Reducing Attention-deficit/hyperactivity Disorder Symptoms Research Articles

Placebo-Controlled Study Examining Effects of Selegiline in Children with Attention-Deficit/Hyperactivity Disorder

There is evidence suggesting a role for dopamine in attention-deficit/hyperactivity disorder (ADHD). Pharmacological treatments that act on the dopamine system have been successful in reducing ADHD symptoms. However, unlike traditional stimulants (i.e., methylphenidate), selegiline is a monoamine oxidase inhibitor (MAOI) that has been shown to reduce ADHD symptoms without producing undesirable side effects. In this study using a randomized, double- blind, placebo-controlled, crossover design, cognitive tasks and behavioral rating scales were administered to measure the effectiveness of selegiline in treating different symptoms of ADHD in 11 children aged 6-13. Results indicate that selegiline may target specific symptoms of ADHD including: sustained attention, the learning of novel information, hyperactivity, and peer interactions. Because the drug was not associated with negative side effects and did not specifically reduce symptoms of impulsivity, selegiline may be a preferred treatment for individuals who present with the primarily inattentive subtype of ADHD.

Mixed Amphetamine Salts Extended-Release in the Treatment of Adult ADHD:A Randomized, Controlled Trial

Attention-deficit/hyperactivity disorder (ADHD) is a serious neurobehavioral disorder of childhood onset that often persists into adolescence and adulthood. Functional impairments, underachievement, and difficult interpersonal relationships illustrate the need for effective treatment of ADHD through adulthood. This prospective, multisite, randomized, double-blind, placebo-controlled, parallel-group, dose-escalation study was conducted to assess the efficacy, safety, and duration of action of mixed amphetamine salts extended-release (MAS XR) in adults with ADHD, combined type. Adults > or =18 years of age were given placebo or MAS XR 20, 40, or 60 mg/day for 4 weeks. The main outcome measures were the ADHD Rating Scale and Conners' Adult ADHD Rating Scale Short Version Self-Report (CAARS-S-S). Two hundred fifty-five subjects were randomly assigned to treatment with MAS XR or placebo. MAS XR treatment was associated with statistically and clinically significant ADHD symptom reduction at endpoint; mean ADHD Rating Scale scores were 18.5 for the 20-mg group (P=.001), 18.4 for the 40-mg group (P<.001), and 18.5 for the 60-mg group (P<.001). Adults with severe symptoms (ADHD Rating Scale score >32 at baseline) had significantly greater symptom reduction with the highest MAS XR dose (60 mg/day), however, this dose-response relationship was determined by post-hoc analysis. The mean MAS XR effect size was 0.8. Statistically significant (P<.05) improvements in CAARS-S-S ADHD index scores occurred at 4- and 12-hours postdose for all MAS XR groups, indicating a 12-hour duration of effect. Symptoms improved within the first treatment week. Most adverse events reported were mild or moderate in intensity, and the most commonly reported adverse events were consistent with the known profile of stimulant medications. Vital signs and electrocardiograms showed no clinically significant cardiovascular changes. These results suggest that MAS XR is safe and effective in adults with ADHD and controlled ADHD symptoms for up to 12 hours.

Comparison of the clinical efficacy of twice-daily Ritalin® and once-daily Equasym™ XL with placebo in children with Attention Deficit/Hyperactivity Disorder

To compare the efficacy and safety of two methylphenidate (MPH) formulations--once-daily modified-release MPH (EqXL, Equasym XL) and twice-daily immediate-release methylphenidate (MPH-IR, Ritalin)--and placebo in children with Attention Deficit/Hyperactivity Disorder (ADHD). Children aged 6-12 years on a stable dose of MPH were randomized into a double-blind, three-arm, parallel-group, multi-center study and received 3 weeks of EqXL (20, 40, or 60 mg qd), MPH-IR (10, 20, or 30 mg bid) or placebo. Non-inferiority of EqXL to MPH-IR was assessed by the difference in the inattention/overactivity component of the overall teacher's IOWA Conners' Rating Scale on the last week of treatment (per protocol population). Safety was monitored by adverse events, laboratory parameters, vital signs, physical exam, and a Side Effect Rating Scale. The lower 97.5% confidence interval bound of the difference between MPH groups fell above the non-inferiority margin (-1.5 points) not only during the last week of treatment but during all three treatment weeks. Both MPH-treatment groups experienced superior benefit when compared to placebo during all treatment weeks (P < 0.001). All treatments were well tolerated. EqXL given once-daily was non-inferior to MPH-IR given twice-daily. Both treatments were superior to placebo in reducing ADHD symptoms.

A Randomized, Double-Blind, Placebo-Controlled Study of Modafinil Film-Coated Tablets in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder

To evaluate the efficacy and tolerability of modafinil in children and adolescents, ages 7 to 17, with attention-deficit/hyperactivity disorder (ADHD). In this 9-week, double-blind, flexible-dose study, patients were randomized to once-daily modafinil (170-425 mg) or placebo. Assessments included ADHD Rating Scale-IV (ADHD-RS-IV) School and Home Versions and Clinical Global Impression of Improvement (CGI-I) scale. Two hundred patients were randomized. Modafinil produced significant reductions in ADHD-RS-IV total scores at school (n = 128; mean change +/- SD: -17.5 +/- 13.1 points) compared with placebo (n = 66; -9.7 +/- 10.3 points; p < .0001). Similarly, modafinil reduced ADHD-RS-IV total scores at home compared with placebo (-17.6 +/- 13.3 versus -7.5 +/- 11.8 points; p < .0001). Fifty-two percent of patients randomized to modafinil and 18% of those randomized to placebo met prestudy criteria for responder on the CGI-I (p < .0001). Randomization to modafinil was associated with significantly more insomnia, headache, decreased appetite, and weight loss than randomization to placebo, but discontinuation attributed to adverse events did not differ statistically between treatment groups (modafinil, 5%; placebo, 6%). Modafinil was well tolerated and reduced ADHD symptoms at school and home compared with placebo.

A Double-blind Comparison of Galantamine Hydrogen Bromide and Placebo in Adults With Attention-Deficit/Hyperactivity Disorder

Galantamine hydrogen bromide (HBr) is a competitive and reversible inhibitor of acetylcholinesterase. Because of its cholinergic nicotinic mechanism of action, galantamine HBr was hypothesized to have therapeutic activity in the treatment of attention-deficit/hyperactivity disorder (ADHD). We conducted a 12-week, double-blind, placebo-controlled, randomized clinical trial using daily doses of up to 24 mg/d of galantamine HBr in the treatment of adults who met full Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for ADHD with childhood-onset and persistent adult symptoms. All analyses were intention to treat with the last observation carried forward for subjects who did not complete the full study schedule. The mean daily doses at week 12 were 19.8 +/- 6.4 mg for galantamine HBr and 21.8 +/- 4.6 mg for placebo (P = 0.3). There was no statistically or clinically significant greater reduction in ADHD symptoms in subjects treated with galantamine HBr relative to those receiving placebo (P = 0.5). Using last observation carried forward, 4 (22%) of 18 of patients receiving galantamine HBr were considered responders (much or very much improved on the Clinical Global Impression Improvement Scale and at least a 30% reduction on the ADHD Investigator Symptom Report Scale compared with 11% [2/18] on placebo; P = 0.4). These results do not support the clinical utility of galantamine HBr in the treatment of ADHD at the doses used in this pilot study.

The reinforcing effects of nicotine and stimulant medication in the everyday lives of adult smokers with ADHD: A preliminary examination

Whereas the smoking prevalence rates in the general population are declining, rates among people diagnosed with attention-deficit/hyperactivity disorder (ADHD) continue to be elevated. Previous research has shown that nicotine may improve attention and mood, suggesting that nicotine may help ameliorate the attentional and emotional problems associated with ADHD. The present study examined the effects of nicotine with and without stimulant medication on ADHD symptoms, moods, and arousal in the everyday lives of smokers with ADHD. A total of 10 smokers with ADHD who were being treated with stimulant medication were asked to abstain from smoking while participating in the study. Participants underwent four conditions in randomized order: (a) Nicotine patch+stimulant medication, (b) nicotine patch only, (c) placebo patch+stimulant medication, and (d) placebo patch only. Each condition continued for 2 days, during which self-reports of ADHD symptoms and moods were obtained using electronic diaries. Lightweight ambulatory monitors recorded cardiovascular activity at each diary entry. Smoking abstinence was verified by expired carbon monoxide and salivary cotinine analysis. Results showed that nicotine patches and stimulant medication alone and in combination reduced difficulty concentrating and core ADHD symptoms compared with placebo patch only. Borderline improvement in impatience and self-control was seen with nicotine patch administration primarily on day 1. Nicotine patches also tended to elevate systolic and diastolic blood pressure compared with placebo patch during day 2. The findings suggest that smokers with ADHD experience nicotine-related reductions in ADHD symptoms during their everyday lives.

Methylphenidate Skin Patch Approved for ADHD

Methylphenidate Skin Patch Approved for ADHD

Methylphenidate Controlled-Delivery Capsules (Equasym???XL, Metadate CD???)

Controlled-delivery methylphenidate (methylphenidate CD) [EquasymXL, Metadate CD], an oral stimulant, is approved in the US and EU to treat children aged>or=6 years who have been diagnosed with attention-deficit hyperactivity disorder (ADHD). Once-daily methylphenidate CD is generally well tolerated and effective in the treatment of children and adolescents with ADHD. Methylphenidate CD resulted in superior control of ADHD symptoms compared with osmotic release oral system (OROS) methylphenidate over a time period corresponding to that of an average school day in a laboratory classroom. In 3-week clinical trials conducted in a community setting, methylphenidate CD was superior to placebo and noninferior to methylphenidate immediate-release (IR) in the treatment of children and adolescents with ADHD. Thus, methylphenidate CD should be considered an important primary treatment on its own or in addition to behavioral and psychosocial interventions, for when a reduction in ADHD symptoms is required during the school day in preference to the evening.

Multisite Controlled Study of OROS Methylphenidate in the Treatment of Adolescents With Attention-Deficit/Hyperactivity Disorder

Despite the persistence of attention-deficit/hyperactivity disorder (ADHD) into adolescence, little is known about the efficacy and tolerability of stimulant medications in this age group. To report the results of a multisite controlled study among adolescents with ADHD evaluating the efficacy and tolerability of osmotic-release oral system (OROS) methylphenidate. Adolescents (N = 220) having a confirmed Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of ADHD underwent dose titration to identify dosages of OROS methylphenidate that improved symptoms to predefined criteria. Subjects successfully completing the dose titration phase (n = 177) (ie, tolerated and responded to treatment and adhered to the protocol) were randomized to receive 2 weeks' treatment with their individualized dosage of OROS methylphenidate (18, 36, 54, or 72 mg once daily) or placebo. Treatment effectiveness was measured using investigator, parent, and adolescent assessments of ADHD. A significant reduction from baseline in the investigator-rated ADHD Rating Scale, the primary efficacy measure, was found with OROS methylphenidate treatment compared with placebo. Similar findings were noted with parent- and adolescent-report measures. Based on a Clinical Global Impression improvement subscale score of much or very much improved, 52% of subjects in the OROS methylphenidate group improved compared with 31% receiving placebo. Thirty-seven percent of subjects required the maximum dosage of 72 mg/d. The incidence of drug-related adverse events was similar between the 2 study groups. In adolescents, once-daily OROS methylphenidate significantly reduced ADHD symptoms and was well tolerated using dosages up to 72 mg/d.

A controlled trial of methylphenidate in adults with attention deficit/hyperactivity disorder and substance use disorders

Attention deficit/hyperactivity disorder (ADHD) is common among adult patients with substance use disorders. The benefits of treating ADHD in these patients are uncertain and the prescription of psychostimulants is disputed, because of the risk of abuse. This study examined the short-term effectiveness of methylphenidate treatment for ADHD in adults with substance use disorders. Double-blind, placebo-controlled, multiple cross-over (A-B-A-B design) comparative trial of methylphenidate versus placebo. In-patient addiction treatment facility. Twenty-five patients with ADHD who were receiving in-patient treatment for various substance use disorders. During the course of 8 weeks, each participant completed two phases of placebo and two phases of active medication treatment, in a fixed low-dosage schedule (up to 0.6 mg/kg/day). Abstinence was maintained during the study. The outcome measure was ADHD symptomatology, as measured with the ADHD rating scale-IV. The results were compared using MANOVA repeated measures. Nineteen of the 25 patients completed the trial. A significant reduction in ADHD symptoms was observed in the first week in both conditions. The positive response to active treatment (nine patients; 36%) was not significantly higher than that to placebo (five patients; 20%). In this small pilot study, the effect of low-dose methylphenidate in adult ADHD patients with concomitant substance use disorders is limited. ADHD symptoms in adults were susceptible to a distinct short-term placebo response.

Efficacy of atomoxetine in adult attention-Deficit/Hyperactivity Disorder: a drug-placebo response curve analysis

BackgroundThe objective of this study was to evaluate the efficacy of atomoxetine, a new and highly selective inhibitor of the norepinephrine transporter, in reducing symptoms of attention-deficit/hyperactivity disorder (ADHD) among adults by using drug-placebo response curve methods.MethodsWe analyzed data from two double-blind, placebo-controlled, parallel design studies of adult patients (Study I, N = 280; Study II, N = 256) with DSM-IV-defined ADHD who were recruited by referral and advertising. Subjects were randomized to 10 weeks of treatment with atomoxetine or placebo, and were assessed with the Conners Adult ADHD Rating Scales and the Clinical Global Impression of ADHD Severity scale before and after treatment.ResultsThose treated with atomoxetine were more likely to show a reduction in ADHD symptoms than those receiving placebo. Across all measures, the likelihood that an atomoxetine-treated subject improved to a greater extent than a placebo-treated subject was approximately 0.60. Furthermore, atomoxetine prevented worsening of most symptom classes.ConclusionFrom these findings, we conclude that atomoxetine is an effective treatment for ADHD among adults when evaluated using several criteria.

Atomoxetine Alone or Combined With Fluoxetine for Treating ADHD With Comorbid Depressive or Anxiety Symptoms

Symptoms of depression and anxiety are commonly comorbid with attention-deficit/hyperactivity disorder (ADHD). The authors assessed the safety and effectiveness of atomoxetine monotherapy compared with combined atomoxetine/fluoxetine therapy in a population of children and adolescents with ADHD and concurrent symptoms of depression or anxiety. Patients were randomized to treatment with fluoxetine (n = 127) or placebo (n = 46) under double-blind conditions for 8 weeks, with concomitant atomoxetine use the last 5 weeks. At end point, reductions in ADHD, depressive, and anxiety symptoms were marked for both treatment groups (p < .001 for the relevant scale in each symptom cluster). Some differences between treatment groups for depressive symptoms were significant, but the magnitudes of the differences were small and likely of limited clinical importance. Completion rates for the two groups were similar, as were discontinuation rates for adverse events. The combination group had greater increases in blood pressure and pulse than did the monotherapy group. In pediatric patients with ADHD and comorbid symptoms of depression or anxiety, atomoxetine monotherapy appears to be effective for treating ADHD. Anxiety and depressive symptoms also improved, but the absence of a placebo-only arm does not allow us to conclude that these effects are specifically the result of treatment with atomoxetine. Combined atomoxetine/fluoxetine therapy was well tolerated.

Comparison of Risperidone and Methylphenidate for Reducing ADHD Symptoms in Children and Adolescents With Moderate Mental Retardation

To evaluate the short-term efficacy and tolerability of risperidone and methylphenidate for reducing symptoms related to attention-deficit/hyperactivity disorder (ADHD) in children and adolescents with moderate mental retardation. In a 4-week, single-blind, parallel-group trial, 45 subjects with moderate mental retardation and ADHD were randomized to risperidone or methylphenidate and assessed using objective rating scales for efficacy (SNAP [Swanson, Nolan, and Pelham]-IV and Nisonger Child Behavior Rating Form) and side effects (Barkley's Side Effects Rating Scale and Udvalg for Kliniske Undersøgelser). Both groups had reduced ADHD symptoms during the trial. Repeated-measures analysis of variance yielded a significant effect for the interaction between time and group assignment in SNAP-IV Total scores (F = 3.26; p = .05), suggesting a more pronounced effect for risperidone. There was a significant weight reduction in the methylphenidate group and a weight gain in the risperidone group. Our findings suggest that risperidone is associated with greater reductions in ADHD Total score than methylphenidate in children with moderate mental retardation and ADHD. Comorbidity and the side effects profile might be of importance in choosing between the medications, although it is usually prudent to try stimulants before antipsychotics in such children.

L’atomoxétine : un nouveau traitement du trouble déficitaire de l’attention/hyperactivité de l’enfant et de l’adolescent

L’atomoxétine : un nouveau traitement du trouble déficitaire de l’attention/hyperactivité de l’enfant et de l’adolescent

KUO AND FABER TAYLOR RESPOND

There is much that we agree with in Canu and Gordon’s assessment. We agree that our text might easily be interpreted as dismissing the value of psychosocial treatments. This is unfortunate and we regret it. In stating that “among . . . children for whom medication is not an option, a regular regime of . . . green time outdoors might offer the only relief from symptoms available,” our focus was on treatments that reduce symptoms. While to our knowledge psychosocial treatments do not actually reduce attention-deficit/hyperactivity disorder (ADHD) symptoms, their value in helping ADHD sufferers function despite their symptoms is undisputed. We agree regarding many of the limitations Canu and Gordon discuss. The effects of exposure to nature on impulsivity need to be addressed. And, as we acknowledged in the article, parent report is fallible, verbal descriptions of activities are insufficiently specific, and it is not clear how large any effects are or how long they last. Our purpose in this study was to test for the generality of the nature–ADHD connection; in other research we have begun to quantify the effects under carefully specified conditions, using objective measures. We disagree with Canu and Gordon in some respects. The heterogeneity of our sample was deliberate, and we regard the consistency of the findings across such a large and diverse sample as a hopeful sign. Similarly, we did not include non-ADHD children because our question was not whether ADHD children benefit more from nature than other children but whether they benefit at all. We did not hope for readers to be persuaded by unpublished data, nor did we rely on statistical significance to draw conclusions about effect sizes. The unpublished data are clearly indicated as such, to be taken with a liberal helping of salt, and we drew no conclusions about effect sizes. We strongly object to Canu and Gordon’s depiction of our conclusions. It would indeed be premature to conclude that nature is widely effective in reducing ADHD symptoms, or to portray nature as a well-established treatment. We made no such claims. Suggesting that nature may be widely effective is a far cry from claiming that it is widely effective, and referring to nature as a potential treatment falls well short of portraying it as well established. In a study of 452 parents nationwide, we found that activities conducted in relatively natural outdoor settings were reported to reduce ADHD symptoms more than activities conducted in other settings. This finding held across a wide variety of activities, environments, children, and case characteristics. These findings raise the possibility of a new tool for managing ADHD; we call for this exciting possibility to be investigated.

MOTHER NATURE AS TREATMENT FOR ADHD: OVERSTATING THE BENEFITS OF GREEN

In the September issue of the Journal, Kuo and Faber Taylor1 suggest that activities in green (i.e., natural) surroundings are “widely effective” in reducing symptoms associated with attention-deficit/hyperactivity disorder (ADHD). However, because this Internet-based study is rife with methodological limitations, it does not offer convincing scientific evidence of this treatment’s effectiveness. For example, participants were designated as having ADHD not on the basis of research criteria but on the basis of parental reports of a professional diagnosis. Given long-appreciated inconsistencies in how care-givers in the community evaluate children for ADHD,2,3 the sample must have been highly heterogeneous in symptom presentation and impairment level. Because the study did not include any healthy controls or controls with psychiatric illnesses, it is entirely unclear whether the “green effects” addressed ADHD-type impairments any more than they would have enhanced attention across other groups. It is also cause for concern that the survey asked parents to rate primarily inattentive behaviors associated with ADHD, neglecting equally prevalent (and generally more impairing) impulsive/hyperactive symptoms. Even if the treatment effects were legitimate, they would be narrow in scope. Furthermore, the authors’ claim that natural surroundings reduce ADHD symptoms is based solely on global, retrospective impressions, not on direct observations of how children behaved following activities held constant except for the setting. The article does not specify the exact nature of each activity, why parental recollections should be considered accurate, or whether any effects lasted longer than an hour after the green dose. Kuo and Faber Taylor draw their conclusions on the basis of statistical significance, not actual clinical impact. For instance, the largest mean “aftereffects” difference between green outdoor activities and indoor activities was 4.34 (apparently on a 40-point scale), suggesting a fairly modest effect for environmental setting. Finally, the authors frequently cite unpublished data as corroborating their conclusions. Such data hold little sway because they have not been peer reviewed. While the pursuit of effective nonmedical interventions for ADHD is certainly noble, we worry when unproven ideas are presented as if they were well-established treatments. That the authors imply that exposure to green surroundings may be the only alternative to medication for some children also bothers us. This conclusion ignores an extensive literature on psychosocial treatments that includes parent training programs and classroom management techniques.4 As it stands, these other programs currently enjoy far more scientific rigor than programs involving a walk in the park.

Comparative Pharmacodynamics and Plasma Concentrations of d-threo-Methylphenidate Hydrochloride After Single Doses of d-threo-Methylphenidate Hydrochloride and d,l-threo-Methylphenidate Hydrochloride in a Double-Blind, Placebo-Controlled, Crossover Laboratory School Study in Children With Attention-Deficit/Hyperactivity Disorder

Methylphenidate has four optical isomers due to two asymmetries (erythro-threo and dextro-levo). The initial commercial formulation eliminated the erythro isomer, but the dextro-levo asymmetry was racemic, with equal amounts of d and l-threo isomers (d,l-MPH). Previous work has suggested that the d-threo isomer methylphenidate (d-MPH) rather than the l-threo isomer (l-MPH) is responsible for the clinical effects in children with attention-deficit/hyperactivity disorder (ADHD). This study compared the efficacy of acute equimolar doses of d-MPH and dl-MPH in reducing ADHD symptoms over an 8-hour period in a laboratory school setting and investigated the relationship of efficacy to plasma levels of MPH. Thirty-two children with ADHD enrolled in this double-blind, placebo-controlled, crossover study, and 31 completed the study. On seven separate occasions separated by at least 6 days, the children received a single morning dose of d-MPH (2.5, 5, or 10 mg), d,l-MPH (5, 10, or 20 mg), or placebo and then were observed in a laboratory classroom setting for 8 hours. At specified intervals, blinded observers rated behavior, and the children performed a computerized math test. The plasma levels of MPH were related to the response to study medication. The safety profiles of the two formulations were compared. For both formulations, the responses to both MPH preparations were dose related, the plasma concentrations of l-MPH were negligible and of d-MPH were indistinguishable, and clinical efficacy was highly correlated with plasma concentrations of d-MPH. The efficacy of the d-isomer was equivalent to the racemic preparation in reducing ADHD symptoms and increasing academic productivity. The efficacy of MPH resides in the d-isomer. The elimination of the l-isomer does not diminish the efficacy of an acute dose of methylphenidate.

A potential natural treatment for attention-deficit/hyperactivity disorder: evidence from a national study.

We examined the impact of relatively "green" or natural settings on attention-deficit/hyperactivity disorder (ADHD) symptoms across diverse subpopulations of children. Parents nationwide rated the aftereffects of 49 common after-school and weekend activities on children's symptoms. Aftereffects were compared for activities conducted in green outdoor settings versus those conducted in both built outdoor and indoor settings. In this national, nonprobability sample, green outdoor activities reduced symptoms significantly more than did activities conducted in other settings, even when activities were matched across settings. Findings were consistent across age, gender, and income groups; community types; geographic regions; and diagnoses. Green outdoor settings appear to reduce ADHD symptoms in children across a wide range of individual, residential, and case characteristics.

Polymorphisms of the dopamine transporter gene: influence on response to methylphenidate in attention deficit-hyperactivity disorder.

Attention deficit-hyperactivity disorder (ADHD) is a very common and heterogeneous childhood-onset psychiatric disorder, affecting between 3% and 5% of school age children worldwide. Although the neurobiology of ADHD is not completely understood, imbalances in both dopaminergic and noradrenergic systems have been implicated in the origin and persistence of core symptoms, which include inattention, hyperactivity, and impulsivity. The role of a genetic component in its etiology is strongly supported by genetic studies, and several investigations have suggested that the dopamine transporter gene (DAT1; SLC6A3 locus) may be a small-effect susceptibility gene for ADHD. Stimulant medication has a well-documented efficacy in reducing ADHD symptoms. Methylphenidate, the most prescribed stimulant, seems to act mainly by inhibiting the dopamine transporter protein and dopamine reuptake. In fact, its effect is probably related to an increase in extracellular levels of dopamine, especially in brain regions enriched in this protein (i.e. striatum). It is also important to note that dopamine transporter densities seem to be particularly elevated in the brain of ADHD patients, decreasing after treatment with methylphenidate. Altogether, these observations suggest that the dopamine transporter does play a major role in ADHD. Among the several polymorphisms already described in the SLC6A3 locus, a 40 bp variable number of tandem repeats (VNTR) polymorphism has been extensively investigated in association studies with ADHD. Although there are some negative results, the findings from these reports indicate the allele with ten copies of the 40 bp sequence (10-repeat allele) as the risk allele for ADHD. Some investigations have suggested that this polymorphism can be implicated in dopamine transporter gene expression in vitro and dopamine transporter density in vivo, even though it is located in a non-coding region of the SLC6A3 locus. Despite all these data, few studies have addressed the relationship between genetic markers (specifically the VNTR) at the SLC6A3 locus and response to methylphenidate in ADHD patients. A significant effect of the 40 bp VNTR on response to methylphenidate has been detected in most of these reports. However, the findings are inconsistent regarding both the allele (or genotype) involved and the direction of this influence (better or worse response). Thus, further investigations are required to determine if genetic variation due to the VNTR in the dopamine transporter gene is able to predict different levels of clinical response and palatability to methylphenidate in patients with ADHD, and how this information would be useful in clinical practice.

Treatment of ADHD with methylphenidate may sensitize brain substrates of desire

Aims. Currently, methylphenidate (MPH, trade name Ritalin) is the most widely prescribed medication for attention deficit/hyperactivity disorder (ADHD). We examined the ability of repeated MPH administration to produce a sensitized appetitive eagerness type response in laboratory rats, as indexed by 50-kHz ultrasonic vocalizations (50-kHz USVs). We also examined the ability of MPH to reduce play behavior in rats which may be partially implicated in the clinical efficacy of MPH in ADHD. Design. 56 adolescent rats received injections of either 5.0 mg/kg MPH, or vehicle each day for 8 consecutive days, and a week later received a challenge injection of either MPH or vehicle. Measurements. Both play behavior (pins) and 50-kHz USVs were recorded after each drug or vehicle administration. Results. MPH challenge produced a substantial 73% reduction in play behavior during the initial treatment phase, and during the last test (1 week post drug), 50-kHz USVs were elevated approximately threefold only in animals with previous MPH experience. Conclusions. These data suggest that MPH treatment may lead to psychostimulant sensitization in young animals, perhaps by increasing future drug-seeking tendencies due to an elevated eagerness for positive incentives. Further, we hypothesize that MPH may be reducing ADHD symptoms, in part, by blocking playful tendencies, whose neuro-maturational and psychological functions remain to be adequately characterized.