Debbie Tallon

Reporting on quality of life in randomised controlled trials : bibliographic study

Objectives : To examine the frequency and quality of reporting on quality of life in randomised controlled trials. Design : Search of the Cochrane Controlled Trials Register 1980 to 1997 to identify trials from all disciplines, from oncology, and from cardiovascular medicine that reported on quality of life. Assessment of abstracts from articles published from 1993 to 1996. Assessment of a sample of full reports with a standardised instrument. Main outcome measures : Prevalence of reporting on quality of life. Conditions and interventions studied in trials reporting on quality of life. Quality of reporting on quality of life. Results : During 1980-97 reporting on quality of life increased from 0.63% to 4.2% for trials from all disciplines, from 1.5% to 8.2% for cancer trials, and from 0.34% to 3.6% for cardiovascular trials. Of 364 abstracts, 65% reported on drug interventions. Of a sample of 67 full reports, authors of 48 (72%) used 62 established quality of life instruments. In 15 reports (22%) authors developed their own measures, and in 2 (3%) methods were unclear. Response rates were given in 38 (57%), and complete reporting on all items and scales occurred in 31 (46%) Conclusions : Less than 5% of all randomised controlled trials reported on quality of life, and this proportion was below 10% even for cancer trials. A plethora of instruments was used in different studies, and the reporting of methods and results was often inadequate. Standards for the measurement and reporting of quality of life in clinical trials research need to be developed.

Relation between agendas of the research community and the research consumer

BACKGROUND Previous studies have suggested that research agendas can be biased. To determine whether there is a mismatch between available research evidence and the research preferences of consumers we examined research on interventions for the treatment of osteoarthritis of the knee joint. METHODS We searched published and unpublished studies on interventions in this condition to assess the structure of the evidence base. Focus groups and a postal survey of research consumers were then undertaken to examine their views and research priorities. FINDINGS Review of published and unpublished reports showed that the evidence base was dominated by studies of pharmaceutical (550, 59%) and surgical (238, 26%) interventions. 24 (36%) of 67 survey respondents ranked knee replacement as the highest priority for research, whereas 14 (21%) chose education and advice as their first choice. INTERPRETATION There is a mismatch between the amount of published work on different interventions, and the degree of interest of consumers. We suggest that broadening of the research agenda would be more in line with current treatment patterns and consumer views. If this mismatch is not addressed, then evidence-based medicine will not be representative of consumer needs.

An investigation into the relationship between salivary cortisol, stress, anxiety and depression.

This study examined the relationship between indices of self-reported emotional distress and absolute versus change in cortisol levels. Fifty-four women attending a diagnostic breast clinic completed scales measuring stress, anxiety and depression and provided five saliva samples over the course of a single day for the measurement of cortisol. No significant relationships were evident between absolute cortisol levels and the distress measures. Analysis of the change in cortisol levels revealed a non-linear interaction effect between stress and anxiety and time of day. There was a non-linear relation between time of day and cortisol levels, but the extent of the non-linearity was dependent upon levels of stress and anxiety, not depression. A relationship was apparent between indices of distress and change in cortisol levels, but not absolute levels of the hormone.

Computerised cognitive behaviour therapy (cCBT) as treatment for depression in primary care (REEACT trial): large scale pragmatic randomised controlled trial.

Study question How effective is supported computerised cognitive behaviour therapy (cCBT) as an adjunct to usual primary care for adults with depression? Methods This was a pragmatic, multicentre, three arm, parallel randomised controlled trial with simple randomisation. Treatment allocation was not blinded. Participants were adults with symptoms of depression (score ≥10 on nine item patient health questionnaire, PHQ-9) who were randomised to receive a commercially produced cCBT programme (“Beating the Blues”) or a free to use cCBT programme (MoodGYM) in addition to usual GP care. Participants were supported and encouraged to complete the programme via weekly telephone calls. Control participants were offered usual GP care, with no constraints on the range of treatments that could be accessed. The primary outcome was severity of depression assessed with the PHQ-9 at four months. Secondary outcomes included health related quality of life (measured by SF-36) and psychological wellbeing (measured by CORE-OM) at four, 12, and 24 months and depression at 12 and 24 months. Study answer and limitations Participants offered commercial or free to use cCBT experienced no additional improvement in depression compared with usual GP care at four months (odds ratio 1.19 (95% confidence interval 0.75 to 1.88) for Beating the Blues v usual GP care; 0.98 (0.62 to 1.56) for MoodGYM v usual GP care). There was no evidence of an overall difference between either programme compared with usual GP care (0.99 (0.57 to 1.70) and 0.68 (0.42 to 1.10), respectively) at any time point. Commercially provided cCBT conferred no additional benefit over free to use cCBT or usual GP care at any follow-up point. Uptake and use of cCBT was low, despite regular telephone support. Nearly a quarter of participants (24%) had dropped out by four months. The study did not have enough power to detect small differences so these cannot be ruled out. Findings cannot be generalised to cCBT offered with a much higher level of guidance and support. What this study adds Supported cCBT does not substantially improve depression outcomes compared with usual GP care alone. In this study, neither a commercially available nor free to use computerised CBT intervention was superior to usual GP care. Funding, competing interests, data sharing Commissioned and funded by the UK National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme (project No 06/43/05). The authors have no competing interests. Requests for patient level data will be considered by the REEACT trial management group Trial registration Current Controlled Trials ISRCTN91947481.

Epidemiology of research into interventions for the treatment of osteoarthritis of the knee joint

OBJECTIVE To assess the published research base for interventions for osteoarthritis of the knee, and to identify areas in need of further research. METHODS Literature searches were conducted on electronic databases (Medline, Embase, ISI, and Cochrane library), bibliographies of existing review articles were hand searched, and a postal questionnaire was sent to members of the Osteoarthritis Research Society International. All relevant articles were copied and searched for treatment type, study methodology, statistical results, conclusions, funding source, researcher affiliations, and year of publication, using a predetermined data extraction form. RESULTS There have been marked changes in the literature over the period studied (1950–98), with a recent rise in trials of physical therapy, educational interventions, and complementary treatments. However, overall, most research was either drug (59.1%) or surgically (25.6%) related. Most of the studies reported positive results (94%). Research on oral drugs was significantly more likely to provide a positive result than research on any other intervention (p<0.001 by χ2 test). Commercially funded studies were significantly more likely to produce a positive result than non-commercially funded research (p=0.0027 by χ2 test). CONCLUSIONS Analysis of time trends indicates that the research agenda does shadow changes in consumer demands. However, there are significant gaps in the research base that need to be considered.

Enhancement of antibody responses to influenza vaccination in the elderly following a cognitive-behavioural stress management intervention.

Background: Previous research has demonstrated that the psychological morbidity experienced by informal caregivers is associated with increased vulnerability to infectious diseases, in particular influenza. A pragmatic trial was conducted to examine whether a stress management intervention (SMI) could reduce psychological morbidity and enhance the antibody response to influenza vaccination in the elderly, and whether changes in immune response of SMI participants were associated with hypothalamic-pituitary-adrenal (HPA) axis activity. Methods: Forty-three elderly spousal carers of dementia patients and 27 non-carer controls were recruited. Sixteen carers were allocated to an 8-week SMI or a non-intervention condition (n = 27). The non-carers formed a no treatment, ‘normal’ comparison group. At the end of the SMI or its equivalent time period, all participants received an influenza vaccination. IgG antibody titres to the vaccine were measured 0, 2, 4 and 6 weeks post-vaccine. Results: There was evidence of elevated distress in both carer groups compared with non-carer controls throughout the SMI period, but no between-group differences in salivary cortisol. Immune responses to the vaccine revealed that 50% of SMI carers, 7% of non-intervention carers and 29% of non-carer controls produced a four-fold increase in antibody titre. Conclusions: The immune response to influenza vaccination appears amenable to improvement through stress management, although the mechanisms underlying this effect remain unclear.

Polymorphism of the 5-HT transporter and response to antidepressants: randomised controlled trial.

BACKGROUND Antidepressants exhibit a variety of pharmacological actions including inhibition of the serotonin and noradrenaline transporters. We wished to investigate whether genetic variation could be used to target or personalise treatment, in a comparison of selective serotonin reuptake inhibitors (SSRIs) with noradrenaline reuptake inhibitors (NARIs). AIMS To test the hypothesis that patients homozygous for the long (insertion) polymorphism of the serotonin transporter (5-HTTLPR) have an increased response to SSRI antidepressants but not to NARI antidepressants. METHOD In an individually randomised, parallel-group controlled trial, people meeting criteria for a depressive episode who were referred by their general practitioner were randomised to receive either citalopram (an SSRI) or reboxetine (an NARI). Randomisation was by means of a remote automated system accessed by telephone. The main outcome was depressive symptoms, measured by Beck Depression Inventory (BDI) total score 6 weeks after randomisation. The trial was registered with the International Standard Randomised Controlled Trials Number registry (ISRCTN31345163). RESULTS Altogether 298 participants were randomised to receive citalopram and 303 were randomised to reboxetine. At 6 weeks follow-up, complete data were available for 258 participants taking citalopram and 262 taking reboxetine. We found no evidence to support an influence of 5-HTTLPR on outcome following antidepressant treatment. The interaction term for BDI score at 6 weeks was 0.50 (95% CI -2.04 to 3.03, P = 0.70), which indicated that responses to the SSRI and NARI were similar irrespective of 5-HTTLPR genotype. CONCLUSIONS It is unlikely that the 5-HTTLPR polymorphism alone will be clinically useful in predicting response to antidepressants in people with depression.

A pragmatic randomised controlled trial to compare antidepressants with a community-based psychosocial intervention for the treatment of women with postnatal depression: the RESPOND trial.

OBJECTIVES To evaluate clinical effectiveness at 4 weeks of antidepressant therapy for mothers with postnatal depression (PND) compared with general supportive care; to compare outcome at 18 weeks of those randomised to antidepressant therapy with those randomised to listening visits as the first intervention (both groups were to be allowed to receive the alternative intervention after 4 weeks if the woman or her doctor so decided); and to assess acceptability of antidepressants and listening visits to users and health professionals. DESIGN A pragmatic two-arm individually randomised controlled trial. SETTING Participants were recruited from 77 general practices: 21 in Bristol, 21 in south London and 35 in Manchester. PARTICIPANTS A total of 254 women who fulfilled International Classification of Diseases version 10 criteria for major depression in the first 6 postnatal months were recruited and randomised. INTERVENTIONS Women were randomised to receive either an antidepressant, usually a selective serotonin reuptake inhibitor prescribed by their general practitioner (GP), or non-directive counselling (listening visits) from a specially trained research health visitor (HV). The trial was designed to compare antidepressants with general supportive care for the first 4 weeks, after which women allocated to listening visits commenced their sessions. It allowed for women to receive the alternative intervention if they had not responded to their allocated intervention or wished to change to, or add in, the alternative intervention at any time after 4 weeks. MAIN OUTCOME MEASURES The duration of the trial was 18 weeks. Primary outcome, measured at 4 weeks and 18 weeks post randomisation, was the proportion of women improved on the Edinburgh Postnatal Depression Scale (EPDS), that is scoring < 13. Secondary outcomes were the EPDS measured as a continuous variable at 4 and 18 weeks, and scores on various other questionnaires. RESULTS At 4 weeks, women were more than twice as likely to have improved if they had been randomised to antidepressants compared with listening visits, which started after the 4-week follow-up, i.e. after 4 weeks of general supportive care [primary intention-to-treat (ITT), 45% versus 20%; odds ratio (OR) 3.4, 95% confidence interval (CI) 1.8 to 6.5, p < 0.001]. Explanatory analyses emphasised these findings. At 18 weeks, ITT analysis revealed that the proportion of women improving was 11% greater in the antidepressant group, but logistic regression analysis showed no clear benefit for one group over the other [62% versus 51%, OR 1.5 (95% CI 0.8 to 2.6), p = 0.19]. Overall, there was a difference between the groups in favour of the antidepressant group of about 25 percentage points at 4 weeks, which reduced at 18 weeks. No statistical support existed for a benefit of antidepressants at 18 weeks, but 95% CIs could not rule out a clinically important benefit. It was difficult for GPs not to prescribe antidepressants to women randomised to listening visits after the initial 4 weeks, so many women received both interventions in both groups by 18 weeks and consequently power was reduced. Qualitative interviews with women revealed a preference for listening visits but an acceptance that antidepressants might be necessary. They wished to be reassured that their GP and HV were offering continuity of care focusing on their particular set of circumstances. Interviews with GPs and HVs revealed lack of collaboration in managing care for women with PND; neither professional group was willing to assume responsibility. CONCLUSIONS At 4 weeks, antidepressants were significantly superior to general supportive care. Trial design meant that by 18 weeks many of the women initially randomised to listening visits were also receiving antidepressants, and more vice versa. The lack of evidence for differences at 18 weeks is likely to reflect a combination of reduced power and the considerable degree of switching across the two interventions. Qualitative study revealed that women found both antidepressants and listening visits effective depending on their circumstances and preferences. The trial indicates that early treatment with antidepressants leads to clinical benefit for women with PND.

A randomised controlled trial of computerised cognitive behaviour therapy for the treatment of depression in primary care: the Randomised Evaluation of the Effectiveness and Acceptability of Computerised Therapy (REEACT) trial

BACKGROUND Computerised cognitive behaviour therapy (cCBT) has been developed as an efficient form of therapy delivery with the potential to enhance access to psychological care. Independent research is needed which examines both the clinical effectiveness and cost-effectiveness of cCBT over the short and longer term. OBJECTIVES To compare the clinical effectiveness and cost-effectiveness of cCBT as an adjunct to usual general practitioner (GP) care against usual GP care alone, for a free-to-use cCBT program (MoodGYM; National Institute for Mental Health Research, Australian National University, Canberra, Australia) and a commercial pay-to-use cCBT program (Beating the Blues(®); Ultrasis, London, UK) for adults with depression, and to determine the acceptability of cCBT and the experiences of users. DESIGN A pragmatic, multicentre, three-armed, parallel, randomised controlled trial (RCT) with concurrent economic and qualitative evaluations. Simple randomisation was used. Participants and researchers were not blind to treatment allocation. SETTING Primary care in England. PARTICIPANTS Adults with depression who scored ≥ 10 on the Patient Health Questionnaire-9 (PHQ-9). INTERVENTIONS Participants who were randomised to either of the two intervention groups received cCBT (Beating the Blues or MoodGYM) in addition to usual GP care. Participants who were randomised to the control group were offered usual GP care. MAIN OUTCOME MEASURES The primary outcome was depression at 4 months (PHQ-9). Secondary outcomes were depression at 12 and 24 months; measures of mental health and health-related quality of life at 4, 12 and 24 months; treatment preference; and the acceptability of cCBT and experiences of users. RESULTS Clinical effectiveness: 210 patients were randomised to Beating the Blues, 242 patients were randomised to MoodGYM and 239 patients were randomised to usual GP care (total 691). There was no difference in the primary outcome (depression measured at 4 months) either between Beating the Blues and usual GP care [odds ratio (OR) 1.19, 95% confidence interval (CI) 0.75 to 1.88] or between MoodGYM and usual GP care (OR 0.98, 95% CI 0.62 to 1.56). There was no overall difference across all time points for either intervention compared with usual GP care in a mixed model (Beating the Blues versus usual GP care, p = 0.96; and MoodGYM versus usual GP care, p = 0.11). However, a small but statistically significant difference between MoodGYM and usual GP care at 12 months was found (OR 0.56, 95% CI 0.34 to 0.93). Free-to-use cCBT (MoodGYM) was not inferior to pay-to-use cCBT (Beating the Blues) (OR 0.91, 90% CI 0.62 to 1.34; p = 0.69). There were no consistent benefits of either intervention when secondary outcomes were examined. There were no serious adverse events thought likely to be related to the trial intervention. Despite the provision of regular technical telephone support, there was low uptake of the cCBT programs. Cost-effectiveness: cost-effectiveness analyses suggest that neither Beating the Blues nor MoodGYM appeared cost-effective compared with usual GP care alone. Qualitative evaluation: participants were often demotivated to access the computer programs, by reason of depression. Some expressed the view that a greater level of therapeutic input would be needed to promote engagement. CONCLUSIONS The benefits that have previously been observed in developer-led trials were not found in this large pragmatic RCT. The benefits of cCBT when added to routine primary care were minimal, and uptake of this mode of therapy was relatively low. There remains a clinical and economic need for effective low-intensity psychological treatments for depression with improved patient engagement. TRIAL REGISTRATION This trial is registered as ISRCTN91947481. FUNDING This project was funded by the National Institute for Health Research Health Technology Assessment programme.

GENetic and clinical Predictors Of treatment response in Depression: the GenPod randomised trial protocol

BackgroundThe most effective pharmacological treatments for depression inhibit the transporters that reuptake serotonin (Selective Serotonin Reuptake Inhibitors – SSRIs) and noradrenaline (Noradrenaline Reuptake Inhibitors – NaRIs) into the presynaptic terminal. There is evidence to suggest that noradrenaline and serotonin enhancing drugs work through separate mechanisms to produce their clinical antidepressant action. Although most of the current evidence suggests there is little difference in overall efficacy between SSRIs and NaRIs, there are patients who respond to one class of compounds and not another. This suggests that treatment response could be predicted by genetic and/or clinical characteristics.Firstly, this study aims to investigate the influence of a polymorphism (SLC6A4) in the 5HT transporter in altering response to SSRI medication. Secondly, the study will investigate whether those with more severe depression have a better response to NaRIs than SSRIs.Methods/designThe GenPod trial is a multi-centre randomised controlled trial. GPs referred patients aged between 18–74 years presenting with a new episode of depression, who did not have any medical contraindications to antidepressant medication and who had no history of psychosis or alcohol/substance abuse. Patients were interviewed to ascertain their suitability for the study. Eligible participants (with a primary diagnosis of depression according to ICD10 criteria and a Beck Depression Inventory (BDI) score > 14) were randomised to receive one of two antidepressant treatments, either the SSRI Citalopram or the NaRI Reboxetine, stratified according to severity. The final number randomised to the trial was 601. Follow-up assessments took place at 2, 6 and 12 weeks following randomisation. Primary outcome was measured at 6 weeks by the BDI. Outcomes will be analysed on an intention-to-treat basis and will use multiple regression models to compare treatments.DiscussionThe results of the trial will provide information about targeting antidepressant treatment for individual patients; in turn this may increase prescribing efficacy, thereby speeding recovery and reducing the cost to the NHS. It will also help to understand the different roles that noradrenaline and serotonin might play in the biology of depression.The trial is expected to report in the autumn of 2008.Trial RegistrationISRCTN 31345163