A randomised, double blind, placebo-controlled trial of a fixed dose of N-acetyl cysteine in children with autistic disorder

OBJECTIVE: Oxidative stress, inflammation and heavy metals have been implicated in the aetiology of autistic disorder. N-acetyl cysteine has been shown to modulate these pathways, providing a rationale to trial N-acetyl cysteine for autistic disorder. There are now two published pilot studies suggesting efficacy, particularly in symptoms of irritability. This study aimed to explore if N-acetyl cysteine is a useful treatment for autistic disorder.

METHOD: This was a placebo-controlled, randomised clinical trial of 500 mg/day oral N-acetyl cysteine over 6 months, in addition to treatment as usual, in children with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision diagnosis of autistic disorder. The study was conducted in Victoria, Australia. The primary outcome measures were the Social Responsiveness Scale, Children's Communication Checklist-Second Edition and the Repetitive Behavior Scale-Revised. Additionally, demographic data, the parent-completed Vineland Adaptive Behavior Scales, Social Communication Questionnaire and clinician-administered Autism Diagnostic Observation Schedule were completed.

RESULTS: A total of 102 children were randomised into the study, and 98 (79 male, 19 female; age range: 3.1-9.9 years) attended the baseline appointment with their parent/guardian, forming the Intention to Treat sample. There were no differences between N-acetyl cysteine and placebo-treated groups on any of the outcome measures for either primary or secondary endpoints. There was no significant difference in the number and severity of adverse events between groups.

CONCLUSION: This study failed to demonstrate any benefit of adjunctive N-acetyl cysteine in treating autistic disorder. While this may reflect a true null result, methodological issues particularly the lower dose utilised in this study may be confounders.

Multicentre phase I/II study of PI-88, a heparanase inhibitor in combination with docetaxel in patients with metastatic castrate-resistant prostate cancer

Background: Docetaxel (Taxotere) improve survival and prostate-specific antigen (PSA) response rates in patients with metastatic castrate-resistant prostate cancer (CRPC). We studied the combination of PI-88, an inhibitor of angiogenesis and heparanase activity, and docetaxel in chemotherapy-naive CRPC.

Patients and methods: We conducted a multicentre open-label phase I/II trial of PI-88 in combination with docetaxel. The primary end point was PSA response. Secondary end points included toxicity, radiologic response and overall survival. Doses of PI-88 were escalated to the maximum tolerated dose; whereas docetaxel was given at a fixed 75 mg/m2 dose every three weeks

Results: Twenty-one patients were enrolled in the dose-escalation component. A further 35 patients were randomly allocated to the study to evaluate the two schedules in phase II trial. The trial was stopped early by the Safety Data Review Board due to a higher-than-expected febrile neutropenia of 27%. In the pooled population, the PSA response (50% reduction) was 70%, median survival was 61 weeks (6–99 weeks) and 1-year survival was 71%.

Conclusions: The regimen of docetaxel and PI-88 is active in CRPC but associated with significant haematologic toxicity. Further evaluation of different scheduling and dosing of PI-88 and docetaxel may be warranted to optimise efficacy with a more manageable safety profile.

Olanzapine / fluoxetine combination for treatment resistant depression : efficacy and clinical utility

Antidepressant monotherapy is a first-line treatment for depression; however, not all sufferers will adequately respond to treatment. When treating a patient with treatment-resistant depression, the clinician needs to consider all factors which may contribute to an inadequate response to an antidepressant. These include accuracy of diagnosis and medication adherence, as well as the patient’s personality, lifestyle, life events and social circumstances. If it is determined that treatment resistance is due to failure of efficacy of antidepressant monotherapy, then an augmentation strategy using an atypical antipsychotic may be considered. Treatment using olanzapine/fluoxetine combination (OFC) is one of many options. Four randomized, acute-phase trials have suggested OFC is useful for reducing Montgomery–Åsberg Depression Rating Scale scores after inadequate response to antidepressant monotherapy. OFC has been useful at doses of olanzapine/fluoxetine 6/25, 6/50, 12/25 and 12/50 mg/day, with 1/5 mg/day suggested to be an ineffective dose. Treatment with OFC has been associated with some side effects, including weight gain and the metabolic syndrome, somnolence, dry mouth, increased appetite and headache. Treatment decisions therefore need to be made to balance the risks and benefits.

A survey of combination antidepressant use in Australia

Objective: The aim of this study was to survey doctors working in psychiatry in Australia about the practice of using two antidepressants simultaneously.

Method: A postal survey was sent to all doctors in psychiatry in Australia enquiring about their prescribing history and their attitudes to combination antidepressants and related issues.

Results: Seventy-nine percent of respondents had used combination antidepressants. The most frequently reported combination was a selective serotonin reuptake inhibitor combined with a tricyclic antidepressant. Combinations of mirtazepine with venlafaxine and other antidepressants were the next most frequently used. Seventeen percent of respondents reported having seen a complication from combination antidepressants, 75% believed that Australian GPs should be given information on the use of combination antidepressants, 89% wished for more information on this topic, and 88% believed patients had a right to be informed of this option in their treatment. Use of combination antidepressants was more frequent than exceeding the recommended maximum dose of an individual antidepressant.

Conclusion: Combination antidepressants are used far more frequently in Australia than suspected previously. Research into safe and evidence-based practice is strongly indicated.

Epidemiologic merit of obese-years, the combination of degree and duration of obesity

This study aims to test the effect of combining the degree and the duration of obesity into a single variable-obese-years-and to examine whether obese-years is a better predictor of the risk of diabetes than simply body mass index (BMI) or duration of obesity. Of the original cohort of the Framingham Heart Study, 5,036 participants were followed up every 2 years for up to 48 years (from 1948). The variable, obese-years, was defined by multiplying for each participant the number of BMI units above 30 kg/m(2) by the number of years lived at that BMI. Associations with diabetes were analyzed by using time-dependent Cox proportional hazards regression models adjusted for potential confounders. The incidence of type-2 diabetes increased as the number of obese-years increased, with adjusted hazard ratios of 1.07 (95% confidence interval: 1.06, 1.09) per additional 10 obese-years. The dose-response relation between diabetes incidence and obese-years varied by sex and smoking status. The Akaike Information Criterion was lowest in the model containing obese-years compared with models containing either the degree or duration of obesity alone. A construct of obese-years is strongly associated with risk of diabetes and could be a better indicator of the health risks associated with increasing body weight than BMI or duration of obesity alone.

Capecitabine and oral cyclophosphamide : a novel oral treatment combination for advanced cancer

Background: This dose escalation study assessed feasibility of a totally oral chemotherapy regimen using cyclophosphamide and capecitabine. The rationale for this combination was based on the observation that preclinical models of cyclophosphamide up-regulated tumor thymidine phosphorylase and increased the activation of capecitabine. Methods: Eligible patients with advanced cancer were treated with oral cyclophosphamide and capecitabine on a 28-day cycle. If no dose limiting toxicities (DLT) were encountered during the first two treatment cycles, the next patient group was assigned to the next highest dose level until the maximum tolerable dose (MTD) was determined. Results: Twenty-seven patients entered treatment. The majority of non-DLT were grades 1 and 2. DLT experienced in the first 8-week observation period were grade 3 diarrhea (one patient, level III) and grade 3 emesis (two patients, level V). MTD was observed at level 5, 1331 mg/m2/day capecitabine days 1–28 with 125 mg/m2/day cyclophosphamide days 1–14 of the 28-day cycle. The recommended phase II dose is therefore 1331 mg/m2/day capecitabine with 100 mg/m2/day cyclophosphamide. The best response evaluation showed four partial responses (breast, colon, ovary and pancreas). Conclusion: Cyclophosphamide and capecitabine can be combined at their full oral single agent dose with promising tolerability and activity.

A combination of omega-3 fatty acids, folic acid and B-group vitamins is superior at lowering homocysteine than omega-3 alone: a meta-analysis

The aim of the study was to assess whether omega-3 polyunsaturated fatty acid supplementation alone or in combination with folic acid and B-group vitamins is effective in lowering homocysteine. The Medline Ovid, Embase and Cochrane databases were searched for randomized-controlled trial studies that intervened with omega-3 supplementation (with or without folic acid) and measured changes in homocysteine concentration. Studies were pooled using a random effects model for meta-analysis. Three different models were analyzed: all trials combined, omega-3 polyunsaturated fatty acid trials, and omega-3 polyunsaturated fatty acids with folic acid and B-group vitamin trials. Nineteen studies were included, consisting of 3267 participants completing 21 trials. Studies were heterogeneous; varying by dose, duration and participant health conditions. Across all trials, omega-3 supplementation was effective in lowering homocysteine by an average of 1.18μmol/L (95%CI: (-1.89, -0.48), P=.001). The average homocysteine-lowering effect was greater when omega-3 supplementation was combined with folic acid and B-group vitamins (-1.37μmol/L, 95%CI: (-2.38, -0.36), P<.01) compared to omega-3 supplementation alone (-1.09μmol/L 95%CI: (-2.04, -0.13), P=.03). Omega-3 polyunsaturated fatty acid supplementation was associated with a modest reduction in homocysteine. For the purposes of reducing homocysteine, a combination of omega-3s (0.2-6g/day), folic acid (150 - 2500μg/day) and vitamins B6 and B12 may be more effective than omega-3 supplementation alone.