Spotlight on methylphenidate controlled-delivery capsules (Equasym XL, Metadate CD) in the treatment of children and adolescents with attention-deficit hyperactivity disorder

Controlled-delivery methylphenidate (methylphenidate CD) [Equasym XL, 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 non-inferior to methylphenidate immediate-release 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 behavioural and psychosocial interventions, for when a reduction in ADHD symptoms is required during the school day in preference to the evening.     

Methylphenidate controlled-delivery capsules (EquasymXL, Metadate CD): a review of its use in the treatment of children and adolescents with attention-deficit hyperactivity disorder

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.     

Attention-deficit hyperactivity disorder

The epidemiology, etiology, pathogenesis, clinical presentation, diagnostic criteria, and clinical course of attention-deficit hyperactivity disorder (ADHD) are described and the role of pharmacotherapy in the management of this disorder is discussed. ADHD is a behavioral disorder of unknown etiology characterized by inattention, impulsiveness, and hyperactivity. The behavior, which may be manifest at home, at school, or in social situations, is generally worse in settings requiring sustained attention; as a result, academic underachievement is frequently an associated problem. Although the onset usually occurs before the age of four years, ADHD is most commonly diagnosed when the child enters school. It is up to six times more common in boys than in girls. Nearly one third of all children with ADHD continue to show symptoms of the disorder in adulthood. While many questions about the pathophysiology of ADHD remain unanswered and a cure has not yet been found, pharmacotherapy can effectively control the symptoms of the disorder in most patients. Three psychostimulant medications--dextroamphetamine sulfate, methylphenidate hydrochloride, and pemoline--are considered the drugs of first choice for management of the behavioral manifestations of ADHD. Dextroamphetamine and methylphenidate are equally effective in improving the symptoms of ADHD. Pemoline, a newer agent, may be tried in patients who cannot tolerate or do not respond to these two first-line agents. Common adverse effects associated with stimulant medications include anorexia, insomnia, stomach pain, and weight loss; these are generally transient and decrease with time. Imipramine hydrochloride and desipramine hydrochloride are less effective and may produce more serious adverse effects than the psychostimulants and are therefore considered second-line agents for the treatment of ADHD. Dextroamphetamine sulfate, methylphenidate hydrochloride, and pemoline have been shown to effectively control the behavioral symptoms of ADHD. For maximum impact, pharmacotherapy should be accompanied by behavioral, educational, and psychosocial intervention.     

Psychiatric comorbidities in children with attention deficit hyperactivity disorder: implications for management

Attention deficit hyperactivity disorder (ADHD) is frequently comorbid with a variety of psychiatric disorders. These include oppositional defiant disorder and conduct disorder (CD), as well as affective, anxiety, and tic disorders. ADHD and ADHD with comorbid CD appear to be distinct subtypes; children with ADHD/CD are at higher risk of antisocial personality and substance abuse as adults. Stimulants are often effective treatments for aggressive or antisocial behavior in patients with ADHD, but mood stabilizers or atypical antipsychotics may be used to treat explosive aggressive outbursts. Response to stimulants is not affected by comorbid anxiety, but children with ADHD/anxiety disorder may show greater benefit from psychosocial interventions than those with ADHD alone. The degree of prevalence of major depressive disorder (MDD) and bipolar disorder among children with ADHD is controversial, but a subgroup of severely emotionally labile ADHD children who present serious management issues for the clinician clearly exists. Antidepressants may be used in conjunction with stimulants to treat MDD, while mood stabilizers and atypical antipsychotics are often required to treat manic symptoms or aggression. After resolution of the manic episode, stimulant treatment of the comorbid ADHD may be safely undertaken. Recent research suggests that stimulants can be safely used in children with comorbid ADHD and tic disorders, but the addition of anti-tic agents to stimulants is often necessary. Clinicians who work with patients with ADHD should be prepared to deal with a wide range of emotional and behavioral problems beyond the core symptoms of inattention and impulsivity/hyperactivity.     

Switching from neurostimulant therapy to atomoxetine in children and adolescents with attention-deficit hyperactivity disorder : clinical approaches and review of current available evidence

This review provides practical information on and clinical reasons for switching children and young people with attention-deficit hyperactivity disorder (ADHD) from neurostimulants to atomoxetine, detailing currently available evidence, and switching options. The issue is of particular relevance following recent guidance from the National Institute for Health and Clinical Excellence and European ADHD guidelines endorsing the use of atomoxetine, along with the stimulants methylphenidate and dexamphetamine, in the management of ADHD in children and adolescents in the UK. The selective norepinephrine (noradrenaline) reuptake inhibitor, atomoxetine, is a non-stimulant drug licensed for the treatment of ADHD in children and adolescents, and in adults who have shown a response in childhood. Following the once-daily morning dose, its therapeutic effects extend through the waking hours, into late evening, and in some patients, through to early the next morning. Atomoxetine may be considered for patients who are unresponsive or incompletely responsive to stimulant treatment, have co-morbid conditions (e.g. tics, anxiety, depression), and have sleep disturbances or eating problems, for patients in whom stimulants are poorly tolerated, and for situations where there is potential for drug abuse or diversion. Atomoxetine has been shown to be effective in relapse prevention and there is suggestion that atomoxetine may have a positive effect on global functioning; specifically health-related quality of life, self-esteem, and social and family functioning. According to one study, approximately 50% of non-responders to methylphenidate will respond to atomoxetine therapy and approximately 75% of responders to methylphenidate will also respond to atomoxetine. Atomoxetine may be initiated by a schedule of dose increases and cross-tapering with methylphenidate. A slow titration schedule with divided doses minimizes the impact of adverse events within the first several weeks of treatment. Atomoxetine may be co-administered with methylphenidate during the switching period without undue concern for adverse events, such as cardiovascular effects (although monitoring of blood pressure and heart rate is necessary). Atomoxetine may be discontinued abruptly and patients may miss the occasional dose without rebound effects or discontinuation syndrome. A trial period of at least 6-8 weeks, perhaps longer, is recommended before evaluation of the overall tolerability and efficacy of atomoxetine. We conclude that patients with ADHD can be switched from neurostimulants, specifically methylphenidate, to atomoxetine, and may benefit from symptom improvement.     

Treatment of methadone-maintained patients with adult ADHD: double-blind comparison of methylphenidate, bupropion and placebo

The purpose of this double-blind, three-arm, 12-week trial was to compare the efficacy of sustained-release methylphenidate or sustained-release bupropion to placebo in treating adult attention deficit hyperactivity disorder (ADHD) symptoms. The randomized sample consisted of 98 methadone-maintained patients who were pre-dominantly male (57%) and 40% Caucasian, 40% Hispanic and 20% African American. All participants met DSM-IV criteria for adult ADHD, with 53% meeting DSM-IV criteria for cocaine dependence/abuse. In addition to medication and treatment as usual at a methadone program, individuals received weekly individual cognitive behavioral treatment. Other than current employment status, there were no significant demographic differences across the three treatment groups. Seventy percent completed the 12-week trial. There were no differences in retention rate based on treatment group. A reduction in ADHD symptoms using the adult ADHD rating scale was observed in all three groups, but there were no significant differences in outcome between treatments. The placebo response rate was high, with 46% of the placebo group self-reporting substantial improvement in their ADHD symptoms (>30% reduction in adult ADHD rating scale). Using other ADHD outcome measures, the placebo response and medication response rates were substantially lower. There was no evidence of misuse of medication or worsening of cocaine use among those randomized to methylphenidate. Taken together, sustained-release methylphenidate or sustained-release bupropion did not provide a clear advantage over placebo in reducing ADHD symptoms or additional cocaine use in methadone-maintained patients.     

Atomoxetine, a novel treatment for attention-deficit-hyperactivity disorder

Atomoxetine is the first nonstimulant drug approved by the United States Food and Drug Administration (FDA) for the treatment of attention-deficit-hyperactivity disorder (ADHD), and the only agent approved by the FDA for the treatment of ADHD in adults. Atomoxetine is a norepinephrine transport inhibitor that acts almost exclusively on the noradrenergic pathway. Its mechanism of action in the control and maintenance of ADHD symptoms is thought to be through the highly specific presynaptic inhibition of norepinephrine. Clinical trials to evaluate the short-term effects of atomoxetine in children and adults have shown that atomoxetine is effective in maintaining control of ADHD. Likewise, long-term trials have determined that atomoxetine is effective in preventing relapse of ADHD symptoms without an increase in adverse effects. A comparative trial of atomoxetine with methylphenidate in school-aged children indicated similar safety and efficacy without the abuse liability associated with some psychostimulants. The most commonly reported adverse effects in children and adolescents are dyspepsia, nausea, vomiting, decreased appetite, and weight loss. The rates of adverse events in the trials were similar for both the once- and twice-daily dosing regimens. The discontinuation rate was 3.5% in patients treated with atomoxetine versus 1.4% for placebo and appeared to be dose dependent, wit a higher percentage of discontinuation at dosages greater than 1.5 mg/kg/day. In clinical trials involving adults, the emergence of clinically significant or intolerable adverse events was low. The most common adverse events in adults were dry mouth, insomnia, nausea, decreased appetite, constipation, urinary retention or difficulties with micturition, erectile disturbance, dysmenorrhea, dizziness, and decreased libido. Sexual dysfunction occurred in approximately 2% of patients treated with atomoxetine. Atomoxetine should be used with caution in patients who have hypertension or any significant cardiovascular disorder. Overall, atomoxetine therapy in patient with ADHD appears to be effective in controlling symptoms and maintaining remission, with the advantages being comparable efficacy with that of methylphenidate, a favorable safety profile, and non-controlled substance status. Additional long-term studies are needed to determine its continued efficacy for those who require lifelong treatment, and comparative trials against other stimulant and nonstimulant agents.     

Polymorphisms of the Dopamine Transporter Gene

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.     

Attention-deficit/hyperactivity disorder and the explore/exploit trade-off

The ability to maximize rewards and minimize the costs of obtaining them is vital to making advantageous explore/exploit decisions. Exploratory decisions are theorized to be greater among individuals with attention-deficit/hyperactivity disorder (ADHD), potentially due to deficient catecholamine transmission. Here, we examined the effects of ADHD status and methylphenidate, a common ADHD medication, on explore/exploit decisions using a 6-armed bandit task. We hypothesized that ADHD participants would make more exploratory decisions than controls, and that MPH would reduce group differences. On separate study days, adults with (n = 26) and without (n = 23) ADHD completed the bandit task at baseline, and after methylphenidate or placebo in counter-balanced order. Explore/exploit decisions were modeled using reinforcement learning algorithms. ADHD participants made more exploratory decisions (i.e., chose options without the highest expected reward value) and earned fewer points than controls in all three study days, and methylphenidate did not affect these outcomes. Baseline exploratory choices were positively associated with hyperactive ADHD symptoms across all participants. These results support several theoretical models of increased exploratory choices in ADHD and suggest the unexplained variance in ADHD decisions may be due to less value tracking. The inability to suppress actions with little to no reward value may be a key feature of hyperactive ADHD symptoms.Subject terms: ADHD, Cognitive control     

Do phenotypic characteristics, parental psychopathology, family functioning, and environmental stressors have a role in the response to methylphenidate in children with attention-deficit/hyperactivity disorder? A naturalistic study from a developing country

Little is known about the effect of clinical characteristics, parental psychopathology, family functioning, and environmental stressors in the response to methylphenidate in children with attention-deficit/hyperactivity disorder (ADHD) followed up in a naturalistic setting. Data from cultures outside the United States are extremely scarce. This is a longitudinal study using a nonrandom assignment, quasi-experimental design. One hundred twenty-five children with ADHD were treated with methylphenidate according to standard clinical procedures, and followed up for 6 months. The severity of ADHD symptoms was assessed by the Swanson, Nolan, and Pelham rating scale. In the final multivariate model, ADHD combined subtype (P < 0.001) and comorbidity with oppositional defiant disorder (P = 0.03) were both predictors of a worse clinical response. In addition, the levels of maternal ADHD symptoms were also associated with worse prognosis (P < 0.001). In the context of several adverse psychosocial factors assessed, only undesired pregnancy was associated with poorer response to methylphenidate in the final comprehensive model (P = 0.02). Our study provides evidence for the involvement of clinical characteristics, maternal psychopathology, and environmental stressors in the response to methylphenidate. Clinicians may consider adjuvant strategies when negative predictors are present to increase the chances of success with methylphenidate treatment.     

Dexmethylphenidate

Dexmethylphenidate comprises only the d-enantiomer (the pharmacologically effective isomer) of racemic methylphenidate and is indicated for the treatment of patients aged > or =6 years with attention deficit hyperactivity disorder (ADHD). In a 4-week, double-blind trial in 132 children with ADHD, significantly greater improvements from baseline in teacher-rated Swanson, Nolan and Pelham (SNAP)-ADHD scores were seen in dexmethylphenidate and methylphenidate recipients, compared with placebo recipients. In addition, significantly more dexmethylphenidate and methylphenidate recipients, compared with placebo recipients, were much improved or very much improved according to Clinical Global Impression-Improvement of Illness scale scores. In the same study, parent-rated SNAP-ADHD scores had decreased by a significantly greater extent in dexmethylphenidate recipients at 3pm and 6pm and in methylphenidate recipients at 3pm, compared with placebo recipients. Significantly fewer dexmethylphenidate than placebo recipients failed treatment in a double-blind, treatment-withdrawal trial in 75 children with ADHD (17.1 vs 61.5%). In a noncomparative study in 22 children with ADHD, symptoms of ADHD, as assessed by teachers and parents, were controlled during the entire school day in 68 and 86% of dexmethylphenidate recipients, respectively, with a median duration of effect of 6.3 and 7.5 hours, respectively. Dexmethylphenidate was generally well tolerated in children with ADHD; adverse events were consistent with those known to be associated with agents containing methylphenidate.     

Neurocognitive effects of methylphenidate in adult attention-deficit/hyperactivity disorder

Rationale Features of childhood attention-deficit/hyperactivity disorder (ADHD) often persist into adulthood. It has been shown that adult ADHD is associated with various neurocognitive deficits, including impairments in spatial working memory (SWM) and attention. It is not known whether these deficits are ameliorated by methylphenidate in adult ADHD.Objectives The aim of this study was to evaluate the neurocognitive effects of a single dose of methylphenidate on SWM, visual memory, spatial span and sustained attention in adult ADHD.Methods Twenty-four adult patients, recruited from a specialised clinic for the assessment of adult ADHD, were entered into a double-blind, randomised, placebo-controlled crossover study using a single 30 mg dose of methylphenidate.Results Eighteen patients met DSM-IV criteria for adult ADHD. Methylphenidate resulted in an improvement in SWM performance and sustained attention, together with a speeding in response time, in these patients. Six patients with attentional difficulties, who did not meet a DSM-IV diagnosis of ADHD, showed a different pattern of response to methylphenidate compared to the ADHD group. For the combined group, moderate correlations were shown between childhood ratings of ADHD (both self-reported and informant ratings) and response to methylphenidate on the SWM task.Conclusions Adults with ADHD had a similar neurocognitive response to methylphenidate to that previously reported for childhood ADHD. Our results provide further support for the validity of the ADHD syndrome as defined by DSM-IV and indicate possible neurocognitive substrates for clinical improvement with chronic methylphenidate.     

Long-acting methylphenidate reduces collision rates of young adult drivers with attention-deficit/hyperactivity disorder

This study investigated whether methylphenidate delivered through a long-acting transdermal system (MTS) would reduce collision rates of young adult drivers with attention-deficit/hyperactivity disorder (ADHD).Seventeen young adults completing the study (mean [SD] age, 20.82 [2.40] years; 14 men and 13 white) met the following inclusion criteria: ADHD diagnoses but not routinely taking ADHD medication, previously responsive to ADHD medication, active drivers with more than 1 collision or citation in the past 2 years, and no significant comorbidities. In this open-labeled, crossover design drivers were randomly assigned either to the no-medication condition for 3 months and then MTS for 3 months or to the reverse sequence. In-car video monitoring of routine driving occurred during these 6 months. At baseline and after each condition, participants completed the Conners Adult ADHD Rating Scale and the Cox Assessment of Risky Driving Scale, and their blood pressure, heart rate, and body weight were monitored.Compared with the no-medication condition, participants in the MTS condition self-reported fewer total ADHD (P < 0.04) and inattentive symptoms (P = 0.014) and a trend for risky driving behaviors (P = 0.059) and had fewer video-recorded collisions (P < 0.005) and other problematic driving events. There were no significant changes in blood pressure, heart rate, or body weight across conditions or any significant skin reactions to the MTS patch.This is the first study demonstrating that long-acting methylphenidate improves activities of daily living among young adults with ADHD. Specifically, methylphenidate improved safety in routine driving while reducing ADHD symptoms with minimal adverse effects.     

Effect of switching drug formulations from immediate-release to extended-release OROS methylphenidate : a chart review of Spanish adults with attention-deficit hyperactivity disorder

BACKGROUND: The potential advantages of osmotic-release oral system (OROS) methylphenidate (Concerta) over immediate-release (IR) methylphenidate (Rubifen) in adults with attention-deficit hyperactivity disorder (ADHD), with respect to medication adherence, effectiveness and tolerability, are yet to be determined. OBJECTIVE: To compare the adherence, effectiveness and tolerability of OROS methylphenidate versus IR methylphenidate in adults with ADHD. It was hypothesized (after data collection) that adherence and effectiveness would be higher with OROS methylphenidate than with the IR formulation. STUDY DESIGN: A chart review was carried out from April 2004 until April 2005. SETTING: Adult ADHD outpatient program in a general hospital in Spain. PATIENTS: Seventy adults with ADHD who met DSM-IV-TR criteria and who did not have any other current major psychiatric disorder. INTERVENTION: Patients were treated with IR methylphenidate three times daily for 3 months and then switched to OROS methylphenidate once daily. MAIN OUTCOME MEASURE: Effectiveness was assessed by means of the ADHD rating scale-IV (ADHD-RS-IV) and the Clinical Global Impression-Improvement (CGI-I) scale at 3 months (coinciding with treatment switch) and at 6 months. The Simplified Medication Adherence Questionnaire (SMAQ) was used to assess treatment adherence, and was administered at both 3 and 6 months. RESULTS: Seventy adult ADHD patients (mean age +/- SD: 30 +/- 9.6 years; n = 48 men [68.6%]) were included in this study. The mean baseline ADHD-RS-IV score was 34.6 (SD = 10.9). The mean daily dose of IR methylphenidate was 52.1 mg (SD = 13.8 mg) administered as three divided doses. After the treatment switch, the mean OROS methylphenidate daily dose was 57.9 mg (SD = 16.5 mg) administered once daily.The switch from IR methylphenidate to OROS methylphenidate was associated with a statistically significant improvement in all items of the SMAQ questionnaire. OROS methylphenidate was more effective than IR methylphenidate (p = 0.0005) in reducing symptoms of ADHD. The percentage of responders was 28.6% with IR methylphenidate and 91.4% with the OROS formulation (p = 0.0005). OROS methylphenidate was preferred by 97% of patients. The most common adverse events for each formulation were dry mouth (30% IR methylphenidate) and mood instability (31% OROS methylphenidate). No patients stopped treatment with methylphenidate because of adverse events. CONCLUSIONS: The switch from IR to OROS methylphenidate was associated with an improvement in both adherence and effectiveness. There were no differences between IR and OROS methylphenidate in terms of tolerability.     

Naturalistic long-term use of methylphenidate in bipolar disorder

Antidepressant use seems to be problematic in bipolar disorder. The dopaminergic agent, bupropion, seems to be equally effective to serotoninergic agents but with greater safety. Methylphenidate is a stimulant medication that is sometimes used as an antidepressant in bipolar adults and is frequently used in children with comorbid bipolar and attention-deficit disorder. There are no data available for the safety of long-term methylphenidate in adults. A retrospective chart review of bipolar patients who received methylphenidate while attending a bipolar clinic was conducted. Data regarding side effects and symptoms were collected. Sixteen charts were reviewed. The mean duration of methylphenidate treatment was 14 months (+/-SD, +/-17.5 months; range, 1-60 months). Five had comorbid attention-deficit disorder, the remainder received the methylphenidate for depression. The mean dose was 16.3 mg/d (+/-SD, +/-8.7 mg/d; range, 5-40 mg/d). Several mild to moderate side effects were reported. Two patients (12.5%) discontinued methylphenidate because of adverse side effects. When available (44% of the sample), general assessment of function increased from (+/-SD) 48.3 +/- 9.9 to 69.3 +/- 10.6 (P = 0.006). Methylphenidate seems to be safe in the naturalistic setting. Controlled studies are needed to confirm its efficacy and safety in bipolar depression.     

Aripiprazole as an augmentor of selective serotonin reuptake inhibitors in depression and anxiety disorder patients

More than half of anxiety and depression patients treated with an adequate course of antidepressants fail to fully improve. We retrospectively examined whether treatment-resistant depression and anxiety disorder patients responded to and tolerated augmentation with the atypical antipsychotic, aripiprazole. We report on patients with depression and anxiety disorders, including panic disorder, generalized anxiety disorder, social anxiety and post-traumatic stress disorder, who had an incomplete response to a variety of selective serotonin reuptake inhibitors (SSRIs) and who received augmentation with aripiprazole. The primary outcome measure was the Clinical Global Impression of Improvement (CGI-I). In the intent-to-treat analysis, the mean+/-SD CGI-S was 3.8+/-1.3 at endpoint. Fifty-nine percent of subjects received CGI-I ratings of 1 or 2, 'much improved' or 'very much improved,' in terms of their depression and anxiety symptoms at the end of 12 weeks. Several patients showed an early (weeks 1-5), as well as sustained, response to augmentation with doses of aripiprazole between 15 and 30 mg/day. The results suggest that aripiprazole may be effective as an augmentation for patients with persistent depressive and anxiety disorders despite initial SSRI treatment. Because this is a retrospective case review, further prospective studies are required to confirm these findings.     

Association of the catechol-O-methyltransferase polymorphism with methylphenidate response in a classroom setting in children with attention-deficit hyperactivity disorder

It has been postulated that the prefrontal cortex plays a key role in attention-deficit hyperactivity disorder (ADHD). The catechol-O-methyltransferase (COMT) enzyme degrades synaptic catecholamines and plays a specific role in the catabolism of prefrontal cortex dopamine. We investigated the association between the COMT valine (Val) 108/158 methionine (Met) polymorphism and the response to treatment with methylphenidate (MPH) in children with ADHD. This study included 124 children with ADHD in South Korea. Those patients who had an improvement after 8 weeks of treatment greater than or equal to 50% compared with the baseline ADHD rating scale scores before treatment were considered to be the 'good response' group. After performing genotyping for COMT, we examined the correlation of the COMT polymorphism with response to treatment with MPH using the chi test. We found that whereas 62.5% of the patients showing a good response to MPH treatment had the Val/Val genotype, 41.7 and 11.7% of the patients showing a poor response to MPH treatment as assessed by their teachers had the Val/Met and Met/Met genotypes (chi=6.58, d.f.=2, P=0.035). Our findings provide evidence of an association between the COMT genotype and MPH response as assessed by the teachers of children with ADHD.     

The effects of methylphenidate on prepulse inhibition during attended and ignored prestimuli among boys with attention-deficit hyperactivity disorder

Abstract Rationale and objectives. The present study investigated attentional modification of prepulse inhibition of startle among boys with and without attention-deficit hyperactivity disorder (ADHD). Two hypotheses were tested: (1) whether ADHD is associated with diminished prepulse inhibition during attended prestimuli, but not ignored prestimuli, and (2) whether methylphenidate selectively increases prepulse inhibition to attended prestimuli among boys with ADHD. Methods. Participants were 17 boys with ADHD and 14 controls. Participants completed a tone discrimination task in each of two sessions separated by 1 week. ADHD boys were administered methylphenidate (0.3 mg/kg) in one session and placebo in the other session in a randomized, double-blind fashion. During each series of 72 tones (75 dB; half 1200-Hz, half 400-Hz), participants were paid to attend to one pitch and ignore the other. Bilateral eyeblink electromyogram startle responses were recorded in response to acoustic probes (50-ms, 102-dB white noise) presented following the onset of two-thirds of tones, and during one-third of intertrial intervals. Results. Relative to controls, boys with ADHD exhibited diminished prepulse inhibition 120 ms after onset of attended but not ignored prestimuli following placebo administration. Methylphenidate selectively increased prepulse inhibition to attended prestimuli at 120 ms among boys with ADHD to a level comparable to that of controls, who did not receive methylphenidate. Conclusions. These data are consistent with the hypothesis that ADHD involves diminished selective attention and suggest that methylphenidate ameliorates the symptoms of ADHD, at least in part, by altering an early attentional mechanism. Electronic Publication     

Drug therapy for adults with attention-deficit hyperactivity disorder

Practitioners are increasingly called upon to diagnose and treat attention deficit hyperactivity disorder (ADHD) in adults. Although the use of pharmacotherapy in children with ADHD is well studied, the use of drugs for the treatment of adults with ADHD remains less well established.A systematic review of the literature identified 15 studies (n = 482 patients) of stimulants, and 27 studies of nonstimulant medications (n = 1179 subjects) including antidepressants, norepinephrine reuptake inhibitors, antihypertensive agents, amino acids and wake-promoting agents for the treatment of ADHD in adults.Controlled clinical trials in adults showed that stimulants, antidepressants and norepinephrine reuptake inhibitors demonstrated significant short-term improvements in ADHD symptoms compared with placebo. The two longer term trials with methylphenidate in adults confirmed the ongoing effectiveness and tolerability of stimulants. The response to amphetamine and methylphenidate appears to be dose-dependent. Methylphenidate and amphetamine had an immediate onset of action, whereas responses to pemoline, antidepressants and norepinephrine reuptake inhibitors appeared delayed. Controlled data on nicotinic/cholinergic compounds appear promising. Considerable variability was found in the diagnostic criteria for ADHD in adults, drug dosages and response rates between the various studies.Under controlled conditions, the aggregate literature comprised mainly of short-term studies, shows that stimulants, norepinephrine reuptake inhibitors and specific antidepressants had clinically and statistically significant beneficial effects in the treatment of ADHD in adults. Cholinergic agents appear promising. Further studies are necessary to evaluate the long-term effectiveness and tolerability of various agents, functional and neuropsychological outcomes, and the use of various agents in specific subgroups of adults with ADHD.     

Extended-release methylphenidate (Ritalin LA)

An extended-release formulation of methylphenidate (Ritalin LA), a CNS stimulant that inhibits dopamine and noradrenaline (norepinephrine) reuptake into presynaptic neurons, has been developed for use in patients with attention deficit/hyperactivity disorder (ADHD). In children with ADHD and healthy male adults, extended-release methylphenidate 20mg was rapidly absorbed and demonstrated two distinct peak plasma concentrations approximately 4 hours apart. The absorption pharmacokinetics of extended-release methylphenidate 20mg, which closely mimics those of immediate-release methylphenidate 10mg given in two doses 4 hours apart, permits once-daily administration. In a 2-week randomised, double-blind, placebo-controlled trial in 134 evaluable children aged 6 to 12 years with ADHD, symptoms improved to a significantly greater extent with extended-release methylphenidate 10 to 40mg once daily than with placebo. Extended-release methylphenidate improved both inattention and hyperactivity symptoms and was effective in children with combined- (inattentive and hyperactive/impulsive) type or predominantly inattentive-type ADHD. In clinical trials, the safety and tolerability profiles of extended-release methylphenidate were consistent with that of the immediate-release formulation.