Heparin-Induced Thrombocytopenia in a Pediatric Population: Implications for Clinical Probability Scores and Testing.

OBJECTIVES: To determine the applicability of the 4Ts score and the Heparin-Induced Thrombocytopenia (HIT) Expert Probability (HEP) score in children with suspected HIT and to estimate the number of children potentially at risk of HIT. STUDY DESIGN: We retrospectively estimated 4Ts and HEP scores in a cohort of 50 children referred for laboratory screening with enzyme immunoassay. In addition, minor modifications were introduced to the 4Ts score (modified 4Ts score) to adapt it for use in the pediatric setting. All patients with positive enzyme immunoassays were tested with serotonin release assay. We also extracted the number of patients started on heparins in a similar period of time. RESULTS: The median age at the time of testing was 4 years (25th-75th percentile, 8.7 months to 13.5 years); 78% of patients had low and 22% had intermediate risk pretest probability scores using the original 4Ts score; 86% had low risk and 14% had intermediate risk scores using the modified 4Ts score; 54% of children had a HEP score of ≥2. Six patients (12%) had a positive (≥0.40 optical density units) enzyme immunoassay, but none had a positive serotonin release assay. Based on anticoagulation dose, there were 1-2 new daily potentially high-risk exposures to heparinoids at our institution. CONCLUSIONS: The modified 4Ts and original 4Ts scores may be more adequate than the HEP score to determine HIT pretest probability in children. Despite the number of patients potentially at risk, HIT is rare in pediatrics.

Testimonial Therapy: Impact on social participation and emotional wellbeing among Indian survivors of torture and organized violence.

INTRODUCTION: Traumatizing events, such as torture, cause considerable impairments in psycho-social functioning. In developing countries, where torture is often perpetrated, few resources exist for the provision of therapeutic or rehabilitating interventions. The current study investigated the effectiveness of Testimonial Therapy (TT) as a brief psycho-social intervention to ameliorate the distress of Indian survivors of torture and related violence. METHOD: Three outcome measures (the WHO-5 Well-Being Scale, Social Participation-Scale and Pain and Anger Analogue) were compared before and after receiving TT, and semi structured interviews were conducted with survivors who had previously received TT. FINDINGS: Participants showed significant improvements in emotional well-being, social participation, and self-perceived pain and anger. Furthermore, three qualitative interviews with survivors indicated that TT had a positive impact at the community level. DISCUSSION: Although the study was conducted without a control group for comparison, TT appeared to be an effective method for improving well-being and ameliorating distress among survivors of torture. Furthermore, TT can potentially promote community empowerment. However, more research on this aspect is needed.

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.

Placebo response in depression: a perspective for clinical practice.

Practicing clinicians appreciate that depression is not an easy disorder to treat and manage. Despite the plethora of new treatments-both pharmacological and non pharmacological-that has flooded the market in the past years, we are still nowhere close to obtaining full symptom relief for all patients and eradicating the morbidity and mortality associated with depression. In this context, recent methodological research, concentrating on the effectiveness of antidepressants has raised doubts about their therapeutic index. Because of obtuseness of the methodology and biased interpretations, we are submitting this perspective to clinicians so that they can appreciate some of the deficits of the recent research publications. For the practicing clinician, the best available data suggest that clinically depressed patients warrant treatment and the most robust available body of data (published and unpublished) would favor the use of antidepressants.

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.

Suicide rates in clinical trials of SSRIs, other antidepressants, and placebo: analysis of FDA reports.

OBJECTIVE: Previous reports suggesting that selective serotonin reuptake inhibitor (SSRI) use is associated with increased suicidal risk have not assessed completed suicides. The authors analyzed reports from randomized controlled trials to compare suicide rates among depressed patients assigned to an SSRI, other antidepressants, or placebo. METHOD: Food and Drug Administration (FDA) summary reports of the controlled clinical trials for nine modern FDA-approved antidepressants provided data for comparing rates of suicide. RESULTS: Of 48,277 depressed patients participating in the trials, 77 committed suicide. Based on patient exposure years, similar suicide rates were seen among those randomly assigned to an SSRI (0.59%, 95% confidence interval [CI]=0.31%-0.87%), a standard comparison antidepressant (0.76%, 95% CI=0.49%-1.03%), or placebo (0.45%, 95% CI=0.01%-0.89%). CONCLUSIONS: These findings fail to support either an overall difference in suicide risk between antidepressant- and placebo-treated depressed subjects in controlled trials or a difference between SSRIs and either other types of antidepressants or placebo.

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.

Frequency of positive studies among fixed and flexible dose antidepressant clinical trials: an analysis of the food and drug administration summary basis of approval reports.

The assumption that the design of an antidepressant clinical trial affects the outcome of that trial is based on sparse data. We sought to examine if the dosing schedule, either a fixed dose or a flexible dose type, in an antidepressant clinical trial affects the frequency with which antidepressants show statistical superiority over placebo. Randomized, placebo-controlled clinical trials of nine antidepressants approved by the Food and Drug Administration between 1985 and 2000 were reviewed. These trials comprised 9313 depressed patients who participated in 51 antidepressant clinical trials consisting of 92 treatment arms with eventual approved doses. In the flexible dose trials, 59.6% (34/57) of the antidepressant treatment arms were statistically significant compared to placebo, whereas in the fixed dose trials only 31.4% (11/35) of the antidepressant treatment arms were statistically significant compared to placebo (chi(2)=6.9, df=1, p<0.01). These data suggest that the antidepressant dose schedule may influence trial outcome due in part to a significantly lower magnitude of symptom reduction with placebo in flexible dose trials (F=4.08, df=1, 48, p&<0.05) compared to fixed dose trials. Symptom reduction was similar with antidepressants in the flexible and fixed dose trials. Further, the primary function of finding a dose-response relationship was not found among the fixed dose studies.

Weight, lipids, glucose, and behavioral measures with ziprasidone treatment in a population with mental retardation.

BACKGROUND: Atypical antipsychotics effectively reduce maladaptive behavior in individuals with mental retardation, yet bring significant weight gain and metabolic anomalies. Ziprasidone, a weight-neutral antipsychotic in patients with schizophrenia or schizoaffective disorder, has not been studied in a population with mental retardation and maladaptive behaviors. METHOD: Forty patients with mental retardation and maladaptive behaviors who had gained excessive weight or were inadequately responsive to other agents were switched to ziprasidone. Weight, total cholesterol, HDL, LDL, triglycerides, and frequency of maladaptive behavior were recorded at baseline and after 6 months of ziprasidone treatment. RESULTS: Ziprasidone treatment was associated with a significant weight loss of 8.1 lb (3.6 kg) as well as a significant reduction in total cholesterol and triglycerides (p < or =.05). The monthly frequency of the maladaptive behavior remained unchanged or improved in 72% (18/25) of the patients in whom maladaptive behavior was assessed. CONCLUSION: Ziprasidone effectively reduces the frequency of maladaptive behavior in a patient group with mental retardation without causing weight gain or metabolic disturbances.

Are placebo controls necessary to test new antidepressants and anxiolytics?

One measure of a treatment's effectiveness is the regularity with which it proves superior to placebo. That measure also tells us about the consequences of using a treatment as a standard against which to test a new agent. To assess the frequency with which approved and presumably effective antidepressants and anxiolytics show statistical superiority over placebo, we reviewed placebo-controlled clinical trials of antidepressants and anxiolytics in a singularly large database free of publication bias. We evaluated clinical-trial data from the nine antidepressants approved by the FDA between 1985 and 2000. These trials comprised 10030 depressed patients who participated in 52 antidepressant clinical trials evaluating 93 treatment arms of a new or established antidepressant. Similarly, we examined clinical trials data from the 13 anxiolytics approved by the FDA between 1985 and 2000. These trials comprised 8,340 anxious patients, 40 anxiolytic clinical trials and 75 treatment arms of a new or established anxiolytic. Fewer than half (48%, 45/93) of the antidepressant treatment arms showed superiority to placebo. Among anxiolytics, 48% (36/75) of anxiolytic treatment arms showed superiority over placebo. These data suggest that conventional psychopharmacologic treatments for depression and anxiety are superior to placebo less than half the time and call into serious question the widely propagated notion that placebo controls can be dispensed with in clinical trials of these agents. Exclusion of placebo controls in favour of non-inferiority trials would result in a high likelihood that ineffective antidepressants and anxiolytics would be foisted on the public and, less dangerous but also problematic, that potentially effective agents would be missed.

An application of the revised CONSORT standards to FDA summary reports of recently approved antidepressants and antipsychotics.

BACKGROUND: Recent years have seen the introduction of many antidepressants and antipsychotics. Typically, efficacy of these agents is based on published positive clinical trials; however, the Food and Drug Administration (FDA) compiles summary reports of all pivotal randomized clinical trials, which are available for public review under the Freedom of Information Act. They are rarely accessed but may have public health utility. Thus, we assessed these reports to evaluate if the clinical data can be used for comparing psychotropics. METHODS: We examined FDA summary reports of 58 pivotal trials from 10 antidepressants and 7 pivotal trials from three antipsychotics approved in the United States between 1985 and 1998. We evaluated each FDA report based on criteria derived from the recently revised Consolidated Standards of Reporting Trials (CONSORT standards) proposed by the Journal of the American Medical Association to improve randomized clinical trial reports. RESULTS: Overall, the FDA reports of antidepressant and antipsychotic trials adequately met 38.1% of the CONSORT criteria. Among the antidepressant reports, 36.7% adequately met CONSORT criteria compared with 49.0% among the antipsychotic reports. The proportions meeting CONSORT criteria have increased over the past 15 years; 21.0% for those approved between 1985 and 1989, 37.8% for those between 1990 and 1994, and 40.5% for those between 1995 and 1998. CONCLUSIONS: The large and inclusive public domain FDA summary reports may provide balanced efficacy clinical trial data. With minor changes in the preparation of reporting by using CONSORT or similar guidelines, the data would be even more valuable.

Suicide risk in patients with anxiety disorders: a meta-analysis of the FDA database.

BACKGROUND: Previous reports of suicide risk in patients with anxiety disorders have been inconsistent. METHODS: Using the FDA database, we assessed suicide and suicide attempt risk among patients, participating in recent clinical trials evaluating new anti-anxiety medications, with diagnosis of panic disorder (PD), social anxiety disorder or social phobia (SP), generalized anxiety disorder (GAD), post traumatic stress disorder (PTSD), and obsessive compulsive disorder (OCD). RESULTS: Overall, among 20076 participating anxious patients, 12 committed suicide and 28 attempted suicide. The annual suicide risk rate was 193/100000 patients and annual suicide attempt risk was 1350/100000 patients. LIMITATIONS: Clinical trial data have limited applicability to clinical practice. Participants in clinical trials are a highly selected, nonrepresentative sample of the clinical population. A number of patients never complete clinical trials and thus data are based on a limited sub-sample. These trials were not primarily designed to assess suicide risk. CONCLUSIONS: Suicide risk in patients with anxiety disorders is higher than previously thought. Patients with anxiety disorders warrant explicit evaluation for suicide risk.

Severity of depression and response to antidepressants and placebo: an analysis of the Food and Drug Administration database.

Some studies suggest that more severely ill patients with depression respond well to antidepressants and poorly to placebo, whereas those who are mildly ill respond equally well to antidepressants and placebo. This notion has implications for the design of clinical trials. To further assess and substantiate these putative predictors of antidepressant and placebo response, we assessed the Food and Drug Administration database of 45 phase II and III antidepressant clinical trials. The frequency of statistically significant differences between antidepressants and placebo was higher in the trials that included patients with more severe depression. In the antidepressant-treated groups, the magnitude of symptom reduction was significantly related to mean initial Hamilton Rating Scale for Depression (HAM-D) score; the higher the mean initial HAM-D score, the larger the change. With placebo treatment, however, the higher the mean initial HAM-D score, the smaller the change. Early discontinuation was more frequent among patients whose mean initial HAM-D scores were higher. These data may help inform the design of future antidepressant clinical trials.