Summary of the practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults.

This practice parameter describes treatment with stimulant medication. It uses an evidence-based medicine approach derived from a detailed literature review and expert consultation. Stimulant medications in clinical use include methylphenidate, dextroamphetamine, mixed salts of amphetamine, and pemoline. They carry U.S. Food and Drug Administration indications for the treatment of attention-deficit hyperactivity disorder.

Randomized, controlled trial of oros methylphenidate once a day in children with attention-deficit/hyperactivity disorder.

OBJECTIVE: A new once-a-day methylphenidate (MPH) formulation, Concerta (methylphenidate HCl) extended-release tablets (OROS MPH), has been developed. This study was conducted to determine the safety and efficacy of OROS MPH in a multicenter, randomized, clinical trial. METHODS: Children with attention-deficit/hyperactivity disorder (ADHD; n = 282), all subtypes, ages 6 to 12 years, were randomized to placebo (n = 90), immediate-release methylphenidate (IR MPH) 3 times a day (tid; dosed every 4 hours; n = 97), or OROS MPH once a day (qd; n = 95) in a double-blind, 28-day trial. Outcomes in multiple domains were assessed, and data were analyzed using analysis of variance and Kaplan Meier product limit estimates for time to study cessation. The primary time point for analysis was the last available patient visit using last observation carried forward. RESULTS: Children in the OROS and IR MPH groups showed significantly greater reductions in core ADHD symptoms than did children on placebo. This was true both at the end of week 1 and at the end of treatment on the basis of mean teacher and parent IOWA Conners ratings. IR MPH tid and OROS MPH qd did not differ significantly on any direct comparisons. Forty-eight percent of the placebo group discontinued early compared with 14% and 16% in the IR MPH and OROS MPH groups, respectively. CONCLUSIONS: For the treatment of core ADHD symptoms, OROS MPH dosed qd and IR MPH dosed tid were superior to placebo and were not significantly different from each other.attention-deficit/hyperactivity disorder, methylphenidate, OROS, Concerta.

Correlations between motor persistence and plasma levels in methylphenidate-treated boys with ADHD.

Following a 0.9 mg/kg methylphenidate loading dose, serial plasma level determinations, self-scored mood ratings, and measures of motor persistence were gathered on eight previously unmedicated boys with attention deficit disorder with hyperactivity (ADHD) during a 9-h period. The measures were repeated using the same loading dose after 6 months of maintenance treatment with methylphenidate (1.3 mg/kg x d). Kinetic-dynamic modelling suggests inverse correlative relationships between motor performance errors and plasma levels. Pharmacokinetic parameters did not change between acute and maintenance drug treatment phases, and there was no evidence of long-term tolerance.

Findings from the NIMH Multimodal Treatment Study of ADHD (MTA): implications and applications for primary care providers.

In 1992, the National Institute of Mental Health and 6 teams of investigators began a multisite clinical trial, the Multimodal Treatment of Attention-Deficit Hyperactivity Disorder (MTA) study. Five hundred seventy-nine children were randomly assigned to either routine community care (CC) or one of three study-delivered treatments, all lasting 14 months. The three MTA treatments-monthly medication management (usually methylphenidate) following weekly titration (MedMgt), intensive behavioral treatment (Beh), and the combination (Comb)-were designed to reflect known best practices within each treatment approach. Children were assessed at four time points in multiple outcome. Results indicated that Comb and MedMgt interventions were substantially superior to Beh and CC interventions for attention-deficit hyperactivity disorder symptoms. For other functioning domains (social skills, academics, parent-child relations, oppositional behavior, anxiety/depression), results suggested slight advantages of Comb over single treatments (MedMgt, Beh) and community care. High quality medication treatment characterized by careful yet adequate dosing, three times daily methylphenidate administration, monthly follow-up visits, and communication with schools conveyed substantial benefits to those children that received it. In contrast to the overall study findings that showed the largest benefits for high quality medication management (regardless of whether given in the MedMgt or Comb group), secondary analyses revealed that Comb had a significant incremental effect over MedMgt (with a small effect size for this comparison) when categorical indicators of excellent response and when composite outcome measures were used. In addition, children with parent-defined comorbid anxiety disorders, particularly those with overlapping disruptive disorder comorbidities, showed preferential benefits to the Beh and Comb interventions. Parental attitudes and disciplinary practices appeared to mediate improved response to the Beh and Comb interventions.

Symptom profiles in children with ADHD: effects of comorbidity and gender.

OBJECTIVE: To examine ratings and objective measures of attention-deficit/hyperactivity disorder (ADHD) symptoms to assess whether ADHD children with and without comorbid conditions have equally high levels of core symptoms and whether symptom profiles differ as a function of comorbidity and gender. METHOD: Four hundred ninety-eight children from the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA) were divided into comorbid groups based on the parent Diagnostic Interview Schedule for Children and assessed via parents' and teachers' Swanson, Nolan, and Pelham (SNAP) ratings and a continuous performance test (CPT). Comorbidity and gender effects were examined using analyses of covariance controlled for age and site. RESULTS: CPT inattention, impulsivity, and dyscontrol errors were high in all ADHD groups. Children with ADHD + oppositional defiant or conduct disorder were rated as more impulsive than inattentive, while children with ADHD + anxiety disorders (ANX) were relatively more inattentive than impulsive. Girls were less impaired than boys on most ratings and several CPT indices, particularly impulsivity, and girls with ADHD + ANX made fewer CPT impulsivity errors than girls with ADHD-only. CONCLUSIONS: Children with ADHD have high levels of core symptoms as measured by rating scales and CPT, irrespective of comorbidity. However, there are important differences in symptomatology as a function of comorbidity and gender.

ADHD comorbidity findings from the MTA study: comparing comorbid subgroups.

OBJECTIVES: Previous research has been inconclusive whether attention-deficit/hyperactivity disorder (ADHD), when comorbid with disruptive disorders (oppositional defiant disorder [ODD] or conduct disorder [CD]), with the internalizing disorders (anxiety and/or depression), or with both, should constitute separate clinical entities. Determination of the clinical significance of potential ADHD + internalizing disorder or ADHD + ODD/CD syndromes could yield better diagnostic decision-making, treatment planning, and treatment outcomes. METHOD: Drawing upon cross-sectional and longitudinal information from 579 children (aged 7-9.9 years) with ADHD participating in the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA), investigators applied validational criteria to compare ADHD subjects with and without comorbid internalizing disorders and ODD/CD. RESULTS: Substantial evidence of main effects of internalizing and externalizing comorbid disorders was found. Moderate evidence of interactions of parent-reported anxiety and ODD/CD status were noted on response to treatment, indicating that children with ADHD and anxiety disorders (but no ODD/CD) were likely to respond equally well to the MTA behavioral and medication treatments. Children with ADHD-only or ADHD with ODD/CD (but without anxiety disorders) responded best to MTA medication treatments (with or without behavioral treatments), while children with multiple comorbid disorders (anxiety and ODD/CD) responded optimally to combined (medication and behavioral) treatments. CONCLUSIONS: Findings indicate that three clinical profiles, ADHD co-occurring with internalizing disorders (principally parent-reported anxiety disorders) absent any concurrent disruptive disorder (ADHD + ANX), ADHD co-occurring with ODD/CD but no anxiety (ADHD + ODD/CD), and ADHD with both anxiety and ODD/CD (ADHD + ANX + ODD/CD) may be sufficiently distinct to warrant classification as ADHD subtypes different from "pure" ADHD with neither comorbidity. Future clinical, etiological, and genetics research should explore the merits of these three ADHD classification options.

Multimodal treatment of ADHD in the MTA: an alternative outcome analysis.

OBJECTIVE: To conduct a post hoc investigation of the utility of a single composite measure of treatment outcome for the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA) at 14 months postbaseline. BACKGROUND: Examination of multiple measures one at a time in the main MTA intent-to-treat outcome analyses failed to detect a statistically significant advantage of combined treatment (Comb) over medication management (MedMgt). A measure that increases power and precision using a single outcome score may be a useful alternative to multiple outcome measures. METHOD: Factor analysis of baseline scores yielded two "source factors" (parent and teacher) and one "instrument factor" (parent-child interactions). A composite score was created from the average of standardized parent and teacher measures. RESULTS: The composite was internally consistent (alpha = .83), reliable (test-retest over 3 months = 0.86), and correlated 0.61 with clinician global judgments. In an intent-to-treat analysis, Comb was statistically significantly better than all other treatments, with effect sizes ranging from small (0.28) versus MedMgt, to moderately large (0.70) versus a community comparison group. CONCLUSIONS: A composite of ADHD variables may be an important tool in future treatment trials with ADHD and may avoid some of the statistical limitations of multiple measures.

Clinical relevance of the primary findings of the MTA: success rates based on severity of ADHD and ODD symptoms at the end of treatment.

OBJECTIVES: To develop a categorical outcome measure related to clinical decisions and to perform secondary analyses to supplement the primary analyses of the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA). METHOD: End-of-treatment status was summarized by averaging the parent and teacher ratings of attention-deficit/hyperactivity disorder and oppositional defiant disorder symptoms on the Swanson, Nolan, and Pelham, version IV (SNAP-IV) scale, and low symptom-severity ("Just a Little") on this continuous measure was set as a clinical cutoff to form a categorical outcome measure reflecting successful treatment. Three orthogonal comparisons of the treatment groups (combined treatment [Comb], medication management [MedMgt], behavioral treatment [Beh], and community comparison [CC]) evaluated hypotheses about the MTA medication algorithm ("Comb + MedMgt versus Beh + CC"), multimodality superiority ("Comb versus MedMgt"), and psychosocial substitution ("Beh versus CC"). RESULTS: The summary of SNAP-IV ratings across sources and domains increased the precision of measurement by 30%. The secondary analyses of group differences in success rates (Comb = 68%; MedMgt = 56%; Beh = 34%; CC = 25%) confirmed the large effect of the MTA medication algorithm and a smaller effect of multimodality superiority, which was now statistically significant (p < .05). The psychosocial substitution effect remained negligible and nonsignificant. CONCLUSION: These secondary analyses confirm the primary findings and clarify clinical decisions about the choice between multimodal and unimodal treatment with medication.

Methylphenidate dosage for children with ADHD over time under controlled conditions: lessons from the MTA.

OBJECTIVES: To examine the trajectory of methylphenidate (MPH) dosage over time, following a controlled titration, and to ascertain how accurately the titration was able to predict effective long-term treatment in children with attention-deficit/hyperactivity disorder (ADHD). METHOD: Using the 14-month-treatment database of the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA), the outcome of the initial placebo-controlled, double-blind, randomized daily switch titration of MPH was compared with the subsequent maintenance pharmacotherapy. Children received monthly monitoring visits and, when needed, medication adjustments. RESULTS: Of the 198 children for whom MPH was the optimal treatment at titration (mean +/- SD dose: 30.5 +/- 14.2 mg/day), 88% were still taking MPH at the end of maintenance (mean dose 34.4 +/- 13.3 mg/day). Titration-determined dose and end-of-maintenance dose were significantly correlated (r = 0.52-0.68). Children receiving combined pharmacotherapy and behavioral treatment ended maintenance on a lower dose (31.1 +/- 11.7 mg/day) than did children receiving pharmacotherapy only (38.1 +/- 14.2 mg/day). Of the 230 children for whom titration identified an optimal treatment, 17% continued both the assigned medication and dosage throughout maintenance. The mean number of pharmacological changes per child was 2.8 +/- 1.8 (SD), and time to first change was 4.7 months +/- 0.3 (SE). CONCLUSIONS: For most children, initial titration found a dose of MPH in the general range of the effective maintenance dose, but did not prevent the need for subsequent maintenance adjustments. For optimal pharmacological treatment of ADHD, both careful initial titration and ongoing medication management are needed.

Impairment and deportment responses to different methylphenidate doses in children with ADHD: the MTA titration trial.

OBJECTIVE: Results of the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA) were analyzed to determine whether a double-blind, placebo-controlled methylphenidate (MPH) titration trial identified the best MPH dose for each child with attention-deficit/hyperactivity disorder (ADHD). METHOD: Children with ADHD assigned to MTA medication treatment groups (n = 289) underwent a controlled 28-day titration protocol that administered different MPH doses (placebo, low, middle, and high) on successive days. RESULTS: A repeated-measures analysis of variance revealed main effects for MPH dose with greater effects on teacher ratings of impairment and deportment (F3 = 100.6, n = 223, p = .0001; effect sizes 0.8-1.3) than on parent ratings of similar endpoints (F3 = 55.61, n = 253, p = .00001; effect sizes 0.4-0.6). Dose did not interact with period, dose order, comorbid diagnosis, site, or treatment group. CONCLUSIONS: The MTA titration protocol validated the efficacy of weekend MPH dosing and established a total daily dose limit of 35 mg of MPH for children weighing less than 25 kg. It replicated previously reported MPH response rates (77%), distribution of best doses (10-50 mg/day) across subjects, effect sizes on impairment and deportment, as well as dose-related adverse events.

Psychosocial treatment strategies in the MTA study: rationale, methods, and critical issues in design and implementation.

The Collaborative Multimodal Treatment Study of Children with Attention Deficit Hyperactivity Disorder (ADHD), the MTA, is the first multisite, cooperative agreement treatment study of children, and the largest psychiatric/psychological treatment trial ever conducted by the National Institute of Mental Health. It examines the effectiveness of Medication vs. Psychosocial treatment vs. their combination for treatment of ADHD and compares these experimental arms to each other and to routine community care. In a parallel group design, 579 (male and female) ADHD children, aged 7-9 years, 11 months, were randomly assigned to one of the four experimental arms, and then received 14 months of prescribed treatment (or community care) with periodic reassessments. After delineating the theoretical and empirical rationales for Psychosocial treatment of ADHD, we describe the MTA's Psychosocial Treatment strategy applied to all children in two of the four experimental arms (Psychosocial treatment alone; Combined treatment). Psychosocial treatment consisted of three major components: a Parent Training component, a two-part School Intervention component, and a child treatment component anchored in an intensive Summer Treatment Program. Components were selected based on evidence of treatment efficacy and because they address comprehensive symptom targets, settings, comorbidities, and functional domains. We delineate key conceptual and logistical issues faced by clinical researchers in design and implementation of Psychosocial research with examples of how these issues were addressed in the MTA study.

Anxiety as a predictor and outcome variable in the multimodal treatment study of children with ADHD (MTA).

Initial moderator analyses in the Multimodal Treatment Study of Children with ADHD (MTA) suggested that child anxiety ascertained by parent report on the Diagnostic Interview Schedule for Children 2.3 (DISC Anxiety) differentially moderated the outcome of treatment. Left unanswered were questions regarding the nature of DISC Anxiety, the impact of comorbid conduct problems on the moderating effect of DISC Anxiety, and the clinical significance of DISC Anxiety as a moderator of treatment outcome. Thirty-three percent of MTA subjects met DSM-III-R criteria for an anxiety disorder excluding simple phobias. Of these, two-thirds also met DSM-III-R criteria for comorbid oppositional-defiant or conduct disorder whereas one-third did not, yielding an odds ratio of approximately two for DISC Anxiety, given conduct problems. In this context, exploratory analyses of baseline data suggest that DISC Anxiety may reflect parental attributions regarding child negative affectivity and associated behavior problems (unlike fearfulness), particularly in the area of social interactions, another core component of anxiety that is more typically associated with phobic symptoms. Analyses using hierarchical linear modeling (HLM) indicate that the moderating effect of DISC Anxiety continues to favor the inclusion of psychosocial treatment for anxious ADHD children irrespective of the presence or absence of comorbid conduct problems. This effect, which is clinically meaningful, is confined primarily to parent-reported outcomes involving disruptive behavior, internalizing symptoms, and inattention; and is generally stronger for combined than unimodal treatment. Contravening earlier studies, no adverse effect of anxiety on medication response for core ADHD or other outcomes in anxious or nonanxious ADHD children was demonstrated. When treating ADHD, it is important to search for comorbid anxiety and negative affectivity and to adjust treatment strategies accordingly.

Parenting and family stress treatment outcomes in attention deficit hyperactivity disorder (ADHD): an empirical analysis in the MTA study.

Parenting and family stress treatment outcomes in the MTA study were examined. Male and female (579), 7-9-year-old children with combined type Attention Deficit Hyperactivity Disorder (ADHD), were recruited at six sites around the United States and Canada, and randomly assigned to one of four groups: intensive, multi-faceted behavior therapy program alone (Beh); carefully titrated and monitored medication management strategy alone (MedMgt); a well-integrated combination of the two (Comb); or a community comparison group (CC). Treatment occurred over 14 months, and assessments were taken at baseline, 3, 9, and 14 months. Parenting behavior and family stress were assessed using parent-report and child-report inventories. Results showed that Beh alone, MedMgt alone, and Comb produced significantly greater decreases in a parent-rated measure of negative parenting, Negative/Ineffective Discipline, than did standard community treatment. The three MTA treatments did not differ significantly from each other on this domain. No differences were noted among the four groups on positive parenting or on family stress variables. Results are discussed in terms of the theoretical and empirically documented importance of negative parenting in the symptoms, comorbidities and long-term outcomes of ADHD.

Family processes and treatment outcome in the MTA: negative/ineffective parenting practices in relation to multimodal treatment.

To elucidate processes underlying therapeutic change in a large-scale randomized clinical trial, we examined whether alterations in self-reported parenting practices were associated with the effects of behavioral, medication, or combination treatments on teacher-reported outcomes (disruptive behavior, social skills, internalizing symptoms) in children with attention-deficit hyperactivity disorder (ADHD). Participants were 579 children with Combined-type ADHD, aged 7-9.9 years, in the Multimodal Treatment Study of Children with ADHD (MTA). We uncovered 2 second-order factors of parenting practices, entitled Positive Involvement and Negative/Ineffective Discipline. Although Positive Involvement was not associated with amelioration of the school-based outcome measures, reductions in Negative/Ineffective Discipline mediated improvement in children's social skills at school. For families showing the greatest reductions in Negative/Ineffective Discipline, effects of combined medication plus behavioral treatment were pronounced in relation to regular community care. Furthermore, only in combination treatment (and not in behavioral treatment alone) was decreased Negative/Ineffective Discipline associated with reduction in children's disruptive behavior at school. Here, children in families receiving combination treatment who showed the greatest reductions in Negative/Ineffective Discipline had teacher-reported disruptive behavior that was essentially normalized. Overall, the success of combination treatment for important school-related outcomes appears related to reductions in negative and ineffective parenting practices at home; we discuss problems in interpreting the temporal sequencing of such process-outcome linkages and the means by which multimodal treatment may be mediated by psychosocial processes related to parenting.

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.

Effects of desipramine on autonomic input to the heart.

OBJECTIVE: To examine the impact of age on the effects of desipramine (DMI) on autonomic input to the heart. METHOD: Twenty-four-hour electrocardiograms were obtained from 42 subjects, aged 7 to 66 years, while off and on DMI. To obtain measures of autonomic input to the heart, heart rate variability was assessed via spectral analysis of RR interval variability. RESULTS: DMI treatment was associated with a significant increase in 24-hour mean heart rate and significant decreases in RR interval variability in all spectral bands, including in the high-frequency band, which provides a measure of parasympathetic input to the heart. RR interval variability was greater in younger individuals both off and on DMI. CONCLUSIONS: DMI treatment was associated with a marked decline in RR interval variability, indicating that DMI affects autonomic input to the heart. Specifically, DMI reduced parasympathetic input, which, in theory, may increase vulnerability to arrhythmias. However, the magnitude of DMI's impact on RR interval variability did not vary with age.

Stimulant medications.

OBJECTIVE: To review the short- and long-term safety and efficacy of stimulants for the treatment of children with attention-deficit/hyperactivity disorder (ADHD). METHOD: A Medline search was conducted for both randomized controlled trials and reviews to determine the efficacy and safety of stimulant drugs for treating children with ADHD. Information was obtained on adverse events associated with their use, including their impact on height and weight gain during childhood. Animal data were reviewed for information on tolerance, sensitization, and the impact of high-dose stimulant effects on neurons and on the development of hepatic tumors. Human data on dopamine transporter occupancy by stimulants were also included. RESULTS: Stimulant treatment studies show robust short-term efficacy and a good safety profile. Longer-term studies are few in number but have produced no conclusive evidence that careful therapeutic use of these medications is harmful. CONCLUSION: Current evidence indicates that stimulants show efficacy and safety in studies lasting up to 24 months.

Cardiovascular effects of desipramine in children and adults during exercise testing.

OBJECTIVE: In light of recent reports of sudden death in children being treated with desipramine (DMI), 3 of which were associated with physical exercise, the authors examined the effects of DMI on exercise in children and adults before and during DMI treatment. METHOD: Before treatment, 22 subjects (9 children, 13 adults) participated in a graded treadmill exercise test. Outcome measures included exercise tolerance, cardiovascular, and electrocardiographic parameters at progressive intensity levels and serum norepinephrine (NE) levels before and after exercise testing. Subjects were then treated with DMI, titrated to an average DMI dosage of 3 mg/kg, and underwent repeated exercise testing. RESULTS: DMI treatment was associated with a significant elevation of circulating NE levels in the pre-exercise assessment. Exercise tolerance was not affected by DMI, and blood pressure and heart rate effects were modest. The cardiovascular impact of DMI treatment was similar in children and adults. One 31-year-old subject exhibited a brief episode of ventricular tachycardia associated with exercise during DMI treatment. CONCLUSIONS: DMI has only minor effects on the cardiovascular response to exercise, and these effects do not appear age-related. However, DMI may increase the risk of exercise-associated arrhythmias in rare individuals.