Onset of response in relation to outcome in depressed outpatients with placebo and imipramine

We have retrospectively analyzed the results of the pooled data from three 6-week placebo controlled double blind phase III clinical trials, initially designed to assess the efficacy of newer antidepressants, in order to study the relationship of early onset improvement with later outcome in 145 depressed outpatients receiving placebo (n = 98) or imipramine (n = 47). The early onset response was seen in a subgroup of subjects receiving either imipramine or placebo and appeared to be independent of treatment assignment. Furthermore, the early onset response predicted outcome for the duration of the trial and was not selective as defined by specific changes in subscales measuring insomnia, anxiety or endogenous features. Exclusion of early onset responders resulted in the augmentation of the difference in outcome with drug and placebo. We recommend that future placebo controlled trials assessing therapeutic efficacy of active treatments in depressed outpatients take into account the early onset response in the analysis of results.     

Low-molecular-weight heparin-induced thrombocytopenia in a child

OBJECTIVE: To report a case of probable acute venous thrombosis caused by heparin-induced thrombocytopenia (HIT) in a pediatric patient with a normal platelet count after prolonged enoxaparin therapy. CASE SUMMARY: An 11-year-old African American female with Crohn's disease developed extensive vena cava thrombosis. Her deep vein thrombosis (DVT) was treated with intravenous unfractionated heparin followed by extended outpatient warfarin therapy. Four months later, the warfarin was stopped and subcutaneous enoxaparin 1.5 mg/kg once daily was substituted prior to an elective colonoscopy. She was readmitted 6 weeks later with acute DVT with a platelet count of 233 x 10(3)/mm3, significantly lower than the count of 550-700 x 10(3)/mm3 5 months previously and the count of 433 x 10(3)/mm3 3 months earlier. An enzyme-linked immunosorbent assay for heparin-platelet factor 4 antibodies was strongly positive and a d-dimer was elevated at 2.9 mg/L (normal <1.5). She was treated with lepirudin followed by warfarin when repeat d-dimer on day 3 was normal. An ultrasound at that time showed no clot extension, and the platelet count had risen to >300 x 10(3)/mm3. Over the next 4 months, there was no further thrombosis. DISCUSSION: HIT appears to be rare in the pediatric population, and only a few cases treated with a direct thrombin inhibitor have been reported. This is the first case report to our knowledge of a pediatric patient developing HIT secondary to enoxaparin. An interesting feature of this case is the development of HIT in the face of a normal platelet count, which is rare but has been reported in adults. CONCLUSIONS: Pediatric patients receiving low-molecular-weight heparin are still at risk for developing HIT. Treatment of HIT should involve the initial use of a direct thrombin inhibitor to manage thrombosis until the platelet count returns to higher values. Once the platelet count returns, warfarin can be used for long-term thrombosis management.     

Variability of plasma anti-Xa activities with different lots of enoxaparin

BACKGROUND: Previous studies have indicated the variability of anti-Xa activity in different sources of heparin and the variability of different methods used for measuring anti-Xa activity. Manufacturers of low-molecular-weight heparins (LMWHs) determine each lot's anti-Xa activity against the World Health Organization standard, but little information is known about anti-Xa activity variation between lots of LMWH and the impact on reported anti-Xa activity in patient samples. OBJECTIVE: To determine the variation of plasma anti-Xa activity in patients receiving enoxaparin when different lots of enoxaparin are used for test calibration. METHODS: We obtained 7 lots of enoxaparin containing approximately 10,000 IU/mL and one lot containing approximately 15,000 IU/mL of anti-Xa activity. For each lot, a 2.0 anti-Xa IU/mL dilution was prepared and a calibration curve performed using a chromogenic method. To test the variation in reported results between the different calibration lots, 20 patient samples were tested. Nineteen patients receiving enoxaparin and one patient not receiving enoxaparin (negative control) were tested in a blinded fashion, and the changes in light absorbance recorded. Anti-Xa activity results from tested plasmas were then extrapolated from each enoxaparin lot calibration curve. RESULTS: Using Student's paired t-test, there were statistically significant differences between the plasma anti-Xa activities generated from the various enoxaparin lots. In the range of 0.5-1.0 IU/mL of anti-Xa activity, 3 (4.2%) samples had a >0.2 IU/mL difference (maximum difference 0.33 IU/mL) in anti-Xa activity between 2 lots of enoxaparin. For samples that had supratherapeutic anti-Xa activities (1.0-1.5 IU/mL anti-Xa activity), there was a wider variation (>0.2 IU/mL) in anti-Xa activity, which may have resulted in a dosing change. CONCLUSIONS: The statistical differences in plasma anti-Xa activities noted between enoxaparin lots are not clinically significant. However, anti-Xa activities in the upper therapeutic and supratherapeutic ranges (>1.0 IU/mL of anti-Xa activity) resulted in a deviation of >0.3 IU/mL in reported anti-Xa activity, which may result in dosing changes.     

Language delay aggregates in toddler siblings of children with autism spectrum disorder

Background

Language delay is extremely common in children with autism spectrum disorder (ASD), yet it is unclear whether measurable variation in early language is associated with genetic liability for ASD. Assessment of language development in unaffected siblings of children with ASD can inform whether decreased early language ability aggregates with inherited risk for ASD and serves as an ASD endophenotype.

Methods

We implemented two approaches: (1) a meta-analysis of studies comparing language delay, a categorical indicator of language function, and language scores, a continuous metric, in unaffected toddlers at high and low familial risk for ASD, and (2) a parallel analysis of 350 unaffected 24-month-olds in the Infant Brain Imaging Study (IBIS), a prospective study of infants at high and low familial risk for ASD. An advantage of the former was its detection of group differences from pooled data across unique samples; an advantage of the latter was its sensitivity in quantifying early manifestations of language delay while accounting for covariates within a single large sample.

Results

Meta-analysis showed that high-risk siblings without ASD (HR-noASD) were three to four times more likely to exhibit language delay versus low-risk siblings without ASD (LR-noASD) and had lower mean receptive and expressive language scores. Analyses of IBIS data corroborated that language delay, specifically receptive language delay, was more frequent in the HR-noASD (n?=?235) versus LR-noASD group (n?=?115). IBIS language scores were continuously and unimodally distributed, with a pathological shift towards decreased language function in HR-noASD siblings. The elevated inherited risk for ASD was associated with lower receptive and expressive language scores when controlling for sociodemographic factors. For receptive but not expressive language, the effect of risk group remained significant even when controlling for nonverbal cognition.

Conclusions

Greater frequency of language delay and a lower distribution of language scores in high-risk, unaffected toddler-aged siblings support decreased early language ability as an endophenotype for ASD, with a more pronounced effect for receptive versus expressive language. Further characterization of language development is warranted to refine genetic investigations of ASD and to elucidate factors influencing the progression of core autistic traits and related symptoms.

     

Binge drinking differentially affects adolescent male and female brain morphometry

Rationale  

Adolescent binge drinking is concerning, as important neurodevelopments occur during this stage. Previous research suggests that binge drinking may disrupt typical brain development, and females may be particularly vulnerable.     

Amygdalar volume and behavioral development in autism

CONTEXT: The amygdala is associated with socioemotional function and has been implicated in the pathophysiology of autism. OBJECTIVE: To examine the relationship between amygdalar volume at ages 3 and 4 years and severity of clinical course and outcome at 6 years of age in children with autism spectrum disorder. DESIGN: Magnetic resonance images acquired at 3 and 4 years of age were used to measure total cerebral, amygdalar, and hippocampal volumes. Acquisition of social and communication skills was assessed semiannually using the Vineland Adaptive Behavior Scales. Hierarchical linear models were used to predict variability in individual linear growth trajectories as a function of IQ, total cerebral, and amygdalar or hippocampal volumes. SETTING: Longitudinal study of children with autism spectrum disorder. PARTICIPANTS: Forty-five children with autism spectrum disorders between 3 and 6 years of age. MAIN OUTCOME MEASURE: Linear growth trajectory of age equivalence Vineland communication and social scores. RESULTS: Larger right amygdalar volume was associated with more severe social and communication impairments at ages 3 and 4 years. Larger right amygdalar volume also was predictive of poorer social and communication abilities at age 6 years, even after controlling for IQ and total cerebral volume. Parallel analyses with hippocampal volumes found no relationship to social or communication development. CONCLUSIONS: Larger right amygdalar volume at 3 and 4 years of age, but not left amygdalar, hippocampal, or total cerebral volume, is associated with a more severe clinical course and worse outcome at age 6 years in children with autism spectrum disorder. These results provide additional evidence that amygdalar development is implicated in the behavioral impairments found in autism.