Outcome measures and serious asthma exacerbation in clinical trials of asthma controller medications.

BACKGROUND: With the introduction and approval of several new asthma controller medications for pediatric use, the risk-benefit ratio of these medications has not been fully evaluated. OBJECTIVE: To determine whether physiologic pulmonary measurements are superior to other measures in evaluating outcomes and to determine whether asthmatic children have a higher risk of serious adverse events than adults. METHODS: We obtained data on asthma controller medications approved between 1997 and 2010 from the US Food and Drug Administration archives. Six medications were approved for use in children and adults during this time. Of these, we were able to analyze 23 trials of 5 medications. Nine of the trials were conducted in pediatric patients and 14 in adults. RESULTS: We determined whether the primary outcome measure was a physiologic pulmonary measure or another measure and compared trial outcomes. We also evaluated serious adverse events, including mortality rates for both adult and pediatric trials. The frequency of successfully demonstrating efficacy was far superior using physiologic pulmonary measures (13/14 [93%]) compared with other outcome measures (4/9 [44%]). The frequency of serious asthma exacerbations, although less than 1%, was higher in the pediatric group of patients (18/1,948 [0.9%]) compared with adults (4/2,460 [0.2%]), regardless of assignment to placebo or drug. CONCLUSION: These results suggest that physiologic pulmonary function measures should be used in evaluating the efficacy of asthma controller medications. These data also indicate that pediatric patients may be more prone to serious asthma exacerbations during clinical trials.

Differential pattern of response in mood symptoms and suicide risk measures in severely ill depressed patients assigned to citalopram with placebo or citalopram combined with lithium: role of lithium levels.

The assumption that antidepressants may reduce suicide risk by reducing depressive symptoms is not based on data. Further, it is unclear if the retrospectively based anti-suicidal effects of lithium can be prospectively evaluated using lithium as an augmenting agent to antidepressants. To verify our hypothesis, we designed and conducted an exploratory proof of concept trial of four weeks duration using a randomized, double-blind, parallel group method. Forty patients were assigned to citalopram + lithium and 40 were assigned to citalopram + placebo. The primary dependent measures were the Sheehan-Suicidality Tracking Scale (S-STS) and the Montgomery-Asberg Depression Rating Scale (MADRS). The reduction of S-STS scores was large (43%) and twice that seen in MADRS scores (25%) among the eighty patients included in the trial. Both response (χ(2) = 8.8, p < 0.01) and remission (χ(2) = 4.6, p = 0.03) rates showed similar patterns. There were no significant differences in mean total S-STS change scores among patients assigned to citalopram with placebo (4.8 ± 5.1) and patients assigned to citalopram with lithium (5.1 ± 5.2). When explored further, a subgroup of the patients assigned to citalopram and lithium achieved therapeutic serum levels and had significantly higher S-STS remission rates (45% compared to 19%, p < 0.05). There were no deaths by suicide or other causes indicating that trials enrolling acutely suicidal patients are feasible. These results suggest that citalopram may have a direct therapeutic effect on suicidal thoughts and behaviors. Further, lithium when used in therapeutic doses may augment such effects. These data warrant further exploration of lithium and an antidepressant combination for anti-suicidal effects.

The effect of a switch to ziprasidone in an adult population with autistic disorder: chart review of naturalistic, open-label treatment.

BACKGROUND: The present investigation retrospectively assessed the effect of an open-label switch to ziprasidone from other atypical antipsychotics on behavior, weight, and lipid levels in an adult population with autistic disorder. METHOD: We conducted a chart review of 10 adults (mean +/- SD age = 43.8 +/- 6.0 years) with DSM-IV autistic disorder who were switched from other atypical antipsychotics to ziprasidone, primarily due to weight gain, but other reasons included hypercholesterolemia, maladaptive behaviors, drowsiness, and depression. They had been treated with ziprasidone for at least 6 months. Our review focused on frequency of maladaptive behaviors, weight, and lipid levels. RESULTS: The mean +/- SD daily dose of ziprasidone was 128 +/- 41 mg, and all 10 patients continued with this same treatment after completion of the 6-month trial. Seven patients were found to have an improvement or no change in their maladaptive behavior. Eight patients (80%) lost weight (mean change = -13.1 +/- 7.0 lb [-5.9 +/- 3.2 kg]), 4 (80%) of 5 patients had a decrease in total cholesterol level, and 3 (60%) of 5 had a decrease in triglyceride levels. Data on lipid levels were available for 5 of the 10 patients. Behavioral activation was not noted in this population. There were no significant adverse effects associated with ziprasidone. CONCLUSION: In adults with autism, a switch to ziprasidone from other atypical antipsychotics appears to have the potential for maintaining beneficial effect on behavior while improving major health indices including weight and lipid levels.

Placebo response and antidepressant clinical trial outcome.

Placebo response magnitude is suspected to affect the outcome of antidepressant clinical trials. To evaluate this, 52 randomized, double-blind, placebo-controlled clinical trials obtained from the FDA were examined to correlate placebo response magnitude with trial outcome. The magnitude of symptom reduction, percentage mean change from baseline in the Hamilton Depression Rating Scale (HAM-D), was assessed for patients assigned to placebo or an antidepressant. Correlation coefficients between symptom reduction with placebo and antidepressants and between symptom reduction with placebo and magnitude of advantage of antidepressants over placebo were assessed. A statistically significant positive correlation was seen between placebo and antidepressant response magnitude (r =.40, p <.001) and between placebo response magnitude and the advantage of antidepressants over placebo (r = -.592, p <.0001). Only 21.1% of antidepressant treatment arms in trials with high placebo response (>30% mean change from baseline) showed statistical superiority over placebo compared with 74.2% in trials with a low placebo response (< or =30). Response magnitude varies and has an important effect on antidepressant clinical trials, illustrating the need for a placebo arm to determine if the trial was sensitive to treatment differences and highlighting the dangers of cross-study comparisons.