Type 1 diabetes is a common chronic condition of childhood that requires subcutaneous injection of insulin in doses calculated according to carbohydrate consumption, physical activity and blood glucose measurements. Poor glycaemic control is associated with poor clinical outcomes, including impaired memory, poorer cognitive outcomes, increased risk of depression and poor growth. In the longer term, vascular complications result in blindness, renal failure, premature heart disease, stroke and amputation. Substantial uncertainty exists as to whether newer forms of treatment, particularly continuous subcutaneous insulin infusion (CSII) are clinically superior to multiple daily injections (MDI).

The present study was a pragmatic, multicentre, open-label, parallel group, randomised controlled trial, randomising participants to either CSII or MDI. Study centres were paediatric diabetes clinics experienced in the use of CSII. Eligible participants had a new diagnosis of type 1 diabetes and were aged between 7 months and 15 years. Randomised treatment started within 14 days of diagnosis of type 1 diabetes. All participants completed a structured education programme on type 1 diabetes and its treatment, which included training on CSII and MDI. Study visits were at 3, 6, 9 and 12 months. The primary outcome measure was HbA1c measured at 12 months. There were a number of secondary outcomes, including the percentage of participants in each arm with HbA1c within the national target range and the incidence of severe hypoglycaemia and diabetic ketoacidosis.

Potential participants were identified from 15 centres in the UK. A total of 976 individuals were assessed for eligibility and of these 689 met eligibility and were invited to participate. A total of 293 consented to participate and were randomised resulting in 144 allocated to CSII and 149 allocated to MDI. Baseline characteristics were similar between the two arms. Intention to treat analysis showed no difference in the primary outcome of HbA1c at 12 months between the two arms (adjusted mean [95% CI] mmol/mol; CSII 60.9 [58.5 to 63.3] vs. MDI 58.5 [56.1 to 60.9]; adjusted mean difference 2.4 [-0.4 to 5.3], P=0.09). There were also no significant differences between the groups for all but one of the secondary outcomes (insulin requirements were slightly higher in those treated with CSII, adjusted mean difference 0.1 units/kg/day, 95% confidence interval 0.0 to 0.2, P=0.01).

In conclusion, the authors state that CSII is neither more clinically effective nor more cost effective than MDI.

You can read the full report here.

By 2030, depression is predicted to be the leading cause of disability in high-income countries. Antidepressants are often the first line treatment, however, many patients do not respond to treatment with one study finding that half of those treated failed to experience at least a 50% reduction in depressive symptoms after 12-14 weeks of treatment with a single antidepressant.

Clinical guidelines recommend reconsidering treatment options if the patient shows no response after 4-6 weeks of antidepressant use. Further treatment options are varied and include increasing the dose, switching antidepressants, combining two antidepressants, and including another psychotropic drug, such as lithium or an antipsychotic. A new treatment option is the drug mirtazapine, which is a selective noradrenaline α2 adrenoreceptor and serotonin receptors 2 and 3 antagonist. The present trial determined the effects on depression and quality of life of adding mirtazapine to existing antidepressant medication compared to placebo in treatment resistant depression.

Patients were identified from general practices in the UK. Eligible participants were at least 18 years, had used a serotonin-noradrenaline reuptake inhibitor (SNRI) or selective serotonin reuptake inhibitor (SSRI) antidepressant for at least six weeks, were adherent to treatment, had a Beck Depression Inventory, second revision (BDI II) score of 14 or more and met the ICD-10 criteria for depression. Patients were excluded who had bipolar disorder, psychosis, major alcohol or substance misuse and a diagnosis of dementia.

Following informed consent, eligible participants were randomised to either one 15mg capsule of mirtazapine daily for two weeks followed by two 15 mg capsules of mirtazapine for up to 50 weeks, or to identical placebo. Participants were followed up at 6, 12, 24, and 52 weeks. The primary outcome was BDI II at 12 weeks. Analysis was by intention-to-treat.

856 patients were identified as eligible for the baseline assessment and of these 105 declined to take part. A total of 751 attended the baseline interview, but a large number (271) were determined to be ineligible (mostly due to not meeting the depression severity criteria). A total of 480 were randomised comprising 241 randomised to mirtazapine and 239 to placebo.

The two groups had similar baseline characteristics, but some evidence showed that participants in the mirtazapine group had more severe depression. For the primary outcome the mean BDI II score at 12 weeks in those randomised to mirtazapine was 18.0 (SD 12.3) compared to 19.7 (12.4) in those allocated to placebo. After adjustment for the baseline BDI II score and stratification and minimisation variables the confidence interval included the null (adjusted difference in means -1.83, 95% confidence interval -3.92 to 0.27, P=0.09).

For the secondary outcomes the adjusted difference in BDI II score between the groups at 24 and 52 weeks was smaller and included the null (24 weeks: adjusted difference in means −0.85 (−3.12 to 1.43); 52 weeks: adjusted difference in means 0.17 (−2.13 to 2.46). For the other secondary outcomes, the adjusted difference in scores between the groups was small and with only two exceptions included the null. Patients in the mirtazapine were more likely to report adverse events and stop taking treatment.

In conclusion, the authors state that the trial did not find convincing evidence of a clinically important benefit of mirtazapine over placebo when given in addition to an SSRI or SNRI antidepressant for patients who remained depressed after at least six weeks of antidepressant treatment.

You can read the full report here.

The results from animal models have indicated that physical activity might slow cognitive decline in dementia. However, systematic reviews of randomised trials have shown conflicting results with one review showing a benefit on cognitive decline and another recent review showing no effect. These reviews included small trials of low methodological quality. The present trial was commissioned to provide reliable evidence on the effects of exercise on cognitive decline in people with dementia.

The Dementia And Physical Activity (DAPA) trial was a multicentre, pragmatic, investigator masked, randomised controlled trial. Random allocation was 2:1 in favour of the exercise arm. Eligible participants had mild to moderate dementia with a diagnosis in accordance with the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) and a standardised Mini Mental State Examination (MMSE) of greater than 10. Participants also needed to be able to sit on a chair and walk 10 feet (3.05m) without assistance.

The exercise arm was delivered by physiotherapists and exercise assistants and consisted of a four month twice weekly 60-90 minute sessions supplemented by a one hour session of home-based exercise. The exercise programme was individualised according to the participant’s level of fitness and health status and the exercises included aerobic activity using a static cycle and strength training using free weights. Following the four month period of supervised exercise participants were requested to continue exercising at home for a total of 150 minutes per week. The control arm only received brief advice on physical activity as part of their clinical assessment.

The primary outcome was the Alzheimer disease assessment scale cognitive subscale (ADAS-cog) at 12 months. Secondary outcomes measured at 6 and 12 months included the Bristol activity of daily living index, the neuropsychiatric index, the three level version of the EQ-5D quality of life measure, the quality of life Alzheimer’s disease scale and the ADAS praxis, language and memory subscales (the ADAS-cog was also measured as a secondary outcome at 6 months). The assessors were blinded to the randomised treatment allocation. All analyses were according to intention-to-treat principles.

A total of 2,929 patients were screened with 1,847 potentially eligible and invited to participate and a total of 494 were randomised (329 to the exercise arm and 165 to the control group). The two groups were well matched according to the baseline measures assessed. For the exercise group, the total weight lifted and the duration of high intensity aerobic activity improved across the sessions. A 6-minute walk test was undertaken to assess physical fitness and at 6 weeks the total distance covered had improved significantly (95% confidence interval 11.6 m to 24.6 m; P<0.001). The majority (88%) of participants in the exercise arm reported continuing with the exercise programme after the end of the 4 month supervised programme.

For the main outcome, cognitive impairment declined in both arms during the 12 months follow up with ADAS-cog scores higher (higher scores indicate worse cognition) in the exercise arm at 12 months (adjusted mean difference −1.4, 95% confidence interval −2.6 to −0.2). No difference was observed in any of the secondary outcomes measured.

The authors conclude that a four month aerobic and strengthening exercise programme of moderate to high intensity added to usual care does not slow cognitive decline in people with mild to moderate dementia. The exercise programme improved physical fitness in the short term and the results suggest the possibility that exercise might worsen cognition in people with dementia.

The full report of the study can be read here.