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This practice parameter describes the assessment and treatment of children and adolescents with attention-deficit/ hyperactivity disorder (ADHD) based on the current scientific evidence and clinical consensus of experts in the field. This parameter discusses the clinical evaluation for ADHD, comorbid conditions associated with ADHD, research on the etiology of the disorder, and psychopharmacological and psychosocial interventions for ADHD. J. Am. Acad. Child Adolesc. Psychiatry, 2007;46(7):894Y921. Key Words: attention-deficit/hyperactivity disorder, evaluation, treatment, practice parameter.

OBJECTIVES. Patients receiving methylphenidate for the management of attention-deficit/hyperactivity disorder are recommended to receive periodic hematologic monitoring. The objective of this study was to evaluate the long-term effects of methylphenidate treatment on blood biochemistry and hematologic values. METHODS. This study involved a detailed analysis of changes in hematologic and blood biochemistry values over the course of a 2-year study of once-daily OROS methylphenidate in otherwise healthy children aged 6 to 13 years with attention-deficit/hyperactivity disorder. Routine hematologic and blood biochemistry assessments were performed at baseline, at 6 and 12 months during study treatment, and at the end of the study. RESULTS. Of the 407 subjects enrolled in the study, 289 completed year 1, and 229 completed 21 of 24 months. No subject was excluded from entry into the study or discontinued from the study because of abnormalities of any of the blood chemistries evaluated. There were no clinically significant changes from baseline in mean values for hematologic or blood biochemistry parameters. For most values, the mean change in value over the course of the study was CONCLUSIONS. These longer-term data suggest that chronic therapy with OROS methylphenidate has no clinically significant impact on laboratory values, challenging the necessity of routine hematologic monitoring in otherwise healthy children with attention-deficit/hyperactivity disorder who are treated with methylphenidate.

BackgroundStudies of adults with attention deficit hyperactivity disorder (ADHD) show an elevated prevalence of substance use disorders (SUDs) and the substance abuse literature shows that ADHD is elevated in substance users. Some researchers postulate that stimulant treatment of ADHD increases the risk for SUD in ADHD patients but follow-up studies suggest treatment protects patients from subsequent SUDs. This report uses retrospective data to assess the impact of prior ADHD pharmacotherapy on SUDs in 206 ADHD adults (n=79 late-onset ADHD, n=127 full ADHD) grouped by lifetime history of ADHD treatment (no treatment, past treatment, current and past treatment).MethodStructured Clinical Interview for DSM-IV (SCID) data were used to establish abuse and dependence, and Drug Use Screening Inventory (DUSI) responses were used to establish prevalence of use, preference for cigarettes, alcohol and drugs of abuse, complications from use, and motivation for use (get high, change mood, sleep better).ResultsNo differences were found in the prevalence of cigarette smoking, alcohol or drug abuse or dependence, as well as no significant differences in 1-month prevalence of any use or use more than 20 times. No differences were found in complications of drug or alcohol use across groups. Subjects with current treatment rated getting high as a motivating factor significantly more frequently than subjects in the past treatment group; this result lost significance when we included ADHD diagnostic category.ConclusionsOur results are consistent across substances and ADHD diagnoses, and support the hypothesis that pharmacotherapy does not cause subsequent SUDs.

Despite the continuity of attention-deficit/hyperactivity disorder (ADHD) into adolescence, little is known regarding use of nonstimulants to treat ADHD in adolescents. This phase 3 trial evaluated the safety and efficacy of guanfacine extended release (GXR) in adolescents with ADHD.This 13-week, multicenter, randomized, double-blind, placebo-controlled trial evaluated once-daily GXR (1-7 mg per day) in adolescents with ADHD aged 13 to 17 years. The primary endpoint was the change from baseline in the ADHD Rating Scale-IV (ADHD-RS-IV) total score; key secondary endpoints included scores from the Clinical Global Impressions-Severity of Illness (CGI-S), and Learning and School domain and Family domain scores from the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P) at week 13.A total of 314 participants were randomized (GXR, n = 157; placebo, n = 157). The majority of participants received optimal doses of 3, 4, 5, or 6 mg (30 [22.9%], 26 [19.8%], 27 [20.6%], or 24 [18.3%] participants, respectively), with 46.5% of participants receiving an optimal dose above the currently approved maximum dose limit of 4 mg. Participants receiving GXR showed improvement in ADHD-RS-IV total score compared with placebo (least-squares mean score change, -24.55 [GXR] versus -18.53 [placebo]; effect size, 0.52; p.001). More participants on GXR also showed significant improvement in CGI-S scores compared with placebo (50.6% versus 36.1%; p = .010). There was no statistically significant difference between treatments at week 13 in the 2 WFIRS-P domains. Most treatment-emergent adverse events were mild to moderate, with sedation-related events reported most commonly.GXR was associated with statistically significant improvements in ADHD symptoms in adolescents. GXR was well tolerated, with no new safety signals reported.Dose-Optimization in Adolescents Aged 13-17 Diagnosed With Attention-Deficit/Hyperactivity Disorder (ADHD) Using Extended-Release Guanfacine HCl; http://ClinicalTrials.gov/; NCT01081132.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent neuropsychiatric disorders of adulthood. Although clinical guidelines recommend monotherapy with stimulants or atomoxetine, combination pharmacotherapy is a common practice among clinicians. There are four main situations in which combination medications may be necessary: partial response, dose-limiting side effects, associated disorders, and comorbid diagnoses. We present data from two chart reviews that support existing research on combination pharmacotherapy. Adjunct treatment of d-methylphenidate to stimulant medications extended the duration of therapeutic effect. Adjunct treatment of mirtazapine to stimulant medications reduced associated insomnia. These data support previous research that validates the use of combination pharmacotherapy for adults with ADHD.

Several medications have been demonstrated effective in treating individuals with attention-deficit/hyperactivity disorder (ADHD). There appears to be some commonality in the physiologic mechanisms of action of these agents relevant to the treatment of ADHD. Either direct or indirect attenuation of dopamine and norepinephrine neurotransmission appears related to both the stimulant and nonstimulant medications efficacious in ADHD. However, important differences exist both between and within the specific classes of agents. Elucidating the various mechanisms of action of ADHD medications may lead to better choices in matching potential response to the characteristics (e.g., genotype) of individuals.

Although, family, twin, and adoption studies indicate that genes play a significant etiologic role in the development of substance use disorders (SUDs), the specific genes involved have been difficult to detect due, in part, to uncertainties about how best to define SUDs, the possibility of genetic heterogeneity and the variable phenotypic expression of SUD genotypes. The goal of the present work was to determine if phenotypes external to the diagnosis of SUD such as psychopathology and cognitive functioning would show evidence of utility as phenotypes for genetic studies of SUD. We did this by applying factor analysis to multiple measures collected from our family-study program and then determining if these factors were heritable and were co-familial with SUDs. We used data from families recruited into six contemporaneous studies of four psychiatric conditions in children and adults. We found evidence for two SUD related phenotypes. One was an index of Psychopathology and Psychosocial Impairment; the other was an index of school failure and cognitive dysfunction. Both factors showed evidence of heritability, longitudinal stability and familial association with Parental SUD but these findings were stronger for the index of school failure and cognitive dysfunction. Results provide some support for the idea that candidate SUD phenotypes such as psychopathology and cognitive functioning, which are external to the diagnostic criteria for SUDs, may be useful for genetic studies of SUD.

To evaluate the short-term tolerability of an extended-release preparation of the stimulant medication mixed amphetamine salts (MAS XR) in adults with attention-deficit/hyperactivity disorder (ADHD) whose hypertension has been successfully treated with antihypertensive medications.An 8-week, 2-phase, open-label study design was implemented. All adults had ADHD (DSM-IV diagnosis) and essential hypertension and were required to be normotensive (blood pressure135/85 mm Hg, treated) for at least 4 weeks at entry into the study. MAS XR was given for a 6-week period, titrated once each week to a target maximum dose of 60 mg/day given once daily in the morning (phase 1), and then discontinued for 2 weeks at the end of the study (phase 2). At baseline, subjects underwent a comprehensive clinical assessment, medical history, vital signs assessment, and electrocardiogram (ECG). Rating scales were used throughout the study to assess response to treatment, and blood pressure was measured manually at each study visit. The primary outcome was the effect of MAS XR on blood pressure and the development of hypertension.Thirteen subjects receiving antihypertensive therapy were entered and placed on MAS XR treatment and completed the trial. There were no serious adverse events. No sustained elevated blood pressure (140/90 mm Hg at 2 consecutive visits) was observed in the subjects treated with MAS XR. Similar rates of single episodes of hypertension were observed in phases 1 and 2. Similarly, there was no group mean increase in systolic or diastolic blood pressure or pulse during treatment with MAS XR. No clinically significant changes in the ECG were observed. During the 6-week medication phase, significant improvement was found on rating scales assessing ADHD symptoms and severity that reversed with discontinuation of MAS XR.The results of this open study suggest that adults with ADHD and controlled hypertension can be safely treated with MAS XR.

Journal of the American Academy of Child & Adolescent Psychiatry - Vol. 45 - N° 10 - p. 1147-1150

This 8-week, open-label extension of a double-blind study reports on safety data for 171 adolescents with attention-deficit/hyperactivity disorder (ADHD) who received once-daily OROS methylphenidate (MPH) (18-72 mg/day). Headache, anorexia, and insomnia were the most frequently reported treatment-related adverse events. The incidence of adverse events was not related to dose. OROS MPH was safe and well tolerated at doses up to 72 mg/day.

Objective Little is known about the risks and characteristics of attention-deficit/hyperactivity disorder (ADHD) patients who misuse or divert their stimulant medications. As part of a 10-year longitudinal study of youths with ADHD, the authors evaluated medication diversion or misuse at the last follow-up period. Method Structured psychiatric interviews for diagnosis and a self-report questionnaire regarding medication use in medicated subjects with ADHD compared with controls without ADHD receiving psychotropics for non-ADHD treatment were employed. Results Of 98 subjects receiving psychotropic medications (mean age of 20.8 ± 5 years), 55 (56%) were ADHD subjects and 43 (44%) were controls receiving medications for other purposes. The authors found that 11% of the ADHD group reported selling their medications compared with no subjects in the control group ( z = 0.00, p z = 1.7 p =.09) and that those with conduct or substance use disorders accounted for the misuse and diversion. A minority of subjects reported escalating their doses and concomitant use with alcohol and drugs. Conclusions The data indicate that the majority of ADHD individuals, particularly those without conduct or substance use disorders, use their medications appropriately. The authors' findings also highlight the need to monitor medication use in ADHD individuals with conduct and/or substance use disorders and to carefully select agents with a low likelihood of diversion or misuse in this group. J. Am. Acad. Child Adolesc. Psychiatry , 2006;45(4):408-414.

Background: Recent studies reported ADHD-like symptoms and cognitive deficits in pervasive developmental disorder (PDD). Because work in dementia documents improvement in executive function deficits with the acetylcholinesterase inhibitor donepezil, the authors reason that similar benefits could be obtained in PDD. Method: The authors describe eight cases of PDD youth ages 10 to 17 treated with donepezil targeting ADHD-like symptoms associated with PDD. Results: Most participants improve ADHD-like symptomatology. In addition, improvement in communication and socialization is noted. Conclusion: Donepezil may have a role in treating ADHD-like symptoms in children with PDD.

Objective Controversy exists over changes in tolerability and response to medications across the life span. Here the authors report data contrasting the efficacy and tolerability of atomoxetine between children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Method Data were analyzed for children ages 6-11 (510 atomoxetine, 341 placebo) and adolescents ages 12-17 (107 atomoxetine, 69 placebo) with DSM-IV -defined ADHD enrolled in similarly designed, double-blind, placebo-controlled trials. Efficacy measures included response rates, times to response, and mean changes from baseline to endpoint in the ADHD Rating Scale, Conners' Parent Rating Scale, and Clinical Global Impressions. Results Adolescents had lower baseline ADHD scores compared with children. There were no statistically significant differences in the overall effects on ADHD symptoms, response rates, or time to response between age groups. Children, but not adolescents, had higher rates of somnolence and headache relative to placebo. No other clinically meaningful treatment differences were seen in adverse event rates, vital signs, weight, height, laboratory values, or ECG between children and adolescents. Conclusions Acute atomoxetine treatment appears to be equally effective and tolerated in children and adolescents. These findings suggest that pharmacological differences in tolerability or ADHD symptom response are negligible between children and adolescents.

Background We systematically examined potential aggression/hostility-related events in a meta-analysis of acute clinical trials of atomoxetine for attention-deficit/hyperactivity disorder (ADHD). Methods Pediatric patients from 14 trials of atomoxetine were subdivided into a placebo-controlled (atomoxetine n = 1308, placebo n = 806) or active comparator databases (atomoxetine n = 566, methylphenidate n = 472). A third database comprised adult patients from placebo-controlled studies (atomoxetine n = 541, placebo n = 405). A computerized search of adverse events and comments identified patients with potential aggression/hostility events. Mantel–Haenszel incidence differences (MHID) were calculated. Results In the placebo-controlled database, we observed 21 atomoxetine and 9 placebo patients with reported aggression/hostility events, MHID of .6% (95% confidence interval [CI]: –.4, 1.7). In the active comparator database, there were seven events in atomoxetine and four in methylphenidate patients, MHID = .2% (95% CI: –1.0,1.3). In the adult database, there were no events in 0 atomoxetine and one placebo patient, MHID = –.3% (95% CI: –.8, .2). Conclusions Aggression/hostility-related events occurred in less than 2% of patients and were more frequent in pediatric patients treated with atomoxetine versus placebo (risk ratio of 1.33; not statistically significant). The risk of aggression/hostility events was similar in patients treated with atomoxetine or methylphenidate.

Despite available pharmacotherapeutics, a number of youths with attentiondeficit/ hyperactivity disorder (ADHD) continue to experience residual symptoms and prominent executive function (EF) deficits resulting in impairment in multiple domains. We sought to determine if donepezil, used adjunctively to stimulant medication, would improve residual symptoms of ADHD and EF deficits.In a 12-week open trial, we treated 7 children and 6 adults who had ADHD and evidence of further EF deficits with adjunctive donepezil. All subjects were stabilized on stimulants, at which time donepezil was initiated at 2.5 mg daily and increased to a maximum of 10 mg over the 12-week trial.Of 13 subjects receiving medication, 7 completed the trial. There was no clinically or statistically significant improvement in the ADHD Rating Scale and the Executive Function Checklist, our primary outcome measures. A majority of individuals experienced nonserious adverse events.Results of this small open study suggest that donepezil augmentation of stimulants is not well tolerated and does not appear useful for the treatment of residual ADHD and/or EF deficits.

Objective: To assess long-term cardiovascular effects of mixed amphetamine salts extended release (MAS XR) in adults with attention-deficit/hyperactivity disorder (ADHD) combined subtype.Methods: 223 otherwise healthy adults (≥18 years of age) with ADHD combined subtype were exposed to ≤24 months of MAS XR (20–60 mg/day). Resting sitting diastolic blood pressure (DBP) and systolic blood pressur (SBP) and pulse were measured at baseline and weekly, then monthly during long-term treatment. Twelve-lead electrocardiograms were obtained at screening/baseline, weekly, then at 3-and 6-month intervals up to 24 months.Findings: With MAS XR 20–60 mg/day, mean changes in DBP (1.3±9.2 mm Hg; P=.O42), SBP (2.3±12.5 mmHg; P=.OO6), and pulse (2.1±13.4 bpm; P=.019) were small and not clinically significant. A clinically insignificant increase in QTcB (corrected by Bazett's formula) interval (7.2 msec; P480 msec (QTcF [corrected by Fridericia's formula] >454 msec). Seven subjects discontinued due to a car-diovascular adverse event (hypertension, n=5, palpitation/tachycardia, n=2); none of these events was reported as serious. Few subjects with normal baseline vital signs (using approved parameters at the time of study initiation) exhibited clinically significant abnormalities at end point; several subjects with borderline baseline values exhibited shifts to abnormal values during MAS XR therapy.Conclusion: Cardiovascular effects of long-term MAS XR (≤60 mg/day) were minimal in otherwise healthy adults with ADHD. Nevertheless, vital signs should be monitored prior to and during treatment with any stimulant.

Adolescents and adults with attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUD) are increasingly recognized in clinical practice. The role of pharmacological treatment for ADHD in these comorbid individuals remains unclear.A systematic review of the medical literature was conducted through PubMed, supplemented with data from scientific presentations, to evaluate the role of medication treatment of ADHD in substance abusing individuals with ADHD. Meta-analysis was used to evaluate the effects of medication therapy on ADHD and SUD outcomes in general, while specifically addressing trial design, trial duration, retention, class of medication, age group, concurrent psychotherapy, and outcome in both SUD and ADHD domains.Four studies in adolescents and five studies in adults with ADHD plus SUD were identified (two controlled and seven open studies; n = 222 subjects). The standard mean difference (SMD) indicated statistically significant improvements in ADHD and SUD that were not maintained when evaluating controlled studies only. Albeit limited by power, trial duration, retention rate, and age group did not influence outcome. No worsening of SUD or drug-drug interactions were observed in any of the studies. The results could not be accounted for by any single study or by publication bias.Treating ADHD pharmacologically in individuals with ADHD plus SUD has a moderate impact on ADHD and SUD that is not observed in controlled trials and does not result in worsening of SUD or adverse interactions specific to SUD. Further controlled trials evaluating the effect of novel combinations of psychotherapy and ADHD pharmacotherapy on SUD relapse in these groups are warranted.

Substance use disorders (SUD) are increasingly conceptualized as developing during adolescence. Moreover, adolescent SUD are viewed as one of the most difficult mental health conditions to treat. The role of pharmacotherapy for adolescents with SUD is not well delineated. We systematically reviewed existing pharmacotherapy studies of adolescent SUD.A computerized search of the literature addressing the pharmacotherapy of SUD in adolescents was performed. Data from relevant peer-reviewed scientific presentations were also included.Five case reports (n = 8 subjects), six open studies that primarily addressed SUD with comorbid psychiatric disorders (n = 73 subjects), and five placebo-controlled studies (n = 156 subjects) on the pharmacological treatment of youths with SUD were identified. Pharmacological agents appear to reduce comorbid psychopathology with a milder reduction in SUD symptoms. The most robust evidence exists for the treatment of SUD comorbid with affective disorders. There is a limited database supporting the use of agents to reduce substance craving and the preventative effects of pharmacotherapy on subsequent SUD development in adolescents with specific psychiatric disorders.Further controlled studies directed at reducing drug use and craving, and guiding the integration of pharmacotherapy and psychosocial interventions for SUD with the treatment of comorbid psychiatric illness, are necessary.

The objective of the study was to investigate the characteristics of adults with Attention Deficit Hyperactivity Disorder (ADHD) or substance use disorder (SUD), especially in the context of comorbid psychiatric disorders. Subjects were adults (n = 78) participating in a controlled family study of ADHD and SUD. Four groups were identified based on a diagnosis of ADHD or SUD: ADHD, SUD, ADHD + SUD, and neither ADHD nor SUD. All diagnoses were determined by structured clinical interview for DSM IV. Rates of psychiatric comorbidity were lowest in the controls, intermediate in the ADHD and SUD groups, and highest in the ADHD + SUD group. Relative to controls, the ADHD, SUD, and ADHD + SUD groups had higher rates of major depression (z = 1.98, p = 0.05), conduct disorder (z = 2.0, p = 0.04), antisocial personality disorder (z = 2.6, p = 0.009), agoraphobia (z = 2.5, p = 0.01) and social phobia (z = 2.7, p = 0.007). Higher rates of psychiatric comorbidity, especially mood and anxiety disorders, exist in subjects with SUD + ADHD relative to subjects with SUD, ADHD, or controls. Clinicians need to be attentive to other psychiatric disorders that may occur in the large group of adults with ADHD + SUD.

As part of a pilot-controlled family-based study of the children of parents with and without substance use disorders (SUD), the influence of parental SUD and ADHD on the risk for ADHD in offspring was evaluated. Using structured psychiatric interviews, 96 families (183 youth; mean age 11.6 years) were assessed. To evaluate the effect of parental ADHD and SUD, the offspring were stratified into four groups based on parental status: children of parents with neither ADHD nor SUD, children of parents with SUD only, children of parents with ADHD only, and children of parents with both ADHD and SUD. Using generalized estimating equation models, parental SUD and ADHD were used to predict ADHD in the offspring. The rate of children with ADHD increased among children of parents with neither disorder (3%), children of parents with SUD (13%), children of parents with ADHD (25%), and children of parents with both ADHD and SUD (50%) (p = .001). Children of parents with ADHD or ADHD plus SUD were more likely to have ADHD in comparison to children of parents with neither diagnosis (p < 0.05). Children of parents with ADHD plus SUD were at greater risk of ADHD in comparison to children of parents with SUD only (p = 0.01). Despite the small sample size, the results of this study seem to suggest that the offspring of SUD or ADHD parents are at elevated risk for ADHD compared to controls. The offspring of parents with both ADHD and SUD appear to be at the highest risk for ADHD, highlighting the need for careful screening of this group of youth for ADHD. Replication studies clarifying the nature and strength of the association are necessary.

To determine the efficacy and safety of atomoxetine in adolescent subjects treated for attention-deficit/hyperactivity disorder (ADHD) for up to 2 years.Data from 13 atomoxetine studies (6 double-blind, 7 open-label) were pooled for subjects age 12 to 18 with ADHD as defined by the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders IV.Of the 601 atomoxetine-treated subjects in this meta-analysis, 537 (89.4%) completed 3 months of acute treatment. A total of 259 subjects (48.4%) are continuing atomoxetine treatment; 219 of these subjects have completed at least 2 years of treatment. The mean dose of atomoxetine at endpoint was 1.41 mg/kg/day. Mean ADHD Rating Scale IV, parent version, investigator-administered and -scored total scores showed significant improvement (P.001) over the first 3 months. Symptoms remained improved up to 24 months without dosage escalation. During the 2-year treatment period, 99 (16.5%) subjects discontinued treatment due to lack of effectiveness, and 31 (5.2%) subjects discontinued treatment due to adverse events. No clinically significant abnormalities in height, weight, blood pressure, pulse, mean laboratory values, or electrocardiography parameters were found.Two-year data from this ongoing study indicate that atomoxetine maintains efficacy among adolescents with ADHD, with no evidence of drug tolerance and no new or unexpected safety concerns.

Attention-deficit/hyperactivity disorder (ADHD) is the most common mental disorder in childhood, and primary care clinicians provide a major component of the care for children with ADHD. However, because of limited available evidence, the American Academy of Pediatrics guidelines did not include adolescents and young adults. Contrary to previous beliefs, it has become clear that, in most cases, ADHD does not resolve once children enter puberty. This article reviews the current evidence about the diagnosis and treatment of adolescents and young adults with ADHD and describes how the information informs practice. It describes some of the unique characteristics observed among adolescents, as well as how the core symptoms change with maturity. The diagnostic process is discussed, as well as approaches to the care of adolescents to improve adherences. Both psychosocial and pharmacologic interventions are reviewed, and there is a discussion of these patients' transition into young adulthood. The article also indicates that research is needed to identify the unique adolescent characteristics of ADHD and effective psychosocial and pharmacologic treatments.

Background The goal of this study was to assess whether cigarette smoking is a gateway drug for subsequent alcohol and illicit drug abuse and dependence in youth with Attention Deficit Hyperactivity Disorder (ADHD), and to test if this association is stronger in ADHD youth relative to controls. Methods We used data from a case-control family study of female youth with and without ADHD. We studied 97 ADHD and 203 control youth of both sexes, aged at least 12 years. We assessed ADHD, smoking, and substance use status using structured diagnostic interviews. We tested the association between cigarette smoking and subsequent substance use outcomes using Cox proportional hazard regression models. Results ADHD youth who smoked cigarettes (n = 15) were significantly more likely to subsequently use alcohol and illicit drugs as well as to develop abuse and dependence compared to ADHD youth who did not smoke (n = 76; p Conclusions These results extend the gateway hypothesis to an ADHD sample and provide evidence that this effect may be particularly robust in ADHD youth. If replicated in larger, community-based samples, these findings have important public health consequences, and underscore the already pressing need to prevent smoking in ADHD children.

The association between executive function deficits (EFDs) and functional outcomes were examined among children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Participants were children and adolescents with (n = 259) and without (n = 222) ADHD, as ascertained from pediatric and psychiatric clinics. The authors defined EFD as at least 2 executive function measures impaired. Significantly more children and adolescents with ADHD had EFDs than did control participants. ADHD with EFDs was associated with an increased risk for grade retention and a decrease in academic achievement relative to (a) ADHD alone, (b) controlled socioeconomic status, (c) learning disabilities, and (d) IQ. No differences were noted in social functioning or psychiatric comorbidity. Children and adolescents with ADHD and EFDs were found to be at high risk for significant impairments in academic functioning. These results support screening children with ADHD for EFDs to prevent academic failure.

A substantial literature supports the viability of nonstimulant treatments for ADHD. Despite their chemical differences, the various compounds with documented anti-ADHD activity share a common noradrenergic/dopaminergic activity. Although TCAs are established alternative treatments forADHD, particularly the more noradrenergic secondary amines (DMI and nortriptyline), their narrow therapeutic index and potential for cardiovascular toxicity have limited their use. The atypical mixed noradrenergic/dopaminergic antidepressant bupropion also has been documented to be effective in treating adults with ADHD in a controlled clinical trial. Recent work with the novel noradrenergic specific agent, atomoxetine, has produced convincing evidence of substantial efficacy, tolerability, and safety in children and adults. Despite these advances, more work is needed to further document the short- and long-term safety and efficacy of stimulants and alternative agents for treating adults with ADHD. It also is hoped that advances in the understanding of the underlying neurobiology of ADHDwill lead to the development of a new generation of safe and effective treatments for this disorder. Such developments have the promise of improving the quality of life of the millions of affected patients and their families worldwide.

To develop treatment guidelines for the stimulant treatment of adults, the authors reviewed the available literature of medication trials in attentiondeficit/hyperactivity disorder (ADHD), attentive to issues of psychiatric comorbidity, age, gender, and ethnic background [1]. The review showed stimulants to be the most established treatment for ADHD. Over 100 controlled studies with more than 5000 children and adolescents have documented their efficacy in about 70% of subjects. The literature clearly documents that stimulants not only improve abnormal behaviors of ADHD, but also self-esteem, cognition, and social and family functioning. Efficacy varied with age and psychiatric comorbidities, however. In addition, most studies have focused on latency age Caucasian boys. Little is known about other subgroups. Most of the existing studies are very brief, lasting a few weeks at most, with until recently [2,3]. A very limited literature exists for stimulants at other ages, for females [4–6] and for ethnic minorities [7]. A potential barrier to therapeutics is the increasing recognition that ADHD is a heterogeneous disorder with considerable comorbidity with conduct, mood, and anxiety disorders [8] and tic disorders [9]. It is not clear if these groups respond preferentially to different psychotropics. For example, an emerging literature suggests that anxious and depressed children with ADHD respond more poorly to stimulants than children with only ADHD in their ADHD symptoms [10–14]. In addition, stimulants are thought to be anxiogenic and depressogenic; however, the effect of stimulants on the comorbid anxiety and depression symptoms has been assessed rarely in any study. Although stimulants may be depressogenic, it is

Attention-deficit/hyperactivity disorder (ADHD) is a risk factor for substance abuse in adults. Additional psychiatric comorbidity increases this risk. ADHD is associated with different characteristics of substance abuse: substance abuse transitions more rapidly to dependence, and lasts longer in adults with ADHD than those without ADHD. Self-medication may be a factor in the high rate of substance abuse in adults with ADHD. While previous concerns arose whether stimulant therapy would increase the ultimate risk for substance abuse, recent studies have indicated that pharmacologic treatment appears to reduce the risk of substance abuse in individuals with ADHD. When treating adults with ADHD and substance abuse, clinicians should assess the relative severity of the substance abuse, the symptoms of ADHD, and any other comorbid disorders. Generally, stabilizing or addressing the substance abuse should be the first priority when treating an adult with substance abuse and ADHD. Treatment for adults with ADHD and substance abuse should include a combination of addiction treatment/psychotherapy and pharmacotherapy. The clinician should begin pharmacotherapy with medications that have little likelihood of diversion or low liability, such as bupropion and atomoxetine, and, if necessary, progress to the stimulants. Careful monitoring of patients during treatment is necessary to ensure compliance with the treatment plan.

Despite its common onset in preschool years, few studies have examined the characteristics of bipolar disorder (BPD) in preschoolers. This study reports on the clinical characteristics, psychiatric comorbidity, and functioning of preschoolers identified with BPD who were referred to a pediatric psychiatric clinic.Structured psychiatric interviews assessing lifetime psychopathology by Diagnostic and Statistical Manual of Mental Disorders (third edition, revised) criteria were completed with parents about their children and confirmed by clinical interview of the child. Family, social, and overall functioning were also assessed at intake. Findings from preschoolers ages 4 to 6 years were compared with a group of children ages 7 to 9 years (school age).We identified 44 preschoolers and 29 consecutively ascertained school-age youth with BPD. Preschoolers had similar rates of comorbid psychopathology compared to school-age youth with BPD. Preschoolers and school-age children with BPD typically manifest symptoms of mania and major depression simultaneously (mixed states). Both preschoolers and school-age children had substantial impairment in school, social, and overall functioning.These results suggest that clinically referred preschoolers with BPD share with school-age children with BPD high rates of comorbid psychopathology and impaired functioning. Follow-up of these clinically referred preschoolers with BPD evaluating the stability of their diagnoses, treatment response, and their long-term outcome is necessary.

Increasingly, multiple agents are being used for the treatment of psychiatric disorders in children and adolescents. The need to use combinations of medications has arisen out of the often less than satisfactory response to single agents, an emerging awareness of the high rates of psychiatric comorbidity (Bird ct al., 1993), and the apparent synergy of combined agents for certain disorders. Gerald Klerman has noted "current medical thinking is driven by Thomas Kuhn's paradigm presupposing a nosologic concept of disease: each disease has its specific etiology, and hence, specific treatment. Given that in current psychiatric practice there is a lack of specific treatments (i.e., those directed at etiology), the practitioner is often left with the use of nonspecific treatments for syndromal disorders or target symptoms" (Meltzer, 1987, p. 1700). In addition, "specific" has often been misconstrued to mean single and may represent a set or combination of interventions. Finally, medications such as the selective serotonergic reuptake inhibitors (SSRls) may have a narrow scope of activity addressing only a limited number of target symptoms. Although clinicians hope that patients will respond to single psychotherapeutic agents, with difficult cases this may be the exception as opposed to the rule. Given the vast array of potential combinations, clinicians should become familiar with commonly used medication regimens and those associated with adverse effects (c.g., excessive sedation) or drug interactions (i.c., Huoxcrinc plus tricyclic antidepressants). In the following sections, we will highlight some of

Despite a rapidly growing literature on the efficacy of the selective serotonin reuptake inhibitors (SSRI) in the treatment of juvenile psychiatric disorders, relatively little is described about emotional, behavioral, and cognitive adverse effects associated with their use. To this end we completed a retrospective analysis of medical charts to determine the incidence, nature, and clinical correlates of treatment emergent adverse effects in the behavioral, cognitive, and emotional domains.We systematically evaluated the medical charts of children treated with SSRI for depressive or obsessive-compulsive disorders for a mean (+/- SD) of 26.9 + 20.8 months to determine the incidence, nature, and clinical correlates of treatment emergent psychiatric adverse events (PAE). Charts were reviewed for diagnoses, type and dose of SSRI and adjunct medication, specific type of PAE, and time to onset and offset of PAE.In total, 82 charts of children and adolescents (mean age 12.2 +/- 3.2 years) were examined. PAE occurred in 22% of children and were most commonly related to disturbances in mood. PAE were not associated with psychiatric diagnosis(es), age, sex, concurrent medications, doses or specific serotonin reuptake inhibitors. The onset of PAE was observed typically 3 months after SSRI exposure (median = 91 days). Although PAE diminished with SSRI discontinuation, those that emerged early in treatment diminished significantly more rapidly than those that emerged later (median offset was 10 and 49 days, respectively). Re-exposure to an SSRI resulted in another PAE in 44% (n = 18) of the group.Based on the retrospective review of medical charts, youth receiving SSRI appear to be at risk for treatment emergent PAE and recurrence with re-exposure to an SSRI. Prospective longer term studies evaluating the course and prognosis of youths manifesting PAE to SSRI are necessary.

Despite data describing the overlap of attention deficit hyperactivity disorder (ADHD) and bipolar disorder (BPD) in youth, little is known about adults with these co-occurring disorders. We now evaluate the clinical characteristics of referred adults with (n = 24) and without BPD (n = 27).Referred adults to clinical trials of ADHD were evaluated by psychiatric evaluation using DSM-IV criteria. Structured psychiatric interviews were used to systematically assess adult and childhood disorders.The vast majority of patients with ADHD plus BPD had bipolar II disorder (88%). Adults with ADHD plus BPD had higher rates of the combined subtype of ADHD compared to ADHD without BPD (chi(2) = 8.7, p =.003), a greater number of DSM-IV ADHD symptoms (14.8 +/- 2.9 and 11.4 +/- 4.0; t = -3.4, p.01), more attentional symptoms of ADHD (8.1 +/- 1.4 and 6.8 +/- 2.1; t = -2.5, p.02; trend), poorer global functioning (47 +/- 5.9 and 52 +/- 7.4, t = 2.6, p.02; trend), and additional comorbid psychiatric disorders (3.7 +/- 2.5 and 2.0 +/- 1.9; t = -2.9, p.01).These results suggest that adults with ADHD plus BPD have prototypic symptoms of both disorders, suggesting that both disorders are present and are distinguishable clinically.

Despite ongoing controversy, the view that paediatric bipolar disorder is rare or non-existent has been increasingly challenged not only by case reports but also by systematic research. This research strongly suggests that paediatric bipolar disorder may not be rare but that it may be difficult to diagnose. Since children with bipolar disorder are likely to become adults with bipolar disorder, the recognition and characterization of childhood-onset bipolar disorder may help identify a meaningful developmental subtype of bipolar disorder worthy of further investigation. As recommended by Robins and Guze [ American Journal of Psychiatry (1970), 126 , 983–987], a psychiatric disorder may be considered a valid diagnostic entity if it can be shown to have differentiating features, evidence of familiality, specific treatment responsivity and a unique course. The goal of this article is to review our work and the extant literature within this framework to describe the evidence supporting bipolar disorder in children as a valid clinical diagnosis.

Objective Few treatment studies of attention-deficit/hyperactivity disorder (ADHD) extend beyond a few months. This article reports an interim analysis of a 24-month study evaluating the 12-month tolerability and effectiveness of a once-daily OROS ® formulation of methylphenidate (OROS MPH) in children with ADHD. Method Children, aged 6–13 years, with ADHD who participated in previous controlled studies and were MPH responders, received once-daily OROS MPH in this multicenter, open-label, nonrandomized study. Effectiveness was evaluated monthly by parents/caregivers and schoolteachers using validated rating scales (e.g., IOWA Conners). Safety and adverse events assessments involved objective (e.g., vital signs, growth) and subjective (sleep quality, tics) reporting. Results Seventy-one percent of subjects (289/407) completed 12 months' treatment. Effectiveness was maintained throughout 12 months as demonstrated by stable IOWA Conners ratings and sustained improvements in peer interaction and Global Assessment Scale scores. OROS MPH was well tolerated, with adverse events similar to those expected with short-acting stimulant medication. OROS MPH had minimal impact on sleep quality and tics. There were no clinically meaningful changes in blood pressure, pulse, or height. The apparent absence of meaningful changes is tempered by the fact that children were MPH responders and were medicated at baseline, most for extended periods prior to enrollment. Conclusion In this open-label study, once-daily OROS MPH treatment appears to be well tolerated and effectiveness was maintained for up to 12 months in these children with ADHD.

Optimal medications for children with attention-deficit/hyperactivity disorder (ADHD) would be effective, well tolerated, and long acting and not cause mood swings or worsen comorbid conditions. Current medications work on brain dopamine and/or norepinephrine systems, which are thought to be involved in ADHD. The medication class with the most evidence of efficacy in ADHD is stimulants, but they may be abused, are effective for only 4 to 12 hours, and may cause mood swings or increase tic severity. In recent years, alternative treatments have been explored. Tricyclic antidepressants have efficacy comparable to that of stimulants but may cause constipation, dry mouth, tremors, blood pressure changes, and potentially serious side effects including cardiac conduction and repolarization delays. Monoamine oxidase inhibitors may improve ADHD symptoms but are associated with severe dietary restrictions. Serotonin reuptake inhibitors have little or no effect in ADHD but may improve comorbid depression. Bupropion, although less effective than stimulants, may improve both ADHD symptoms and comorbid depression. Antihypertensive agents may improve impulsivity, hyperactivity, and comorbid tics but cause sedation or rebound hypertension. Atomoxetine, which is being developed for ADHD, reduces symptoms of ADHD without exacerbating comorbid conditions and is associated with only minor side effects, including subtle changes in blood pressure and heart rate. Before prescribing a treatment, physicians should consider the appropriateness and effectiveness of any medication for children with ADHD, who may be less tolerant of side effects and less able to monitor and express concerns about their well-being than adults.

Although attention-deficit/hyperactivity disorder (ADHD) impairs millions of people worldwide, both the prevalence and existence of the disorder are being reevaluated at the phenotypic level. To safeguard against overdiagnosis, the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), demands that individuals with ADHD have pervasive impairment, that is, impairment in more than 1 setting. However, the appropriateness of the DSM-IV classification of ADHD is also undergoing reevaluation. Like the symptoms of a developmental disability, the symptoms of ADHD must be evaluated in the context of age-based norms; therefore, the current criteria for ADHD, which are not age referenced, may minimize the rate of persistence of ADHD into adulthood. In an effort to better understand the pathophysiology of ADHD, recent research has focused on identifying the etiology of ADHD. These studies have revealed that the disorder is highly heritable and may be associated with neurobiological deficits in the prefrontal cortex and related subcortical systems. Etiologic studies have also identified candidate genes and prenatal and perinatal risk factors for ADHD. As the causes and course of ADHD are better understood, a new generation of medications is being developed for the disorder. Although stimulants are often effective in reducing the symptoms of the disorder, as a class they have limitations such as a lack of 24-hour-a-day coverage, unwanted side effects, potential for abuse, and lessened effectiveness in the context of some comorbidities. Therefore, the treatment characteristics of newer, more selective treatments such as atomoxetine should continue to be explored in ADHD.

Objective.Concerns exist that stimulant therapy of youths with attention-deficit/hyperactivity disorder (ADHD) may result in an increased risk for subsequent substance use disorders (SUD). We investigated all long-term studies in which pharmacologically treated and untreated youths with ADHD were examined for later SUD outcomes. Methods.A search of all available prospective and retrospective studies of children, adolescents, and adults with ADHD that had information relating childhood exposure to stimulant therapy and later SUD outcome in adolescence or adulthood was conducted through PubMed supplemented with data from scientific presentations. Meta-analysis was used to evaluate the relationship between stimulant therapy and subsequent SUD in youths with ADHD in general while addressing specifically differential effects on alcohol use disorders or drug use disorders and the potential effects of covariates. Results.Six studies—2 with follow-up in adolescence and 4 in young adulthood—were included and comprised 674 medicated subjects and 360 unmedicated subjects who were followed at least 4 years. The pooled estimate of the odds ratio indicated a 1.9-fold reduction in risk for SUD in youths who were treated with stimulants compared with youths who did not receive pharmacotherapy for ADHD (z = 2.1; 95% confidence interval for odds ratio [OR]: 1.1–3.6). We found similar reductions in risk for later drug and alcohol use disorders (z = 1.1). Studies that reported follow-up into adolescence showed a greater protective effect on the development of SUD (OR: 5.8) than studies that followed subjects into adulthood (OR: 1.4). Additional analyses showed that the results could not be accounted for by any single study or by publication bias. Conclusion.Our results suggest that stimulant therapy in childhood is associated with a reduction in the risk for subsequent drug and alcohol use disorders.

Neben der Beratung und den psychosozialen Interventionen nimmt die Pharmakotherapie im multimodalen Therapiekonzept von ADS/ADHS eine zentrale Rolle ein. Derzeit gelten Stimulanzien wie Methylphenidat als Mittel der Wahl. Neue medikamentose Optionen wie Atomoxetin versprechen zukunftig moglicherweise Fortschritte in der Behandlung von ADS/ADHS.

The objective of this study was to evaluate the pharmacokinetic profile of fluoxetine (FLX) and its major metabolite, norfluoxetine (NORFLX), in children and adolescent patients undergoing psychiatric treatment. Twenty-one pediatric subjects--10 children (6-12 years) and 11 adolescents (13-18 years)--were administered 20 mg FLX for 60 days, with sparse blood samples taken throughout the open-label study. Subjects contributed 168 plasma concentrations. Pharmacokinetic parameters were estimated using a mixed effects nonlinear model. Mean steady-state FLX and NORFLX of 127 ng/mL and 151 ng/mL, respectively, were achieved in children and adolescents after 4 weeks of treatment, with high between-patient variability. FLX was 2-fold higher and NORFLX was 1.7-fold higher in children relative to adolescents; however, when normalized to body weight, FLX and NORFLX were similar for both age groups. Age, body weight, body mass index, and body surface area, modeled independently as continuous variables, significantly improved the population pharmacokinetic model when evaluated as patient factors. Body weight was the covariate retained in the final model. In conclusion, children have 2-fold higher FLX and NORFLX relative to adolescents that appear to be related to indices of body size. The accumulation profile and steady-state concentrations in adolescents appear similar to those in adults.

Objective Although the literature documents that attention-deficit/hyperactivity disorder (ADHD) commonly onsets prior to age 6, little is known about the disorder in preschool children. We evaluated the clinical characteristics, psychiatric comorbidity, and functioning of preschool children and school-age youths with ADHD referred to a pediatric psychiatric clinic for evaluation. Method Structured psychiatric interviews assessing lifetime psychopathology by DSM-III-R criteria were completed with parents about their children. Family, social, and overall functioning were also assessed at intake. Results We identified 165 children with ADHD aged 4 to 6 years (preschool children) and 381 youths aged 7 to 9 years (school-age) with ADHD. Despite being younger, preschool children had similar rates of comorbid psychopathology compared with school-age youths with ADHD. There was an earlier onset of ADHD and co-occurring psychopathology in the preschool children compared to school-age youths. Both preschool children and school-age youths had substantial impairment in school, social, and overall functioning. Conclusions The results of this study suggest that despite being significantly younger, clinically referred preschool children with ADHD are reminiscent of school-age youths with ADHD in the quality of ADHD, high rates of comorbid psychopathology, and impaired functioning. Follow-up of these clinically referred preschool children with ADHD to evaluate the stability of their diagnoses, treatment response, and their long-term outcome are necessary.

In this article, the author sought to use a high-risk study design focused on the children of parents with opioid or alcohol use disorders and children of parents with no substance use disorder (SUD) to evaluate the specificity of the risk conferred by the type of parental SUD. Using structured psychiatric interviews, cognitive assessments, and measures of social, academic, and family functioning, the authors studied 96 families (187 parents and 183 children, mean age of 11.6 years). Sixteen families had parental opioid dependence (22 children; 64% male), 14 families had parental alcohol dependence (22 children; 59% male), and 66 families had no SUD (controls; 139 children; 58% male). Fifty-nine percent of children of opioid-dependent parents had at least one major psychopathological condition, compared to 41% of the alcohol group and 28% of the control group (p < 0.01). The children of opioid- and alcohol-dependent parents were of lower socioeconomic status and had significantly more difficulties in academic, social, and family functioning than did controls. Children of opioid- and alcohol-dependent parents have significantly higher rates of psychopathology as well as more difficulties in academic, social, and family functioning compared to the children of non-SUD parents. In addition, notable trends emerged for the opioid group to have more psychopathology and functional impairment than the alcohol group. With a growing consensus that certain risk factors for later SUD start in childhood with potentially treatable childhood-onset disorders, new preventive approaches for individuals at risk may be developed targeting childhood precursors of SUD.

▪ Abstract Attention deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder presenting for treatment in youth. ADHD is often chronic with prominent symptoms and impairment spanning into adulthood. ADHD is often associated with co-occurring anxiety, mood, and disruptive disorders, as well as substance abuse. The diagnosis of ADHD by careful review of symptoms and impairment is both reliable and valid. Recent genetic, imaging, neurochemistry, and neuropsychological data support the biological underpinning of the disorder. All aspects of an individual's life must be considered in the diagnosis and treatment of ADHD. Pharmacotherapy, including stimulants, antidepressants, and antihypertensives, plays a fundamental role in the management of ADHD across the lifespan.