New stimulant formulations for pediatric attention-deficit/hyperactivity disorder: a case-based approach for the primary care provider.

PURPOSE OF REVIEW: To provide an up-to-date clinical review of U.S. Food and Drug Administration (FDA)-approved stimulant medications for attention-deficit/hyperactivity disorder (ADHD), including a framework for individualized treatment by primary care pediatric providers. RECENT FINDINGS: Stimulant medications are first-line agents for pediatric ADHD. Since 2012, 11 novel stimulant medications have been approved by the FDA for the treatment of ADHD. Because of an expanded formulary of available methylphenidate-based and amphetamine-based stimulants, primary care providers may be unfamiliar with some novel medications outside a select formulary. SUMMARY: The current broad formulary of methylphenidate-based and amphetamine-based stimulants provides primary care clinicians with a greater opportunity for personalized medicine within the patient-centered medical home. Through a systematic review of prior relevant medication trials, a consideration of daily symptom burden and thoughtful pragmatics, primary care providers can offer a more precise, customized stimulant treatment.

A randomized controlled trial of cognitive behavioral therapy for ADHD in medication-treated adolescents.

OBJECTIVE: To test cognitive behavioral therapy (CBT) for persistent attention-deficit hyperactivity disorder (ADHD) symptoms in a sample of medication-treated adolescents. METHODS: Forty-six adolescents (ages 14-18), with clinically significant ADHD symptoms despite stable medication treatment were randomly assigned to receive CBT for ADHD or wait list control in a cross-over design. Twenty-four were randomized to CBT, 22 to wait list, and 15 crossed-over from wait list to CBT. A blind independent evaluator (IE) rated symptom severity on the ADHD Current Symptom Scale, by adolescent and parent report, and rated each subject using the Clinical Global Impression Severity Scale (CGI), a global measure of distress and impairment. These assessments were performed at baseline, 4-months (post-CBT or post wait list), and 8-months (post-treatment for those originally assigned to the wait list condition and 4-month follow-up for those originally assigned to CBT). TRIAL REGISTRATION: http://clinicaltrials.gov/show/NCT01019252. RESULTS: Using all available data, mixed effects modeling, and pooling for the wait list cross-over, participants who received CBT received a mean score 10.93 lower on the IE-rated parent assessment of symptom severity (95% CI: -12.93, -8.93; p < .0001), 5.24 lower on the IE-rated adolescent assessment of symptom severity (95% CI: -7.21, -3.28; p < .0001), and 1.17 lower IE-rated CGI (95% CI: -1.39, -.94; p < .0001). Results were consistent across 100 multiple imputations (all p < .0001). There was a greater proportion of responders after CBT by parent (50% vs. 18%, p = .00) and adolescent (58% vs. 18% p = .02) report. CONCLUSIONS: This study demonstrates initial efficacy of CBT for adolescents with ADHD who continued to exhibit persistent symptoms despite medications.

Treatment of Attention-Deficit/Hyperactivity Disorder in Adolescents: A Systematic Review.

IMPORTANCE: Although attention-deficit/hyperactivity disorder (ADHD) is highly prevalent in adolescents and often persists into adulthood, most studies about treatment were performed in children. Less is known about ADHD treatment in adolescents. OBJECTIVE: To review the evidence for pharmacological and psychosocial treatment of ADHD in adolescents. EVIDENCE REVIEW: The databases of CINAHL Plus, MEDLINE, PsycINFO, ERIC, and the Cochrane Database of Systematic Reviews were searched for articles published between January 1, 1999, and January 31, 2016, on ADHD treatment in adolescents. Additional studies were identified by hand-searching reference lists of retrieved articles. Study quality was rated using McMaster University Effective Public Health Practice Project criteria. The evidence level for treatment recommendations was based on Oxford Centre for Evidence-Based Medicine criteria. FINDINGS: Sixteen randomized clinical trials and 1 meta-analysis, involving 2668 participants, of pharmacological and psychosocial treatments for ADHD in adolescents aged 12 years to 18 years were included. Evidence of efficacy was stronger for the extended-release methylphenidate and amphetamine class stimulant medications (level 1B based on Oxford Centre for Evidence-Based Medicine criteria) and atomoxetine than for the extended-release α2-adrenergic agonists guanfacine or clonidine (no studies). For the primary efficacy measure of total symptom score on the ADHD Rating Scale (score range, 0 [least symptomatic] to 54 [most symptomatic]), both stimulant and nonstimulant medications led to clinically significant reductions of 14.93 to 24.60 absolute points. The psychosocial treatments combining behavioral, cognitive behavioral, and skills training techniques demonstrated small- to medium-sized improvements (range for mean SD difference in Cohen d, 0.30-0.69) for parent-rated ADHD symptoms, co-occurring emotional or behavioral symptoms, and interpersonal functioning. Psychosocial treatments were associated with more robust (Cohen d range, 0.51-5.15) improvements in academic and organizational skills, such as homework completion and planner use. CONCLUSIONS AND RELEVANCE: Evidence supports the use of extended-release methylphenidate and amphetamine formulations, atomoxetine, and extended-release guanfacine to improve symptoms of ADHD in adolescents. Psychosocial treatments incorporating behavior contingency management, motivational enhancement, and academic, organizational, and social skills training techniques were associated with inconsistent effects on ADHD symptoms and greater benefit for academic and organizational skills. Additional treatment studies in adolescents, including combined pharmacological and psychosocial treatments, are needed.

Complex ADHD Challenging Case: Managing Co-Occurring Attention-Deficit Hyperactivity Disorder and Congenital Heart Disease with a Limited Medication Formulary: A Case from Mexico.

CASE: DL is an 8-year-old Mexican boy with a posterior atrial septal defect and partial anomalous pulmonary venous return of the right lower pulmonary vein with resultant right heart dilation with normal right ventricular systolic and diastolic function and no arrhythmias. Surgical repair was deferred, and DL's condition was being medically managed with furosemide 0.5 mg/kg BID and spironolactone 0.5 mg/kg BID.DL presents for developmental assessment due to poor performance in school following a lifting of COVID-19 pandemic restrictions and return to in-person classes. He has been attending full-time classes for 3 months without improvements in math, reading, and writing skills. Current attentional concerns at school include an inability to complete tasks without getting distracted by minimal stimuli and highly impulsive behavior.At the first assessment, DL was performing below grade expectations (e.g., reading by syllable without text comprehension, demonstrating preoperational addition and subtraction skills, inability to take dictation)-all of which was viewed as negatively impacted by attentional deficits. DL met DSM-5 criteria for ADHD, predominantly inattentive type. He was started on 10-mg immediate-release methylphenidate PO at 8 am with breakfast and a second dose of 10-mg immediate-release methylphenidate PO 4 hours after the first dose.After a month, at the first follow-up consultation, improvement in attention span, impulsivity, and school performance were observed, including reading skills and math proficiency. However, DL's mother raised concerns about circumoral cyanosis and acrocyanosis in the fingers of both hands after playing outside. These signs were not previously observed. During physical examination at the same visit, heart rate, blood pressure, and oximetry were within baseline ranges and his cardiac examination was unchanged. DL's dosage of methylphenidate was lowered to 10-mg immediate-release methylphenidate PO QD in the mornings with breakfast (8 am).DL did not return to clinic for another 2 months, having discontinued the medication after 2 months of treatment given financial limitations. His mother reported that DL's exertional circumoral cyanosis and acrocyanosis resolved while he was off medication. However, she observed an increase in inattentive symptoms and impulsivity and decline in his academic skills. She asked if our team was able continue the treatment despite the drug side effects, since she believed the benefits outweighed the disadvantages.Given these concerns, the team requested an updated cardiology assessment. The Cardiologist recommended discontinuation of methylphenidate and recommended follow-up with cardiothoracic surgery for reassessment of the surgical timeline.Given the limited treatment options in Mexico, what would you do next as the treating developmental-behavioral clinician…?

Do stimulants reduce the risk for cigarette smoking in youth with attention-deficit hyperactivity disorder? A prospective, long-term, open-label study of extended-release methylphenidate.

OBJECTIVE: Although attention-deficit hyperactivity disorder (ADHD) is a well-known risk factor for cigarette smoking, prospective studies aimed at reducing smoking risk in this population are critically needed. STUDY DESIGN: This was a 2-year, prospective, open-label clinical trial of extended-release methylphenidate for smoking prevention in adolescents with ADHD (n = 154). Smoking outcomes were assessed with the Fagerstrom Tolerance Questionnaire. Comparisons were made using data from a historical, naturalistic sample of ADHD (n = 103) and non-ADHD comparators (n = 188) of similar age and sex assessed with the same assessment battery as that used in subjects participating in the clinical trial. RESULTS: The smoking rate at endpoint (mean, 10 months of methylphenidate treatment) was low in the clinical trial subjects and not significantly different from that in the non-ADHD comparators or the ADHD comparators receiving stimulants naturalistically (7.1% vs 8.0% vs 10.9%; P > .20). In contrast, the smoking rate was significantly lower in the clinical trial subjects than in the naturalistic sample of ADHD comparators who were not receiving stimulant treatment (7.1% vs 19.6%; P = .009 [not significant], adjusting for comorbid conduct disorder and alcohol and drug abuse). CONCLUSION: Although considered preliminary until replicated in future randomized clinical trials, the findings from this single-site, open-label study suggest that stimulant treatment may contribute to a decreased risk for smoking in adolescents with ADHD. If confirmed, this finding would have significant clinical and public health impacts.

Effectiveness of collaborative tele-mental health care for children with attention deficit hyperactivity disorder in United Arab Emirates.

Background: Attention deficit hyperactivity disorder is a common neurodevelopmental disorder. Accessing services for this disorder is a worldwide challenge and requires innovative interventions. Aims: We aimed to investigate the effectiveness of tele-collaborative care for attention deficit hyperactivity disorder in primary health care centres in Dubai. Methods: Six trained physicians started collaborative care clinics across Dubai. Eligible children aged 6-12 years attending primary health care centres with attention deficit hyperactivity disorder were randomly selected to receive telehealth collaborative care, or standard treatment. Baseline assessments were conducted using the Vanderbilt Behavioral Assessment Scale, the Columbia Impairment Scale, the Childhood Behavior Checklist, and the Strength and Difficulties Questionnaire. Waiting times and clinical and functional outcomes were measured in both groups and compared. Continuous variables were presented as means and standard deviations, categorical variables such as sex were presented as numbers and percentages, and continuous outcome variables were compared using the Student t-test. Results: Among the referred children (n = 112), 11 boys and 6 girls met the eligibility criteria (mean age 7.8 years). The dropout rate at 6 months in the control group was 80%, compared with 50% in the intervention group. The mean waiting time was significantly shorter in the intervention group (1.3 weeks) than the control group (7.1 weeks); P = 0.026. The mean difference in the Childhood Behavior Checklist total score over time was significantly higher in the intervention group (P = 0.042), but the mean difference in the Vanderbilt scale was not significant. Conclusion: Tele-collaborative care for children with attention deficit hyperactivity disorder within primary health care is feasible.

Cigarette smoking as a risk factor for other substance misuse: 10-year study of individuals with and without attention-deficit hyperactivity disorder.

BACKGROUND: We previously documented that cigarette smoking is a risk factor for subsequent alcohol and drug misuse and dependence in adolescent girls with attention-deficit hyperactivity disorder (ADHD). AIMS: To revisit this hypothesis with a large longitudinal sample of both genders followed up for 10 years into young adulthood. METHOD: We used data from two identically designed, longitudinal, case-control family studies of boys and girls with and without ADHD ascertained from psychiatric and paediatric sources. We studied 165 individuals with ADHD and 374 controls followed up longitudinally and masked for 10 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: Youth with ADHD who smoked cigarettes (n = 27) were significantly more likely to subsequently develop drug misuse and dependence compared with youth with ADHD who did not smoke (n = 138, P<0.05). CONCLUSIONS: These results confirm that cigarette smoking increases the risk for subsequent drug and alcohol use disorders among individuals with ADHD. These findings have important public health implications, and underscore the already pressing need to prevent smoking in children with ADHD.

Cardiovascular Considerations for Stimulant Class Medications.

The cardiovascular (CV) impact of stimulants has been examined for decades, with investigations ranging from small sample targeted studies of heart rate (HR) and blood pressure (BP), to large scale epidemiologic investigations. The preponderance of evidence is reassuring, albeit generally based on healthy samples using variable methodology, excluding those at theoretic high risk (eg, comorbid cardiac illness). Screening for theoretically vulnerable patients are recommended, as well as monitoring for CV symptoms and BP/HR, with shared inquiry/further evaluation if concerned. Future investigations to support the identification of risk are needed, while attention to stimulant-associated CV risk is an opportunity for clinicians to engage in general CV risk identification and intervention.

Clinically Meaningful Improvements in Early Morning and Late Afternoon/Evening Functional Impairment in Children with ADHD Treated with Delayed-Release and Extended-Release Methylphenidate.

OBJECTIVE: The Before School Functioning Questionnaire and Parent Rating of Evening and Morning Behavior-Revised assess early morning (BSFQ, PREMB-R AM subscale) and late afternoon/evening (PREMB-R PM subscale) functional impairment in children with ADHD. Clinically meaningful improvements were identified and applied to a trial of delayed-release and extended-release methylphenidate (DR/ER-MPH) in children with ADHD (NCT02520388) to determine if the statistically-determined improvements in functional impairment were also clinically meaningful. METHOD: Clinically meaningful improvements in BSFQ/PREMB-R were established post hoc by receiver operating characteristics curves, using anchors of Clinical Global Impression-Improvement (CGI-I) = 1 and CGI-I ≤ 2. Percentages of participants achieving these thresholds were calculated. RESULTS: Thresholds for CGI-I = 1/CGI-I ≤ 2, respectively, were 27/20 (BSFQ), 5/3 (PREMB-R AM), and 9/5 (PREMB-R PM)-point decreases. More children achieved clinically meaningful improvements with DR/ER-MPH versus placebo (all p < .05). CONCLUSION: DR/ER-MPH increased proportions of children achieving clinically meaningful improvements in BSFQ and PREMB-R.

Adult attention-deficit/hyperactivity disorder treatment and cardiovascular implications.

Attention-deficit/hyperactivity disorder (ADHD) is a chronic neurobehavioral disorder afflicting adults worldwide. This article is an update on the evidence supporting medications for adult ADHD, with particular emphasis on cardiovascular implications. Relevant clinical literature was sought using PubMed searches, with an emphasis on new reports from April 2009 to April 2011. This review describes the efficacy and general tolerability of stimulant and nonstimulant medications for adults with ADHD as seen in contemporary clinical trials. Cardiovascular response to medications for ADHD is primarily seen in heart rate and blood pressure elevations, while less is known about the etiology of rare cardiovascular events or long-term sequelae. Further research is indicated to delineate clinical and functional outcomes for adults with ADHD, as well as long-term safety of medication treatment.

Assessment and Treatment of a Young Adult with Congenital Heart Disease and ADHD.

CASE: Phillip is a young man born with hypoplastic left heart syndrome referred to your practice for a range of mental health concerns. He underwent palliation to an extracardiac Fontan in infancy and experienced multiple complications over the next decade including valvular regurgitation and arrhythmias necessitating a pacemaker. Phillip continued to have systolic heart failure with New York Heart Association class II symptoms, managed with 4 medications and anticoagulation.Despite this complex history, Phillip had intact cognitive abilities, achieved typical milestones, and performed well academically in secondary school. His first year of college proved to be more challenging, and Phillip presented to the outpatient psychiatry service with an acute depressive episode. His family history included depression, without known attention-deficit/hyperactivity disorder (ADHD). Treatment, including a selective serotonin reuptake inhibitor, cognitive behavioral therapy, and family support, led to near resolution of his symptoms of depression.In subsequent appointments, Phillip described a long history of inattention and disorganization with onset in childhood. This contributed to the decision to leave college, despite remission of symptoms of depression. Phillip was unable to study for any extended period without "perfect conditions," described as the absence of potential distractions except for background music. Despite attempts to maintain "perfect conditions," Phillip was often off task and "hyperfocusing" on irrelevant topics. Phillip struggled with planning and time management and would misplace items daily. Moreover, although the importance of self-care was well understood, Phillip often forgot to take his cardiac medication or to exercise, and he admitted to inconsistent sleep habits because of losing track of time.Based on a comprehensive psychiatric evaluation including retrospective report from a parent, Phillip was diagnosed with ADHD, coexisting with major depressive disorder, in remission. Significant ADHD symptoms were documented by interview, self-report, and administration of an abbreviated neuropsychological battery.Considering concerns regarding use of stimulants in a patient with congenital heart disease, including death, stroke, and myocardial infarction,1,2 how would you assess the risks-benefits of use of stimulants with Phillip? REFERENCES: 1. Wilens TE, Prince JB, Spencer TJ, et al. Stimulants and sudden death: what is a physician to do? Pediatrics. 2006;118:1215-1219.2. Zito JM, Burcu M. Stimulants and pediatric cardiovascular risk. J Child Adolesc Psychopharmacol. 2017;27:538-545.

A randomized, 3-phase, 34-week, double-blind, long-term efficacy study of osmotic-release oral system-methylphenidate in adults with attention-deficit/hyperactivity disorder.

We conducted a 3-phase, double-blind, placebo-controlled, parallel study design of osmotic-release oral system (OROS)-methylphenidate (MPH) in adults (19-60 years of age) with attention deficit/hyperactivity disorder as classified by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Phase 1 of the study was a 6-week, acute efficacy trial (n = 223), phase 2 was a 24-week, double-blind continuation study of responders (n = 96), and phase 3 was a double-blind, placebo-controlled, 4-week discontinuation study (n = 23). The mean daily dosage at phase 1 endpoint was 78.4 ± 31.7 mg (0.97 ± 0.32 mg/kg) OROS-MPH and 96.6 ± 26.5 mg (1.16 ± 0.19 mg/kg) placebo (P < 0.0001). Clinical response at phase 1 endpoint was significantly greater in the OROS-MPH group (62%, n = 67 vs 37%, n = 41; P < 0.001) and was maintained throughout 24 weeks of double-blind treatment. With double-blind, placebo-controlled discontinuation, however, there was no statistically significant difference in the rate of relapse between OROS-MPH responders randomized to placebo and those randomized to continue active treatment (18%, n = 2 vs 0%, n = 0; P = 0.1). As expected, decreased appetite, insomnia, being tense/jittery, mucosal dryness, and neurological symptoms were statistically significantly associated with OROS-MPH treatment. More work is needed to be conducted with larger samples being followed to study completion to better understand the long-lasting impact of pharmacotherapy for adult attention-deficit/hyperactivity disorder.

Does ADHD moderate the manifestation of anxiety disorders in children?

The main aim of this study was to examine the moderating effects of attention deficit hyperactivity disorder (ADHD) on anxiety disorders in children. Data were analyzed from a large referred sample of children with anxiety disorder without comorbid ADHD (anxiety disorder, N = 253), anxiety disorder plus comorbid ADHD (anxiety disorder + ADHD, N = 704), and ADHD without comorbid anxiety disorder (ADHD, N = 511). Children were comprehensively assessed, including by structured diagnostic interview (K-SADS-E). Overall rates of individual anxiety disorders, as well as age of onset and severity of illness were not significantly different in the presence of comorbid ADHD. School functioning in children with anxiety disorders was negatively impacted by the presence of comorbid ADHD. Frequency of mental health treatment in children with anxiety disorders was significantly increased in the presence of comorbid ADHD. ADHD had a limited impact on the manifestation of anxiety disorder in children suggesting that ADHD and anxiety disorders are independently expressed.

Cardiovascular effects of longer-term, high-dose OROS methylphenidate in adolescents with attention deficit hyperactivity disorder.

OBJECTIVE: To examine the effects of high doses of extended-release methylphenidate (OROS MPH) on cardiovascular variables in adolescents with attention deficit hyperactivity disorder (ADHD). STUDY DESIGN: ECG indices plus systolic blood pressure (SBP), diastolic BP (DBP) and heart rate (HR) were assessed during an open-label study of OROS MPH in 114 adolescents with ADHD (doses up to 1.5 mg/kg/d). Cardiovascular parameters were assessed at 6 weeks and 6 months. RESULTS: Small but statistically significant changes in DBP and HR were observed at 6 weeks, without further increases up to 6 months' follow-up. A small but statistically significant increase in SBP was observed over time. Twenty-nine percent of patients had isolated elevations in BP readings prior to study entry, and 14% had >3 consecutive visits at which elevated BP were observed during OROS MPH treatment. No clinically significant changes in ECG parameters were observed. No serious cardiovascular adverse events occurred. CONCLUSIONS: Treatment with relatively high doses of OROS MPH was associated with small but statistically significant mean increases in BP and HR, primarily during the first 6 weeks of treatment, without clinically meaningful changes in ECG. These observations are consistent with previous reports using lower doses.

Atomoxetine in children with attention-deficit hyperactivity disorder with prior stimulant therapy: a prospective open-label study.

The objective of the study is to evaluate the effectiveness and tolerability of atomoxetine in youth, ages 6-17 years with ADHD, who had a prior trial of stimulant treatment. This was a 6-week prospective open-label study of atomoxetine, dosage up to 1.4 mg/kg per day in 34 children and adolescents with DSM-IV ADHD. Primary measures of response included the ADHD Rating Scale (ADHD RS) and the Clinical Global Impression (CGI) Scale. Analyses were intention-to-treat. The treatment with atomoxetine was associated with statistical and clinical significant reduction in clinician rated ADHD RS symptoms, compared with baseline. Statistical significant improvement was attained by the second week of treatment. Fifty-six percent (N = 18) met criteria for our a priori definition of response; much or very much improved on the CGI plus more than 30% reduction in ADHD RS symptoms. In conclusion, atomoxetine was generally well tolerated; 85% of subjects completed the trial. Atomoxetine was effective and well tolerated in a 6-week open study of ADHD youth with a prior history of stimulant treatment.

Characterizing non-OCD anxiety disorders in psychiatrically referred children and adolescents.

BACKGROUND: To characterize childhood and adolescent anxiety disorders in a psychiatric clinic. METHODS: Subjects were 1375 youth referred to a pediatric psychopharmacology program at a major academic center from 1991-2002. DSM-III-R diagnoses were obtained by Schedule for Affective Disorders and Schizophrenia for School-Age Children. RESULTS: Of 1375 referred youth, 794 had at least one non-obsessive-compulsive anxiety disorder, and 581 psychiatric comparison subjects had at least one disruptive behavior disorder and no anxiety disorders. There were 367 (46%) youth with one anxiety disorder, 224 (28%) with two disorders. Most prevalent were separation anxiety (49%), and overanxious disorder (47%). Mean ages of onset ranged from simple phobia (4.1) to panic disorder (8.5). Risk analyses revealed anxiety disorders significantly increased risk for anxiety and mood disorders. CONCLUSIONS: The full complement of anxiety disorders occurs in youth.

Update on adult attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent and highly morbid neurobehavioral disorder afflicting children, adolescents, and adults throughout the world. This article discusses the clinical assessment of adult ADHD, reviews the results of recent adult ADHD treatment studies with an emphasis on medications currently approved by the US Food and Drug Administration, and discusses the clinical management and monitoring of ADHD pharmacotherapy.

Reliability and Validity of the Before-School Functioning Scale in Children With ADHD.

OBJECTIVE: Children with ADHD frequently manifest behavioral difficulties in the morning prior to school. We sought to assess the reliability and validity of the Before-School Functioning Questionnaire (BSFQ) as a measure of morning behaviors impaired by ADHD. METHOD: We used pre-treatment data from a randomized crossover study of 6- to 12-year-old participants comparing the methylphenidate transdermal delivery system (MTS) with a placebo transdermal system (PTS) for a total of 4 weeks. RESULTS: The BSFQ investigator-rated scale shows very good internal homogeneity (Cronbach's α = .91), good test-retest reliability ( r = .60), good concurrent validity ( r range = .42-.86), and a strong treatment effect (effect size = -.93). The self-rated BSFQ showed lower levels of reliability and validity. CONCLUSION: The investigator-rated BSFQ should be used in future trials of ADHD medications aimed at assessing efficacy in the morning before school.

Mania, glutamate/glutamine and risperidone in pediatric bipolar disorder: a proton magnetic resonance spectroscopy study of the anterior cingulate cortex.

BACKGROUND: The purpose of this study was to investigate the anterior cingulate cortex (ACC) glutamate/glutamine (Glx) to creatine ratio (Glx/Cr) in two groups of children with Bipolar Disorder (BPD): those exhibiting manic symptoms requiring treatment and those being stably treated with the atypical antipsychotic risperidone. Atypical antipsychotics have been shown to increase serum glutamate levels and ACC Glx/Cr in subjects with schizophrenia. In this study, we hypothesized that the children with BPD in need of treatment would have lower Glx/Cr compared with the children with BPD being stably treated with risperidone. METHODS: Proton MR spectra were acquired, at 1.5 T, from the ACC of eighteen subjects with a DSM-IV diagnosis of BPD: ten (11.10+/-3.48 years; five female) were manic and not medicated with any antipsychotic and eight (10.88+/-2.99 years; one female) were medicated with the atypical antipsychotic risperidone. RESULTS: Children with BPD exhibiting manic symptoms requiring treatment had lower Glx/Cr than children with BPD being stably treated with the atypical antipsychotic risperidone. The children treated with risperidone also had significantly lower YMRS and CGI-Mania scores than the children not treated with risperidone. Both YMRS and CGI-Mania scores correlated negatively with ACC Glx/Cr levels. LIMITATIONS: The cross-sectional design, small sample size, the use of Glx rather than glutamate or glutamine and the use of Cr ratios rather than absolute concentrations are limitations of this study. CONCLUSIONS: Children with mania have lower Glx/Cr levels than children with BPD being stably treated with the atypical antipsychotic risperidone. Mania may be associated with reduced glutamate/glutamine levels in the ACC: other imaging studies have shown mania associated with hypometabolism in the ACC. These reductions in glutamate/glutamine may be increased following successful treatment with glutamatergic agents.

An open-label trial of aripiprazole monotherapy in children and adolescents with bipolar disorder.

INTRODUCTION: Aripiprazole is a novel second-generation antipsychotic approved for the treatment of bipolar disorder in adults but there is no systematic data available in pediatric bipolar disorder. METHODS: This was an 8-week, open-label, prospective study of aripiprazole 9.4+/-4.2 mg/day monotherapy to assess the efficacy and tolerability of this compound in treating pediatric bipolar disorder. Assessments included the Young Mania Rating Scale, Clinical Global Impressions-Improvement scale, and Brief Psychiatric Rating Scale. Adverse events were assessed through spontaneous self-reports, vital signs weight monitoring, and laboratory analysis. RESULTS: Fifteen of the 19 bipolar youth (79%) completed the study. Aripiprazole treatment was associated with clinically and statistically significant improvement in mean Young Mania Rating Scale scores (-18.0+/-6.9, P<.0001). With the important exception of two cases of extrapyramidal symptoms that precipitated dropout, aripiprazole was well tolerated with no statistically significant increase in body weight (1.8+/-1.7 kg, P=.2). CONCLUSION: Open-label aripiprazole treatment was beneficial in the treatment of mania in youth with bipolar disorder. Future placebo-controlled, double-blind studies are warranted.