorder (ADHD) in juveniles, adolescents, and adults. These agents are now also becoming increasingly popular among healthy individuals from all walks of life (e.g. military, students) and age groups (teenagers thru senior citizens) to promote wakefulness and improve attention. While there is agreement regarding the primary biochemical action of MPH, the physiological basis for its efficacy in normal individuals and ADHD patients is lacking. Study of the behavioral and physiological actions of clinically and behaviorally relevant doses of MPH in normal animals provides an opportunity to explore the role of catecholamine transmitters in prefrontal cortical function and attentional processes as they relate to normal operation of brain circuits and ADHD pathology. The goal of ongoing studies has been to: 1) assess the effects of low dose MPH on rodent performance in a well characterized sensory-guided sustained attention task, 2) examine the effects of the same low-dose chronic MPH administration on task-related discharge of prefrontal cortical (PFC) neurons and 3) investigate the effects of NE and DA on membrane response properties and synaptic transmission in identified subsets of PFC neurons. Combinations of these approaches can be used in adolescent, adult and aged animals to identify the parameters of cell and neural circuit function that are regulated by MPH and to establish an overarching explanation of how MPH impacts PFC operations from cellular through behavioral functional domains.
To investigate the possible association between untreated Attention Deficit Hyperactivity Disorder (ADHD) symptoms, as measured the Adult ADHD Self-Report Scale, and persistent nonmedical use of prescription stimulants.
Multinomial regression modeling was used to compare ADHD symptoms among three groups of college students enrolled in a longitudinal study over four years: 1) persistent nonmedical users of prescription stimulants; 2) persistent users of marijuana who did not use prescription stimulants nonmedically; and, 3) consistent non-users of drugs.
ADHD symptoms were associated with being a persistent nonmedical user of prescription stimulants, after adjustment for race/ethnicity, sex, SES, and other illicit drug use. No associations were observed between ADHD symptoms and being a persistent marijuana user or non-user.
ADHD symptoms, and in particular inattention symptoms, appear to be associated with nonmedical use of prescription stimulants. Future studies are needed to clinically validate these observations.
Attention Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder characterised by the symptoms of inattention, impulsivity and hyperactivity. ADHD was once perceived as a condition of childhood only; however increasing evidence has highlighted the existence of ADHD in older adolescents and adults. Estimates for the prevalence of ADHD in adults range from 2.5–4%. Few data exist on the prescribing trends of the stimulants methylphenidate and dexamfetamine, and the non-stimulant atomoxetine in the UK. The aim of this study was to investigate the annual prevalence and incidence of pharmacologically treated ADHD in children, adolescents and adults in UK primary care.
The Health Improvement Network (THIN) database was used to identify all patients aged over 6 years with a diagnosis of ADHD/hyperkinetic disorder and a prescription for methylphenidate, dexamfetamine or atomoxetine from 2003–2008. Annual prevalence and incidence of pharmacologically treated ADHD were calculated by age category and sex.
The source population comprised 3,529,615 patients (48.9% male). A total of 118,929 prescriptions were recorded for the 4,530 patients in the pharmacologically treated ADHD cohort during the 6-year study. Prevalence (per 1000 persons in the mid-year THIN population) increased within each age category from 2003 to 2008 [6–12 years: from 4.8 (95% CI: 4.5–5.1) to 9.2 (95% CI: 8.8–9.6); 13–17 years: from 3.6 (95% CI: 3.3–3.9) to 7.4 (95% CI: 7.0–7.8); 18–24 years: from 0.3 (95% CI: 0.2–0.3) to 1.1 (95% CI: 1.0–1.3); 25–45 years: from 0.02 (95% CI: 0.01–0.03) to 0.08 (95% CI: 0.06–0.10); >45 years: from 0.01 (95% CI: 0.00–0.01) to 0.02 (95% CI: 0.01–0.03). Whilst male patients aged 6-12 years had the highest prevalence; the relative increase in prescribing was higher amongst female patients of the same age - the increase in prevalence in females aged 6–12 years was 2.1 fold compared to an increase of 1.9 fold for their male counterparts. Prevalence of treated ADHD decreased with increasing age. Incidence (per 1000 persons at risk in the mid-year THIN population) was highest for children aged 6–12 years.
A trend of increasing prescribing prevalence of ADHD drug treatment was observed over the period 2003–2008. Prevalence of prescribing to adult patients increased; however the numbers treated are much lower than published estimates of the prevalence of ADHD. This study has added to the limited knowledge on ADHD prescribing in primary care, particularly in the area of drug treatment in adulthood.
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.
Gender differences; Methamphetamine; Methylphenidate; Prescription stimulants; Substance use disorders
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.
Attention-deficit hyperactivity disorder (ADHD/ADD) is a neurobehavioral disorder of childhood onset characterized by severe, developmentally inappropriate motor hyperactivity, inattention, and impulsiveness that result in impairment in more than one setting. It affects the home, school, and community life of 39% of school-going children worldwide. There is increasing recognition that ADHD symptoms and clinically defined disorder can persist into adult life and are associated with later drug and alcohol misuse and social and work difficulties. Added to that is the extreme variability of the disorder over time, within the same individual, between individuals, and across different circumstances. Treatment with stimulants and nonstimulants has proven effective in different subgroups, with the effectiveness of specific agents most likely related to the primary neurotransmitter involved. However, stimulants with a short duration of action have been problematic for some patients. Parent training and cognitive behavioral therapies represent the most widely adjunct psychosocial interventions to pharmacotherapy.
Attention-deficit hyperactivity disorder; stimulants; atomoxetine
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.
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.
Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral psychiatric disorder that afflicts children, with a reported prevalence of 2.4% to 19.8% worldwide. Stimulants (methylphenidate [MPH] and amphetamine) are considered first-line ADHD pharmacotherapy. MPH is a catecholamine reuptake inhibitor, whereas amphetamines have additional presynaptic activity. Although MPH and amphetamine can effectively manage ADHD symptoms in most pediatric patients, many still fail to respond optimally to either. After administration, the prodrug stimulant lisdexamfetamine dimesylate (LDX) is converted to l-lysine and therapeutically active d-amphetamine in the blood. The objective of this study was to evaluate the clinical efficacy of LDX in children with ADHD who remained symptomatic (ie, nonremitters; ADHD Rating Scale IV [ADHD-RS-IV] total score > 18) on MPH therapy prior to enrollment in a 4-week placebo-controlled LDX trial, compared with the overall population.
In this post hoc analysis of data from a multicenter, randomized, double-blind, forced-dose titration study, we evaluated the clinical efficacy of LDX in children aged 6-12 years with and without prior MPH treatment at screening. ADHD symptoms were assessed using the ADHD-RS-IV scale, Conners' Parent Rating Scale-Revised short form (CPRS-R), and Clinical Global Impressions-Improvement scale, at screening, baseline, and endpoint. ADHD-RS-IV total and CPRS-R ADHD Index scores were summarized as mean (SD). Clinical response for the subgroup analysis was defined as a ≥ 30% reduction from baseline in ADHD-RS-IV score and a CGI-I score of 1 or 2. Dunnett test was used to compare change from baseline in all groups. Number needed to treat to achieve one clinical responder or one symptomatic remitter was calculated as the reciprocal of the difference in their proportions on active treatment and placebo at endpoint.
Of 290 randomized participants enrolled, 28 received MPH therapy at screening, of which 26 remained symptomatic (ADHD-RS-IV > 18). ADHD-RS-IV total scores, changes from baseline, clinical responsiveness, and rates of symptomatic remission in this subgroup were comparable to the overall population. The safety and tolerability profiles for LDX were comparable to other stimulants currently available.
In this analysis, children with significant clinical ADHD symptoms despite MPH treatment improved during treatment with LDX and experienced similar improvements in their symptoms as the overall study population.
Attention-deficit/hyperactivity disorder (ADHD); lisdexamfetamine dimesylate (LDX); methylphenidate; children; efficacy
Impulsivity is a central component of attention-deficit/hyperactivity disorder (ADHD). Delay discounting, or a preference for smaller, immediate rewards over larger, delayed rewards is considered an important aspect of impulsivity, and delay-related impulsivity has been emphasized in etiological models of ADHD. The current study examined whether stimulant medication, an effective treatment for ADHD, reduces discounting of delayed experiential and hypothetical rewards among 49 children (age 9–12 years) with ADHD. Following a practice day, participants completed a 3-day double-blind placebo-controlled acute medication assessment. Active doses were long-acting methylphenidate (Concerta), with the nearest equivalents of 0.3 and 0.6 mg/kg TID immediate-release methylphenidate. On each testing day, participants completed experiential (real-world money in real time) and hypothetical discounting tasks. Relative to placebo, methylphenidate reduced discounting of delayed experiential rewards, but not hypothetical rewards. Broadly consistent with etiological models that emphasize delay-related impulsivity among children with ADHD, these findings provide initial evidence that stimulant medication reduces delay discounting among those with the disorder. The present results also draw attention to task parameters that may influence the sensitivity of various delay discounting measures to medication effects.
Adults with attention-deficit/hyperactivity disorder (ADHD) are more frequently presenting for diagnosis and treatment. Medication is considered to be appropriate among available treatments for ADHD; however, the evidence supporting the use of pharmacotherapeutics for adults with ADHD remains less established. In this article, the effectiveness and dosing parameters of the various agents investigated for adult ADHD are reviewed. In adults with ADHD, short-term improvements in symptomatology have been documented through the use of stimulants and antidepressants. Studies suggest that methylphenidate and amphetamine maintained an immediate onset of action, whereas the ADHD response to the nonstimulants appeared to be delayed. At a group level, there appears to be some, albeit not entirely consistent, dose-dependent responses to amphetamine and methylphenidate. Generally speaking, variability in diagnostic criteria, dosing parameters and response rates between the various studies was considerable, and most studies were of a relatively short duration. The aggregate literature shows that the stimulants and catecholaminergic nonstimulants investigated had a clinically significant beneficial effect on treating ADHD in adults.
adult; amphetamine; antidepressants; atomoxetine; attention-deficit/hyperactivity disorder; methylphenidate; pharmacotherapy; stimulants
The use of stimulant drugs for the treatment of children with attention-deficit hyperactivity disorder (ADHD) is one of the most widespread pharmacological interventions in child psychiatry and behavioral pediatrics. This treatment is well grounded on controlled studies showing efficacy of low oral doses of methylphenidate and amphetamine in reducing the behavioral symptoms of the disorder as reported by parents and teachers, both for the cognitive (inattention and impulsivity) and non-cognitive (hyperactivity) domains. Our main aim is to review the objectively measured cognitive effects that accompany the subjectively assessed clinical responses to stimulant medications. Recently, methods from the cognitive neurosciences have been used to provide information about brain processes that underlie the cognitive deficits of ADHD and the cognitive effects of stimulant medications. We will review some key findings from the recent literature, and then offer interpretations of the progress that has been made over the past decade in understanding the cognitive effects of stimulant medication on individuals with ADHD.
methylphenidate; amphetamine; dopamine; prefrontal cortex; executive function; cognitive enhancement; psychostimulants; neuropharmacology; development/developmental disorders; neurochemistry; ADHD; methylphenidate; stimulants
The persistence of attention deficit hyperactivity disorder (ADHD) into adolescence and adulthood has now been accepted as a clinical entity. The rate of prevalence among adults is assumed to be from 2% to 4%. With increasing age, a symptom change has to be considered; disturbance of attention becomes more prominent, whereas hyperactivity often diminishes or changes to inactivity. Neuroimaging studies show a high striatal dopamine transporter (DAT) availability in most adults with ADHD; this can be reduced by stimulants. Nicotine seems to have a stimulant-like action on the DAT. In most adults with ADHD, therapy has to be multimodal, combining psychotherapy and medication. Methylphenidate is the first-line drug in adult ADHD; further options are amphetamine and noradrenaline reuptake inhibitors. Nonresponders to methylphenidate seem to have no elevated DAT availability prior to therapy. Combination with other psychiatric disorders occurs frequently in adults with ADHD; in these patients additional pharmacological treatment with special regard to the comorbid disease is recommended.
attention deficit hyperactivity disorder; adolescence; adulthood; brain imaging techniques; single photon emission computed tomography; dopamine transporter; nicotine; diagnosis; therapy; methylphenidate
Methylphenidate (MPH), commercially called Ritalin or Concerta, has been widely used as a drug for Attention Deficit Hyperactivity Disorder (ADHD). Noteworthily, growing numbers of young people using prescribed MPH improperly for pleasurable enhancement, take high risk of addiction. Thus, understanding the mechanism underlying high level of MPH action in the brain becomes an important goal nowadays. As a blocker of catecholamine transporters, its therapeutic effect is explained as being due to proper modulation of D1 and α2A receptor. Here we showed that higher dose of MPH facilitates NMDA-receptor mediated synaptic transmission via a catecholamine-independent mechanism, in layer V∼VI pyramidal cells of the rat medial prefrontal cortex (PFC). To indicate its postsynaptic action, we next found that MPH facilitates NMDA-induced current and such facilitation could be blocked by σ1 but not D1/5 and α2 receptor antagonists. And this MPH eliciting enhancement of NMDA-receptor activity involves PLC, PKC and IP3 receptor mediated intracellular Ca2+ increase, but does not require PKA and extracellular Ca2+ influx. Our additional pharmacological studies confirmed that higher dose of MPH increases locomotor activity via interacting with σ1 receptor. Together, the present study demonstrates for the first time that MPH facilitates NMDA-receptor mediated synaptic transmission via σ1 receptor, and such facilitation requires PLC/IP3/PKC signaling pathway. This novel mechanism possibly explains the underlying mechanism for MPH induced addictive potential and other psychiatric side effects.
the maintenance of attention may underlie problems in attention deficit
hyperactivity disorder (ADHD). Children with ADHD also show asymmetric
attention deficits in traditional lateralisation and visuospatial
orienting tasks, suggesting right hemispheric (and left hemispace)
attentional disturbance. This study aimed to examine the lateralisation
of selective attention in ADHD; specifically, the effect of a moving,
random dot background, and stimulant medication in the line bisection task.
performance of children with ADHD, on and off methylphenidate, was
examined using a computerised horizontal line bisection task with
moving and blank backgrounds. Twenty children with a DSM-IV diagnosis
of ADHD participated with 20 controls, individually matched for age,
sex, grade at school, and IQ. Twelve of the 20children with ADHD were
on stimulant medication at the time of testing. Horizontal lines of
varying length were presented in the centre of a computer screen, with
either a blank background, or a moving, random dot field. The random
dots moved either leftward or rightward across the screen at either 40 mm/s or 80 mm/s.
with ADHD off medication bisected lines significantly further to the
right compared with controls, who showed a small leftward error.
Methylphenidate normalised the performance of the children with ADHD
for the task with the moving dots.
results support previous evidence for a right hemispheric hypoarousal
theory of attentional dysfunction, and are consistent with the emerging
picture of a lateralised dysfunction of frontostriatal circuitry in ADHD.
Attention deficit hyperactivity disorder (ADHD) is a neurocognitive behavioral developmental disorder most commonly seen in childhood and adolescence, which often extends to the adult years. Relative to a decade ago, there has been extensive research into understanding the factors underlying ADHD, leading to far more treatment options available for both adolescents and adults with this disorder. Novel stimulant formulations have made it possible to tailor treatment to the duration of efficacy required by patients, and to help mitigate the potential for abuse, misuse and diversion. Several new non-stimulant options have also emerged in the past few years. Among these, cognitive behavioral interventions have proven popular in the treatment of adult ADHD, especially within the adult population who cannot or will not use medications, along with the many medication-treated patients who continue to show residual disability.
Children with attention-deficit/hyperactivity disorder (ADHD) frequently display poor judgment and risk taking in their everyday behavior, but there are little empirical data on decision-making cognition in this disorder. The objectives of the study were to assess the effects of stimulant medication on decision making in ADHD and compare performance on the Cambridge Gamble Task between boys with and without ADHD.
Twenty-one boys (aged 7–13) diagnosed with ADHD underwent a double-blind, placebo-controlled trial of methylphenidate (.5 mg/kg) during which they performed the Cambridge Gamble Task (CGT). A healthy age-matched control group was tested on two occasions off drug.
The ADHD group bet more conservatively on the methylphenidate session than on the placebo session. In comparison with healthy control subjects, the ADHD group made more poor decisions, placed their bets more impulsively, and adjusted their bets less according to the chances of winning. Poor decision making was correlated with parent-reported symptoms and disruptive behavior in the ADHD group.
Methylphenidate reduced risk-prone betting behavior on the CGT. Compared with control subjects, children with ADHD display a number of decision-making deficits on the task, and the measure of rational decision making may serve as an ecologically valid neuropsychological marker of impairment.
Attention-deficit/hyperactivity disorder (ADHD); Cambridge Gamble Task (CGT); decision making; methylphenidate (MPH)
At low and clinically-relevant doses, psychostimulants enhance cognitive and behavioral function dependent on the prefrontal cortex (PFC) and extended frontostriatal circuitry. These actions are observed in individuals with attention deficit hyperactivity disorder (ADHD) as well as in normal human and animal subjects. Despite the widespread use of these drugs, the sites of action involved in their cognition-enhancing and therapeutic effects are poorly understood. Indirect and/or correlative evidence suggests the cognition-enhancing/therapeutic effects of psychostimulants may involve actions directly within the PFC or extended frontostriatal circuitry. The current studies examined the degree to which methylphenidate (MPH; Ritalin®) acts within distinct frontostriatal subfields to improve PFC-dependent cognition as measured in a delayed-response test of spatial working memory.
Working memory performance was assessed following microinfusion of vehicle or varying doses of MPH (0.03-8.0 μg/500 nl) directly into the dorsomedial PFC (dorsal prelimbic and dorsal anterior cingulate cortex), the ventromedial PFC (infralimbic) and the dorsomedial striatum of rats (n=69).
MPH infusion into the dorsomedial PFC, but not ventromedial PFC, elicited an inverted-U shaped facilitation of PFC-dependent cognition as measured in this task. The magnitude of this improvement was comparable to that seen with systemic administration. Additional studies demonstrated that although the dorsomedial striatum is necessary for accurate performance in this task, MPH infusion into this region did not affect working memory performance.
These observations provide the first definitive evidence that the PFC is a site of action in the cognition-enhancing and presumably therapeutic actions of low-dose psychostimulants.
ADHD; Psychostimulants; Ritalin; Cognition; Striatum; Executive Function
Psychostimulants are effective treatments for attention-deficit/hyperactivity disorder (ADHD) but may be associated with euphoric effects, misuse/diversion, and adverse effects. These risks are perceived by some clinicians to be greater in substance-abusing adolescents relative to non–substance-abusing adults. The present study evaluates the subjective effects, misuse/diversion, and adverse effects associated with the use of osmotic-release oral system methylphenidate (OROS-MPH), relative to placebo, for treating ADHD in adolescents with a substance use disorder (SUD) as a function of substance use severity and compared these risks with those associated with the treatment of ADHD in adults without a non-nicotine SUD.
Datasets from two randomized placebo-controlled trials of OROS-MPH for treating ADHD, one conducted with 303 adolescents (13–18) with at least one non-nicotine SUD and one with 255 adult smokers (18–55), were analyzed. Outcome measures included the Massachusetts General Hospital Liking Scale, self-reported medication compliance, pill counts, and adverse events (AEs).
Euphoric effects and misuse/diversion of OROS-MPH were not significantly affected by substance use severity. The euphoric effects of OROS-MPH did not significantly differ between the adolescent and adult samples. Adults rated OROS-MPH as more effective in treating ADHD, whereas adolescents reported feeling more depressed when taking OROS-MPH. The adolescents lost more pills relative to the adults regardless of treatment condition, which suggests the importance of careful medication monitoring. Higher baseline use of alcohol and cannabis was associated with an increased risk of experiencing a treatment-related AE in OROS-MPH, but baseline use did not increase the risk of serious AEs or of any particular category of AE and the adolescents did not experience more treatment-related AEs relative to the adults.
With good monitoring, and in the context of substance abuse treatment, OROS-MPH can be safely used in adolescents with an SUD despite non-abstinence.
Smith and Farah (2011) presented a scholarly review of critical areas related to their intriguing title “Are Prescription Stimulants ‘Smart Pills’?” We contend that they accomplished the main goal of the article, to get the facts straight about possible cognitive enhancement via the nonmedical use of stimulant drugs by individuals without a diagnosis of attention-deficit/hyperactivity disorder (ADHD). At the same time, they justified their main conclusions that (a) individuals are seeking and engaging in nonmedical use of stimulant drugs with the expectations of cognitive enhancement despite uncertainty whether such expectations are valid and (b) on some tasks, there are small average benefits of nonmedical use, but the overall pattern is not clear (e.g., small beneficial effects across most individuals or large beneficial effects only in a few individuals, both of which result in small average effects). We offer comments in 3 areas to amplify key topics mentioned but not emphasized by Smith and Farah: (a) characterization of the cognitive effects of medical use of stimulants to contrast with the cognitive effects of nonmedical use; (b) justification of medical use of stimulants by placement on a normally distributed dimension of behavior rather than categorical diagnosis of ADHD, which varies widely across countries; and (c) evaluation of the potential risks of nonmedical use to individuals and to society (e.g., the likelihood of addiction to stimulant drugs in a small minority of the population) rather than just the potential benefits of cognitive enhancement.
ADHD; stimulant drugs; medical use of stimulants; diversion of stimulants; addiction to stimulants