Stepped Treatment for Attention-Deficit/Hyperactivity Disorder and Aggressive Behavior: A Randomized, Controlled Trial of Adjunctive Risperidone, Divalproex Sodium, or Placebo After Stimulant Medication Optimization.

OBJECTIVE: Stimulant medications are the most prevalent first-line pharmacotherapy for attention-deficit/hyperactivity disorder, but children with aggressive behavior often receive multiagent treatment. There is sparse evidence for the benefits of adjunctive medications when stimulant monotherapy provides inadequate benefit for aggressive behavior, yet the adverse effects of common adjuncts are well established. This study compared the efficacy in reducing aggressive behavior of risperidone (RISP), divalproex sodium (DVPX), and placebo (PBO) added to stimulant medication among childrenwhose symptoms persisted after individually optimized stimulant treatment. METHOD: This trial enrolled 6- to 12-year-old with attention-deficit/hyperactivity disorder, a disruptive disorder, significant aggressive behavior, and prior stimulant treatment. Open, systematically titrated stimulant treatment identified patients with inadequate reductions in aggressive behavior, who were then randomly assigned to receive adjunctive RISP, DVPX, or PBO under double-blinded conditions for 8 weeks. Family-based behavioral treatment was offered throughout the trial. The primary outcome was the parent-completed Retrospective Modified Overt Aggression Scale. RESULTS: Participants included 175 children (mean [SD] age 9.48 [2.04] years, 19% female). Of participants, 151 completed the stimulant optimization phase, with aggression remitting among 96 (63%), and 45 were randomly assigned to adjunctive treatment groups. The adjunctive RISP group showed greater reductions in aggression ratings than the PBO group (least squares means difference [ΔLSM], -2.33; 95% CI, -3.83 to -0.82; effect size [ES], -1.32), as did the DVPX group (ΔLSM, -1.60; 95% CI, -3.18 to -0.03; ES, -0.91). Mean standardized body mass index scores increased more among RISP-treated participants than participants receiving PBO (ΔLSM, 1.54; 95% CI, 0.68 to 2.40; ES, 0.58). CONCLUSION: High response rate during the trial's open stimulant optimization phase suggests that rigorous titration of stimulant medication and concurrent behavioral therapy may avert the need for additional medications. Among nonremitters, RISP and DVPX were efficacious adjunctive treatments, although RISP was associated with weight gain. CLINICAL TRIAL REGISTRATION INFORMATION: Effectiveness of Combined Medication Treatment for Aggression in Children With Attention Deficit With Hyperactivity Disorder (The SPICY Study); https://www.clinicaltrials.gov; NCT00794625.

Clonidine for attention-deficit/hyperactivity disorder: I. Efficacy and tolerability outcomes.

OBJECTIVE: To determine the efficacy and safety of clonidine, used alone or in combination with methylphenidate, in treating attention-deficit/hyperactivity disorder (ADHD). METHOD: A 16-week, randomized, double-blind, placebo-controlled clinical trial was conducted in 122 children, ages 7 to 12, with any subtype of ADHD, randomly assigned to clonidine, methylphenidate, clonidine in combination with methylphenidate, or placebo according to a 2 x 2 factorial design. In two successive 4-week titration periods, clonidine (or matching placebo) and added methylphenidate (or matching placebo) were adjusted to optimal doses and then continued for 8 weeks. The primary efficacy outcome was changed from baseline to week 16 on the Conners Teachers Abbreviated Symptom Questionnaire. Secondary outcomes included the Conners Abbreviated Symptom Questionnaire for Parents and the Children's Global Assessment Scale. RESULTS: On the Conners Teachers Abbreviated Symptom Questionnaire, clonidine was not found to improve ADHD symptoms, whereas subjects treated with methylphenidate showed significant improvement compared to those not treated with methylphenidate. Subjects treated with clonidine had greater improvements on the Conners Abbreviated Symptom Questionnaire for Parents and Children's Global Assessment Scale, but also a higher rate of sedation compared with subjects not treated with clonidine. CONCLUSIONS: Based on the Conners Teachers Abbreviated Symptom Questionnaire, methylphenidate offers the best combination of efficacy and tolerability for ADHD. Clonidine was well tolerated despite the frequency of sedation and did offer some benefit.

Clonidine for attention-deficit/hyperactivity disorder: II. ECG changes and adverse events analysis.

OBJECTIVE: To examine the safety and tolerability of clonidine used alone or with methylphenidate in children with attention-deficit/hyperactivity disorder (ADHD). METHOD: In a 16-week multicenter, double-blind trial, 122 children with ADHD were randomly assigned to clonidine (n = 31), methylphenidate (n = 29), clonidine and methylphenidate (n = 32), or placebo (n = 30). Doses were flexibly titrated up to 0.6 mg/day for clonidine and 60 mg/day for methylphenidate (both with divided dosing). Groups were compared regarding adverse events and changes from baseline to week 16 in electrocardiograms and vital signs. RESULTS: There were more incidents of bradycardia in subjects treated with clonidine compared with those not treated with clonidine (17.5% versus 3.4%; p =.02), but no other significant group differences regarding electrocardiogram and other cardiovascular outcomes. There were no suggestions of interactions between clonidine and methylphenidate regarding cardiovascular outcomes. Moderate or severe adverse events were more common in subjects on clonidine (79.4% versus 49.2%; p =.0006) but not associated with higher rates of early study withdrawal. Drowsiness was common on clonidine, but generally resolved by 6 to 8 weeks. CONCLUSIONS: Clonidine, used alone or with methylphenidate, appears safe and well tolerated in childhood ADHD. Physicians prescribing clonidine should monitor for bradycardia and advise patients about the high likelihood of initial drowsiness.

Differentiating major depressive disorder in youths with attention deficit hyperactivity disorder.

BACKGROUND: Youths with attention deficit hyperactivity disorders (ADHD) frequently have comorbid major depressive disorders (MDD) sharing overlapping symptoms. Our objective was to examine which depressive symptoms best discriminate MDD among youths with ADHD. METHODS: One-hundred-eleven youths with ADHD (5.2-17.8 years old) and their parents completed interviews with the K-SADS-PL and respective versions of the child or the parent Mood and Feelings Questionnaire (MFQ-C, MFQ-P). Controlling for group differences, logistic regression was used to calculate odds ratios reflecting the accuracy with which various depressive symptoms on the MFQ-C or MFQ-P discriminated MDD. Stepwise logistic regression then identified depressive symptoms that best discriminated the groups with and without MDD, using cross-validated misclassification rate as the criterion. RESULTS: Symptoms that discriminated youths with MDD (n=18) from those without MDD (n=93) were 4 of 6 mood/anhedonia symptoms, all 14 depressed cognition symptoms, and only 3 of 11 physical/vegetative symptoms. Mild irritability, miserable/unhappy moods, and symptoms related to sleep, appetite, energy levels and concentration did not discriminate MDD. A stepwise logistic regression correctly classified 89% of the comorbid MDD subjects, with only age, anhedonia at school, thoughts about killing self, thoughts that bad things would happen, and talking more slowly remaining in the final model. LIMITATIONS: Results of this study may not generalize to community samples because subjects were drawn largely from a university-based outpatient psychiatric clinic. CONCLUSIONS: These findings stress the importance of social withdrawal, anhedonia, depressive cognitions, suicidal thoughts, and psychomotor retardation when trying to identify MDD among ADHD youths.

Steady-state clinical pharmacokinetics of bupropion extended-release in youths.

OBJECTIVE: To examine in children and adolescents the 24-hour, steady-state clinical pharmacokinetics of an extended-release (XL) formulation of bupropion (Wellbutrin XL). METHOD: Subjects were six male and four female patients (ages 11.5-16.2 years) prescribed bupropion XL in morning daily doses of either 150 mg (n = 5) or 300 mg (n = 5) for at least 14 days. During an overnight hospitalization, subjects had serial blood draws every 1.5 to 3 hours from an intravenous port to measure plasma levels of bupropion and its metabolites. Pharmacokinetic variables were determined by noncompartmental analysis for bupropion and exponential analyses for metabolites. RESULTS: Bupropion and metabolites demonstrated linear pharmacokinetics. Bupropion's mean maximum concentration (Cmax) was lower (p = .021) and its mean time to Cmax longer (p = .057) in the current sample on bupropion XL relative to a previously studied sample of youths on bupropion sustained-release (Wellbutrin SR). Mean 24-hour area under the curve ratios of metabolites to bupropion ranged from 1.0 for erythrohydrobupropion to 16.4 for hydroxybupropion. CONCLUSIONS: Once-daily dosing is justified in youths prescribed bupropion XL. The active metabolite hydroxybupropion probably has key pharmacodynamic effects, given its higher and more sustained levels relative to the other metabolites or to bupropion.

Steady-state pharmacokinetics of bupropion SR in juvenile patients.

OBJECTIVE: To examine the steady-state pharmacokinetic properties of bupropion sustained release (SR) and their potential developmental differences in youths. METHOD: Eleven boys and eight girls aged 11 to 17 years old were prescribed bupropion SR monotherapy for attention-deficit/hyperactivity disorder (n = 16) and/or depressive disorders (n = 16). Bupropion SR was given in morning doses of 100 mg/day (n = 11) or 200 mg/day (n = 8) for 14 days or less, with five subjects studied on both doses. All subjects had blood draws from an intravenous port every 1 to 3 hours for 24 hours after their usual morning doses. Pharmacokinetic variables were determined by noncompartmental and compartmental analyses for bupropion and metabolites, respectively. RESULTS: Bupropion and its metabolites exhibited linear pharmacokinetics. Areas under the concentration curves for the hydroxybupropion, threohydrobupropion, and erythrohydrobupropion were 20, 12, and 2.7 times higher, respectively, than for bupropion. Relative to adults, the mean half-lives of bupropion (12.1 hours) and threohydrobupropion (26.3 hours) were significantly shorter, and areas under the concentration curve ratios of metabolites to bupropion were 19% to 80% higher. CONCLUSIONS: Youths metabolize bupropion SR faster to hydroxybupropion and other active metabolites than adults. Until the clinical importance of bupropion's metabolites is clarified, bupropion SR should be given in divided doses to youths, as the manufacturer recommends for adults taking higher doses.

A chart review of cyproheptadine for stimulant-induced weight loss.

Youths with attention deficit hyperactivity disorder often experience weight loss on stimulants, which may limit optimal dosing and compliance. Cyproheptadine has been shown in medical samples to stimulate weight gain. We conducted a retrospective chart review of 28 consecutive pediatric psychiatry outpatients prescribed cyproheptadine for weight loss or insomnia while on stimulants. Of these, 4 patients never took cyproheptadine consistently, and 3 discontinued it within the first 7 days due to intolerable side effects. Data were analyzed for 21 other patients (age range 4-15 years) who continued with 4-8 mg of cyproheptadine nightly (mean final dose = 4.9 mg/day) for at least 14 days (mean duration = 104.7 days). Most had lost weight on stimulant alone (mean weight loss was 2.1 kg, mean weight velocity was -19.3 g/day). All 21 gained weight taking concomitant cyproheptadine, with a mean gain of 2.2 kg (paired t = 6.87, p < 0.0001) and a mean weight velocity of 32.3 g/day. Eleven of 17 patients who had reported initial insomnia on stimulant alone noted significant improvements in sleep with cyproheptadine added. We conclude that concomitant cyproheptadine may be useful in youths with attention deficit hyperactivity disorder for stimulant-induced weight loss, pending future randomized controlled trials.

Suicidal behaviors in adolescents with ADHD: associations with depressive and other comorbidity, parent-child conflict, trauma exposure, and impairment.

OBJECTIVE: To examine potential predictors of lifetime suicidal behaviors (SBs) in adolescents with ADHD. METHOD: Participants were 101 adolescents with ADHD aged 11 to 18 years, evaluated for lifetime SB and psychopathology with semistructured interviews, and for lifetime trauma exposure, parent-child conflict, ADHD symptoms, and functional impairment with child, parent, and teacher ratings. RESULTS: Controlling for the effects of age, female sex, and comorbid depressive and other disorders, lifetime SB (n = 28) remained significantly associated (p = .001) with parent-child conflict, and to a lesser extent (p < .05) with impairment in nonacademic domains of function and breadth of exposure to victimization events. Measures related to past and current ADHD symptoms and signs were not associated with lifetime SB. CONCLUSION: Apart from depression, clinicians should pay particular attention to parent-child conflict, victimization trauma, and social impairment rather than levels of ADHD symptoms when weighing the likelihood of SB in youth with ADHD.

Callous-unemotional traits, proactive aggression, and treatment outcomes of aggressive children with attention-deficit/hyperactivity disorder.

OBJECTIVE: Stimulant treatment improves impulse control among children with attention-deficit/hyperactivity disorder (ADHD). Decreased aggression often accompanies stimulant pharmacotherapy, suggesting that impulsiveness is integral to aggressive behavior in these children. However, children with high callous-unemotional (CU) traits and proactive aggression may benefit less from ADHD pharmacotherapy, because their aggressive behavior seems more purposeful and deliberate. This study's objective was to determine whether pretreatment CU traits and proactive aggression affect treatment outcomes among aggressive children with ADHD receiving stimulant monotherapy. METHOD: We implemented a stimulant optimization protocol with 160 children 6 to 13 years of age (mean [SD] age of 9.31 [2.02] years; 78.75% male) with ADHD, oppositional defiant or conduct disorder, and significant aggressive behavior. Family-focused behavioral intervention was provided concurrently. The primary outcome was the Retrospective Modified Overt Aggression Scale. The Antisocial Process Screening Device and the Aggression Scale, also completed by parents, measured CU traits and proactive aggression, respectively. Analyses examined moderating effects of CU traits and proactive aggression on outcomes. RESULTS: In all, 82 children (51%) experienced remission of aggressive behavior. Neither CU traits nor proactive aggression predicted remission (CU traits: odds ratio [OR] = 0.94, 95% CI = 0.80-1.11; proactive aggression, OR = 1.05, 95% CI = 0.86-1.29). Children whose overall aggression remitted showed decreases in CU traits (effect size = -0.379, 95% CI = -0.60 to -0.16) and proactive aggression (effect size = -0.463, 95% CI = -0.69 to -0.23). CONCLUSIONS: Findings suggest that pretreatment CU traits and proactive aggression do not forecast worse outcomes for aggressive children with ADHD receiving optimized stimulant pharmacotherapy. With such treatment, CU traits and proactive aggression may decline alongside other behavioral improvements. Clinical trial registration information--Medication Strategies for Treating Aggressive Behavior in Youth With Attention Deficit Hyperactivity Disorder; http://clinicaltrials.gov/; NCT00228046; and Effectiveness of Combined Medication Treatment for Aggression in Children With Attention Deficit With Hyperactivity Disorder (The SPICY Study); http://clinicaltrials.gov/; NCT00794625.

Does comorbid depression predict subsequent adverse life events in youth with attention-deficit/hyperactivity disorders?

OBJECTIVES: Studies have primarily focused on adverse life events (ALEs) as potential causes rather than as outcomes of pediatric depression. The current study prospectively examines ALEs in a sample of youth with attention-deficit/hyperactivity disorders (ADHD) to determine whether having a major depressive disorder (MDD) at baseline (T1) predicts counts of child-dependent or child-independent ALEs at a second assessment (T2) ≈ 8 months later. METHODS: Subjects with ADHD 11-18 years old were drawn mostly from a tertiary mental health clinic and evaluated with semi-structured diagnostic interviews, and parent and teacher questionnaires of ADHD severity. Eighteen with and 61 without initial MDD at T1 were compared at T2 regarding counts of subsequent overall, child-dependent, and child-independent ALEs reported on life events questionnaires by the child or parent. RESULTS: The group initially with MDD had higher overall ALEs (p=0.01) and child-dependent ALEs (p ≤ 0.001) but not child-independent ALEs (p=0.12) at T2 relative to the nondepressed group, although only 3 of 18 continued to meet full criteria for MDD. The group initially with MDD also had a higher baseline ADHD severity (p=0.04) and proportion of oppositional or conduct disorders (p=0.004). In multivariate analyses, the group initially having MDD had a higher adjusted mean at T2 of child-dependent ALEs (p=0.02), but not of overall ALEs (p=0.06), after controlling for other T1 variables, including ALEs of the same type, ADHD severity, externalizing disorders, and the interaction of externalizing disorders with MDD. CONCLUSIONS: These findings suggest that child-dependent ALEs are potentially an important outcome after youth with ADHD have an episode of MDD. Youth with ADHD who develop comorbid MDD should be closely monitored and offered interventions to address the potential burden of child-dependent ALEs lingering after a depressive episode.

Associations of lifetime depression with trauma exposure, other environmental adversities, and impairment in adolescents with ADHD.

Depression is a common, potentially devastating comorbidity in youth with attention-deficit/hyperactivity disorders (ADHD). Various environmental adversities are well-described as correlates of depression in general pediatric populations, but not in youth with ADHD. In 104 adolescents with ADHD, we examined potential environmental correlates of lifetime depression, including trauma exposure, recent negative life events and current parent-child conflict, along with current and past ADHD severity and current impairment. Controlling for demographic variables, comorbid disorders, and ADHD severity, we noted significant associations between lifetime depression and environmental adversities, including victimization trauma, parent-child conflict, and behaviorally-independent negative life events. Current impairment but not ADHD severity was also highly associated with lifetime depression, controlling for the same covariates. Findings from this preliminary, cross-sectional study suggest that environmental adversities and impairment in youth with ADHD should also be targeted along with the ADHD when contemplating strategies to treat or prevent comorbid depression.

A review of co-morbid depression in pediatric ADHD: etiology, phenomenology, and treatment.

This paper reviews the literature and highlights the need for further research regarding the phenomenology, etiology, assessment, and treatment of co-morbid depression in patients with attention-deficit/hyperactivity disorders (ADHD). Depression occurs in youths with ADHD at a significantly higher rate than in youths without ADHD. Youths with ADHD and depression together have a more severe course of psychopathology and a higher risk of long-term impairment and suicide than youths with either disorder alone. Assessment of such co-morbid depression is complicated by overlapping symptoms with ADHD and with other disorders that commonly occur with ADHD. Depressive disorders typically emerge several years after the onset of ADHD and may arise from environmental difficulties associated with chronic ADHD that interact with genetic risks as the child gets older. Despite a scarcity of well-designed treatment studies for youths with ADHD and co-morbid depression, there is increasing preliminary evidence for the role of stimulants, selective serotonergic reuptake inhibitors, bupropion, and atomoxetine to target either or both disorders. There is also some indirect evidence for the benefit of combining pharmacological treatments with psychosocial interventions that specifically target relevant environmental factors and functional impairments.

Does pharmacotherapy for attention-deficit/hyperactivity disorder predict risk of later major depression?

OBJECTIVE: This study's goal was to determine among youths with attention-deficit/hyperactivity disorder (ADHD) how the history of ADHD pharmacotherapy influenced the risk of developing major depressive disorder (MDD), compared to other commonly reported predictors. METHOD: Diagnostic and treatment history data were analyzed retrospectively in 75 youths 11-18 years old with definite or probable ADHD, enrolled in an observational study at a tertiary mental health clinic. Subjects with histories of MDD (H/o MDD) (n = 36) were compared to others who had never been depressed (Never-Depressed) (n = 39) regarding histories of ADHD pharmacotherapy, psychopathology and other potential covariates of MDD risk. RESULTS: H/o MDD subjects reported longer delays before initiating ADHD pharmacotherapy, were more often female, reported having experienced more traumatic event types, and had higher rates of early anxiety and externalizing disorders. With all covariates allowed to enter a backward stepwise Cox regression of survival time till first episodes of MDD, only two variables remained in the model. The time-dependent variable, ADHD pharmacotherapy, prolonged survival times (p = .012), while having experienced more traumatic event types shortened them (p = .001). CONCLUSIONS: This study provides preliminary evidence that pharmacotherapy for ADHD may have a protective effect in ADHD youths, reducing the risk of later MDD.

Criterion validity of the Mood and Feelings Questionnaire for depressive episodes in clinic and non-clinic subjects.

BACKGROUND: Previous measures of pediatric depression have shown inconsistent validity in groups with differing demographics, comorbid diagnoses, and clinic or non-clinic origins. The current study re-examines the criterion validity of child- and parent-versions of the Mood and Feelings Questionnaire (MFQ-C, MFQ-P) in a heterogeneous sample of children and adolescents from clinic and non-clinic sources. METHODS: Among 470 consecutive youth completing semi-structured interviews at a university-based child psychiatry center, total scores from the 33-item MFQ-C and 34-item MFQ-P were examined across subjects with and without mood disorders using analysis of variance, and receiver operating characteristics analysis. RESULTS: Mean scores of the MFQ-C and MFQ-P, respectively, differed significantly (p < .0005) across youth having major depressive episodes (MDE) (33 and 32, n = 77), mood disorders not meeting criteria for current MDE (24 and 28, n = 75), and no mood disorders (12 and 10, n = 318). In the overall sample, areas under the curve (AUC) for discriminating MDE and any mood disorder, respectively, were .85 and .83 on the MFQ-C, .86 and .90 on the MFQ-P, and .89 and .90 on the MFQ-C and MFQ-P averaged together, suggesting moderate to high criterion validity. Similar findings were noted in subgroups divided by age, sex, race, comorbid psychopathology, and clinic or non-clinic origins. AUCs of these MFQ scores compared favorably with those of the Beck's Depressive Inventory, the Child Behavior Checklist's Anxious/Depressed scale and the Children's Depressive Rating Scale-Revised by the same raters. A score of 29 on the MFQ-C (positive screen rate 21%, sensitivity 68%, specificity 88%) or 27 on the MFQ-P (positive screen rate 23%, sensitivity 61%, specificity 85%) optimally discriminated youth with MDE from the rest of the sample. CONCLUSIONS: The MFQ-C and MFQ-P, especially used in combination, validly identify MDE or other mood disorders in youth diverse in demographic and clinical characteristics.

Acute antidepressant response and plasma levels of bupropion and metabolites in a pediatric-aged sample: an exploratory study.

Studies examining associations between antidepressant response and plasma levels of bupropion and its metabolites have yielded contradictory findings. There have been no such studies in youth. This study explored such associations in 8 boys and 8 girls, age 11 to 17 years, all prescribed bupropion sustained release (SR) for major depression (n = 6) or depressive disorder not otherwise specified (n = 10) as part of a pharmacokinetic (PK) study. All were started on morning doses of bupropion SR of 100 mg/day, and most eventually had doses increased to 200 mg/day because of inadequate clinical response. After taking prescribed dose of bupropion SR at least 14 days (median = 21 days), subjects had steady-state serial plasma levels of bupropion and its metabolites measured during a 24-hour period after morning doses. A total of 9 subjects underwent these PK assessments on doses of 100 mg/day, and 6 underwent these on doses of 200 mg/day, with 4 studied on both doses. In this 24-hour assessment, the treating psychiatrist rated subjects' antidepressant response using the Clinical Global Impression's Improvement scale (CGI-I), blind to plasma levels, but informed by child and parent rating scales of depressive symptoms and clinical interviews. Relative to 7 nonresponders, 9 responders (CGI-I < or = 2) had significantly higher mean areas under concentration curves for bupropion (P = 0.03), threohydrobupropion (P = 0.02), and erythrohydrobupropion (P = 0.02), and especially hyroxybupropion (P = 0.006). Plasma levels 7.5 hours after morning doses reaching the following cut points discriminated responders from nonresponders: bupropion > or = 37 ng/mL (P = 0.001), hydroxybupropion > or = 575 ng/mL (P = 0.003), threohydrobupropion > or = 240 ng/mL (P = 0.009), or erythrohydrobupropion > or = 45 ng/mL (P = 0.009). These preliminary findings suggest that plasma levels of bupropion and metabolites, particularly hydroxybupropion, may predict acute antidepressant response in depressed youths taking bupropion SR.

Bupropion for attention deficit hyperactivity and comorbid disorders.

Bupropion is a unique antidepressant with noradrenergic and to a lesser extent dopaminergic effects. These have led investigators to explore bupropion's efficacy in attention deficit hyperactivity disorders, which are believed to be related to aberrations in catecholamines. An expanding body of research has demonstrated bupropion's efficacy in attention deficit hyperactivity disorders over the lifespan. Despite early reports of seizures in select samples, bupropion is generally well-tolerated. While stimulants remain the first-line pharmacological treatments for attention deficit hyperactivity disorders, bupropion offers promise as a medication that treats not only attention deficit hyperactivity disorders, but also common comorbid disorders, including unipolar and bipolar depression, anxiety and substance abuse.