Adelaide S. Robb

A Multiple-Center, Randomized, Double-Blind, Placebo- Controlled Study of Oral Aripiprazole for Treatment of Adolescents With Schizophrenia

OBJECTIVE Aripiprazole is a dopamine partial agonist approved for use in adults for short- and long-term treatment of schizophrenia and bipolar disorder. This study was designed to examine the acute efficacy, safety, and tolerability of aripiprazole for adolescents with schizophrenia. METHOD This was a 6-week multicenter, double-blind, randomized, placebo-controlled trial. Subjects 13 to 17 years old with a DSM-IV diagnosis of schizophrenia and a Positive and Negative Syndrome Scale (PANSS) total score of 70 or more were randomly assigned (1:1:1 ratio) to placebo or 10 or 30 mg/day of aripiprazole. The primary endpoint was mean change from baseline to endpoint (last observation carried forward) in PANSS total score. Assessments of safety and tolerability included spontaneously reported adverse events, extrapyramidal symptom scores, serum prolactin concentration, body weight, and metabolic measures. RESULTS Of 302 patients, 85% completed the 6-week study. The mean baseline PANSS score was 94.1. At the end of the study, both aripiprazole doses showed statistically significant differences from placebo in reduction in PANSS total score. Adverse events occurring in more than 5% of either aripiprazole group and with a combined incidence at least twice the rate for placebo were extrapyramidal disorder, somnolence, and tremor. Mean changes in prolactin were -8.45, -11.93, and -15.14 ng/ml for placebo and 10 mg and 30 mg of aripirazole, respectively. Mean body weight changes were -0.8, 0.0, and 0.2 kg for placebo and 10 mg and 30 mg of aripiprazole, respectively. CONCLUSION Both 10- and 30-mg/day doses of aripiprazole were superior to placebo in the acute treatment of adolescents with schizophrenia. Aripiprazole was generally well tolerated.

Eating disorders in males

Eating disorders are one of the rare psychiatric disorders with a large preponderance of female patients. The other articles in this issue review eating disorders in children and adolescents and focus primarily on female patients. This article reviews the eating disorders that occur in male children and teenagers, including anorexia nervosa, bulimia nervosa, binge eating disorder, a subtype of body dysmorphic disorder named muscle dysmorphobia, and obesity. This article reviews subgroups of boys who are at higher risk for developing eating disorders. The article commences with the difference in male perceptions of body image and dieting behaviors.

A randomized controlled trial of risperidone, lithium, or divalproex sodium for initial treatment of bipolar I disorder, manic or mixed phase, in children and adolescents.

CONTEXT There was a paucity of comparative pharmacological research for initial treatment of bipolar I disorder, manic or mixed phase, in children and adolescents. OBJECTIVE To investigate which medication to administer first to antimanic medication-naive subjects. DESIGN, SETTING, AND PARTICIPANTS The Treatment of Early Age Mania (TEAM) study recruited 6- to 15-year-old children and adolescents with DSM-IV bipolar I disorder (manic or mixed phase) at 5 US sites from 2003 to 2008 into a controlled, randomized, no-patient-choice, 8-week protocol. Blinded, independent evaluators conducted all baseline and end-point assessments. INTERVENTIONS Subjects received a titrated schedule of lithium, divalproex sodium, or risperidone. Medications were increased weekly only if there was inadequate response, and no dose-limiting adverse effects, to maximum doses of lithium carbonate (1.1-1.3 mEq/L), divalproex sodium (111-125 μg/mL), and risperidone (4-6 mg). MAIN OUTCOME MEASURES Primary outcome measures were the Clinical Global Impressions for Bipolar Illness Improvement-Mania and the Modified Side Effects Form for Children and Adolescents. RESULTS There were 279 antimanic medication-naive subjects (mean [SD] age, 10.1 [2.8] years; 50.2% female) who had the following characteristics: 100% elated mood and/or grandiosity, 77.1% psychosis, 97.5% mixed mania, 99.3% daily rapid cycling, and mean (SD) mania duration of 4.9 (2.5) years. The mean (SD) titrated lithium level was 1.09 (0.34) mEq/L, and the mean (SD) divalproex sodium level was 113.6 (23.0) μg/mL. The mean (SD) titrated risperidone dose was 2.57 (1.21) mg. Higher response rates occurred with risperidone vs lithium (68.5% vs 35.6%; χ(2)(1) = 16.9, P < .001) and vs divalproex sodium (68.5% vs 24.0%; χ(2)(1) = 28.3, P < .001). Response to lithium vs divalproex sodium did not differ. The discontinuation rate was higher for lithium than for risperidone (χ(2)(1) = 6.4, P = .011). Increased weight gain, body mass index, and prolactin level occurred with risperidone vs lithium (F(1,212) = 45.5, P < .001; F(1,212) = 39.1, P < .001; and F(1,213) = 191.4, P < .001, respectively) and vs divalproex sodium (F(1,212) = 34.7, P < .001; F(1,212) = 45.3, P < .001; and F(1,213) = 209.4, P < .001, respectively). The thyrotropin level increased in subjects taking lithium (t(62) = 11.3, P < .001). CONCLUSIONS Risperidone was more efficacious than lithium or divalproex sodium for the initial treatment of childhood mania but had potentially serious metabolic effects. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00057681

Dopamine Transporter Genotype and Methylphenidate Dose Response in Children with ADHD

Stimulant medications, such as methylphenidate (MPH), are the most commonly used, effective treatment for ADHD. MPH acts primarily by inhibiting the dopamine transporter (DAT), a protein responsible for the reuptake of dopamine from the synapse into presynaptic terminals. We sought to evaluate the relationship between DAT1 3′-untranslated region (3′-UTR) variable number tandem repeats (VNTR) genotypes and dose response to MPH. Children with ADHD (n=47), ages 5–16 years (mean=9.02 years), underwent a 4-week, double-blinded, crossover trial with forced weekly dosage changes. Children were genotyped for the DAT1 VNTR and evaluated on placebo and three dosage levels of OROS® MPH. Parents and clinicians who were blind to genotype and medication status rated ADHD symptoms, impairment, and stimulant side effects each week. Children who were homozygous for the less common, 9-repeat DAT1 3′-UTR genotype displayed a distinct dose–response curve from that of the other genotype groups, with an absence of typical linear improvement when the dose was increased from 18 mg to 36 and 54 mg. Further research is needed to determine the mechanisms related to poor response in patients with the 9/9-repeat genotype, and to determine if this group responds differentially to alternative treatments.

A Randomized, Double-Blind Study of Paliperidone Extended-Release in Treatment of Acute Schizophrenia in Adolescents

BACKGROUND Paliperidone extended-release (ER) is approved for treatment of schizophrenia in adults but has not been evaluated in adolescents. METHODS In this 6-week, double-blind, parallel-group study, participants (n = 201) aged 12 to 17 years, with a Positive and Negative Syndrome Scale (PANSS) total score of 60 to 120 were randomly allocated (1:1:1:1) to receive either placebo or one of three weight-based, fixed doses of paliperidone ER, once-daily (patients weighing 29 to < 51 kg at baseline: 1.5 mg [Low], 3 mg [Medium], or 6 mg [High]; patients weighing ≥ 51 kg: 1.5 mg [Low], 6 mg [Medium], or 12 mg [High]). RESULTS The mean (SD) change in PANSS total score from baseline to endpoint (primary efficacy variable) was significant for the paliperidone ER Medium-treatment (-17.3 [14.33]; p < .05; n = 54) but not for Low- (-9.8 [16.31]; n = 48) or High-treatment groups (-13.8 [15.74]; n = 47) versus placebo (-7.9 [20.15]; n = 51). By actual dose, the mean (SD) change in PANSS total score was significant for the 3-, 6-, and 12-mg doses (3 mg: -19.0 [15.45]), 6 mg: -13.8 [14.75], and 12 mg: -16.3 [15.41;] all ps < .05), compared with placebo (-7.9 [20.15]). The total percentages of treatment-emergent adverse events were dose-related for the three weight-based treatment groups. CONCLUSIONS With weight-based treatment, only paliperidone ER Medium-treatment (3-6 mg) resulted in significant improvement in symptoms of schizophrenia in adolescents, as did 3, 6, and 12 mg by actual dose strengths. Weight-based dosing of paliperidone ER in adolescents with schizophrenia does not appear to be necessary. Paliperidone ER (1.5-12 mg, once daily) was tolerable, and no new safety concerns were reported.

Treatment Moderators and Predictors of Outcome in the Treatment of Early Age Mania (TEAM) Study

OBJECTIVE Both the diagnosis and treatment of bipolar disorder in youth remain the subject of debate. In the Treatment of Early Age Mania (TEAM) study, risperidone was more effective than lithium or divalproex in children diagnosed with bipolar mania and highly comorbid with attention-deficit/hyperactivity disorder (ADHD). We searched for treatment moderators and predictors of outcome. METHOD TEAM was a multi-site, 8-week, randomized clinical trial of risperidone, lithium, or divalproex in 279 medication-naïve patients, aged 6 through 15 years, with a DSM-IV diagnosis of bipolar disorder currently in manic or mixed phase. Outcome measures included binary end-of-treatment responder status and change in the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) Mania Rating Scale (KMRS). Baseline demographics and clinical characteristics were tested as modifiers of treatment effect and as overall predictors of outcome. RESULTS Moderator effects were detected for site, ADHD, and obesity. Across sites, the response ratio (RR) for risperidone versus lithium ranged from 1.2 (95% confidence interval [CI] = 0.8-1.7) to 8.3 (95% CI = 1.1-60.8), and for risperidone versus divalproex from 1.3 (95% CI = 0.8-2.2) to 10.5 (95% CI = 1.4-77.7). The RR for risperidone versus lithium was 2.1 for patients with ADHD, but 1.0 for those without ADHD, and 2.3 (95% CI = 1.6-3.3) for nonobese patients, but 1.1 (95% CI = 0.6-2.0) for obese ones. Older age and less severe ADHD symptoms were associated with greater improvement on the KMRS. CONCLUSIONS Risperidone was more effective than lithium or divalproex across the demographics and clinical characteristics of the sample, but the magnitude of its effect was influenced by site-related characteristics and presence of ADHD. Clinical trial registration information--Treatment of Early Age Mania; http://clinicaltrials.gov/; NCT00057681.

Effects of Maternal Stimulant Medication on Observed Parenting in Mother–Child Dyads With Attention-Deficit/Hyperactivity Disorder

This pilot study of 23 mothers with attention-deficit/hyperactivity disorder (ADHD) and their offspring with ADHD examined the effects of maternal stimulant medication on observed interactions. Parent–child interactions were observed using a structured protocol before and after mothers underwent a 5-week, double-blind stimulant titration. Despite dramatic effects of medication on adult ADHD symptoms, this small pilot and open label laboratory-based study did not identify maternal stimulant effects on observed parenting or child behavior. Given the documented impairments in parenting displayed by adults with ADHD, behavioral parenting interventions may be needed in conjunction with medication for mothers with ADHD to optimize family outcomes.

Lithium in the Acute Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled Study.

BACKGROUND: Lithium is a benchmark treatment for bipolar disorder in adults. Definitive studies of lithium in pediatric bipolar I disorder (BP-I) are lacking. METHODS: This multicenter, randomized, double-blind, placebo-controlled study of pediatric participants (ages 7–17 years) with BP-I/manic or mixed episodes compared lithium (n = 53) versus placebo (n = 28) for up to 8 weeks. The a priori primary efficacy measure was change from baseline to the end of study (week 8/ET) in the Young Mania Rating Scale (YMRS) score, based on last-observation-carried-forward analysis. RESULTS: The change in YMRS score was significantly larger in lithium-treated participants (5.51 [95% confidence interval: 0.51 to 10.50]) after adjustment for baseline YMRS score, age group, weight group, gender, and study site (P = .03). Overall Clinical Global Impression–Improvement scores favored lithium (n = 25; 47% very much/much improved) compared with placebo (n = 6; 21% very much/much improved) at week 8/ET (P = .03). A statistically significant increase in thyrotropin concentration was seen with lithium (3.0 ± 3.1 mIU/L) compared with placebo (–0.1 ± 0.9 mIU/L; P < .001). There was no statistically significant between-group difference with respect to weight gain. CONCLUSIONS: Lithium was superior to placebo in reducing manic symptoms in pediatric patients treated for BP-I in this clinical trial. Lithium was generally well tolerated in this patient population and was not associated with weight gain, distinguishing it from other agents commonly used to treat youth with bipolar disorder.

Managing irritability and aggression in autism spectrum disorders in children and adolescents.

Children with autism and autism spectrum disorders have a high rate of irritability and aggressive symptoms. In one study up to 20% of children with autism have symptoms of irritability and aggression including aggression, severe tantrums, and deliberate self injurious behavior (Lecavalier [2006] J. Autism Dev. Disord. 36:1101-1114.). These symptoms can lead to impairment and distress in both home and school settings. Medications to treat the irritability will be discussed across categories of antipsychotics, antidepressants, antihypertensive agents, and others. Emphasis will be placed on medications with the most safety and efficacy and FDA approval.

Nocturnal nasogastric refeeding for hospitalized adolescent boys with anorexia nervosa.

ABSTRACT. Boys with anorexia nervosa have nutritional needs exceeding those of their female counterparts. For many males with anorexia nervosa, oral refeeding alone may result in low discharge weight, a critical risk factor in relapse. This study compared the short-term outcomes of oral refeeding (OR) and a combination of OR with supplemental nocturnal nasogastric refeeding (NNGR) in a sample of hospitalized boys. This was a retrospective chart review with a cohort design. Subjects were partitioned into: The OR group (n = 8, mean age = 14.9, SD = 1.7) and the OR + NNGR group (n = 6, mean age = 13.8, SD = 2.0). The NNGR group had greater increase in weight and Body Mass Index. Their average length of hospitalization was also shorter. Nocturnal nasogastric refeeding, complementing oral refeeding, should be considered as an alternative initial therapy for weight restoration in males with anorexia nervosa.