Dataset Information

Mirtazapine added to SSRIs or SNRIs for treatment resistant depression in primary care: phase III randomised placebo controlled trial (MIR).

ABSTRACT:

Objective

To investigate the effectiveness of combining mirtazapine with serotonin-noradrenaline reuptake inhibitor (SNRI) or selective serotonin reuptake inhibitor (SSRI) antidepressants for treatment resistant depression in primary care.

Design

Two parallel group multicentre phase III randomised placebo controlled trial.

Setting

106 general practices in four UK sites; Bristol, Exeter, Hull, and Keele/North Staffs, August 2013 to October 2015.

Participants

480 adults aged 18 or more years who scored 14 or more on the Beck depression inventory, second revision, fulfilled ICD-10 (international classification of diseases, 10th revision) criteria for depression, and had used an SSRI or SNRI for at least six weeks but were still depressed. 241 were randomised to mirtazapine and 239 to placebo, both given in addition to usual SSRI or SNRI treatment. Participants were stratified by centre and minimised by baseline Beck depression inventory score, sex, and current psychological therapy. They were followed up at 12, 24, and 52 weeks. 431 (89.8%) were included in the (primary) 12 week follow-up.

Main outcome measures

Depressive symptoms at 12 weeks after randomisation, measured using the Beck depression inventory II score as a continuous variable. Secondary outcomes included measures of anxiety, quality of life, and adverse effects at 12, 24, and 52 weeks.

Results

Beck depression inventory II scores at 12 weeks were lower in the mirtazapine group after adjustment for baseline scores and minimisation or stratification variables, although the confidence interval included the null (mean (SD) scores at 12 weeks: 18.0 (12.3) in the mirtazapine group, 19.7 (12.4) in the placebo group; adjusted difference between means -1.83 (95% confidence interval -3.92 to 0.27); P=0.09). Adverse effects were more common in the mirtazapine group and were associated with the participants stopping the trial drug.

Conclusion

This study did not find evidence of a clinically important benefit for mirtazapine in addition to an SSRI or SNRI over placebo in a treatment resistant group of primary care patients with depression. This remains an area of important unmet need where evidence of effective treatment options is limited.

Trial registration

Current Controlled Trials ISRCTN06653773.

SUBMITTER: Kessler DS

PROVIDER: S-EPMC6207929 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BACKGROUND:People with depression are usually managed in primary care and antidepressants are often the first-line treatment, but only one third of patients respond fully to a single antidepressant. This paper describes the protocol for a randomised controlled trial (MIR) to investigate the extent to which the addition of the antidepressant mirtazapine is effective in reducing the symptoms of depression compared with placebo in patients who are still depressed after they have been treated with a selective serotonin reuptake inhibitor (SSRI) or serotonin and noradrenaline reuptake inhibitor (SNRI) for at least 6 weeks in primary care. METHODS/DESIGN:MIR is a two-parallel group, multi-centre, pragmatic, placebo controlled, randomised trial with allocation at the level of the individual. Eligible participants are those who: are aged 18 years or older; are currently taking an SSRI/SNRI antidepressant (for at least 6 weeks at an adequate dose); score ? 14 on the Beck Depression Inventory (BDI-II); have adhered to their medication; and meet ICD-10 criteria for depression (assessed using the Clinical Interview Schedule-Revised version). Participants who give written, informed consent, will be randomised to receive either oral mirtazapine or matched placebo, starting at 15 mg daily for 2 weeks and increasing to 30 mg daily thereafter, for up to 12 months (to be taken in addition to their usual antidepressant). Participants, their GPs, and the research team will all be blind to the allocation. The primary outcome will be depression symptoms at 12 weeks post randomisation, measured as a continuous variable using the BDI-II. Secondary outcomes (measured at 12, 24 and 52 weeks) include: response (reduction in depressive symptoms (BDI-II score) of at least 50% compared to baseline); remission of depression symptoms (BDI-II <10); change in anxiety symptoms; adverse effects; quality of life; adherence to antidepressant medication; health and social care use, time off work and cost-effectiveness. All outcomes will be analysed on an intention-to-treat basis. A qualitative study will explore patients' views and experiences of either taking two antidepressants, or an antidepressant and a placebo; and GPs' views on prescribing a second antidepressant in this patient group. DISCUSSION:The MIR trial will provide evidence on the clinical and cost-effectiveness of mirtazapine as an adjunct to SSRI/SNRI antidepressants for patients in primary care who have not responded to monotherapy. TRIAL REGISTRATION:EudraCT Number: 2012-000090-23 (Registered January 2012); ISRCTN06653773 (Registered September 2012).

Project description:BackgroundAgitation is common in people with dementia and negatively affects the quality of life of both people with dementia and carers. Non-drug patient-centred care is the first-line treatment, but there is a need for other treatment when this care is not effective. Current evidence is sparse on safer and effective alternatives to antipsychotics. We assessed the efficacy and safety of mirtazapine, an antidepressant prescribed for agitation in dementia.MethodsThis parallel-group, double-blind, placebo-controlled trial-the Study of Mirtazapine for Agitated Behaviours in Dementia trial (SYMBAD)-was done in 26 UK centres. Participants had probable or possible Alzheimer's disease, agitation unresponsive to non-drug treatment, and a Cohen-Mansfield Agitation Inventory (CMAI) score of 45 or more. They were randomly assigned (1:1) to receive either mirtazapine (titrated to 45 mg) or placebo. The primary outcome was reduction in CMAI score at 12 weeks. This trial is registered with ClinicalTrials.gov, NCT03031184, and ISRCTN17411897.FindingsBetween Jan 26, 2017, and March 6, 2020, 204 participants were recruited and randomised. Mean CMAI scores at 12 weeks were not significantly different between participants receiving mirtazapine and participants receiving placebo (adjusted mean difference -1·74, 95% CI -7·17 to 3·69; p=0·53). The number of controls with adverse events (65 [64%] of 102 controls) was similar to that in the mirtazapine group (67 [66%] of 102 participants receiving mirtazapine). However, there were more deaths in the mirtazapine group (n=7) by week 16 than in the control group (n=1), with post-hoc analysis suggesting this difference was of marginal statistical significance (p=0·065).InterpretationThis trial found no benefit of mirtazapine compared with placebo, and we observed a potentially higher mortality with use of mirtazapine. The data from this study do not support using mirtazapine as a treatment for agitation in dementia.FundingUK National Institute for Health Research Health Technology Assessment Programme.

Project description:IntroductionCurrent pharmacological treatment options for hyperemesis gravidarum have been introduced based on scarce evidence and are often not sufficiently effective. Several case reports suggest that mirtazapine, an antidepressant, may be an effective treatment for hyperemesis gravidarum, but so far there are no controlled trials investigating the potential effect of mirtazapine on hyperemesis gravidarum. The antiemetic ondansetron is currently widely used to treat hyperemesis gravidarum despite sparse evidence of effect in pregnant women. This study aims to investigate the effect of mirtazapine on hyperemesis gravidarum while also providing data on the effect of ondansetron.Methods and analysisThis randomised double-blind placebo-controlled multicentre trial will be conducted in eight Danish hospitals. One hundred and eighty pregnant women referred to secondary care for hyperemesis gravidarum will be randomly allocated to 14-day treatment with either mirtazapine, ondansetron or placebo. Main inclusion criterion will be Pregnancy Unique Quantification of Emesis (PUQE-24) score ≥13 or PUQE-24 score ≥7 if accompanied by weight loss >5% of pre-pregnancy weight or hospitalisation. Participants are eligible regardless of whether other antiemetics, including ondansetron, have been tried. The coprimary outcomes are effects of mirtazapine and ondansetron, respectively, on PUQE-24 score tested hierarchically on day 2 and day 14. Secondary outcomes include, but are not limited to, differences between the three groups in number of daily vomiting episodes, dropout due to treatment failure, use of rescue medication, weight change and side effects.Ethics and disseminationThe trial has been approved by the Regional Committees on Health Research Ethics in the Capital Region of Denmark, the Danish Medicines Agency and the Danish Data Protection Agency. Results will be published in peer-reviewed journals and submitted to relevant conferences.Trial registration numberNCT03785691.

Project description:Purpose Treating small-cell lung cancer (SCLC) remains a therapeutic challenge. Experimental studies show that statins exert additive effects with agents, such as cisplatin, to impair tumor growth, and observational studies suggest that statins combined with anticancer therapies delay relapse and prolong life in several cancer types. To our knowledge, we report the first large, randomized, placebo-controlled, double-blind trial of a statin with standard-of-care for patients with cancer, specifically SCLC. Patients and Methods Patients with confirmed SCLC (limited or extensive disease) and performance status 0 to 3 were randomly assigned to receive daily pravastatin 40 mg or placebo, combined with up to six cycles of etoposide plus cisplatin or carboplatin every 3 weeks, until disease progression or intolerable toxicity. Primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), response rate, and toxicity. Results Eight hundred forty-six patients from 91 United Kingdom hospitals were recruited. The median age of recruited patients was 64 years of age, 43% had limited disease, and 57% had extensive disease. There were 758 deaths and 787 PFS events. No benefit was found for pravastatin, either in all patients or in several subgroups. For pravastatin versus placebo, the 2-year OS rate was 13.2% (95% CI, 10.0 to 16.7) versus 14.1% (95% CI, 10.9 to 17.7), respectively, with a hazard ratio of 1.01 (95% CI, 0.88 to 1.16; P = .90. The median OS was 10.7 months v 10.6 months, respectively. The median PFS was 7.7 months v 7.3 months, respectively. The median OS (pravastatin v placebo) was 14.6 months in both groups for limited disease and 9.1 months versus 8.8 months, respectively, for extensive disease. Adverse events were similar between groups. Conclusion Pravastatin 40 mg combined with standard SCLC therapy, although safe, does not benefit patients. Our conclusions are the same as those found in all four much smaller, randomized, placebo-controlled trials specifically designed to evaluate statin therapy in patients with cancer.

Project description:BackgroundMultidrug-resistant (MDR) tuberculosis (TB) presents a challenge for global TB control. Treating individuals with MDR-TB infection to prevent progression to disease could be an effective public health strategy. Young children are at high risk of developing TB disease following infection and are commonly infected by an adult in their household. Identifying young children with household exposure to MDR-TB and providing them with MDR-TB preventive therapy could reduce the risk of disease progression. To date, no trials of MDR-TB preventive therapy have been completed and World Health Organization guidelines suggest close observation with no active treatment.MethodsThe tuberculosis child multidrug-resistant preventive therapy (TB-CHAMP) trial is a phase III cluster randomised placebo-controlled trial to assess the efficacy of levofloxacin in young child contacts of MDR-TB cases. The trial is taking place at three sites in South Africa where adults with MDR-TB are identified. If a child aged <?5?years lives in their household, we assess the adult index case, screen all household members for TB disease and evaluate any child aged <?5?years for trial eligibility. Eligible children are randomised by household to receive daily levofloxacin (15-20?mg/kg) or matching placebo for six months. Children are closely monitored for disease development, drug tolerability and adverse events. The primary endpoint is incident TB disease or TB death by one year after recruitment. We will enrol 1556 children from approximately 778 households with an average of two eligible children per household. Recruitment will run for 18-24?months with all children followed for 18?months after treatment. Qualitative and health economic evaluations are embedded in the trial.DiscussionIf the TB-CHAMP trial demonstrates that levofloxacin is effective in preventing TB disease in young children who have been exposed to MDR-TB and that it is safe, well tolerated, acceptable and cost-effective, we would expect that that this intervention would rapidly transfer into policy.Trial registrationISRCTN Registry, ISRCTN92634082 . Registered on 31 March 2016.

Project description:BackgroundIntranasal drug delivery offers a non-invasive and convenient dosing option for patients and physicians, especially for conditions requiring chronic/repeated-treatment administration. However, in some cases such delivery may be harmful to nasal and olfactory epithelia.ObjectiveThe aim of this study was to assess the potential impact of long-term intermittent treatment with esketamine nasal spray, taken in conjunction with an oral antidepressant (AD), on olfactory function and nasal tolerability in patients with treatment-resistant depression (TRD).MethodsA total of 1142 patients with TRD participated from four multicenter, randomized, double-blind, phase III studies: three short-term studies (two in patients aged 18-64 years, one in patients ≥65 years), and one long-term maintenance study of esketamine nasal spray + AD versus placebo nasal spray + AD. Across the four studies, assessments were performed at 208 sites in 21 countries. Olfactory function was measured using the 40-item University of Pennsylvania Smell Identification Test (UPSIT®) and the single-staircase Snap & Sniff® Odor Detection Threshold Test (S&S-T). Nasal tolerability, including nasal examinations and a quantitative, self-administered nasal symptom questionnaire (NSQ), was also assessed. Data were analyzed using analyses of covariance.ResultsOf 1142 participants, 734 were women (64.3%). The mean age of all participants ranged from 45.7 to 70.0 years across the studies. Overall, 855 patients received esketamine nasal spray + AD and 432 received placebo nasal spray + AD. Objective evaluation of nasal function showed no evidence of an adverse impact following esketamine administration. Based on the UPSIT® and S&S-T results, intranasal administration of esketamine had no effect on the odor identification or threshold test scores compared with placebo nasal spray + oral AD. Similarly, repeated administration with esketamine nasal spray had no meaningful impact on assessments of nasal function. No dose-response relationship was observed between esketamine doses and the olfactory test scores. Esketamine nasal spray was well tolerated, as indicated by responses on the NSQ and negative nasal examination findings.ConclusionFindings from this analysis indicate that there was no evidence of adverse effect on either olfactory or nasal health measures with repeated intermittent administration of esketamine nasal spray at any dose over the course of short-term (4 weeks) or long-term (16-100 weeks) studies.Clinical trial registrationTRANSFORM-1: NCT02417064, date of registration: 15/04/2015; TRANSFORM-2: NCT02418585, date of registration: 16/04/2015; TRANSFORM-3: NCT02422186, date of registration: 21/04/2015; SUSTAIN-1: NCT02493868, date of registration: 10/07/2015.