Med Check

• Clonidine appears to be associated with significantly higher rates of adverse events rated at least“ moderate” when used along with methylphenidate or alone for the treatment of ADHD in children. The data were reported by W. Burl Daviss, M.D. (University of Pittsburgh Medical Center) on behalf of the Clonidine in ADHD Treatment Study Group.

In a 16-week trial, 122 children (aged 7-12) with ADHD were randomly assigned to take clonidine alone (n=31), methylphenidate alone (n=29), both medications together (n=32), or placebo (n=30). Doses were flexible, up to a maximum of 0.6mg/d for clonidine and 60 mg/d for methylphenidate. Doses were titrated by clinicians to optimize tolerability and clinical response.

Rates of adverse events (AEs) and changes in electrocardiograms, blood pressure, and pulse were compared. Both groups taking clonidine had higher rates of AEs rated by a study investigator as “moderate” or“ severe,” compared with the two groups of patients not receiving clonidine (79 percent compared with 49 percent). However, groups taking clonidine also had lower drop-out rates compared with those taking methylphenidate alone or placebo.

The most common AEs were nervousness, somnolence, apathy, depression, and dyspepsia. However, rates of somnolence and fatigue were significantly higher in those taking clonidine. In both groups taking clonidine, heart rate was on average four beats per minute slower, compared with all patients not receiving clonidine. No other significant cardiovascular differences were seen in any of the four groups, and there was no evidence of an interactive effect between methylphenidate and clonidine in patients who received both.

• Atomoxetine may be associated with a potentially higher risk of aggression or hostility-related adverse events compared with placebo, according to a meta-analysis reported by John Polzer, D.V.M. (Lilly Research Laboratories). The analysis included data from acute, double-blind, clinical trials that were either placebo or comparator controlled. A total of 1,308 children and adolescents were randomly assigned to atomoxetine and compared with 806 patients randomly assigned to placebo. An additional 566 patients randomly assigned to atomoxetine were compared with 472 patients who randomly received methylphenidate as an active comparator.

In the 11 placebo-controlled trials, there were 21 aggression/hostility events in patients taking atomoxetine (1.6 percent occurrence rate) compared with nine events in those on placebo (1.1 percent), a difference that was not statistically significant. In six trials comparing atomoxetine with methylphenidate, there were seven events in atomoxetine patients (1.2 percent) compared with four events in those receiving methylphenidate (0.8 percent); again no statistical significance.

The overall relative risk of an aggression/hostility-related adverse event occurring to a patient taking atomoxetine, relative to placebo, was 1.33. The relative risk for atomoxetine versus methylphenidate was 0.96. Although the risk of a patient developing aggressive or hostile behavior appears numerically greater with atomoxetine compared with placebo, the meta-analysis found the differences were not statistically significant.

• A new film-coated formulation of modafinil, being referred to as modafinil-ADHD, is effective and safe for treating ADHD in children and adolescents aged 6-17, according to clinical trials data presented by Joseph Biederman, M.D. (Massachusetts General Hospital/Harvard Medical School) and Christopher Kratochvil, M.D. (University of Nebraska Medical Center). The tablet has release and absorption characteristics that are significantly different from the formulation already approved for sleep disorders and sleep apnea. In addition, modafinil-ADHD contains a higher dose than modafinil. (The U.S. FDA issued an“ approvable letter” for modafinil-ADHD—one step before final marketing approval of a product—on October 21, one day after these data were presented in Toronto.)

The data were pooled from three randomized, double-blind, placebo-controlled studies, two of which allowed flexible dosing of modafinil, while the third used a fixed-dose protocol. A total of 638 patients received either modafinil (n=423) or placebo (n=215). Modafinil-ADHD was associated with significantly greater improvements in ADHD symptoms, compared with placebo. Patients were assessed using the ADHD-Rating Scale-IV school and home versions, including total scores and subscores for inattention and hyperactivity-impulsivity. Scores on the Clinical Global Impression-Improvement scale also improved significantly greater in those on modafinil-ADHD, compared with changes in scores in those taking placebo. Both parent ratings and teacher ratings showed the same patterns, indicating improvements in symptoms both at home and at school.

In the pooled safety/tolerability analysis, the most common AEs seen in patients receiving modafinil-ADHD at a statistically significantly greater rate than placebo were insomnia (27 percent), headache (20 percent), decreased appetite (16 percent), abdominal pain (10 percent), and fever and nervousness (5 percent each). A total of eight serious AEs occurred in four patients taking the drug, versus no serious AEs in those taking placebo. No clinically significant differences were seen in cardiovascular changes (HR, BP) or in weight changes between the groups. Abrupt discontinuation of modafinil-ADHD did not appear to result in emergence of acute withdrawal symptoms or rebound effects.

• Lithium appears to be safe and effective in treatment of adolescent bipolar depression, according to a small study presented by Nick Patel, PharmD., Ph.D. (University of Cincinnati). A series of 27 adolescents (aged 12-18) hospitalized with a depressive episode and diagnosed with DSM-IV bipolar I disorder, were included in the six-week, open-label exploratory trial. Seven patients did not complete all six weeks of lithium treatment, primarily due to lack of effectiveness. However, in the remaining patients, a highly statistically significant reduction in scores on the Children's Depression Rating Scale-Revised was seen as early as week 1, and the improvement was maintained through week 6.

At week 6, 48 percent of the patients were responders to lithium (at least a 50 percent reduction in CDRS-R score), and 30 percent achieved remission (an endpoint CDRS-R score of 28 or less and a Clinical Global Impression-Bipolar score of 1 or 2.)

The most common adverse events seen were those already known to be associated with lithium, such as headache (74 percent), nausea/vomiting (67 percent), polyuria (33 percent), stomach ache (30 percent), polydipsia (26 percent), and abdominal cramps (19 percent).

• Quetiapine and divalproex show similar efficacy in treatment of aggression in patients with bipolar disorder and comorbid disruptive behavior disorders, reported Drew Barzman, M.D. (University of Cincinnati Children's Hospital Medical Center). Thirty-three adolescents (aged 12-18) were randomly assigned to either quetiapine or divalproex for 28 days. Patients with bipolar I disorder and a comorbid disruptive behavior disorder were included only if they scored 14 or higher on the Positive and Negative Syndrome-Excited Component (PANSS-EC). Both patients taking quetiapine and those taking divalproex showed statistically significant reductions in PANSS-EC ratings, with no statistically significant differences between the two groups in change in PANSS-EC or rate of improvement in scores.

Sedation and fatigue were the most common AEs in both groups, with both occurring statistically significantly more often with quetiapine. Gastrointestinal upset and headache also occurred in both groups, with no statistically significant difference between groups.

• Antidepressants are not linked to increased suicidality in youth, according to an analysis of nearly 2,500“ real-world” trials of antidepressant medications in 1,742 patients. The report, by Daniel Deutschman, M.D. (Case Western Reserve University) found that overall, apparent increases in suicidality after beginning medication were more likely due to obvious intervening stressors or interruption of treatment. On average, about half of the patients improved symptomatically with medication treatment, but no significant differences were found among different drugs. Suicidal thoughts did increase in a small number of patients (2.6 percent), compared with a decrease in suicidal thoughts in 11 percent of patients and decreased suicidal threats/gestures in 12.4 percent of patients. An electronic medical record review of every patient with an increase in any risk signal for suicidal thoughts or behaviors revealed that, in each case, medication was not believed to be the proximal cause. Obvious intervening stressors were identified in 38 percent of cases, interruption of treatment was evident in 27 percent of cases, and documentation error accounted for 26 percent of cases recorded as an increase in suicidal thoughts or behaviors.

• Both olanzapine and risperidone appear to be effective in maintenance treatment of youth with psychosis, reported Linmarie Sikich, M.D. (University of North Carolina at Chapel Hill). A small study randomly assigned 50 youngsters (aged 8-19) to eight weeks of double-blind therapy with either olanzapine, risperidone, or haloperidol. While diagnoses varied, all patients had at least one positive psychotic symptom of moderate or greater severity on the Brief Psychiatric Rating Scale for Children. At the end of week 8, 29 of the 50 patients were considered responders and continued for an additional 12 weeks of double-blind treatment.

Although all patients experienced significant reductions in psychotic symptoms in the acute trial, few patients gained any additional benefit during the extension of the trial through 20 weeks. AEs varied little between the three groups. However, 3 of 8 patients taking haloperidol reported blurry vision, compared with no such reports in patients taking the other drugs. Dry mouth was most common in those taking risperidone (5 of 8 patients) versus haloperidol (4 of 8 patients) and olanzapine (2 of 13 patients). Sedation was most commonly seen in those taking haloperidol (all 8 patients), followed by risperidone (7 of 8) and olanzapine (6 of 13). Weight gain was observed in all three groups and was most significant during the first eight weeks. Changes in blood glucose levels were significantly more likely to occur in those taking olanzapine, while changes in triglyceride levels were more common with both olanzapine and risperidone, compared with haloperidol.