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.

Following a stroke around two-thirds of patients suffer long-term disability. Many preclinical and clinical studies have suggested that selective serotonin reuptake inhibitors (SSRIs) might improve functional outcomes after stroke, including a number of small randomised trials.

The present trial was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were 18 or older, had a clinical diagnosis of acute stroke with brain imaging compatible with intracerebral haemorrhage or ischaemic stroke. Further, eligible patients were randomised between 2 and 15 days from stroke onset and had a persisting focal neurological deficit at the time of randomisation to warrant 6 months treatment. Patients were excluded if they had subarachnoid haemorrhage except where secondary to a primary intracerebral haemorrhage.

Patients were randomly assigned in a 1:1 ratio to either receive fluoxetine or placebo for 6 months. The primary outcome measure was functional status assessed using the simplified modified Rankin scale. Secondary outcomes were survival at 6 and 12 months, functional status at 12 months measured with the simplified modified Rankin scale and health status assessed using the Stroke Impact Scale.

A total of 3,127 patients were enrolled comprising 1,564 allocated to fluoxetine and 1,563 allocated to placebo. Baseline characteristics were well balanced between the two groups and were similar to unselected stroke patients admitted to UK hospitals. The primary outcome, an ordinal comparison of the distribution of patients across the modified Rankin Scale categories at 6 months, adjusted for variables included in the minimisation algorithm, was similar in the two groups (common OR 0·951 [95% CI 0·839–1·079]; p=0·439). The unadjusted analysis showed a similar result (common OR 0·961 [95% CI 0·848–1·089]; p=0·531). Analysis of the modified Rankin Scale dichotomised into 0-2 versus 3-6 was also similar between the two groups (adjusted OR 0·955 [95% CI 0·812–1·123], p=0·576).

Secondary outcomes and adverse events at 6 months were generally similar between the groups, with the exception of new onset depression at 6 months which was significantly lower in the fluoxetine group (210 [13·4%] patients vs 269 [17·2%]; difference in proportions 3·78% [95% CI 1·26–6·30]; p=0·0033). Mood as assessed using the Mental Health Inventory (MHI-5) was significantly higher in the fluoxetine group (median 76 [IQR 60–88] vs 72 [56–88]; p=0·0100). Further, bone fractures were significantly higher in the fluoxetine group (45 [2·88%] patients vs 23 [1·47%]; difference in proportions 1·41% [95% CI 0·38–2·43]; p=0·0070)

In summary, the results of the FOCUS trial show that fluoxetine 20 mg given daily for 6 months after an acute stroke did not influence patients’ functional outcomes but did decrease the occurrence of depression and increase the occurrence of bone fractures.

The full report is available here.

Gout is the most common inflammatory arthritis worldwide with a prevalence in the UK of around 2.5%. Gout results from sodium urate crystals that form when sodium urate persistently exceeds saturation. Deposition of sodium urate crystals causes extremely painful gout flares, joint damage and subcutaneous nodules, known as tophi.

Despite a good understanding of the disease and the availability of effective treatment, gout care remains suboptimum. In the UK, gout is managed predominantly in primary care by general practitioners (GPs), but less than half of patients receive urate-lowering therapy. Further, in those who do receive urate-lowering therapy the dose is usually fixed without titration to achieve a target serum urate concentration.

The present trial was conducted at 56 general practices. Potential participants were identified from practice databases and screened by postal questionnaire. Patient eligibility was confirmed by a research nurse. All eligible participants were greater than 21 years old, had a confirmed diagnosis of gout and had at least one gout flare in the previous 12 months. Randomisation was undertaken by the research nurse telephoning a central co-ordinating centre and the allocation was 1:1 to either nurse-led care or usual GP-led care. The trial duration was 2 years.

Nurses delivering the nurse-led arm received full training in gout and its management according to national and international guidelines and recommendations. Follow up patient assessments, including sodium urate concentrations, were done as often as the nurse required. Urate-lowering therapy was prescribed according to a guideline. First line treatment was oral allopurinol, started at 100mg once per day and titrated upwards in 100mg increments every 3-4 weeks according to the serum urate concentrations, to a maximum of 900mg once per day. As second-line options, oral febuxostat could be started at 80 mg and if required increased to the maximum dose of 120 mg once per day or benzbromarone could be started at 50 mg and titrated up in 50 mg increments to a maximum of 200 mg once per day. Combination urate-lowering therapy (xanthine oxidase inhibitor plus uricosuric) could be used as the final treatment option.

By contrast, the usual care group could discuss treatment of flares at the baseline and annual assessments, but all other enquiries were directed to their GP.

The primary outcome was the percentage of patients who had achieved serum urate concentrations less than 360 μmol/L at 2 years. Secondary outcomes were other serum urate measures (percentage of patients who had achieved serum urate concentrations <360 μmol/L at 1 year, <300 μmol/L at 1 and 2 years, and group mean serum urate concentrations at 1 and 2 years); frequency of gout flares during years 1 and 2; the percentage of patients with tophi overall; the median number of tophi and the maximum diameter of the largest tophus at 1 and 2 years among patients with tophi at baseline; quality of life (physical and mental components) and Gout Impact Scale at 1 and 2 years; and cost-effectiveness, calculated as cost per quality-adjusted life-year (QALY) gained.

A total of 6,806 questionnaires were sent by GP practices with 41% (2,815) being returned. 1,071 reported have flares in the last 12 months and were willing to be contacted further. From these, 505 patients were randomised. In addition, a small number (12) of participants were identified from advertisements giving a total randomised population of 517, comprising 255 assigned to nurse-led care and 262 assigned to usual GP-led care.

The two groups were similar in terms of baseline characteristics. Most were middle-aged white men with average gout duration of 12 years. 203 (39%) were taking urate-lowering therapy at baseline and only around 20% had a serum urate concentration less than 360 μmol/L.

Of 517 patients who started the study, 482 (93%) completed 1 year and 441 (85%) completed 2 years. At 2 years, multiple imputation showed that 95% of participants in the nurse-led group had achieved serum urate concentrations less than 360 μmol/L compared with 30% in the usual care group (RR 3·18, 95% CI 2·42–4·18). A similar difference was seen after 1 year. Use of urate-lowering therapy increased in both groups, but was significantly higher in the nurse-led group: at 2 years, 96% of patients in the nurse-led group were using urate-lowering therapy compared to 56% in the usual-care group. The nurse-led group showed improvements compared to usual care in a range of the secondary outcomes, including flare frequency, presence of tophi and quality of life.

The authors conclude that nurse-led care can achieve high uptake of urate-lowering therapy and good adherence at 2 years. 95% of participants in the nurse-led group achieved the recommended target serum urate concentration of less than 360 μmol/L and patient-centred outcomes, including flare frequency, presence of tophi, and quality of life, improved significantly compared with those in the usual-care group.

You can read the full report here