Raul R. Silva

Lithium in Hospitalized Aggressive Children with Conduct Disorder: A Double-Blind and Placebo-Controlled Study

OBJECTIVE To assess critically the efficacy and safety of lithium and replicate earlier findings in a larger sample of aggressive children with conduct disorder and to assess the utility of the Profile of Mood States (POMS) in this population. METHODS Children hospitalized for treatment-refractory severe aggressiveness and explosiveness and with diagnosed conduct disorder were subjects in this double-blind, placebo-controlled clinical trial. After a 2-week placebo baseline period, children were randomly assigned to lithium or placebo treatment for 6 weeks of placebo. The main outcome measures were the Global Clinical Judgments (Consensus) Scale, Childrens Psychiatric Rating Scale, Conners Teacher Questionnaire, Parent-Teacher Questionnaire, and the POMS. RESULTS Fifty children (mean age 9.4 years) completed this study. The mean optimal daily dose of lithium was 1,248 mg and the mean serum level was 1.12 mEq/L. Lithium was superior to placebo, although the effects on some measures were more modest than in a previous study. CONCLUSIONS Lithium appears to be an effective treatment for some severely aggressive children with conduct disorder. Although the POMS appeared to be reliable, it did not detect any response to lithium.

Reflections of depression in acoustic measures of the patient’s speech

BACKGROUND The literature on acoustic measures of voice in depression is reviewed. Authors have separated results derived from studies of automatic speech, such as counting or reading, from free speech. Free speech requires cognitive activity such as word finding and discourse planning in addition to the motor activity of automatic speech. Also, results have been less ambiguous if homogeneous groups of agitated or retarded depressed patients were examined. METHODS These distinctions are applied to the results of a 12-week double-blind treatment trial that compared response to nortriptyline (25-100 mg/day) with sertraline (50-150 mg/day). Twelve male and ten female elderly depressed patients and an age-matched normal control group (n=19) were studied. Patients were divided into retarded or agitated groups on the basis of ratings. Results from measures of fluency (speech productivity and pausing) and prosody (emphasis and inflection) are described. RESULTS Depressed patients showed less prosody than the normal subjects. Improvement in the retarded group was reflected in briefer pauses but not longer utterances. There was a trend in the agitated group for improvement to be reflected in the utterance but not the pause measure. CONCLUSIONS Clinical impressions are substantially related to acoustic parameters. Temporal changes associated with depression appear to reflect the depressed state whereas prosodic features seem to reflect a depressed trait. Acoustic measures of the patients speech may provide objective procedures to aid in the evaluation of depression. Limitations of the study are discussed.

Factors related to posttraumatic stress disorder in adolescence.

Studies of posttraumatic stress disorder (PTSD) in adolescence published from 2000 to 2011 indicate that adolescents are at greater risk of experiencing trauma than either adults or children, and that the prevalence of PTSD among adolescents is 3–57%. Age, gender, type of trauma, and repeated trauma are discussed as factors related to the increased rates of adolescent PTSD. PTSD in adolescence is also associated with suicide, substance abuse, poor social support, academic problems, and poor physical health. PTSD may disrupt biological maturational processes and contribute to the long-term emotion and behavior regulation problems that are often evident in adolescents with the disorder. Recommendations are presented for practice and research regarding the promotion of targeted prevention and intervention services to maximize adolescents’ strengths and minimize vulnerabilities. Public policy implications are discussed.

Comparative Efficacy of Two Once Daily Methylphenidate Formulations (Ritalin® LA™1 and Concerta®) and Placebo in Children with Attention Deficit Hyperactivity Disorder Across the School Day

AbstractObjectivesThe primary objective was to compare the differences in clinical efficacy of the starting dose of Ritalin® LA™ (20mg) to the starting dose of Concerta® (18mg), in a laboratory school setting for the duration of an entire school day. Secondary objectives were to compare Ritalin® LA™ 20mg with Concerta® 36mg, and Ritalin® LA™ and both Concerta® doses versus placebo across the school day.MethodsThirty-six children (29 males, 7 females), aged 6–12 years, with attention deficit hyperactivity disorder, previously stabilized on methylphenidate (MPH), completed this four-way, randomized, single-blind crossover, analog classroom study. Patients were evaluated on day 0 and randomized to receive treatment on days 7, 14, 21, and 28 (Ritalin® LA™ 20mg, Concerta® 18mg, Concerta® 36mg, or placebo).ResultsSwanson, Kotkin, Agler, M-Flynn and Pelham Rating Scale (SKAMP)-attention: The effect of Ritalin® LA™ 20mg across the morning was statistically different from that of Concerta 18mg and 36mg, as demonstrated by the change in the area under the curve (AUC) during the first 4 hours (0–4) from pre-dose. AUC(0–4) for Ritalin®LA™ was −2.48 versus −1.36 for Concerta® 18mg (p = 0.015), and −1.55 for Concerta® 36mg (p = 0.043). AUC(0–8) change from pre-dose for Ritalin® LA™ was −4.48 versus −2.72 for Concerta® 18mg (p = 0.074), and −3.24 for Concerta® 36mg (p = 0.208). SKAMP-deportment: AUC(0–4) for Ritalin® LA™ was −1.67 compared with −0.28 for Concerta® 18mg (p < 0.001), and −0.55 for Concerta® 36mg (p = 0.004). AUC(0–8) change from pre-dose for Ritalin® LA™ was −2.81 compared with −0.82 for Concerta® 18mg (p = 0.018), and −1.34 for Concerta® 36mg (p = 0.078). Combined: Mean AUC(0–4) change from pre-dose for Ritalin® LA™ was −2.05 compared with −0.78 for Concerta® 18mg (p < 0.001), −1.01 for Concerta® 36mg (p = 0.003). The mean AUC(0–8) change from pre-dose for Ritalin® LA™ was −3.58 compared with −1.70 for Concerta® 18mg (p = 0.010), −2.22 for Concerta® 36mg (p = 0.061). Math test-attempted: Mean pre-dose score for Ritalin® LA™ was about 73 compared with 74, 90, and 81 for Concerta® 18mg, 36mg, and placebo, respectively. Mean AUC(0–8) change from pre-dose for Ritalin® LA™ was 202 compared with 115 for Concerta® 18mg (p = 0.135), 137 for Concerta® 36mg (p = 0.265). Math test-correct: Mean pre-dose score for Ritalin® LA™ was 68 compared with 64, 78, and 76 for Concerta® 18mg, 36mg, and placebo, respectively. Mean AUC(0–8) change from pre-dose for Ritalin® LA™ was 183 compared with 100 for Concerta® 18mg (p = 0.144), and 117 for Concerta® 36mg (p = 0.245). Safety: One patient from each treatment group experienced a single mild adverse event that included abdominal pain, nausea, and dyspnea.ConclusionWhile both Ritalin® LA™ and Concerta® were shown to be effective, the different release profiles of each formulation can result in distinct differences between the effects on measures of attention and deportment.

Carbamazepine Use in Children and Adolescents with Features of Attention-Deficit Hyperactivity Disorder: A Meta-Analysis

OBJECTIVE In the United States approximately 750,000 children receive psychostimulants to treat attention-deficit hyperactivity disorder (ADHD); up to 25% may not respond. The purpose of this study was to evaluate the reports in the international literature concerning the efficacy of carbamazepine (CBZ) in children with ADHD features by means of meta-analysis. METHOD A review of the world literature located 29 reports that dealt with behavior problems, activity levels, and CBZ in children. Of these, only 10 reports provided sufficient or pertinent information for the meta-analysis. RESULTS In all seven open studies, therapeutic responses were significant (ranging from p = .05 to .0001, two-tailed t test). Meta-analysis using weighted variables revealed a significant positive correlation (r = .88; p < .02) between duration of treatment and positive outcome. In three double-blind placebo-controlled studies, treatment effects for CBZs superiority over placebo ranged from p = .07 to .0001. A meta-analysis of these three studies revealed that CBZ was significantly (p = .018) more effective than placebo at controlling target symptoms. CONCLUSIONS Despite the general lack of attention that CBZ has received for treating ADHD, there is preliminary evidence that CBZ may be an effective alternate treatment in children with features of ADHD.

Neuroleptic malignant syndrome in children and adolescents on atypical antipsychotic medication: a review.

OBJECTIVE Neuroleptic malignant syndrome (NMS) is a severe iatrogenic complication of treatment with antipsychotic medication. The purpose of this report is to examine the published cases of NMS in children and adolescents receiving atypical antipsychotic medication and review early warning symptoms, risk factors, and treatment in this population. METHOD An extensive review of the literature from 1990 to 2008 was conducted via computerized searches (PubMed and Ovid) to identify case reports. Descriptive statistics were employed to describe our findings. RESULTS There were 23 episodes in 20 subjects, with ages ranging from 11 to 18 years. Increased creatine phosphokinase (CPK) was the most common finding (100%), followed by fever (78%), tachycardia (74%), rigidity (70%), and altered mental status (61%). The number of NMS symptoms ranged from 1 to 11 (mean 4.7 +/- 2.4) and positive laboratory findings ranged from 1 to 4 (2.2 +/- 1). The duration of NMS (mean 6.1 +/- 6.4 days) was one third of the duration associated with typical antipsychotics. Patients treated with bromocriptine had a shorter duration of illness, whereas the same was not true for those receiving dantrolene. In all cases, the NMS symptoms eventually resolved and there were no reported deaths or permanent sequelae. CONCLUSIONS NMS is a serious condition. Symptom presentation related to atypical agents differs from that seen with older antipsychotic medications.

A randomized, double-blind, crossover study of once-daily dexmethylphenidate in children with attention-deficit hyperactivity disorder: rapid onset of effect.

AbstractBackground: Long-acting methylphenidate formulations provide control of attention-deficit hyperactivity disorder (ADHD) symptoms for up to 12 hours; however, not all formulations have rapid onset of therapeutic effect, which is essential for providing symptom control during morning hours. The primary objective of this randomized, double-blind, crossover study was to assess the efficacy of dexmethylphenidate extended release (ER) versus placebo by measuring the change from pre-dose to 0.5 hours post-dose on the Swanson, Kotkin, Agler, M-Flynn and Pelham (SKAMP) rating scale. Methods: Eighty-six children (6–12 years) with ADHD diagnosed using the DSM-IV criteria were randomized to receive dexmethylphenidate ER 20 mg/day or placebo, sequentially, for 7 days, with the final dose administered in a laboratory classroom setting on day 7 of each treatment period. The primary efficacy comparison was change in the SKAMP-Combined score from pre-dose to 0.5 hours post-dose, with additional secondary assessments at 1, 2, 4, 6 and 8 hours post-dose. Secondary efficacy measures included change from pre-dose at all timepoints in the SKAMP-Attention and SKAMP-Deportment, Math Test-Attempted and Math Test-Correct scores, and change from baseline on the Conners’ ADHD/DSM-IV Scale for Parents (CADS-P). In an exploratory analysis, a daily diary card was completed by parents on the children’s in-home behaviour before school. Safety was assessed by occurrence of adverse events, monitoring of vital signs and interpretation of ECGs. Results: Significant improvements were noted at 0.5 hours and at all timepoints post-dose throughout the 8-hour laboratory classroom day for dexmethylphenidate ER vs placebo in the primary outcome measure of the SKAMP-Combined scores (p < 0.001), as well as SKAMP-Attention, SKAMP-Deportment, Math Test-Attempted and Math Test-Correct scores (p < 0.05). The changes from baseline in CADS-P scores were significantly greater with dexmethylphenidate ER than placebo (−16.382 vs −4.622; p < 0.001). Responses to all diary questions indicated significant improvement with dexmethylphenidate ER treatment versus placebo (all p < 0.001). The most common adverse events were abdominal pain (dexmethylphenidate ER 3.5%; placebo 4.7%), headache (dexmethylphenidate ER 3.5%; placebo 2.3%) and increased appetite (dexmethylphenidate ER 0%; placebo 3.5%). Conclusion: Compared with placebo, once-daily dexmethylphenidate ER 20 mg provided rapid and significant improvement at 0.5 hours post-dose in attention, deportment and academic performance, which was sustained for 8 hours post-dose. Overall, once-daily dexmethylphenidate ER 20 mg was well tolerated. In an analysis of parental assessment of diary responses, children appeared more organized, and morning preparation for school was smoother and less frustrating with once-daily dexmethylphenidate ER compared with placebo.

Efficacy and safety of extended-release dexmethylphenidate compared with d,l-methylphenidate and placebo in the treatment of children with attention-deficit/hyperactivity disorder: a 12-hour laboratory classroom study.

OBJECTIVE This study compared the efficacy and safety of extended-release dexmethylphenidate (d-MPH-ER) 20 mg/day and 30 mg/day with extended-release racemic methylphenidate hydrochloride (d,l-MPH-ER) 36 mg/day and 54 mg/day, and placebo in children with attention-deficit/hyperactivity disorder (ADHD) in a laboratory classroom setting. METHODS This multicenter, double-blind, crossover study included children (N = 84) 6-12 years of age, stabilized on total daily doses of 40 mg to 60 mg d,l-MPH or 20 mg/day or 30 mg/day d-MPH who were randomized to different treatment sequences. Primary efficacy was measured by the change from pre-dose in Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale-Combined scores at 2 hours post-dose (d-MPH-ER 20 mg/day versus d,l-MPH- ER 36 mg/day). Adverse events were monitored throughout the study period. RESULTS Mean change in SKAMP-Combined score at 2 hours post-dose was significantly larger for d-MPH-ER 20 mg/day versus d,l-MPH-ER 36 mg/day (p < 0.001). Both doses of d-MPH-ER had a more rapid onset and greater morning effect relative to d,l-MPH-ER while d,l-MPH-ER had a greater effect at the end of the 12-hour day. All active treatments provided a significant benefit over placebo at most time points to 12 hours post-dosing. Both treatments were well tolerated. CONCLUSIONS d-MPH-ER and d,l-MPH-ER improved ADHD symptoms and were well tolerated. While d-MPH-ER had a faster onset of action, d,l-MPH-ER retained greater effect at the end of the 12- hour classroom day.

Persistent Tardive Dyskinesia and Other Neuroleptic-Related Dyskinesias in Tourette's Disorder

ABSTRACT Two new cases are reported of persistent tardive dyskinesia associated with neuroleptic treatment of patients with Tourettes disorder. Previously, 44 cases were described in 8 published reports, including 36 children and adolescents, but diagnostic criteria were infrequently specified. In our review of these cases, using the criteria of Schooler and Kane but modified by Gualtieris more conservative duration criteria of 16 weeks, only 2 of these cases were consistent with a diagnosis of persistent tardive dyskinesia. The 2 new cases are reported here. A 12-year-old, who was treated with haloperidol 4 mg daily since the age of 8, developed fine vermicular movements of the tongue of moderate severity. Despite discontinuation of the neuroleptic, symptoms of tardive dyskinesia still persisted at age 15 and were associated with difficulty in speech production. A 42-year-old, who was treated with haloperidol 1 mg three times daily for 7 years, developed jaw movements and lip smacking that persisted for more than 2 years. Abnormal involuntary movement scale (AIMS) ratings supported a diagnosis of tardive dyskinesia in both patients with Tourettes disorder. The identification of tardive dyskinesia in the setting of a preexisting movement disorder is discussed. Features that helped distinguish the movements of tardive dyskinesia and Tourettes disorder in these patients included the premonitory urges of Tourettes symptoms and a differential response of the symptoms to distracting voluntary motor tasks. Clinicians should be attentive and thorough in searching for symptoms of tardive dyskinesia following treatment with relatively low doses of haloperidol in patients with Tourettes disorder.

Review of Benzodiazepine use in Children and Adolescents

Clinically, benzodiazepines are used in adult populations much more frequently than in children and adolescents. There may be a number of reasons for this disparity including a dearth of well controlled clinical studies and the issue of dependence associated with long term use. However, over a ten year span there has been nearly a three fold increase in the use patterns for these agents in the child population. In open studies much of the literature has indicated potentially useful results, but these findings have not been replicated when more refined methodological studies have been conducted. The lack of encouraging results in these later studies may be attributable to a number of factors such as modest sample sizes and less than optimal patient selection. Nonetheless, with increasing prescriptions being written for these agents it is not clear what is compelling clinicians to use them. In this paper we will review the available literature on benzodiazepine use in the child and adolescent population, focusing primarily on psychiatric applications.