Jennifer Hellier

Sertraline or mirtazapine for depression in dementia (HTA-SADD): a randomised, multicentre, double-blind, placebo-controlled trial

BACKGROUND Depression is common in dementia but the evidence base for appropriate drug treatment is sparse and equivocal. We aimed to assess efficacy and safety of two of the most commonly prescribed drugs, sertraline and mirtazapine, compared with placebo. METHODS We undertook the parallel-group, double-blind, placebo-controlled, Health Technology Assessment Study of the Use of Antidepressants for Depression in Dementia (HTA-SADD) trial in participants from old-age psychiatry services in nine centres in England. Participants were eligible if they had probable or possible Alzheimers disease, depression (lasting ≥4 weeks), and a Cornell scale for depression in dementia (CSDD) score of 8 or more. Participants were ineligible if they were clinically critical (eg, suicide risk), contraindicated to study drugs, on antidepressants, in another trial, or had no carer. The clinical trials unit at Kings College London (UK) randomly allocated participants with a computer-generated block randomisation sequence, stratified by centre, with varying block sizes, in a 1:1:1 ratio to receive sertraline (target dose 150 mg per day), mirtazapine (45 mg), or placebo (control group), all with standard care. The primary outcome was reduction in depression (CSDD score) at 13 weeks (outcomes to 39 weeks were also assessed), assessed with a mixed linear-regression model adjusted for baseline CSDD, time, and treatment centre. This study is registered, number ISRCTN88882979 and EudraCT 2006-000105-38. FINDINGS Decreases in depression scores at 13 weeks did not differ between 111 controls and 107 participants allocated to receive sertraline (mean difference 1·17, 95% CI -0·23 to 2·58; p=0·10) or mirtazapine (0·01, -1·37 to 1·38; p=0·99), or between participants in the mirtazapine and sertraline groups (1·16, -0·25 to 2·57; p=0·11); these findings persisted to 39 weeks. Fewer controls had adverse reactions (29 of 111 [26%]) than did participants in the sertraline group (46 of 107, 43%; p=0·010) or mirtazapine group (44 of 108, 41%; p=0·031), and fewer serious adverse events rated as severe (p=0·003). Five patients in every group died by week 39. INTERPRETATION Because of the absence of benefit compared with placebo and increased risk of adverse events, the present practice of use of these antidepressants, with usual care, for first-line treatment of depression in Alzheimers disease should be reconsidered. FUNDING UK National Institute of Health Research HTA Programme.

Study of the use of antidepressants for depression in dementia: the HTA-SADD trial--a multicentre, randomised, double-blind, placebo-controlled trial of the clinical effectiveness and cost-effectiveness of sertraline and mirtazapine

OBJECTIVE Depression is common in dementia, causing considerable distress and other negative impacts. Treating it is a clinical priority, but the evidence base is sparse and equivocal. This trial aimed to determine clinical effectiveness of sertraline and mirtazapine in reducing depression 13 weeks post randomisation compared with placebo. DESIGN Multicentre, parallel-group, double-blind placebo-controlled randomised controlled trial of the clinical effectiveness of sertraline and mirtazapine with 13- and 39-week follow-up. SETTING Nine English old-age psychiatry services. PARTICIPANTS A pragmatic trial. Eligibility: probable or possible Alzheimers disease (AD), depression (4+ weeks) and Cornell Scale for Depression in Dementia (CSDD) score of 8+. EXCLUSIONS clinically too critical (e.g. suicide risk); contraindication to medication; taking antidepressants; in another trial; and having no carer. INTERVENTIONS (1) Sertraline; (2) mirtazapine; and (3) placebo, all with normal care. Target doses: 150 mg of sertraline or 45 mg of mirtazapine daily. MAIN OUTCOME MEASURES OUTCOME CSDD score. Randomisation: Allocated 1 : 1 : 1 through Trials Unit, independently of trial team. Stratified block randomisation by centre, with randomly varying block sizes; computer-generated randomisation. Blinding: Double blind: medication and placebo identical for each antidepressant. Referring clinicians, research workers, participants and pharmacies were blind. Statisticians blind until analyses completed. RESULTS Numbers randomised: 326 participants randomised (111 placebo, 107 sertraline and 108 mirtazapine). OUTCOME Differences in CSDD at 13 weeks from an adjusted linear-mixed model: mean difference (95% CI) placebo-sertraline 1.17 (-0.23 to 2.78; p = 0.102); placebo-mirtazapine 0.01 (-1.37 to 1.38; p = 0.991); and mirtazapine-sertraline 1.16 (-0.27 to 2.60; p = 0.112). HARMS Placebo group had fewer adverse reactions (29/111, 26%) than sertraline (46/107, 43%) or mirtazapine (44/108, 41%; p = 0.017); 39-week mortality equal, five deaths in each group. CONCLUSIONS This is a trial with negative findings but important clinical implications. The data suggest that the antidepressants tested, given with normal care, are not clinically effective (compared with placebo) for clinically significant depression in AD. This implies a need to change current practice of antidepressants being the first-line treatment of depression in AD. From the data generated we formulated the following recommendations for future work. (1) The secondary analyses presented here suggest that there would be value in carrying out a placebo-controlled trial of the clinical effectiveness and cost-effectiveness of mirtazapine in the management of Behavioural and Psychological Symptoms of Dementia. (2) A conclusion from this study is that it remains both ethical and essential for trials of new medication for depression in dementia to have a placebo arm. (3) Further research is required to evaluate the impact that treatments for depression in people with dementia can have on their carers not only in terms of any impacts on their quality of life, but also the time they spend care-giving. (4) There is a need for research into alternative biological and psychological therapies for depression in dementia. These could include evaluations of new classes of antidepressants (such as venlafaxine) or antidementia medication (e.g. cholinesterase inhibitors). (5) Research is needed to investigate the natural history of depression in dementia in the community when patients are not referred to secondary care services. (6) Further work is needed to investigate the cost modelling results in this rich data set, investigating carer burden and possible moderators to the treatment effects. (7) There is scope for reanalysis of the primary outcome in terms of carer and participant CSDD results.

Cognitive behavioural treatment for women who have menopausal symptoms after breast cancer treatment (MENOS 1): a randomised controlled trial

Summary Background Hot flushes and night sweats (HFNS) affect 65–85% of women after breast cancer treatment; they are distressing, causing sleep problems and decreased quality of life. Hormone replacement therapy is often either undesirable or contraindicated. Safe, effective non-hormonal treatments are needed. We investigated whether cognitive behavioural therapy (CBT) can help breast cancer survivors to effectively manage HFNS. Methods In this randomised controlled trial, we recruited women from breast clinics in London, UK, who had problematic HFNS (minimum ten problematic episodes a week) after breast-cancer treatment. Participants were randomly allocated to receive either usual care or usual care plus group CBT (1:1). Randomisation was done in blocks of 12–20 participants, stratifying by age (younger than 50 years, 50 years or older), and was done with a computer-generated sequence. The trial statistician and researchers collecting outcome measures were masked to group allocation. Group CBT comprised one 90 min session a week for 6 weeks, and included psycho-education, paced breathing, and cognitive and behavioural strategies to manage HFNS. Assessments were done at baseline, 9 weeks, and 26 weeks after randomisation. The primary outcome was the adjusted mean difference in HFNS problem rating (1–10) between CBT and usual care groups at 9 weeks after randomisation. Analysis of the primary endpoint was done by modified intention to treat. The trial is registered, ISRCTN13771934, and was closed March 15, 2011. Findings Between May 5, 2009, and Aug 27, 2010, 96 women were randomly allocated to group CBT (n=47) or usual care (n=49). Group CBT significantly reduced HFNS problem rating at 9 weeks after randomisation compared with usual care (mean difference −1·67, 95% CI −2·43 to −0·91; p<0·0001) and improvements were maintained at 26 weeks (mean difference −1·76, −2·54 to −0·99; p<0·0001). We recorded no CBT-related adverse events. Interpretation Group CBT seems to be a safe and effective treatment for women who have problematic HFNS after breast cancer treatment with additional benefits to mood, sleep, and quality of life. The treatment could be incorporated into breast cancer survivorship programmes and delivered by trained breast cancer nurses. Funding Cancer Research UK.

Effectiveness of group and self-help cognitive behavior therapy in reducing problematic menopausal hot flushes and night sweats (MENOS 2): a randomized controlled trial

Objective The aim of this study was to examine the effectiveness of group cognitive behavioral therapy (CBT) and guided self-help CBT in reducing hot flush and night sweat (HF/NS) problem rating at 6 and 26 weeks after randomization. Methods This was a randomized control trial of 140 women having 10 or more problematic HF/NS a week for at least a month. The primary outcome was HF/NS problem rating (1-10) at 6 weeks after randomization. Secondary outcomes were physiologically measured HF/NS at 6 weeks; HF/NS problem rating at 6 weeks; and frequency, mood (Women’s Health Questionnaire), and health-related quality of life (General Health Survey Short Form–36) at 6 and 26 weeks. Intention-to-treat analysis was used, and between-group differences were estimated using linear mixed models. Results Baseline mean (SD) HF/NS weekly frequency was 63.15 (49.24), and problem rating was 5.87 (2.28). Group and self-help CBT both significantly reduced HF/NS problem rating at 6 weeks—group CBT versus no treatment control (NTC; adjusted mean difference, 2.12; 95% CI, 1.36-2.88; P < 0.001) and self-help CBT versus NTC (adjusted mean difference, 2.08; 95% CI, 1.29-2.86; P < 0.001)—and at 26 weeks—group CBT versus NTC (adjusted mean difference, 1.33; 95% CI, 0.54-2.13; P = 0.001) and self-help CBT versus NTC (adjusted mean difference, 1.19; 95% CI, 0.36-2.02; P = 0.005). Group and self-help CBT significantly reduced night sweat frequency at 6 and 26 weeks. There were improvements in mood and quality of life at 6 weeks and improved emotional and physical functioning for group CBT at 26 weeks. Conclusions These results suggest that CBT delivered in group or self-help format is an effective treatment option for women during the menopause transition and postmenopause with problematic HF/NS.

Use of contingency management incentives to improve completion of hepatitis B vaccination in people undergoing treatment for heroin dependence: a cluster randomised trial

BACKGROUND Poor adherence to treatment diminishes its individual and public health benefit. Financial incentives, provided on the condition of treatment attendance, could address this problem. Injecting drug users are a high-risk group for hepatitis B virus (HBV) infection and transmission, but adherence to vaccination programmes is poor. We aimed to assess whether contingency management delivered in routine clinical practice increased the completion of HBV vaccination in individuals receiving opioid substitution therapy. METHODS In our cluster randomised controlled trial, we enrolled participants at 12 National Health Service drug treatment services in the UK that provided opioid substitution therapy and nurse-led HBV vaccination with a super-accelerated schedule (vaccination days 0, 7, and 21). Clusters were randomly allocated 1:1:1 to provide vaccination without incentive (treatment as usual), with fixed value contingency management (three £10 vouchers), or escalating value contingency management (£5, £10, and £15 vouchers). Both contingency management schedules rewarded on-time attendance at appointments. The primary outcome was completion of clinically appropriate HBV vaccination within 28 days. We also did sensitivity analyses that examined vaccination completion with full adherence to appointment times and within a 3 month window. The trial is registered with Current Controlled Trials, number ISRCTN72794493. FINDINGS Between March 16, 2011, and April 26, 2012, we enrolled 210 eligible participants. Compared with six (9%) of 67 participants treated as usual, 35 (45%) of 78 participants in the fixed value contingency management group met the primary outcome measure (odds ratio 12·1, 95% CI 3·7-39·9; p<0·0001), as did 32 (49%) of 65 participants in the escalating value contingency management group (14·0, 4·2-46·2; p<0·0001). These differences remained significant with sensitivity analyses. INTERPRETATION Modest financial incentives delivered in routine clinical practice significantly improve adherence to, and completion of, HBV vaccination programmes in patients receiving opioid substitution therapy. Achievement of this improvement in routine clinical practice should now prompt actual implementation. Drug treatment providers should employ contingency management to promote adherence to vaccination programmes. The effectiveness of routine use of contingency management to achieve long-term behaviour change remains unknown. FUNDING National Institute for Health Research (RP-PG-0707-10149).

A randomised controlled trial of a cognitive behavioural intervention for women who have menopausal symptoms following breast cancer treatment (MENOS 1): Trial protocol

BackgroundThis trial aims to evaluate the effectiveness of a group cognitive behavioural intervention to alleviate menopausal symptoms (hot flushes and night sweats) in women who have had breast cancer treatment. Hot flushes and night sweats are highly prevalent but challenging to treat in this population. Cognitive behaviour therapy has been found to reduce these symptoms in well women and results of an exploratory trial suggest that it might be effective for breast cancer patients. Two hypotheses are tested:Compared to usual care, group cognitive behavioural therapy will:1. Significantly reduce the problem rating and frequency of hot flushes and nights sweats after six weeks of treatment and at six months post-randomisation.2. Improve mood and quality of life after six weeks of treatment and at six months post-randomisation.Methods/DesignNinety-six women who have completed their main treatment for breast cancer and who have been experiencing problematic hot flushes and night sweats for over two months are recruited into the trial from oncology and breast clinics in South East London. They are randomised to either six weekly group cognitive behavioural therapy (Group CBT) sessions or to usual care. Group CBT includes information and discussion about hot flushes and night sweats in the context of breast cancer, monitoring and modifying precipitants, relaxation and paced respiration, stress management, cognitive therapy for unhelpful thoughts and beliefs, managing sleep and night sweats and maintaining changes.Prior to randomisation women attend a clinical interview, undergo 24-hour sternal skin conductance monitoring, and complete questionnaire measures of hot flushes and night sweats, mood, quality of life, hot flush beliefs and behaviours, optimism and somatic amplification. Post-treatment measures (sternal skin conductance and questionnaires) are collected six to eight weeks later and follow-up measures (questionnaires and a use of medical services measure) at six months post-randomisation.DiscussionMENOS 1 is the first randomised controlled trial of cognitive behavioural therapy for hot flushes and night sweats that measures both self-reported and physiologically indexed symptoms. The results will inform future clinical practice by developing an evidence-based, non-medical treatment, which can be delivered by trained health professionals.Trial RegistrationCurrent Controlled Trials ISRCTN13771934

Joint crisis plans for people with borderline personality disorder: feasibility and outcomes in a randomised controlled trial.

BACKGROUND People with borderline personality disorder frequently experience crises. To date, no randomised controlled trials (RCTs) of crisis interventions for this population have been published. AIMS To examine the feasibility of recruiting and retaining adults with borderline personality disorder to a pilot RCT investigating the potential efficacy and cost-effectiveness of using a joint crisis plan. METHOD An RCT of joint crisis plans for community-dwelling adults with borderline personality disorder (trial registration: ISRCTN12440268). The primary outcome measure was the occurrence of self-harming behaviour over the 6-month period following randomisation. Secondary outcomes included depression, anxiety, engagement and satisfaction with services, quality of life, well-being and cost-effectiveness. RESULTS In total, 88 adults out of the 133 referred were eligible and were randomised to receive a joint crisis plan in addition to treatment as usual (TAU; n = 46) or TAU alone (n = 42). This represented approximately 75% of our target sample size and follow-up data were collected on 73 (83.0%) participants. Intention-to-treat analysis revealed no significant differences in the proportion of participants who reported self-harming (odds ratio (OR) = 1.9, 95% CI 0.53-6.5, P = 0.33) or the frequency of self-harming behaviour (rate ratio (RR) = 0.74, 95% CI 0.34-1.63, P = 0.46) between the two groups at follow-up. No significant differences were observed between the two groups on any of the secondary outcome measures or costs. CONCLUSIONS It is feasible to recruit and retain people with borderline personality disorder to a trial of joint crisis plans and the intervention appears to have high face validity with this population. However, we found no evidence of clinical efficacy in this feasibility study.

Cost-effectiveness analyses for mirtazapine and sertraline in dementia: randomised controlled trial

BACKGROUND Depression is a common and costly comorbidity in dementia. There are very few data on the cost-effectiveness of antidepressants for depression in dementia and their effects on carer outcomes. AIMS To evaluate the cost-effectiveness of sertraline and mirtazapine compared with placebo for depression in dementia. METHOD A pragmatic, multicentre, randomised placebo-controlled trial with a parallel cost-effectiveness analysis (trial registration: ISRCTN88882979 and EudraCT 2006-000105-38). The primary cost-effectiveness analysis compared differences in treatment costs for patients receiving sertraline, mirtazapine or placebo with differences in effectiveness measured by the primary outcome, total Cornell Scale for Depression in Dementia (CSDD) score, over two time periods: 0-13 weeks and 0-39 weeks. The secondary evaluation was a cost-utility analysis using quality-adjusted life years (QALYs) computed from the Euro-Qual (EQ-5D) and societal weights over those same periods. RESULTS There were 339 participants randomised and 326 with costs data (111 placebo, 107 sertraline, 108 mirtazapine). For the primary outcome, decrease in depression, mirtazapine and sertraline were not cost-effective compared with placebo. However, examining secondary outcomes, the time spent by unpaid carers caring for participants in the mirtazapine group was almost half that for patients receiving placebo (6.74 v. 12.27 hours per week) or sertraline (6.74 v. 12.32 hours per week). Informal care costs over 39 weeks were £1510 and £1522 less for the mirtazapine group compared with placebo and sertraline respectively. CONCLUSIONS In terms of reducing depression, mirtazapine and sertraline were not cost-effective for treating depression in dementia. However, mirtazapine does appear likely to have been cost-effective if costing includes the impact on unpaid carers and with quality of life included in the outcome. Unpaid (family) carer costs were lower with mirtazapine than sertraline or placebo. This may have been mediated via the putative ability of mirtazapine to ameliorate sleep disturbances and anxiety. Given the priority and the potential value of supporting family carers of people with dementia, further research is warranted to investigate the potential of mirtazapine to help with behavioural and psychological symptoms in dementia and in supporting carers.

The quality of reporting of phase II and III trials for new antipsychotics: a systematic review

BACKGROUND The findings of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study and the Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS) called previous trials of antipsychotics into question, including pre-licensing trials. Concerns regarding methodological robustness and quality of reporting increased. This systematic review aimed to examine the quality of reporting of phase II and III trials for new antipsychotics in the aftermath of the CATIE and CUtLASS studies. METHOD Electronic searches were conducted in EMBASE, Medline and Cochrane databases and also ClinicalTrials.gov for antipsychotic trials (published between January 2006 and February 2012). Phase II and III randomized controlled trials (RCTs) for iloperidone, asenapine, paliperidone, olanzapine, lurasidone and pomaglumetad methionil were selected for schizophrenia and schizoaffective disorder. The reporting of the methodology was evaluated in accordance with Consolidated Standards of Reporting Trials (CONSORT) guidelines. RESULTS Thirty-one articles regarding 32 studies were included. There was insufficient reporting of design in 47% of studies and only 13% explicitly stated a primary hypothesis. Exclusion criteria were poorly reported for diagnosis in 22% of studies. Detail regarding comparators, particularly placebos, was suboptimal for 56% of studies, and permitted concomitant medication was often not reported (19%). Randomization methods were poorly described in 56% of studies and reporting on blinding was insufficient in 84% of studies. Sample size calculations were insufficiently reported in 59% of studies. CONCLUSIONS The quality of reporting of phase II and III trials for new antipsychotics does not reach the standards outlined in the CONSORT guidelines. Authors often fail to adequately report design and methodological processes, potentially impeding the progress of research on antipsychotic efficacy. Both policymakers and clinicians require high quality reporting before decisions are made regarding licensing and prescribing of new antipsychotics.

Drug use, health and social outcomes of hard-to-treat heroin addicts receiving supervised injectable opiate treatment: secondary outcomes from the Randomized Injectable Opioid Treatment Trial (RIOTT)

AIMS The Randomized Injectable Opioid Treatment Trial (RIOTT) compared supervised injectable heroin (SIH) and supervised injectable methadone (SIM) with optimized oral methadone (OOM) (ISRCTN0133807). Heroin addicts (previously unresponsive to treatment) made significant reductions in street heroin use at 6 months when treated with SIH. We now examine secondary outcomes. DESIGN Multi-site randomized controlled trial (RCT) comparing SIH versus OOM and SIM versus OOM. SETTING Three supervised injectable opiate clinics in England. PARTICIPANTS Chronic refractory heroin addicts continuing to inject street heroin virtually daily despite oral substitution treatment (n = 127), randomized to either SIH(n = 43), SIM(n = 42) or OOM(n = 42). All received high levels of medical and psychosocial support. MEASUREMENTS SECONDARY OUTCOMES wider drug use, crime, health and social functioning at 6 months. FINDINGS At 6 months, no significant differences were found between treatment groups in wider drug use (crack/cocaine, benzodiazepines, alcohol), physical and mental health (SF-36) or social functioning. Within each treatment group, significant reductions were observed in crime [SIH = odds ratio (OR) 0.05; P < 0.001; SIM = OR 0.11; P = 0.002; OOM = OR 0.11; P = 0.003] and money spent per week on illicit drugs (SIH = mean change £-289.43; P < 0.001; SIM = mean change £-183.41; P < 0.001; OOM = mean change £-162.80; P < 0.001), with SIH significantly more likely to have reduced money spent on illicit drugs versus OOM (mean difference £-92.04; P < 0.001). Significant improvements were seen in physical health for SIH and SIM (SIH = mean change 3.97; P = 0.008; SIM = mean change 4.73; P = 0.002) and mental health for OOM (mean change 6.04; P = 0.013). CONCLUSIONS Supervised injectable heroin treatment and supervised injectable methadone treatment showed no clearly identified benefit over optimized oral methadone in terms of wider drug use, crime, physical and mental health within a 6-month period, despite reducing street heroin use to a greater extent. However, all interventions were associated with improvements in these outcomes.