Randomised controlled trial to determine the clinical and cost-effectiveness of selective serotonin reuptake inhibitors plus supportive care, versus supportive care alone, for mild to moderate depression with somatic symptoms in primary care. The THREAD (THREshold for AntiDepressant response) study

Article history

The research reported in this issue of the journal was commissioned by the HTA programme as project number 01/70/05. The contractual start date was in September 2003. The draft report began editorial review in May 2008 and was accepted for publication in November 2008. As the funder, by devising a commissioning brief, the HTA programme specified the research question and study design. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

Tony Kendrick has received fees for presenting at educational meetings and/or research funding from Lilly, Lundbeck, Servier and Wyeth pharmaceuticals, and has also received HTA funding for research into psychological treatments. Christopher Dowrick has received research funding from Lilly, Lundbeck, Servier and Wyeth pharmaceuticals, and MRC and EU research funding for research into psychological treatments, and has written about the limited value of antidepressants. André Tylee has received fees for presenting at educational meetings and/or research funding from Lilly, Lundbeck, Servier, Wyeth and GlaxoSmithKline pharmaceuticals. Richard Morriss has received fees for presenting at educational meetings from Lilly and AstraZeneca pharmaceuticals, and MRC funding for research into psychological treatments. Robert Peveler has received fees for presenting at educational meetings and/or consultancy from Lilly, GlaxoSmithKline, Pfizer, Lundbeck, Wyeth, AstraZeneca, Bristol Myers Squibb, Servier and Organon pharmaceuticals. Richard Byng has received fees for speaking at an educational meeting from Lilly pharmaceuticals and has written about the limited value of antidepressants. Paul McCrone has received fees for speaking at educational meetings and/or consultancy from Lilly, Lundbeck, Organon, Servier and Janssen-Cilag pharmaceuticals. Tirril Harris and George Brown have published articles on the importance of social factors in determining the course and outcome of depression. The remaining authors have declared no competing interests.

Copyright statement

© 2009 Queen’s Printer and Controller of HMSO. This monograph may be freely reproduced for the purposes of private research and study and may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NETSCC, Health Technology Assessment, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

2009 Queen’s Printer and Controller of HMSO

The increasing use of antidepressants in general practice

Antidepressant prescribing rates in the UK have been rising year on year since the early 1990s. This is costly and may not be appropriate. Expenditure on antidepressants in England rose from £147 million to £279 million between 1995 and 1998, with the bulk of the increase being due to increased prescribing in general practice. 1 Prescribing of antidepressants has continued to increase annually since the turn of the century. The National Health Service (NHS) Prescription Pricing Authority reported a 36% increase between 2000 and 2005, to 7.3 million items, costing £91 million, in the quarter to June 2005 (www.nhsbsa.nhs.uk/PrescriptionServices/Documents/PrescriptionServices/imPACTjan2006.pdf). Prescription numbers have continued to rise since then, to more than 9.6 million items in the last quarter of 2007 (Alison Bowes, Prescription Analysis Service, NHSBSA Prescription Pricing Division, personal communication).

The Defeat Depression Campaign, mounted by the Royal Colleges of Psychiatrists and General Practitioners in the 1990s, was a promotional campaign designed specifically to increase both doctor and patient awareness of depressive disorders. 2 The message has been caricatured as ‘see more, treat more’3 and was probably part of the reason for the increase in antidepressant prescribing in general practice starting in the early 1990s. Another likely reason was the introduction of the selective serotonin reuptake inhibitors (SSRIs), starting with fluoxetine in 1990, as they were perceived to be better tolerated by patients than the older tricyclic antidepressants. 4 However, much of this increased prescribing probably falls outside current guideline recommendations and may not be appropriate. This is because antidepressants are frequently being prescribed for relatively mild depression, for which they are not recommended in the guidelines. Guidelines recommend drug treatment only for ‘major depression’ of a minimum level of severity.

Depression and its classification

Depressive symptoms range along a continuous spectrum from everyday sadness to suicidal ideas, and any cut-off between ‘normal’ and ‘depressed’ patients is, to an extent, arbitrary, but categorical classifications are necessary in order to make decisions about intervening in clinical practice. Depression is classified in two ways: categorically, in descriptive diagnostic classification systems; and dimensionally, in terms of scores on continuous self-rating questionnaire measures.

The threshold for drug treatment

In common with other depression guidelines, the UK’s National Institute for Health and Clinical Excellence (NICE) clinical guidelines for the management of depression recommend antidepressant medication as first-line treatment for depression in primary care only for major depression, with at least five of the symptoms as listed above, and of at least moderate severity in terms of impairment of functioning. 5,11 The NICE guidelines recommend that antidepressants should not normally be prescribed for mild depression, which is defined in terms of a maximum of four symptoms, although it should not be ignored, but should be monitored for a period of 2 weeks or more (‘watchful waiting’), in case the patient goes on to develop more severe symptoms. 11 During this period, a variety of self-help measures are recommended, including advice on sleep hygiene and anxiety management, regular exercise, and the provision of books (‘bibliotherapy’) or interactive computer programs based on the principles of cognitive–behavioural therapy (computerised CBT),15 which encourage patients to identify and tackle their depressive thoughts, and to become more active.

Despite the guideline recommendations, however, antidepressants are frequently prescribed for depressive symptoms below the threshold for major depression, perhaps as a result of the perceived pressure to treat more patients, in the context of a severe lack of availability of alternative treatments, particularly psychological therapies. 16–18 Another reason is that the recommendations on the threshold for treatment are not supported by a great deal of good research evidence. Previous research on antidepressant treatment has mostly been carried out in secondary, specialist care settings, with patients with relatively severe depression, and there has been comparatively little research in primary care on patients with mild depression to guide GPs on the threshold at which antidepressants should be offered.

Predictors of response to treatment

The need for a new study

A new study was needed for several reasons. First, we considered that the findings from the US that SSRIs may benefit some patients with ‘minor’ depression or dysthymia25 might not generalise to primary care in the UK, as the type of supportive care usually provided in the UK may differ in quality or quantity from the ‘watchful waiting’ provided in the US study.

Second, we considered that, even if SSRI treatment is efficacious compared with placebo in mild depression, its effectiveness and cost-effectiveness in practice need to be established. All the studies referred to above were placebo-controlled studies aimed at determining the efficacy of antidepressants. To establish effectiveness and cost-effectiveness, a pragmatic open-label trial is necessary, comparing active drug treatment plus supportive care with supportive care without prescription of a drug, as opposed to a placebo-controlled trial, as placebos are not used in practice and cannot be costed as part of usual health care. Cost-effectiveness also needed to be established within the UK health-care system, which is quite different from the US system. For example, GPs in the UK act as gatekeepers to secondary care, whereas in the US patients commonly self-refer to specialists.

Third, another issue that needed to be addressed was whether predictors of response to antidepressant treatment could be identified, to help GPs decide which patients should be offered such treatment. Important predictors to include were sociodemographic factors, the presence of recent adverse life events and ongoing life difficulties, the duration of depression, previous depression and previous experience of using antidepressants, the presence of somatic symptoms, symptom attribution to a physical cause rather than a psychological cause and level of alcohol use.

Our research questions were, therefore:

1. Is treatment with an SSRI plus supportive care more effective and cost-effective than supportive care alone?

2. If it is more effective, does this apply across the whole range of severity of symptoms of mild to moderate depression?

3. What patient factors might predict the need for antidepressant treatment and a beneficial response?

To answer these questions, we designed a randomised controlled trial of SSRI treatment plus supportive care versus supportive care alone, measuring a number of possible predictors of response.

Objectives and hypothesis

The research objectives were:

1. To determine the clinical effectiveness and cost-effectiveness of SSRI treatment plus supportive care versus supportive care alone, for mild to moderate depression in patients with somatic symptoms in primary care. Our first hypothesis was that SSRI treatment plus supportive care would be more effective and cost-effective than supportive care alone.

2. To determine the impact of the initial severity of depression on the effectiveness and relative costs of these two approaches. Our second hypothesis was that SSRI treatment plus supportive care would be relatively more effective and cost-effective than supportive care alone among patients scoring 16–19 on the HDRS, compared with those scoring 12–15.

3. To carry out exploratory analyses of the impact of the following factors on the effectiveness of these two approaches:

   1. demographic and social variables including age, gender, and employment status

   2. life events and difficulties

   3. the patient’s self-reported duration of depressive symptoms

   4. the patient’s previous experience of antidepressant use

   5. the number of physical symptoms

   6. the patient’s self-rating of the cause of his or her illness (physical versus psychological)

   7. alcohol consumption.

Trial design

The study design was a randomised controlled trial comparing treatment by means of an SSRI plus GP supportive care with GP supportive care alone, over 26 weeks of follow-up. The aim was to establish the clinical effectiveness and cost-effectiveness of SSRI antidepressants prescribed by the GP over and above supportive care (defined below) in normal clinical practice conditions.

Setting

Patients were recruited in general practice surgeries around three academic centres: the University of Southampton; the University of Liverpool; and the Institute of Psychiatry, King’s College London.

Ethical approval and Primary Care Trust Research Management and Governance approval

Ethical approval was awarded by the West Midlands Multi-Centre Research Committee (MREC): reference number 02/7/091. Research Management and Governance approval was obtained from 57 primary care trusts (PCTs) during the course of the study: 21 around Southampton, 27 around Liverpool and nine around London.

Practice and general practitioner recruitment

Initially, practices in each centre known to the research teams from previous research studies were approached and asked to take part. However, only a small proportion of practices approached were willing to participate. It soon became apparent, therefore, that referrals from these practices would be insufficient to meet the required target, so all practices in neighbouring PCTs were systematically approached with a letter which had been previously approved by the MREC (see Appendix 1). This was then followed up with a telephone call to the practice manager to ascertain any interest in participating among the GPs within each practice. Where the response was positive, one or more members of the research team (including one of the medical team members where possible) arranged to visit the practice to explain the study in detail and to answer questions about it. Interested GPs were informed verbally and in writing of the patient inclusion and exclusion criteria (see Appendix 2), how to refer patients into the study, the consent procedure involving both the GPs and the researchers, the randomisation procedure and the details of interventions to be offered in each arm of the trial.

No financial incentive was offered to the GPs for taking part but they were advised that they would be reimbursed for their involvement at the rate of £49 per patient referred to the study. This money was provided through the ad hoc NHS Research and Development (R&D) funding arrangement for service support costs, and was calculated to cover the cost of an extra hour of GP time for referring and monitoring study patients, based on the prevailing cost of employing locum tenens doctors at the rate of £45 per hour, plus 20 minutes of clerical time based on the prevailing average rate of £12 per hour.

Over the 41 months during which patients were recruited, various strategies were adopted to keep the study in the GPs’ minds when seeing potential participants in their surgeries. They included sending emails about the study approximately once a month; visiting them face to face whenever possible and appropriate; sending quarterly study newsletters by both post and email; sending Christmas cards; delivering desktop reminders in the form of THREAD-branded computer screen stickers (furry worms) and notepads; and sending letters at intervals, pointing out items on depression in the popular or medical press. The researchers also attempted to make contact with the GPs when visiting the surgery to collect medical record data after participating patients had completed the study, and took the opportunity to request further referrals.

Clinical support officers of the Mental Health Research Network were also helpful in contacting practices to promote the study, particularly in the London and Liverpool centres.

Patient recruitment

Patient consent

The task of referral of patients into the study was kept as simple as possible for the participating GPs, who were asked only to give a brief verbal explanation of the study to eligible patients and to obtain their consent for the research team to contact them. In the original proposal, only verbal consent was envisaged, but early in the course of the study, in July 2004, it was decided to change this to written consent, as some of the referring GPs were not happy to pass on patient details without such consent. The change was approved by the MREC and a form (see Appendix 3) was provided to the GPs to use for this purpose. The form was sent by fax to the research team, who then contacted the patient to arrange a visit to explain in detail what the study involved, prior to obtaining informed consent to take part. The patient was given a study information sheet (see Appendix 4) by the referring GP to read before the first visit from the researcher, which was usually within a few days of referral into the study, at which point the researcher dealt with any questions the patient had about the study. The patient was then given a further week to consider whether or not they wanted to take part and if they were happy to do so, the researcher returned to obtain written consent (see Appendix 5), before establishing the patient’s eligibility for the study and conducting the baseline assessment. This procedure, involving two researcher visits to obtain consent, was stipulated by the MREC, in order to give potential participants at least a week to consider joining the study.

In the original design, referred patients were given only two choices when asked for their written consent to participate: ‘yes’ or ‘no’. However, it was apparent early in the study that some patients remained undecided about taking part despite having had more than a week to consider it. Under the terms of the original protocol they were forced to make a decision at that point, and the default for those still undecided was to decline. As a relatively large number of possible participants who accepted referral to the study subsequently declined to take part at the point of obtaining written consent (see Chapter 4), it was decided, in July 2004, to give them a third option in order not to lose those who needed longer to decide whether or not to take part. In addition to an immediate ‘yes’ or ‘no’, they were offered a third option of ‘undecided’ which, it was explained, meant that they could be approached again 4 weeks later to reconsider participation. This change was approved by the MREC (see Appendix 6).

Piloting of partial patient preference design

Another strategy designed to tackle the issue of the large number of potential participants referred to the study who subsequently declined to take part was suggested by the Chair of the Data Monitoring and Ethics Committee (DMEC), Professor Michael King. He pointed out that a considerable number of patients declared that the reason they declined was because they could not accept possible randomisation to antidepressant drug treatment. He suggested adding a third, patient preference arm, in which patients could take part but have the treatment of their choice. Early in the course of the study, in December 2004, approval was gained from both the sponsor and the MREC to pilot a partial preference design. This was piloted in two of the three centres (Southampton and Liverpool) between January and April 2005. At the end of the pilot, the results were reviewed by the Study Group and Trial Steering Committee (TSC), and it was agreed not to change over to a partial preference design, as it was apparent that, while the total number of patients referred into the study did not increase significantly during the pilot, some patients who would have been prepared to be randomised had the choice of treatment not been offered, were deciding to enter the preference arm instead. So, although more patients in total could have been enrolled into the study by including a preference arm, this would have been at the expense of reduced numbers in the two randomised arms. The results of the partial preference pilot are shown in Chapter 4.

Randomisation and concealment of allocation

Block randomisation with random block sizes, stratified by severity subgroup (HDRS scores 12–15 and 16–19 respectively) and by recruiting centre, was carried out independently of the research team by the Institute of Psychiatry Mental Health and Neuroscience Clinical Trials Unit. Following completion of the baseline assessment, if the patient was eligible for randomisation, the researcher faxed the patient’s details to the study co-ordinator, who either emailed or telephoned the remote randomisation service. The study co-ordinator then faxed the allocation details to the GP (see Appendix 7) and informed the patient by telephone. If the patient was unsuitable, the GP received a fax explaining why the patient was not able to be entered into the study (see Appendix 8). The researcher who had visited and carried out the baseline assessment, therefore, remained blind to the treatment allocation. Wherever possible, the researchers were kept blind to the treatment arm while carrying out the follow-up interviews. Participating patients were asked, when contacted prior to the follow-up interviews, not to reveal whether or not they had been prescribed antidepressants. All instances where researchers became aware of the patient’s allocation to treatment arm were recorded.

Interventions

Patient assessments

The baseline assessment took place immediately after consent was obtained from the patient and follow-up interviews were carried out as close as possible to dates 12 and 26 weeks after randomisation. After 26 weeks, whether or not the patient had been assessed in follow-up interviews as planned, the researcher visited the patient’s practice and extracted data from their medical records, on health service contacts (including practice, community, and hospital contacts with GPs, nurses, hospital staff and community mental health professionals) and treatments received, including numbers of antidepressants prescribed. Figure 1 shows the flow of patients through the study.

FIGURE 1.

Flow of patients through the study.

Outcome measures

Potential predictors

Data entry

The data arising from each baseline or follow-up interview were entered by each of the researchers as the study proceeded. A proportion of the data was double entered by the study co-ordinator JC (12 baseline interviews, ten 12-week interviews and ten 26-week interviews). Comparison of the two sets of data for these interviews confirmed the accuracy of the researchers’ data entry. Table 1 summarises the measures that were used at each point.

Sample size calculation

The sample size calculation was based on a planned analysis of the HDRS score as the primary outcome for two severity subgroups, corresponding to mild and moderate depression (with HDRS scores of 12–15 and 16–19 respectively). Hollyman et al. 73 found the standard deviation (SD) of the HDRS to be around 3.5, and reported roughly similar numbers of patients in these two severity ranges. We assumed this SD, equal numbers in the two subgroups and a pre–post correlation of 0.5.

Using analysis of covariance controlling for baseline values, we calculated that 49 patients at follow-up in each treatment/severity combination would allow the following effects to be detected at a significance level of 0.05 (standard effect sizes in brackets): an overall average difference in HDRS scores between the two treatment arms of 1.4 (0.4) with 90% power; an interaction (difference between effects in the two severity subgroups) of 2.5 (0.7) with 80% power; and a difference between treatment arms within the more severe group of 2.0 (0.6) with 90% power. The last two calculations were conservative (tending to underestimate the power) because we considered that the SDs could turn out to be lower within the severity subgroups. A difference of 1.4 on the HDRS is relatively small (SD 0.4) and any difference smaller than this we regarded as clinically insignificant. In the trial of amitriptyline by Hollyman et al. 73 the HDRS scores fell by a mean of around 10 points in the mildly depressed group and around 13 in the more severely affected group. Therefore, we calculated that the sample size should be sufficient to detect clinically significant differences.

We therefore needed to follow up 196 patients to detect these differences (98 in each of the two arms). To allow for up to 25% loss to follow-up at 12 weeks, we calculated that 261 (87 at each of the three sites) would be needed. The agreed initial aim was to recruit even more than that number, 300 patients in all, aiming for 100 at each recruitment site (Southampton, Liverpool and London).

Statistical analysis

The primary analysis was by intention to treat (all available data analysed in the groups as randomised) using double-sided significance tests. We used analysis of covariance, controlling for baseline value and recruitment site, to estimate the overall treatment effectiveness (difference between arms in HDRS score) at both follow-ups separately (with 12-week outcome as the primary outcome). Longitudinal analysis, in which 12-week and 26-week outcomes were modelled simultaneously, was also performed. Time point, and time point × treatment interaction effects were tested in these models. Baseline predictors of a lack of follow-up data (‘missingness’) at either follow-up were investigated by means of logistic regression, and the models of predictors of 12- and 26-week outcomes were refitted including these variables. In all models, the patient’s GP was included as a random effect and, as a sensitivity analysis, the overall (longitudinal model) was also fitted including GP practice as an alternative random effect. The interaction between severity subgroup and treatment was also tested, and further exploratory analyses assessed the impact of other potential predictors.

The main aim of the economic analysis was to compare the two treatment groups in terms of mean costs and cost-effectiveness. A secondary aim was to examine differences between the subgroups defined by severity, if differences in effectiveness were found for the severity subgroups. Given that cost data are frequently skewed, which can cause a violation of the assumptions of standard significance tests, bootstrapped estimates (multiple resampling within treatment arms) were planned, so that mean costs could still be compared while imposing no prior assumptions regarding the data distribution.

Cost-effectiveness was expressed in terms of incremental cost-effectiveness ratios (ICERs) and cost–utility ratios. In addition, cost-effectiveness acceptability curves (CEACs) were generated, synthesising data on costs and outcomes, for varying levels of acceptability of costs.

Recruitment of practices and GPs

Prior to commencement of the study, NHS R&D approval was sought from those PCTs closest to the study centres and most accessible for the research teams. Very early on in the process of recruitment, it became apparent that progress was going to prove challenging, and therefore it was essential to recruit new practices further afield. A rolling plan of seeking NHS R&D approval from additional PCTs was therefore introduced across all three centres, and throughout 2004, 2005 and 2006 the team wrote to successive groups of GPs, in practices progressively further away from the centres, asking for their interest in participating.

Table 2 shows that, around the three centres, 6015 GPs in1787 practices were approached, and 576 GPs (9.6% of those approached) were inducted into the study from 212 (11.8%) of the practices approached. It should be noted that the number of GPs agreeing to participate is an approximation. If a practice agreed to participate, and all the GPs were present when the research team visited to discuss the study, it was assumed that they were all interested in taking part but it was not possible to be certain that all doctors within any one practice had, in fact, agreed.

The Royal College of General Practitioners (RCGP)74 estimated that there were 8451 practices in England in 2006, which means that during the course of the study approximately one in five of all practices in England were approached from the three centres.

Tables 3–5 show the number of GPs, by PCT, who were approached to assess their interest. Table 3 shows that agreement to take part was secured from 10% of the GPs approached from 18.5% of the practices in PCTs around the Southampton centre. Table 4 shows that the corresponding figures for the London centre were 10.9% of GPs from 8.9% of practices approached. Table 5 shows that the figures for the Liverpool centre were 8.6% of GPs from 9.5% of practices approached.

Table 6 shows that, compared with the RCGP figures for England as a whole, the participating GPs were broadly representative in terms of gender and whether they were part time or full time. However, the study practices were larger on average than practices in England generally.

Table 7 shows the range of locations of participating practices by recruitment centre. In 30 cases (14%) no information was received from the practice manager or GPs about practice location.

Table 8 shows the number of practices and GPs who referred patients into the study by centre and the number of practices and GPs who had patients randomised into the study. Overall, only around half of the practices agreeing to participate actually referred patients into the study. Of those practices who did refer patients, only 37% overall had patients randomised into the study. The lowest ratio of randomised patients to referred patients was found in Liverpool. Reasons for this are considered in Recruitment of patients, below.

The mean and range of referrals per practice was 5.23 (1–32) and the mean and range of patients randomised was 2.68 (1–15).

Recruitment of patients

During the recruitment phase of the study, between December 2003 and May 2007 (42 months), 602 patients in total were referred to the study team across the three centres. However, only 220 of these were actually randomised into the study. Table 9 shows the reasons why the remaining 382 patients were either excluded or declined to participate having had the study explained to them in more detail.

Table 9 shows that more patients declined to take part in Liverpool, which was due mainly to a greater proportion having a strong preference against taking antidepressants (18%, versus 10% in Southampton and 10% in London), as well as a greater proportion declining to participate but giving no reason for their decision (7%, versus 3% in Southampton and 1% in London). Discussion with the Liverpool team about the reasons for this identified as a possible factor the apparently much greater availability of counselling in Liverpool than in London and Southampton. It seemed likely that patients in Liverpool had more options for treatment besides drug treatment and more support from the GP, because the waiting list for counselling was only a matter of days, compared with months in London and Southampton.

Follow-up assessments

The first follow-up assessments were scheduled for as close as possible to 12 weeks (84 days) after the baseline assessment and the second for as close as possible to 26 weeks (182 days). Table 15 shows the range of timing of the follow-up assessments.

The follow-up rates for each of the time points remained consistent throughout the study. Figure 2 shows that a total of 186 patients were interviewed at the 12-week follow-up and 167 at the 26-week follow-up. Table 16 shows the follow-up rates for each of the three recruiting centres.

FIGURE 2.

CONSORT diagram. * 84.5% follow-up at 12 weeks; † 75.9% follow-up at 26 weeks.

Patients were encouraged to make appointments for the next follow-up assessment by the researchers at the baseline or 12-week interview, but this was not always possible. If they did, letters were sent out 2 weeks prior to the appointment to remind them and the researcher would carry out the visit as planned. Sometimes the patient did not attend, in which case repeated attempts were made, if necessary, to contact the patient by means of telephone calls and letters to reschedule the follow-up visit. If no contact was made within 4 weeks, it was considered inappropriate to continue to pursue the patient at that time point, but patients unobtainable at 12 weeks were contacted again when the 26-week time point was reached. Figure 2 shows that in five cases it was possible to collect data at the 26-week time point for patients who had not been followed-up at the 12-week time point.

Figure 2 also shows that there was a slight difference in rate of follow-up between the SSRI plus supportive care group and the supportive care alone group at the 12-week follow-up point (86% versus 83%), which became greater at the 26-week follow-up (80% versus 71%).

Inter-rater reliability

The inter-rater reliability of the HDRS ratings was assessed at 3 months, as described in Chapter 2, and again at four points during the 47 months of recruitment and follow-up: at 14, 17, 32 and 39 months (October 2004, January 2005, April 2006 and November 2006). Data from all possible pairs of the four raters were obtained in each of the four inter-rater reliability sessions. Within a session, each researcher took the role of primary rater (having taped the interview) an equal number of times, and everyone re-rated each other’s tapes, so that raters and modes of rating were balanced within sessions. Each patient provided two sets of ratings, apart from one, who was assessed by two pairs of raters. A total of 84 ratings from 10 different pairs of raters for 42 patients were available. The patients included in the inter-rater reliability exercise had a mean age of 43.7 years (SD 17.1, range 18–78); 31 (87%) were female; and patients had a mean total score on the 17-item HDRS of 14.9 (SD 4.8, range 5–27). Sixty-six per cent of the total HDRS scores were in the 12–19 range used for inclusion in the THREAD study.

For individual items, the distribution of scores for the primary rater was examined, and overall percentage agreement and both weighted and unweighted kappa statistics were calculated. Weights were lower for disagreements that were further apart (Table 18).

Most weighted kappa coefficients were above 0.6, indicating good agreement; the items for depressed mood and suicidal tendencies were just below this level. The kappa for hypochondriasis was relatively low, but this item had a very skewed distribution, with only 7% having a positive rating. Insight appeared to be the most difficult to rate, with a weighted kappa of only 0.3 and overall agreement of 76%.

Table 19 shows the inter-rater agreement for the total scores in each of the four sessions and overall. Total scores were pro-rated from 15 items to the equivalent of 17 items because items 8 and 9, retardation and agitation, were visually assessed and could not be rated from the audiotapes. Both intraclass correlations (and concordance coefficients, which are not shown as they were almost identical) showed very good agreement in all sessions. The overall estimate of the measurement variance was 1.55 (standard error 0.75), equivalent to a measurement error for an individual score of 1.25. The measurement error decreased in session 3 but the patient-level variance also decreased, thus resulting in a slightly lower reliability coefficient. However, this difference was not statistically significant. There was no evidence of systematic bias, with one rater tending to score higher or lower than the others (based on a regression with raters as fixed effects), or bias between the primary ratings and the corresponding secondary ratings, based on audiotapes (using paired t-tests).

Figure 3 shows the difference between a pair of raters in total HDRS score plotted against the level of severity of depression as reflected in the average HDRS score; there is no evidence of variation in measurement error with severity.

FIGURE 3.

Difference in HDRS scores between two raters on the same individuals plotted against their mean score.

The reference range (–3.31 to 3.69) shows where 95% of the points lie; only one point is outside these limits. The proportion who would have been assigned to a different severity subgroup depending on the rater was 2/42 (5%).

Descriptive data

As described above, a total of 602 patients were referred into the study by 177 GPs from 115 practices. Of these, 172 (29%) were excluded and 210 (35%) declined to participate, so 220 patients were randomised: 112 to SSRI plus supportive care and 108 to supportive care alone. In the sample analysed at follow-up, there were 186 patients from 103 GPs (average 1.8 patients per GP, range 1–8) at 12 weeks and 167 patients from 96 GPs (average 1.7 patients per GP, range 1–7) at 26 weeks. For the primary outcome (HDRS), 162 patients had both 12- and 26-week data; 29 had neither follow-up, 24 had only the 12-week follow-up; and five had only the 26-week follow-up. Intraclass correlations by GP (after controlling for arm, centre and baseline value) were 0 and 0.012 at 12 and 26 weeks respectively.

Primary outcome

HDRS scores at 12 weeks

Table 23 and Figure 4 show the baseline and 12-week HDRS scores by treatment arm and severity subgroup. It can be seen that the mean HDRS score fell on average in all four groups, but that in each of the two severity subgroups the fall was greater in the SSRI plus supportive care arm.

TABLE 23 - Baseline and 12-week HDRS scores by treatment arm and severity subgroup

	Severity subgroup	Supportive care alone		SSRI plus supportive care
		Number of missing values	Mean (SD)	Number of missing values	Mean (SD)
HDRS at baseline	Mild (12–15)	–	13.34 (1.12)	–	13.54 (1.11)
	Moderate (16–19)	–	17.71 (1.15)	–	17.10 (1.01)
	Overall	–	15.68 (2.46)	–	15.45 (2.09)
HDRS at 12-weeks	Mild (12–15)	9	9.15 (4.95)	9	7.30 (5.05)
	Moderate (16–19)	9	12.96 (5.90)	7	9.89 (5.07)
	Overall	18	11.22 (5.78)	16	8.73 (5.2)
HDRS change from baseline	Mild (12–15)	9	4.32 (4.79)	9	6.28 (5.08)
	Moderate (16–19)	9	4.73 (5.67)	7	7.25 (4.78)
	Overall	18	4.54 (5.26)	16	6.81 (4.91)

FIGURE 4.

Mean values for HDRS scores by treatment arm and severity subgroup (bars around mean values are standard errors).

Figure 4 expresses graphically the results shown in Table 23, showing that the difference between trial arms persisted for both subgroups, although attenuated slightly, at the 26-week follow-up.

The box plots in Figure 5 show the variability in the HDRS scores at both follow-up points. The relatively low variability at baseline resulted from the specified inclusion criterion of an HDRS score of 12–19. The plots show that, in terms of their HDRS scores, most patients were better at follow-up but the variability in scores increased and some patients had worse scores at follow-up.

FIGURE 5.

Box plots of HDRS scores at each time point for the two trial arms.

Numbers of patients achieving remission or significant improvement on the HDRS

Table 24 shows the numbers of patients achieving remission (a reduction to an HDRS score of less than 8) and the numbers achieving clinically important improvement (a 50% reduction in HDRS score from the baseline value) at the 12- and 26-week follow-up points.

TABLE 24 - Number of patients achieving remission or significant improvement on the HDRS at 12 and 26 weeks, including breakdown by severity subgroup

		12 weeks		26 weeks
		Remission to < 8 [n (%)]	Reduction by 50% [n (%)]	Remission to < 8 [n (%)]	Reduction by 50% [n (%)]
Total sample	Supportive care alone	22 (24)	26 (29)	28 (36)	28 (36)
	SSRI plus supportive care	40 (42)	42 (44)	49 (54)	53 (59)
Mild subgroup (HDRS 12–15)	Supportive care alone	15 (37)	14 (34)	16 (47)	14 (41)
	SSRI plus supportive care	21 (49)	20 (47)	24 (59)	23 (56)
Moderate subgroup (HDRS 16–19)	Supportive care alone	7 (14)	12 (24)	12 (28)	14 (33)
	SSRI plus supportive care	19 (36)	22 (42)	25 (51)	30 (61)

At 12 weeks, 22 patients in the supportive care alone arm (24.4% of those followed up) had HDRS scores below 8, compared with 40 (41.7%) in the SSRI plus supportive care arm. The absolute risk reduction (ARR) was therefore 17.2% and the number needed to treat (NNT) to achieve one remission at 12 weeks was 6 (95% CI 4 to 26). At 26 weeks, the corresponding numbers in remission were 28 (36.4%) and 49 (54.4%) respectively, so the ARR was 18.1% and the NNT to achieve one remission at 26 weeks was also 6 (95% CI 3 to 31). At 12 weeks, 26 patients (28.9%) in the supportive care alone arm had a 50% or greater fall in HDRS score from baseline, compared with 42 (43.8%) in the SSRI plus supportive care arm. The ARR was therefore 14.9% and the NNT to achieve improvement in one patient at 12 weeks was 7 (95% CI 4 to 83). At 26 weeks, the corresponding rates of improvement were 28 (36.4%) and 53 (58.9%) respectively, so the ARR was 22.5% and the NNT to achieve improvement in one patient was 5 (95% CI 3 to 13).

Regression analyses for HDRS scores

Table 25 shows the results of the analysis of covariance for the primary outcome, the HDRS score at 12 weeks, including treatment arm, HDRS baseline score and recruitment centre, with the patient’s GP fitted as a random effect. Treatment arm coefficients are for intervention versus control.

TABLE 25 - HDRS scores at 12 weeks: analysis of covariance

Variable	Coefficient	95% CI	p-value
Treatment arm	–2.293	–3.741 to –0.845	0.002
Baseline HDRS score	0.874	0.544 to 1.204	< 0.001
London vs Southampton	1.211	–0.658 to 3.080	0.204
Liverpool vs Southampton	1.287	–0.524 to 3.098	0.164

This shows a statistically significant difference between the treatment arms in HDRS depression scores after 12 weeks, after adjustment for baseline HDRS score, recruitment centre and clustering by GP. It also shows that baseline HDRS score was a statistically significant independent predictor of 12-week HDRS score. The differences between the arms for the two severity groups when analysed separately were –1.919 (95% CI –3.962 to 0.124) and –2.149 (95% CI –4.229 to –0.069) for the mild and moderate subgroups respectively. The interaction term (difference in treatment effect) for a 4-point increase in baseline severity was 1.10 (95% CI –3.73 to 1.54, p = 0.414) and the significance of the interaction with baseline severity as a continuous variable was p = 0.773, i.e. there was no evidence for a differential effect between the severity subgroups with respect to the differences between arms in HDRS scores.

Table 26 shows that the statistically significant differences in HDRS depression scores at 12 weeks between treatment arms remained after adjustment for the missingness predictors of age and employment status, along with baseline HDRS score, recruitment centre and GP. Once again, the interaction between arm and severity subgroup was not significant (p = 0.667).

TABLE 26 - HDRS score at 12 weeks: analysis of covariance, including missingness predictors

Variable	Coefficient	95% CI	p-value
Treatment arm	–2.091	–3.544 to –0.638	0.005
Baseline HDRS score	0.858	0.520 to 1.196	< 0.001
London vs Southampton	0.939	–0.935 to 2.814	0.326
Liverpool vs Southampton	1.018	–0.815 to 2.851	0.276
Age at randomisation	0.001	–0.051 to 0.054	0.962
Employment status (unemployed vs employed)	1.563	0.013 to 3.113	0.048

Table 27 shows the baseline and 26-week HDRS scores by treatment arm and severity subgroup. Table 28 shows the results of the analysis of covariance for the HDRS score at 26 weeks, including treatment arm, HDRS baseline score and recruitment centre, with the patient’s GP fitted as a random effect.

TABLE 27 - Baseline and 26-week HDRS scores by treatment arm and severity subgroup

	Severity subgroup	Supportive care alonew		SSRI plus supportive care
		Number of missing values	Mean (SD)	Number of missing values	Mean (SD)
HDRS at baseline	Mild (12–15)	–	13.34 (1.12)	–	13.54 (1.11)
	Moderate (16–19)	–	17.71 (1.15)	–	17.12 (1.04)
	Overall	–	15.68 (2.46)	–	15.45 (2.09)
HDRS at 26 weeks	Mild (12–15)	16	7.56 (4.01)	11	6.83 (5.02)
	Moderate (16–19)	15	11.44 (6.06)	11	8.84 (6.05)
	Overall	31	9.73 (5.57)	22	7.92 (5.67)
HDRS change from baseline	Mild (12–15)	16	5.71 (4.29)	11	6.73 (5.22)
	Moderate (16–19)	15	6.19 (5.97)	11	8.27 (5.92)
	Overall	31	5.97 (5.27)	22	7.57 (5.64)

Table 28 shows that the difference between the treatment arms in changes in the HDRS depression scores after 26 weeks was of borderline statistical significance in this analysis, after adjustment for the other variables. The interaction term, for a 4-point increase in baseline severity, was –1.54 (95% CI –4.18 to 1.35, p = 0.297) and the significance of the interaction with baseline severity as a continuous variable was p = 0.283, indicating that there was no evidence for a differential effect between the severity subgroups with respect to the changes in HDRS scores.

TABLE 28 - HDRS scores at 26 weeks: analysis of covariance

Variable	Coefficient	95% CI	p-value
Treatment arm	–1.688	–3.326 to –0.049	0.043
Baseline HDRS score	0.606	0.238 to 0.974	0.001
London vs Southampton	1.157	–1.273 to 3.587	0.351
Liverpool vs Southampton	0.651	–1.465 to 2.766	0.547

The additional missingness predictors (age at randomisation and employment status) were included in the results shown in Table 29. Again, the difference between the treatment arms in changes in HDRS depression scores after 26 weeks was of borderline statistical significance after adjustment for the missingness predictors of age and employment status, along with the baseline HDRS score, recruitment centre and referring GP. The interaction between arm and severity subgroup was not significant (p = 0.181).

TABLE 29 - HDRS score at 26 weeks: analysis of covariance, including missingness predictors

Variable	Coefficient	95% CI	p-value
Treatment arm	–1.336	–2.951 to 0.278	0.105
Baseline HDRS score	0.620	0.251 to 0.990	0.001
London vs Southampton	0.839	–1.486 to 3.165	0.479
Liverpool vs Southampton	0.110	–1.958 to 2.179	0.917
Age at randomisation	0.024	–0.033 to 0.081	0.413
Employment status (unemployed vs employed)	2.594	0.865 to 4.322	0.003

Longitudinal analysis of HDRS scores at 12 and 26 weeks

Maximum likelihood mixed-effects models were used for the longitudinal analyses, with GP and subject as random effects, and time as a covariate, coded as 1 for 12 weeks and 2 for 26 weeks. The ‘time’ coefficient, therefore, represents the drop in score over 14 weeks, averaged over both treatment arms. Tables 30 and 31 show the results of the longitudinal analysis of HDRS scores at 12 and 26 weeks, excluding and including factors associated with missing status at either time point. Interaction between treatment arm and time was also included in the longitudinal models to test for any evidence for a drop-off or increase in effect over time. Although there was an overall reduction in HDRS scores over time, there was no evidence for a time × treatment interaction (p = 0.574). Severity by arm interaction was assessed using the baseline HDRS score as a continuous variable and, as with the separate time point analyses presented above, was found not to be significant (p = 0.219).

TABLE 30 - Longitudinal analysis of HDRS scores at 12 and 26 weeks

Variable	Coefficient	95% CI	p-value
Treatment arm	–2.145	–3.516 to –0.774	0.002
Baseline HDRS score	0.760	0.449 to 1.072	< 0.001
London vs Southampton	1.115	–0.668 to 2.899	0.220
Liverpool vs Southampton	0.878	–0.839 to 2.594	0.316
Time	–1.129	–1.794 to –0.464	0.001

TABLE 31 - Longitudinal analysis of HDRS scores at 12 and 26 weeks, including missingness predictors

Variable	Coefficient	95% CI	p-value
Treatment arm	–1.866	–3.224 to –0.508	0.007
Baseline HDRS score	0.754	0.440 to 1.068	< 0.001
London vs Southampton	0.785	–0.980 to 2.549	0.383
Liverpool vs Southampton	0.471	–1.246 to 2.188	0.591
Time	–1.126	–1.795 to –0.457	0.001
Age at randomisation	0.014	–0.034 to 0.063	0.562
Employment status (unemployed vs employed)	–2.172	–3.621 to –0.722	0.003

The model shown in Table 31 includes the variables which were found to predict missingness. These analyses show that there is a highly significant effect of treatment arm over time when the outcomes at both 12 and 26 weeks are included. Once again, the severity by arm interaction was assessed and found not to be significant (p = 0.378). This time × treatment interaction was also tested using the baseline HDRS score as a continuous variable and was found not to be significant (p = 0.239).

Once again, HDRS scores at follow-up are significantly associated with baseline HDRS scores. In addition, employment status is a highly significant predictor of outcome, and the coefficient shows that the effect size is very similar to that of treatment status (with higher scores at follow-up among patients who were unemployed at baseline).

The results from Table 31 are also illustrated in Figure 6, which gives predicted HDRS over time by treatment arm, adjusting for the other variables in the model. For illustration, the reference baseline HDRS score has been set at 15.6, centre to Southampton, age to 40 and employment status to being currently employed.

FIGURE 6.

Estimated mean difference in HDRS scores between treatment arms (longitudinal analysis of HDRS scores at 12 and 26 weeks, including missingness predictors). Bars around estimates give the standard errors. See Table 31 for model.

Secondary outcomes

Exploratory analysis of predictor variables

Process of care

Service use

Service use during the 6-month periods leading up to the baseline assessment and 26-week follow-up was measured with an adapted version of the CSRI. Services included those provided in the primary care setting (face-to-face GP consultations, GP telephone contacts, practice nurse contacts), secondary care services (inpatient, outpatient, day patient, accident and emergency), community health services (e.g. health visitors, district nurses, counselling or psychological therapists) and social care services (e.g. social workers, housing workers). The CSRI asked patients to state whether they had used specific services, how many contacts they had received and – where relevant – the average duration of service contact (i.e. across all contacts the individual made with each service). Informal care provided by family members and friends was recorded, by asking patients how much extra help (measured in hours per week) they had received specifically because of their health problems. This time was broken down into personal care, childcare, help in the home and help outside the home. The CSRI recorded use of medication for mental health and physical health reasons. The names of medications were recorded along with doses, frequency and duration of use. In addition to service use, the CSRI recorded employment status and interruptions to work as a result of health problems (absenteeism).

The CSRI was not applied at the 12-week follow-up because there were concerns that the information contained within it would ‘unblind’ the researchers conducting the HDRS interviews. Therefore, the CSRI used at 26 weeks was adapted to include questions on the number of service contacts that were received during the previous 3 months, so that the use up to 12 weeks from baseline could be identified as well as that in the 3 months before the 26-week follow-up.

Combining CSRI data and GP record data

CSRI data were augmented with data collected from general practice computerised medical records. These covered a range of services, and for the purposes of the economic evaluation data we used data on GP consultations (surgery, telephone or home visits), practice nurse contacts and prescriptions of mental health medications (specifically antidepressants, anxiolytics and hypnotics). This was the main data source for mental health problem prescribing, while information on drugs for physical health problems was taken from the CSRI. Regarding GP and practice nurse contacts, a comparison between the CSRI and medical record information was made and the source recording the highest level of contact was used (which would differ by patient).

Service use data are summarised in Table 45. In the 6 months before baseline assessment, all patients had GP contacts, which occurred approximately every 6 weeks on average. Slightly less than half also had contacts with practice nurses. More than half were receiving medication for physical health problems, and around one-third had outpatient contacts during the 6 months prior to baseline, which indicates a considerable level of physical health comorbidity in the trial population, as might be expected in a population selected on the basis of having somatic symptoms. A small number of patients (three in the supportive care alone group and one in the SSRI plus supportive care group) were prescribed SSRIs during the 6 months prior to baseline. However, records indicated that none of these four prescriptions was ‘cashed’. Most other services were used by relatively few patients. Overall, there were few noticeable differences between the two groups at baseline, although the group randomised to supportive care alone did have a higher rate of GP telephone contacts.

During the period between baseline assessment and 12-week follow-up, the vast majority of patients again had contact with GPs. (The few for whom no contacts were recorded had also dropped out of the study.) There was a reduction in contacts with practice nurses and outpatient consultations compared with baseline. The number of prescriptions of psychotropic drugs other than SSRIs remained similar to baseline. (Drugs for physical health problems were recorded with the CSRI but these data were not separated into the two follow-up periods.) The only key difference was in the use of SSRIs, which, not surprisingly, was higher in the SSRI plus supportive care group. However, it is important to note that 13% of patients in the SSRI plus supportive care group were not prescribed an SSRI, while 20% of patients in the supportive care alone group were prescribed one.

Between baseline assessment and the 26-week follow-up, slightly more patients in the SSRI plus supportive care group were admitted to hospital, but overall the numbers in each group were small at 4–7% (including day care). Again, one-third of patients had used outpatient services. Prescriptions for physical health problems continued to be received by more than half of the sample. As before, differences between the samples were small with the exception of the prescription of SSRIs. Therefore, there appeared to be no evidence that the intervention was reducing the reliance on other services. (Informal care costs are discussed later, alongside the costs of lost employment.)

Service costs

Service use data were combined with information on unit costs obtained from recognised sources. Most unit costs were taken from the annual publication of the Personal Social Services Research Unit (University of Kent). 75 These costs reflect salaries, overheads and capital, and are divided by the amount of face-to-face time that professionals spend with patients. Medication costs were derived from the British National Formulary for September 2007, assuming generic prescribing. 76 Finally, NHS reference costs were used to cost the use of hospital-based services. 77 The unit costs used in the cost calculations are shown in Appendix 24. The year used for unit costs was 2006–7, with the exception of the hospital costs, which were based on the most recently available data, for 2005–6, but inflated to estimate costs in 2006–7.

At baseline, mean costs were highest for GP surgery consultations, outpatient contacts and inpatient episodes (Table 46). Inpatient and outpatient costs were higher for the supportive care alone group, as were the costs of complementary health care and community support workers. The cost of medication for physical health problems was higher for the SSRI plus supportive care group. However, the variation around the means was substantial, as indicated by the SDs.

In the 12 weeks after randomisation, the use of inpatient and outpatient care and GP surgery consultations again incurred the highest costs. There were few substantial cost differences between the two groups, with the exception of the SSRI costs. Over the entire 26-week follow-up, the SSRI plus supportive care group had inpatient costs that were double those for the supportive care alone group. This group also had higher GP surgery consultation costs and SSRI costs.

Mean service costs in the 6 months to baseline were £94 higher in the supportive care alone group than in the SSRI plus supportive care group (Table 47). Costs up to the 12-week follow-up were closely matched between the groups, and the difference adjusted for baseline was £28. The 95% CI shows this to be non-significant. (Owing to cost data being skewed, bootstrapping with 10,000 resamples was used to produce percentile CIs. This assumes that the distribution of the original sample is representative of the population from which it is drawn. However, calculation of the CIs is the same, regardless of the nature of this distribution.) However, by the 26-week follow-up the mean costs for the SSRI plus supportive care group were £153 higher than for the supportive care alone group, after adjusting for differences in baseline costs. However, the SDs were large and this difference was also non-significant.

Incremental cost-effectiveness ratios

Service costs were linked with the HDRS to assess cost-effectiveness at 12 weeks and 26 weeks. Chapter 4 has shown that at the 12-week follow-up the mean fall in HDRS score for the SSRI plus supportive care group was 2.3 points greater than the fall for the supportive care alone group. Therefore, the SSRI plus supportive care group had a better outcome and lower costs and may be described as ‘dominant’. At 26 weeks, the mean fall in HDRS scores was 1.7 points greater in the SSRI plus supportive care group. Given that this group also had a cost that was £153 higher than the supportive care alone group, it was necessary to compute an ICER to assist decision makers in assessing whether adding SSRIs to supportive care represents value for money. An ICER is defined as the difference in costs between two groups divided by the difference in outcomes. At 26 weeks, the ICER is therefore £153 divided by 1.7, i.e. £90. This is the extra cost incurred by the SSRI plus supportive care group in achieving an extra unit of improvement on the HDRS compared with the supportive care alone group.

Cost-effectiveness planes

The above calculations of dominance at 12 weeks and an ICER of £90 at 26 weeks are based on the average cost and HDRS differences and therefore do not take uncertainty around these estimates into account. To address such uncertainty, cost-effectiveness planes were produced to show the probability of the SSRI plus supportive care group having (1) lower costs and better outcomes, (2) higher costs and better outcomes, (3) lower costs and worse outcomes and (4) higher costs and worse outcomes in comparison with supportive care alone. To construct the cost-effectiveness planes, four regression models were run using 1000 bootstrapped resamples. The models used service costs and HDRS scores at 12 weeks and 26 weeks as the dependent variables. The independent variables were the group identifier and the baseline measure of cost or HDRS. The 1000 coefficients for the group identifier variable are 1000 estimates of the cost/outcome differences and these were plotted against each other.

The cost-effectiveness plane showing cost and HDRS differences at 12 weeks is shown in Figure 7. The ‘south-east’ quadrant indicates the situation where the SSRI plus supportive care group has lower costs and better outcome than the supportive care alone group, and 54.9% of resamples showed this result. By contrast, 45.0% of cost–outcome differences were in the ‘north-east’ quadrant, where the SSRI plus supportive care group has better outcomes but also higher costs. Only 0.1% of resamples showed the SSRI plus supportive care group having lower costs and worse outcomes (‘south-west’ quadrant) and none showed higher costs and worse outcomes (‘north-west’ quadrant).

FIGURE 7.

Cost-effectiveness plane of cost and HDRS differences at 12 weeks.

At the 26-week follow-up, the majority (76.7%) of resamples showed that the SSRI plus supportive care group had higher costs and better outcomes (Figure 8). In 22.2% of resamples there were lower costs and better outcomes, while 0.8% of resamples showed higher costs and worse outcomes. Finally, 0.3% of resamples showed the SSRI plus supportive care group to have lower costs and worse outcomes.

FIGURE 8.

Cost-effectiveness plane of cost and HDRS differences at 26 weeks.

At both 12 weeks and 26 weeks, there was a high likelihood of the SSRI plus supportive care group having higher costs and better outcomes as measured by the HDRS. Whether this incremental improvement in outcome represents good value for money given the likelihood of higher service costs is a value judgement. However, this judgement can be informed by constructing CEACs, which show the likelihood that adding SSRIs to supportive care is more cost-effective than supportive care alone for different values placed on a unit improvement on the HDRS.

Cost-effectiveness acceptability curves

CEACs were constructed using the net-benefit approach. 5 There is a theoretical, but unknown, value (represented by the term λ ) that society would place on a one-unit reduction in depression as measured by the HDRS. Net benefit can be defined as:

where NB = net benefit, E = effectiveness (i.e. reduction in the HDRS score over 12 and 26 weeks compared with baseline) and SC = service costs. For example, if, for a particular patient, the HDRS score is reduced by 8 points during the follow-up period and if their service cost is £250, then we can calculate their net benefit if we know λ. If λ = £0, then the net benefit is –£250, whereas if λ = £40, then the net benefit is £70. Net benefits for all patients were estimated by assuming different values for λ, ranging between £0 and £200 in £20 increments. Then a regression model was used to determine the mean difference in net benefit between the supportive care alone and SSRI plus supportive care groups for every value of λ. For each model, 1000 regression coefficients for the group identifier variable were generated using bootstrapping, and the proportion of these that were greater than 0 indicated the probability that SSRI plus supportive care was more cost-effective (i.e. it resulted in a mean incremental net benefit greater than 0). These probabilities were subsequently used to generate the CEACs.

The 12-week and 26-week CEACs are shown in Figure 9. With regard to the 12-week curve, even if society would not be willing to attach any monetary value to a one-unit reduction in the HDRS there would remain a likelihood of 55% that SSRIs plus supportive care is the most cost-effective option. As a unit improvement is valued at higher levels, this likelihood goes on increasing. While we do not know the true societal value that should be placed on a unit improvement on the HDRS, it can be seen that beyond around £100 the curve flattens out, meaning that further increases have a diminishing impact on the likelihood that adding an SSRI will be the most cost-effective option.

FIGURE 9.

Cost-effectiveness acceptability curves showing probability that SSRIs plus supportive care is most cost-effective option.

The 26-week CEAC is below the 12-week CEAC, which reflects the reduced difference between the two groups at 26 weeks and the higher cost for the SSRI plus supportive care group. The latter intervention has a greater than 50% likelihood of being the most cost-effective option only if the value placed on a unit reduction on the HDRS is above £80.

Cost–utility analysis

Measuring outcomes using the HDRS has obvious clinical relevance and allows the results of this study to be compared with those of many other depression trials. However, policy makers need to make decisions regarding interventions across all areas of health care, and therefore a generic measure of outcome is also required. The most commonly used generic measure is the QALY, where the time spent in a health state is adjusted by a figure between 0 and 1 to reflect quality of life. This ‘utility’ value was generated from the SF-36 using an algorithm developed by Brazier and colleagues. 78 Clearly, there are other ways of estimating QALYs, and indeed alternative algorithms for calculating utility scores do exist. These may have produced different findings. However, the Brazier et al. method seemed most appropriate because it was based on the SF-36 (rather than the SF-12, as used elsewhere) and on a UK sample. The utility scores at baseline assessment and each follow-up are shown in Table 48. Scores at 12-week follow-up were significantly higher in the SSRI plus supportive care group. At 26-weeks the difference was non-significant.

Calculation of quality-adjusted life-years

Quality-adjusted life-years were calculated using area under the curve methodology. 79 The baseline utility score was added to the score at 12 weeks and this total was divided by 2, based on the assumption of a linear change over the 12-week period. This figure was then multiplied by 0.25, as only one-quarter of a QALY could be gained over the 12-week period. The QALY gain in the 12-week to 26-week period was calculated in a similar way. Gains in QALYs over the entire 26-week follow-up period were calculated by adding these two 3-month QALY gains. The mean QALY gain between baseline and 12-week follow-up was 0.1522 for the supportive care alone group and 0.1588 for the SSRI plus supportive care group. The difference adjusting for baseline was 0.0045 in favour of the SSRI plus supportive care group. As with the HDRS measure, adding SSRIs to supportive care was ‘dominant’ as costs were lower and QALY gains greater. By 26 weeks, the QALY gain in the supportive care alone group was 0.3176 and in the SSRI plus supportive care group it was 0.3305. The adjusted difference was 0.0103. Dividing the incremental cost of £153 by 0.0103 produced an ICER of £14,854, i.e. a cost of £14,854 would be incurred to gain an extra QALY as a result of prescribing SSRIs along with supportive care.

Uncertainty around the finding of dominance at 12 weeks and the ICER of £14,854 at 26 weeks were explored, as before, using cost-effectiveness planes. At 12 weeks, 52.1% of the resamples showed lower costs and a greater QALY gain for the SSRI plus supportive care group while 44.8% showed higher costs and more QALYs (Figure 10). Only 1.0% showed lower costs and a lower QALY gain and 2.1% showed higher costs and a lower QALY gain. The cost-effectiveness plane for the QALY gain and cost differences by 26 weeks is similar to that for the HDRS at 26 weeks (Figure 11). Most resamples (72.1%) showed higher costs and a greater QALY gain for the SSRI plus supportive care group. Lower costs and more QALYs were revealed in 24.3% of resamples. Lower costs and fewer QALYs were shown by 0.2% of resamples and higher costs and fewer QALYs by 3.4%.

FIGURE 10.

Cost-effectiveness plane of cost and QALY differences at 12 weeks.

FIGURE 11.

Cost-effectiveness plane of cost and QALY differences at 26 weeks.

CEACs were produced using the net-benefit approach as described above. The range of λ values was between £0 and £50,000 in £5000 intervals. (This range was chosen as values above this would usually mean that the intervention would not be recommended by NICE.) Figure 12 shows that with a zero value attached to a QALY gain at 12 weeks, there is still a 53% likelihood of SSRIs plus supportive care being cost-effective. With a QALY gain valued at £20,000–£30,000 (the thresholds usually associated with NICE recommendations), there is an 80–85% likelihood of this being the most cost-effective option. The CEAC related to QALYs at 26 weeks is again below the 12-week CEAC. However, there remains a high likelihood that SSRIs plus supportive care are cost-effective: 65% to 75% for a value of £20,000 to £30,000 per QALY respectively.

FIGURE 12.

Cost-effectiveness acceptability curves showing probability that SSRIs plus supportive care is most cost-effective option.

Impact on carers and employment

The above analyses focus on health and social care costs. However, it is likely that people with depression will require help from family members/friends as a result of their condition. In addition, it is well known that depression has a major impact on work. Data on the use and costs of informal care and the impact on work are shown in Table 49.

While relatively few patients received informal care, the cost was high. The unit cost used was the hourly cost of a homecare worker, and those who did receive informal care did so for a substantial number of hours per week. It can be seen that informal care costs were greatest for the SSRI plus supportive care group during the follow-up period but that this difference was not statistically significant. The costs of informal care were high, and this may be seen as surprising. For some disorders (e.g. dementia), high levels of informal care would be expected, but perhaps not for depression. Informal care costs were not included in the cost-effectiveness analyses because in the UK, NICE generally takes an NHS perspective. However, we have shown that these costs are important and should be investigated further.

Lost employment was experienced by a small number of patients. This could, however, be an underestimate as patients were asked to describe interruptions to work rather than asked specifically for the amount of time off, although many did provide this information. Lost employment costs were, though, substantial if costed at the median wage in the UK in 2007 of £457 per week. These costs increased during the follow-up period but did not differ significantly between the groups. It is interesting, however, that the apparent health improvement for those in the SSRI group was not matched by reductions in lost employment. This may be because (1) receipt of SSRIs ‘reinforced’ the feeling of being unwell and/or (2) doctors may be more likely to sign a patient off work at the same time as issuing a prescription of antidepressants. As with informal care costs, we did not include lost employment costs in the cost-effectiveness analyses because of the perspective taken by NICE.

Summary of the main findings

Strengths of the study

Even though practitioner referral rates into the study were lower than anticipated and one in three patients referred declined to be randomised, the research team managed to achieve the assessment of our primary outcome in 186 patients, close to our target sample size of 196, through the recruitment of more and more practitioners over more than 3 years. This was particularly challenging, owing to a steady stream of adverse publicity in the media about the effects of antidepressants throughout the course of the trial. 80–83 However, as a result of the team’s efforts, the study had sufficient power to determine a relatively small difference in outcome between the two arms of around 1.5 points on the HDRS. The randomisation process was also successful, with well balanced numbers in the two arms and in the two severity subgroups within each arm. We achieved higher than expected follow-up rates at both time points, reducing the likelihood of bias due to patients dropping out. Patients were followed up for 26 weeks, which is considerably longer than most commercial drug trials which have only 6–12 weeks’ follow-up, and the two follow-up points allowed longitudinal analyses of outcomes, which maximised the power of the sample to detect differences between arms.

A range of relevant primary and secondary outcomes were measured, including depressive symptoms, generic health status, patient satisfaction and costs. Costs were carefully gathered from a health service perspective using both patient questionnaires and GP medical records to maximise completeness,70 and informal care costs, including interruption of work and costs to family and friends, were also gathered. Most of the assessments carried out were self-completed, avoiding the possibility of observer bias. Interviewer training and frequent inter-rater reliability checks ensured high quality and consistent measurement of the HDRS primary outcome, and greatly reduced the likelihood of observer bias.

Data were collected on patients seen in surgeries who were eligible for the study but were not referred and on patients who were referred but not randomised, which allowed exploration of the representativeness of randomised patients. In addition, reasons for non-participation were gathered from those patients referred to the study team who did not consent to be randomised.

Therefore, in a number of respects, this study compares very favourably with primary care trials of antidepressants identified in a recent systematic review, most of which were small, commercially funded studies of short duration and low methodological quality. 23,84 It is crucial that clinicians working in primary care have good quality evidence from primary care studies to inform their practice. The 2004 NICE guidelines on antidepressant treatment were based on a review including 31 outpatient-based studies, three inpatient studies, 13 mixed studies and only one from primary care. 11 Among the 19 studies for which it was possible to determine baseline severity, four were of moderate depression, six of severe depression and nine of very severe depression. 11 Therefore, there was clearly a need for further, comparable studies of the treatment of mild to moderate depression in primary care.

Limitations of the study

The study was powered to detect only a relatively large difference in outcome, of 2.5 points on the HDRS, between the mild and moderate severity subgroups, and was not powered to detect equivalence in the effect of treatment. Therefore, while we found little evidence of a differential response to treatment between the two severity subgroups, we cannot say that adding an SSRI to supportive care is as effective in mild depression as in moderate depression. The power of the study was even more limited for the analyses of the other possible predictors of outcome and response to treatment, which must be regarded as exploratory.

We allowed GPs to prescribe antidepressants to patients in the supportive care alone arm if their depression persisted or worsened, so the drug treatment of 20% of patients in that arm was not a protocol violation as such. We did not collect any data on why GPs failed to prescribe SSRIs to 13% of the patients randomised to the SSRI plus supportive care arm, although this was probably because the GP and patient between them decided they did not want to use them after all. Qualitative interviews with the participating GPs might have shed light on why they failed to follow the randomisation recommendations in a minority of cases in both arms.

In an open label pragmatic trial of this nature, it is often not possible to keep the researchers responsible for assessing outcome in the patients blind to allocation to trial arm. In this study, the researchers were unblinded in 25% of cases at 12 weeks and 33% at 26 weeks, which raises the possibility of observer bias. In this respect, it is also important to note that we did not see similar changes in the self-completed BDI to the observer-rated changes in the HDRS. However, we consider that observer bias is an unlikely explanation for the effects found on the HDRS, for a number of reasons. First, the careful training and frequent inter-rater reliability checks would have greatly reduced the likelihood of observer bias, as the researchers were taught how to interpret patient responses to the individual items on the HDRS in a consistent way, and they were aware that a random sample of their audiotaped interviews would be rated again by a second researcher and discussed with one of the trainers. Second, we did see corresponding changes to the HDRS findings in the self-completed MH and VT subscales of the SF-36, as well as in self-rated patient satisfaction scores, so the lack of changes in the BDI may have been due to a relative insensitivity to change (see below), rather than because it was self-completed. Third, there was no expectation in the study group either way about the likely outcome which might have biased the researchers towards finding an effect. The study group included investigators holding a range of contrasting views about the effectiveness of antidepressants, and we consciously and explicitly maintained equipoise about the likely findings in discussion in study group meetings, stressing that we were interested in the outcome whatever the result.

We experienced greater loss to follow-up in the London centre than in the other two, which was due partly to a member of the team leaving the study and a gap in the availability of a researcher in London to carry out follow-up assessments for a few months until a replacement could be appointed. There was also differential loss to follow-up between the two treatment arms, raising the possibility of attrition bias. More patients were lost to follow-up in the supportive care alone arm, perhaps because they did not receive ‘active’ treatment, but we cannot say whether they were likely to fare better or worse than those remaining in the study. However, the difference in follow-up rates was relatively small (only 3% at the 12-week follow-up point, at which the primary outcome was determined) and we took steps to take account of these issues, by inclusion of recruitment centre and predictors of missing data in the adjusted analyses of outcome. The validity of this approach assumes that the predictors have been correctly identified; if the data were not missing at random (NMAR) then there is still a possibility of bias in the estimates.

Generalisability

The design of the study was very close to real-life practice in terms of the decision GPs face, i.e. whether or not to treat patients with new episodes of depression with SSRI antidepressants, as well as providing support by means of follow-up consultations. It was also close to real-life practice in that the GPs themselves delivered the treatment, so the results are readily generalisable to UK primary care. The pattern of treatment recorded in the GP records in this trial is comparable to that found in routine practice, judging from previous studies of medical record data in UK general practice. 85–87 It is possible to estimate treatment effects, including allowance for both non-compliance with treatment and loss to follow-up, using a complier average causal effect (CACE) analysis,88 which we will explore and may present in a subsequent publication.

The tallies of surgery logs completed by a number of the study GPs at various points during the study showed that only around 1 in 10 patients with a new episode of depression were referred into the study, mainly because the rest did not fulfil the inclusion criteria, particularly in terms of a lack of equipoise about the benefits of drug treatment on the part of the doctor or patient or both. This raises the question of how representative were the participating patients of all patients presenting with depression, but inevitably we could include in a randomised trial only those patients who were in equipoise about treatment, and whose doctors were in equipoise. It is more difficult to carry out a randomised trial of treatment that is already established in practice, as most doctors and many patients already have opinions about its effectiveness, which would not be such a problem for a trial of a new treatment. We found evidence that male patients were less likely to be referred into the study, but referred patients were representative in terms of age. We also had relatively few patients referred in the upper age group even though we had issued no age restriction to the GPs. This may reflect known lower rates of treatment in older people (which Age Concern has highlighted in a recent report89) or possibly a reluctance to enter older people into a trial, because of the extra demands for assessments which are then placed on them. Qualitative interviews with the participating GPs might have given better insight into why some eligible patients were not referred than did the limited information written in the surgery logs.

Only one in three referred patients was randomised, due partly to a number having HDRS scores outside the required range of severity, but also again due in part to a lack of patient equipoise about the effects of treatment and a subsequent unwillingness to be randomised, especially to the drug treatment arm. However, those patients who were randomised were generally representative in terms of both gender and age of the patients referred into the study. No preference arms were included in the study design, which it might be supposed would have allowed more patients to join the study given that many declined to be randomised owing to a strong preference against having antidepressants. However, piloting of preference arms partway through the study suggested that adding them tended to reduce the numbers of patients agreeing to be randomised, compromising the most important objective of the trial. Again, qualitative interviews might have engendered greater understanding of why so many patients declined to be randomised after accepting referral into the study than did the relatively brief questions asked when consent was withheld.

The inclusion criteria were kept as wide as possible given the constraints of the trial. In addition to the 87 who were excluded because of an HDRS score outside the defined range, a further 50 patients were excluded because they had received antidepressant treatment within the last 12 months. This exclusion criterion was designed to limit the sample to patients presenting with new bouts of depression; it was set at 12 months because depression is a relapsing condition and recurrence of symptoms within 12 months is common, and probably represents a relapse rather than a new episode. We wanted to determine the effectiveness and cost-effectiveness in new episodes and to be clear that we were not dealing with relapsing chronic depression. It is possible that we may have excluded fewer patients if we had relaxed this criterion, but we thought it was important. We do not have any data on the number who would have been excluded if the criterion had been 6 months instead of 12, for example, so we are unable to say whether this criterion was unnecessarily strict.

However, unlike some antidepressant studies, we did not exclude people on the basis of physical comorbidities, and the sample included many patients with physical health problems, evidenced by the number of medications and outpatient attendances for non-mental health problems. This is to be expected in a relatively non-selected primary care sample where one of the inclusion criteria is the presence of somatic symptoms. The patients were found to be similar, in terms of their levels of use of services and generic health status on the SF-36, to those in previous primary care trials of depression treatment. 90–92 We also measured the number of physical symptoms and alcohol consumption so that we could explore the effects on outcome of depression and response to treatment of these very common complicating factors.

Interpretation of the study findings in light of previous research

Implications for practice

The results of this study demonstrate that GP prescribing of SSRI antidepressants for patients with mild to moderate depression, on top of supportive care provided over four consultations in 12 weeks, is more effective than supportive care alone, and is cost-effective at the levels used by NICE to make judgements about recommending treatments within the NHS. However, the results do not support a policy of indiscriminate prescribing to all general practice patients with depression, and we should emphasise certain caveats.

First, our inclusion criteria included persistent symptoms of depression for at least 8 weeks. This study has not provided any evidence to support prescribing for patients with a shorter duration of symptoms. Current NICE guidance advises a period of watchful waiting before considering prescription of antidepressants, and our results support a policy of waiting until patients have had symptoms for at least 8 weeks, and then treating them with an SSRI if they have not improved, in line with NICE guidance.

Second, patients had to score at least 12 on the HDRS for inclusion which, while close to the mildest end of the spectrum of depression, does not include all patients diagnosed as depressed by their GPs. We excluded 47 patients out of 602 referred into the study as a result of HDRS scores of less than 12. We chose this threshold as it corresponded to the lower end of the severity range on the HDRS for which benefit has been shown in placebo-controlled trials. 20,25,31 Previous research has shown evidence of functional impairment due to very mild depression,12,13 right down to a level of 7 on the HDRS,115 but this study has not provided any evidence to support prescribing for very mild depression below a score of 12. This score on the HDRS is at the threshold level of severity for diagnosing mild major depressive disorder, as discussed in Chapter 1, and corresponds approximately to a score of 12 on the Patient Health Questionnaire, 9-item version (PHQ-9),116,117 or a score of 9 on the Hospital Anxiety and Depression Scale depression subscale (HADS-D). 116 These two measures are now commonly used to measure the severity of depression in UK practices as a result of the inclusion of incentives to measure severity in the UK GP contract quality and outcomes framework in April 2006. We can therefore recommend, on the basis of these findings, that SSRI antidepressants should be considered in someone who has been experiencing symptoms for at least 8 weeks and has a PHQ-9 score of 12 or more or a HADS-D score of 9 or more.

Given that there may be benefits to be gained from prescribing SSRIs for mild depression, we need to consider whether these benefits outweigh the possible adverse effects in any individual patient. It is important to consider the risk of overdose, as illustrated by two patients who took overdoses of paracetamol during the course of this trial, although fortunately none took an overdose of SSRIs. The side effects of medication are generally minor, as we found in this study, but occasionally can be severe and include, for example, the potentially fatal serotonin syndrome. Patients with epilepsy may suffer fits due to the lowering of the seizure threshold by antidepressant medication, which may stop them driving and cause them to lose their job. In addition to these physical risks of medication, prescribing may be perceived as ‘disposing’ of the patient, precluding a greater exploration of their life difficulties,118,119 and of non-drug strategies to tackle depression, although we found no evidence of differences between arms in reported discussion of non-drug strategies in this study. The increasing availability of non-drug treatment alternatives such as computerised CBT-based self-help15 and psychological therapies120 may obviate the need to risk prescribing for more and more practitioners in the future.

Implications for further research

More research is needed on the natural history of mild to moderate depression and predictors of chronicity because, although many patients recover within weeks in the absence of treatment, a significant proportion do not remit in the short term (more than 45% at 6 months in this study). Better ways of early identification of those who are less likely to recover in the short term would help GPs to target additional treatment or referral for psychological or psychiatric treatment to those more likely to need extra help.

More placebo-controlled studies of antidepressants for mild depression in primary care are needed, as the evidence base for the treatment of mild depression in particular is still relatively small. 11,23,84,95 More research is also needed into self-help, exercise, diet and novel non-drug treatments for mild depression, as the evidence base for non-drug treatments is also very small. 11

More research is required into the differences between the HDRS and BDI and other measures of depression, to explore whether they measure different aspects of depression and whether there are differences between them in sensitivity to change in relation to drug, psychological and other treatments. 103 This would help to inform the choice of the most appropriate measure for future trials. We intend to look at the elements of the HDRS and BDI in this study for a possible future publication.

More research is needed into supportive care or watchful waiting,11 to explore the therapeutic aspects, what supportive care should include and how to optimise it. We intend to look further into the relationship between reported consultation content, life events and difficulties and outcome in this study, including patient satisfaction. We will also carry out an exploratory factor analysis of underlying constructs in the MISS measure of satisfaction used in this study.

Finally, better measures of outcome for depression studies need to be developed, including patient-derived measures. The Psychological Outcome Profiles (PSYCHLOPS) measure developed at King’s College London is one such instrument, which is intended to measure change in those issues of importance to the individual patient or client, and is ideally suited to situations where clients present with varied mental health issues that might not be adequately captured by standardised instruments (see www.psychlops.org.uk).

Conclusion

Treatment with an SSRI plus supportive care is more effective than supportive care alone for patients with mild to moderate depression in UK primary care, at least for those with symptoms persisting for 8 weeks and with an HDRS score of 12 or more. The additional benefit is relatively small, and may be at least in part a placebo effect, but is probably cost-effective at the levels used by NICE to make judgements about recommending treatments within the NHS.

Contribution of authors

Tony Kendrick (Professor of Primary Care) was the Chief Investigator and was involved in the conception and design of the study, interpretation of data, drafting and revising the report and approving the final version. Judy Chatwin (Trial Co-ordinator) was involved in modifying the design of the study, data collection, analysis, drafting and revising the report and approving the final version. Chris Dowrick (Professor of Primary Medical Care), André Tylee (Professor of Primary Medical Care and Mental Health), Richard Morriss (Professor of Psychiatry and Community Mental Health), Robert Peveler (Professor of Liaison Psychiatry) and Tirril Harris (Visiting Research Fellow) were involved in the conception and design of the study, interpretation of data, drafting and revising the report and approving the final version. Morven Leese (Reader in Medical Statistics) and Paul McCrone (Reader in Health Economics) were involved in the conception and design of the study, analysis and interpretation of data, drafting and revising the report and approving the final version. Michael Moore (Senior Lecturer), Richard Byng (Senior Clinical Research Fellow), George Brown (Professor Emeritus), Mark Gabbay (Head of Division of Primary Care) and Tom Craig (Professor of Social and Community Psychiatry) were involved in modification of the design, interpretation of data, drafting and revising the report and approving the final version. Sophie Barthel (Research Associate) was involved in analysis and interpretation of data, drafting and revising the report and approving the final version. Helen Mander (Researcher), Adele Ring (Researcher), Vikki Kelly (Researcher) and Vuokko Wallace (Researcher) were involved in modification of the design, data collection, revising the report and approving the final version. Anthony Mann (Professor Emeritus) was involved in the conception and design of the study, revising the final report and approving the final version.

Publications

Chatwin J, Kendrick TR. Protocol for the THREAD (THREshold for AntiDepressants) study: a randomised controlled trial to determine the clinical and cost effectiveness of antidepressants plus supportive care, versus supportive care alone, for mild to moderate depression in UK general practice. BMC Fam Pract 2007;8(1):2.

Morriss R, Leese M, Chatwin J, Baldwin D. Inter-rater reliability of the Hamilton depression rating scale as a diagnostic and outcome measure of depression in primary care. J Affect Disord 2008;111(2)204–13.

Disclaimers

The views expressed in this publication are those of the authors and not necessarily those of the HTA programme or the Department of Health.

Trial of SSRIs for mild to moderate depression in primary care

We would like your help with an important study of treatment for depression. This project has been funded by the NHS R&D Health Technology Assessment programme and we are aiming to recruit patients from general practices around three centres: Southampton, London (co-ordinated by the Institute of Psychiatry and King’s College London) and Liverpool.

STUDY OF SSRIs PLUS SUPPORTIVE CARE vs SUPPORTIVE CARE ALONE FOR MILD TO MODERATE DEPRESSION IN PRIMARY CARE

(THREshold for AntiDepressants STUDY)

The purpose of the study is to consider whether treatment with an SSRI plus supportive care is more effective and cost-effective than supportive care alone. If it is more effective, does this apply across the whole range of severity of symptoms of mild depression? The study will also consider what patient factors might predict a beneficial response.

Study of antidepressants for mild to moderate depression

You are being invited to take part in a research study. Before you decide it is important for you to understand why the research is being done and what it will involve. Please take time to read the following information carefully and discuss it with others if you wish. Ask us if there is anything that is not clear or if you would like more information. Take time to decide whether or not you wish to take part. Thank you for reading this.

What is mild to moderate depression?

Most people have changes in mood throughout each day. Most people also have days or even weeks when their mood is lower than usual. Such disturbances of mood are usually mild and pass with time. Occasionally low mood may last longer and, if you seek help, your GP might consider a diagnosis of mild depression. We recognise that some people may feel ‘down’ or ‘stressed’ but might not consider themselves to be depressed. Depression is defined clinically by the number of symptoms (see below) that are present; they have to be there for at least two weeks. Moderate and severe depression is distinguished from mild depression because the symptoms are worse and have more of an effect on everyday life. Your GP thinks that the symptoms you are experiencing are in the mild end of the spectrum and are different from severe depression. This spectrum is represented in the diagram below.

Health Technology Assessment reports published to date

1. Home parenteral nutrition: a systematic review.

   By Richards DM, Deeks JJ, Sheldon TA, Shaffer JL.

2. Diagnosis, management and screening of early localised prostate cancer.

   A review by Selley S, Donovan J, Faulkner A, Coast J, Gillatt D.

3. The diagnosis, management, treatment and costs of prostate cancer in England and Wales.

   A review by Chamberlain J, Melia J, Moss S, Brown J.

4. Screening for fragile X syndrome.

   A review by Murray J, Cuckle H, Taylor G, Hewison J.

5. A review of near patient testing in primary care.

   By Hobbs FDR, Delaney BC, Fitzmaurice DA, Wilson S, Hyde CJ, Thorpe GH, et al.

6. Systematic review of outpatient services for chronic pain control.

   By McQuay HJ, Moore RA, Eccleston C, Morley S, de C Williams AC.

7. Neonatal screening for inborn errors of metabolism: cost, yield and outcome.

   A review by Pollitt RJ, Green A, McCabe CJ, Booth A, Cooper NJ, Leonard JV, et al.

8. Preschool vision screening.

   A review by Snowdon SK, Stewart-Brown SL.

9. Implications of socio-cultural contexts for the ethics of clinical trials.

   A review by Ashcroft RE, Chadwick DW, Clark SRL, Edwards RHT, Frith L, Hutton JL.

10. A critical review of the role of neonatal hearing screening in the detection of congenital hearing impairment.

    By Davis A, Bamford J, Wilson I, Ramkalawan T, Forshaw M, Wright S.

11. Newborn screening for inborn errors of metabolism: a systematic review.

    By Seymour CA, Thomason MJ, Chalmers RA, Addison GM, Bain MD, Cockburn F, et al.

12. Routine preoperative testing: a systematic review of the evidence.

    By Munro J, Booth A, Nicholl J.

13. Systematic review of the effectiveness of laxatives in the elderly.

    By Petticrew M, Watt I, Sheldon T.

14. When and how to assess fast-changing technologies: a comparative study of medical applications of four generic technologies.

    A review by Mowatt G, Bower DJ, Brebner JA, Cairns JA, Grant AM, McKee L.

1. Antenatal screening for Down’s syndrome.

   A review by Wald NJ, Kennard A, Hackshaw A, McGuire A.

2. Screening for ovarian cancer: a systematic review.

   By Bell R, Petticrew M, Luengo S, Sheldon TA.

3. Consensus development methods, and their use in clinical guideline development.

   A review by Murphy MK, Black NA, Lamping DL, McKee CM, Sanderson CFB, Askham J, et al.

4. A cost–utility analysis of interferon beta for multiple sclerosis.

   By Parkin D, McNamee P, Jacoby A, Miller P, Thomas S, Bates D.

5. Effectiveness and efficiency of methods of dialysis therapy for end-stage renal disease: systematic reviews.

   By MacLeod A, Grant A, Donaldson C, Khan I, Campbell M, Daly C, et al.

6. Effectiveness of hip prostheses in primary total hip replacement: a critical review of evidence and an economic model.

   By Faulkner A, Kennedy LG, Baxter K, Donovan J, Wilkinson M, Bevan G.

7. Antimicrobial prophylaxis in colorectal surgery: a systematic review of randomised controlled trials.

   By Song F, Glenny AM.

8. Bone marrow and peripheral blood stem cell transplantation for malignancy.

   A review by Johnson PWM, Simnett SJ, Sweetenham JW, Morgan GJ, Stewart LA.

9. Screening for speech and language delay: a systematic review of the literature.

   By Law J, Boyle J, Harris F, Harkness A, Nye C.

10. Resource allocation for chronic stable angina: a systematic review of effectiveness, costs and cost-effectiveness of alternative interventions.

    By Sculpher MJ, Petticrew M, Kelland JL, Elliott RA, Holdright DR, Buxton MJ.

11. Detection, adherence and control of hypertension for the prevention of stroke: a systematic review.

    By Ebrahim S.

12. Postoperative analgesia and vomiting, with special reference to day-case surgery: a systematic review.

    By McQuay HJ, Moore RA.

13. Choosing between randomised and nonrandomised studies: a systematic review.

    By Britton A, McKee M, Black N, McPherson K, Sanderson C, Bain C.

14. Evaluating patient-based outcome measures for use in clinical trials.

    A review by Fitzpatrick R, Davey C, Buxton MJ, Jones DR.

15. Ethical issues in the design and conduct of randomised controlled trials.

    A review by Edwards SJL, Lilford RJ, Braunholtz DA, Jackson JC, Hewison J, Thornton J.

16. Qualitative research methods in health technology assessment: a review of the literature.

    By Murphy E, Dingwall R, Greatbatch D, Parker S, Watson P.

17. The costs and benefits of paramedic skills in pre-hospital trauma care.

    By Nicholl J, Hughes S, Dixon S, Turner J, Yates D.

18. Systematic review of endoscopic ultrasound in gastro-oesophageal cancer.

    By Harris KM, Kelly S, Berry E, Hutton J, Roderick P, Cullingworth J, et al.

19. Systematic reviews of trials and other studies.

    By Sutton AJ, Abrams KR, Jones DR, Sheldon TA, Song F.

20. Primary total hip replacement surgery: a systematic review of outcomes and modelling of cost-effectiveness associated with different prostheses.

    A review by Fitzpatrick R, Shortall E, Sculpher M, Murray D, Morris R, Lodge M, et al.

1. Informed decision making: an annotated bibliography and systematic review.

   By Bekker H, Thornton JG, Airey CM, Connelly JB, Hewison J, Robinson MB, et al.

2. Handling uncertainty when performing economic evaluation of healthcare interventions.

   A review by Briggs AH, Gray AM.

3. The role of expectancies in the placebo effect and their use in the delivery of health care: a systematic review.

   By Crow R, Gage H, Hampson S, Hart J, Kimber A, Thomas H.

4. A randomised controlled trial of different approaches to universal antenatal HIV testing: uptake and acceptability. Annex: Antenatal HIV testing – assessment of a routine voluntary approach.

   By Simpson WM, Johnstone FD, Boyd FM, Goldberg DJ, Hart GJ, Gormley SM, et al.

5. Methods for evaluating area-wide and organisation-based interventions in health and health care: a systematic review.

   By Ukoumunne OC, Gulliford MC, Chinn S, Sterne JAC, Burney PGJ.

6. Assessing the costs of healthcare technologies in clinical trials.

   A review by Johnston K, Buxton MJ, Jones DR, Fitzpatrick R.

7. Cooperatives and their primary care emergency centres: organisation and impact.

   By Hallam L, Henthorne K.

8. Screening for cystic fibrosis.

   A review by Murray J, Cuckle H, Taylor G, Littlewood J, Hewison J.

9. A review of the use of health status measures in economic evaluation.

   By Brazier J, Deverill M, Green C, Harper R, Booth A.

10. Methods for the analysis of quality-of-life and survival data in health technology assessment.

    A review by Billingham LJ, Abrams KR, Jones DR.

11. Antenatal and neonatal haemoglobinopathy screening in the UK: review and economic analysis.

    By Zeuner D, Ades AE, Karnon J, Brown J, Dezateux C, Anionwu EN.

12. Assessing the quality of reports of randomised trials: implications for the conduct of meta-analyses.

    A review by Moher D, Cook DJ, Jadad AR, Tugwell P, Moher M, Jones A, et al.

13. ‘Early warning systems’ for identifying new healthcare technologies.

    By Robert G, Stevens A, Gabbay J.

14. A systematic review of the role of human papillomavirus testing within a cervical screening programme.

    By Cuzick J, Sasieni P, Davies P, Adams J, Normand C, Frater A, et al.

15. Near patient testing in diabetes clinics: appraising the costs and outcomes.

    By Grieve R, Beech R, Vincent J, Mazurkiewicz J.

16. Positron emission tomography: establishing priorities for health technology assessment.

    A review by Robert G, Milne R.

17. The debridement of chronic wounds: a systematic review.

    By Bradley M, Cullum N, Sheldon T.

18. Systematic reviews of wound care management: (2) Dressings and topical agents used in the healing of chronic wounds.

    By Bradley M, Cullum N, Nelson EA, Petticrew M, Sheldon T, Torgerson D.

19. A systematic literature review of spiral and electron beam computed tomography: with particular reference to clinical applications in hepatic lesions, pulmonary embolus and coronary artery disease.

    By Berry E, Kelly S, Hutton J, Harris KM, Roderick P, Boyce JC, et al.

20. What role for statins? A review and economic model.

    By Ebrahim S, Davey Smith G, McCabe C, Payne N, Pickin M, Sheldon TA, et al.

21. Factors that limit the quality, number and progress of randomised controlled trials.

    A review by Prescott RJ, Counsell CE, Gillespie WJ, Grant AM, Russell IT, Kiauka S, et al.

22. Antimicrobial prophylaxis in total hip replacement: a systematic review.

    By Glenny AM, Song F.

23. Health promoting schools and health promotion in schools: two systematic reviews.

    By Lister-Sharp D, Chapman S, Stewart-Brown S, Sowden A.

24. Economic evaluation of a primary care-based education programme for patients with osteoarthritis of the knee.

    A review by Lord J, Victor C, Littlejohns P, Ross FM, Axford JS.

1. The estimation of marginal time preference in a UK-wide sample (TEMPUS) project.

   A review by Cairns JA, van der Pol MM.

2. Geriatric rehabilitation following fractures in older people: a systematic review.

   By Cameron I, Crotty M, Currie C, Finnegan T, Gillespie L, Gillespie W, et al.

3. Screening for sickle cell disease and thalassaemia: a systematic review with supplementary research.

   By Davies SC, Cronin E, Gill M, Greengross P, Hickman M, Normand C.

4. Community provision of hearing aids and related audiology services.

   A review by Reeves DJ, Alborz A, Hickson FS, Bamford JM.

5. False-negative results in screening programmes: systematic review of impact and implications.

   By Petticrew MP, Sowden AJ, Lister-Sharp D, Wright K.

6. Costs and benefits of community postnatal support workers: a randomised controlled trial.

   By Morrell CJ, Spiby H, Stewart P, Walters S, Morgan A.

7. Implantable contraceptives (subdermal implants and hormonally impregnated intrauterine systems) versus other forms of reversible contraceptives: two systematic reviews to assess relative effectiveness, acceptability, tolerability and cost-effectiveness.

   By French RS, Cowan FM, Mansour DJA, Morris S, Procter T, Hughes D, et al.

8. An introduction to statistical methods for health technology assessment.

   A review by White SJ, Ashby D, Brown PJ.

9. Disease-modifying drugs for multiple sclerosis: a rapid and systematic review.

   By Clegg A, Bryant J, Milne R.

10. Publication and related biases.

    A review by Song F, Eastwood AJ, Gilbody S, Duley L, Sutton AJ.

11. Cost and outcome implications of the organisation of vascular services.

    By Michaels J, Brazier J, Palfreyman S, Shackley P, Slack R.

12. Monitoring blood glucose control in diabetes mellitus: a systematic review.

    By Coster S, Gulliford MC, Seed PT, Powrie JK, Swaminathan R.

13. The effectiveness of domiciliary health visiting: a systematic review of international studies and a selective review of the British literature.

    By Elkan R, Kendrick D, Hewitt M, Robinson JJA, Tolley K, Blair M, et al.

14. The determinants of screening uptake and interventions for increasing uptake: a systematic review.

    By Jepson R, Clegg A, Forbes C, Lewis R, Sowden A, Kleijnen J.

15. The effectiveness and cost-effectiveness of prophylactic removal of wisdom teeth.

    A rapid review by Song F, O’Meara S, Wilson P, Golder S, Kleijnen J.

16. Ultrasound screening in pregnancy: a systematic review of the clinical effectiveness, cost-effectiveness and women’s views.

    By Bricker L, Garcia J, Henderson J, Mugford M, Neilson J, Roberts T, et al.

17. A rapid and systematic review of the effectiveness and cost-effectiveness of the taxanes used in the treatment of advanced breast and ovarian cancer.

    By Lister-Sharp D, McDonagh MS, Khan KS, Kleijnen J.

18. Liquid-based cytology in cervical screening: a rapid and systematic review.

    By Payne N, Chilcott J, McGoogan E.

19. Randomised controlled trial of non-directive counselling, cognitive–behaviour therapy and usual general practitioner care in the management of depression as well as mixed anxiety and depression in primary care.

    By King M, Sibbald B, Ward E, Bower P, Lloyd M, Gabbay M, et al.

20. Routine referral for radiography of patients presenting with low back pain: is patients’ outcome influenced by GPs’ referral for plain radiography?

    By Kerry S, Hilton S, Patel S, Dundas D, Rink E, Lord J.

21. Systematic reviews of wound care management: (3) antimicrobial agents for chronic wounds; (4) diabetic foot ulceration.

    By O’Meara S, Cullum N, Majid M, Sheldon T.

22. Using routine data to complement and enhance the results of randomised controlled trials.

    By Lewsey JD, Leyland AH, Murray GD, Boddy FA.

23. Coronary artery stents in the treatment of ischaemic heart disease: a rapid and systematic review.

    By Meads C, Cummins C, Jolly K, Stevens A, Burls A, Hyde C.

24. Outcome measures for adult critical care: a systematic review.

    By Hayes JA, Black NA, Jenkinson C, Young JD, Rowan KM, Daly K, et al.

25. A systematic review to evaluate the effectiveness of interventions to promote the initiation of breastfeeding.

    By Fairbank L, O’Meara S, Renfrew MJ, Woolridge M, Sowden AJ, Lister-Sharp D.

26. Implantable cardioverter defibrillators: arrhythmias. A rapid and systematic review.

    By Parkes J, Bryant J, Milne R.

27. Treatments for fatigue in multiple sclerosis: a rapid and systematic review.

    By Brañas P, Jordan R, Fry-Smith A, Burls A, Hyde C.

28. Early asthma prophylaxis, natural history, skeletal development and economy (EASE): a pilot randomised controlled trial.

    By Baxter-Jones ADG, Helms PJ, Russell G, Grant A, Ross S, Cairns JA, et al.

29. Screening for hypercholesterolaemia versus case finding for familial hypercholesterolaemia: a systematic review and cost-effectiveness analysis.

    By Marks D, Wonderling D, Thorogood M, Lambert H, Humphries SE, Neil HAW.

30. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of glycoprotein IIb/IIIa antagonists in the medical management of unstable angina.

    By McDonagh MS, Bachmann LM, Golder S, Kleijnen J, ter Riet G.

31. A randomised controlled trial of prehospital intravenous fluid replacement therapy in serious trauma.

    By Turner J, Nicholl J, Webber L, Cox H, Dixon S, Yates D.

32. Intrathecal pumps for giving opioids in chronic pain: a systematic review.

    By Williams JE, Louw G, Towlerton G.

33. Combination therapy (interferon alfa and ribavirin) in the treatment of chronic hepatitis C: a rapid and systematic review.

    By Shepherd J, Waugh N, Hewitson P.

34. A systematic review of comparisons of effect sizes derived from randomised and non-randomised studies.

    By MacLehose RR, Reeves BC, Harvey IM, Sheldon TA, Russell IT, Black AMS.

35. Intravascular ultrasound-guided interventions in coronary artery disease: a systematic literature review, with decision-analytic modelling, of outcomes and cost-effectiveness.

    By Berry E, Kelly S, Hutton J, Lindsay HSJ, Blaxill JM, Evans JA, et al.

36. A randomised controlled trial to evaluate the effectiveness and cost-effectiveness of counselling patients with chronic depression.

    By Simpson S, Corney R, Fitzgerald P, Beecham J.

37. Systematic review of treatments for atopic eczema.

    By Hoare C, Li Wan Po A, Williams H.

38. Bayesian methods in health technology assessment: a review.

    By Spiegelhalter DJ, Myles JP, Jones DR, Abrams KR.

39. The management of dyspepsia: a systematic review.

    By Delaney B, Moayyedi P, Deeks J, Innes M, Soo S, Barton P, et al.

40. A systematic review of treatments for severe psoriasis.

    By Griffiths CEM, Clark CM, Chalmers RJG, Li Wan Po A, Williams HC.

1. Clinical and cost-effectiveness of donepezil, rivastigmine and galantamine for Alzheimer’s disease: a rapid and systematic review.

   By Clegg A, Bryant J, Nicholson T, McIntyre L, De Broe S, Gerard K, et al.

2. The clinical effectiveness and cost-effectiveness of riluzole for motor neurone disease: a rapid and systematic review.

   By Stewart A, Sandercock J, Bryan S, Hyde C, Barton PM, Fry-Smith A, et al.

3. Equity and the economic evaluation of healthcare.

   By Sassi F, Archard L, Le Grand J.

4. Quality-of-life measures in chronic diseases of childhood.

   By Eiser C, Morse R.

5. Eliciting public preferences for healthcare: a systematic review of techniques.

   By Ryan M, Scott DA, Reeves C, Bate A, van Teijlingen ER, Russell EM, et al.

6. General health status measures for people with cognitive impairment: learning disability and acquired brain injury.

   By Riemsma RP, Forbes CA, Glanville JM, Eastwood AJ, Kleijnen J.

7. An assessment of screening strategies for fragile X syndrome in the UK.

   By Pembrey ME, Barnicoat AJ, Carmichael B, Bobrow M, Turner G.

8. Issues in methodological research: perspectives from researchers and commissioners.

   By Lilford RJ, Richardson A, Stevens A, Fitzpatrick R, Edwards S, Rock F, et al.

9. Systematic reviews of wound care management: (5) beds; (6) compression; (7) laser therapy, therapeutic ultrasound, electrotherapy and electromagnetic therapy.

   By Cullum N, Nelson EA, Flemming K, Sheldon T.

10. Effects of educational and psychosocial interventions for adolescents with diabetes mellitus: a systematic review.

    By Hampson SE, Skinner TC, Hart J, Storey L, Gage H, Foxcroft D, et al.

11. Effectiveness of autologous chondrocyte transplantation for hyaline cartilage defects in knees: a rapid and systematic review.

    By Jobanputra P, Parry D, Fry-Smith A, Burls A.

12. Statistical assessment of the learning curves of health technologies.

    By Ramsay CR, Grant AM, Wallace SA, Garthwaite PH, Monk AF, Russell IT.

13. The effectiveness and cost-effectiveness of temozolomide for the treatment of recurrent malignant glioma: a rapid and systematic review.

    By Dinnes J, Cave C, Huang S, Major K, Milne R.

14. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of debriding agents in treating surgical wounds healing by secondary intention.

    By Lewis R, Whiting P, ter Riet G, O’Meara S, Glanville J.

15. Home treatment for mental health problems: a systematic review.

    By Burns T, Knapp M, Catty J, Healey A, Henderson J, Watt H, et al.

16. How to develop cost-conscious guidelines.

    By Eccles M, Mason J.

17. The role of specialist nurses in multiple sclerosis: a rapid and systematic review.

    By De Broe S, Christopher F, Waugh N.

18. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of orlistat in the management of obesity.

    By O’Meara S, Riemsma R, Shirran L, Mather L, ter Riet G.

19. The clinical effectiveness and cost-effectiveness of pioglitazone for type 2 diabetes mellitus: a rapid and systematic review.

    By Chilcott J, Wight J, Lloyd Jones M, Tappenden P.

20. Extended scope of nursing practice: a multicentre randomised controlled trial of appropriately trained nurses and preregistration house officers in preoperative assessment in elective general surgery.

    By Kinley H, Czoski-Murray C, George S, McCabe C, Primrose J, Reilly C, et al.

21. Systematic reviews of the effectiveness of day care for people with severe mental disorders: (1) Acute day hospital versus admission; (2) Vocational rehabilitation; (3) Day hospital versus outpatient care.

    By Marshall M, Crowther R, Almaraz- Serrano A, Creed F, Sledge W, Kluiter H, et al.

22. The measurement and monitoring of surgical adverse events.

    By Bruce J, Russell EM, Mollison J, Krukowski ZH.

23. Action research: a systematic review and guidance for assessment.

    By Waterman H, Tillen D, Dickson R, de Koning K.

24. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of gemcitabine for the treatment of pancreatic cancer.

    By Ward S, Morris E, Bansback N, Calvert N, Crellin A, Forman D, et al.

25. A rapid and systematic review of the evidence for the clinical effectiveness and cost-effectiveness of irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer.

    By Lloyd Jones M, Hummel S, Bansback N, Orr B, Seymour M.

26. Comparison of the effectiveness of inhaler devices in asthma and chronic obstructive airways disease: a systematic review of the literature.

    By Brocklebank D, Ram F, Wright J, Barry P, Cates C, Davies L, et al.

27. The cost-effectiveness of magnetic resonance imaging for investigation of the knee joint.

    By Bryan S, Weatherburn G, Bungay H, Hatrick C, Salas C, Parry D, et al.

28. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of topotecan for ovarian cancer.

    By Forbes C, Shirran L, Bagnall A-M, Duffy S, ter Riet G.

29. Superseded by a report published in a later volume.

30. The role of radiography in primary care patients with low back pain of at least 6 weeks duration: a randomised (unblinded) controlled trial.

    By Kendrick D, Fielding K, Bentley E, Miller P, Kerslake R, Pringle M.

31. Design and use of questionnaires: a review of best practice applicable to surveys of health service staff and patients.

    By McColl E, Jacoby A, Thomas L, Soutter J, Bamford C, Steen N, et al.

32. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of paclitaxel, docetaxel, gemcitabine and vinorelbine in non-small-cell lung cancer.

    By Clegg A, Scott DA, Sidhu M, Hewitson P, Waugh N.

33. Subgroup analyses in randomised controlled trials: quantifying the risks of false-positives and false-negatives.

    By Brookes ST, Whitley E, Peters TJ, Mulheran PA, Egger M, Davey Smith G.

34. Depot antipsychotic medication in the treatment of patients with schizophrenia: (1) Meta-review; (2) Patient and nurse attitudes.

    By David AS, Adams C.

35. A systematic review of controlled trials of the effectiveness and cost-effectiveness of brief psychological treatments for depression.

    By Churchill R, Hunot V, Corney R, Knapp M, McGuire H, Tylee A, et al.

36. Cost analysis of child health surveillance.

    By Sanderson D, Wright D, Acton C, Duree D.

1. A study of the methods used to select review criteria for clinical audit.

   By Hearnshaw H, Harker R, Cheater F, Baker R, Grimshaw G.

2. Fludarabine as second-line therapy for B cell chronic lymphocytic leukaemia: a technology assessment.

   By Hyde C, Wake B, Bryan S, Barton P, Fry-Smith A, Davenport C, et al.

3. Rituximab as third-line treatment for refractory or recurrent Stage III or IV follicular non-Hodgkin’s lymphoma: a systematic review and economic evaluation.

   By Wake B, Hyde C, Bryan S, Barton P, Song F, Fry-Smith A, et al.

4. A systematic review of discharge arrangements for older people.

   By Parker SG, Peet SM, McPherson A, Cannaby AM, Baker R, Wilson A, et al.

5. The clinical effectiveness and cost-effectiveness of inhaler devices used in the routine management of chronic asthma in older children: a systematic review and economic evaluation.

   By Peters J, Stevenson M, Beverley C, Lim J, Smith S.

6. The clinical effectiveness and cost-effectiveness of sibutramine in the management of obesity: a technology assessment.

   By O’Meara S, Riemsma R, Shirran L, Mather L, ter Riet G.

7. The cost-effectiveness of magnetic resonance angiography for carotid artery stenosis and peripheral vascular disease: a systematic review.

   By Berry E, Kelly S, Westwood ME, Davies LM, Gough MJ, Bamford JM, et al.

8. Promoting physical activity in South Asian Muslim women through ‘exercise on prescription’.

   By Carroll B, Ali N, Azam N.

9. Zanamivir for the treatment of influenza in adults: a systematic review and economic evaluation.

   By Burls A, Clark W, Stewart T, Preston C, Bryan S, Jefferson T, et al.

10. A review of the natural history and epidemiology of multiple sclerosis: implications for resource allocation and health economic models.

    By Richards RG, Sampson FC, Beard SM, Tappenden P.

11. Screening for gestational diabetes: a systematic review and economic evaluation.

    By Scott DA, Loveman E, McIntyre L, Waugh N.

12. The clinical effectiveness and cost-effectiveness of surgery for people with morbid obesity: a systematic review and economic evaluation.

    By Clegg AJ, Colquitt J, Sidhu MK, Royle P, Loveman E, Walker A.

13. The clinical effectiveness of trastuzumab for breast cancer: a systematic review.

    By Lewis R, Bagnall A-M, Forbes C, Shirran E, Duffy S, Kleijnen J, et al.

14. The clinical effectiveness and cost-effectiveness of vinorelbine for breast cancer: a systematic review and economic evaluation.

    By Lewis R, Bagnall A-M, King S, Woolacott N, Forbes C, Shirran L, et al.

15. A systematic review of the effectiveness and cost-effectiveness of metal-on-metal hip resurfacing arthroplasty for treatment of hip disease.

    By Vale L, Wyness L, McCormack K, McKenzie L, Brazzelli M, Stearns SC.

16. The clinical effectiveness and cost-effectiveness of bupropion and nicotine replacement therapy for smoking cessation: a systematic review and economic evaluation.

    By Woolacott NF, Jones L, Forbes CA, Mather LC, Sowden AJ, Song FJ, et al.

17. A systematic review of effectiveness and economic evaluation of new drug treatments for juvenile idiopathic arthritis: etanercept.

    By Cummins C, Connock M, Fry-Smith A, Burls A.

18. Clinical effectiveness and cost-effectiveness of growth hormone in children: a systematic review and economic evaluation.

    By Bryant J, Cave C, Mihaylova B, Chase D, McIntyre L, Gerard K, et al.

19. Clinical effectiveness and cost-effectiveness of growth hormone in adults in relation to impact on quality of life: a systematic review and economic evaluation.

    By Bryant J, Loveman E, Chase D, Mihaylova B, Cave C, Gerard K, et al.

20. Clinical medication review by a pharmacist of patients on repeat prescriptions in general practice: a randomised controlled trial.

    By Zermansky AG, Petty DR, Raynor DK, Lowe CJ, Freementle N, Vail A.

21. The effectiveness of infliximab and etanercept for the treatment of rheumatoid arthritis: a systematic review and economic evaluation.

    By Jobanputra P, Barton P, Bryan S, Burls A.

22. A systematic review and economic evaluation of computerised cognitive behaviour therapy for depression and anxiety.

    By Kaltenthaler E, Shackley P, Stevens K, Beverley C, Parry G, Chilcott J.

23. A systematic review and economic evaluation of pegylated liposomal doxorubicin hydrochloride for ovarian cancer.

    By Forbes C, Wilby J, Richardson G, Sculpher M, Mather L, Reimsma R.

24. A systematic review of the effectiveness of interventions based on a stages-of-change approach to promote individual behaviour change.

    By Riemsma RP, Pattenden J, Bridle C, Sowden AJ, Mather L, Watt IS, et al.

25. A systematic review update of the clinical effectiveness and cost-effectiveness of glycoprotein IIb/IIIa antagonists.

    By Robinson M, Ginnelly L, Sculpher M, Jones L, Riemsma R, Palmer S, et al.

26. A systematic review of the effectiveness, cost-effectiveness and barriers to implementation of thrombolytic and neuroprotective therapy for acute ischaemic stroke in the NHS.

    By Sandercock P, Berge E, Dennis M, Forbes J, Hand P, Kwan J, et al.

27. A randomised controlled crossover trial of nurse practitioner versus doctor-led outpatient care in a bronchiectasis clinic.

    By Caine N, Sharples LD, Hollingworth W, French J, Keogan M, Exley A, et al.

28. Clinical effectiveness and cost – consequences of selective serotonin reuptake inhibitors in the treatment of sex offenders.

    By Adi Y, Ashcroft D, Browne K, Beech A, Fry-Smith A, Hyde C.

29. Treatment of established osteoporosis: a systematic review and cost–utility analysis.

    By Kanis JA, Brazier JE, Stevenson M, Calvert NW, Lloyd Jones M.

30. Which anaesthetic agents are cost-effective in day surgery? Literature review, national survey of practice and randomised controlled trial.

    By Elliott RA Payne K, Moore JK, Davies LM, Harper NJN, St Leger AS, et al.

31. Screening for hepatitis C among injecting drug users and in genitourinary medicine clinics: systematic reviews of effectiveness, modelling study and national survey of current practice.

    By Stein K, Dalziel K, Walker A, McIntyre L, Jenkins B, Horne J, et al.

32. The measurement of satisfaction with healthcare: implications for practice from a systematic review of the literature.

    By Crow R, Gage H, Hampson S, Hart J, Kimber A, Storey L, et al.

33. The effectiveness and cost-effectiveness of imatinib in chronic myeloid leukaemia: a systematic review.

    By Garside R, Round A, Dalziel K, Stein K, Royle R.

34. A comparative study of hypertonic saline, daily and alternate-day rhDNase in children with cystic fibrosis.

    By Suri R, Wallis C, Bush A, Thompson S, Normand C, Flather M, et al.

35. A systematic review of the costs and effectiveness of different models of paediatric home care.

    By Parker G, Bhakta P, Lovett CA, Paisley S, Olsen R, Turner D, et al.

1. How important are comprehensive literature searches and the assessment of trial quality in systematic reviews? Empirical study.

   By Egger M, Jüni P, Bartlett C, Holenstein F, Sterne J.

2. Systematic review of the effectiveness and cost-effectiveness, and economic evaluation, of home versus hospital or satellite unit haemodialysis for people with end-stage renal failure.

   By Mowatt G, Vale L, Perez J, Wyness L, Fraser C, MacLeod A, et al.

3. Systematic review and economic evaluation of the effectiveness of infliximab for the treatment of Crohn’s disease.

   By Clark W, Raftery J, Barton P, Song F, Fry-Smith A, Burls A.

4. A review of the clinical effectiveness and cost-effectiveness of routine anti-D prophylaxis for pregnant women who are rhesus negative.

   By Chilcott J, Lloyd Jones M, Wight J, Forman K, Wray J, Beverley C, et al.

5. Systematic review and evaluation of the use of tumour markers in paediatric oncology: Ewing’s sarcoma and neuroblastoma.

   By Riley RD, Burchill SA, Abrams KR, Heney D, Lambert PC, Jones DR, et al.

6. The cost-effectiveness of screening for Helicobacter pylori to reduce mortality and morbidity from gastric cancer and peptic ulcer disease: a discrete-event simulation model.

   By Roderick P, Davies R, Raftery J, Crabbe D, Pearce R, Bhandari P, et al.

7. The clinical effectiveness and cost-effectiveness of routine dental checks: a systematic review and economic evaluation.

   By Davenport C, Elley K, Salas C, Taylor-Weetman CL, Fry-Smith A, Bryan S, et al.

8. A multicentre randomised controlled trial assessing the costs and benefits of using structured information and analysis of women’s preferences in the management of menorrhagia.

   By Kennedy ADM, Sculpher MJ, Coulter A, Dwyer N, Rees M, Horsley S, et al.

9. Clinical effectiveness and cost–utility of photodynamic therapy for wet age-related macular degeneration: a systematic review and economic evaluation.

   By Meads C, Salas C, Roberts T, Moore D, Fry-Smith A, Hyde C.

10. Evaluation of molecular tests for prenatal diagnosis of chromosome abnormalities.

    By Grimshaw GM, Szczepura A, Hultén M, MacDonald F, Nevin NC, Sutton F, et al.

11. First and second trimester antenatal screening for Down’s syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS).

    By Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L, Mackinson AM.

12. The effectiveness and cost-effectiveness of ultrasound locating devices for central venous access: a systematic review and economic evaluation.

    By Calvert N, Hind D, McWilliams RG, Thomas SM, Beverley C, Davidson A.

13. A systematic review of atypical antipsychotics in schizophrenia.

    By Bagnall A-M, Jones L, Lewis R, Ginnelly L, Glanville J, Torgerson D, et al.

14. Prostate Testing for Cancer and Treatment (ProtecT) feasibility study.

    By Donovan J, Hamdy F, Neal D, Peters T, Oliver S, Brindle L, et al.

15. Early thrombolysis for the treatment of acute myocardial infarction: a systematic review and economic evaluation.

    By Boland A, Dundar Y, Bagust A, Haycox A, Hill R, Mujica Mota R, et al.

16. Screening for fragile X syndrome: a literature review and modelling.

    By Song FJ, Barton P, Sleightholme V, Yao GL, Fry-Smith A.

17. Systematic review of endoscopic sinus surgery for nasal polyps.

    By Dalziel K, Stein K, Round A, Garside R, Royle P.

18. Towards efficient guidelines: how to monitor guideline use in primary care.

    By Hutchinson A, McIntosh A, Cox S, Gilbert C.

19. Effectiveness and cost-effectiveness of acute hospital-based spinal cord injuries services: systematic review.

    By Bagnall A-M, Jones L, Richardson G, Duffy S, Riemsma R.

20. Prioritisation of health technology assessment. The PATHS model: methods and case studies.

    By Townsend J, Buxton M, Harper G.

21. Systematic review of the clinical effectiveness and cost-effectiveness of tension-free vaginal tape for treatment of urinary stress incontinence.

    By Cody J, Wyness L, Wallace S, Glazener C, Kilonzo M, Stearns S, et al.

22. The clinical and cost-effectiveness of patient education models for diabetes: a systematic review and economic evaluation.

    By Loveman E, Cave C, Green C, Royle P, Dunn N, Waugh N.

23. The role of modelling in prioritising and planning clinical trials.

    By Chilcott J, Brennan A, Booth A, Karnon J, Tappenden P.

24. Cost–benefit evaluation of routine influenza immunisation in people 65–74 years of age.

    By Allsup S, Gosney M, Haycox A, Regan M.

25. The clinical and cost-effectiveness of pulsatile machine perfusion versus cold storage of kidneys for transplantation retrieved from heart-beating and non-heart-beating donors.

    By Wight J, Chilcott J, Holmes M, Brewer N.

26. Can randomised trials rely on existing electronic data? A feasibility study to explore the value of routine data in health technology assessment.

    By Williams JG, Cheung WY, Cohen DR, Hutchings HA, Longo MF, Russell IT.

27. Evaluating non-randomised intervention studies.

    By Deeks JJ, Dinnes J, D’Amico R, Sowden AJ, Sakarovitch C, Song F, et al.

28. A randomised controlled trial to assess the impact of a package comprising a patient-orientated, evidence-based self- help guidebook and patient-centred consultations on disease management and satisfaction in inflammatory bowel disease.

    By Kennedy A, Nelson E, Reeves D, Richardson G, Roberts C, Robinson A, et al.

29. The effectiveness of diagnostic tests for the assessment of shoulder pain due to soft tissue disorders: a systematic review.

    By Dinnes J, Loveman E, McIntyre L, Waugh N.

30. The value of digital imaging in diabetic retinopathy.

    By Sharp PF, Olson J, Strachan F, Hipwell J, Ludbrook A, O’Donnell M, et al.

31. Lowering blood pressure to prevent myocardial infarction and stroke: a new preventive strategy.

    By Law M, Wald N, Morris J.

32. Clinical and cost-effectiveness of capecitabine and tegafur with uracil for the treatment of metastatic colorectal cancer: systematic review and economic evaluation.

    By Ward S, Kaltenthaler E, Cowan J, Brewer N.

33. Clinical and cost-effectiveness of new and emerging technologies for early localised prostate cancer: a systematic review.

    By Hummel S, Paisley S, Morgan A, Currie E, Brewer N.

34. Literature searching for clinical and cost-effectiveness studies used in health technology assessment reports carried out for the National Institute for Clinical Excellence appraisal system.

    By Royle P, Waugh N.

35. Systematic review and economic decision modelling for the prevention and treatment of influenza A and B.

    By Turner D, Wailoo A, Nicholson K, Cooper N, Sutton A, Abrams K.

36. A randomised controlled trial to evaluate the clinical and cost-effectiveness of Hickman line insertions in adult cancer patients by nurses.

    By Boland A, Haycox A, Bagust A, Fitzsimmons L.

37. Redesigning postnatal care: a randomised controlled trial of protocol-based midwifery-led care focused on individual women’s physical and psychological health needs.

    By MacArthur C, Winter HR, Bick DE, Lilford RJ, Lancashire RJ, Knowles H, et al.

38. Estimating implied rates of discount in healthcare decision-making.

    By West RR, McNabb R, Thompson AGH, Sheldon TA, Grimley Evans J.

39. Systematic review of isolation policies in the hospital management of methicillin-resistant Staphylococcus aureus: a review of the literature with epidemiological and economic modelling.

    By Cooper BS, Stone SP, Kibbler CC, Cookson BD, Roberts JA, Medley GF, et al.

40. Treatments for spasticity and pain in multiple sclerosis: a systematic review.

    By Beard S, Hunn A, Wight J.

41. The inclusion of reports of randomised trials published in languages other than English in systematic reviews.

    By Moher D, Pham B, Lawson ML, Klassen TP.

42. The impact of screening on future health-promoting behaviours and health beliefs: a systematic review.

    By Bankhead CR, Brett J, Bukach C, Webster P, Stewart-Brown S, Munafo M, et al.

1. What is the best imaging strategy for acute stroke?

   By Wardlaw JM, Keir SL, Seymour J, Lewis S, Sandercock PAG, Dennis MS, et al.

2. Systematic review and modelling of the investigation of acute and chronic chest pain presenting in primary care.

   By Mant J, McManus RJ, Oakes RAL, Delaney BC, Barton PM, Deeks JJ, et al.

3. The effectiveness and cost-effectiveness of microwave and thermal balloon endometrial ablation for heavy menstrual bleeding: a systematic review and economic modelling.

   By Garside R, Stein K, Wyatt K, Round A, Price A.

4. A systematic review of the role of bisphosphonates in metastatic disease.

   By Ross JR, Saunders Y, Edmonds PM, Patel S, Wonderling D, Normand C, et al.

5. Systematic review of the clinical effectiveness and cost-effectiveness of capecitabine (Xeloda^®) for locally advanced and/or metastatic breast cancer.

   By Jones L, Hawkins N, Westwood M, Wright K, Richardson G, Riemsma R.

6. Effectiveness and efficiency of guideline dissemination and implementation strategies.

   By Grimshaw JM, Thomas RE, MacLennan G, Fraser C, Ramsay CR, Vale L, et al.

7. Clinical effectiveness and costs of the Sugarbaker procedure for the treatment of pseudomyxoma peritonei.

   By Bryant J, Clegg AJ, Sidhu MK, Brodin H, Royle P, Davidson P.

8. Psychological treatment for insomnia in the regulation of long-term hypnotic drug use.

   By Morgan K, Dixon S, Mathers N, Thompson J, Tomeny M.

9. Improving the evaluation of therapeutic interventions in multiple sclerosis: development of a patient-based measure of outcome.

   By Hobart JC, Riazi A, Lamping DL, Fitzpatrick R, Thompson AJ.

10. A systematic review and economic evaluation of magnetic resonance cholangiopancreatography compared with diagnostic endoscopic retrograde cholangiopancreatography.

    By Kaltenthaler E, Bravo Vergel Y, Chilcott J, Thomas S, Blakeborough T, Walters SJ, et al.

11. The use of modelling to evaluate new drugs for patients with a chronic condition: the case of antibodies against tumour necrosis factor in rheumatoid arthritis.

    By Barton P, Jobanputra P, Wilson J, Bryan S, Burls A.

12. Clinical effectiveness and cost-effectiveness of neonatal screening for inborn errors of metabolism using tandem mass spectrometry: a systematic review.

    By Pandor A, Eastham J, Beverley C, Chilcott J, Paisley S.

13. Clinical effectiveness and cost-effectiveness of pioglitazone and rosiglitazone in the treatment of type 2 diabetes: a systematic review and economic evaluation.

    By Czoski-Murray C, Warren E, Chilcott J, Beverley C, Psyllaki MA, Cowan J.

14. Routine examination of the newborn: the EMREN study. Evaluation of an extension of the midwife role including a randomised controlled trial of appropriately trained midwives and paediatric senior house officers.

    By Townsend J, Wolke D, Hayes J, Davé S, Rogers C, Bloomfield L, et al.

15. Involving consumers in research and development agenda setting for the NHS: developing an evidence-based approach.

    By Oliver S, Clarke-Jones L, Rees R, Milne R, Buchanan P, Gabbay J, et al.

16. A multi-centre randomised controlled trial of minimally invasive direct coronary bypass grafting versus percutaneous transluminal coronary angioplasty with stenting for proximal stenosis of the left anterior descending coronary artery.

    By Reeves BC, Angelini GD, Bryan AJ, Taylor FC, Cripps T, Spyt TJ, et al.

17. Does early magnetic resonance imaging influence management or improve outcome in patients referred to secondary care with low back pain? A pragmatic randomised controlled trial.

    By Gilbert FJ, Grant AM, Gillan MGC, Vale L, Scott NW, Campbell MK, et al.

18. The clinical and cost-effectiveness of anakinra for the treatment of rheumatoid arthritis in adults: a systematic review and economic analysis.

    By Clark W, Jobanputra P, Barton P, Burls A.

19. A rapid and systematic review and economic evaluation of the clinical and cost-effectiveness of newer drugs for treatment of mania associated with bipolar affective disorder.

    By Bridle C, Palmer S, Bagnall A-M, Darba J, Duffy S, Sculpher M, et al.

20. Liquid-based cytology in cervical screening: an updated rapid and systematic review and economic analysis.

    By Karnon J, Peters J, Platt J, Chilcott J, McGoogan E, Brewer N.

21. Systematic review of the long-term effects and economic consequences of treatments for obesity and implications for health improvement.

    By Avenell A, Broom J, Brown TJ, Poobalan A, Aucott L, Stearns SC, et al.

22. Autoantibody testing in children with newly diagnosed type 1 diabetes mellitus.

    By Dretzke J, Cummins C, Sandercock J, Fry-Smith A, Barrett T, Burls A.

23. Clinical effectiveness and cost-effectiveness of prehospital intravenous fluids in trauma patients.

    By Dretzke J, Sandercock J, Bayliss S, Burls A.

24. Newer hypnotic drugs for the short-term management of insomnia: a systematic review and economic evaluation.

    By Dündar Y, Boland A, Strobl J, Dodd S, Haycox A, Bagust A, et al.

25. Development and validation of methods for assessing the quality of diagnostic accuracy studies.

    By Whiting P, Rutjes AWS, Dinnes J, Reitsma JB, Bossuyt PMM, Kleijnen J.

26. EVALUATE hysterectomy trial: a multicentre randomised trial comparing abdominal, vaginal and laparoscopic methods of hysterectomy.

    By Garry R, Fountain J, Brown J, Manca A, Mason S, Sculpher M, et al.

27. Methods for expected value of information analysis in complex health economic models: developments on the health economics of interferon-β and glatiramer acetate for multiple sclerosis.

    By Tappenden P, Chilcott JB, Eggington S, Oakley J, McCabe C.

28. Effectiveness and cost-effectiveness of imatinib for first-line treatment of chronic myeloid leukaemia in chronic phase: a systematic review and economic analysis.

    By Dalziel K, Round A, Stein K, Garside R, Price A.

29. VenUS I: a randomised controlled trial of two types of bandage for treating venous leg ulcers.

    By Iglesias C, Nelson EA, Cullum NA, Torgerson DJ, on behalf of the VenUS Team.

30. Systematic review of the effectiveness and cost-effectiveness, and economic evaluation, of myocardial perfusion scintigraphy for the diagnosis and management of angina and myocardial infarction.

    By Mowatt G, Vale L, Brazzelli M, Hernandez R, Murray A, Scott N, et al.

31. A pilot study on the use of decision theory and value of information analysis as part of the NHS Health Technology Assessment programme.

    By Claxton K, Ginnelly L, Sculpher M, Philips Z, Palmer S.

32. The Social Support and Family Health Study: a randomised controlled trial and economic evaluation of two alternative forms of postnatal support for mothers living in disadvantaged inner-city areas.

    By Wiggins M, Oakley A, Roberts I, Turner H, Rajan L, Austerberry H, et al.

33. Psychosocial aspects of genetic screening of pregnant women and newborns: a systematic review.

    By Green JM, Hewison J, Bekker HL, Bryant, Cuckle HS.

34. Evaluation of abnormal uterine bleeding: comparison of three outpatient procedures within cohorts defined by age and menopausal status.

    By Critchley HOD, Warner P, Lee AJ, Brechin S, Guise J, Graham B.

35. Coronary artery stents: a rapid systematic review and economic evaluation.

    By Hill R, Bagust A, Bakhai A, Dickson R, Dündar Y, Haycox A, et al.

36. Review of guidelines for good practice in decision-analytic modelling in health technology assessment.

    By Philips Z, Ginnelly L, Sculpher M, Claxton K, Golder S, Riemsma R, et al.

37. Rituximab (MabThera^®) for aggressive non-Hodgkin’s lymphoma: systematic review and economic evaluation.

    By Knight C, Hind D, Brewer N, Abbott V.

38. Clinical effectiveness and cost-effectiveness of clopidogrel and modified-release dipyridamole in the secondary prevention of occlusive vascular events: a systematic review and economic evaluation.

    By Jones L, Griffin S, Palmer S, Main C, Orton V, Sculpher M, et al.

39. Pegylated interferon α-2a and -2b in combination with ribavirin in the treatment of chronic hepatitis C: a systematic review and economic evaluation.

    By Shepherd J, Brodin H, Cave C, Waugh N, Price A, Gabbay J.

40. Clopidogrel used in combination with aspirin compared with aspirin alone in the treatment of non-ST-segment- elevation acute coronary syndromes: a systematic review and economic evaluation.

    By Main C, Palmer S, Griffin S, Jones L, Orton V, Sculpher M, et al.

41. Provision, uptake and cost of cardiac rehabilitation programmes: improving services to under-represented groups.

    By Beswick AD, Rees K, Griebsch I, Taylor FC, Burke M, West RR, et al.

42. Involving South Asian patients in clinical trials.

    By Hussain-Gambles M, Leese B, Atkin K, Brown J, Mason S, Tovey P.

43. Clinical and cost-effectiveness of continuous subcutaneous insulin infusion for diabetes.

    By Colquitt JL, Green C, Sidhu MK, Hartwell D, Waugh N.

44. Identification and assessment of ongoing trials in health technology assessment reviews.

    By Song FJ, Fry-Smith A, Davenport C, Bayliss S, Adi Y, Wilson JS, et al.

45. Systematic review and economic evaluation of a long-acting insulin analogue, insulin glargine

    By Warren E, Weatherley-Jones E, Chilcott J, Beverley C.

46. Supplementation of a home-based exercise programme with a class-based programme for people with osteoarthritis of the knees: a randomised controlled trial and health economic analysis.

    By McCarthy CJ, Mills PM, Pullen R, Richardson G, Hawkins N, Roberts CR, et al.

47. Clinical and cost-effectiveness of once-daily versus more frequent use of same potency topical corticosteroids for atopic eczema: a systematic review and economic evaluation.

    By Green C, Colquitt JL, Kirby J, Davidson P, Payne E.

48. Acupuncture of chronic headache disorders in primary care: randomised controlled trial and economic analysis.

    By Vickers AJ, Rees RW, Zollman CE, McCarney R, Smith CM, Ellis N, et al.

49. Generalisability in economic evaluation studies in healthcare: a review and case studies.

    By Sculpher MJ, Pang FS, Manca A, Drummond MF, Golder S, Urdahl H, et al.

50. Virtual outreach: a randomised controlled trial and economic evaluation of joint teleconferenced medical consultations.

    By Wallace P, Barber J, Clayton W, Currell R, Fleming K, Garner P, et al.

1. Randomised controlled multiple treatment comparison to provide a cost-effectiveness rationale for the selection of antimicrobial therapy in acne.

   By Ozolins M, Eady EA, Avery A, Cunliffe WJ, O’Neill C, Simpson NB, et al.

2. Do the findings of case series studies vary significantly according to methodological characteristics?

   By Dalziel K, Round A, Stein K, Garside R, Castelnuovo E, Payne L.

3. Improving the referral process for familial breast cancer genetic counselling: findings of three randomised controlled trials of two interventions.

   By Wilson BJ, Torrance N, Mollison J, Wordsworth S, Gray JR, Haites NE, et al.

4. Randomised evaluation of alternative electrosurgical modalities to treat bladder outflow obstruction in men with benign prostatic hyperplasia.

   By Fowler C, McAllister W, Plail R, Karim O, Yang Q.

5. A pragmatic randomised controlled trial of the cost-effectiveness of palliative therapies for patients with inoperable oesophageal cancer.

   By Shenfine J, McNamee P, Steen N, Bond J, Griffin SM.

6. Impact of computer-aided detection prompts on the sensitivity and specificity of screening mammography.

   By Taylor P, Champness J, Given- Wilson R, Johnston K, Potts H.

7. Issues in data monitoring and interim analysis of trials.

   By Grant AM, Altman DG, Babiker AB, Campbell MK, Clemens FJ, Darbyshire JH, et al.

8. Lay public’s understanding of equipoise and randomisation in randomised controlled trials.

   By Robinson EJ, Kerr CEP, Stevens AJ, Lilford RJ, Braunholtz DA, Edwards SJ, et al.

9. Clinical and cost-effectiveness of electroconvulsive therapy for depressive illness, schizophrenia, catatonia and mania: systematic reviews and economic modelling studies.

   By Greenhalgh J, Knight C, Hind D, Beverley C, Walters S.

10. Measurement of health-related quality of life for people with dementia: development of a new instrument (DEMQOL) and an evaluation of current methodology.

    By Smith SC, Lamping DL, Banerjee S, Harwood R, Foley B, Smith P, et al.

11. Clinical effectiveness and cost-effectiveness of drotrecogin alfa (activated) (Xigris^®) for the treatment of severe sepsis in adults: a systematic review and economic evaluation.

    By Green C, Dinnes J, Takeda A, Shepherd J, Hartwell D, Cave C, et al.

12. A methodological review of how heterogeneity has been examined in systematic reviews of diagnostic test accuracy.

    By Dinnes J, Deeks J, Kirby J, Roderick P.

13. Cervical screening programmes: can automation help? Evidence from systematic reviews, an economic analysis and a simulation modelling exercise applied to the UK.

    By Willis BH, Barton P, Pearmain P, Bryan S, Hyde C.

14. Laparoscopic surgery for inguinal hernia repair: systematic review of effectiveness and economic evaluation.

    By McCormack K, Wake B, Perez J, Fraser C, Cook J, McIntosh E, et al.

15. Clinical effectiveness, tolerability and cost-effectiveness of newer drugs for epilepsy in adults: a systematic review and economic evaluation.

    By Wilby J, Kainth A, Hawkins N, Epstein D, McIntosh H, McDaid C, et al.

16. A randomised controlled trial to compare the cost-effectiveness of tricyclic antidepressants, selective serotonin reuptake inhibitors and lofepramine.

    By Peveler R, Kendrick T, Buxton M, Longworth L, Baldwin D, Moore M, et al.

17. Clinical effectiveness and cost-effectiveness of immediate angioplasty for acute myocardial infarction: systematic review and economic evaluation.

    By Hartwell D, Colquitt J, Loveman E, Clegg AJ, Brodin H, Waugh N, et al.

18. A randomised controlled comparison of alternative strategies in stroke care.

    By Kalra L, Evans A, Perez I, Knapp M, Swift C, Donaldson N.

19. The investigation and analysis of critical incidents and adverse events in healthcare.

    By Woloshynowych M, Rogers S, Taylor-Adams S, Vincent C.

20. Potential use of routine databases in health technology assessment.

    By Raftery J, Roderick P, Stevens A.

21. Clinical and cost-effectiveness of newer immunosuppressive regimens in renal transplantation: a systematic review and modelling study.

    By Woodroffe R, Yao GL, Meads C, Bayliss S, Ready A, Raftery J, et al.

22. A systematic review and economic evaluation of alendronate, etidronate, risedronate, raloxifene and teriparatide for the prevention and treatment of postmenopausal osteoporosis.

    By Stevenson M, Lloyd Jones M, De Nigris E, Brewer N, Davis S, Oakley J.

23. A systematic review to examine the impact of psycho-educational interventions on health outcomes and costs in adults and children with difficult asthma.

    By Smith JR, Mugford M, Holland R, Candy B, Noble MJ, Harrison BDW, et al.

24. An evaluation of the costs, effectiveness and quality of renal replacement therapy provision in renal satellite units in England and Wales.

    By Roderick P, Nicholson T, Armitage A, Mehta R, Mullee M, Gerard K, et al.

25. Imatinib for the treatment of patients with unresectable and/or metastatic gastrointestinal stromal tumours: systematic review and economic evaluation.

    By Wilson J, Connock M, Song F, Yao G, Fry-Smith A, Raftery J, et al.

26. Indirect comparisons of competing interventions.

    By Glenny AM, Altman DG, Song F, Sakarovitch C, Deeks JJ, D’Amico R, et al.

27. Cost-effectiveness of alternative strategies for the initial medical management of non-ST elevation acute coronary syndrome: systematic review and decision-analytical modelling.

    By Robinson M, Palmer S, Sculpher M, Philips Z, Ginnelly L, Bowens A, et al.

28. Outcomes of electrically stimulated gracilis neosphincter surgery.

    By Tillin T, Chambers M, Feldman R.

29. The effectiveness and cost-effectiveness of pimecrolimus and tacrolimus for atopic eczema: a systematic review and economic evaluation.

    By Garside R, Stein K, Castelnuovo E, Pitt M, Ashcroft D, Dimmock P, et al.

30. Systematic review on urine albumin testing for early detection of diabetic complications.

    By Newman DJ, Mattock MB, Dawnay ABS, Kerry S, McGuire A, Yaqoob M, et al.

31. Randomised controlled trial of the cost-effectiveness of water-based therapy for lower limb osteoarthritis.

    By Cochrane T, Davey RC, Matthes Edwards SM.

32. Longer term clinical and economic benefits of offering acupuncture care to patients with chronic low back pain.

    By Thomas KJ, MacPherson H, Ratcliffe J, Thorpe L, Brazier J, Campbell M, et al.

33. Cost-effectiveness and safety of epidural steroids in the management of sciatica.

    By Price C, Arden N, Coglan L, Rogers P.

34. The British Rheumatoid Outcome Study Group (BROSG) randomised controlled trial to compare the effectiveness and cost-effectiveness of aggressive versus symptomatic therapy in established rheumatoid arthritis.

    By Symmons D, Tricker K, Roberts C, Davies L, Dawes P, Scott DL.

35. Conceptual framework and systematic review of the effects of participants’ and professionals’ preferences in randomised controlled trials.

    By King M, Nazareth I, Lampe F, Bower P, Chandler M, Morou M, et al.

36. The clinical and cost-effectiveness of implantable cardioverter defibrillators: a systematic review.

    By Bryant J, Brodin H, Loveman E, Payne E, Clegg A.

37. A trial of problem-solving by community mental health nurses for anxiety, depression and life difficulties among general practice patients. The CPN-GP study.

    By Kendrick T, Simons L, Mynors-Wallis L, Gray A, Lathlean J, Pickering R, et al.

38. The causes and effects of socio-demographic exclusions from clinical trials.

    By Bartlett C, Doyal L, Ebrahim S, Davey P, Bachmann M, Egger M, et al.

39. Is hydrotherapy cost-effective? A randomised controlled trial of combined hydrotherapy programmes compared with physiotherapy land techniques in children with juvenile idiopathic arthritis.

    By Epps H, Ginnelly L, Utley M, Southwood T, Gallivan S, Sculpher M, et al.

40. A randomised controlled trial and cost-effectiveness study of systematic screening (targeted and total population screening) versus routine practice for the detection of atrial fibrillation in people aged 65 and over. The SAFE study.

    By Hobbs FDR, Fitzmaurice DA, Mant J, Murray E, Jowett S, Bryan S, et al.

41. Displaced intracapsular hip fractures in fit, older people: a randomised comparison of reduction and fixation, bipolar hemiarthroplasty and total hip arthroplasty.

    By Keating JF, Grant A, Masson M, Scott NW, Forbes JF.

42. Long-term outcome of cognitive behaviour therapy clinical trials in central Scotland.

    By Durham RC, Chambers JA, Power KG, Sharp DM, Macdonald RR, Major KA, et al.

43. The effectiveness and cost-effectiveness of dual-chamber pacemakers compared with single-chamber pacemakers for bradycardia due to atrioventricular block or sick sinus syndrome: systematic review and economic evaluation.

    By Castelnuovo E, Stein K, Pitt M, Garside R, Payne E.

44. Newborn screening for congenital heart defects: a systematic review and cost-effectiveness analysis.

    By Knowles R, Griebsch I, Dezateux C, Brown J, Bull C, Wren C.

45. The clinical and cost-effectiveness of left ventricular assist devices for end-stage heart failure: a systematic review and economic evaluation.

    By Clegg AJ, Scott DA, Loveman E, Colquitt J, Hutchinson J, Royle P, et al.

46. The effectiveness of the Heidelberg Retina Tomograph and laser diagnostic glaucoma scanning system (GDx) in detecting and monitoring glaucoma.

    By Kwartz AJ, Henson DB, Harper RA, Spencer AF, McLeod D.

47. Clinical and cost-effectiveness of autologous chondrocyte implantation for cartilage defects in knee joints: systematic review and economic evaluation.

    By Clar C, Cummins E, McIntyre L, Thomas S, Lamb J, Bain L, et al.

48. Systematic review of effectiveness of different treatments for childhood retinoblastoma.

    By McDaid C, Hartley S, Bagnall A-M, Ritchie G, Light K, Riemsma R.

49. Towards evidence-based guidelines for the prevention of venous thromboembolism: systematic reviews of mechanical methods, oral anticoagulation, dextran and regional anaesthesia as thromboprophylaxis.

    By Roderick P, Ferris G, Wilson K, Halls H, Jackson D, Collins R, et al.

50. The effectiveness and cost-effectiveness of parent training/education programmes for the treatment of conduct disorder, including oppositional defiant disorder, in children.

    By Dretzke J, Frew E, Davenport C, Barlow J, Stewart-Brown S, Sandercock J, et al.

1. The clinical and cost-effectiveness of donepezil, rivastigmine, galantamine and memantine for Alzheimer’s disease.

   By Loveman E, Green C, Kirby J, Takeda A, Picot J, Payne E, et al.

2. FOOD: a multicentre randomised trial evaluating feeding policies in patients admitted to hospital with a recent stroke.

   By Dennis M, Lewis S, Cranswick G, Forbes J.

3. The clinical effectiveness and cost-effectiveness of computed tomography screening for lung cancer: systematic reviews.

   By Black C, Bagust A, Boland A, Walker S, McLeod C, De Verteuil R, et al.

4. A systematic review of the effectiveness and cost-effectiveness of neuroimaging assessments used to visualise the seizure focus in people with refractory epilepsy being considered for surgery.

   By Whiting P, Gupta R, Burch J, Mujica Mota RE, Wright K, Marson A, et al.

5. Comparison of conference abstracts and presentations with full-text articles in the health technology assessments of rapidly evolving technologies.

   By Dundar Y, Dodd S, Dickson R, Walley T, Haycox A, Williamson PR.

6. Systematic review and evaluation of methods of assessing urinary incontinence.

   By Martin JL, Williams KS, Abrams KR, Turner DA, Sutton AJ, Chapple C, et al.

7. The clinical effectiveness and cost-effectiveness of newer drugs for children with epilepsy. A systematic review.

   By Connock M, Frew E, Evans B-W, Bryan S, Cummins C, Fry-Smith A, et al.

8. Surveillance of Barrett’s oesophagus: exploring the uncertainty through systematic review, expert workshop and economic modelling.

   By Garside R, Pitt M, Somerville M, Stein K, Price A, Gilbert N.

9. Topotecan, pegylated liposomal doxorubicin hydrochloride and paclitaxel for second-line or subsequent treatment of advanced ovarian cancer: a systematic review and economic evaluation.

   By Main C, Bojke L, Griffin S, Norman G, Barbieri M, Mather L, et al.

10. Evaluation of molecular techniques in prediction and diagnosis of cytomegalovirus disease in immunocompromised patients.

    By Szczepura A, Westmoreland D, Vinogradova Y, Fox J, Clark M.

11. Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study.

    By Wu O, Robertson L, Twaddle S, Lowe GDO, Clark P, Greaves M, et al.

12. A series of systematic reviews to inform a decision analysis for sampling and treating infected diabetic foot ulcers.

    By Nelson EA, O’Meara S, Craig D, Iglesias C, Golder S, Dalton J, et al.

13. Randomised clinical trial, observational study and assessment of cost-effectiveness of the treatment of varicose veins (REACTIV trial).

    By Michaels JA, Campbell WB, Brazier JE, MacIntyre JB, Palfreyman SJ, Ratcliffe J, et al.

14. The cost-effectiveness of screening for oral cancer in primary care.

    By Speight PM, Palmer S, Moles DR, Downer MC, Smith DH, Henriksson M, et al.

15. Measurement of the clinical and cost-effectiveness of non-invasive diagnostic testing strategies for deep vein thrombosis.

    By Goodacre S, Sampson F, Stevenson M, Wailoo A, Sutton A, Thomas S, et al.

16. Systematic review of the effectiveness and cost-effectiveness of HealOzone^® for the treatment of occlusal pit/fissure caries and root caries.

    By Brazzelli M, McKenzie L, Fielding S, Fraser C, Clarkson J, Kilonzo M, et al.

17. Randomised controlled trials of conventional antipsychotic versus new atypical drugs, and new atypical drugs versus clozapine, in people with schizophrenia responding poorly to, or intolerant of, current drug treatment.

    By Lewis SW, Davies L, Jones PB, Barnes TRE, Murray RM, Kerwin R, et al.

18. Diagnostic tests and algorithms used in the investigation of haematuria: systematic reviews and economic evaluation.

    By Rodgers M, Nixon J, Hempel S, Aho T, Kelly J, Neal D, et al.

19. Cognitive behavioural therapy in addition to antispasmodic therapy for irritable bowel syndrome in primary care: randomised controlled trial.

    By Kennedy TM, Chalder T, McCrone P, Darnley S, Knapp M, Jones RH, et al.

20. A systematic review of the clinical effectiveness and cost-effectiveness of enzyme replacement therapies for Fabry’s disease and mucopolysaccharidosis type 1.

    By Connock M, Juarez-Garcia A, Frew E, Mans A, Dretzke J, Fry-Smith A, et al.

21. Health benefits of antiviral therapy for mild chronic hepatitis C: randomised controlled trial and economic evaluation.

    By Wright M, Grieve R, Roberts J, Main J, Thomas HC, on behalf of the UK Mild Hepatitis C Trial Investigators.

22. Pressure relieving support surfaces: a randomised evaluation.

    By Nixon J, Nelson EA, Cranny G, Iglesias CP, Hawkins K, Cullum NA, et al.

23. A systematic review and economic model of the effectiveness and cost-effectiveness of methylphenidate, dexamfetamine and atomoxetine for the treatment of attention deficit hyperactivity disorder in children and adolescents.

    By King S, Griffin S, Hodges Z, Weatherly H, Asseburg C, Richardson G, et al.

24. The clinical effectiveness and cost-effectiveness of enzyme replacement therapy for Gaucher’s disease: a systematic review.

    By Connock M, Burls A, Frew E, Fry-Smith A, Juarez-Garcia A, McCabe C, et al.

25. Effectiveness and cost-effectiveness of salicylic acid and cryotherapy for cutaneous warts. An economic decision model.

    By Thomas KS, Keogh-Brown MR, Chalmers JR, Fordham RJ, Holland RC, Armstrong SJ, et al.

26. A systematic literature review of the effectiveness of non-pharmacological interventions to prevent wandering in dementia and evaluation of the ethical implications and acceptability of their use.

    By Robinson L, Hutchings D, Corner L, Beyer F, Dickinson H, Vanoli A, et al.

27. A review of the evidence on the effects and costs of implantable cardioverter defibrillator therapy in different patient groups, and modelling of cost-effectiveness and cost–utility for these groups in a UK context.

    By Buxton M, Caine N, Chase D, Connelly D, Grace A, Jackson C, et al.

28. Adefovir dipivoxil and pegylated interferon alfa-2a for the treatment of chronic hepatitis B: a systematic review and economic evaluation.

    By Shepherd J, Jones J, Takeda A, Davidson P, Price A.

29. An evaluation of the clinical and cost-effectiveness of pulmonary artery catheters in patient management in intensive care: a systematic review and a randomised controlled trial.

    By Harvey S, Stevens K, Harrison D, Young D, Brampton W, McCabe C, et al.

30. Accurate, practical and cost-effective assessment of carotid stenosis in the UK.

    By Wardlaw JM, Chappell FM, Stevenson M, De Nigris E, Thomas S, Gillard J, et al.

31. Etanercept and infliximab for the treatment of psoriatic arthritis: a systematic review and economic evaluation.

    By Woolacott N, Bravo Vergel Y, Hawkins N, Kainth A, Khadjesari Z, Misso K, et al.

32. The cost-effectiveness of testing for hepatitis C in former injecting drug users.

    By Castelnuovo E, Thompson-Coon J, Pitt M, Cramp M, Siebert U, Price A, et al.

33. Computerised cognitive behaviour therapy for depression and anxiety update: a systematic review and economic evaluation.

    By Kaltenthaler E, Brazier J, De Nigris E, Tumur I, Ferriter M, Beverley C, et al.

34. Cost-effectiveness of using prognostic information to select women with breast cancer for adjuvant systemic therapy.

    By Williams C, Brunskill S, Altman D, Briggs A, Campbell H, Clarke M, et al.

35. Psychological therapies including dialectical behaviour therapy for borderline personality disorder: a systematic review and preliminary economic evaluation.

    By Brazier J, Tumur I, Holmes M, Ferriter M, Parry G, Dent-Brown K, et al.

36. Clinical effectiveness and cost-effectiveness of tests for the diagnosis and investigation of urinary tract infection in children: a systematic review and economic model.

    By Whiting P, Westwood M, Bojke L, Palmer S, Richardson G, Cooper J, et al.

37. Cognitive behavioural therapy in chronic fatigue syndrome: a randomised controlled trial of an outpatient group programme.

    By O’Dowd H, Gladwell P, Rogers CA, Hollinghurst S, Gregory A.

38. A comparison of the cost-effectiveness of five strategies for the prevention of nonsteroidal anti-inflammatory drug-induced gastrointestinal toxicity: a systematic review with economic modelling.

    By Brown TJ, Hooper L, Elliott RA, Payne K, Webb R, Roberts C, et al.

39. The effectiveness and cost-effectiveness of computed tomography screening for coronary artery disease: systematic review.

    By Waugh N, Black C, Walker S, McIntyre L, Cummins E, Hillis G.

40. What are the clinical outcome and cost-effectiveness of endoscopy undertaken by nurses when compared with doctors? A Multi-Institution Nurse Endoscopy Trial (MINuET).

    By Williams J, Russell I, Durai D, Cheung W-Y, Farrin A, Bloor K, et al.

41. The clinical and cost-effectiveness of oxaliplatin and capecitabine for the adjuvant treatment of colon cancer: systematic review and economic evaluation.

    By Pandor A, Eggington S, Paisley S, Tappenden P, Sutcliffe P.

42. A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness.

    By Chen Y-F, Jobanputra P, Barton P, Jowett S, Bryan S, Clark W, et al.

43. Telemedicine in dermatology: a randomised controlled trial.

    By Bowns IR, Collins K, Walters SJ, McDonagh AJG.

44. Cost-effectiveness of cell salvage and alternative methods of minimising perioperative allogeneic blood transfusion: a systematic review and economic model.

    By Davies L, Brown TJ, Haynes S, Payne K, Elliott RA, McCollum C.

45. Clinical effectiveness and cost-effectiveness of laparoscopic surgery for colorectal cancer: systematic reviews and economic evaluation.

    By Murray A, Lourenco T, de Verteuil R, Hernandez R, Fraser C, McKinley A, et al.

46. Etanercept and efalizumab for the treatment of psoriasis: a systematic review.

    By Woolacott N, Hawkins N, Mason A, Kainth A, Khadjesari Z, Bravo Vergel Y, et al.

47. Systematic reviews of clinical decision tools for acute abdominal pain.

    By Liu JLY, Wyatt JC, Deeks JJ, Clamp S, Keen J, Verde P, et al.

48. Evaluation of the ventricular assist device programme in the UK.

    By Sharples L, Buxton M, Caine N, Cafferty F, Demiris N, Dyer M, et al.

49. A systematic review and economic model of the clinical and cost-effectiveness of immunosuppressive therapy for renal transplantation in children.

    By Yao G, Albon E, Adi Y, Milford D, Bayliss S, Ready A, et al.

50. Amniocentesis results: investigation of anxiety. The ARIA trial.

    By Hewison J, Nixon J, Fountain J, Cocks K, Jones C, Mason G, et al.