Efficacy of Adderall and methylphenidate in attention deficit hyperactivity disorder: a reanalysis using drug-placebo and drug-drug response curve methodology.

Because methylphenidate (MPH) is currently the most widely prescribed medication for attention deficit hyperactivity disorder (ADHD), several studies have used this as the touch-stone for evaluating the efficacy of a newer stimulant, Adderall. In a parallel-groups study of MPH (n = 20), Adderall (n = 20), and placebo (n = 18), Pliszka et al. (2000) reported that both medications were superior to placebo in improving parent, teacher, and clinician ratings of ADHD and associated behaviors. Compared with MPH, Adderall led to significantly more improvements in teacher and clinician ratings. The present study extends these results by addressing the issue of clinical significance using drug-placebo and drug-drug response curve analyses of the same data. The goal of this method is to answer the following questions about drug-placebo or drug-drug differences: Is the effect clinically meaningful? What does the effect tell us about individual responses? Is the effect due to symptom improvement, the prevention of worsening, or both? Our results show that the efficacy of Adderall to improve functioning is seen throughout the full range of improvement scores. In contrast, MPH showed a substantial effect for "mildly" and "much improved" but not for "very much improved." Our analyses also show that both Adderall and MPH prevent worsening of symptoms. They further suggest that, compared with the Conners Teacher Rating Scale, the Clinical Global Impressions scale may be more sensitive to improvements at the "well end" of the spectrum of functioning.

Validation of the Interview Module for Intermittent Explosive Disorder (M-IED) in children and adolescents: a pilot study.

We identified a subset of impulsive, aggressive children as having symptoms that met criteria for Intermittent Explosive Disorder (IED) using the Interview Module for Intermittent Explosive Disorder (M-IED). The M-IED was administered to 34 children and adolescents between the ages of 10 and 17. These data provide initial evidence for the M-IED as a useful instrument in the diagnosis of IED in adolescents. The M-IED displayed a high level of inter-rater reliability and adequate test-retest reliability. Construct validity was supported by the fact that the subjects with IED symptomatology had significantly more lifetime aggression, oppositionality, inattention and hyperactivity/impulsivity compared to community controls. In addition, the subjects with IED symptomatology had a significantly greater number of episodes of lifetime physical aggression and documented episodes of aggression while in residential treatment compared to psychiatric controls. The subjects with IED symptomatology had a greater number of positive screening questions for DSM-IV diagnoses using the Swanson, Nolan and Pelham questionnaire (SNAP-IV), particularly those related to IED and posttraumatic stress disorder than psychiatric controls.

New developments in psychopharmacology of attention deficit hyperactivity disorder.

Stimulants have been the mainstay of the psychopharmacological treatment of attention deficit hyperactivity disorder (ADHD) for over 60 years. In the last 5 years, there have been a number of important developments in terms of potential new treatments for ADHD. Since stimulants have such a short half-life, considerable research has focused on the development of new delivery systems that will allow once-a-day dosing. New formulations of both amphetamine (AMP) and methylphenidate (MPH) have appeared which differ in terms of their optical isomers from the commonly used compounds. A wide variety of compounds are currently in development as therapeutic agents for ADHD. Some, like the stimulants, primarily impact the noradrenergic and dopaminergic neurotransmitter systems, while others have novel effects on the cholinergic, histaminergic and peptidergic systems. Advances in the pharmacogenetics of ADHD may lead to the development of yet more compounds in the near future.

Inhibitory control in children with attention-deficit/hyperactivity disorder: event-related potentials identify the processing component and timing of an impaired right-frontal response-inhibition mechanism.

BACKGROUND: A core deficit in inhibitory control may account for a wide range of dysfunctional behaviors in attention-deficit/hyperactivity disorder (ADHD). METHODS: Event-related potentials were measured in 10 children with ADHD and 10 healthy children during a task specifically involving response inhibition (Stop signal task). RESULTS: In response to all Stop signals, control participants produced a large negative wave at 200 msec (N200) over right inferior frontal cortex, which was markedly reduced in ADHD children. The N200 amplitude was significantly correlated across subjects with response-inhibition performance. In response to the Go stimuli, ADHD children showed a reduced slow positive wave (250-500 msec) in anticipation of failed inhibitions over right frontal scalp regions. CONCLUSIONS: ADHD children appear to have an abnormality in an early-latency, right inferior frontal processing component critical to the initiation of normal response-inhibition operations. They also appear to have a right frontal abnormality associated to the covert processing of Go stimuli preceding failed inhibitions. By providing timing and processing component specificity, these results extend the findings of recent functional MRI studies of inhibitory control reporting right frontal abnormalities in ADHD.

Patterns of psychiatric comorbidity with attention-deficit/hyperactivity disorder.

Attention deficit/hyperactivity disorder (ADHD) is frequently comorbid with a variety of psychiatric disorders. These disorders include oppositional defiant (ODD) and conduct disorders (CD), and affective, anxiety, and learning disorders. Studies which have examined the comorbidity of these disorders with ADHD are reviewed. ADHD and ADHD with CD seem to be distinct subtypes; children with ADHD/CD are at higher risk of antisocial personality as adults. Coexisting anxiety may attenuate impulsivity in ADHD. Studies examining stimulant response in children with ADHD/anxiety have recently yielded conflicting results. Anxiety and ADHD seem to be inherited independently. The prevalence of major depressive disorder (MDD) and bipolar disorder among children with ADHD is controversial, but there clearly exists a subgroup of severely emotionally labile children with ADHD who present serious management issues for the clinician. About 20% to 25% of children with ADHD meet criteria for a learning disorder (LD), but LD seems to be independent of ADHD.

The Texas Children's Medication Algorithm Project: Report of the Texas Consensus Conference Panel on Medication Treatment of Childhood Attention-Deficit/Hyperactivity Disorder. Part I. Attention-Deficit/Hyperactivity Disorder.

OBJECTIVES: Expert consensus methodology was used to develop evidence-based, consensually agreed-upon medication treatment algorithms for attention-deficit/hyperactivity disorder (ADHD) in the public mental health sector. Although treatment algorithms for adult mental disorders have been developed, this represents one of the first attempts to develop similar algorithms for childhood mental disorders. Although these algorithms were developed initially for the public sector, the goals of this approach are to increase the uniformity of treatment and improve the clinical outcomes of children and adolescents with ADHD in a variety of treatment settings. METHOD: A consensus conference of academic clinicians and researchers, practicing clinicians, administrators, consumers, and families was convened to develop evidence-based consensus algorithms for the pharmacotherapy of childhood ADHD. After a series of presentations of current research evidence and panel discussion, the consensus panel met and drafted the algorithms along with guidelines for implementation. RESULTS: The panel developed consensually agreed-upon algorithms for ADHD with and without specific comorbid disorders. The algorithms consist of systematic strategies for psychopharmacological interventions and tactics to ensure successful implementation of the strategies. While the algorithms focused on the medication management of ADHD, the conference emphasized that psychosocial treatments are often a critical component of the overall management of ADHD. CONCLUSIONS: Medication algorithms for ADHD can be developed with consensus. A companion article will discuss the implementation of these algorithms.

The Texas Children's Medication Algorithm Project: Report of the Texas Consensus Conference Panel on Medication Treatment of Childhood Attention-Deficit/Hyperactivity Disorder. Part II: Tactics. Attention-Deficit/Hyperactivity Disorder.

OBJECTIVES: Expert consensus methodology was used to develop a medication treatment algorithm for attention-deficit/hyperactivity disorder (ADHD). The algorithm broadly outlined the choice of medication for ADHD and some of its most common comorbid conditions. Specific tactical recommendations were developed with regard to medication dosage, assessment of drug response, management of side effects, and long-term medication management. METHOD: The consensus conference of academic clinicians and researchers, practicing clinicians, administrators, consumers, and families developed evidence-based tactics for the pharmacotherapy of childhood ADHD and its common comorbid disorders. The panel discussed specifics of treatment of ADHD and its comorbid conditions with stimulants, antidepressants, mood stabilizers, alpha-agonists, and (when appropriate) antipsychotics. RESULTS: Specific tactics for the use of each of the above agents are outlined. The tactics are designed to be practical for implementation in the public mental health sector, but they may have utility in many practice settings, including the private practice environment. CONCLUSIONS: Tactics for psychopharmacological management of ADHD can be developed with consensus.

A double-blind, placebo-controlled study of Adderall and methylphenidate in the treatment of attention-deficit/hyperactivity disorder.

OBJECTIVE: While Adderall has been available for the treatment of attention-deficit/hyperactivity disorder (ADHD) for several years, there are few controlled studies comparing it to methylphenidate. METHOD: Fifty-eight children with ADHD (mean age 8.1 +/- 1.4 years) were randomly assigned to receive placebo, methylphenidate, or Adderall in a double-blind, parallel-group design for 3 weeks. Dosage was adjusted at the end of weeks 1 and 2 via an algorithm based on teacher and parent ratings. Final doses were 12.5 +/- 4.1 mg/day for Adderall and 25.2 +/- 13.1 mg/day for methylphenidate. Teacher and parent ratings, as well as the psychiatrist's Clinical Global Impression (CGI), were the final outcome measures at the end of week 3. RESULTS: Both medications were superior to placebo at reducing inattentive and oppositional symptoms in the classroom and on the CGI. Adderall produced significantly more improvements on teacher ratings and the CGI than methylphenidate, although the algorithm may have limited dosing in the methylphenidate group. Seventy percent of children in the Adderall group were given medication once a day, compared with 15% of the subjects receiving methylphenidate. CONCLUSIONS: Adderall compared favorably to methylphenidate, and the behavioral effects of Adderall appear to persist longer than those of methylphenidate after individual doses.

Affective disorder in juvenile offenders: A preliminary study.

OBJECTIVE: The authors' goal was to determine the prevalence of major mental disorders and substance abuse in adolescents admitted to a juvenile detention center. METHOD: As part of a routine mental health screening, modules from the Diagnostic Interview Schedule for Children were administered to 50 youths (11-17 years old) at an urban juvenile detention center. RESULTS: A high rate of affective disorder (42%) was found among these adolescents: 10 (20%) met criteria for mania, another 10 met criteria for major depressive disorder, and one met criteria for bipolar disorder, mixed type. Thirty (60%) met criteria for conduct disorder, and very high rates of alcohol, marijuana, and other substance dependence were found. There was a strong association between affective disorder and conduct disorder; adolescents with mania had much higher rates of reported abuse of substances other than alcohol or marijuana. CONCLUSIONS: Juvenile offenders have high rates of affective disorder. Further studies are needed to examine the relationship of affective disorder to substance abuse as well as to antisocial behavior.

The Texas Children's Medication Algorithm Project: report of the Texas Consensus Conference Panel on Medication Treatment of Childhood Major Depressive Disorder.

OBJECTIVES: To develop consensus guidelines for medication treatment algorithms for childhood major depressive disorder (MDD) based on scientific evidence and clinical opinion when science is lacking. The ultimate goal of this approach is to synthesize research and clinical experience for the practitioner and to increase the uniformity of preferred treatment for childhood MDD. A final goal is to develop an approach that can be tested as to whether it improves clinical outcomes for children and adolescents with MDD. METHOD: A consensus conference was held. Participants included academic clinicians and researchers, practicing clinicians, administrators, consumers, and families. The focus was to review and use clinical evidence to recommend specific pharmacological approaches for treatment of MDD in children and adolescents. After a series of presentations of current research evidence and panel discussion, the consensus panel met, agreed on assumptions, and drafted the algorithms. The process initially addressed strategies of treatment and then tactics to implement the strategies. RESULTS: Consensually agreed-upon algorithms for major depressions (with and without psychosis) and comorbid attention deficit disorders were developed. Treatment strategies emphasized the use of selective serotonin reuptake inhibitors. The algorithm consists of systematic strategies for treatment interventions and recommended tactics for implementation of the strategies, including medication augmentation and medication combinations. Participants recommended prospective evaluation of the algorithms in various public sector settings, and many volunteered as sites for such an evaluation. CONCLUSIONS: Using scientific and clinical experience, consensus-derived algorithms for children and adolescents with MDD can be developed.

Nontricyclic antidepressants: current trends in children and adolescents.

OBJECTIVES: First, to review the extant data on the safety and efficacy of the use of nontricyclic antidepressants in children and adolescents; second, to identify the main limitations of our current knowledge in this area; and third, to point to future research directions. METHOD: A Medline search and a review of previous scientific meetings were conducted; all available reports on the efficacy and safety of nontricyclic antidepressants in children and adolescents were critically reviewed. RESULTS: As in adults, also in children nontricyclic antidepressants are potentially useful in treating a variety of psychiatric disorders. The data supporting their efficacy, however, are quite limited. Obsessive-compulsive disorder is the only psychiatric diagnosis for which pediatric use of selective serotonin reuptake inhibitors has been approved. One placebo-controlled study in children and adolescents with major depression supports the efficacy of fluoxetine. Other clinical trials of nontricyclic antidepressants in depressed adolescents are in progress. Available data indicate that the safety of these medications is good, at least in the short term. CONCLUSIONS: The potential usefulness of nontricyclic antidepressants for children and adolescents suffering from a range of disorders is considerable. While information from adults can suggest potential areas of possible efficacy in pediatric patients suffering from similar psychopathology, further research is essential to provide the necessary information on the efficacy, safety, and pharmacokinetics of these medications in children and adolescents.

Comorbidity of attention-deficit/hyperactivity disorder with psychiatric disorder: an overview.

Attention-deficit/hyperactivity disorder (ADHD) has been noted to be comorbid with a variety of psychiatric disorders. These include oppositional defiant and conduct disorders, as well as affective, anxiety, and learning disorders. Considerable debate has revolved as to the meaning of this overlap. Does it occur by chance or is it an artifact of referral bias? Are the comorbid conditions secondary to the ADHD, or can other psychiatric disorders masquerade as attentional problems? Alternatively, ADHD may exist as distinct subtypes, each with its specific comorbidity. Studies that have examined the comorbidity of oppositional, conduct, affective, anxiety, and learning disorders in ADHD are reviewed. ADHD and ADHD with conduct disorder appear to be distinct subtypes, possibly with different etiologies. While the short-term response to stimulants is the same in these two groups, children with ADHD and conduct disorder children have higher rates of antisocial personality as adults. Coexisting anxiety appears to attenuate impulsivity in ADHD, and stimulant response is poorer in ADHD children with comorbid anxiety. Anxiety and ADHD appear to be inherited independently. A subset of ADHD children also meet criteria for bipolar disorder, although the exact prevalence of this diagnosis in ADHD children is strongly debated. Regardless of prevalence, this is a severely impaired group of ADHD children, with high rates of aggression and psychiatric disorder in their families. The comorbidity of ADHD and major depression is much less studied, and few firm conclusions can be made about it. Finally, about 20%-25% of ADHD children meet criteria for a learning disorder, but learning disorders appear to be independent of ADHD.

The use of psychostimulants in the pediatric patient.

The psychostimulant drugs have a long history of safe and effective usage in the treatment of ADHD. They remain the drugs of first choice in this condition. Children with ADHD should be aggressively treated with at least two different classes of psychostimulants before moving to nonpsychostimulant agents. As long as side effects are not troublesome, higher dosages may be used to adequately control the ADHD symptoms, and such high dosages do not impair learning. No evidence shows long-term effects of psychostimulants on growth. Effective use of the psychostimulants is essential for any clinician involved in the treatment of children with ADHD.

Measuring inhibitory control in children.

The Stop Signal Task is a measure of inhibitory control in which subjects must press a button in response to a stimulus. On certain trials, the subject receives a second stimulus (the Stop Signal) after the primary stimulus and must withhold his/her response during those trials. The onset of the Stop Signal is varied, sometimes coming immediately after the primary stimulus (inhibition is easy); at other times, the Stop Signal arrives quite late, making inhibition difficult. Results from the Stop Signal Task were obtained from children with attention-deficit/hyperactivity disorder (ADHD) and from controls; children with ADHD had significantly more difficulty inhibiting their responses than did controls. In a second study, results from the Stop Signal Task were obtained from a large sample of both behaviorally disturbed and community children; variables from the Stop Signal Task correlated well with both laboratory observations and teacher ratings of inattention and hyperactivity.

Catecholamines in attention-deficit hyperactivity disorder: current perspectives.

OBJECTIVE: To provide an update on the "catecholamine hypothesis" of attention-deficit hyperactivity disorder (ADHD). METHOD: Recent work examining the measurement of the norepinephrine, epinephrine, and dopamine systems in ADHD and normal subjects is reviewed and discussed in the context of recent neuroimaging and animal studies. RESULTS: While data clearly indicate a role for all three of the above neurotransmitters in ADHD, a hypothesis suggesting "too much" or "too little" of a single neurotransmitter will no longer suffice. The central norepinephrine system may be dysregulated in ADHD, such that this system does not efficiently "prime" the cortical posterior attention system to external stimuli. Effective mental processing of information involves an anterior "executive" attention system which may depend on dopaminergic input. The peripheral epinephrine system may be a critical factor in the response of individuals with ADHD to stimulant medication. CONCLUSION: A multistage hypothesis is presented which emphasizes the interaction of norepinephrine, epinephrine, and dopamine in modulation of attention and impulse control.

An open trial of venlafaxine in the treatment of attention-deficit/hyperactivity disorder in children and adolescents.

A 5-week open trial of venlafaxine was conducted in 16 children and adolescents (mean age 11.6 years) with attention-deficit/hyperactivity disorder (ADHD) in order to estimate the appropriate dosage range and to determine the extent of side effects. Subjects were evaluated using a structured clinical interview and a computerized diagnostic assessment, and subjects diagnosed with ADHD and without comorbid depression were asked to enter the study. Conners Parent Rating Scale (CPRS) and Conners Continuous Performance Test (CPT) were performed at baseline and at the end of the 5-week trial. Two subjects were lost to follow-up. Of the remaining 14 patients, 7 subjects displayed a decrease of at least one standard deviation from their baseline on one of the CPRS subscale scores and had subjective reports from parents of improved behavior. There were no statistically significant effects of venlafaxine on reaction times or on the number of commission and omission errors on CPT. Three ADHD subjects displayed a worsening of their hyperactivity and required discontinuation of venlafaxine, and nausea led to drug discontinuation in 1 patient. The mean daily dose of venlafaxine was 60 mg (1.4 mg/kg), administered 2-3 divided doses, there were no effects on blood pressure or heart rate. In this sample, low doses of venlafaxine appeared to be effective in reducing behavioral but not cognitive symptoms of ADHD in 7 of 16 children and adolescents (44%), and adverse effects were not tolerable in 4 of 16 patients (25%). These preliminary results suggest that venlafaxine may aggravate symptoms of hyperactivity, consistent with the behavioral activation reported with fluoxetine and sertraline in children.

Urinary catecholamines in attention-deficit hyperactivity disorder with and without comorbid anxiety.

OBJECTIVE: To determine whether there are differences in noradrenergic or adrenergic functioning in children with attention-deficit hyperactivity disorder (ADHD) with and without anxiety. METHOD: ADHD children with and without a comorbid overanxious (ANX) disorder were compared to each other and to normal controls in terms of 2-hour urinary excretion of norepinephrine (NE), epinephrine (EPI), and their metabolites. All subjects performed a fixed series of mentally stressful tasks during the collection period. RESULTS: Children with ADHD, regardless of comorbid anxiety, excreted more normetanephrine (NMN), the chief extracellular metabolite of NE, than controls, as well as more vanillylmandelic acid. Children with ADHD alone had lower NE/NMN and EPI/metanephrine ratios compared to controls. Children with ADHD/ANX excreted more EPI than ADHD children without anxiety. CONCLUSIONS: Children with ADHD may have a higher tonic activity of the noradrenergic system than controls, while children with comorbid ADHD/ANX may be differentiated from those with ADHD alone by higher adrenergic activity.