Service delivery Models and settings for delivery of services

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Service delivery Models and settings for delivery of services

Depression in adults

Evidence review A

NICE Guideline, No. 222

London: National Institute for Health and Care Excellence (NICE); 2022 Jun.

ISBN-13: 978-1-4731-4622-8

Service delivery

This evidence report contains 2 reviews relating to service delivery

Review question 1.1 For adults with depression, what are the relative benefits and harms associated with different models for the coordination and delivery of services?
Review question 1.2 For adults with depression, what are the relative benefits and harms associated with different settings for the delivery of care?

Models of care

Review question

For adults with depression, what are the relative benefits and harms associated with different models for the coordination and delivery of services?

Introduction

To improve the treatment of adult depression, there has been a growing interest in the development of systems of care, with some influences from chronic disease management programmes seen in physical healthcare. Different systems of care have been developed and evaluated to see which may improve access to and efficacy of treatment and the efficiency and cost-efficiency of services. Models widely adopted in the UK include the stepped-care model, often associated with the Improving Access to Psychological Therapies (IAPT) programme. This seeks to offer people their least burdensome, most effective therapy first, usually a low intensity therapy (such as guided self-help) where appropriate, and then have their progress reviewed in conjunction with a therapist at regular intervals, with the option to step-up to higher intensity treatment, or step-across to another treatment of the same intensity, depending on progress. Alternatively, people can start on a higher intensity treatment where appropriate and step across or step down, depending on progress. Another model widely used is collaborative care, where a case manager or key worker is in regular contact with the person with depression to help coordinate their care, often involving liaison with the person’s GP, specialists such as psychiatrists, and other psychological therapists if required. They may also support additional needs such employment. There may be overlap between these models of care where, for example, collaborative care may also include stepped care, and there are a number of other models including medication management, the attached professional (where a mental health professional has direct responsibility for the care of a person), and shared care, which may be delivered separately, or may be delivered within a broader place-based or community-based model of care.

The aim of this review is to identify benefits associated with different models of care for adults with depression.

Summary of the protocol

See Table 1 for a summary of the Population, Intervention, Comparison and Outcome (PICO) characteristics of this review.

For further details see the review protocol in appendix A.

Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual. Methods specific to this review question are described in the review protocol in appendix A.

Declarations of interest were recorded according to NICE’s 2014 conflicts of interest policy until 31 March 2018. From 1 April 2018, declarations of interest were recorded according to NICE’s 2018 conflicts of interest policy. Those interests declared until April 2018 were reclassified according to NICE’s 2018 conflicts of interest policy (see Register of Interests).

Clinical evidence

Included studies

56 randomised controlled trials (RCTs) were identified for inclusion in this review and the model of care described was identified.

For this review, a coding system for classifying the complexity and type of service delivery model was developed by the committee specifically for the purpose of this guideline. The service delivery model was rated on this 17-item coding system to generate an overall rating between 0-20 (see Figure 1). Service delivery models scoring at least 6 were considered a collaborative care intervention. Collaborative care interventions were further sub-divided into simple collaborative care (score of 6-12) and complex collaborative care (score ≥13). Service delivery models scoring below 6 were classified as an alternative service delivery model (e.g. care coordination) or a stand-alone psychological intervention (e.g. self-help with support).

39 RCTS were categorised as collaborative care (Aragones 2012; Araya 2003; Berghofer 2012; Bjorkelund 2018; Bosanquet 2017; Bruce 2004; Buszewicz 2016; Capoccia 2004; Chen 2015; Curth 2020; Dobscha 2006; Ell 2007; Finley 2003; Fortney 2007; Gensichen 2009; Gilbody 2017/Lewis 2017; Harter 2018; Holzel 2018; Huang 2018; Huijbregts 2013; Jarjoura 2004; Jeong 2013; Katon 1999; Katzelnick 2000; Landis 2007; Ludman 2007; Morriss 2016; Ng 2020; Oladeji 2015; Richards 2013/2016; Simon 2004 (CM); Simon 2004 (CM + psych); Simon 2006; Smit 2006; Swindle 2003; Unutzer 2002/Arean 2005; Wells 2000; Yeung 2010; Yeung 2016.

Of the 39 RCTs categorised as collaborative care, 6 were categorised as complex collaborative care (score ≥13) (Fortney 2007; Holzel 2018; Huijbregts 2013; Morris 2016; Simon 2004 CM+psych; Unutzer 2002/Arean 2005) and the remaining 33 RCTs were categorised as simple collaborative care (score of 6 to 12).

1 RCT was categorised as collaborative care for relapse prevention (Katon 2001).

5 RCTs were categorised as stepped care (Adewuya 2019; Callahan 1994; Gureje 2019; Knapstad 2020; Van Der Weele 2012).

1 RCT was categorised as stepped care for relapse prevention (Apil 2012).

5 RCTs were categorised as medication management (Akerblad 2003; Aljumah 2015; Rickles 2005; Rubio-Valera 2013a; Sirey 20105).

2 RCTs were categorised as care coordination (McMahon 2007; Salisbury 2016).

1 RCT was categorised as attached professional model (Bedoya 2014).

1 RCT was categorised as shared care (Banerjee 1996).

1 RCT was categorised as measurement-based care (Guo 2015).

The included studies are summarised in Table 2 to Table 10.

Planned subgroup analyses were outlined in the full review protocol (see appendix A) to include (where possible) for all reviews, the influence of the following subgroups: chronic depression; depression with coexisting personality disorder; psychotic depression; older adults; BME populations; men. For the collaborative care review, planned subgroup analyses included the following which were informed by the collaborative care component score method (in Figure 1): type of collaborative care; stepped care component; case manager background; psychological interventions delivered as part of the model of care; number of contacts/sessions/follow-up visits provided as part of the intervention. The committee were also interested in post-hoc subgroup analyses comparing outcomes by baseline severity. Subgroup analysis was considered for all critical outcomes with at least 2 studies in each subgroup. Subgroup analysis was only possible for the collaborative care dataset, where subgroup analyses were possible for older adults, BME groups, baseline severity, and the different collaborative care components outlined above.

See the literature search strategy in appendix B and study selection flow chart in appendix C.

Excluded studies

Studies not included in this review with reasons for their exclusions are provided in appendix K.

Summary of clinical studies included in the evidence review

Comparison 1. Collaborative care (simple or complex) versus standard care/enhanced standard care

Collaborative care is defined as a multi-professional approach to care for people with depression, involving a structured management plan, scheduled follow-ups and enhanced inter-professional communication. Collaborative care may also include elements of other models, such as stepped care, psychoeducation, psychological interventions or medication management.

Summaries of the studies included for the comparison of collaborative care versus standard care or enhanced standard care are presented in Table 2.

Subgroup analysis of the collaborative care dataset was possible for:

Older adults (mean age ≥ 60 years) versus younger adults (mean age <60 years) for the following outcomes: depression symptomatology at 6 months; depression symptomatology at 12 months; response at 6 months; response at 12 months; remission at 6 months; remission at 12 months
BME groups, comparing studies where less than 50% of the population were from a BME group with studies where 50-100% of the population were from a BME group, for the following outcome: remission at 6 months
Baseline severity, comparing studies where the mean depression scale score indicated less severe depression (corresponding to the traditional categories of mild and subthreshold) with more severe depression (corresponding to the traditional categories of moderate and severe depression), for the following outcomes: depression symptomatology at 6 months; depression symptomatology at 12 months; response at 6 months; response at 12 months; remission at 6 months; remission at 12 months
Type of collaborative care, simple versus complex, for the following outcomes: depression symptomatology at 6 months; depression symptomatology at 12 months; response at 6 months; response at 12 months; remission at 6 months; remission at 12 months
Stepped care component, comparing interventions that included a stepped care component, interventions that included only a medication algorithm, and interventions with no stepped care component or algorithm, for the following outcomes: depression symptomatology at 6 months; depression symptomatology at 12 months; response at 6 months; response at 12 months; remission at 6 months; remission at 12 months
Case manager background, comparing studies where the case manager had a prior mental health background and studies where the case manager did not have a prior mental health background, for the following outcomes: depression symptomatology at 6 months; depression symptomatology at 12 months
Inclusion of psychological interventions, comparing studies where psychological interventions were delivered as part of the model of care with studies where psychological interventions were not part of the service delivery model, for the following outcomes: depression symptomatology at 6 months; depression symptomatology at 12 months; response at 6 months; response at 12 months; remission at 6 months; remission at 12 months
Number of contacts provided as part of the intervention, comparing less than 13 contacts with 13 or more contacts, for the following outcomes: depression symptomatology at 6 months; depression symptomatology at 12 months; response at 6 months; response at 12 months; remission at 6 months; remission at 12 months

There were no statistically significant subgroup differences between older and younger adults for the comparison collaborative care versus standard care or enhanced standard care on: depression symptomatology at 6 months (Test for subgroup differences: Chi² = 0.74, df = 1, p = 0.39); depression symptomatology at 12 months (Test for subgroup differences: Chi² = 1.01, df = 1, p = 0.32); response at 6 months (Test for subgroup differences: Chi² = 1.34, df = 1, p = 0.25); response at 12 months (Test for subgroup differences: Chi² = 1.34, df = 1, p = 0.25); remission at 6 months (Test for subgroup differences: Chi² = 1.20, df = 1, p = 0.27); remission at 12 months (Test for subgroup differences: Chi² = 0.52, df = 1, p = 0.47). Although there was a consistent trend for larger benefits for older adults, for example, for younger adults the effect estimate for collaborative care versus standard care/enhanced standard care on depression symptomatology at 12 months was SMD −0.25 [−0.33, −0.17] (K=7; N=2865) relative to older adults where the effect estimate was SMD −0.47 [−0.88, −0.05] (K=6; N=2543).

There was no statistically significant subgroup differences between studies with a predominantly white population and studies where the majority of participants were from BME groups for the comparison collaborative care versus standard care or enhanced standard care on: remission at 6 months (Test for subgroup differences: Chi² = 0.79, df = 1, p = 0.38).

There was a statistically significant subgroup difference between studies where the mean depression scale score indicated less severe depression and studies where participants had more severe depression, for the comparison collaborative care versus standard care or enhanced standard care, on remission at 6 months (Test for subgroup differences: Chi² = 8.54, df = 1, p = 0.003). Larger benefits were observed for more severe depression populations (RR 2.31 [1.59, 3.36]; K=6; N=1273), relative to less severe depression (RR 1.21 [0.97, 1.51]; K=4; N=1076). However, this pattern was not consistent across outcomes, and subgroup differences were not statistically significant for: depression symptomatology at 6 months (Test for subgroup differences: Chi² = 0.07, df = 1, p = 0.79); depression symptomatology at 12 months (Test for subgroup differences: Chi² = 0.47, df = 1, p = 0.49); response at 6 months (Test for subgroup differences: Chi² = 0.49, df = 1, p = 0.49); response at 12 months (Test for subgroup differences: Chi² = 1.05, df = 1, p = 0.31); remission at 12 months (Test for subgroup differences: Chi² = 0.32, df = 1, p = 0.57).

There were no statistically significant subgroup differences between simple and complex collaborative care for the comparison collaborative care versus standard care or enhanced standard care on: depression symptomatology at 12 months (Test for subgroup differences: Chi² = 0.69, df = 1, p = 0.41); response at 12 months (Test for subgroup differences: Chi² = 0.17, df = 1, p = 0.68); remission at 12 months (Test for subgroup differences: Chi² = 2.79, df = 1, p = 0.09).

There were no statistically significant subgroup differences between interventions that included a stepped care component, interventions that included only a medication algorithm, and interventions with no stepped care component or algorithm for the comparison collaborative care versus standard care or enhanced standard care on: depression symptomatology at 6 months (Test for subgroup differences: Chi² = 2.33, df = 2, p = 0.31); depression symptomatology at 12 months (Test for subgroup differences: Chi² = 5.44, df = 2, p = 0.07); response at 6 months (Test for subgroup differences: Chi² = 2.07, df = 2, p = 0.36); response at 12 months (Test for subgroup differences: Chi² = 3.96, df = 2, p = 0.14); remission at 6 months (Test for subgroup differences: Chi² = 4.02, df = 2, p = 0.13); remission at 12 months (Test for subgroup differences: Chi² = 4.30, df = 2, p = 0.12). Although there was a consistent trend for larger benefits for interventions that included a stepped care component, for example, for interventions that included a stepped care component the effect estimate for collaborative care versus standard care/enhanced standard care on depression symptomatology at 12 months was SMD −0.61 [−1.10, −0.11] (K=5; N=1717) relative to interventions that included a medication algorithm-only where the effect estimate was SMD −0.10 [−0.23, 0.03] (K=3; N=1081), or no stepped care component where the effect estimate was SMD −0.25 [−0.39, −0.12] (K=5; N=2610).

There were no statistically significant subgroup differences between interventions where the case manager had a prior mental health background and interventions where the case manager did not have a prior mental health background, for the comparison collaborative care versus standard care or enhanced standard care on: depression symptomatology at 6 months (Test for subgroup differences: Chi² = 0.18, df = 1, p = 0.67); depression symptomatology at 12 months (Test for subgroup differences: Chi² = 1.02, df = 1, p = 0.31).

There were no statistically significant subgroup differences between studies where psychological interventions were delivered as part of the model of care and studies where psychological interventions were not part of the service delivery model, for the comparison collaborative care versus standard care or enhanced standard care on: depression symptomatology at 6 months (Test for subgroup differences: Chi² = 0.00, df = 1, p = 0.98); depression symptomatology at 12 months (Test for subgroup differences: Chi² = 0.01, df = 1, p = 0.91); response at 6 months (Test for subgroup differences: Chi² = 0.01, df = 1, p = 0.94); response at 12 months (Test for subgroup differences: Chi² = 0.14, df = 1, p = 0.71); remission at 6 months (Test for subgroup differences: Chi² = 1.12, df = 1, p = 0.29); remission at 12 months (Test for subgroup differences: Chi² = 0.09, df = 1, p = 0.76).

There was a statistically significant subgroup difference between interventions with fewer than 13 contacts and interventions with 13 or more contacts, for the comparison collaborative care versus standard care or enhanced standard care, on remission at 12 months (Test for subgroup differences: Chi² = 4.23, df = 1, p = 0.04). Interventions with 13+ contacts showed larger benefits (RR 1.97 [1.33, 2.91]; K=8; N=3188) than interventions with <13 contacts (RR 1.25 [1.06, 1.48]; K=6; N=3067). Although heterogeneity remained fairly high within (as well as between) subgroups, with I² values of 79% for interventions with 13+ contacts and 56% for interventions with <13 contacts. There was a trend for larger benefits associated with more contacts across other outcomes, although subgroup differences were not statistically significant for: depression symptomatology at 6 months (Test for subgroup differences: Chi² = 0.35, df = 1, p = 0.55); depression symptomatology at 12 months (Test for subgroup differences: Chi² = 1.13, df = 1, p = 0.29); response at 6 months (Test for subgroup differences: Chi² = 0.02, df = 1, p = 0.88); response at 12 months (Test for subgroup differences: Chi² = 0.41, df = 1, p = 0.52); remission at 6 months (Test for subgroup differences: Chi² = 0.84, df = 1, p = 0.36).

Comparison 2. Collaborative care versus standard care for relapse prevention

Collaborative care can also be used for those in full or partial remission from depression, particularly those at higher risk of relapse, as a strategy to keep well.

A summary of the study included for the comparison of collaborative care versus standard care for relapse prevention is presented in Table 3.

Comparison 3. Stepped care versus standard care/enhanced standard care

Stepped care provides the most effective yet least burdensome treatment for people with depression first, but if a person does not benefit from an initial intervention they are ‘stepped up’ to a more complex intervention. Typically, stepped care starts by providing a low intensity intervention, but in patient-specific stepped care a higher intensity intervention may be commenced if, for example, a person is very ill or suicidal and a low intensity intervention would not be appropriate.

Summaries of the studies included for the comparison of stepped care versus standard care or enhanced standard care are presented in Table 4.

Comparison 4. Stepped care versus standard care for relapse prevention

Stepped care can also be used for those in full or partial remission from depression, as a strategy to keep well.

A summary of the study included for the comparison of stepped care versus standard care for relapse prevention is presented in Table 5.

Comparison 5. Pure medication management versus standard care

Medication management can be a component of a broader service delivery model (for example, as part of collaborative care) or as a stand-alone intervention (pure medication management). Medication management is an intervention to ensure medication taken for depression has the greatest opportunity to be effective, by working with people to increase understanding of their medication, promote adherence, ensure adequate therapeutic levels are obtained, and allow people to discuss their medicine use and so reduce unnecessary discontinuation of medication due to lack of benefits or side effects.

Summaries of the studies included for the comparison of pure medication management versus standard care are presented in Table 6 Table 4.

Comparison 6. Care coordination versus standard care/enhanced standard care

Care coordination can be a component of a broader service delivery model (for example, as part of collaborative care) or as a stand-alone intervention. Care coordination (also known as case management) is a system where an individual healthcare professional takes responsibility for the coordination of the care of a person with depression, but is not necessarily directly involved in the provision of any intervention; it may also involve the coordination of follow-up.

Summaries of the studies included for the comparison of care coordination versus standard care or enhanced standard care are presented in Table 7 Table 4.

Comparison 7. Attached professional model versus enhanced standard care

In this model a mental health professional has direct responsibility for the care of a person (usually in primary care) focusing on the primary treatment of the depression. The coordination of care remains with the GP/primary care team. Contact with the attached professional is usually limited to treatment and involves little or no follow-up beyond that determined by the specific intervention offered (for example, booster sessions in CBT).

A summary of the study included for the comparison of attached professional model versus enhanced standard care is presented in Table 8.

Comparison 8. Shared care versus standard care

Shared care is the involvement of a multidisciplinary team who work together to plan and deliver individualised care for people with depression. The team will usually include involvement from both primary care and specialist services.

A summary of the study included for the comparison of shared care versus standard care is presented in Table 9.

Comparison 9. Measurement-based care versus standard care

Measurement-based care is similar to stepped care with defined levels of treatment but progression to different steps or alternative treatments is guided by the use of a predefined algorithm that utilises objective measures of efficacy.

A summary of the study included for the comparison of measurement-based care versus standard care is presented in Table 10.

See the full evidence tables in appendix D and the forest plots in appendix E.

Quality assessment of clinical outcomes included in the evidence review

See the clinical evidence profiles in appendix F.

Economic evidence

Included studies

A single economic search was undertaken for all topics included in the scope of this guideline. See the literature search strategy in appendix B and economic study selection flow chart in appendix G. Details on the hierarchy of inclusion criteria for economic studies are provided in supplement 1 (methods supplement).

The systematic search of the literature identified 12 studies (in 13 publications) on the cost effectiveness of different models for the coordination and delivery of services for adults with depression.

There were 3 UK studies that assessed simple collaborative care (Bosanquet 2017; Green 2014; Lewis 2017) and 1 UK study that assessed complex collaborative care (Morriss 2016). Following the hierarchy of inclusion criteria regarding country settings, 1 Dutch (Goorden 2015) and 1 German (Grochtdreis 2019) studies assessing the cost effectiveness of complex collaborative care were also included in the review. In addition, the search identified 1 US study assessing the cost effectiveness of simple collaborative care in relapse prevention (Simon 2002) and given that the study focused on a different population that was not covered by UK studies or other studies ranking higher on the hierarchy of inclusion criteria, this study was also included in the review.

One UK study assessed the cost effectiveness of stepped care (Mukuria 2013). Following the hierarchy of inclusion criteria regarding country settings, 2 Dutch (van der Weele 2012, Meeuwissen 2019) and 1 Canadian economic study (Health Quality Ontario 2019) were also included in the economic review of stepped care.

No UK studies on the cost effectiveness of medication management for adults with depression were identified. Following the hierarchy of inclusion criteria regarding country settings, 1 Spanish study (Rubio-Valera 2013) was included in the review.

No UK studies on the cost effectiveness of shared care for adults with depression were identified. Following the hierarchy of inclusion criteria regarding country settings, 1 US study (Wiley-Exley 2009) was included in the review.

No studies assessing the cost effectiveness of care coordination, the attached professional model, or measurement-based care for adults with depression were identified.

Economic evidence tables are provided in appendix H. Economic evidence profiles are shown in appendix I.

Excluded studies

A list of excluded economic and utility studies, with reasons for exclusion, is provided in supplement 3 - Economic evidence included & excluded studies.

Summary of studies included in the economic evidence review

Simple collaborative care

Bosanquet 2017 performed a cost-utility analysis alongside a RCT (Bosanquet 2017; N=485; at 18 months n=344; cost data available for n=447) that compared simple collaborative care in addition to usual primary care versus primary care alone for older adults who screened positive for major depression in the UK. The perspective of the analysis was the NHS and personal social services (PSS). Healthcare costs consisted exclusively of intervention and primary care costs. National unit costs were used. The outcome measure was the QALY estimated based on SF-6D ratings (UK tariff). The duration of the analysis was 18 months.

Simple collaborative care was found to be more effective and more costly than usual (primary) care alone, with an ICER of £28,765/QALY (uplifted to 2020 prices). The probability of simple collaborative care being cost-effective at the NICE lower (£20,000/QALY) and upper (£30,000/QALY) cost effectiveness threshold was 0.39 and 0.55, respectively. When only participants who engaged with 5 or more sessions of collaborative care were included in the analysis, the ICER fell at £10,922/QALY (in 2020 prices). The study is directly applicable to the UK context but is characterised by potentially serious limitations, mainly the inclusion of intervention and primary care costs only.

Green 2014 conducted a cost-utility analysis alongside a RCT (Richards 2013; N=581, efficacy data available for n=466; resource use data available for n=447) that compared simple collaborative care in addition to usual primary care versus primary care alone for adults with depression in the UK. The perspective of the analysis was the NHS and personal social services (PSS); a broader perspective that included informal care costs and service user expenses was considered in a sensitivity analysis. Healthcare costs consisted of intervention costs, staff time (such as GP, mental health nurse, mental health worker, psychiatrist, psychologist), other outpatient and inpatient care, day care, walk-in-centre, and A&E. National unit costs were used. The outcome measure was the QALY estimated based on EQ-5D ratings (UK tariff); QALY estimates based on the SF-6D (UK tariff) were used in sensitivity analysis. The duration of the analysis was 12 months.

Simple collaborative care was found to be more effective and more costly than usual (primary) care alone, with an Incremental Cost Effectiveness Ratio (ICER) of £16,361/QALY (in 2020 prices). The probability of simple collaborative care being cost-effective at the NICE lower (£20,000/QALY) and upper (£30,000/QALY) cost effectiveness threshold was 0.58 and 0.65, respectively. Results were robust to multiple imputation of missing data, use of SF-6D utility values, and use of alternative collaborative care costs. The study is directly applicable to the UK context and is characterised by minor limitations.

Lewis 2017 also conducted a cost-utility analysis alongside a RCT (Gilbody 2017; N=705, complete data for economic analysis n=448) that compared simple collaborative care in addition to usual primary care versus primary care alone for older adults who screened positive for subthreshold depression in the UK. The perspective of the analysis was the NHS and PSS. Healthcare costs consisted exclusively of intervention and primary care costs. National unit costs were used. The outcome measure was the QALY estimated based on EQ-5D ratings (UK tariff). The duration of the analysis was 12 months.

Simple collaborative care was found to be more effective and more costly than usual (primary) care alone, with an ICER of £10,653/QALY (in 2020 prices). The probability of simple collaborative care being cost-effective at the NICE lower (£20,000/QALY) and upper (£30,000/QALY) cost effectiveness threshold was 0.92 and 0.97, respectively. Accounting for the true observed case manager contact rate (rather than the expected contact rate that was used in the base-case analysis), the ICER fell at £3,681/QALY (in 2020 prices). The study is directly applicable to the UK context but is characterised by potentially serious limitations, mainly the high attrition that was markedly greater in the collaborative care arm, and the consideration of intervention and primary care costs only.

Simple collaborative care for relapse prevention

Simon 2002 assessed the cost effectiveness of simple collaborative care versus usual care alongside a RCT (Katon 2001; N=386, 82% completed all follow-up assessments and 98% remained enrolled throughout the follow-up period) that compared simple collaborative care with treatment as usual for adults with a history of either recurrent major depression or dysthymia that had recovered from a depressive episode following antidepressant treatment in primary care in the US. The study, which adopted a 3rd party payer perspective, considered costs of medication, staff time, as well as costs of any inpatient and outpatient services for mental health or general medical care; local prices were used. The outcome measure was the number of depression-free days, defined as days with a Hopkins Symptoms Checklist (HSCL) depression score ≤ 0.5; days with a HSCL score above 0.5 but < 2 were considered as being 50% depression free. The time horizon of the analysis was 12 months.

Simple collaborative care was found to be more effective and more costly than usual care, with an ICER of $1 per depression-free day (95%CI −$134 to $344, 1998 US$), which translates to £1.2 per depression-free day in 2020 prices. The study is only partially applicable to the NICE decision-making context as it was conducted in the US and does not use the QALY as the outcome measure, which requires judgement on whether the additional benefit is worth the extra cost. It is also characterised by potentially serious limitations, resulting mainly from the fact that analyses of clinical data included only those completing all blinded follow-up assessments; cost analyses included only those remaining enrolled throughout the follow-up period. However, participation in follow-up interviews was significantly greater in the intervention group than in usual care, introducing a possibility of bias.

Complex collaborative care

Morriss 2016 assessed the cost-utility of complex collaborative care versus usual secondary mental health care in the UK. The economic analysis was carried out alongside a RCT (Morriss 2016; N=187; 84% completed at 6 months, 72% at 12 months and 59% at 18 months). Complex collaborating care comprised secondary outpatient specialist depression services offering tailored integrated pharmacological and psychological (CBT, MBCT and compassion focused therapy, as appropriate) treatment within a collaborative care approach for 12-15 months. The analysis adopted a NHS and PSS perspective. Healthcare costs consisted of intervention costs, primary care (GP surgery and home attendances), inpatient and outpatient (psychiatric or other) care, other staff time (practice - district - community psychiatric nurse, psychotherapist), A&E attendances, and medication. National unit costs were used. The outcome measure was the QALY estimated based on EQ-5D ratings (UK tariff). The duration of the analysis was 18 months.

Complex collaborative care was more effective and more costly than usual secondary mental health care, with an ICER of £47,690/QALY (in 2020 prices). Controlling for baseline differences and cluster effects, the probability of complex collaborative care being cost-effective exceeded 50% at a cost effectiveness threshold of £45,500/QALY, which is well above the NICE cost effectiveness threshold of £30,000/QALY. The study is directly applicable to the UK context and is characterised by minor limitations.

Goorden 2015 assessed the cost effectiveness of complex collaborative care versus treatment as usual in a Dutch primary care setting. The study, which was conducted alongside a RCT (Huijbregts 2013), adopted a healthcare perspective, with productivity losses being reported separately. Healthcare costs consisted of intervention costs (care manager), other staff time (such as GP, mental health care professional, psychologist/psychiatrist, social worker, occupational therapist), self-help groups, day care, psychiatric inpatient care and medication. National unit costs were used. The outcome measure was the QALY estimated based on EQ-5D ratings (Dutch tariff). The time horizon was 12 months.

Complex collaborative care was found to be more effective and more costly than treatment as usual, with an ICER of €53,717/QALY in 2013 prices (£54,087 in 2020 prices), and a probability of being cost-effective of 0.20 and 0.70 at a cost effectiveness threshold of £20,100 and £80,500/QALY, respectively. The study is partially applicable to the UK context and is characterised by potentially serious limitations, mainly by the fact that, although the RCT included 150 participants, 93 identified by screening and 47 by GP referral, the cost-utility analysis was based only on the 93 participants that were identified by screening.

Grochtdreis 2019 assessed the cost effectiveness of complex collaborative care versus treatment as usual for adults aged ≥ 60 years with moderate depressive symptoms in Germany. The study was undertaken alongside a cluster RCT (Hölzel 2018; N=246 from 71 clusters) and adopted a healthcare perspective, with informal care costs being reported separately. Healthcare costs consisted of outpatient physician and non-physician services (e.g. physiotherapy, occupational therapy, massage), inpatient care, rehabilitation, formal nursing care (professional nurse or housekeeper), informal nursing care (family or friends), medication and medical devices. National unit costs were used. The outcome measure was the number of depression-free days (DFDs), determined by a PHQ-9 score <5. QALYs were also used as a secondary outcome, estimated based on EQ-5D ratings (UK tariff). The time horizon was 12 months.

Complex collaborative care was found to be more effective and more costly than treatment as usual, with an ICER of €26.07/DFD or €55,800/QALY in 2013 prices (£26/DFD or £56,184/QALY in 2020 prices), and a probability of being cost-effective of 0.95 at a cost-effetiveness threshold of £204/DFD and 0.45 at a cost-effectiveness threshold of £50,400/QALY. The study is partially applicable to the UK context and is characterised by minor limitations.

Stepped care

Mukuria 2013 assessed the cost-utility of stepped care for people with depression or anxiety in the UK, as reflected in the Improving Access to Psychological Therapies (IAPT) service, in addition to treatment as usual, versus treatment as usual alone; the latter comprised GP care, primary care counselling and referral to secondary mental health services. The study was conducted alongside a prospective cohort study with matched sites (N=403), and more than 95% of the study sample included people with a primary diagnosis of depression. The analysis adopted a NHS and social services perspective; productivity losses were assessed separately. Healthcare costs consisted of intervention (staff time, training, equipment, facilities and overheads), other mental healthcare (psychiatrist, psychologist, community psychiatric nurse, etc.), primary and secondary care, and social care; medication costs were not considered. Unit costs were based on IAPT data and national sources. The outcome measures of the analysis were the proportion of people with a reliable and clinically significant (RCS) improvement on the PHQ-9 and the QALY based on SF-6D ratings (UK tariff); QALYs estimated based on predicted EQ-5D ratings (UK tariff), estimated from SF-6D using an empirical mapping function, were used in sensitivity analysis. The duration of the analysis was 8 months.

IAPT added to treatment as usual was more costly and more effective than treatment as usual alone, with ICERs of £11,234 per additional participant with RCS improvement, £35,106/QALY using the SF-6D and £20,059/QALY using predicted EQ-5D scores (figures uplifted to 2020 prices). The probability of IAPT being cost-effective using SF-6D QALYs was less than 0.40 at a cost effectiveness threshold of £30,000/QALY; using QALYs estimated based on predicted EQ-5D ratings the probability of IAPT being cost-effective was 0.38 and 0.53 at cost effectiveness thresholds of £20,000 and £30,000/QALY, respectively. Using national unit costs instead of IAPT financial data resulted in an ICER of £4,522 per additional participant achieving RCS improvement and £14,132/QALY using SF-6D ratings (2020 prices). It is noted that NICE recommends use of EQ-5D for the estimation of QALYs in adults.

The study is directly applicable to the UK context and is characterised by potentially serious limitations such as its short time horizon, its study design, the sensitivity of results to unit costs of IAPT, the low response rate at recruitment (403 out of 3,391, 11.9%); and the fact that the IAPT service was assessed over the first 2 years of establishment, therefore costs associated with learning effects were likely.

Meeuwissen 2019 assessed the cost-utility of stepped care versus treatment as usual for adults with mild, moderate or severe major depression in the Netherlands. The study employed decision-economic modelling and adopted a healthcare perspective. Efficacy data were taken from a literature review, resource use data were based on published literature and national unit costs were likely used. Healthcare costs consisted of health professional time (GP, psychologist, psychiatrist, etc.), antidepressants, telephone consultation, self-help book or information leaflet, group therapy, crisis intervention, inpatient care, day care, homecare, and other out-patient care. The outcome measure of the analysis was the QALY, following transformation of the effect size into a utility increment. The time horizon of the analysis was 5 years.

Stepped care was found to dominate treatment as usual in adults with mild depression; it was more effective and costlier in adults with moderate/severe depression, with an ICER of €3,166/QALY (in 2017 prices) or £3,159/QALY (in 2020 prices). The probability of stepped care being dominant was 0.67 in adults with mild depression and 0.33 in adults with moderate/severe depression. The probability of stepped care being cost-effective at a cost-effectiveness threshold of approximately £20,000/QALY was more than 0.95 in both populations.

The study is partially applicable to the UK NHS context, as it was conducted in the Netherlands and the method of estimation of QALYs was not the one recommended by NICE, and is characterised by minor limitations.

Van der Weele 2012 assessed the cost-utility of stepped care versus treatment as usual for adults aged ≥ 75 years with depressive symptoms in the Netherlands. The study was undertaken alongside a cluster RCT (van der Weele 2012; N=239; completers n=194) and adopted a healthcare perspective, with service user and informal care costs being reported separately. Healthcare costs consisted of intervention costs (individual consultation, course sessions, course instructors, room rental, refreshments, course materials), staff time (psychiatrist, psychologist, GP, physiotherapist), medication, hospitalisation (psychiatric & general), hospital day care, specialist care, paramedical care, service user costs (time & travel) and informal care. National unit costs were used. The outcome measures were the MADRS change score, and the QALY based on EQ-5D and SF-6D ratings (UK tariff). The time horizon was 12 months.

Stepped care was found to be dominated by treatment as usual in adults aged 75-79 years, when QALYs were derived by EQ-5D ratings, and to dominate treatment as usual in adults aged ≥80 years. The study is partially applicable to the UK NHS context, as it was conducted in the Netherlands, and is characterised by potentially serious limitations, mainly because there was no estimation of the uncertainty in the cost effectiveness results.

Health Quality Ontario 2019 assessed the cost-utility of stepped care for people with mild to moderate depression in Canada based on decision-economic modelling. Two separate analyses were conducted: one analysis compared stepped care comprising computerised CBT (cCBT) with support followed by individual or group CBT with treatment as usual; the other analysis assessed stepped care comprising cCBT without support followed by cCBT with support versus individual CBT, group CBT and treatment as usual in people who are likely to drop out of treatment. The perspective of the analysis was that of healthcare and long term care. Efficacy data were taken from a systematic literature review, resource use data were based on published literature and expert opinion and national unit costs were used. Costs consisted of intervention costs (health professional time, training and supervision, equipment), assessment, medication, follow-up care with GP, and psychiatrist time. The outcome measure of the analysis was the QALY; utility data were derived from a literature review; various scales were used for the quality of life ratings. The time horizon was lifetime for the first analysis and 1 year for the second analysis (the one on adults with mild to moderate depression at risk of dropping out).

Stepped care was found to dominate treatment as usual in adults with mild to moderate depression (first analysis); results were robust to change in efficacy, dropout rates, utilities, medication costs, time horizon. The probability of stepped care where cCBT was followed by individual CBT was 0.60 at a cost effectiveness threshold of about £30,000/QALY. Regarding adults with mild to moderate depression at risk of dropping out, stepped care was the most cost-effective option assessed: it was more effective and costlier than treatment as usual, with an ICER of Can$19,454/QALY (in 2018 prices) or £11,666/QALY (in 2019 prices). Individual and group CBT were less cost-effective than stepped care at a cost-effectiveness threshold of about £30,000/QALY, as their ICERs versus stepped care reached or exceeded £40,000/QALY. The probability of stepped care being cost-effective among individual CBT, group CBT and treatment as usual was 0.48 at this threshold.

The study is partially applicable to the UK NHS context, as it was conducted in Canada and the method of estimation of QALYs was not the one recommended by NICE, and is characterised by minor limitations.

Medication management

Rubio-Valera 2013 conducted an economic evaluation of medication management versus treatment as usual for adults with depression treated in primary care. The study was undertaken alongside a RCT (Rubio-Valera 2013, N=179; 71% completed at 6 months; n=151 received intervention as allocated). The study adopted a healthcare and a societal perspective; costs included intervention, publicly funded healthcare services (GP, nurse, psychologist, psychiatrist, other specialists, social worker, hospital emergency visits, hospital stay, diagnostic tests, medication), privately funded healthcare services (psychiatrist, psychologist, medical specialist, GP), and absenteeism from paid labour. Regional unit prices were used. The study used 3 outcome measures: adherence to antidepressant treatment measured using electronic pharmacy records; remission of depressive symptoms defined as a reduction in the Patient Health Questionnaire 9-item (PHQ-9) of at least 50%; and the QALY based on EQ-5D ratings and the Spanish tariff. The time horizon of the analysis was 6 months.

Under the healthcare perspective, medication management was more expensive than treatment is usual. It was also more effective in terms of adherence to antidepressant treatment and the QALYs gained. The respective ICERs were €962 per extra adherent service user and €3,592/QALY (2009 prices; translating into figures of £935 per extra adherent service user and £3,495/QALY in 2020 prices). However, when remission was used as an outcome, medication management was dominated by treatment as usual, as it was more expensive and less effective. The probability of medication management being cost-effective was 0.71 and 0.76 for WTP £5,800/adherent service user and £29,000/QALY, respectively (2020 prices). Using remission as an outcome, the maximum probability of medication management being cost-effective was only 0.46, irrespective of the cost effectiveness threshold used. Results were robust to different scenarios such as a per protocol or complete case analysis, use of different diagnostic criteria for depression, changes in intervention costs or different methodology used for estimating indirect costs. The study is partially applicable to the UK decision-making context, as it was conducted in Spain. The findings of the study are inconsistent across the outcome measures used (i.e. the study appears to be cost-effective using the QALY, but cost-ineffective using remission as measure of outcome). The study was characterised by potentially serious limitations, mainly its contradictory results, its short time horizon and the use of regional unit costs.

Shared care

Wiley-Exley 2009 evaluated the cost effectiveness of integrated (shared) care compared with primary care with a referral system to specialist care for older adults with depression in the US. The study, which was conducted alongside a RCT (N=840), analysed 4 different combinations of populations and settings: people major and minor depression (full sample) in the Veteran Affairs (VA) setting (n=365), full sample outside VA (n=475); people with major depression within VA (n=214), and people with major depression outside VA (n=302). The analysis adopted a healthcare and service users’ and carers’ perspective and included intervention costs, outpatient and inpatient care, nursing home, rehabilitation, emergency room, medication, service users’ and caregivers’ time and travel costs. National unit costs were used. The study included various measures of outcome, such as the CES-D score; the number of depression-free days derived from CES-D; the number of QALYs estimated based on depression-free days, using utility weights of health=1, depression=0.59; the number of QALYs estimated based on SF-36, using preferences for matched vignettes created following cluster analysis of SF-12 mental and physical component scores, elicited by US service users with depression using SG. Only results for the latter are reported here (full results of the study are provided in the study’s evidence table in appendix H). The time horizon of the analysis was 6 months.

Integrated care was found to dominate usual primary care in the full sample (major and minor depression), VA setting. It was more costly and more effective than usual primary care regarding the full sample outside VA setting and major depression sample in the VA setting, with ICERs of £91,674/QALY and £56,799/QALY, respectively (2020 prices). It was less effective and less costly than usual primary care in the major depression sample, outside the VA setting, with an ICER of £76,861/QALY (saving per QALY lost).

The probability of integrated care being cost-effective was more than 0.70 for any cost effectiveness threshold only in the full sample and VA setting. The probability of integrated care being cost-effective was low at levels of willingness to pay that corresponded to NICE cost effectiveness thresholds. The study is partially applicable to the UK as it was conducted in the US, and is characterised by potentially serious limitations, including the short time horizon and the contradictory results across sub-analyses.

Economic model

No economic modelling was undertaken for this review because the committee agreed that other topics were higher priorities for economic evaluation.

Evidence statements

Clinical evidence statements

Comparison 1. Collaborative care (simple or complex) versus standard care/enhanced standard care

Critical outcomes

Depression symptomatology

Very low quality evidence from 9 RCTs (N=2791) shows a statistically significant but not clinically important benefit of collaborative care, relative to standard care or enhanced standard care, on depression symptomatology at 6 months for adults with depression.
Very low quality evidence from 13 RCTs (N=5408) shows a statistically significant but not clinically important benefit of collaborative care, relative to standard care or enhanced standard care, on depression symptomatology at 12 months for adults with depression.

Response

Low quality evidence from 8 RCTs (N=1703) shows a clinically important and statistically significant benefit of collaborative care, relative to standard care or enhanced standard care, on the rate of response at 6 months for adults with depression.
Low quality evidence from 13 RCTs (N=4910) shows a clinically important and statistically significant benefit of collaborative care, relative to standard care or enhanced standard care, on the rate of response at 12 months for adults with depression.

Remission

Low quality evidence from 12 RCTs (N=3933) shows a clinically important and statistically significant benefit of collaborative care, relative to standard care or enhanced standard care, on the rate of remission at 6 months for adults with depression.
Very low quality evidence from 14 RCTs (N=6255) shows a clinically important and statistically significant benefit of collaborative care, relative to standard care or enhanced standard care, on the rate of remission at 12 months for adults with depression.

Important outcomes

Antidepressant use

Very low quality evidence from 11 RCTs (N=4022) shows neither a clinically important nor statistically significant effect of collaborative care, relative to standard care or enhanced standard care, on antidepressant use at 6 months for adults with depression.
Very low quality evidence from 13 RCTs (N=5666) shows a statistically significant but not clinically important benefit of collaborative care, relative to standard care or enhanced standard care, on antidepressant use at 12 months for adults with depression.

Discontinuation

Low quality evidence from 19 RCTs (N=8305) shows neither a clinically important nor statistically significant effect of collaborative care, relative to standard care or enhanced standard care, on discontinuation at 6 months for adults with depression.
Moderate quality evidence from 22 RCTs (N=10,916) shows neither a clinically important nor statistically significant effect of collaborative care, relative to standard care or enhanced standard care, on discontinuation at 12 months for adults with depression

Subgroup analysis 1a: Simple versus complex collaborative care

Subgroup analysis of collaborative care compared to standard care or enhanced standard care for adults with depression, shows no statistically significant difference between simple and complex collaborative care, on any of the outcomes for which sub-analysis was possible: depression symptomatology at 12 months; response at 12 months; remission at 12 months.

Subgroup analysis 1b: Older adults

Subgroup analysis of collaborative care compared to standard care or enhanced standard care for adults with depression, shows no statistically significant difference between older adults and younger adults, on any of the outcomes for which sub-analysis was possible: depression symptomatology at 6 months; depression symptomatology at 12 months; response at 6 months; response at 12 months; remission at 6 months; remission at 12 months. Although there was a consistent trend for larger benefits for older adults.

Subgroup analysis 1c: BME groups

Subgroup analysis of collaborative care compared to standard care or enhanced standard care for adults with depression, shows no statistically significant difference between studies with a predominantly white population and studies where the majority of participants were from BME groups, on the one outcome for which sub-analysis was possible: remission at 6 months.

Subgroup analysis 1d: Stepped care component

Subgroup analysis of collaborative care compared to standard care or enhanced standard care for adults with depression, shows no statistically significant difference between interventions that included a stepped care component, interventions that included only a medication algorithm, and interventions with no stepped care component or algorithm, on any of the outcomes for which sub-analysis was possible: depression symptomatology at 6 months; depression symptomatology at 12 months; response at 6 months; response at 12 months; remission at 6 months; remission at 12 months. Although there was a consistent trend for larger benefits for interventions that included a stepped care component.

Subgroup analysis 1e: Case manager background

Subgroup analysis of collaborative care compared to standard care or enhanced standard care for adults with depression, shows no statistically significant difference between interventions where the case manager had a prior mental health background and interventions where the case manager did not have a prior mental health background, on any of the outcomes for which sub-analysis was possible: depression symptomatology at 6 months; depression symptomatology at 12 months.

Subgroup analysis 1f: Psychological intervention

Subgroup analysis of collaborative care compared to standard care or enhanced standard care for adults with depression, shows no statistically significant difference between studies where psychological interventions were delivered as part of the model of care and studies where psychological interventions were not part of the service delivery model, on any of the outcomes for which sub-analysis was possible: depression symptomatology at 6 months; depression symptomatology at 12 months; response at 6 months; response at 12 months; remission at 6 months; remission at 12 months.

Subgroup analysis 1g: Number of contacts

Subgroup analysis of collaborative care compared to standard care or enhanced standard care for adults with depression, showed a statistically significant subgroup difference between interventions with fewer than 13 contacts and interventions with 13 or more contacts on the rate of remission at 12 months, with larger benefits associated with 13+ contacts. Although heterogeneity remained fairly high within (as well as between) subgroups. There was a trend for larger benefits associated with more contacts across other outcomes, although subgroup differences were not statistically significant for: depression symptomatology at 6 months; depression symptomatology at 12 months; response at 6 months; response at 12 months; remission at 6 months.

Subgroup analysis 1h: Baseline severity

Subgroup analysis of collaborative care compared to standard care or enhanced standard care for adults with depression, showed a statistically significant subgroup difference between studies where the mean depression scale score indicated less severe depression and studies where participants had more severe depression on the rate of remission at 6 months, with larger benefits associated with more severe depression. However, this pattern was not consistent across outcomes, and subgroup differences were not statistically significant for: depression symptomatology at 6 months; depression symptomatology at 12 months; response at 6 months; response at 12 months; remission at 12 months.

Comparison 2: Collaborative care versus standard care for relapse prevention

Critical outcomes

Relapse

Very low quality evidence from 1 RCT (N=386) shows neither a clinically important nor statistically significant effect of collaborative care, relative to standard care, on the rate of relapse for adults with remitted depression.

Important outcomes

Antidepressant use

Low quality evidence from 1 RCT (N=386) shows a statistically significant but not clinically important benefit of collaborative care, relative to standard care, on antidepressant use at 6 months for adults with remitted depression.
Low quality evidence from 1 RCT (N=386) shows a clinically important and statistically significant benefit of collaborative care, relative to standard care, on antidepressant use at 12 months for adults with remitted depression.

Discontinuation

Low quality evidence from 1 RCT (N=386) shows a clinically important and statistically significant benefit of collaborative care, relative to standard care, on discontinuation at 12 months for adults with remitted depression.

Comparison 3: Stepped care versus standard care/enhanced standard care

Critical outcomes

Depression symptomatology

Very low quality evidence from 2 RCTs (N=1614) shows a statistically significant but not clinically important benefit of stepped care, relative to standard care or enhanced standard care, on depression symptomatology endpoint score at 6 months for adults with depression.
Very low quality evidence from 2 RCTs (N=826) shows a clinically important and statistically significant benefit of stepped care, relative to standard care, on depression symptomatology change score at 6 months for adults with depression.
Moderate quality evidence from 1 RCT (N=998) shows neither a clinically important nor statistically significant effect of stepped care, relative to enhanced standard care, on depression symptomatology endpoint score at 12 months for adults with depression.
Low quality evidence from 1 RCT (N=194) shows neither a clinically important nor statistically significant effect of stepped care, relative to standard care, on depression symptomatology change score at 12 months for adults with depression.

Response

Very low quality evidence from 1 RCT (N=239) shows a clinically important but not statistically significant benefit of standard care, relative to stepped care, on the rate of response at 6 months for adults with depression.
Low quality evidence from 1 RCT (N=239) shows a clinically important but not statistically significant benefit of standard care, relative to stepped care, on the rate of response at 12 months for adults with depression.

Remission

Low quality evidence from 2 RCTs (N=1082) shows a clinically important and statistically significant benefit of stepped care, relative to standard care or enhanced standard care, on the rate of remission at 6 months for adults with depression.
Very low quality evidence from 2 RCTs (N=2085) shows a clinically important but not statistically significant benefit of stepped care, relative to enhanced standard care, on the rate of remission at 12 months for adults with depression.

Important outcomes

Antidepressant use

Moderate quality evidence from 1 RCT (N=175) shows a clinically important and statistically significant benefit of stepped care, relative to standard care, on antidepressant use at 6 months for adults with depression.

Discontinuation

Low quality evidence from 5 RCTs (N=3180) shows a clinically important and statistically significant benefit of stepped care, relative to standard care or enhanced standard care, on discontinuation at 6 months for adults with depression.
Moderate quality evidence from 3 RCTs (N=2324) shows a clinically important and statistically significant benefit of stepped care, relative to standard care or enhanced standard care, on discontinuation at 12 months for adults with depression.

Comparison 4: Stepped care versus standard care for relapse prevention

Critical outcomes

Relapse

Low quality evidence from 1 RCT (N=135) shows a clinically important but not statistically significant benefit of standard care, relative to stepped care, on the rate of relapse at 12 months in adults with remitted depression.

Important outcomes

Antidepressant use

Very low quality evidence from 1 RCT (N=94) shows neither a clinically important nor statistically significant effect of stepped care, relative to standard care, on antidepressant use at 12 months for adults with remitted depression.

Discontinuation

Low quality evidence from 1 RCT (N=74) shows neither a clinically important nor statistically significant effect of stepped care, relative to standard care, on discontinuation at 12 months for adults with remitted depression.

Comparison 5: Pure medication management versus standard care

Critical outcomes

Depression symptomatology

High quality evidence from 2 RCTs (N=399) shows neither a clinically important nor statistically significant benefit of pure medication management, relative to standard care, on depression symptomatology at 6 months for adults with depression.

Response

Moderate quality evidence from 1 RCT (N=70) shows a clinically important but not statistically significant benefit of pure medication management, relative to standard care, on the rate of response at 6 months for adults with depression.

Important outcomes

Antidepressant use

Low quality evidence from 3 RCTs (N=904) shows a clinically important and statistically significant benefit of pure medication management, relative to standard care, on antidepressant use at 6 months for adults with depression.

Discontinuation

Moderate quality evidence from 5 RCTs (N=1216) shows neither a clinically important nor statistically significant benefit of pure medication management, relative to standard care, on discontinuation at 6 months for adults with depression.

Comparison 6: Care coordination versus standard care/enhanced standard care

Critical outcomes

Depression symptomatology

Very low quality evidence from 1 RCT (N=62) shows neither a clinically important nor statistically significant benefit of care coordination, relative to enhanced standard care, on depression symptomatology at 6 months for adults with depression.
Moderate quality evidence from 1 RCT (N=516) shows neither a clinically important nor statistically significant benefit of care coordination, relative to standard care, on depression symptomatology at 12 months for adults with depression.

Remission

Low quality evidence from 1 RCT (N=609) shows neither a clinically important nor statistically significant benefit of care coordination, relative to standard care, on the rate of remission at 12 months for adults with depression.

Important outcomes

Discontinuation

Very low quality evidence from 1 RCT (N=62) shows neither a clinically important nor statistically significant effect of care coordination, relative to enhanced standard care, on discontinuation at 6 months for adults with depression.
Low quality evidence from 1 RCT (N=609) shows a clinically important but not statistically significant benefit of standard care, relative to care coordination, on discontinuation at 12 months for adults with depression.

Comparison 7: Attached professional model versus enhanced standard care

Critical outcomes

Depression symptomatology

Very low quality evidence from 1 RCT (N=118) shows neither a clinically important nor statistically significant benefit of attached professional model care, relative to enhanced standard care, on depression symptomatology at 6 months for adults with depression.

Important outcomes

Discontinuation

Very low quality evidence from 1 RCT (N=120) shows a clinically important but not statistically significant benefit of attached professional model care, relative to enhanced standard care, on discontinuation at 6 months for adults with depression.

Comparison 8: Shared care versus standard care

Critical outcomes

Depression symptomatology

High quality evidence from 1 RCT (N=69) shows a clinically important and statistically significant benefit of shared care, relative to standard care, on depression symptomatology at 6 months for adults with depression.

Remission

Moderate quality evidence from 1 RCT (N=69) shows a clinically important and statistically significant benefit of shared care, relative to standard care, on the rate of remission at 6 months for adults with depression.

Important outcomes

Antidepressant use

High quality evidence from 1 RCT (N=69) shows a clinically important and statistically significant benefit of shared care, relative to standard care, on antidepressant use at 6 months for adults with depression.

Discontinuation

Low quality evidence from 1 RCT (N=69) shows neither a clinically important nor statistically significant effect of shared care, relative to standard care, on discontinuation at 6 months for adults with depression.

Comparison 9: Measurement-based care versus standard care

Critical outcomes

Depression symptomatology

Moderate quality evidence from 1 RCT (N=81) shows a clinically important and statistically significant benefit of measurement-based care, relative to standard care, on depression symptomatology at 6 months for adults with depression.

Response

Low quality evidence from 1 RCT (N=120) shows a clinically important and statistically significant benefit of measurement-based care, relative to standard care, on the rate of response at 6 months for adults with depression.

Remission

Moderate quality evidence from 1 RCT (N=120) shows a clinically important and statistically significant benefit of measurement-based care, relative to standard care, on remission at 6 months for adults with depression.

Important outcomes

Discontinuation

Very low quality evidence from 1 RCT (N=120) shows a clinically important but not statistically significant benefit of measurement-based care, relative to standard care, on discontinuation at 6 months for adults with depression.

Economic evidence statements

Collaborative care

Evidence from 3 UK economic evaluations conducted alongside RCTs (N = 1,771; complete data for economic analysis n=1341) suggest that simple collaborative care is possibly a cost-effective model for delivering services to adults or older adults with depression. This evidence is directly applicable to the UK context and is coming from one study with minor and two studies with potentially serious methodological limitations.
Evidence from 1 US study conducted alongside a RCT (N=386) suggests that simple collaborative care aiming at relapse prevention may be cost-effective in adults with depression that is in remission. This evidence is partially applicable to the NICE decision-making context as it comes from a US study and is not using the QALY as the outcome measure. The study is characterised by potentially serious methodological limitations.
Evidence from 1 UK study conducted alongside a RCT (N=187) suggests that complex collaborative care is not cost-effective compared with usual secondary mental health care for adults with depression. This evidence is directly applicable to the UK context and is characterised by minor limitations.
Evidence from 1 Dutch study and 1 German study conducted alongside RCTs (N=396) suggest that complex collaborative care is unlikely to be cost-effective compared with treatment as usual in adults with depression in primary care. This evidence is partially applicable to the NICE decision-making context as the studies were conducted outside the UK and, in the Dutch study, utility values were based on EQ-5D ratings using the Dutch tariff. One study is characterised by potentially serious limitations and the other study by minor limitations.

Stepped care

Evidence from 1 UK study conducted alongside a cohort study with matched sites (N=403), and 3 non-UK studies (2 Dutch and 1 Canadian) based on decision-analytic economic modelling suggests that stepped care might be cost-effective for adults with depression in primary care, although results were inconsistent within and across studies. This evidence is directly applicable (UK study) and partially applicable (Dutch and Canadian studies) to the NICE decision-making context. The UK study is characterised by potentially serious limitations; of the 3 non-UK studies, 1 is characterised by potentially serious limitations and 2 are characterised by minor limitations.

Medication management

Evidence from 1 Spanish study conducted alongside a RCT (N=179) suggests that medication management may be cost-effective for adults with depression. This evidence is partially applicable to the NICE decision-making context as it was conducted outside the UK and is characterised by potentially serious limitations.

Care co-ordination

No evidence on the cost effectiveness of care co-ordination for adults with depression is available.

Attached professional model

No evidence on the cost effectiveness of the attached professional model for adults with depression is available.

Shared care

Evidence from 1 US study conducted alongside a multi-site pragmatic RCT (N=840) is inconclusive regarding the cost effectiveness of shared care compared with usual primary care that includes a referral system to specialist care. The evidence is partially applicable to the NICE decision making context (US study, QALYs based on SF-36 using preferences for matched vignettes created following cluster analysis of SF-12 mental and physical component scores, elicited by US service users with depression using SG) and is characterised by potentially serious limitations.

Measurement-based care

No evidence on the cost effectiveness of measurement-based care for adults with depression is available.

The committee’s discussion of the evidence

Interpreting the evidence

The outcomes that matter most

The aim of this review was to determine if different models of service delivery improved outcomes for people with depression so the committee identified depression symptomatology and response, remission and relapse to be the critical outcomes for this question. Antidepressant use and discontinuation were identified as important outcomes. For all outcomes, time points of 6 and 12 months were used, to ensure comparability across interventions.

Evidence was available for all outcomes and time points of interest for the collaborative care dataset (comparison 1), but for all other comparisons data were only available for some of the outcomes. A number of different care models did not have available data on the outcomes of remission and response. Therefore when considering the evidence the committee placed the greatest emphasis on depression symptomatology and antidepressant use, as these provided the best point of comparison across different interventions.

The quality of the evidence

The committee noted that most outcomes for most of the comparisons had been assessed in GRADE as either low or very low quality. Most outcomes were downgraded due to risk of bias (common reasons for downgrading included a lack of blinding of participants and intervention administrators, and non-blind or unclear blinding of outcome assessment, and significant baseline differences between groups) and imprecision. The committee also noted the absence of evidence identified for head-to-head comparisons of different service delivery models.

Benefits and harms

The committee considered that effective service delivery models would enhance clinical outcomes by improved engagement with effective interventions and thereby improve outcomes in terms of depression symptomatology and response, remission and relapse.

For collaborative care, the committee noted that there was evidence from a number of UK and international trials for clinical benefits associated with the use of collaborative care compared to standard care or enhanced standard care, with higher rates of response and remission at both 6 and 12 months. However, the committee noted that the heterogeneity was very high, and effect sizes for depression symptomatology were small compared to first-line acute treatments. Based on these factors, the committee made a ‘consider’ rather than ‘offer’ recommendation and identified groups where collaborative care may confer significant added value, for example, those with significant physical health problems or who are socially isolated.

Older adults were also identified as a group that may particularly benefit from collaborative care. Subgroup analysis comparing outcomes for older (mean age ≥ 60 years) and younger (mean age <60 years) adults did not identify statistically significant subgroup differences. However, there was a consistent trend for larger benefits of collaborative care for older adults. Considered together with the committee knowledge and experience of difficulties with engagement in older adults particularly for those with physical health problems, and evidence for the cost-effectiveness of collaborative care in older people, the committee agreed to also recommend collaborative care for this group.

The committee defined the components of collaborative care that are important, based both on their expertise and experience and on the results of sub-analyses of the collaborative care dataset. Subgroup analyses examined the impact of complex (relative to simple) collaborative care, case manager background, use of a psychological intervention or stepped care algorithm, and the number of contacts provided as part of the intervention. No significant subgroup differences or consistent pattern in results were observed for analyses comparing outcomes for complex versus simple collaborative care, or case manager with mental health background versus case manager without a mental health background.

The inclusion of a stepped care algorithm showed a trend for larger effect sizes compared to no stepped care algorithm. There were no significant subgroup differences for the inclusion of psychological interventions, however, the committee agreed based on their knowledge and experience that collaborative care should include delivery of psychological and psychosocial interventions within a structured protocol. This was also reinforced by evidence for the benefits of stepped care interventions (that were not integrated into collaborative care models) relative to standard care on depression symptomatology, the rate of remission and antidepressant use at 6 months. The committee agreed that the key principles of stepped care, or more accurately matched care, were covered by existing recommendations and were integrated into a care pathway that emphasises patient choice.

Subgroup analysis comparing the outcomes of collaborative care between interventions with fewer than 13 contacts and interventions with 13 contacts or more contacts, showed a trend for larger effects sizes with more contacts and this difference was statistically significant for remission at 12 months. However, the committee did not consider this evidence sufficiently compelling to specify the number of contacts that a collaborative care intervention should include.

The committee were aware of the importance of medication adherence, in particular, for people with severe and chronic depressive symptoms and noted that although the evidence for pure medication management was limited and did not show significant benefits on clinical outcomes, there were benefits on antidepressant use at 6 months. Based on this limited evidence, the committee agreed not to make any recommendations about the use of medication management as an independent service delivery model. For people with depression who may have specific difficulties with the uptake of, or engagement with, treatment the committee agreed that medication adherence would be more effectively promoted through the delivery of care in a collaborative, multidisciplinary manner and that included medication management as a component within a collaborative care model.

The committee acknowledged that for more severe depression or chronic depression with multiple complicating problems or significant coexisting conditions there was no direct evidence to guide the development of recommendations. The committee were, however, aware of the very significant difficulties that people with severe, chronic and complex depression face and the burden of suffering this represents for families and carers. Such high levels of need are best met by specialist services within specialist secondary care. The committee therefore drew on their expert knowledge and experience of specialist services and used informal consensus to develop a series of recommendations on who might benefit from specialist services, how these services should be co-ordinated and what the nature of the co-ordination of the services should involve. The committee were of the view that the development of a comprehensive multidisciplinary care plan will allow more timely, appropriate, and individualised planning and delivery of care to people with more severe or more chronic depression with multiple complicating problems or significant coexisting conditions, and that these benefits should offset (fully or partially) the costs associated with development of the care plan. In contrast, lack of a detailed care plan may lead to sub-optimal, less clinically and cost-effective care pathways and inappropriate treatments, ultimately leading to sub-optimal outcomes for the person and higher healthcare costs.

Cost effectiveness and resource use

The committee agreed that, overall, the published economic evidence indicated that simple collaborative care is potentially a cost-effective model for delivering services to adults with depression, including older adults. This is because out of the 3 UK cost-utility studies included in the review, 2 found simple collaborative care cost-effective when added to usual primary care compared with usual primary care alone at the NICE lower cost-effectiveness threshold of £20,000/QALY. The third study reported an ICER for simple collaborative care between the NICE lower and upper (£30,000/QALY) cost-effectiveness thresholds. The two studies that found simple collaborative care cost-effective were also somewhat larger than the one that found it cost-ineffective at the lower NICE cost-effectiveness threshold. The committee also noted that, among the 3 studies, there was one with minor methodological limitations (the other two were characterised by potentially serious limitations), and this found simple collaborative care to be cost-effective. In contrast, the only UK study on more resource-intensive complex collaborative care included in the review suggested this is unlikely to be cost-effective compared with usual secondary mental health care, as its ICER was well above the NICE upper cost-effectiveness threshold of £30,000/QALY. Therefore, the committee decided to recommend collaborative care with the characteristics of the less resource-intensive, simple collaborative care, as defined in this review, for organising the delivery of care and treatment of people with depression.

The committee noted, based on the evidence, that stepped care might also be cost-effective for adults with depression. They therefore agreed that the recommendations they made on treatment, which reflected the key principles of stepped (or, more accurately, matched) care, ensured efficient use of resources.

The committee noted that no UK economic evidence was available and non-UK evidence did not provide any substantial support for the cost effectiveness of medication management as an independent service delivery model for adults with depression. They also noted that non-UK economic evidence on shared care was inconclusive.

The committee acknowledged that referring people with more severe depression or chronic depressive symptoms and multiple complicating problems (such as unemployment, poor housing or financial problems) or significant coexisting conditions to specialist mental health services, if they have not benefitted from treatment or if they have impaired functioning, is likely to incur additional costs compared with no referral. However, they agreed that the number of people affected would be small and any additional costs were likely to be offset by cost-savings resulting from more appropriate care for this population following referral (compared with treatment in primary care settings), leading to improved outcomes and reduction in the need for potentially costly care further down the care pathway.

Recommendations supported by this evidence review

This evidence review supports recommendations 1.16.7 to 1.16.10 in the NICE guideline.

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Settings of care

Review question

For adults with depression, what are the relative benefits and harms associated with different settings for the delivery of care?

Introduction

Care for adults with depression can be provided in a variety of different settings, ranging from care in people’s own homes, primary care and day hospitals, through to inpatient care or tertiary settings, and the setting in which care is delivered may have a bearing on the outcomes for individuals, and the effectiveness of the interventions.

The aim of this review is to identify if there is a setting which delivers optimal results for people with depression, and if there is anything about the general management of care that should be done differently when delivered in different settings.

Summary of the protocol

Please see Table 11 for a summary of the Population, Intervention, Comparison and Outcome (PICO) characteristics of this review.

For further details see the review protocol in appendix A.

Methods and process

Clinical evidence

Included studies

No randomised controlled trial (RCT) evidence was identified that specifically addressed the following settings: primary care, and inpatient care, therefore, as specified in the full protocol (see Appendix A), indirect evidence was considered in the form of sub-analyses of the NMA dataset (Evidence report B: Treatment of a new episode of depression).

Comparison 1. Primary care versus secondary care

As outlined above, no RCT evidence was identified that specifically addressed this comparison. Therefore the committee considered indirect evidence in the form of sub-analyses of the NMA dataset (Evidence report B: Treatment of a new episode of depression). Primary versus secondary care differences were examined for critical outcomes that had more than 2 studies in each subgroup.

Subgroup analysis of primary care versus secondary care was possible for 5 comparisons in the NMA dataset, and all 5 comparisons were for adults with more severe depression (corresponding to the categories of moderate and severe depression):

Comparison 1a. Cognitive and cognitive behavioural therapies individual + antidepressant versus antidepressant, with 2 RCTs included for primary care (Naeem 2011; Scott 1997) and 4 RCTs included for secondary care (Ashouri 2013; Hautzinger 1996; Hollon 1992; Zu 2014). Primary care versus secondary care subgroup analysis was possible for the depression symptoms endpoint outcome only.
Comparison 1b. Selective serotonin reuptake inhibitors (SSRIs) versus placebo, with 5 RCTs included for primary care (Bjerkenstedt 2005; Doogan 1994; Lepola 2003; Lopez-Rodriguez 2004; Wade 2002) and 78 RCTs included for secondary care (29060 07 001; Andreoli 2002/ Dubini 1997/ Massana 1998_study 1 [1 study reported across 3 papers]; Baune 2018; Binnemann 2008; Bose 2008; Burke 2002; Byerley 1988; Claghorn 1992a; Claghorn 1992b; Clayton 2006_study 1; Clayton 2006_study 2; CL3-20098-022; CL3-20098-023; CL3-20098-024; Detke 2004; Dube 2010; Dunbar 1993; Eli Lilly HMAT-A; Emsley 2018; Fabre 1992; Fabre 1995a; Fava 1998a; Fava 2005; FDA 245 (EMD 68 843-010); FDA 246 (SB 659746-003); Forest Laboratories 2000; Forest Research Institute 2005; Golden 2002_448; Golden 2002_449; Goldstein 2002; Goldstein 2004; Gual 2003; Higuchi 2009; Hirayasu 2011a; Hirayasu 2011b; Jefferson 2000; Kasper 2012; Katz 2004; Keller 2006_Study 062; Kramer 1998; Kranzler 2006_Group A; Lam 2016; Macias-Cortes 2015; Mathews 2015; Mendels 1999; Miller 1989a; Montgomery 1992; Mundt 2012; MY-1042/BRL-029060/CPMS-251; MY-1042/BRL-029060/1 (PAR 128); Nemeroff 2007; Nierenberg 2007; NKD20006 (NCT00048204); Nyth 1992; Olie 1997; PAR 01 001 (GSK & FDA); Perahia 2006; Peselow 1989a; Peselow 1989b; Rapaport 2009; Ratti 2011_study 096; Ravindran 1995; Reimherr 1990; Rickels 1992; Rudolph 1999; SER 315 (FDA); Sheehan 2009b; Smith 1992; Stark 1985; Study 62b (FDA); Study F1J-MC-HMAQ- Study Group B; Tollefson 1993/1995 [1 study reported across 2 papers]; Valle-Cabrera 2018; VEN XR 367 (FDA); Wang 2014c; WELL AK1A4006; Wernicke 1987; Wernicke 1988). Primary care versus secondary care subgroup analyses were possible for the depression symptoms endpoint, depression symptoms change score, and response outcomes.
Comparison 1c. SSRIs versus tricyclic antidepressants (TCAs), with 10 RCTs included for primary care (Christiansen 1996; Freed 1999; Hutchinson 1992; Kyle 1998; Moon 1994; Moon 1996; PAR 29060/281; PAR MDUK 032; Rosenberg 1994; Serrano-Blanco 2006) and 47 RCTs included for secondary care (29060 07 001; 29060/299; Akhondzadeh 2003; Arminem 1992; Beasley 1993b; Bersani 1994; Bhargava 2012; Bremner 1984; Byerley 1988; Chiu 1996; Cohn 1984b; Cohn 1990b; Danish University Antidepressant Group 1986; Danish University Antidepressant Group 1990; De Ronchi 1998; Demyttenaere 1998; Deuschle 2003; Fabre 1991; Fabre 1992; Fawcett 1989; Feighner 1993; Forlenza 2001; Geretsegger 1995; GSK_29060/103; Hashemi 2012; Keegan 1991; Laakmann 1988; Laakmann 1991; Levine 1989; Marchesi 1998; MDF/29060/III/070/88/MC; Miura 2000; Moller 1993; Moller 1998; Mulsant 1999; Navarro 2001; Ontiveros Sanchez 1998; Peselow 1989a; Peselow 1989b; Peters 1990; Preskorn 1991; Reimherr 1990; Ropert 1989; SER 315 (FDA); Staner 1995; Stark 1985; Suleman 1997). Primary care versus secondary care subgroup analyses were possible for the depression symptoms endpoint, depression symptoms change score, remission and response outcomes.
Comparison 1d. TCAs versus placebo, with 6 RCTs included for primary care (Barge-Schaapveld 2002; Blashki 1971; Lecrubier 1997; Mynors-Wallis 1995; Philipp 1999; Schweizer 1998) and 30 RCTs included for secondary care (29060 07 001; Amsterdam 1986; Bakish 1992b; Bremner 1995; Byerley 1988; Cassano 1986; Elkin 1989/Imber 1990 [1 study reported across 2 papers]; Escobar 1980; Fabre 1992; Feiger 1996; Feighner 1982; Feighner 1989b; Fontaine 1994; Goldberg 1980; Kusalic 1993; McCallum 1975; MIR 003-020 (FDA); Peselow 1989a; Peselow 1989b; Reimherr 1990; Rickels 1982e; Rickels 1991; Rickels 1995_Study 006-1; Rickels 1995_Study 006-2; Schweizer 1994; SER 315 (FDA); Silverstone 1994; Smith 1990; Stark 1985; White 1984). Primary care versus secondary care subgroup analyses were possible for the depression symptoms endpoint, depression symptoms change score, and response outcomes.
Comparison 1e. Serotonin–norepinephrine reuptake inhibitors (SNRIs) versus SSRIs, with 2 RCTs included for primary care (Montgomery 2004; Tylee 1997) and 29 RCTs included for secondary care (Allard 2004; Alves 1999; Bielski 2004; Clerc 1994; Costa 1998; DeNayer 2002; Detke 2004; Diaz-Martinez 1998; Dierick 1996; Eli Lilly HMAT-A; Goldstein 2002; Goldstein 2004; Hao 2014; Higuchi 2009; Hwang 2004; Jiang 2017; Khan 2007; Kornaat 2000; Mehtonen 2000; Nemeroff 2007; Nierenberg 2007; Perahia 2006; Rickels 2000; Rudolph 1999; Sheehan 2009b; Shelton 2006; Sir 2005; Study F1J-MC-HMAQ-Study Group B; Tzanakaki 2000). Primary care versus secondary care subgroup analyses were possible for the remission and response outcomes.

Comparison 2. Crisis resolution team care versus standard care (for adults with non-psychotic severe mental illness)

No RCT evidence was identified that specifically addressed this comparison for adults with depression. The committee therefore agreed to consider a wider evidence base including non-psychotic severe mental illness. A systematic review (Murphy 2015; updated version of Joy 2003 used in 2009 guideline) was identified that examined crisis intervention for people with severe mental illness. This Cochrane review was used as a source of studies with inclusion criteria into this review of over 50% of the population having a non-psychotic disorder. Of the 8 RCTs included in Murphy 2015, 1 of these studies met the >50% non-psychotic disorder inclusion criterion (Johnson 2005).

Comparison 3. Inpatient versus outpatient settings

No randomised controlled trial (RCT) evidence was identified that specifically addressed this comparison. Therefore the committee considered indirect evidence in the form of sub-analyses of the NMA dataset (Evidence report B: Treatment of a new episode of depression). Differences between inpatient and outpatient settings were examined for critical outcomes that had more than 2 studies in each subgroup.

Subgroup analysis of inpatient versus outpatient settings was possible for 6 comparisons in the NMA dataset, and all 6 comparisons were for adults with more severe depression (corresponding to the categories of moderate and severe depression):

Comparison 3a. Selective serotonin reuptake inhibitors (SSRIs) versus placebo, with 3 RCTs included for inpatient settings (29060 07 001; Katz 2004; Sheehan 2009b) and 74 RCTs included for outpatient settings (Baune 2018; Binnemann 2008; Bjerkenstedt 2005; Blumenthal 2007/Hoffman 2011 [1 study reported across 2 papers]; Bose 2008; Burke 2002; Byerley 1988; Claghorn 1992a; Claghorn 1992b; Clayton 2006_study 1; Clayton 2006_study 2; Detke 2004; Doogan 1994; Dube 2010; Dunbar 1993; Eli Lilly HMAT-A; Emsley 2018; Fabre 1992; Fava 1998a; Fava 2005; FDA 245 (EMD 68 843-010); Forest Laboratories 2000; Forest Research Institute 2005; Golden 2002_448; Golden 2002_449; Goldstein 2002; Goldstein 2004; Gual 2003; Hirayasu 2011a; Hirayasu 2011b; Hunter 2010_study 1; Hunter 2011; Jefferson 2000; Keller 2006_Study 062; Komulainen 2018; Kramer 1998; Kranzler 2006_Group A; Lam 2016; Lepola 2003; Macias-Cortes 2015; Mathews 2015; Mendels 1999; Miller 1989a; Mundt 2012; MY-1042/BRL-029060/CPMS-251; MY-1045/BRL-029060/1 (PAR 128); Nemeroff 2007; Nierenberg 2007; NKD20006 (NCT00048204); Olie 1997; PAR 01 001 (GSK & FDA); Perahia 2006; Peselow 1989a; Peselow 1989b; Rapaport 2009; Ratti 2011_study 096; Ravindran 1995; Reimherr 1990; Rickels 1992; Roose 2004; Rudolph 1999; SER 315 (FDA); Smith 1992; Stark 1985; Study 62b (FDA); Study F1J-MC-HMAQ – Study Group B; Tollefson 1993/1995 [1 study reported across 2 papers]; Valle-Cabrera 2018; VEN XR 367 (FDA); Wade 2002; Wang 2014c; WELL AK1A4006; Wernicke 1987; Wernicke 1988). Inpatient versus outpatient subgroup analysis was possible for the depression symptoms change score and response outcomes.
Comparison 3b. SSRIs versus tricyclic antidepressants (TCAs), with 11 RCTs included for inpatient settings (29060/299; 29060 07 001; Arminen 1992; Danish University Antidepressant Group 1986; Danish University Antidepressant Group 1990; Deushle 2003; Geretsegger 1995; Laakmann 1991; Moller 1993; Moller 1998; Staner 1995), and 40 RCTs included for outpatient settings (Akhondzadeh 2003; Beasley 1993b; Bersani 1994; Bhargava 2012; Bremner 1984; Byerley 1988; Christiansen 1996; Cohn 1984b; Cohn 1990b; De Ronchi 1998; Demyttenaere 1998; Fabre 1991; Fabre 1992; Fawcett 1989; Feighner 1993; Forlenza 2001; Freed 1999; Hashemi 2012; Hutchinson 1992; Kyle 1998; Laakmann 1988; Marchesi 1998; MDF/29060/III/070/88/MC; Moller 2000; Moon 1994; Moon 1996; Ontiveros Sanchez 1998; PAR 29060/281; PAR MDUK 032; Peselow 1989a; Peselow 1989b; Peters 1990; Preskorn 1991; Reimherr 1990; Ropert 1989; Rosenberg 1994; SER 315 (FDA); Serrano-Blanco 2006; Stark 1985; Suleman 1997). Inpatient versus outpatient subgroup analysis was possible for the depression symptoms endpoint, depression symptoms change score, remission, and response outcomes.
Comparison 3c. Serotonin–norepinephrine reuptake inhibitors (SNRIs) versus placebo, with 2 RCTs included for inpatient settings (Guelfi 1995; Sheehan 2009b), and 26 RCTs included for outpatient settings (Brannan 2005; Cutler 2009; Detke 2002a; Detke 2002b; Detke 2004; Eli Lilly HMAT-A; Goldstein 2002; Goldstein 2004; Hewett 2009; Hewett 2010; Higuchi 2016; Khan 1998; Levin 2013; Mendels 1993; Nemeroff 2007; Nierenberg 2007; Perahia 2006; Raskin 2007; Robinson 2014; Rudolph 1999; Schweizer 1994; Study F1J-MC-HMAQ-Study Group B; Thase 1997; VEN 600A-303 (FDA); VEN 600A-313 (FDA); VEN XR 367 (FDA)). Inpatient versus outpatient subgroup analysis was possible for the depression symptoms endpoint, depression symptoms change score, and remission outcomes.
Comparison 3d. SNRIs versus SSRIs, with 4 RCTs included for inpatient settings (Clerc 1994; Hwang 2004; Sheehan 2009b; Tzanakaki 2000), and 32 RCTs included for outpatient settings (Allard 2004; Alves 1999; Bielski 2004; Casabona 2004; Chang 2015; Costa 1998; DeNayer 2002; Detke 2004; Diaz-Martinez 1998; Dierick 1996; Eli Lilly HMAT-A; Goldstein 2002; Goldstein 2004; Hackett 1996; Heller 2009; Jiang 2017; Khan 2007; Kornaat 2000; Mehtonen 2000; Montgomery 2004; Mowla 2016; Nemeroff 2007; Nierenberg 2007; Perahia 2006; Rickels 2000; Rudolph 1999; Shelton 2006; Sir 2005; Study F1J-MC-HMAQ-Study Group B; Tylee 1997; VEN XR 367 (FDA); Wade 2007) . Inpatient versus outpatient subgroup analysis was possible for the depression symptoms endpoint, depression symptoms change score, remission, and response outcomes.
Comparison 3e. Mirtazapine versus TCAs, with 2 RCTs included for inpatient settings (Richou 1995; Zivkov 1995), and 4 RCTs included for outpatient settings (Bremner 1995; MIR 003-020 (FDA); MIR 003-021 (FDA); Smith 1990). Inpatient versus outpatient subgroup analysis was only possible for the response outcome.
Comparison 3f. Acupuncture + antidepressants versus antidepressants, with 2 RCTs included for inpatient settings (Wang 2014a; Zhang 2007a), and 2 RCTs included for outpatient settings (Qu 2013; Zhao 2019a). Inpatient versus outpatient subgroup analysis was only possible for the depression symptoms change score outcome.

Comparison 4. Acute psychiatric day hospital care versus inpatient care (for adults with depression and non-psychotic severe mental illness)

Acute psychiatric day hospitals are units that provide diagnostic and treatment services for acutely ill individuals who would otherwise be treated in traditional psychiatric inpatient units. 1 RCT (Dinger 2014) was identified that specifically addressed acute psychiatric day hospital care for adults with depression. The committee therefore agreed to consider a wider evidence base including non-psychotic severe mental illness. A systematic review (Marshall 2011) was identified that compared day hospital to inpatient care for people with acute psychiatric disorders. This Cochrane review was used as a source of studies with inclusion criteria into this review of over 50% of the population having a non-psychotic disorder.

Of the 10 RCTs included in Marshall 2011, 5 of these studies met the >50% non-psychotic disorder inclusion criterion (Creed 1990; Creed 1997; Dick 1985; Kallert 2007; Schene 1993).

Comparison 5. Non-acute day hospital care versus outpatient care (for adults with depression and non-psychotic severe mental illness)

No RCT evidence was identified that specifically addressed this setting for adults with depression. The committee therefore agreed to consider a wider evidence base including non-psychotic severe mental illness. A systematic review (Marshall 2001) was identified that examined the use of day hospitals as an alternative to outpatient care for people with psychiatric disorders. This Cochrane review was used as a source of studies with inclusion criteria into this review of over 50% of the population having a non-psychotic disorder.

Of the 8 studies included in Marshall 2001, 3 of these studies met the >50% non-psychotic disorder inclusion criterion (Dick 1991; Glick 1986; Tyrer 1979).

Comparison 6. Community mental health teams versus standard care (for adults with non-psychotic severe mental illness)

No RCT evidence was identified that specifically addressed this setting for adults with depression. The committee therefore agreed to consider a wider evidence base including non-psychotic severe mental illness. A systematic review (Malone 2007) was identified that examined community mental health teams (CMHTs) for people with severe mental illnesses and disordered personality. This Cochrane review was used as a source of studies with inclusion criteria into this review of over 50% of the population having a non-psychotic disorder.

Of the 3 studies included in Malone 2007, 1 of these studies met the >50% non-psychotic disorder inclusion criterion (Merson 1992).

See the literature search strategy in appendix B and study selection flow chart in appendix C.

Excluded studies

Studies not included in this review with reasons for their exclusions are provided in appendix K.

Summary of clinical studies included in the evidence review

Comparison 1. Primary care versus secondary care

Summaries of the studies included in the primary care versus secondary care subgroup analysis of the cognitive and cognitive behavioural therapies individual + antidepressant versus antidepressant comparison are presented in Table 12.

There were no significant subgroup differences between primary care and secondary care for the comparison cognitive and cognitive behavioural therapies individual + antidepressant versus antidepressant on: depression symptoms endpoint (Test for subgroup differences: Chi² = 0.27, df = 1, p = 0.60).

Summaries of the studies included in the primary care versus secondary care subgroup analysis of the selective serotonin reuptake inhibitors (SSRIs) versus placebo comparison are presented in Table 13.

There were no significant subgroup differences between primary care and secondary care for the comparison SSRIs versus placebo on: depression symptoms endpoint (Test for subgroup differences: Chi² = 0.01, df = 1, p = 0.91); depression symptoms change score (Test for subgroup differences: Chi² = 0.26, df = 1, p = 0.61); response (Test for subgroup differences: Chi² = 1.75, df = 1, p = 0.19).

Summaries of the studies included in the primary care versus secondary care subgroup analysis of the SSRIs versus tricyclic antidepressants (TCAs) comparison are presented in Table 14.

There were no significant subgroup differences between primary care and secondary care for the comparison SSRIs versus TCAs on: depression symptoms endpoint (Test for subgroup differences: Chi² = 0.09, df = 1, p = 0.76); depression symptoms change score (Test for subgroup differences: Chi² = 1.46, df = 1, p = 0.23); remission (Test for subgroup differences: Chi² = 2.19, df = 1, p = 0.14); response (Test for subgroup differences: Chi² = 2.22, df = 1, p = 0.14).

Summaries of the studies included in the primary care versus secondary care subgroup analysis of the TCAs versus placebo comparison are presented in Table 15.

There were no significant subgroup differences between primary care and secondary care for the comparison TCAs versus placebo on: depression symptoms endpoint (Test for subgroup differences: Chi² = 0.49, df = 1, p = 0.49); depression symptoms change score (Test for subgroup differences: Chi² = 0.32, df = 1, p = 0.57); response (Test for subgroup differences: Chi² = 2.87, df = 1, p = 0.09).

Summaries of the studies included in the primary care versus secondary care subgroup analysis of the serotonin–norepinephrine reuptake inhibitors (SNRIs) versus SSRIs comparison are presented in Table 16.

There were no significant subgroup differences between primary care and secondary care for the comparison SNRIs versus SSRIs on: remission (Test for subgroup differences: Chi² = 1.55, df = 1, p = 0.21); response (Test for subgroup differences: Chi² = 0.62, df = 1, p = 0.43).

Comparison 2. Crisis resolution team care versus standard care (for adults with non-psychotic severe mental illness)

Summary of the study included in the crisis resolution team care and standard care comparison is presented in Table 17.

Comparison 3. Inpatient versus outpatient settings

Summaries of the studies included in the inpatient versus outpatient subgroup analysis of the selective serotonin reuptake inhibitors (SSRIs) versus placebo comparison are presented in Table 18Table 38.

There were no significant subgroup differences between inpatient and outpatient settings for the comparison SSRIs versus placebo on: depression symptoms change score (Test for subgroup differences: Chi² = 2.47, df = 1, p = 0.12); response (Test for subgroup differences: Chi² = 0.11, df = 1, p = 0.74).

Summaries of the studies included in the inpatient versus outpatient subgroup analysis of the SSRIs versus tricyclic antidepressants (TCAs) comparison are presented in Table 19.

There were no significant subgroup differences between inpatient and outpatient settings for the comparison SSRIs versus TCAs on: depression symptoms endpoint (Test for subgroup differences: Chi² = 1.08, df = 1, p = 0.30); remission (Test for subgroup differences: Chi² = 2.11, df = 1, p = 0.15); response (Test for subgroup differences: Chi² = 1.03, df = 1, p = 0.31). There was a statistically significant subgroup difference between inpatient and outpatient settings for depression change score (Test for subgroup differences: Chi² = 7.03, df = 1, p = 0.008). In inpatient settings TCAs showed a small benefit over SSRIs (SMD 0.27 [0.08, 0.47]), whereas in outpatient settings SSRIs showed a small benefit over TCAs (SMD −0.05 [−0.19, 0.09]), however, in both inpatient and outpatient settings the difference between TCAs and SSRIs was non-significant.

Summaries of the studies included in the inpatient versus outpatient subgroup analysis of the serotonin–norepinephrine reuptake inhibitors (SNRIs) versus placebo comparison are presented in Table 20.

There were no significant subgroup differences between inpatient and outpatient settings for the comparison SNRIs versus placebo on: depression symptoms endpoint (Test for subgroup differences: Chi² = 0.03, df = 1, p = 0.87); depression symptoms change score (Test for subgroup differences: Chi² = 3.12, df = 1, p = 0.08); remission (Test for subgroup differences: Chi² = 0.25, df = 1, p = 0.62).

Summaries of the studies included in the inpatient versus outpatient subgroup analysis of the SNRIs versus SSRIs comparison are presented in Table 21.

There were no significant subgroup differences between inpatient and outpatient settings for the comparison SNRIs versus SSRIs on: depression symptoms endpoint (Test for subgroup differences: Chi² = 2.03, df = 1, p = 0.15); remission (Test for subgroup differences: Chi² = 1.08, df = 1, p = 0.30); response (Test for subgroup differences: Chi² = 0.49, df = 1, p = 0.48). There was a statistically significant subgroup difference between inpatient and outpatient settings for depression change score (Test for subgroup differences: Chi² = 8.03, df = 1, p = 0.005). SNRIs showed a benefit over SSRIs in both settings, although this effect was larger in inpatient settings (SMD −0.48 [−0.73, −0.23]) relative to outpatient settings (SMD −0.09 [−0.19, 0.01]), however, this was a difference in magnitude rather than direction and even in inpatient settings the difference was not clinically important.

Summaries of the studies included in the inpatient versus outpatient subgroup analysis of the mirtazapine versus TCAs comparison are presented in Table 22Table 38.

There was not a significant subgroup difference between inpatient and outpatient settings for the comparison mirtazapine versus TCAs on response (Test for subgroup differences: Chi² = 0.19, df = 1, p = 0.66).

Summaries of the studies included in the inpatient versus outpatient subgroup analysis of the acupuncture + antidepressants versus antidepressants comparison are presented in Table 23Table 38.

There was not a significant subgroup difference between inpatient and outpatient settings for the comparison acupuncture + antidepressants versus antidepressants on depression symptoms change score (Test for subgroup differences: Chi² = 1.18, df = 1, p = 0.28).

Comparison 4. Acute psychiatric day hospital care versus inpatient care (for adults with depression and non-psychotic severe mental illness)

Comparison 5. Non-acute day hospital care versus outpatient care (for adults with depression and non-psychotic severe mental illness)

Comparison 6. Community mental health teams versus standard care (for adults with non-psychotic severe mental illness)

See the full evidence tables in appendix D and the forest plots in appendix E.

Quality assessment of clinical outcomes included in the evidence review

See the clinical evidence profiles in appendix F.

Economic evidence

Included studies

A single economic search was undertaken for all topics included in the scope of this guideline but no economic studies were identified which were applicable to this review question. See the literature search strategy in appendix B and economic study selection flow chart in appendix G.

Excluded studies

A list of excluded economic and utility studies, with reasons for exclusion, is provided in supplement 3 - Health economic included & excluded studies.

Economic model

No economic modelling was undertaken for this review because the committee agreed that other topics were higher priorities for economic evaluation.

Evidence statements

Clinical evidence statements

Comparison 1. Primary care versus secondary care

Primary care versus secondary care subgroup analysis for Comparison 1a Cognitive and cognitive behavioural therapies individual + antidepressant versus antidepressant

Critical outcomes

Depression symptomatology

Subgroup analysis of primary care and secondary care, for the comparison of combined individual CBT and antidepressant versus antidepressant-only, shows no statistically significant subgroup difference in depression symptomatology at endpoint for adults receiving first-line treatment for depression.

Primary care versus secondary care subgroup analysis for Comparison 1b. Selective serotonin reuptake inhibitors (SSRIs) versus placebo

Critical outcomes

Depression symptomatology

Subgroup analysis of primary care and secondary care, for the comparison of SSRIs versus placebo, shows no statistically significant subgroup difference in depression symptomatology at endpoint, or change from baseline to endpoint, for adults receiving first-line treatment for depression.

Response

Subgroup analysis of primary care and secondary care, for the comparison of SSRIs versus placebo, shows no statistically significant subgroup difference in the rate of response for adults receiving first-line treatment for depression.

Primary care versus secondary care subgroup analysis for Comparison 1c. SSRIs versus tricyclic antidepressants (TCAs)

Critical outcomes

Depression symptomatology

Subgroup analysis of primary care and secondary care, for the comparison of SSRIs versus TCAs, shows no statistically significant subgroup difference in depression symptomatology at endpoint, or change from baseline to endpoint, for adults receiving first-line treatment for depression.

Remission

Subgroup analysis of primary care and secondary care, for the comparison of SSRIs versus TCAs, shows no statistically significant subgroup difference in the rate of remission for adults receiving first-line treatment for depression.

Response

Subgroup analysis of primary care and secondary care, for the comparison of SSRIs versus TCAs, shows no statistically significant subgroup difference in the rate of response for adults receiving first-line treatment for depression.

Primary care versus secondary care subgroup analysis for Comparison 1d. TCAs versus placebo

Critical outcomes

Depression symptomatology

Subgroup analysis of primary care and secondary care, for the comparison of TCAs versus placebo, shows no statistically significant subgroup difference in depression symptomatology at endpoint, or change from baseline to endpoint, for adults receiving first-line treatment for depression.

Response

Subgroup analysis of primary care and secondary care, for the comparison of TCAs versus placebo, shows no statistically significant subgroup difference in the rate of response for adults receiving first-line treatment for depression.

Primary care versus secondary care subgroup analysis for Comparison 1e. Serotonin–norepinephrine reuptake inhibitors (SNRIs) versus SSRIs

Critical outcomes

Remission

Subgroup analysis of primary care and secondary care, for the comparison of SNRIs versus SSRIs, shows no statistically significant subgroup difference in the rate of remission for adults receiving first-line treatment for depression.

Response

Subgroup analysis of primary care and secondary care, for the comparison of SNRIs versus SSRIs, shows no statistically significant subgroup difference in the rate of response for adults receiving first-line treatment for depression.

Comparison 2. Crisis resolution team care versus standard care (for adults with non-psychotic severe mental illness)

Critical outcomes

Psychiatric symptom severity

Very low quality evidence from 1 RCT (N=211) shows a statistically significant but not clinically important benefit of crisis resolution team care relative to standard care on psychiatric symptom severity 8 weeks after crisis, for adults with non-psychotic severe mental illness.

Important outcomes

Service utilisation

Very low quality evidence from 1 RCT (N=258) shows a clinically important and statistically significant benefit of crisis resolution team care relative to standard care on the rate of inpatient admission 6 months after crisis, for adults with nonpsychotic severe mental illness.
Very low quality evidence from 1 RCT (N=257) shows a statistically significant but not clinically important benefit of crisis resolution team care relative to standard care on the number of bed days in hospital 6 months after crisis, for adults with non-psychotic severe mental illness.

Psychological functioning

Very low quality evidence from 1 RCT (N=217) shows neither a clinically important nor statistically significant difference between crisis resolution team care and standard care on quality of life 8 weeks after crisis, for adults with non-psychotic severe mental illness.

Social functioning

Very low quality evidence from 1 RCT (N=255-257) shows neither a clinically important nor statistically significant difference between crisis resolution team care and standard care on social functioning at 8 weeks or 6 months after crisis, for adults with non-psychotic severe mental illness.

Satisfaction

Very low quality evidence from 1 RCT (N=226) shows neither a clinically important nor statistically significant difference between crisis resolution team care relative and standard care on patient satisfaction ratings 8 weeks after crisis, for adults with non-psychotic severe mental illness.

Comparison 3. Inpatient versus outpatient settings

Inpatient versus outpatient subgroup analysis for Comparison 3a Selective serotonin reuptake inhibitors (SSRIs) versus placebo

Critical Outcomes

Depression symptomatology

Subgroup analysis of inpatient and outpatient settings, for the comparison of SSRIs versus placebo, shows no statistically significant subgroup difference in depression symptomatology change score for adults receiving first-line treatment for depression.

Response

Subgroup analysis of inpatient and outpatient settings, for the comparison of SSRIs versus placebo, shows no statistically significant subgroup difference in the rate of response for adults receiving first-line treatment for depression.

Inpatient versus outpatient subgroup analysis for Comparison 3b SSRIs versus Tricyclic Antidepressants (TCAs)

Critical Outcomes

Depression symptomatology

Subgroup analysis of inpatient and outpatient settings, for the comparison of SSRIs versus TCAs, shows no statistically significant subgroup difference in depression symptomatology at endpoint for adults receiving first-line treatment for depression.
Subgroup analysis of inpatient and outpatient settings, for the comparison of SSRIs versus TCAs, shows a statistically significant subgroup difference in depression symptomatology change score for adults receiving first-line treatment for depression. In inpatient settings TCAs show a small benefit over SSRIs, and in outpatient settings SSRIs show a small benefit over TCAs, however, in both inpatient and outpatient settings the difference between TCAs and SSRIs is non-significant.

Remission

Subgroup analysis of inpatient and outpatient settings, for the comparison of SSRIs versus TCAs, shows no statistically significant subgroup difference in the rate of remission for adults receiving first-line treatment for depression.

Response

Subgroup analysis of inpatient and outpatient settings, for the comparison of SSRIs versus TCAs, shows no statistically significant subgroup difference in the rate of response for adults receiving first-line treatment for depression.

Inpatient versus outpatient subgroup analysis for Comparison 3c Serotonin–norepinephrine reuptake inhibitors (SNRIs) versus placebo

Critical Outcomes

Depression symptomatology

Subgroup analysis of inpatient and outpatient settings, for the comparison of SNRIs versus placebo, shows no statistically significant subgroup difference in depression symptomatology at endpoint for adults receiving first-line treatment for depression.
Subgroup analysis of inpatient and outpatient settings, for the comparison of SNRIs versus placebo, shows no statistically significant subgroup difference in depression symptomatology change scores for adults receiving first-line treatment for depression.

Remission

Subgroup analysis of inpatient and outpatient settings, for the comparison of SNRIs versus placebo, shows no statistically significant subgroup difference in the rate of remission for adults receiving first-line treatment for depression.

Inpatient versus outpatient subgroup analysis for Comparison 3d SNRIs versus SSRIs

Critical Outcomes

Depression symptomatology

Subgroup analysis of inpatient and outpatient settings, for the comparison of SNRIs versus SSRIs, shows no statistically significant subgroup difference in depression symptomatology at endpoint for adults receiving first-line treatment for depression.
Subgroup analysis of inpatient and outpatient settings, for the comparison of SNRIs versus SSRIs, shows a statistically significant subgroup difference in depression symptomatology change score for adults receiving first-line treatment for depression. In both inpatient and outpatient settings SNRIs show a benefit over SSRIs however this effect is larger in inpatient relative to outpatient settings, although this is a difference in magnitude rather than direction and even in inpatient settings the difference is not clinically important.

Remission

Subgroup analysis of inpatient and outpatient settings, for the comparison of SNRIs versus SSRIs, shows no statistically significant subgroup difference in the rate of remission for adults receiving first-line treatment for depression.

Response

Subgroup analysis of inpatient and outpatient settings, for the comparison of SNRIs versus SSRIs, shows no statistically significant subgroup difference in the rate of response for adults receiving first-line treatment for depression.

Inpatient versus outpatient subgroup analysis for Comparison 3e Mirtazapine versus TCAs

Critical Outcomes

Response

Subgroup analysis of inpatient and outpatient settings, for the comparison of mirtazapine versus TCAs, shows no statistically significant subgroup difference in the rate of response for adults receiving first-line treatment for depression.

Inpatient versus outpatient subgroup analysis for Comparison 3f Acupuncture + antidepressants versus antidepressants

Critical Outcomes

Depression symptomatology

Subgroup analysis of inpatient and outpatient settings, for the comparison of combined acupuncture and antidepressant versus antidepressants-only, shows no statistically significant subgroup difference in depression symptomatology change score for adults receiving first-line treatment for depression.

Comparison 4. Acute psychiatric day hospital care versus inpatient care (for adults with depression and non-psychotic severe mental illness)

Critical outcomes

Psychiatric symptom severity

Very low quality evidence from 2-3 RCTs (N=1249-1281) shows neither clinically important nor statistically significant differences between acute day hospital care compared to inpatient care on psychiatric symptom severity at 2-3 months or 12-14 months post-admission, for adults with depression or non-psychotic severe mental illness.

Remission

Very low quality evidence from 2 RCTs (N=151) shows neither clinically important nor statistically significant effects differences between acute day hospital care compared to inpatient care on the rate of remission at 3 or 13 months post-admission, for adults with depression or non-psychotic severe mental illness.

Response

Very low quality evidence from 1 RCT (N=44) including only adults with depression shows a clinically important but not statistically significant benefit of inpatient care relative to acute day hospital care on the rate of response at 3 months post-admission.

Important outcomes

Service utilisation

Very low quality evidence from 4 RCTs (N=1535) shows a clinically important and statistically significant benefit of inpatient care, relative to acute day hospital care, on the duration of index admission for adults with depression or non-psychotic severe mental illness.
Very low quality evidence from 3 RCTs (N=372) shows a clinically important but not statistically significant benefit of acute day hospital care relative to inpatient care on readmission at 4 months or 12 months post-admission, for adults with depression or non-psychotic severe mental illness.
Very low quality evidence from 1 RCT (N=83) shows clinically important but not statistically significant benefits of inpatient care relative to acute day hospital care on the number of emergency contacts and the number of outpatient contacts, for adults with non-psychotic severe mental illness.

Psychological functioning

Very low quality evidence from 1 RCT (N= 1117) shows neither clinically important nor statistically significant differences between acute day hospital care compared to inpatient care on quality of life at 2 or 14 months post-admission, for adults with non-psychotic severe mental illness.

Social functioning

Very low quality evidence from 1 RCT (N= 1117) shows a statistically significant but not clinically important benefit of acute day hospital care relative to inpatient care on social functioning impairment at 2 and 14 months post-admission, for adults with non-psychotic severe mental illness.
Very low quality evidence from 2 RCTs (N=181) shows a clinically important but not statistically significant benefit of acute day hospital care relative to inpatient care on the number of people achieving significant improvement in social functioning at 12-13 months post-admission, for adults with non-psychotic severe mental illness.

Satisfaction

Very low quality evidence from 1 RCT (N= 83) shows a clinically important and statistically significant benefit of acute day hospital care relative to inpatient care in the number of people who are satisfied or very satisfied with their treatment, for adults with non-psychotic severe mental illness.
Very low quality evidence from 1 RCT (N=1117) shows neither clinically important nor statistically significant differences between acute day hospital care compared to inpatient care on patient satisfaction ratings at 2 months post-admission, for adults with non-psychotic severe mental illness.

Carer distress

Very low quality evidence from 1 RCT (N=55-77) shows neither clinically important nor statistically significant differences between acute day hospital care compared to inpatient care on carer distress at 3 or 12 months post-admission, for adults with non-psychotic severe mental illness.

Comparison 5. Non-acute day hospital care versus outpatient care (for adults with depression and non-psychotic severe mental illness)

Critical outcomes

Psychiatric symptom severity

Low to very low quality evidence from 2 RCTs (N=139-144) shows neither clinically important nor statistically significant differences between non-acute day hospital care compared to outpatient care on psychiatric symptom severity at 4-6 months and 8-12 months post-admission, for adults with non-psychotic severe mental illness.

Important outcomes

Service utilisation

Very low quality evidence from 3 RCTs (N=281) shows a clinically important but not statistically significant benefit of outpatient care relative to non-acute day hospital care on the number of people admitted as an inpatient at 6-12 months post-admission, for adults with non-psychotic severe mental illness.

Social functioning

Very low quality evidence from 2 RCTs (N=141) shows neither clinically important nor statistically significant differences between non-acute day hospital care compared to outpatient care on social functioning at 4-6 or 8-12 months post-admission, for adults with non-psychotic severe mental illness.
Very low quality evidence from 1 RCT (N=51-52) shows neither clinically important nor statistically significant differences between non-acute day hospital care compared to outpatient care on global functioning at 6 and 12 months post-admission, for adults with non-psychotic severe mental illness.

Satisfaction

Very low quality evidence from 2 RCTs (N=198) shows neither clinically important nor statistically significant differences between non-acute day hospital care compared to outpatient care on the number of people satisfied or very satisfied with their treatment at 4-6 months post-admission, for adults with non-psychotic severe mental illness.

Comparison 6. Community mental health teams versus standard care (for adults with non-psychotic severe mental illness)

Critical outcomes

Psychiatric symptom severity

Low quality evidence from 1 RCT (N=100) shows neither a clinically important nor statistically significant difference between community mental health team care compared to standard care on psychiatric symptom severity at 3 months post-entry, for adults with non-psychotic severe mental illness.

Important outcomes

Service utilisation

Very low quality evidence from 1 RCT (N=100) shows a clinically important but not statistically significant benefit of community mental health team care relative to standard care on the number of people admitted to inpatient care, and a clinically important and statistically significant benefit on the number of people admitted to inpatient care for longer than 10 days, for adults with non-psychotic severe mental illness.

Satisfaction

Very low quality evidence from 1 RCT (N=87) shows clinically important and statistically significant benefits of community mental health team care, relative to standard care, on both continuous and dichotomous measures of satisfaction for adults with non-psychotic severe mental illness.

Economic evidence statements

No economic evidence was identified which was applicable to this review question.

The committee’s discussion of the evidence

Interpreting the evidence

The outcomes that matter most

The aim of this review was to determine if different settings for the delivery of care improved outcomes for people with depression so the committee identified depression symptomatology, response, remission and relapse to be the critical outcomes for this question. If the evidence specific to depression was limited, it was pre-defined in the protocol that the inclusion criteria would be expanded to include those with non-psychotic severe mental illness, and for these populations psychiatric symptom severity was a critical outcome. Service utilisation and resource use were identified as important outcomes, as a measure of uptake and persistence with treatment. Psychological functioning, social functioning, satisfaction, and carer distress were also considered important outcomes, in order to assess the broader impact of setting on the person with depression and their family or carer.

For all comparisons there was evidence for at least one critical outcome – most commonly symptom severity – and at least one important outcome. Carer distress was rarely reported and this outcome was only available for comparison 4.

The quality of the evidence

The committee noted that all outcomes had been assessed as either very low or low in GRADE. Most outcomes were downgraded due to imprecision and/or risk of bias. A number of the comparisons also included people with non-psychotic severe mental illness, and so were not specific to the population of people with depression, and these comparisons were downgraded again due to indirectness.

Benefits and harms

The comparisons included in this review included a number of different settings such as the primary care setting (where people are living in their own home and are cared for by their GPs), and a number of different secondary care or specialist services, where care is provided to people in their own homes, as outpatients, or as inpatients.

During the protocol development, the committee had noted that the best evidence to examine the benefits and harms associated with settings would require randomised controlled trials (RCTs) that randomised the same population to different settings for the delivery of care. However, trials of interventions delivered in certain settings will recruit populations considered to be relevant to that setting. Evidence is particularly limited where the comparison includes inpatient care, as the large majority of people with depression are never admitted to hospital. The committee therefore agreed to consider a wider evidence base for settings where there was limited direct RCT evidence by including evidence on the care of people with severe, non-psychotic mental illness as well as or instead of, those with depression. The committee also agreed that where specific RCT evidence was limited for particular comparisons, indirect evidence in the form of subgroup analyses of the NMA dataset (Evidence report B: Treatment of a new episode of depression) may be informative.

For crisis resolution team care, no RCT evidence was identified that specifically addressed this setting for adults with depression, and only 1 RCT was identified that included people with severe non-psychotic mental illness. The evidence showed a small but statistically significant benefit of crisis resolution team care (relative to standard care) on psychiatric symptom severity, and benefits in terms of service utilisation (on the number of people admitted as an inpatient, and bed days in hospital). Based on their experience, the committee recognised the potential benefits that crisis resolution team care may bring to adults with severe depression (particularly those at significant risk of harming themselves through suicide attempts or self-neglect) in providing an alternative to inpatient treatment and thus potentially avoiding the stigma and costs associated with hospital admission. They also recognised that crisis resolution and home treatment team care may have an important role in supporting people at home after an inpatient stay and so facilitate an early discharge, reducing the likelihood of a readmission to hospital. The committee therefore included in their recommendations some guidance on the type of people with depression who should be seen by crisis resolution teams, and what that care should involve. However, given the limited and indirect evidence base, the committee agreed that a ‘consider’ rather than ‘offer’ recommendation was appropriate.

There was no specific RCT evidence for inpatient settings. Therefore the committee considered indirect evidence in the form of subgroup analyses of the NMA dataset (acute treatment of depressive episodes). Differences between delivery in inpatient and outpatient settings were explored for depression symptomatology, remission, and response for all treatment comparisons with at least 2 studies in each subgroup (SSRIs versus placebo; SSRIs versus TCAs; SNRIs versus placebo; SNRIs versus SSRIs; mirtazapine versus TCAs; acupuncture + antidepressant versus antidepressant). Most subgroup differences were non-significant. There was, however, a statistically significant subgroup difference between inpatient and outpatient settings for depression change score for the SSRIs versus TCAs comparison, with TCAs showing a small benefit over SSRIs in inpatient settings and SSRIs showing a small benefit over TCAs in outpatient settings, however, the difference between TCAs and SSRIs was non-significant in both inpatient and outpatient settings. There was also a statistically significant subgroup difference between inpatient and outpatient settings for depression change score for the SNRIs versus SSRIs comparison, however, this was a difference in magnitude rather than direction with a benefit of SNRIs relative to SSRIs shown in both inpatient and outpatient settings but larger effects shown in inpatient settings. Despite the lack of evidence for clear clinical benefits associated with inpatient care, the committee drew on their clinical knowledge and expertise, and recognised that inpatient care may be necessary for people with more severe depression who could not be adequately supported by a crisis resolution and home treatment team, particularly if they were socially isolated, and so they made a recommendation to this effect.

For primary care compared to secondary care, no RCT evidence was identified that specifically addressed this setting. Therefore the committee considered indirect evidence in the form of subgroup analyses of the NMA dataset (acute treatment of depressive episodes). For all valid treatment comparisons (at least 2 studies per subgroup), subgroup analyses compared whether different outcomes were associated with delivery of treatment in primary compared to secondary care. For all comparisons (combined individual CBT and antidepressant versus antidepressant-only; SSRIs versus placebo; SSRIs versus TCAs; TCAs versus placebo; SNRIs versus SSRIs) there was no good evidence to show any difference between delivery in primary care or secondary care on depression symptomatology, response, or remission. Based on this evidence and their knowledge and experience, the committee agreed that there was no need to add a recommendation that specified whether interventions should be delivered in primary or secondary care, except where there were safety concerns for certain pharmacological interventions but this was captured in the specific treatment recommendations.

For all other comparisons, very few RCTs were identified that included only adults with depression (only 2 RCTs across 2 separate comparisons of non-acute day hospital versus outpatient care, and acute psychiatric day hospital versus inpatient care), and a wider evidence base including those with non-psychotic severe mental illness was considered. For acute psychiatric day hospital care (relative to inpatient care), non-acute day hospital care (relative to outpatient care), and community mental health team care (relative to standard care) no significant (both clinically important and statistically significant) differences were shown for the critical outcomes of psychiatric symptom severity, remission or response. No eligible evidence was identified for specialist tertiary affective disorders settings or residential settings. On the basis of the limited evidence base, the committee agreed that there were no grounds (including their clinical knowledge and experience) on which to base a recommendation that care for people with depression should be delivered in these specific settings.

The committee raised the importance of equity of access to interventions in inpatient care that is equivalent to those available in community settings. They therefore recommended that the full range of psychological interventions available in community settings should also be available in inpatient settings. They also recognised that the intensity and/or duration of these interventions may need to be altered commensurate with the level of severity and need in inpatient settings.

Cost effectiveness and resource use

No evidence on the cost-effectiveness of different settings for the delivery of care for adults with depression was identified and no further economic analysis was undertaken. The committee considered the costs associated with crisis resolution and home treatment and estimated that these are higher than routine primary care but significantly lower than inpatient care. The committee expressed the opinion that, compared with routine primary care, crisis resolution treatment is often more appropriate for people with more severe depression who are at significant risk of suicide, harm to self or to others, self-neglect or complications in response to their treatment, leading to better outcomes and reduced need for more costly inpatient care.

The committee took into account the high costs associated with inpatient care, and decided to recommend inpatient treatment only for people with more severe depression who cannot be adequately supported by a crisis resolution and home treatment team.

Considering the benefits and costs of crisis resolution and home treatment teams (CRHT teams) relative to other care settings, the committee expressed the opinion that CRHT comprises an effective and likely cost-effective model of care for people with depression who would benefit from early discharge from hospital after a period of inpatient care.

The committee took into account the cost effectiveness of psychological treatments in the acute treatment of people with depression based on the results of the economic analysis undertaken for this guideline (Evidence report B: Treatment of a new episode of depression), and expressed the view that the full range of such treatments should also be available in inpatient settings, to allow provision of clinically and cost-effective care in populations treated in such settings. The committee acknowledged the fact that increasing the intensity and duration of psychological interventions for people with depression in inpatient settings has resource implications, but expressed the view that the benefits of more intensive treatment in this group would outweigh the additional intervention costs. Moreover, if improved outcomes result in earlier discharge, then cost-savings may outweigh the intervention costs of more intensive psychological treatment.

Recommendations supported by this evidence review

This evidence review supports recommendations 1.16.11 to 1.16.14 in the NICE guideline.

References

This reference list does not include studies analysed as a sub-set of the NMA data for comparisons 1 and 3. Please see evidence review B.

Creed 1990
Creed F, Black D, Anthony P, Osborn M, Thomas P, Tomenson B. Randomised controlled trial of day patient versus inpatient psychiatric treatment. Br Med J. 1990 Apr 21;300(6731):1033–7. [PMC free article: PMC1662770] [PubMed: 2188696]
Creed 1997
Creed F, Mbaya P, Lancashire S, Tomenson B, Williams B, Holme S. Cost effectiveness of day and inpatient psychiatric treatment: results of a randomised controlled trial. Br Med J. 1997 May 10;314(7091):1381. [PMC free article: PMC2126667] [PubMed: 9161310]
Dick 1985
Dick P, Cameron L, Cohen D, Barlow M, Ince AN. Day and full time psychiatric treatment: a controlled comparison. The British Journal of Psychiatry. 1985 Sep 1;147(3):246–9. [PubMed: 4063589]
Dick 1991
Dick PH, Sweeney ML, Crombie IK. Controlled comparison of day-patient and out-patient treatment for persistent anxiety and depression. The BritishJjournal of Psychiatry. 1991 Jan 1;158(1):24–7. [PubMed: 2015447]
Dinger 2014
Dinger U, Klipsch O, Köhling J, Ehrenthal JC, Nikendei C, Herzog W, Schauenburg H. Day-clinic and inpatient psychotherapy for depression (DIP-D): a randomized controlled pilot study in routine clinical care. Psychotherapy andPpsychosomatics. 2014 Apr 17;83(3):194–5. [PubMed: 24752281]
Glick 1986
Glick ID, Fleming L, DeChillo N, Meyerkopf N, Jackson C, Muscara D, Good-Ellis M. A controlled study of transitional day care for non-chronically ill patients. American Journal of Psychiatry. 1986 Dec 1;143(12):1551–6. [PubMed: 3789208]
Johnson 2005
Johnson S, Nolan F, Pilling S, Sandor A, Hoult J, McKenzie N, White IR, Thompson M, Bebbington P. Randomised controlled trial of acute mental health care by a crisis resolution team: the north Islington crisis study. Br Med J. 2005 Sep 15;331(7517):599. [PMC free article: PMC1215550] [PubMed: 16103032]
Kallert 2007
Kallert TW, Priebe S, McCabe R, Kiejna A, Rymaszewska J, Nawka P, Ocvár L, Raboch J, Stárková-Kalisová L, Koch R, Schutzwohl M. Are Day Hospitals Effective for Acutely III Psychiatric Patients? A European Multicenter Randomized Controlled Trial. Journal of Clinical Psychiatry. 2007 Feb 15;68(2):278–87. [PubMed: 17335327]
Merson 1992
Merson S, Tyrer P, Lack S, Birkett P, Lynch S, Onyett S, Johnson T. Early intervention in psychiatric emergencies: a controlled clinical trial. The Lancet. 1992 May 30;339(8805):1311–4. [PubMed: 1349990]
Schene 1993
Schene AH, Wijngaarden BV, Poelijoe NW, Gersons BP. The Utrecht comparative study on psychiatric day treatment and inpatient treatment. Acta Psychiatrica Scandinavica. 1993 Jun 1;87(6):427–36. [PubMed: 8356895]
Tyrer 1979
Tyrer PJ, Remington M. Controlled comparison of day-hospital and outpatient treatment for neurotic disorders. The Lancet. 1979 May 12;313(8124):1014–6. [PubMed: 86727]

Appendices

Appendix D. Clinical evidence tables

Clinical evidence tables for review question 1.1 For adults with depression, what are the relative benefits and harms associated with different models for the coordination and delivery of services?

Please refer to the clinical evidence tables in supplement A1 – Clinical evidence tables for review 1.1

Clinical evidence tables for review question 1.2 For adults with depression, what are the relative benefits and harms associated with different settings for the delivery of care?

Please refer to the clinical evidence tables in supplement A2 – Clinical evidence tables for review 1.2

Appendix E. Forest plots

Forest plots for review question 1.1 For adults with depression, what are the relative benefits and harms associated with different models for the coordination and delivery of services? (PDF, 669K)

Forest plots for review question 1.2 For adults with depression, what are the relative benefits and harms associated with different settings for the delivery of care? (PDF, 2.3M)

Appendix F. GRADE tables

GRADE tables for review question 1.1 For adults with depression, what are the relative benefits and harms associated with different models for the coordination and delivery of services? (PDF, 589K)

GRADE tables for review question 1.2 For adults with depression, what are the relative benefits and harms associated with different settings for the delivery of care? (PDF, 469K)

Appendix G. Economic evidence study selection

Economic evidence study selection for review question 1.1 For adults with depression, what are the relative benefits and harms associated with different models for the coordination and delivery of services? (PDF, 228K)

Economic evidence study selection for review question 1.2 For adults with depression, what are the relative benefits and harms associated with different settings for the delivery of care? (PDF, 227K)

Appendix H. Economic evidence tables

Economic evidence tables for review question 1.1 For adults with depression, what are the relative benefits and harms associated with different models for the coordination and delivery of services?

Download PDF (364K)

Economic evidence tables for review question 1.2 For adults with depression, what are the relative benefits and harms associated with different settings for the delivery of care?

No economic evidence was identified which was applicable to this review question.

Appendix I. Economic evidence profiles

Economic evidence profiles for review question 1.1 For adults with depression, what are the relative benefits and harms associated with different models for the coordination and delivery of services?

Download PDF (294K)

Economic evidence profiles for review question 1.2 For adults with depression, what are the relative benefits and harms associated with different settings for the delivery of care?

No economic evidence was identified which was applicable to this review question.

Appendix J. Economic analysis

Economic evidence analysis for review question 1.1 For adults with depression, what are the relative benefits and harms associated with different models for the coordination and delivery of services?

No economic analysis was conducted for this review question.

Economic evidence analysis for review question 1.2 For adults with depression, what are the relative benefits and harms associated with different settings for the delivery of care?

No economic analysis was conducted for this review question.

Appendix K. Excluded studies

Excluded clinical and economic studies for review question 1.1 For adults with depression, what are the relative benefits and harms associated with different models for the coordination and delivery of services?

Clinical studies

Please refer to the excluded studies in supplement A1 – Clinical evidence tables for review 1.1

Economic studies

Please refer to supplement 3 - Economic evidence included & excluded studies.

Excluded clinical and economic studies for review question 1.2 For adults with depression, what are the relative benefits and harms associated with different settings for the delivery of care?

Clinical studies

Please refer to the excluded studies in supplement A2 – Clinical evidence tables for review 1.2

Economic studies

Please refer to supplement 3 - Economic evidence included & excluded studies.

Appendix L. Research recommendations

Research recommendations for review question 1.1 For adults with depression, what are the relative benefits and harms associated with different models for the coordination and delivery of services?

No research recommendations were made for this review question.

Research recommendations for review question 1.2 For adults with depression, what are the relative benefits and harms associated with different settings for the delivery of care?

No research recommendations were made for this review question.

Supplemental Data

a1: Clinical evidence tables for review question 1.1 (Excel)

a2: Clinical evidence tables for review question 1.2 (Excel)

Figures

Figure 1Coding system for service delivery models (Collaborative Care Component Score Method)

Item	Score
1. Active and integrated case recognition/identification^* (Systematic identification- from a clinical database or screened positive for depression)	0 1
2. Collaborative assessment and plan included (Collaborative assessment with the patient)	0 1
3. Case Management (Case manager present- can include pharmacist for medication management)	0 1
4. Active liaison with primary care and other services (System set up for structured liaison/ regular meetings)	0 1
5. Case Manager has MH background (A prior mental health background, not just training in mental health)	0 1
6. Supervision provided for case manager	0 1
7. Senior MH professional consultation/involvement (Broad definition- just need to be available)	0 1
8. Psychoeducation delivered	0 1
9. Algorithm(s) used to determine care^*	0 1
10. Integration with physical health care where necessary	0 1
11. Social/psychosocial interventions provided	0 1
12. Case manager delivers intervention	0 1
13. Medication management provided	0 1
14. Routine outcome monitoring (Scheduled, using a tool)	0 1
15. Psychological interventions provided None Low intensity High intensity	0 1 2
16. Duration of programme contact ≤6 mths 7-12mths 1year plus	0 1 2
17. Number of sessions (F-t-F and Telephone) ≤6 sessions 6 – 12 sessions 13 + sessions	0 1 2
Total (maximum 20)

*

Including stepped care

Rating

<5 – not collaborative care
6-12 – simple collaborative care
13+ – complex collaborative care

Tables

Table 1Summary of the protocol (PICO table)

Population	Adults with a diagnosis of depression according to DSM, ICD or similar criteria, or depressive symptoms as indicated by baseline depression scores on validated scales (and including those with subthreshold [just below threshold] depressive symptoms) For studies on relapse prevention: Adults whose depression has responded to treatment (in full or partial remission) according to DSM, ICD or similar criteria, or indicated by below clinical threshold depression symptom scores on validated scales
Intervention	Models for the coordination and delivery of services, including: Collaborative care (simple and complex) Stepped care Medication management Attached professional model Care co-ordination Integrated care pathways (including primary care liaison or shared care) Measurement-based care
Comparison	Treatment as usual Waitlist Any other service delivery model
Outcomes	Critical Depression symptomatology (mean endpoint score or change in depression score from baseline) at 6 and 12 months Response (usually defined as at least 50% improvement from the baseline score on a depression scale) at 6 and 12 months Remission (usually defined as a score below clinical threshold on a depression scale) at 6 and 12 months Relapse (number of people who returned to a depressive episode whilst in remission) at 6 and 12 months Important Antidepressant use at 6 and 12 months Discontinuation (due to any reason) at 6 and 12 months

: DSM: Diagnostic and Statistical Manual of Mental Disorders; ICD: International Classification of Diseases.

Table 2Summary of included studies for Comparison 1: Collaborative care (simple or complex) versus standard care/enhanced standard care

Study

Population

Intervention

Comparison

Comments

Aragones 2012

RCT

Spain

N=360

Baseline severity: More severe

Mean age (years): 47.6

Sex (% female): 79

Ethnicity (% BME): NR

Simple collaborative care

Collaborative care component score: 9

Standard care

Duration of programme contact (in months): NR

Outcomes:

Depression symptomatology at 6 months
Depression symptomatology at 12 months
Response at 6 months
Response at 12 months
Remission at 6 months
Remission at 12 months
Antidepressant use at 6 months
Antidepressant use at 12 months
Discontinuation at 6 months
Discontinuation at 12 months

Araya 2003

RCT

Chile

N=240

Baseline severity: More severe

Mean age (years): 42.6

Sex (% female): 100

Ethnicity (% BME): NR

Simple collaborative care

Collaborative care component score: 7

Standard care

Duration of programme contact (in months): 3

Outcomes:

Response at 6 months
Remission at 6 months
Antidepressant use at 6 months
Discontinuation at 6 months

Berghofer 2012

RCT

Germany

N=63

Baseline severity: More severe

Mean age (years): 49.7

Sex (% female): 73

Ethnicity (% BME): NR

Simple collaborative care

Collaborative care component score: 10

Standard care

Duration of programme contact (in months): 6

Outcomes:

Response at 6 months
Response at 12 months

Bjorkelund 2018

RCT

Sweden

N=385

Baseline severity: Less severe

Mean age (years): 41.2

Sex (% female): 71

Ethnicity (% BME): NR

Simple collaborative care

Collaborative care component score: 9

Standard care

Duration of programme contact (in months): 3

Outcomes:

Remission at 6 months
Antidepressant use at 6 months
Discontinuation at 6 months

Bosanquet 2017

RCT

N=485

Baseline severity: Less severe

Mean age (years): 72.2

Sex (% female): 62

Ethnicity (% BME): 2

Simple collaborative care

Collaborative care component score: 8

Enhanced standard care

Duration of programme contact (in months): 2

Outcomes:

Depression symptomatology at 12 months
Antidepressant use at 12 months
Discontinuation at 12 months

Bruce 2004

RCT

N=598

Baseline severity: More severe

Mean age (years): NR (>60)

Sex (% female): 72

Ethnicity (% BME): 28

Simple collaborative care

Collaborative care component score: 11.5

Enhanced standard care

Duration of programme contact (in months): 12

Outcomes:

Depression symptomatology at 12 months
Response at 12 months
Remission at 12 months
Antidepressant use at 12 months
Discontinuation at 12 months

Buszewicz 2016

RCT

N=558

Baseline severity: More severe

Mean age (years): 48.4

Sex (% female): 75

Ethnicity (% BME): 12

Simple collaborative care

Collaborative care component score: 11

Standard care

Duration of programme contact (in months): 24

Outcomes:

Depression symptomatology at 6 months
Depression symptomatology at 12 months
Discontinuation at 6 months
Discontinuation at 12 months

Capoccia 2004

RCT

N=74

Baseline severity: NR

Mean age (years): 38.7

Sex (% female): 77

Ethnicity (% BME): 22

Simple collaborative care

Collaborative care component score: 8

Standard care

Duration of programme contact (in months): 12

Outcomes:

Antidepressant use at 12 months
Discontinuation at 12 months

Chen 2015

RCT

China

N=326

Baseline severity: More severe

Mean age (years): NR (>60)

Sex (% female): 63

Ethnicity (% BME): NR

Simple collaborative care

Collaborative care component score: 12

Enhanced standard care

Duration of programme contact (in months): 4

Outcomes:

Depression symptomatology at 6 months
Depression symptomatology at 12 months
Response at 6 months
Response at 12 months
Remission at 6 months
Remission at 12 months
Discontinuation at 6 months
Discontinuation at 12 months

Curth 2020

RCT

Denmark

N=325

Baseline severity: Less severe

Mean age (years): 39

Sex (% female): 67

Ethnicity (% BME): NR

Simple collaborative care

Collaborative care component score: 11

Standard care

Duration of programme contact (in months): 4

Outcomes:

Depression symptomatology at 6 months
Discontinuation at 6 months

Dobscha 2006

RCT

N=375

Baseline severity: Less severe

Mean age (years): 56.8

Sex (% female): 7

Ethnicity (% BME): 3

Simple collaborative care

Collaborative care component score: 9

Enhanced standard care

Duration of programme contact (in months): 12

Outcomes:

Antidepressant use at 12 months
Discontinuation at 12 months

Ell 2007

RCT

N=311

Baseline severity: NR

Mean age (years): NR (>60)

Sex (% female): 72

Ethnicity (% BME): 27

Simple collaborative care

Collaborative care component score: 10.5

Enhanced standard care

Duration of programme contact (in months): 12

Outcomes:

Response at 12 months
Remission at 12 months
Antidepressant use at 12 months
Discontinuation at 12 months

Finley 2003

RCT

N=125

Baseline severity: NR

Mean age (years): 54.3

Sex (% female): 85

Ethnicity (% BME): NR

Simple collaborative care

Collaborative care component score: 6.5

Standard care

Duration of programme contact (in months): 6

Outcomes:

Antidepressant use at 6 months
Discontinuation at 6 months

Fortney 2007

RCT

N=395

Baseline severity: More severe

Mean age (years): 59.2

Sex (% female): 8

Ethnicity (% BME): 25

Complex collaborative care

Collaborative care component score: 13

Enhanced standard care

Duration of programme contact (in months): 12

Outcomes:

Antidepressant use at 12 months
Discontinuation at 12 months

Gensichen 2009

RCT

Germany

N=626

Baseline severity: More severe

Mean age (years): 51.1

Sex (% female): 76

Ethnicity (% BME): NR

Simple collaborative care

Collaborative care component score: 7

Standard care

Duration of programme contact (in months): 12

Outcomes:

Depression symptomatology at 12 months
Response at 12 months
Remission at 12 months
Antidepressant use at 12 months
Discontinuation at 12 months

Gilbody 2017/Lewis 2017

RCT

N=705

Baseline severity: Less severe

Mean age (years): 77.3

Sex (% female): 58

Ethnicity (% BME): 1

Simple collaborative care

Collaborative care component score: 10

Standard care

Duration of programme contact (in months): 2

Outcomes:

Depression symptomatology at 12 months
Antidepressant use at 12 months
Discontinuation at 12 months

Harter 2018

RCT

Germany

N=779

Baseline severity: Less severe

Mean age (years): 42.9

Sex (% female): 73

Ethnicity (% BME): NR

Simple collaborative care

Collaborative care component score: 11

Standard care

Duration of programme contact (in months): NR

Outcomes:

Depression symptomatology at 6 months
Depression symptomatology at 12 months
Response at 12 months
Remission at 12 months
Discontinuation at 6 months
Discontinuation at 12 months

Holzel 2018

RCT

Germany

N=248

Baseline severity: Less severe

Mean age (years): 71.4

Sex (% female): 77

Ethnicity (% BME): NR

Complex collaborative care

Collaborative care component score: 14

Standard care

Duration of programme contact (in months): 12

Outcomes:

Depression symptomatology at 12 months
Response at 12 months
Remission at 12 months

Huang 2018

RCT

China

N=280

Baseline severity: More severe

Mean age (years): 47.4

Sex (% female): 85

Ethnicity (% BME): 100

Simple collaborative care

Collaborative care component score: 10

Standard care

Duration of programme contact (in months): 6

Outcomes:

Depression symptomatology at 6 months
Discontinuation at 6 months

Huijbregts 2013

RCT

Netherlands

N=150

Baseline severity: Less severe

Mean age (years): 48.7

Sex (% female): 73

Ethnicity (% BME): 29

Complex collaborative care

Collaborative care component score: 13

Standard care

Duration of programme contact (in months): 12

Outcomes:

Response at 6 months
Response at 12 months
Remission at 6 months
Remission at 12 months
Discontinuation at 6 months
Discontinuation at 12 months

Jarjoura 2004

RCT

N=61

Baseline severity: More severe

Mean age (years): 45.5

Sex (% female): 69

Ethnicity (% BME): NR

Simple collaborative care

Collaborative care component score: 6

Enhanced standard care

Duration of programme contact (in months): NR

Outcomes:

Antidepressant use at 12 months

Jeong 2013

RCT

Korea

N=57

Baseline severity: More severe

Mean age (years): NR (>60)

Sex (% female): 58

Ethnicity (% BME): NR

Simple collaborative care

Collaborative care component score: 7

Standard care

Duration of programme contact (in months): 6

Outcomes:

Remission at 6 months
Antidepressant use at 6 months
Discontinuation at 6 months

Katon 1999

RCT

N=228

Baseline severity: NR

Mean age (years): 47

Sex (% female): 75

Ethnicity (% BME): 20

Simple collaborative care

Collaborative care component score: 6

Standard care

Duration of programme contact (in months): 3

Outcomes:

Remission at 6 months
Antidepressant use at 6 months

Katzelnick 2000

RCT

N=407

Baseline severity: More severe

Mean age (years): 45.5

Sex (% female): 77

Ethnicity (% BME): 21

Simple collaborative care

Collaborative care component score: 9

Standard care

Duration of programme contact (in months): 7

Outcomes:

Response at 12 months
Remission at 12 months
Discontinuation at 12 months

Landis 2007

RCT

N=45

Baseline severity: More severe

Mean age (years): 39.7

Sex (% female): 96

Ethnicity (% BME): 28

Simple collaborative care

Collaborative care component score: 9

Enhanced standard care

Duration of programme contact (in months): 6

Outcome:

Depression symptomatology at 6 months

Ludman 2007

RCT

N=52

Baseline severity: NR

Mean age (years): 50.3

Sex (% female): 69

Ethnicity (% BME): 13

Simple collaborative care

Collaborative care component score: 9

Standard care

Duration of programme contact (in months): NR

Outcomes:

Remission at 12 months
Antidepressant use at 12 months
Discontinuation at 12 months

Morris 2016

RCT

N=187

Baseline severity: More severe

Mean age (years): 46.5

Sex (% female): 61

Ethnicity (% BME): NR

Complex collaborative care

Collaborative care component score: 14

Standard care

Duration of programme contact (in months): 12

Outcomes:

Depression symptomatology at 12 months
Response at 12 months
Remission at 12 months
Discontinuation at 12 months

Ng 2020

RCT

Singapore

N=274

Baseline severity: Less severe

Mean age (years): 73.5

Sex (% female): 56

Ethnicity (% BME): NR

Simple collaborative care

Collaborative care component score: 9

Standard care

Duration of programme contact (in months): 6

Outcomes:

Depression symptomatology at 6 months
Depression symptomatology at 12 months
Response at 6 months
Response at 12 months
Remission at 6 months
Remission at 12 months
Discontinuation at 6 months
Discontinuation at 12 months

Oladeji 2015

RCT

Nigeria

N=234

Baseline severity: Less severe

Mean age (years): 43.2

Sex (% female): 80

Ethnicity (% BME): NR

Simple collaborative care

Collaborative care component score: 12

Enhanced standard care

Duration of programme contact (in months): 6

Outcomes:

Depression symptomatology at 6 months
Discontinuation at 6 months

Richards 2013/2016

RCT

N=581

Baseline severity: More severe

Mean age (years): 44.8

Sex (% female): 72

Ethnicity (% BME): 15

Simple collaborative care

Collaborative care component score: 12

Standard care

Duration of programme contact (in months): 3

Outcomes:

Depression symptomatology at 12 months
Response at 12 months
Remission at 12 months
Antidepressant use at 12 months
Discontinuation at 12 months

Simon 2004 (CM)

RCT

N=402

Baseline severity: Less severe

Mean age (years): 44.5

Sex (% female): 75

Ethnicity (% BME): 20

Simple collaborative care

Collaborative care component score: 9

Standard care

Duration of programme contact (in months): 5

Outcomes:

Antidepressant use at 6 months
Discontinuation at 6 months

Simon 2004 (CM + psych)

RCT

N=393

Baseline severity: Less severe

Mean age (years): 44.4

Sex (% female): 76

Ethnicity (% BME): 23

Complex collaborative care

Collaborative care component score:13

Standard care

Duration of programme contact (in months): 5

Outcomes:

Antidepressant use at 6 months
Discontinuation at 6 months

Simon 2006

RCT

N=207

Baseline severity: Less severe

Mean age (years): 43

Sex (% female): 65

Ethnicity (% BME): 11

Simple collaborative care

Collaborative care component score: 9

Standard care

Duration of programme contact (in months): 3

Outcomes:

Antidepressant use at 6 months
Discontinuation at 6 months

Smit 2006

RCT

Netherlands

N=267

Baseline severity: Less severe

Mean age (years): 42.8

Sex (% female): 64

Ethnicity (% BME): NR

Simple collaborative care

Collaborative care component score: 9.5

Standard care

Duration of programme contact (in months): 6

Outcomes:

Remission at 6 months
Antidepressant use at 6 months
Discontinuation at 6 months

Swindle 2003

RCT

N=268

Baseline severity: Less severe

Mean age (years): 56.3

Sex (% female): 3

Ethnicity (% BME): 15

Simple collaborative care

Collaborative care component score: 8

Enhanced standard care

Duration of programme contact (in months): 2

Outcomes:

Depression symptomatology at 12 months
Discontinuation at 12 months

Unutzer 2002/Arean 2005

RCT

N=1901

Baseline severity: NR

Mean age (years): 71.2

Sex (% female): 65

Ethnicity (% BME): 23

Complex collaborative care

Collaborative care component score: 14.5

Standard care

Duration of programme contact (in months): 12

Outcomes:

Antidepressant use at 6 months
Antidepressant use at 12 months
Discontinuation at 6 months
Discontinuation at 12 months

Wells 2000

RCT

N=1356

Baseline severity: NR

Mean age (years): 43.7

Sex (% female): 71

Ethnicity (% BME): 43

Simple collaborative care

Collaborative care component score: 8.5

Standard care

Duration of programme contact (in months): 12

Outcomes:

Remission at 6 months
Remission at 12 months
Discontinuation at 6 months
Discontinuation at 12 months

Yeung 2010

RCT

N=100

Baseline severity: More severe

Mean age (years): 49

Sex (% female): 68

Ethnicity (% BME): 100

Simple collaborative care

Collaborative care component score: 8

Standard care

Duration of programme contact (in months): 6

Outcomes:

Response at 6 months
Remission at 6 months

Yeung 2016

RCT

N=190

Baseline severity: More severe

Mean age (years): 50

Sex (% female): 63

Ethnicity (% BME): 100

Simple collaborative care

Collaborative care component score: 8

Enhanced standard care

Duration of programme contact (in months): 6

Outcomes:

Response at 6 months
Remission at 6 months

: BME: black minority ethnic; N: number; NR: not reported; RCT: randomised controlled trial

Table 3Summary of included studies for Comparison 2: Collaborative care versus standard care for relapse prevention

Study

Population

Intervention

Comparison

Comments

Katon 2001

RCT

N=386

Baseline severity: Recovered but at high risk of relapse (<4 DSM-IV MDD symptoms and a history of ≥3 episodes of MDD or dysthymia or 4 residual depressive symptoms but mean SCL-20 depression score < 1.0 and a history of MDD/dysthymia)

Mean age (years): 46

Sex (% female): 74

Ethnicity (% BME): 10

Simple collaborative care

Collaborative care component score: 9

Standard care

Duration of programme contact (in months): 12

Outcomes:

Relapse at 12 months
Antidepressant use at 6 months
Antidepressant use at 12 months
Discontinuation at 12 months

: BME: black minority ethnic; DSM: diagnostic statistical manual; MDD: major depressive disorder; N: number; NR: not reported; RCT: randomised controlled trial; SCL-20: symptom checklist

Table 4Summary of included studies for Comparison 3: Stepped care versus standard care/enhanced standard care

Study

Population

Intervention

Comparison

Comments

Adewuya 2019

RCT

Nigeria

N=907

Baseline severity: More severe

Mean age (years): 34.3

Sex (% female): 53

Ethnicity (% BME): NR

Stepped care

Step 1: Psychoeducation;

Step 2: Problem solving or amitriptyline (if contraindicated, fluoxetine) monotherapy

Step 3: Combination from step 2

Step 4: Support and supervision from mental health team

Enhanced standard care

Duration of programme contact (in months): NR

Outcomes:

Remission at 6 months
Remission at 12 months
Discontinuation at 6 months
Discontinuation at 12 months

Callahan 1994

RCT

N=175

Baseline severity: More severe

Mean age (years): 65.3

Sex (% female): 76

Ethnicity (% BME): 51

Stepped care

Step 1: Nortriptyline or desipramine

Step 2: Fluoxetine

Step 3: Psychiatry consultation

Standard care

Duration of programme contact (in months): 3

Outcomes:

Remission at 6 months
Antidepressant use at 6 months
Discontinuation at 6 months

Gureje 2019

RCT

Nigeria

N=1178

Baseline severity: Less severe

Mean age (years): 47.3

Sex (% female): 83

Ethnicity (% BME): NR

Stepped care

Step 1: Psychological intervention (BA & problem solving) for mild, combined psychological intervention and amitriptyline for moderate and severe

Step 2: Additional therapy sessions or psychological intervention + AD

Step 3: Cases discussed with a psychiatrist

Enhanced standard care

Duration of programme contact (in months): NR

Outcomes:

Depression symptomatology at 6 months
Depression symptomatology at 12 months
Remission at 12 months
Discontinuation at 6 months
Discontinuation at 12 months

Knapstad 2020

RCT

Norway

N=774

Baseline severity: Less severe

Mean age (years): 34.8

Sex (% female): 67

Ethnicity (% BME): NR

Stepped care

Norwegian version of IAPT - low-intensity (guided self-help, psychoeducational courses) and high-intensity (individual treatment)

Standard care

Duration of programme contact (in months): NR

Outcomes:

Depression symptomatology at 6 months
Discontinuation at 6 months

Van Der Weele 2012

RCT

Netherlands

N=239

Baseline severity: Less severe

Mean age (years): NR (median 80)

Sex (% female): NR

Ethnicity (% BME): NR

Stepped care

Step 1: Individual counselling concerning treatment needs and motivation

Step 2: Coping with depression course

Step 3: Referral back to GP

Standard care

Duration of programme contact (in months): NR

Outcomes:

Depression symptomatology at 6 months
Depression symptomatology at 12 months
Response at 6 months
Response at 12 months
Discontinuation at 6 months
Discontinuation at 12 months

: AD: antidepressant; BA: behavioural activation; BME: black minority ethnic; IAPT: improving access to psychological therapies service; N: number; NR: not reported; RCT: randomised controlled trial

Table 5Summary of included studies for Comparison 4: Stepped care versus standard care for relapse prevention

Study

Population

Intervention

Comparison

Comments

Apil 2012

RCT

Netherlands

N=136

Baseline severity: Less severe

Mean age (years): 65.6

Sex (% female): 72

Ethnicity (% BME): NR

Stepped care relapse prevention programme

Step 1: Watchful waiting for 6 weeks (no intervention offered)

Step 2: Cognitive bibliotherapy for 6 weeks

Step 3: Individual coping with depression course (12x weekly sessions of 45 mins)

Step 4: Indicated treatment (referred to a physician/psychot herapist and treatment could consist of any intervention considered necessary)

Standard care

Duration of programme contact (in months): 12

Outcomes:

Relapse at 12 months
Antidepressant use at 12 months
Discontinuation at 12 months

: BME: black minority ethnic; N: number; NR: not reported; RCT: randomised controlled trial

Table 6Summary of included studies for Comparison 5: Pure medication management versus standard care

Study

Population

Intervention

Comparison

Comments

Akerblad 2003

RCT

Sweden

N=665

Baseline severity: More severe

Mean age (years): 48.5

Sex (% female): 72

Ethnicity (% BME): NR

Pure medication management

Therapeutic drug monitoring (TDM). All patients were treated with sertraline. Plasma levels of sertraline and desmethylsertrali ne were determined at weeks 4 and 12 and reported back to the GP for continued discussion with the patients. Intervention included monitoring for side effects

Standard care

Duration of programme contact (in months): 6

Outcomes:

Antidepressant use at 6 months
Discontinuation at 6 months

Aljumah 2015

RCT

Saudi Arabia

N=239

Baseline severity: More severe

Mean age (years): NR

Sex (% female): 55

Ethnicity (% BME): NR

Pure medication management

Pharmacist intervention involving assessing patients’ beliefs and knowledge about antidepressants and distribution of a decision aid to patients

Standard care

Duration of programme contact (in months): 3

Outcomes:

Depression symptomatology at 6 months
Antidepressant use at 6 months
Discontinuation at 6 months

Rickles 2005

RCT

N=63

Baseline severity: Less severe

Mean age (years): 38

Sex (% female): 84

Ethnicity (% BME): 8

Pure medication management

Pharmacist-guided education and monitoring (PGEM) included assessing patient’s antidepressant knowledge and beliefs, adverse effects and other concerns, treatment goals, and how the medication was being used, reviewing of current adherence, and any new adverse effects and concerns

Standard care

Duration of programme contact (in months): 3

Outcomes:

Antidepressant use at 6 months
Discontinuation at 6 months

Rubio-Valera 2013a

RCT

Spain

N=179

Baseline severity: Less severe

Mean age (years): 46.6

Sex (% female): 75

Ethnicity (% BME): NR

Pure medication management

Community pharmacist intervention included provision of an educational intervention aimed at improving patients’ knowledge of antidepressants and awareness of the importance of adherence, and monitoring of patient progress (improvement, appearance of side effects, or queries)

Standard care

Duration of programme contact (in months): 6

Outcomes:

Depression symptomatology at 6 months
Antidepressant use at 6 months
Discontinuation at 6 months

Sirey 2010

RCT

N=70

Baseline severity: More severe

Mean age (years): 76

Sex (% female): 77

Ethnicity (% BME): 29

Pure medication management

Treatment Initiation and Participation (TIP) programme, included reviewing symptoms and antidepressant therapy regimen and conducting a barriers assessment, defining personal treatment goal, provision of education about depression and antidepressants, discussing barriers to adherence, creating an adherence strategy, and encouraging the patient to talk directly with the primary care physician about treatment

Standard care

Duration of programme contact (in months): 2

Outcomes:

Response at 6 months
Discontinuation at 6 months

: BME: black minority ethnic; N: number; NR: not reported; RCT: randomised controlled trial

Table 7Summary of included studies for Comparison 6: Care coordination versus standard care/enhanced standard care

Study

Population

Intervention

Comparison

Comments

McMahon 2007

RCT

N=62

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Care coordination

Case management from graduate primary care mental health workers + TAU from GP. Minimal supportive counselling provided and could recommend increase in antidepressant dosage to GP

Enhanced standard care

Duration of programme contact (in months): 4

Outcomes:

Depression symptomatology at 6 months
Discontinuation at 6 months

Salisbury 2016

RCT

N=609

Baseline severity: More severe

Mean age (years): 49.6

Sex (% female): 68

Ethnicity (% BME): 3

Care coordination

Telephone calls with health adviser, includes information signposting, access to computerized CBT (CCBT) and support in use of CCBT, minimal supportive counselling and could recommend increase in antidepressant dosage to GP

Standard care

Duration of programme contact (in months): 10

Outcomes:

Depression symptomatology at 12 months
Remission at 12 months
Discontinuation at 12 months

: BME: black minority ethnic; N: number; NR: not reported; RCT: randomised controlled trial; TAU: treatment as usual

Table 8Summary of included studies for Comparison 7: Attached professional model versus enhanced standard care

Study

Population

Intervention

Comparison

Comments

Bedoya 2014

RCT

N=120

Baseline severity: More severe

Mean age (years): 42.4

Sex (% female): 69

Ethnicity (% BME): 100

Attached professional model

Culturally focused psychiatric (CFP) consultation service. Study clinicians (psychologists or psychiatrists) provided a psychiatric assessment, psychoeducation, cognitive-behavioural tools, and tailored treatment recommendations; primary care providers were provided a consultation summary

Enhanced standard care

Duration of programme contact (in months): 0.5

Outcomes:

Depression symptomatology at 6 months
Discontinuation at 6 months

: BME: black minority ethnic; N: number; NR: not reported; RCT: randomised controlled trial

Table 9Summary of included studies for Comparison 8: Shared care versus standard care

Study

Population

Intervention

Comparison

Comments

Banerjee 1996

RCT

N=69

Baseline severity: More severe

Mean age (years): 80.7

Sex (% female): 83

Ethnicity (% BME): NR

Shared care

Individual package of care formulated by the community psychogeriatric team in their catchment area and implemented by a researcher working as a member of that team. Each case was presented at a multidisciplinary team meeting which included CPNs, OTs, senior and junior medical staff, a social worker, and a psychologist. A management plan was formulated by the team for each person on an individual basis and could include any combination of antidepressants, psychological interventions and social interventions. A psychiatrist acted as each person’s keyworker

Standard care

Duration of programme contact (in months): 6

Outcomes:

Depression symptomatology at 6 months
Remission at 6 months
Antidepressant use at 6 months
Discontinuation at 6 months

: BME: black minority ethnic; CPN: community psychiatric nurse; N: number; NR: not reported; OT: occupational therapist; RCT: randomised controlled trial

Table 10Summary of included studies for Comparison 9: Measurement-based care versus standard care

Study

Population

Intervention

Comparison

Comments

Guo 2015

RCT

China

N=120

Baseline severity: More severe

Mean age (years): 41.1

Sex (% female): 64

Ethnicity (% BME): NR

Measurement-based care

Guideline- and rating scale-based decisions. The treating psychiatrists made treatment decisions about starting dosages, dose adjustments and medication changes of paroxetine (20–60mg/day) or mirtazapine (15–45mg/day), on the basis of ratings on QIDS-SR and the Frequency, Intensity, and Burden of Side Effects Rating scale

Standard care

Duration of programme contact (in months): 3

Outcomes:

Depression symptomatology at 6 months
Response at 6 months
Remission at 6 months
Discontinuation at 6 months

: BME: black minority ethnic; N: number; NR: not reported; QIDS-SR: quick inventory of depressive symptomatology-self report; RCT: randomised controlled trial; SR: self-report

Table 11Summary of the protocol (PICO table)

Population	Adults with a diagnosis of depression according to DSM, ICD or similar criteria, or depressive symptoms as indicated by baseline depression scores on validated scales (and including those with subthreshold [just below threshold] depressive symptoms)
Intervention	Settings for the delivery of care, which may include: Primary care Crisis resolution and home treatment teams Inpatient setting Acute psychiatric day hospital care Non-acute day hospital care and recovery centres Specialist tertiary affective disorders settings Community mental health teams Residential services
Comparison	Any other setting for the delivery of care
Outcomes	Critical: Depression symptomatology (mean endpoint score or change in depression score from baseline) Remission (usually defined as a score below clinical threshold on a depression scale) Response (usually defined as at least 50% improvement from the baseline score on a depression scale) Relapse (number of people who returned to a depressive episode whilst in remission) Important: Service utilisation/resource use (e.g. antidepressant use) Psychological functioning Social functioning Satisfaction Carer distress

: DSM: diagnostic and statistical manual of mental disorders; ICD: international classification of diseases

Table 12Summary of included studies for primary care versus secondary care subgroup analysis for comparison 1a Cognitive and cognitive behavioural therapies individual + antidepressant versus antidepressant

Study	Population	Intervention	Comparison	Comments
Primary care (K=2, N=82)
Naeem 2011 RCT Pakistan	Primary care N=34 Baseline severity: More severe Mean age (years): 33.0 Sex (% female): 74 Ethnicity (% BME): NR	CBT individual (9 weekly or fortnightly sessions) + SSRI (paroxetine or fluoxetine 20mg/day)	SSRI (paroxetine or fluoxetine 20mg/day)	Treatment duration (weeks): 12 Outcomes (for primary versus secondary care subgroup analysis): Depression symptoms endpoint
Scott 1997 RCT UK	Primary care N=48 Baseline severity: More severe Mean age (years): 41.0 Sex (% female): 67 Ethnicity (% BME): NR	CBT individual (6x weekly 30-min sessions) + any antidepressant	Any antidepressant	Treatment duration (weeks): 7 Outcomes (for primary versus secondary care subgroup analysis): Depression symptoms endpoint
Secondary care (K=4, N=311)
Ashouri 2013 RCT Iran	Secondary care N=33 Baseline severity: More severe Mean age (years): 32.5 Sex (% female): 61 Ethnicity (% BME): NR	Third-wave cognitive therapy individual or CBT individual (number of sessions not reported) + any antidepressant	Any antidepressant	Treatment duration (weeks): NR Outcomes (for primary versus secondary care subgroup analysis): Depression symptoms endpoint
Hautzinger 1996^a RCT Germany	Secondary care N=76 Baseline severity: More severe Mean age (years): NR Sex (% female): NR Ethnicity (% BME): NR	CBT individual (24x 50-60 min sessions) + amitriptyline 150mg/day	Amitriptyline 150mg/day	Treatment duration (weeks): 8 Outcomes (for primary versus secondary care subgroup analysis): Depression symptoms endpoint
Hollon 1992^a RCT US	Secondary care N=82 Baseline severity: More severe Mean age (years): 32.6 Sex (% female): 80 Ethnicity (% BME): 9	CBT individual (maximum 20x 50-min weekly or fortnightly sessions) + imipramine 75-450mg/day	Imipramine 75-450mg/day	Treatment duration (weeks): 12 Outcomes (for primary versus secondary care subgroup analysis): Depression symptoms endpoint
Zu 2014^b RCT China	Secondary care N=120 Baseline severity: More severe Mean age (years): 38.3 Sex (% female): 49 Ethnicity (% BME): NR	CBT individual (20x 1-hour sessions) + any SSRI (dose NR, within recommended therapeutic dose ranges)	Any SSRI (dose NR, within recommended therapeutic dose ranges)	Treatment duration (weeks): 24 Outcomes (for primary versus secondary care subgroup analysis): Depression symptoms endpoint

a: Three-armed trial but where possible the demographics reported here are for only the two relevant arms.
b: Four-armed trial but where possible the demographics reported here are for only the two relevant arms.
: BME: black, minority, ethnic; CBT: cognitive behavioural therapy; K: number of studies; mg: milligrams; N: number of participants; NR: not reported; RCT: randomised controlled trial; SSRI: selective serotonin reuptake inhibitor.

Table 13Summary of included studies for primary care versus secondary care subgroup analysis for comparison 1b Selective serotonin reuptake inhibitors (SSRIs) versus placebo

Study

Population

Intervention

Comparison

Comments

Primary care (K=5, N=1,184)

Bjerkenstedt 2005

RCT

Sweden

Primary care

N=115

Baseline severity: More severe

Mean age (years): 50.9

Sex (% female): 79

Ethnicity (% BME): 0

Fluoxetine 20mg/day

Placebo

Treatment duration (weeks): 4

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Response

Doogan 1994

RCT

Primary care

N=200

Baseline severity: More severe

Mean age (years): 45.7

Sex (% female): 68

Ethnicity (% BME): NR

Sertraline 50-100mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Response

Lepola 2003

RCT

Belgium, Canada, Finland, France, Norway, Sweden, Switzerland & UK

Primary care

N=469

Baseline severity: More severe

Mean age (years): 43.3

Sex (% female): 72

Ethnicity (% BME): NR

Escitalopram 10-20mg/day or citalopram 20-40mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Response

Lopez-Rodriguez 2004

RCT

South America

Primary care

N=20

Baseline severity: More severe

Mean age (years): 31.9

Sex (% female): NR

Ethnicity (% BME): NR

Fluoxetine 20mg/day

Placebo

Treatment duration (weeks): 9

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint

Wade 2002

RCT

Canada, Estonia, France, Netherlands & UK

Primary care

N=380

Baseline severity: More severe

Mean age (years): 40.5

Sex (% female): 76

Ethnicity (% BME): 3

Escitalopram 10mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Response

Secondary care (K=78, N=18,070)

29060 07 001a

RCT

Secondary care

N=25

Baseline severity: More severe

Mean age (years): 42.5

Sex (% female): 56

Ethnicity (% BME): NR

Paroxetine 10-60mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score

Andreoli 2002/Dubini 1997/Massana 1998_study 1

RCT

Brazil, France, Ireland, Italy, Poland, and UK

Secondary care

N=255

Baseline severity: More severe

Mean age (years): 42.2

Sex (% female): 60

Ethnicity (% BME): NR

Fluoxetine 20-40mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Baune 2018

RCT

Estonia, Finland, Germany, & Lithuania

Secondary care

N=104

Baseline severity: More severe

Mean age (years): 45.7

Sex (% female): 64

Ethnicity (% BME): 2

Paroxetine 20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score

Binnemann 2008

RCT

US, Serbia and Montenegro, & the Russian Federation

Secondary care

N=82

Baseline severity: More severe

Mean age (years): 49

Sex (% female): 39

Ethnicity (% BME): NR

Sertraline 100mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Bose 2008

RCT

Secondary care

N=267

Baseline severity: More severe

Mean age (years): 68.3

Sex (% female): 59

Ethnicity (% BME): 11

Escitalopram 10-20mg/day

Placebo

Treatment duration (weeks): 12

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Burke 2002

RCT

Secondary care

N=491

Baseline severity: More severe

Mean age (years): 40.1

Sex (% female): 65

Ethnicity (% BME): NR

Escitalopram 10mg/day or 20mg/day, or citalopram 40mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Byerley 1988a

RCT

Secondary care

N=61

Baseline severity: More severe

Mean age (years): 38.3

Sex (% female): 68

Ethnicity (% BME): NR

Fluoxetine 40-80mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Response

Claghorn 1992a

RCT

Secondary care

N=59

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 10-50mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score

Claghorn 1992b

RCT

Secondary care

N=72

Baseline severity: More severe

Mean age (years): 35

Sex (% female): 32

Ethnicity (% BME): NR

Paroxetine 10-50mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Clayton 2006_study 1

RCT

Secondary care

N=283

Baseline severity: More severe

Mean age (years): 35

Sex (% female): 61

Ethnicity (% BME): 35

Escitalopram 10-20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Clayton 2006_study 2

RCT

Secondary care

N=286

Baseline severity: More severe

Mean age (years): 36.5

Sex (% female): 56

Ethnicity (% BME): 27

Escitalopram 10-20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

CL3-20098-022

RCT

Europe

Secondary care

N=286

Baseline severity: More severe

Mean age (years): 43

Sex (% female): 67

Ethnicity (% BME): NR

Fluoxetine 20mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Response

CL3-20098-023

RCT

Cross-continental

Secondary care

N=275

Baseline severity: More severe

Mean age (years): 41.1

Sex (% female): 75

Ethnicity (% BME): NR

Paroxetine 20mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint

CL3-20098-024

RCT

Cross-continental

Secondary care

N=306

Baseline severity: More severe

Mean age (years): 41.5

Sex (% female): 73

Ethnicity (% BME): NR

Fluoxetine 20mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Response

Detke 2004b

RCT

Secondary care

N=179

Baseline severity: More severe

Mean age (years): 42.9

Sex (% female): 71

Ethnicity (% BME): 0

Paroxetine 20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Dube 2010

RCT

India, US, Mexico & Romania

Secondary care

N=200

Baseline severity: More severe

Mean age (years): 36.5

Sex (% female): 44

Ethnicity (% BME): NR

Escitalopram 10-20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Dunbar 1993

RCT

Secondary care

N=341

Baseline severity: More severe

Mean age (years): 41

Sex (% female): 51

Ethnicity (% BME): NR

Paroxetine 10-50mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Response

Eli Lilly HMAT-Aa

RCT

Secondary care

N=179

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Emsley 2018

RCT

Bulgaria, Estonia, Finland, France, Republic of Korea, Malaysia, Mexico, Poland, Romania, & Slovakia

Secondary care

N=206

Baseline severity: More severe

Mean age (years): 70.6

Sex (% female): 75

Ethnicity (% BME): NR

Escitalopram 10mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Response

Fabre 1992a

RCT

Secondary care

N=80

Baseline severity: More severe

Mean age (years): 35.8

Sex (% female): 59

Ethnicity (% BME): NR

Paroxetine 10-50mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score

Fabre 1995a

RCT

Secondary care

N=369

Baseline severity: More severe

Mean age (years): 37.6

Sex (% female): 53

Ethnicity (% BME): 9

Sertraline 50mg/day, 100mg/day, or 200mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Fava 1998a

RCT

Secondary care

N=128

Baseline severity: More severe

Mean age (years): 41.3

Sex (% female): 51

Ethnicity (% BME): NR

Paroxetine 20-50mg/day or fluoxetine 20-80mg/day

Placebo

Treatment duration (weeks): 12

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Response

Fava 2005

RCT

Secondary care

N=90

Baseline severity: More severe

Mean age (years): 37.2

Sex (% female): 59

Ethnicity (% BME): NR

Fluoxetine 20mg/day

Placebo

Treatment duration (weeks): 12

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score

FDA 245 (EMD 68 843-010)

RCT

Secondary care

N=191

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Fluoxetine 20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score

FDA 246 (SB 659746-003)

RCT

Secondary care

N=246

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Citalopram 20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint

Forest Laboratories 2000

RCT

Secondary care

N=386

Baseline severity: More severe

Mean age (years): 42

Sex (% female): 52

Ethnicity (% BME): NR

Escitalopram 10-20mg/day or citalopram 20-40mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Response

Forest Research Institute 2005

RCT

Secondary care

N=409

Baseline severity: More severe

Mean age (years): 40

Sex (% female): 56

Ethnicity (% BME): NR

Escitalopram 10-20mg/day or sertraline 50-200mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Golden 2002_448

RCT

Secondary care

N=315

Baseline severity: More severe

Mean age (years): 39

Sex (% female):NR

Ethnicity (% BME): NR

Paroxetine 20-62.5mg/day

Placebo

Treatment duration (weeks): 12

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score

Golden 2002_449

RCT

Secondary care

N=330

Baseline severity: More severe

Mean age (years): 41.2

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 20-62.5mg/day

Placebo

Treatment duration (weeks): 12

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score

Goldstein 2002a

RCT

Secondary care

N=103

Baseline severity: More severe

Mean age (years): 40.9

Sex (% female): 65

Ethnicity (% BME): 21

Fluoxetine 20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Response

Goldstein 2004a

RCT

Secondary care

N=176

Baseline severity: More severe

Mean age (years): 40

Sex (% female): 64

Ethnicity (% BME): 22

Paroxetine 20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Response

Gual 2003

RCT

Spain

Secondary care

N=83

Baseline severity: More severe

Mean age (years): 46.7

Sex (% female): 47

Ethnicity (% BME): NR

Sertraline 50-150mg/day

Placebo

Treatment duration (weeks): 24

Outcomes (for primary versus secondary care subgroup analysis):

Response

Higuchi 2009a

RCT

Japan

Secondary care

N=294

Baseline severity: More severe

Mean age (years): 38.3

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 20-40mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Hirayasu 2011a

RCT

Japan

Secondary care

N=310

Baseline severity: More severe

Mean age (years): 34.6

Sex (% female): NR

Ethnicity (% BME): NR

Escitalopram 10mg/day or 20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Response

Hirayasu 2011b

RCT

Japan

Secondary care

N=485

Baseline severity: More severe

Mean age (years): 36.2

Sex (% female): NR

Ethnicity (% BME): NR

Escitalopram 10mg/day or 20mg/day, or paroxetine 20-40mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Response

Jefferson 2000

RCT

Secondary care

N=415

Baseline severity: More severe

Mean age (years): 39.9

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 25mg/day, or citalopram 20mg/day or 40mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Kasper 2012

RCT

Russia & Austria

Secondary care

N=211

Baseline severity: More severe

Mean age (years): 41.9

Sex (% female): 71

Ethnicity (% BME): 0

Escitalopram 20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Katz 2004

RCT

Secondary care

N=53

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 20-60mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Response

Keller 2006_Study 062

RCT

Cross-continental

Secondary care

N=325

Baseline severity: More severe

Mean age (years):41

Sex (% female): 67

Ethnicity (% BME): 43

Paroxetine 20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score

Kramer 1998

RCT

Secondary care

N=142

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 20mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Response

Kranzler 2006_Group A

RCT

Secondary care

N=189

Baseline severity: More severe

Mean age (years): 42.9

Sex (% female): 35

Ethnicity (% BME): 10

Sertraline 50-200mg/day

Placebo

Treatment duration (weeks): 10

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Lam 2016b

RCT

Canada

Secondary care

N=61

Baseline severity: More severe

Mean age (years): 36.8

Sex (% female): 72

Ethnicity (% BME): NR

Fluoxetine 20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Macias-Cortes 2015

RCT

Mexico

Secondary care

N=89

Baseline severity: More severe

Mean age (years): 49

Sex (% female): 100

Ethnicity (% BME): 100

Fluoxetine 20mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Response

Mathews 2015

RCT

Secondary care

N=579

Baseline severity: More severe

Mean age (years): 42.3

Sex (% female): 57

Ethnicity (% BME): 32

Citalopram 40mg/day

Placebo

Treatment duration (weeks): 10

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Response

Mendels 1999

RCT

Secondary care

N=180

Baseline severity: More severe

Mean age (years): 43

Sex (% female): 33

Ethnicity (% BME): 13

Citalopram 20-80mg/day

Placebo

Treatment duration (weeks): 4

Outcomes (for primary versus secondary care subgroup analysis):

Response

Miller 1989a

RCT

Secondary care

N=47

Baseline severity: More severe

Mean age (years): 42.5

Sex (% female): 68

Ethnicity (% BME): NR

Paroxetine 30mg/day

Placebo

Treatment duration (weeks): 4

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score

Montgomery 1992

RCT

Secondary care

N=199

Baseline severity: More severe

Mean age (years): 44

Sex (% female): 69

Ethnicity (% BME): NR

Citalopram 20mg/day or 40mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score

Mundt 2012

RCT

Secondary care

N=165

Baseline severity: More severe

Mean age (years): 37.8

Sex (% female): 63

Ethnicity (% BME): 24

Sertraline 50-100mg/day

Placebo

Treatment duration (weeks): 4

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Response

MY-1042/BRL-029060/CPMS-251

RCT

Secondary care

N=254

Baseline severity: More severe

Mean age (years): 41.9

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 20-50mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

MY-1042/BRL-029060/1 (PAR 128)

RCT

Secondary care

N=848

Baseline severity: More severe

Mean age (years): 41.8

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 20-50mg/day or fluoxetine 20-80mg/day

Placebo

Treatment duration (weeks): 12

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Nemeroff 2007a

RCT

Secondary care

N=206

Baseline severity: More severe

Mean age (years): 39.1

Sex (% female): 61

Ethnicity (% BME): 7

Fluoxetine 20-60mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Response

Nierenberg 2007a

RCT

Secondary care

N=411

Baseline severity: More severe

Mean age (years): 43

Sex (% female): 66

Ethnicity (% BME): 21

Escitalopram 10mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

NKD20006 (NCT00048204)

RCT

Secondary care

N=250

Baseline severity: More severe

Mean age (years): 38

Sex (% female): 60

Ethnicity (% BME): NR

Paroxetine 20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Nyth 1992

RCT

Denmark, Norway & Sweden

Secondary care

N=149

Baseline severity: More severe

Mean age (years): 76.7

Sex (% female): 69

Ethnicity (% BME): NR

Citalopram 10-30mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Response

Olie 1997

RCT

France

Secondary care

N=258

Baseline severity: More severe

Mean age (years): 43.8

Sex (% female): 63

Ethnicity (% BME): 1

Sertraline 50-200mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Response

PAR 01 001 (GSK & FDA)

RCT

Secondary care

N=50

Baseline severity: More severe

Mean age (years): 43.1

Sex (% female): 35

Ethnicity (% BME): NR

Paroxetine 10-50mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Perahia 2006b

RCT

Bulgaria, Croatia, Hungary, Poland, Romania, Russia, & Slovakia

Secondary care

N=196

Baseline severity: More severe

Mean age (years): 45.2

Sex (% female): 68

Ethnicity (% BME): 0

Paroxetine 20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Response

Peselow 1989aa

RCT

Secondary care

N=73

Baseline severity: More severe

Mean age (years): 43.2

Sex (% female): 38

Ethnicity (% BME): NR

Paroxetine 10-50mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Response

Peselow 1989ba

RCT

Secondary care

N=82

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 20-50mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Response

Rapaport 2009

RCT

Secondary care

N=357

Baseline severity: More severe

Mean age (years): 67.5

Sex (% female): 62

Ethnicity (% BME): 17

Paroxetine 25mg/day

Placebo

Treatment duration (weeks): 10

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Ratti 2011_study 096

RCT

11 countries in Europe and Latin America

Secondary care

N=236

Baseline severity: More severe

Mean age (years): 44

Sex (% female): 72

Ethnicity (% BME): NR

Paroxetine 20-30mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Response

Ravindran 1995

RCT

Canada

Secondary care

N=66

Baseline severity: More severe

Mean age (years): 38.9

Sex (% female): 62

Ethnicity (% BME): NR

Sertraline 50-200mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Response

Reimherr 1990a

RCT

US & Canada

Secondary care

N=299

Baseline severity: More severe

Mean age (years): 39.6

Sex (% female): 53

Ethnicity (% BME): 8

Sertraline 20-200mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Rickels 1992

RCT

Secondary care

N=111

Baseline severity: More severe

Mean age (years): 44.7

Sex (% female): 48

Ethnicity (% BME): NR

Paroxetine (dose NR)

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Response

Rudolph 1999a

RCT

Secondary care

N=201

Baseline severity: More severe

Mean age (years): 40

Sex (% female): 66

Ethnicity (% BME): NR

Fluoxetine 20-60mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Response

SER 315 (FDA)^a

RCT

Europe

Secondary care

N=165

Baseline severity: More severe

Mean age (years): 42.0

Sex (% female): 72

Ethnicity (% BME): NR

Sertraline 50-200mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score

Sheehan 2009ba

RCT

Secondary care

N=194

Baseline severity: More severe

Mean age (years): 38.8

Sex (% female): 66

Ethnicity (% BME): NR

Fluoxetine 60-80mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Response

Smith 1992

RCT

Secondary care

N=77

Baseline severity: More severe

Mean age (years): 44.8

Sex (% female): 50

Ethnicity (% BME): NR

Paroxetine 10-50mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Response

Stark 1985a

RCT

Secondary care

N=354

Baseline severity: More severe

Mean age (years): 40.5

Sex (% female): 68

Ethnicity (% BME): NR

Fluoxetine 60-80mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Study 62b (FDA)

RCT

Country NR

Secondary care

N=356

Baseline severity: More severe

Mean age (years): 40

Sex (% female): 57

Ethnicity (% BME): NR

Fluoxetine 20mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score

Study F1J-MC-HMAQ- Study Group Ba

RCT

Secondary care

N=112

Baseline severity: More severe

Mean age (years): 40.8

Sex (% female): NR

Ethnicity (% BME): NR

Fluoxetine 20mg/day

Placebo

Treatment duration (weeks): 10

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Tollefson 1993/1995

RCT

Secondary care

N=671

Baseline severity: More severe

Mean age (years): 67.7

Sex (% female): 55

Ethnicity (% BME): 6

Fluoxetine maximum 20mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Response

Valle-Cabrera 2018

RCT

Cuba

Secondary care

N=77

Baseline severity: More severe

Mean age (years): 45.2

Sex (% female): 92

Ethnicity (% BME): NR

Sertraline 50-200mg/day

Placebo

Treatment duration (weeks): 10

Outcomes (for primary versus secondary care subgroup analysis):

Response

VEN XR 367 (FDA)^b

RCT

Europe

Secondary care

N=164

Baseline severity: More severe

Mean age (years): NR

Sex (% female): 61

Ethnicity (% BME): NR

Paroxetine 20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis): Depression symptoms change score

Wang 2014c

RCT

Canada, China, Finland, South Korea, Malaysia, Mexico, The Philippines, South Africa, & Spain

Secondary care

N=314

Baseline severity: More severe

Mean age (years): 40

Sex (% female): 71

Ethnicity (% BME): 46

Escitalopram 10-20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Response

WELL AK1A4006

RCT

Secondary care

N=309

Baseline severity: More severe

Mean age (years): 37.9

Sex (% female): NR

Ethnicity (% BME): NR

Fluoxetine 20-60mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Wernicke 1987

RCT

Secondary care

N=356

Baseline severity: More severe

Mean age (years): 39.8

Sex (% female): 57

Ethnicity (% BME): NR

Fluoxetine 20mg/day, 40mg/day, or 60mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Wernicke 1988

RCT

Secondary care

N=267

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Fluoxetine 20mg/day or 40mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

a: Three-armed trial but where possible the demographics reported here are for only the two relevant arms.
b: Four-armed trial but where possible the demographics reported here are for only the two relevant arms.
: BME: black, minority, ethnic; K: number of studies; mg: milligrams; N: number of participants; NR: not reported; RCT: randomised controlled trial.

Table 14Summary of included studies for primary care versus secondary care subgroup analysis for comparison 1c SSRIs versus tricyclic antidepressants (TCAs)

Study

Population

Intervention

Comparison

Comments

Primary care (K=10, N=2,014)

Christiansen 1996

RCT

Denmark

Primary care

N=144

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 20-40mg/day

Amitriptyline 75-150mg/day

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Response

Freed 1999

RCT

Australia

Primary care

N=375

Baseline severity: More severe

Mean age (years): 48

Sex (% female): 65

Ethnicity (% BME): NR

Paroxetine 20mg/day

Amitriptyline 75mg/day

Treatment duration (weeks): 9

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score

Hutchinson 1992

RCT

Primary care

N=90

Baseline severity: More severe

Mean age (years): 71.8

Sex (% female): 77

Ethnicity (% BME): NR

Paroxetine 30mg/day

Amitriptyline 100mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Remission
Response

Kyle 1998

RCT

Primary care

N=365

Baseline severity: More severe

Mean age (years): 73.8

Sex (% female): 73

Ethnicity (% BME): NR

Citalopram 20-40mg/day

Amitriptyline 50-100mg/day

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Remission

Moon 1994

RCT

Primary care

N=106

Baseline severity: More severe

Mean age (years): 43.7

Sex (% female): 52

Ethnicity (% BME): NR

Sertraline 50-150mg/day

Clomipramine 50-150mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Response

Moon 1996

RCT

Primary care

N=138

Baseline severity: More severe

Mean age (years): 43.7

Sex (% female): 71

Ethnicity (% BME): NR

Paroxetine 20-30mg/day

Lofepramine 70-210mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Remission
Response

PAR 29060/281

RCT

Europe

Primary care

N=162

Baseline severity: More severe

Mean age (years): 38.8

Sex (% female): 77

Ethnicity (% BME): NR

Paroxetine 30mg/day

Amitriptyline 75-150mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint

PAR MDUK 032

RCT

Country NR

Primary care

N=59

Baseline severity: More severe

Mean age (years): 44.4

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 20-30mg/day

Amitriptyline 100-150mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint

Rosenberg 1994

RCT

Denmark, Norway, Sweden & Finland

Primary care

N=472

Baseline severity: More severe

Mean age (years): 47.6

Sex (% female): 69

Ethnicity (% BME): NR

Citalopram 10-30mg/day or 20-60mg/day

Imipramine 50-150mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Response

Serrano-Blanco 2006

RCT

Spain

Primary care

N=103

Baseline severity: More severe

Mean age (years): 43.5

Sex (% female): 73

Ethnicity (% BME): NR

Fluoxetine 10-40mg/day

Imipramine 25-125mg/day

Treatment duration (weeks): 24

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score

Secondary care (K=47, N=5,482)

29060 07 001a

RCT

Secondary care

N=26

Baseline severity: More severe

Mean age (years): 42.3

Sex (% female): 65

Ethnicity (% BME): NR

Paroxetine 10-60mg/day

Amitriptyline (dose NR)

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score

29060/299

RCT

Europe

Secondary care

N=217

Baseline severity: More severe

Mean age (years): 40.4

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 20-50mg/day

Amitriptyline 100-250mg/day

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score

Akhondzadeh 2003

RCT

Iran

Secondary care

N=48

Baseline severity: More severe

Mean age (years): 35.8

Sex (% female): 40

Ethnicity (% BME): NR

Fluoxetine 60mg/day

Nortriptyline 150mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score

Arminem 1992

RCT

Finland

Secondary care

N=57

Baseline severity: More severe

Mean age (years): NR

Sex (% female): 54

Ethnicity (% BME): NR

Paroxetine 20-40mg/day

Imipramine 100-200mg/day

Treatment duration (weeks): 12

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint

Beasley 1993b

RCT

Secondary care

N=136

Baseline severity: More severe

Mean age (years): 44.8

Sex (% female): 70

Ethnicity (% BME): 4

Fluoxetine 40-80mg/day

Amitriptyline 150-300mg/day

Treatment duration (weeks): 5

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Remission
Response

Bersani 1994

RCT

Italy

Secondary care

N=68

Baseline severity: More severe

Mean age (years): 47.1

Sex (% female): 63

Ethnicity (% BME): NR

Sertraline 50-150mg/day

Amitriptyline 50-150mg/day

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score

Bhargava 2012

RCT

India

Secondary care

N=60

Baseline severity: More severe

Mean age (years): 36.2

Sex (% female): 52

Ethnicity (% BME): NR

Sertraline 50-150mg/day

Imipramine 75-150mg/day

Treatment duration (weeks): 12

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score

Bremner 1984

RCT

Secondary care

N=40

Baseline severity: More severe

Mean age (years): 42.6

Sex (% female): 51

Ethnicity (% BME): NR

Fluoxetine 60-80mg/day

Imipramine 125-300mg/day

Treatment duration (weeks): 5

Outcomes (for primary versus secondary care subgroup analysis):

Response

Byerley 1988a

RCT

Secondary care

N=66

Baseline severity: More severe

Mean age (years): 39.1

Sex (% female): 68

Ethnicity (% BME): NR

Fluoxetine 40-80mg/day

Imipramine 150-300mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Response

Chiu 1996

RCT

Taiwan

Secondary care

N=40

Baseline severity: More severe

Mean age (years): 45.7

Sex (% female): 63

Ethnicity (% BME): NR

Paroxetine 20-30mg/day

Imipramine 125-150mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Response

Cohn 1984b

RCT

Secondary care

N=66

Baseline severity: More severe

Mean age (years): 42

Sex (% female): NR

Ethnicity (% BME): NR

Fluoxetine (dose NR)

Imipramine (dose NR)

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint

Cohn 1990b

RCT

Secondary care

N=241

Baseline severity: More severe

Mean age (years): 70.3

Sex (% female): 49

Ethnicity (% BME): NR

Sertraline 50-200mg/day

Amitriptyline 50-150mg/day

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Danish University Antidepressant Group 1986

RCT

Denmark

Secondary care

N=114

Baseline severity: More severe

Mean age (years): NR

Sex (% female): 70

Ethnicity (% BME): NR

Citalopram 40mg/day

Clomipramine 150mg/day

Treatment duration (weeks): 5

Outcomes (for primary versus secondary care subgroup analysis):

Remission

Danish University Antidepressant Group 1990

RCT

Denmark

Secondary care

N=120

Baseline severity: More severe

Mean age (years): NR

Sex (% female): 66

Ethnicity (% BME): NR

Paroxetine 30mg/day

Clomipramine 150mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Remission

De Ronchi 1998

RCT

Italy

Secondary care

N=65

Baseline severity: More severe

Mean age (years): 68.9

Sex (% female): 72

Ethnicity (% BME): NR

Fluoxetine 20mg/day

Amitriptyline 50-100mg/day

Treatment duration (weeks): 10

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Response

Demyttenaere 1998

RCT

Belgium

Secondary care

N=66

Baseline severity: More severe

Mean age (years): 41.7

Sex (% female): 55

Ethnicity (% BME): NR

Fluoxetine 20mg/day

Amitriptyline 50mg/day

Treatment duration (weeks): 9

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Response

Deuschle 2003

RCT

Germany

Secondary care

N=126

Baseline severity: More severe

Mean age (years): 54.1

Sex (% female): 67

Ethnicity (% BME): NR

Paroxetine 40mg/day

Amitriptyline 150mg/day

Treatment duration (weeks): 5

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score

Fabre 1991

RCT

Secondary care

N=205

Baseline severity: More severe

Mean age (years): 37

Sex (% female): 57

Ethnicity (% BME): NR

Fluoxetine 40mg/day

Nortriptyline 100mg/day

Treatment duration (weeks): 5

Outcomes (for primary versus secondary care subgroup analysis):

Response

Fabre 1992a

RCT

Secondary care

N=80

Baseline severity: More severe

Mean age (years): 35.4

Sex (% female): 61

Ethnicity (% BME): NR

Paroxetine 10-50mg/day

Imipramine 65-275mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score

Fawcett 1989

RCT

Secondary care

N=40

Baseline severity: More severe

Mean age (years): 42.2

Sex (% female): 65

Ethnicity (% BME): NR

Fluoxetine 20-60mg/day

Amitriptyline 50-200mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Remission
Response

Feighner 1993a

RCT

Secondary care

N=477

Baseline severity: More severe

Mean age (years): 40.4

Sex (% female): 53

Ethnicity (% BME): NR

Paroxetine 10-50mg/day

Imipramine 65-275mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Remission

Forlenza 2001

RCT

Brazil

Secondary care

N=55

Baseline severity: More severe

Mean age (years): 68.5

Sex (% female): 69

Ethnicity (% BME): NR

Sertraline 50mg/day

Imipramine 150mg/day

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Remission
Response

Geretsegger 1995

RCT

Austria & Germany

Secondary care

N=91

Baseline severity: More severe

Mean age (years): 71.2

Sex (% female): 86

Ethnicity (% BME): NR

Paroxetine 20-30mg/day

Amitriptyline 100-150mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Remission
Response

GSK_29060/103

RCT

Secondary care

N=106

Baseline severity: More severe

Mean age (years): 75.3

Sex (% female): 74

Ethnicity (% BME): NR

Paroxetine 20-30mg/day

Lofepramine 70-210mg/day

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Response

Hashemi 2012

RCT

Iran

Secondary care

N=120

Baseline severity: More severe

Mean age (years): 34.8

Sex (% female): 53

Ethnicity (% BME): NR

Fluoxetine maximum 60mg/day

Nortriptyline maximum 150mg/day

Treatment duration (weeks): 26

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score

Keegan 1991

RCT

Canada

Secondary care

N=42

Baseline severity: More severe

Mean age (years): 43.8

Sex (% female): NR

Ethnicity (% BME): NR

Fluoxetine 20-80mg/day

Amitriptyline 100-250mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Remission
Response

Laakmann 1988

RCT

Germany

Secondary care

N=128

Baseline severity: More severe

Mean age (years): NR

Sex (% female): 72

Ethnicity (% BME): NR

Fluoxetine 20-60mg/day

Amitriptyline 50-150mg/day

Treatment duration (weeks): 5

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Response

Laakmann 1991

RCT

Germany

Secondary care

N=174

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Fluoxetine (dose NR)

Amitriptyline 100-200mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint

Levine 1989

RCT

Secondary care

N=60

Baseline severity: More severe

Mean age (years): 45.8

Sex (% female): 70

Ethnicity (% BME): NR

Fluoxetine 40-60mg/day

Imipramine 75-150mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Remission

Marchesi 1998

RCT

Italy

Secondary care

N=142

Baseline severity: More severe

Mean age (years): 43.6

Sex (% female): 74

Ethnicity (% BME): NR

Fluoxetine 20mg/day

Amitriptyline 75-225mg/day

Treatment duration (weeks): 10

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Response

MDF/29060/III/07 0/88/MC

RCT

Europe

Secondary care

N=62

Baseline severity: More severe

Mean age (years): 73

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 20-30mg/day

Clomipramine 60-75mg/day

Treatment duration (weeks): 5

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Remission
Response

Miura 2000

RCT

Japan

Secondary care

N=228

Baseline severity: More severe

Mean age (years): 46.5

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 20-40mg/day

Amitriptyline 50-150mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score

Moller 1993

RCT

Germany and Hungary

Secondary care

N=223

Baseline severity: More severe

Mean age (years): 47.1

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 30-50mg/day

Amitriptyline 150-250mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Remission
Response

Moller 1998

RCT

Germany, Hungary, & Czech Republic

Secondary care

N=160

Baseline severity: More severe

Mean age (years): 48.6

Sex (% female): 70

Ethnicity (% BME): NR

Sertraline 50-150mg/day

Amitriptyline 75-150mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Mulsant 1999

RCT

Secondary care

N=80

Baseline severity: More severe

Mean age (years): 65

Sex (% female): 74

Ethnicity (% BME): 15

Paroxetine 20-30mg/day

Nortriptyline (Mean dose 51.4mg/day)

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Remission

Navarro 2001

RCT

Spain

Secondary care

N=58

Baseline severity: More severe

Mean age (years): 70.7

Sex (% female): 64

Ethnicity (% BME): NR

Citalopram 30-40mg/day

Nortriptyline 50-100mg/day

Treatment duration (weeks): 12

Outcomes (for primary versus secondary care subgroup analysis):

Remission

Ontiveros Sanchez 1998

RCT

South America

Secondary care

N=42

Baseline severity: More severe

Mean age (years): 37.6

Sex (% female): 53

Ethnicity (% BME): NR

Fluoxetine 20mg/day

Amitriptyline 150-250mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Response

Peselow 1989aa

RCT

Secondary care

N=66

Baseline severity: More severe

Mean age (years): 45.9

Sex (% female): 35

Ethnicity (% BME): NR

Paroxetine 10-50mg/day

Imipramine 65-275mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Response

Peselow 1989ba

RCT

Secondary care

N=80

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 20-50mg/day

Imipramine 65-275mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Response

Peters 1990

RCT

Germany

Secondary care

N=102

Baseline severity: More severe

Mean age (years): 44.5

Sex (% female): 63

Ethnicity (% BME): NR

Fluoxetine 20mg/day

Amitriptyline 100mg/day

Treatment duration (weeks): 5

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Response

Preskorn 1991

RCT

Secondary care

N=61

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): 2

Fluoxetine 20-60mg/day

Amitriptyline 50-200mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score

Reimherr 1990a

RCT

US & Canada

Secondary care

N=298

Baseline severity: More severe

Mean age (years): 38.4

Sex (% female): 55

Ethnicity (% BME): 10

Sertraline 20-200mg/day

Amitriptyline 50-150mg/day

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Ropert 1989

RCT

France

Secondary care

N=143

Baseline severity: More severe

Mean age (years): 43.8

Sex (% female): 64

Ethnicity (% BME): NR

Fluoxetine

Clomipramine

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score

SER 315 (FDA)^a

RCT

Europe

Secondary care

N=162

Baseline severity: More severe

Mean age (years): 42.4

Sex (% female): 69

Ethnicity (% BME): NR

Sertraline 50-200mg/day

Amitriptyline 50-200mg/day

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score

Staner 1995

RCT

Belgium

Secondary care

N=40

Baseline severity: More severe

Mean age (years): 42.1

Sex (% female): 83

Ethnicity (% BME): NR

Paroxetine 30mg/day

Amitriptyline 150mg/day

Treatment duration (weeks): 5

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Response

Stark 1985a

RCT

Secondary care

N=371

Baseline severity: More severe

Mean age (years): 41.0

Sex (% female): 69

Ethnicity (% BME): NR

Fluoxetine 60-80mg/day

Imipramine 100-300mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Suleman 1997

RCT

Zimbabwe

Secondary care

N=30

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Fluoxetine 20mg/day

Amitriptyline 100mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score

a: Three-armed trial but where possible the demographics reported here are for only the two relevant arms.
: BME: black, minority, ethnic; K: number of studies; mg: milligrams; N: number of participants; NR: not reported; RCT: randomised controlled trial.

Table 15Summary of included studies for primary care versus secondary care subgroup analysis for comparison 1d TCAs versus placebo

Study

Population

Intervention

Comparison

Comments

Primary care (K=6, N=597)

Barge-Schaapveld 2002

RCT

Netherlands

Primary care

N=63

Baseline severity: More severe

Mean age (years): 43.4

Sex (% female): 73

Ethnicity (% BME): NR

Imipramine 200mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint

Blashki 1971

RCT

Australia

Primary care

N=45

Baseline severity: More severe

Mean age (years): 36.7

Sex (% female): 100

Ethnicity (% BME): NR

Amitriptyline 75mg/day or 150mg/day

Placebo

Treatment duration (weeks): 4

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score

Lecrubier 1997a

RCT

France, Italy & UK

Primary care

N=151

Baseline severity: More severe

Mean age (years): 40.6

Sex (% female): 66

Ethnicity (% BME): NR

Imipramine 75-150mg/day

Placebo

Treatment duration (weeks): 13

Outcomes (for primary versus secondary care subgroup analysis):

Response

Mynors-Wallis 1995a

RCT

Primary care

N=61

Baseline severity: More severe

Mean age (years): 37.1

Sex (% female): 74

Ethnicity (% BME): 5

Amitriptyline maximum 150mg/day

Placebo

Treatment duration (weeks): 12

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score

Philipp 1999

RCT

Germany

Primary care

N=157

Baseline severity: More severe

Mean age (years): 46.5

Sex (% female): 75

Ethnicity (% BME): NR

Imipramine 100mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Schweizer 1998

RCT

Primary care

N=120

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Imipramine 50-150mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Response

Secondary care (K=30, N=3,444)

29060 07 001a

RCT

Secondary care

N=25

Baseline severity: More severe

Mean age (years): 44.8

Sex (% female): 52

Ethnicity (% BME): NR

Amitriptyline (dose NR)

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score

Amsterdam 1986

RCT

Secondary care

N=109

Baseline severity: More severe

Mean age (years): 41

Sex (% female): 33

Ethnicity (% BME): NR

Amitriptyline 200-600mg/day

Placebo

Treatment duration (weeks): 4

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Response

Bakish 1992b

RCT

Canada

Secondary care

N=115

Baseline severity: More severe

Mean age (years): 43

Sex (% female): 43

Ethnicity (% BME): NR

Amitriptyline 150mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Response

Bremner 1995a

RCT

Secondary care

N=100

Baseline severity: More severe

Mean age (years): 38.0

Sex (% female): 72

Ethnicity (% BME): NR

Amitriptyline 40-280mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Response

Byerley 1988a

RCT

Secondary care

N=63

Baseline severity: More severe

Mean age (years): 38.5

Sex (% female): 61

Ethnicity (% BME): NR

Imipramine 150-300mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Response

Cassano 1986

RCT

US, Canada, UK, & France

Secondary care

N=314

Baseline severity: More severe

Mean age (years): 41.7

Sex (% female): 62

Ethnicity (% BME): NR

Imipramine 50-300mg/day

Placebo

Treatment duration (weeks): 4

Outcomes (for primary versus secondary care subgroup analysis):

Response

Elkin 1989/Imber 1990b

RCT

Secondary care

N=125

Baseline severity: More severe

Mean age (years): 35

Sex (% female): 70

Ethnicity (% BME): 11

Imipramine (mean final dose 185mg/day)

Placebo

Treatment duration (weeks): 16

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score

Escobar 1980a

RCT

Colombia

Secondary care

N=27

Baseline severity: More severe

Mean age (years): 46.1

Sex (% female): 59

Ethnicity (% BME): NR

Imipramine 100-300mg/day

Placebo

Treatment duration (weeks): 4

Outcomes (for primary versus secondary care subgroup analysis):

Response

Fabre 1992a

RCT

Secondary care

N=80

Baseline severity: More severe

Mean age (years): 35.5

Sex (% female): 66

Ethnicity (% BME): NR

Imipramine 65-275mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score

Feiger 1996

RCT

Secondary care

N=81

Baseline severity: More severe

Mean age (years): 39.7

Sex (% female): 56

Ethnicity (% BME): 11

Imipramine 50-300mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Response

Feighner 1982

RCT

Secondary care

N=139

Baseline severity: More severe

Mean age (years): NR

Sex (% female): 71

Ethnicity (% BME): NR

Lofepramine 105-280mg/day or Imipramine 75-200mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Response

Feighner 1989b

RCT

Secondary care

N=30

Baseline severity: More severe

Mean age (years): 44

Sex (% female): 50

Ethnicity (% BME): NR

Imipramine 50-250mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Response

Fontaine 1994

RCT

Canada

Secondary care

N=90

Baseline severity: More severe

Mean age (years): 43.1

Sex (% female): 58

Ethnicity (% BME): NR

Imipramine 50-250mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Response

Goldberg 1980a

RCT

Secondary care

N=122

Baseline severity: More severe

Mean age (years): 36.1

Sex (% female): 74

Ethnicity (% BME): NR

Amitriptyline 75-200mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Response

Kusalic 1993

RCT

Canada

Secondary care

N=28

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Amitriptyline (mean final dose 109.93mg/day)

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Response

McCallum 1975

RCT

Secondary care

N=24

Baseline severity: More severe

Mean age (years): 41.5

Sex (% female): 83

Ethnicity (% BME): NR

Amitriptyline 150mg/day

Placebo

Treatment duration (weeks): 3

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score

MIR 003-020 (FDA)^a

RCT

Secondary care

N=86

Baseline severity: More severe

Mean age (years): 44.0

Sex (% female): 55

Ethnicity (% BME): NR

Amitriptyline 40-280mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Peselow 1989aa

RCT

Secondary care

N=71

Baseline severity: More severe

Mean age (years): 44.7

Sex (% female): 35

Ethnicity (% BME): NR

Imipramine 65-275mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Response

Peselow 1989ba

RCT

Secondary care

N=82

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Imipramine 65-275mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Response

Reimherr 1990a

RCT

US & Canada

Secondary care

N=299

Baseline severity: More severe

Mean age (years): 39.0

Sex (% female): 54

Ethnicity (% BME): 9

Amitriptyline 50-150mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

Rickels 1982e

RCT

Secondary care

N=97

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Imipramine 150-200mg/day

Placebo

Treatment duration (weeks): 4

Outcomes (for primary versus secondary care subgroup analysis):

Response

Rickels 1991

RCT

Secondary care

N=131

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Imipramine minimum 150mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Response

Rickels 1995_Study 006-1

RCT

Secondary care

N=77

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Imipramine 100-300mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Response

Rickels 1995_Study 006-2

RCT

Secondary care

N=80

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Imipramine 100-300mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Response

Schweizer 1994a

RCT

Secondary care

N=151

Baseline severity: More severe

Mean age (years): 42.5

Sex (% female): 64

Ethnicity (% BME): NR

Imipramine 75-225mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

SER 315 (FDA)^a

RCT

Europe

Secondary care

N=157

Baseline severity: More severe

Mean age (years): 43.5

Sex (% female): 75

Ethnicity (% BME): NR

Amitriptyline 50-200mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score

Silverstone 1994

RCT

Secondary care

N=166

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Imipramine 150mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Response

Smith 1990a

RCT

Secondary care

N=100

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Amitriptyline 80-280mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Response

Stark 1985a

RCT

Secondary care

N=355

Baseline severity: More severe

Mean age (years): 41.5

Sex (% female): 68

Ethnicity (% BME): NR

Imipramine 100-300mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score
Response

White 1984

RCT

Secondary care

N=120

Baseline severity: More severe

Mean age (years): 37.1

Sex (% female): 48

Ethnicity (% BME): NR

Nortriptyline 75-150mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Depression symptoms change score

a: Three-armed trial but where possible the demographics reported here are for only the two relevant arms.
: BME: black, minority, ethnic; K: number of studies; mg: milligrams; N: number of participants; NR: not reported; RCT: randomised controlled trial.

Table 16Summary of included studies for primary care versus secondary care subgroup analysis for comparison 1e Serotonin–norepinephrine reuptake inhibitors (SNRIs) versus SSRIs

Study

Population

Intervention

Comparison

Comments

Primary care (K=2, N=634)

Montgomery 2004

RCT

Denmark, Finland, France, Germany, Ireland, Spain, & Switzerland

Primary care

N=293

Baseline severity: More severe

Mean age (years): 48

Sex (% female): 71

Ethnicity (% BME): NR

Venlafaxine 75-150mg/day

Escitalopram 10-20mg/day

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Remission
Response

Tylee 1997

RCT

Primary care

N=341

Baseline severity: More severe

Mean age (years): 44.5

Sex (% female): 71

Ethnicity (% BME): NR

Venlafaxine 75mg/day

Fluoxetine 20mg/day

Treatment duration (weeks): 12

Outcomes (for primary versus secondary care subgroup analysis):

Remission
Response

Secondary care (K=29, N=5,484)

Allard 2004

RCT

Sweden & Denmark

Secondary care

N=151

Baseline severity: More severe

Mean age (years): 73

Sex (% female): 80

Ethnicity (% BME): NR

Venlafaxine 75-150mg/day

Citalopram 10-20mg/day

Treatment duration (weeks): 22

Outcomes (for primary versus secondary care subgroup analysis):

Remission
Response

Alves 1999

RCT

Portugal

Secondary care

N=87

Baseline severity: More severe

Mean age (years): 43.7

Sex (% female): 92

Ethnicity (% BME): NR

Venlafaxine 75-150mg/day

Fluoxetine 20-40mg/day

Treatment duration (weeks): 12

Outcomes (for primary versus secondary care subgroup analysis):

Remission
Response

Bielski 2004

RCT

Secondary care

N=202

Baseline severity: More severe

Mean age (years): 37.4

Sex (% female): 58

Ethnicity (% BME): 25

Venlafaxine 225mg/day

Escitalopram 20mg/day

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Remission
Response

Clerc 1994

RCT

France & Belgium

Secondary care

N=68

Baseline severity: More severe

Mean age (years): 51.3

Sex (% female): 68

Ethnicity (% BME): NR

Venlafaxine 200mg/day

Fluoxetine 40mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Response

Costa 1998

RCT

Argentina, Brazil, Chile, Colombia, Uruguay, & Venezuela

Secondary care

N=382

Baseline severity: More severe

Mean age (years): 40.2

Sex (% female): 79

Ethnicity (% BME): NR

Venlafaxine 75-150mg/day

Fluoxetine 20-40mg/day

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Remission
Response

DeNayer 2002

RCT

Belgium

Secondary care

N=146

Baseline severity: More severe

Mean age (years): 42.8

Sex (% female): 68

Ethnicity (% BME): NR

Venlafaxine 75-150mg/day

Fluoxetine 20-40mg/day

Treatment duration (weeks): 12

Outcomes (for primary versus secondary care subgroup analysis):

Remission
Response

Detke 2004^a

RCT

Secondary care

N=274

Baseline severity: More severe

Mean age (years): 43.3

Sex (% female): 72

Ethnicity (% BME): 0

Duloxetine 80mg/day or 120mg/day

Paroxetine 20mg/day

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Remission
Response

Diaz-Martinez 1998

RCT

Mexico

Secondary care

N=145

Baseline severity: More severe

Mean age (years): NR

Sex (% female): 72

Ethnicity (% BME): NR

Venlafaxine 75-150mg/day

Fluoxetine 20-40mg/day

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Response

Dierick 1996

RCT

Belgium, Italy, Switzerland & France

Secondary care

N=314

Baseline severity: More severe

Mean age (years): 43.4

Sex (% female): 65

Ethnicity (% BME): NR

Venlafaxine 75-150mg/day

Fluoxetine 20mg/day

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Response

Eli Lilly HMAT-Aa

RCT

Secondary care

N=173

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Duloxetine 80mg/day

Paroxetine 20mg/day

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Remission
Response

Goldstein 2002^a

RCT

Secondary care

N=103

Baseline severity: More severe

Mean age (years): 41.5

Sex (% female): 61

Ethnicity (% BME): 17

Duloxetine 40-120mg/day

Fluoxetine 20mg/day

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Remission
Response

Goldstein 2004^a

RCT

Secondary care

N=178

Baseline severity: More severe

Mean age (years): 40.5

Sex (% female): 63

Ethnicity (% BME): 21

Duloxetine 80mg/day

Paroxetine 20mg/day

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Remission
Response

Hao 2014

RCT

China

Secondary care

N=281

Baseline severity: More severe

Mean age (years): 38.5

Sex (% female): 59

Ethnicity (% BME): NR

Duloxetine 60mg/day

Paroxetine 20mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Remission
Response

Higuchi 2009^a

RCT

Japan

Secondary care

N=223

Baseline severity: More severe

Mean age (years): 38.3

Sex (% female): NR

Ethnicity (% BME): NR

Duloxetine 60mg/day

Paroxetine 20-40mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Remission
Response

Hwang 2004

RCT

Taiwan

Secondary care

N=105

Baseline severity: More severe

Mean age (years): 65.1

Sex (% female): 58

Ethnicity (% BME): NR

Venlafaxine 75-150mg/day

Paroxetine 20-40mg/day

Treatment duration (weeks): 4

Outcomes (for primary versus secondary care subgroup analysis):

Response

Jiang 2017

RCT

China

Secondary care

N=26

Baseline severity: More severe

Mean age (years): 45.5

Sex (% female): 73

Ethnicity (% BME): NR

Duloxetine (mean final dose 60mg/day)

Escitalopram (mean final dose 13.13mg/day)

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Response

Khan 2007

RCT

Secondary care

N=278

Baseline severity: More severe

Mean age (years): 42.4

Sex (% female): 61

Ethnicity (% BME): 20

Duloxetine 60mg/day

Escitalopram 10-20mg/day

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Remission
Response

Kornaat 2000

RCT

Country NR

Secondary care

N=156

Baseline severity: More severe

Mean age (years): NR

Sex (% female): 64

Ethnicity (% BME): NR

Venlafaxine 75-225mg/day

Fluoxetine 20-40mg/day

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Remission
Response

Mehtonen 2000

RCT

Finland

Secondary care

N=147

Baseline severity: More severe

Mean age (years): 42.6

Sex (% female): 66

Ethnicity (% BME): NR

Venlafaxine 75-150mg/day

Sertraline 50-100mg/day

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Remission
Response

Nemeroff 2007^a

RCT

Secondary care

N=206

Baseline severity: More severe

Mean age (years): 39

Sex (% female): 65

Ethnicity (% BME): 11

Venlafaxine 75-225mg/day

Fluoxetine 20-60mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Remission
Response

Nierenberg 2007^a

RCT

Secondary care

N=547

Baseline severity: More severe

Mean age (years): 42.2

Sex (% female): 66

Ethnicity (% BME): 24

Duloxetine 60mg/day

Escitalopram 10mg/day

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Remission
Response

Perahia 2006^a

RCT

Bulgaria, Croatia, Hungary, Poland, Romania, Russia, & Slovakia

Secondary care

N=293

Baseline severity: More severe

Mean age (years): 45.4

Sex (% female): 71

Ethnicity (% BME): 0

Duloxetine 80mg/day or 120mg/day

Paroxetine 20mg/day

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Remission
Response

Rickels 2000

RCT

Country NR

Secondary care

N=51

Baseline severity: More severe

Mean age (years): 37.4

Sex (% female): 75

Ethnicity (% BME): NR

Venlafaxine 150-225mg/day

Fluoxetine 20-40mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Remission

Rudolph 1999^a

RCT

Secondary care

N=203

Baseline severity: More severe

Mean age (years): 40

Sex (% female): 72

Ethnicity (% BME): NR

Venlafaxine 75-225mg/day

Fluoxetine 20-60mg/day

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Remission
Response

Sheehan 2009b^a

RCT

Secondary care

N=194

Baseline severity: More severe

Mean age (years): 39.7

Sex (% female): 59

Ethnicity (% BME): NR

Venlafaxine 225-375mg/day

Fluoxetine 60-80mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Remission
Response

Shelton 2006

RCT

Secondary care

N=160

Baseline severity: More severe

Mean age (years): 39.3

Sex (% female): 53

Ethnicity (% BME): 17

Venlafaxine 75-225mg/day

Sertraline 50-150mg/day

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Remission
Response

Sir 2005

RCT

Australia & Turkey

Secondary care

N=163

Baseline severity: More severe

Mean age (years): 37

Sex (% female): 69

Ethnicity (% BME): 2

Venlafaxine 75-225mg/day

Sertraline 50-150mg/day

Treatment duration (weeks): 8

Outcomes (for primary versus secondary care subgroup analysis):

Remission
Response

Study F1J-MCHMAQ- Study Group Ba

RCT

Secondary care

N=119

Baseline severity: More severe

Mean age (years): 39.8

Sex (% female): NR

Ethnicity (% BME): NR

Duloxetine 40-120mg/day

Fluoxetine 20mg/day

Treatment duration (weeks): 10

Outcomes (for primary versus secondary care subgroup analysis):

Remission
Response

Tzanakaki 2000

RCT

Greece & Italy

Secondary care

N=109

Baseline severity: More severe

Mean age (years): 48

Sex (% female): 79

Ethnicity (% BME): NR

Venlafaxine 225mg/day

Fluoxetine 60mg/day

Treatment duration (weeks): 6

Outcomes (for primary versus secondary care subgroup analysis):

Remission
Response

a: Three-armed trial but where possible the demographics reported here are for only the two relevant arms.
: BME: black, minority, ethnic; K: number of studies; mg: milligrams; N: number of participants; NR: not reported; RCT: randomised controlled trial.

Table 17Summary of included studies for comparison 2 Crisis resolution versus standard care

Study

Population

Intervention

Comparison

Comments

Johnson 2005

RCT

N=260

Non-psychotic severe mental illness

Diagnosis: 25% schizophrenia or schizoaffective disorder; 10% bipolar affective disorder; 7% other psychosis; 30% unipolar depression; 13% personality disorder; 4% other nonpsychotic disorder; 5% substance misuse only (data only reported for 123/135 of experimental group so percentages do not add up to 100%)

Mean age (years): 37.9

Sex (% female): 49

Ethnicity (% BME): 22

Crisis resolution team augmented existing acute services and aimed to assess all patients and manage them at home if feasible. Staff were available 24 hours but on call from home after 10pm

Standard care included care from the inpatient unit, crisis houses, and community mental health teams

Outcomes assessed at 8 weeks and 6 months after crisis

Outcomes:

Symptom severity (BPRS) 8 weeks after crisis
Admission as inpatient 6 months after crisis
Bed days in hospital 6 months after crisis
Patient satisfaction (CSQ-8) 8 weeks after crisis
Quality of life (MANSA) 8 weeks after crisis
Social functioning (LSP) 8 weeks after crisis
Social functioning (LSP) 6 months after crisis

: BME: black, minority, ethnic; BPRS: brief psychiatric rating scale; CSQ-8: client satisfaction questionnaire - 8 item version; LSP: life skills profile; MANSA: Manchester short assessment of quality of life; N: number of participants; RCT: randomised controlled trial

Table 18Summary of included studies for inpatient versus outpatient subgroup analysis for comparison 3a Selective serotonin reuptake inhibitors (SSRIs) versus placebo

Study

Population

Intervention

Comparison

Comments

Inpatient setting (K=3, N=272)

29060 07 001^a

RCT

Inpatient

N=25

Baseline severity: More severe

Mean age (years): 42.5

Sex (% female): 56

Ethnicity (% BME): NR

Paroxetine 10-60mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score

Katz 2004

RCT

Inpatient

N=53

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 20-60mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

Sheehan 2009^b^a

RCT

Inpatient

N=194

Baseline severity: More severe

Mean age (years): 38.8

Sex (% female): 66

Ethnicity (% BME): NR

Fluoxetine 60-80mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Outpatient setting (K=74, N=16,736)

Baune 2018

RCT

Estonia, Finland, Germany, & Lithuania

Outpatient

N=104

Baseline severity: More severe

Mean age (years): 45.7

Sex (% female): 64

Ethnicity (% BME): 2

Paroxetine 20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score

Binnemann 2008

RCT

US, Serbia and Montenegro, & the Russian Federation

Outpatient

N=82

Baseline severity: More severe

Mean age (years): 49

Sex (% female): 39

Ethnicity (% BME): NR

Sertraline 100mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Bjerkenstedt 2005

RCT

Sweden

Outpatient

N=115

Baseline severity: More severe

Mean age (years): 50.9

Sex (% female): 79

Ethnicity (% BME): 0

Fluoxetine 20mg/day

Placebo

Treatment duration (weeks): 4

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Blumenthal 2007/Hoffman 2011^b

RCT

Outpatient

N=98

Baseline severity: More severe

Mean age (years): 52

Sex (% female): 77

Ethnicity (% BME): 33

Sertraline 50-200mg/day

Placebo

Treatment duration (weeks): 16

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score

Bose 2008

RCT

Outpatient

N=267

Baseline severity: More severe

Mean age (years): 68.3

Sex (% female): 59

Ethnicity (% BME): 11

Escitalopram 10-20mg/day

Placebo

Treatment duration (weeks): 12

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Burke 2002

RCT

Outpatient

N=491

Baseline severity: More severe

Mean age (years): 40.1

Sex (% female): 65

Ethnicity (% BME): NR

Escitalopram 10mg/day or 20mg/day, or citalopram 40mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Byerley 1988^a

RCT

Outpatient

N=61

Baseline severity: More severe

Mean age (years): 38.2

Sex (% female): 68

Ethnicity (% BME): NR

Fluoxetine 40-80mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

Claghorn 1992^a

RCT

Outpatient

N=59

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 10-50mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score

Claghorn 1992^b

RCT

Outpatient

N=72

Baseline severity: More severe

Mean age (years): 35

Sex (% female): 32

Ethnicity (% BME): NR

Paroxetine 10-50mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Clayton 2006_study 1

RCT

Outpatient

N=283

Baseline severity: More severe

Mean age (years): 35

Sex (% female): 61

Ethnicity (% BME): 35

Escitalopram 10-20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Clayton 2006_study 2

RCT

Outpatient

N=286

Baseline severity: More severe

Mean age (years): 36.5

Sex (% female): 56

Ethnicity (% BME): 27

Escitalopram 10-20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Detke 2004^a

RCT

Outpatient

N=179

Baseline severity: More severe

Mean age (years): 42.9

Sex (% female): 71

Ethnicity (% BME): 0

Paroxetine 20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Doogan 1994

RCT

Outpatient

N=200

Baseline severity: More severe

Mean age (years): 45.7

Sex (% female): 68

Ethnicity (% BME): NR

Sertraline 50-100mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

Dube 2010

RCT

India, US, Mexico & Romania

Outpatient

N=200

Baseline severity: More severe

Mean age (years): 36.5

Sex (% female): 44

Ethnicity (% BME): NR

Escitalopram 10-20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Dunbar 1993

RCT

Outpatient

N=341

Baseline severity: More severe

Mean age (years): 41

Sex (% female): 51

Ethnicity (% BME): NR

Paroxetine 10-50mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

Eli Lilly HMAT-Aa

RCT

Outpatient

N=179

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Emsley 2018

RCT

Bulgaria, Estonia, Finland, France, Republic of Korea, Malaysia, Mexico, Poland, Romania, & Slovakia

Outpatient

N=206

Baseline severity: More severe

Mean age (years): 70.6

Sex (% female): 75

Ethnicity (% BME): NR

Escitalopram 10mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Fabre 1992^a

RCT

Outpatient

N=80

Baseline severity: More severe

Mean age (years): 35.8

Sex (% female): 59

Ethnicity (% BME): NR

Paroxetine 10-50mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score

Fava 1998^a

RCT

Outpatient

N=128

Baseline severity: More severe

Mean age (years): 41.3

Sex (% female): 51

Ethnicity (% BME): NR

Paroxetine 20-50mg/day or fluoxetine 20-80mg/day

Placebo

Treatment duration (weeks): 12

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score

Response

Fava 2005

RCT

Outpatient

N=90

Baseline severity: More severe

Mean age (years): 37.2

Sex (% female): 59

Ethnicity (% BME): NR

Fluoxetine 20mg/day

Placebo

Treatment duration (weeks): 12

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score

FDA 245 (EMD 68 843-010)

RCT

Outpatient

N=191

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Fluoxetine 20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score

Forest Laboratories 2000

RCT

Outpatient

N=386

Baseline severity: More severe

Mean age (years): 42

Sex (% female): 52

Ethnicity (% BME): NR

Escitalopram 10-20mg/day or citalopram 20-40mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Forest Research Institute 2005

RCT

Outpatient

N=409

Baseline severity: More severe

Mean age (years): 40

Sex (% female): 56

Ethnicity (% BME): NR

Escitalopram 10-20mg/day or sertraline 50-200mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Golden 2002_448

RCT

Outpatient

N=315

Baseline severity: More severe

Mean age (years): 39

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 20-62.5mg/day

Placebo

Treatment duration (weeks): 12

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score

Golden 2002_449

RCT

Outpatient

N=330

Baseline severity: More severe

Mean age (years): 41.2

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 20-62.5mg/day

Placebo

Treatment duration (weeks): 12

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score

Goldstein 2002^a

RCT

Outpatient

N=103

Baseline severity: More severe

Mean age (years): 40.9

Sex (% female): 65

Ethnicity (% BME): 21

Fluoxetine 20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

Goldstein 2004^a

RCT

Outpatient

N=176

Baseline severity: More severe

Mean age (years): 40

Sex (% female): 64

Ethnicity (% BME): 22

Paroxetine 20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

Gual 2003

RCT

Spain

Outpatient

N=83

Baseline severity: More severe

Mean age (years): 46.7

Sex (% female): 47

Ethnicity (% BME): NR

Sertraline 50-150mg/day

Placebo

Treatment duration (weeks): 24

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

Hirayasu 2011^a

RCT

Japan

Outpatient

N=310

34.6

Sex (% female): NR

Ethnicity (% BME): NR

Escitalopram 10mg/day or 20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

Hirayasu 2011^b

RCT

Japan

Outpatient

N=485

Baseline severity: More severe

Mean age (years): 36.2

Sex (% female): NR

Ethnicity (% BME): NR

Escitalopram 10mg/day or 20mg/day, or paroxetine 20-40mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

Hunter 2010_study 1

RCT

Outpatient

N=28

Baseline severity: More severe

Mean age (years): 42.4

Sex (% female): 68

Ethnicity (% BME): NR

Fluoxetine 20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

Hunter 2011

RCT

Outpatient

N=24

Baseline severity: More severe

Mean age (years): 40.4

Sex (% female): 65

Ethnicity (% BME): NR

Fluoxetine 20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Jefferson 2000

RCT

Outpatient

N=415

Baseline severity: More severe

Mean age (years): 39.9

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 25mg/day, or citalopram 20mg/day or 40mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Keller 2006_Study 062

RCT

Cross-continental

Outpatient

N=325

Baseline severity: More severe

Mean age (years): 41

Sex (% female): 67

Ethnicity (% BME): 43

Paroxetine 20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score

Komulainen 2018

RCT

Finland

Outpatient

N=37

Baseline severity: More severe

Mean age (years): median 25.1

Sex (% female): 44

Ethnicity (% BME): NR

Escitalopram 10mg/day

Placebo

Treatment duration (weeks): 1

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score

Kramer 1998

RCT

Outpatient

N=142

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 20mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

Kranzler 2006_Group A

RCT

Outpatient

N=189

Baseline severity: More severe

Mean age (years): 42.9

Sex (% female): 35

Ethnicity (% BME): 10

Sertraline 50-200mg/day

Placebo

Treatment duration (weeks): 10

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Lam 2016^b

RCT

Canada

Outpatient

N=61

Baseline severity: More severe

Mean age (years): 36.8

Sex (% female): 72

Ethnicity (% BME): NR

Fluoxetine 20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Lepola 2003

RCT

Belgium, Canada, Finland, France, Norway, Sweden, Switzerland & UK

Outpatient

N=469

Baseline severity: More severe

Mean age (years): 43.3

Sex (% female): 72

Ethnicity (% BME): NR

Escitalopram 10-20mg/day or citalopram 20-40mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

Macias-Cortes 2015

RCT

Mexico

Outpatient

N=89

Baseline severity: More severe

Mean age (years): 49

Sex (% female): 100

Ethnicity (% BME): 100

Fluoxetine 20mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Mathews 2015

RCT

Outpatient

N=579

Baseline severity: More severe

Mean age (years): 42.3

Sex (% female): 57

Ethnicity (% BME): 32

Citalopram 40mg/day

Placebo

Treatment duration (weeks): 10

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Mendels 1999

RCT

Outpatient

N=180

Baseline severity: More severe

Mean age (years): 43

Sex (% female): 33

Ethnicity (% BME): 13

Citalopram 20-80mg/day

Placebo

Treatment duration (weeks): 4

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

Miller 1989^a

RCT

Outpatient

N=47

Baseline severity: More severe

Mean age (years): 42.5

Sex (% female): 68

Ethnicity (% BME): NR

Paroxetine 30mg/day

Placebo

Treatment duration (weeks): 4

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score

Mundt 2012

RCT

Outpatient

N=165

Baseline severity: More severe

Mean age (years): 37.8

Sex (% female): 63

Ethnicity (% BME): 24

Sertraline 50-100mg/day

Placebo

Treatment duration (weeks): 4

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

MY-1042/BRL-029060/CPMS-251

RCT

Outpatient

N=254

Baseline severity: More severe

Mean age (years): 41.9

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 20-50mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

MY-1045/BRL-029060/1 (PAR 128)

RCT

Outpatient

N=848

Baseline severity: More severe

Mean age (years): 41.8

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 20-50mg/day or fluoxetine 20-80mg/day

Placebo

Treatment duration (weeks): 12

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Nemeroff 2007^a

RCT

Outpatient

N=206

Baseline severity: More severe

Mean age (years): 39.1

Sex (% female): 61

Ethnicity (% BME): 10

Fluoxetine 20-60mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

Nierenberg 2007^a

RCT

Outpatient

N=411

Baseline severity: More severe

Mean age (years): 43

Sex (% female): 66

Ethnicity (% BME): 21

Escitalopram 10mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

NKD20006 (NCT00048204)

RCT

Outpatient

N=250

Baseline severity: More severe

Mean age (years): 38

Sex (% female): 60

Ethnicity (% BME): NR

Paroxetine 20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Olie 1997

RCT

France

Outpatient

N=258

Baseline severity: More severe

Mean age (years): 43.8

Sex (% female): 63

Ethnicity (% BME): 1

Sertraline 50-200mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

PAR 01 001 (GSK & FDA)

RCT

Outpatient

N=50

Baseline severity: More severe

Mean age (years): 43.1

Sex (% female): 35

Ethnicity (% BME): NR

Paroxetine 10-50mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score

Response

Perahia 2006^a

RCT

Bulgaria, Croatia, Hungary, Poland, Romania, Russia, & Slovakia

Outpatient

N=196

Baseline severity: More severe

Mean age (years): 68.4

Sex (% female): 68

Ethnicity (% BME): 0

Paroxetine 20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

Peselow 1989a^a

RCT

Outpatient

N=73

Baseline severity: More severe

Mean age (years): 46.1

Sex (% female): 38

Ethnicity (% BME): NR

Paroxetine 10-50mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

Peselow 1989b^a

RCT

Outpatient

N=82

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 10-50mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

Rapaport 2009

RCT

Outpatient

N=357

Baseline severity: More severe

Mean age (years): 67.5

Sex (% female): 62

Ethnicity (% BME): 17

Paroxetine 25mg/day

Placebo

Treatment duration (weeks): 10

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Ratti 2011_study 096

RCT

11 countries in Europe and Latin America

Outpatient

N=236

Baseline severity: More severe

Mean age (years): 44

Sex (% female): 72

Ethnicity (% BME): NR

Paroxetine 20-30mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

Ravindran 1995

RCT

Canada

Outpatient

N=66

Baseline severity: More severe

Mean age (years): 38.9

Sex (% female): 62

Ethnicity (% BME): NR

Sertraline 50-200mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

Reimherr 1990

RCT

US & Canada

Outpatient

N=299

Baseline severity: More severe

Mean age (years): 39.6

Sex (% female): 53

Ethnicity (% BME): 8

Sertraline 20-200mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Rickels 1992

RCT

Outpatient

N=111

Baseline severity: More severe

Mean age (years): 44.7

Sex (% female): 48

Ethnicity (% BME): NR

Paroxetine (dose NR)

Placebo

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

Roose 2004

RCT

Outpatient

N=178

Baseline severity: More severe

Mean age (years): 79.6

Sex (% female): 58

Ethnicity (% BME): NR

Citalopram 20-40mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

Rudolph 1999^a

RCT

Outpatient

N=200

Baseline severity: More severe

Mean age (years): 40

Sex (% female): 66

Ethnicity (% BME): NR

Fluoxetine 20-60mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

SER 315 (FDA)^a

RCT

Europe

Outpatient

N=165

Baseline severity: More severe

Mean age (years): 42.0

Sex (% female): 72

Ethnicity (% BME): NR

Sertraline 50-200mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score

Smith 1992

RCT

Outpatient

N=77

Baseline severity: More severe

Mean age (years): 44.8

Sex (% female): 50

Ethnicity (% BME): NR

Paroxetine 10-50mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

Stark 1985^a

RCT

Outpatient

N=354

Baseline severity: More severe

Mean age (years): 40.5

Sex (% female): 68

Ethnicity (% BME): NR

Fluoxetine 60-80mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Study 62b (FDA)

RCT

Country NR

Outpatient

N=356

Baseline severity: More severe

Mean age (years): 40

Sex (% female): 57

Ethnicity (% BME): NR

Fluoxetine 20mg/day, 40mg/day, or 60mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score

Study F1J-MC-HMAQ – Study Group Ba

RCT

Outpatient

N=112

Baseline severity: More severe

Mean age (years): 40.8

Sex (% female): NR

Ethnicity (% BME): NR

Fluoxetine 20mg/day

Placebo

Treatment duration (weeks): 10

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Tollefson 1993/1995

RCT

Outpatient

N=671

Baseline severity: More severe

Mean age (years): 67.7

Sex (% female): 55

Ethnicity (% BME): 6

Fluoxetine maximum 20mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Valle-Cabrera 2018

RCT

Cuba

Outpatient

N=77

Baseline severity: More severe

Mean age (years): 45.2

Sex (% female): 92

Ethnicity (% BME): NR

Sertraline 50-200mg/day

Placebo

Treatment duration (weeks): 10

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

VEN XR 367 (FDA)^a

RCT

Europe

Outpatient

N=164

Baseline severity: More severe

Mean age (years): NR

Sex (% female): 61

Ethnicity (% BME): NR

Paroxetine 20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score

Wade 2002

RCT

Canada, Estonia, France, Netherlands & UK

Outpatient

N=380

Baseline severity: More severe

Mean age (years): 40.5

Sex (% female): 76

Ethnicity (% BME): 3

Escitalopram 10mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Wang 2014c

RCT

Canada, China, Finland, South Korea, Malaysia, Mexico, The Philippines, South Africa, & Spain

Outpatient

N=314

Baseline severity: More severe

Mean age (years): 40

Sex (% female): 71

Ethnicity (% BME): 46

Escitalopram 10-20mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

WELL AK1A4006

RCT

Outpatient

N=309

Baseline severity: More severe

Mean age (years): 37.9

Sex (% female): NR

Ethnicity (% BME): NR

Fluoxetine 20-60mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Wernicke 1987

RCT

Outpatient

N=356

Baseline severity: More severe

Mean age (years): 39.8

Sex (% female): 57

Ethnicity (% BME): NR

Fluoxetine 20mg/day, 40mg/day, or 60mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Wernicke 1988

RCT

Outpatient

N=267

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Fluoxetine 20mg/day or 40mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

a: Three-armed trial but where possible the demographics reported here are for only the two relevant arms.
b: Four-armed trial but where possible the demographics reported here are for only the two relevant arms
: BME: black, minority, ethnic; mg: milligrams; N: number of participants; NR: not reported; RCT: randomised controlled trial.

Table 19Summary of included studies for inpatient versus outpatient subgroup analysis for comparison 3b SSRIs versus tricyclic antidepressants (TCAs)

Study

Population

Intervention

Comparison

Comments

Inpatient setting (K=11, N=1,347)

29060/299

RCT

Europe

Inpatient

N=217

Baseline severity: More severe

Mean age (years): 40.4

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 20-50mg/day

Amitriptyline 100-250mg/day

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score

29060 07 001a

RCT

Inpatient

N=26

Baseline severity: More severe

Mean age (years): 42.3

Sex (% female): 65

Ethnicity (% BME): NR

Paroxetine 10-60mg/day

Amitriptyline (dose NR)

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score

Arminen 1992

RCT

Finland

Inpatient

N=57

Baseline severity: More severe

Mean age (years): NR

Sex (% female): 54

Ethnicity (% BME): NR

Paroxetine 20-40mg/day

Imipramine 100-200mg/day

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint

Danish University Antidepressant Group 1986

RCT

Denmark

Inpatient

N=114

Baseline severity: More severe

Mean age (years): NR

Sex (% female): 70

Ethnicity (% BME): NR

Citalopram 40mg/day

Clomipramine 150mg/day

Treatment duration (weeks): 5

Outcomes (for inpatient versus outpatient subgroup analysis):

Remission

Danish University Antidepressant Group 1990

RCT

Denmark

Inpatient

N=120

Baseline severity: More severe

Mean age (years): NR

Sex (% female): 66

Ethnicity (% BME): NR

Paroxetine 30mg/day

Clomipramine 150mg/day

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Remission

Deushle 2003

RCT

Germany

Inpatient

N=126

Baseline severity: More severe

Mean age (years): 54.1

Sex (% female): 67

Ethnicity (% BME): NR

Paroxetine 40mg/day

Amitriptyline 150mg/day

Treatment duration (weeks): 5

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score

Geretsegger 1995

RCT

Austria & Germany

Inpatient

N=91

Baseline severity: More severe

Mean age (years): 71.2

Sex (% female): 86

Ethnicity (% BME): NR

Paroxetine 20-30mg/day

Amitriptyline 100-150mg/day

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Remission
Response

Laakmann 1991

RCT

Germany

Inpatient

N=174

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Fluoxetine (dose NR)

Amitriptyline 100-200mg/day

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint

Moller 1993

RCT

Germany & Hungary

Inpatient

N=222

Baseline severity: More severe

Mean age (years): 47.1

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 30-50mg/day

Amitriptyline 150-250mg/day

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Remission
Response

Moller 1998

RCT

Germany, Hungary, & Czech Republic

Inpatient

N=160

Baseline severity: More severe

Mean age (years): 48.6

Sex (% female): 70

Ethnicity (% BME): NR

Sertraline 50-150mg/day

Amitriptyline 75-150mg/day

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Staner 1995

RCT

Belgium

Inpatient

N=40

Baseline severity: More severe

Mean age (years): 42.1

Sex (% female): 83

Ethnicity (% BME): NR

Paroxetine 30mg/day

Amitriptyline 150mg/day

Treatment duration (weeks): 5

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Response

Outpatient setting (K=40, N=5,774)

Akhondzadeh 2003

RCT

Iran

Outpatient

N=48

Baseline severity: More severe

Mean age (years): 35.8

Sex (% female): 40

Ethnicity (% BME): NR

Fluoxetine 60mg/day

Nortriptyline 150mg/day

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score

Beasley 1993b

RCT

Outpatient

N=136

Baseline severity: More severe

Mean age (years): 44.8

Sex (% female): 70

Ethnicity (% BME): 4

Fluoxetine 40-80mg/day

Amitriptyline 150-300mg/day

Treatment duration (weeks): 5

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Remission
Response

Bersani 1994

RCT

Italy

Outpatient

N=68

Baseline severity: More severe

Mean age (years): 47.1

Sex (% female): 63

Ethnicity (% BME): NR

Sertraline 50-150mg/day

Amitriptyline 50-150mg/day

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score

Bhargava 2012

RCT

India

Outpatient

N=60

Baseline severity: More severe

Mean age (years): 36.2

Sex (% female): 52

Ethnicity (% BME): NR

Sertraline 50-150mg/day

Imipramine 75-150mg/day

Treatment duration (weeks): 12

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score

Bremner 1984

RCT

Outpatient

N=40

Baseline severity: More severe

Mean age (years): 42.6

Sex (% female): 51

Ethnicity (% BME): NR

Fluoxetine 60-80mg/day

Imipramine 125-300mg/day

Treatment duration (weeks): 5

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

Byerley 1988a

RCT

Outpatient

N=66

Baseline severity: More severe

Mean age (years): 39.3

Sex (% female): 68

Ethnicity (% BME): NR

Fluoxetine 40-80mg/day

Imipramine 150-300mg/day

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Response

Christiansen 1996

RCT

Denmark

Outpatient

N=144

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 20-40mg/day

Amitriptyline 75-150mg/day

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Response

Cohn 1984b

RCT

Outpatient

N=66

Baseline severity: More severe

Mean age (years): 42

Sex (% female): NR

Ethnicity (% BME): NR

Fluoxetine (dose NR)

Imipramine (dose NR)

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint

Cohn 1990b

RCT

Outpatient N=241

Baseline severity: More severe

Mean age (years): 70.3

Sex (% female): 49

Ethnicity (% BME): NR

Sertraline 50-200mg/day

Amitriptyline 50-150mg/day

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

De Ronchi 1998

RCT

Italy

Outpatient

N=65

Baseline severity: More severe

Mean age (years): 68.9

Sex (% female): 72

Ethnicity (% BME): NR

Fluoxetine 20mg/day

Amitriptyline 50-100mg/day

Treatment duration (weeks): 10

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Response

Demyttenaere 1998

RCT

Belgium

Outpatient

N=66

Baseline severity: More severe

Mean age (years): 41.7

Sex (% female): 55

Ethnicity (% BME): NR

Fluoxetine 20mg/day

Amitriptyline 50mg/day

Treatment duration (weeks): 9

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Response

Fabre 1991

RCT

Outpatient

N=205

Baseline severity: More severe

Mean age (years): 37

Sex (% female): 57

Ethnicity (% BME): NR

Fluoxetine 40mg/day

Nortriptyline 100mg/day

Treatment duration (weeks): 5

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

Fabre 1992a

RCT

Outpatient

N=80

Baseline severity: More severe

Mean age (years): 35.4

Sex (% female): 61

Ethnicity (% BME): NR

Paroxetine 10-50mg/day

Imipramine 65-275mg/day

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score

Fawcett 1989

RCT

Outpatient

N=40

Baseline severity: More severe

Mean age (years): 42.2

Sex (% female): 65

Ethnicity (% BME): NR

Fluoxetine 20-60mg/day

Amitriptyline 50-200mg/day

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Remission
Response

Feighner 1993a

RCT

Outpatient

N=477

Baseline severity: More severe

Mean age (years): 40.1

Sex (% female): 53

Ethnicity (% BME): NR

Paroxetine 10-50mg/day

Imipramine 65-275mg/day

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Remission

Forlenza 2001

RCT

Brazil

Outpatient

N=55

Baseline severity: More severe

Mean age (years): 68.5

Sex (% female): 69

Ethnicity (% BME): NR

Sertraline 50mg/day

Imipramine 150mg/day

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Remission
Response

Freed 1999

RCT

Australia

Outpatient

N=375

Baseline severity: More severe

Mean age (years): 48

Sex (% female): 65

Ethnicity (% BME): NR

Paroxetine 20mg/day

Amitriptyline 75mg/day

Treatment duration (weeks): 9

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score

Hashemi 2012

RCT

Iran

Outpatient

N=120

Baseline severity: More severe

Mean age (years): 34.8

Sex (% female): 53

Ethnicity (% BME): NR

Fluoxetine maximum 60mg/day

Nortriptyline maximum 150mg/day

Treatment duration (weeks): 26

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score

Hutchinson 1992

RCT

Outpatient

N=90

Baseline severity: More severe

Mean age (years): 71.8

Sex (% female): 77

Ethnicity (% BME): NR

Paroxetine 30mg/day

Amitriptyline 100mg/day

Treatment duration (weeks): 26

Outcomes (for inpatient versus outpatient subgroup analysis):

Remission
Response

Kyle 1998

RCT

Outpatient

N=365

Baseline severity: More severe

Mean age (years): 73.8

Sex (% female): 73

Ethnicity (% BME): NR

Citalopram 20-40mg/day

Amitriptyline 50-100mg/day

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Remission

Laakmann 1988

RCT

Germany

Outpatient

N=128

Baseline severity: More severe

Mean age (years): NR

Sex (% female): 72

Ethnicity (% BME): NR

Fluoxetine 20-60mg/day

Amitriptyline 50-150mg/day

Treatment duration (weeks): 5

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Response

Marchesi 1998

RCT

Italy

Outpatient

N=142

Baseline severity: More severe

Mean age (years): 43.6

Sex (% female): 74

Ethnicity (% BME): NR

Fluoxetine 20mg/day

Amitriptyline 75-225mg/day

Treatment duration (weeks): 10

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Response

MDF/29060/III/07 0/88/MC

RCT

Europe

Outpatient

N=62

Baseline severity: More severe

Mean age (years): 73

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 20-30mg/day

Clomipramine 60-75mg/day

Treatment duration (weeks): 5

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Remission
Response

Moller 2000

RCT

Germany

Outpatient

N=240

Baseline severity: More severe

Mean age (years): 47.9

Sex (% female): 67

Ethnicity (% BME): NR

Sertraline 50-100mg/day

Amitriptyline 75-150mg/day

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Moon 1994

RCT

Outpatient

N=106

Baseline severity: More severe

Mean age (years): 43.7

Sex (% female): 52

Ethnicity (% BME): NR

Sertraline 50-150mg/day

Clomipramine 50-150mg/day

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

Moon 1996

RCT

Outpatient

N=138

Baseline severity: More severe

Mean age (years): 43.7

Sex (% female): 71

Ethnicity (% BME): NR

Paroxetine 20-30mg/day

Lofepramine 70-210mg/day

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Remission
Response

Ontiveros Sanchez 1998

RCT

South America

Outpatient

N=42

Baseline severity: More severe

Mean age (years): 37.6

Sex (% female): 53

Ethnicity (% BME): NR

Fluoxetine 20mg/day

Amitriptyline 150-250mg/day

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Response

PAR 29060/281

RCT

Europe

Outpatient

N=162

Baseline severity: More severe

Mean age (years): 38.8

Sex (% female): 77

Ethnicity (% BME): NR

Paroxetine 30mg/day

Amitriptyline 75-150mg/day

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint

PAR MDUK 032

RCT

Country NR

Outpatient

N=59

Baseline severity: More severe

Mean age (years): 44.4

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 20-30mg/day

Amitriptyline 100-150mg/day

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint

Peselow 1989aa

RCT

Outpatient

N=66

Baseline severity: More severe

Mean age (years): 45.9

Sex (% female): 35

Ethnicity (% BME): NR

Paroxetine 10-50mg/day

Imipramine 65-275mg/day

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

Peselow 1989ba

RCT

Outpatient

N=80

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Paroxetine 20-50mg/day

Imipramine 65-275mg/day

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

Peters 1990

RCT

Germany

Outpatient

N=102

Baseline severity: More severe

Mean age (years): 44.5

Sex (% female): 63

Ethnicity (% BME): NR

Fluoxetine 20mg/day

Amitriptyline 100mg/day

Treatment duration (weeks): 5

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Response

Preskorn 1991

RCT

Outpatient

N=61

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): 2

Fluoxetine 20-60mg/day

Amitriptyline 50-200mg/day

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score

Reimherr 1990a

RCT

US & Canada

Outpatient

N=298

Baseline severity: More severe

Mean age (years): 38.4

Sex (% female): 55

Ethnicity (% BME): 10

Sertraline 20-200mg/day

Amitriptyline 50-150mg/day

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Ropert 1989

RCT

France

Outpatient

N=143

Baseline severity: More severe

Mean age (years): 43.8

Sex (% female): 64

Ethnicity (% BME): NR

Fluoxetine 20mg/day

Clomipramine 75mg/day

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score

Rosenberg 1994

RCT

Denmark, Norway, Sweden & Finland

Outpatient

N=472

Baseline severity: More severe

Mean age (years): 47.6

Sex (% female): 69

Ethnicity (% BME): NR

Citalopram 10-30mg/day or 20-60mg/day

Imipramine 50-150mg/day

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Response

SER 315 (FDA)^a

RCT

Europe

Outpatient

N=162

Baseline severity: More severe

Mean age (years): 42.4

Sex (% female): 69

Ethnicity (% BME): NR

Sertraline 50-200mg/day

Amitriptyline 50-200mg/day

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score

Serrano-Blanco 2006

RCT

Spain

Outpatient

N=103

Baseline severity: More severe

Mean age (years): 43.5

Sex (% female): 73

Ethnicity (% BME): NR

Fluoxetine 10-40mg/day

Imipramine 25-125mg/day

Treatment duration (weeks): 24

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score

Stark 1985a

RCT

Outpatient

N=371

Baseline severity: More severe

Mean age (years): 41.0

Sex (% female): 69

Ethnicity (% BME): NR

Fluoxetine 60-80mg/day

Imipramine 100-300mg/day

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Response

Suleman 1997

RCT

Zimbabwe

Outpatient

N=30

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Fluoxetine 20mg/day

Amitriptyline 100mg/day

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score

a: Three-armed trial but where possible the demographics reported here are for only the two relevant arms.
: BME: black, minority, ethnic; mg: milligrams; N: number of participants; NR: not reported; RCT: randomised controlled trial.

Table 20Summary of included studies for inpatient versus outpatient subgroup analysis for comparison 3c Serotonin–norepinephrine reuptake inhibitors (SNRIs) versus placebo

Study

Population

Intervention

Comparison

Comments

Inpatient setting (K=2, N=283)

Guelfi 1995

RCT

France

Inpatient

N=93

Baseline severity: More severe

Mean age (years): 56

Sex (% female): 85

Ethnicity (% BME): NR

Venlafaxine 150-375mg/day

Placebo

Treatment duration (weeks): 4

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Remission

Sheehan 2009ba

RCT

Inpatient

N=190

Baseline severity: More severe

Mean age (years): 40.8

Sex (% female): 56

Ethnicity (% BME): NR

Venlafaxine 225-375mg/day

Placebo

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Remission

Outpatient setting (K=26, N=6,784)

Brannan 2005

RCT

Outpatient

N=282

Baseline severity: More severe

Mean age (years): 40.6

Sex (% female): 65

Ethnicity (% BME): 20

Duloxetine 60mg/day

Placebo 2 capsules/day

Treatment duration (weeks): 7

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Remission

Cutler 2009

RCT

Outpatient

N=308

Baseline severity: More severe

Mean age (years): 41.3

Sex (% female): 63

Ethnicity (% BME): 28

Duloxetine 60mg/day

Placebo

Treatment duration (weeks): 6

Outcome (for inpatient versus outpatient subgroup analysis):

Remission

Detke 2002a

RCT

Outpatient

N=267

Baseline severity: More severe

Mean age (years): 41

Sex (% female): 69

Ethnicity (% BME): 22

Duloxetine 60mg/day

Placebo 3 capsules/day

Treatment duration (weeks): 9

Outcome (for inpatient versus outpatient subgroup analysis):

Remission

Detke 2002b

RCT

Outpatient

N=245

Baseline severity: More severe

Mean age (years): 42.4

Sex (% female): 67

Ethnicity (% BME): 14

Duloxetine 40-60mg/day

Placebo 2-3 capsules/day

Treatment duration (weeks): 9

Outcome (for inpatient versus outpatient subgroup analysis):

Remission

Detke 2004a

RCT

Outpatient

N=281

Baseline severity: More severe

Mean age (years): 43.8

Sex (% female): 74

Ethnicity (% BME): 0

Duloxetine 80mg/day or 120mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Remission

Eli Lilly HMAT-Aa

RCT

Outpatient

N=174

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Duloxetine 80mg/day or 120mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Remission

Goldstein 2002a

RCT

Outpatient

N=140

Baseline severity: More severe

Mean age (years): 41.9

Sex (% female): 66

Ethnicity (% BME): 15

Duloxetine 40-120mg/day

Placebo

Treatment duration (weeks): 8

Outcome (for inpatient versus outpatient subgroup analysis):

Remission

Goldstein 2004a

RCT

Outpatient

N=180

Baseline severity: More severe

Mean age (years): 40.5

Sex (% female): 63

Ethnicity (% BME): 16

Duloxetine 80mg/day

Placebo

Treatment duration (weeks): 8

Outcome (for inpatient versus outpatient subgroup analysis):

Remission

Hewett 2009

RCT

Country NR

Outpatient

N=384

Baseline severity: More severe

Mean age (years): 42.2

Sex (% female): 70

Ethnicity (% BME): 3

Venlafaxine 75-150mg/day

Placebo

Treatment duration (weeks): 8

Outcome (for inpatient versus outpatient subgroup analysis):

Remission

Hewett 2010

RCT

Country NR

Outpatient

N=385

Baseline severity: More severe

Mean age (years): 44.3

Sex (% female): 68

Ethnicity (% BME): 5

Venlafaxine 75-150mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Remission

Higuchi 2016

RCT

Japan

Outpatient

N=538

Baseline severity: More severe

Mean age (years): 38.4

Sex (% female): NR

Ethnicity (% BME): 100

Venlafaxine 75mg/day or 75-225mg/day

Placebo

Treatment duration (weeks): 8

Outcome (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score

Khan 1998

RCT

Outpatient

N=403

Baseline severity: More severe

Mean age (years): 41.7

Sex (% female): 63

Ethnicity (% BME): NR

Venlafaxine 75mg/day, 150mg/day or 200mg/day

Placebo

Treatment duration (weeks): 12

Outcome (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint

Levin 2013

RCT

Outpatient

N=103

Baseline severity: More severe

Mean age (years): 35.1

Sex (% female): 26

Ethnicity (% BME): 54

Venlafaxine maximum 375mg/day

Placebo

Treatment duration (weeks): 12

Outcome (for inpatient versus outpatient subgroup analysis):

Remission

Mendels 1993

RCT

Outpatient

N=157

Baseline severity: More severe

Mean age (years): 38.5

Sex (% female): 65

Ethnicity (% BME): NR

Venlafaxine 150-200mg/day

Placebo

Treatment duration (weeks): 6

Outcome (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score

Nemeroff 2007a

RCT

Outpatient

N=204

Baseline severity: More severe

Mean age (years): 40.2

Sex (% female): 59

Ethnicity (% BME): 10

Venlafaxine 75-225mg/day

Placebo

Treatment duration (weeks): 6

Outcome (for inpatient versus outpatient subgroup analysis):

Remission

Nierenberg 2007a

RCT

Outpatient

N=410

Baseline severity: More severe

Mean age (years): 41.6

Sex (% female): 63

Ethnicity (% BME): 22

Duloxetine 60mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Remission

Perahia 2006a

RCT

Bulgaria, Croatia, Hungary, Poland, Romania, Russia, & Slovakia

Outpatient

N=295

Baseline severity: More severe

Mean age (years): 45

Sex (% female): 69

Ethnicity (% BME): 0

Duloxetine 80mg/day or 120mg/day

Placebo

Treatment duration (weeks): 8

Outcome (for inpatient versus outpatient subgroup analysis):

Remission

Raskin 2007

RCT

Outpatient

N=311

Baseline severity: More severe

Mean age (years): 72.8

Sex (% female): 59

Ethnicity (% BME): 22

Duloxetine 60mg/day

Placebo

Treatment duration (weeks): 8

Outcome (for inpatient versus outpatient subgroup analysis):

Remission

Robinson 2014

RCT

France, Mexico, Puerto Rico, & US

Outpatient

N=370

Baseline severity: More severe

Mean age (years): 72.9

Sex (% female): 63

Ethnicity (% BME): 22

Duloxetine 60mg/day

Placebo

Treatment duration (weeks): 12

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Remission

Rudolph 1999a

RCT

Outpatient

N=192

Baseline severity: More severe

Mean age (years): 40

Sex (% female): 71

Ethnicity (% BME): NR

Venlafaxine 75-225mg/day

Placebo

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Remission

Schweizer 1994a

RCT

Outpatient

N=151

Baseline severity: More severe

Mean age (years): 41.5

Sex (% female): 69

Ethnicity (% BME): NR

Venlafaxine 75-225mg/day

Placebo

Treatment duration (weeks): 6

Outcome (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score

Study F1J-MC-HMAQ-Study Group Ba

RCT

Outpatient

N=157

Baseline severity: More severe

Mean age (years): 40.6

Sex (% female): NR

Ethnicity (% BME): NR

Duloxetine 40-120mg/day

Placebo

Treatment duration (weeks): 10

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Remission

Thase 1997

RCT

Outpatient

N=197

Baseline severity: More severe

Mean age (years): 41

Sex (% female): 61

Ethnicity (% BME): NR

Venlafaxine 75-225mg/day

Placebo 1-3 capsules/day

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Remission

VEN 600A-303 (FDA)

RCT

Outpatient

N=165

Baseline severity: More severe

Mean age (years): 38.5

Sex (% female): 69

Ethnicity (% BME): NR

Venlafaxine 150-225mg/day

Placebo

Treatment duration (weeks): 6

Outcome (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score

VEN 600A-313 (FDA)

RCT

Outpatient

N=237

Baseline severity: More severe

Mean age (years): 38.4

Sex (% female): 67

Ethnicity (% BME): NR

Venlafaxine 75mg/day or 200mg/day

Placebo

Treatment duration (weeks): 6

Outcome (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score

VEN XR 367 (FDA)^a

RCT

Europe

Outpatient

N=248

Baseline severity: More severe

Mean age (years): NR

Sex (% female): 66

Ethnicity (% BME): NR

Venlafaxine 75mg/day or 150mg/day

Placebo

Treatment duration (weeks): 8

Outcome (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score

a: Three-armed trial but where possible the demographics reported here are for only the two relevant arms.
: BME: black, minority, ethnic; mg: milligrams; N: number of participants; NR: not reported; RCT: randomised controlled trial.

Table 21Summary of included studies for inpatient versus outpatient subgroup analysis for comparison 3d SNRIs versus SSRIs

Study

Population

Intervention

Comparison

Comments

Inpatient setting (K=4, N=476)

Clerc 1994

RCT

France & Belgium

Inpatient

N=68

Baseline severity: More severe

Mean age (years): 51.3

Sex (% female): 68

Ethnicity (% BME): NR

Venlafaxine 200mg/day

Fluoxetine 40mg/day

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Response

Hwang 2004

RCT

Taiwan

Inpatient

N=105

Baseline severity: More severe

Mean age (years): 65.1

Sex (% female): 58

Ethnicity (% BME): NR

Venlafaxine 75-150mg/day

Paroxetine 20-40mg/day

Treatment duration (weeks): 4

Outcome (for inpatient versus outpatient subgroup analysis):

Response

Sheehan 2009ba

RCT

Inpatient

N=194

Baseline severity: More severe

Mean age (years): 39.7

Sex (% female): 59

Ethnicity (% BME): NR

Venlafaxine 225-375mg/day

Fluoxetine 60-80mg/day

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Remission
Response

Tzanakaki 2000

RCT

Greece & Italy

Inpatient

N=109

Baseline severity: More severe

Mean age (years): 48

Sex (% female): 79

Ethnicity (% BME): NR

Venlafaxine 225mg/day

Fluoxetine 60mg/day

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Remission
Response

Outpatient setting (K=32, N=6,238)

Allard 2004

RCT

Sweden & Denmark

Outpatient

N=151

Baseline severity: More severe

Mean age (years): 73

Sex (% female): 80

Ethnicity (% BME): NR

Venlafaxine 75-150mg/day

Citalopram 10-20mg/day

Treatment duration (weeks): 22

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Remission
Response

Alves 1999

RCT

Portugal

Outpatient

N=87

Baseline severity: More severe

Mean age (years): 43.7

Sex (% female): 92

Ethnicity (% BME): NR

Venlafaxine 75-150mg/day

Fluoxetine 20-40mg/day

Treatment duration (weeks): 12

Outcomes (for inpatient versus outpatient subgroup analysis):

Remission
Response

Bielski 2004

RCT

Outpatient

N=202

Baseline severity: More severe

Mean age (years): 37.4

Sex (% female): 58

Ethnicity (% BME): 25

Venlafaxine 225mg/day

Escitalopram 20mg/day

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Remission
Response

Casabona 2004

RCT

Country NR

Outpatient

N=114

Baseline severity: More severe

Mean age (years): NR

Sex (% female): 77

Ethnicity (% BME): NR

Venlafaxine 75mg/day

Paroxetine 20mg/day

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Remission
Response

Chang 2015

RCT

Taiwan

Outpatient

N=112

Baseline severity: More severe

Mean age (years): 39.7

Sex (% female): 73

Ethnicity (% BME): NR

Venlafaxine 75-225mg/day

Fluoxetine 20-80mg/day

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score

Costa 1998

RCT

Argentina, Brazil, Chile, Colombia, Uruguay, & Venezuela

Outpatient

N=382

Baseline severity: More severe

Mean age (years): 40.2

Sex (% female): 79

Ethnicity (% BME): NR

Venlafaxine 75-150mg/day

Fluoxetine 20-40mg/day

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Remission
Response

DeNayer 2002

RCT

Belgium

Outpatient

N=146

Baseline severity: More severe

Mean age (years): 42.8

Sex (% female): 68

Ethnicity (% BME): NR

Venlafaxine 75-150mg/day

Fluoxetine 20-40mg/day

Treatment duration (weeks): 12

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Remission
Response

Detke 2004a

RCT

Outpatient

N=274

Baseline severity: More severe

Mean age (years): 43.3

Sex (% female): 72

Ethnicity (% BME): 0

Duloxetine 80mg/day or 120mg/day

Paroxetine 20mg/day

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Remission
Response

Diaz-Martinez 1998

RCT

Mexico

Outpatient

N=145

Baseline severity: More severe

Mean age (years): NR

Sex (% female): 72

Ethnicity (% BME): NR

Venlafaxine 75-150mg/day

Fluoxetine 20-40mg/day

Treatment duration (weeks): 8

Outcome (for inpatient versus outpatient subgroup analysis):

Response

Dierick 1996

RCT

Belgium, Italy, Switzerland & France

Outpatient

N=314

Baseline severity: More severe

Mean age (years): 43.4

Sex (% female): 65

Ethnicity (% BME): NR

Venlafaxine 75-150mg/day

Fluoxetine 20mg/day

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Response

Eli Lilly HMAT-Aa

RCT

Outpatient

N=173

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Duloxetine 80mg/day

Paroxetine 20mg/day

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Remission
Response

Goldstein 2002a

RCT

Outpatient

N=103

Baseline severity: More severe

Mean age (years): 41.5

Sex (% female): 61

Ethnicity (% BME): 17

Duloxetine 40-120mg/day

Fluoxetine 20mg/day

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Remission
Response

Goldstein 2004a

RCT

Outpatient

N=178

Baseline severity: More severe

Mean age (years): 40.5

Sex (% female): 63

Ethnicity (% BME): 21

Duloxetine 80mg/day

Paroxetine 20mg/day

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Remission
Response

Hackett 1996

RCT

Europe

Outpatient

N=241

Baseline severity: More severe

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Venlafaxine 150mg/day

Paroxetine (dose NR)

Treatment duration (weeks): 8

Outcome (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint

Heller 2009

RCT

Outpatient

N=29

Baseline severity: More severe

Mean age (years): 31.9

Sex (% female): 55

Ethnicity (% BME): NR

Venlafaxine 75-300mg/day

Fluoxetine 20-80mg/day

Treatment duration (weeks): 26

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score

Jiang 2017

RCT

China

Outpatient

N=26

Baseline severity: More severe

Mean age (years): 45.5

Sex (% female): 73

Ethnicity (% BME): NR

Duloxetine (dose NR)

Escitalopram (dose NR)

Treatment duration (weeks): 8

Outcome (for inpatient versus outpatient subgroup analysis):

Response

Khan 2007

RCT

Outpatient

N=278

Baseline severity: More severe

Mean age (years): 42.4

Sex (% female): 61

Ethnicity (% BME): 20

Duloxetine 60mg/day

Escitalopram 10-20mg/day

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Remission
Response

Kornaat 2000

RCT

Country NR

Outpatient

N=156

Baseline severity: More severe

Mean age (years): NR

Sex (% female): 64

Ethnicity (% BME): NR

Venlafaxine 75-225mg/day

Fluoxetine 20-40mg/day

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Remission
Response

Mehtonen 2000

RCT

Finland

Outpatient

N=147

Baseline severity: More severe

Mean age (years): 42.6

Sex (% female): 66

Ethnicity (% BME): NR

Venlafaxine 75-150mg/day

Sertraline 50-100mg/day

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Remission
Response

Montgomery 2004

RCT

Denmark, Finland, France, Germany, Ireland, Spain, & Switzerland

Outpatient

N=293

Baseline severity: More severe

Mean age (years): 48

Sex (% female): 71

Ethnicity (% BME): NR

Venlafaxine 75-150mg/day

Escitalopram 10-20mg/day

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Remission
Response

Mowla 2016

RCT

Iran

Outpatient

N=63

Baseline severity: More severe

Mean age (years): 41.2

Sex (% female): 60

Ethnicity (% BME): NR

Duloxetine 20-60mg/day

Sertraline 50-200mg/day

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score

Nemeroff 2007a

RCT

Outpatient

N=206

Baseline severity: More severe

Mean age (years): 39

Sex (% female): 65

Ethnicity (% BME): 11

Venlafaxine 75-225mg/day

Fluoxetine 20-60mg/day

Treatment duration (weeks): 6

Outcomes (for inpatient versus outpatient subgroup analysis):

Remission
Response

Nierenberg 2007a

RCT

Outpatient

N=547

Baseline severity: More severe

Mean age (years): 42.2

Sex (% female): 66

Ethnicity (% BME): 24

Duloxetine 60mg/day

Escitalopram 10mg/day

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Remission
Response

Perahia 2006a

RCT

Bulgaria, Croatia, Hungary, Poland, Romania, Russia, & Slovakia

Outpatient

N=293

Baseline severity: More severe

Mean age (years): 45.4

Sex (% female): 71

Ethnicity (% BME): 0

Duloxetine 80mg/day or 120mg/day

Paroxetine 20mg/day

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Remission
Response

Rickels 2000

RCT

Country NR

Outpatient

N=51

Baseline severity: More severe

Mean age (years): 37.4

Sex (% female): 75

Ethnicity (% BME): NR

Venlafaxine 150-225mg/day

Fluoxetine 20-40mg/day

Treatment duration (weeks): 6

Outcome (for inpatient versus outpatient subgroup analysis):

Remission

Rudolph 1999a

RCT

Outpatient

N=203

Baseline severity: More severe

Mean age (years): 40

Sex (% female): 72

Ethnicity (% BME): NR

Venlafaxine 75-225mg/day

Fluoxetine 20-60mg/day

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Remission
Response

Shelton 2006

RCT

Outpatient

N=160

Baseline severity: More severe

Mean age (years): 39.3

Sex (% female): 53

Ethnicity (% BME): 17

Venlafaxine 75-225mg/day

Sertraline 50-150mg/day

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms endpoint
Depression symptoms change score
Remission
Response

Sir 2005

RCT

Australia & Turkey

Outpatient

N=163

Baseline severity: More severe

Mean age (years): 37

Sex (% female): 69

Ethnicity (% BME): 2

Venlafaxine 75-225mg/day

Sertraline 50-150mg/day

Treatment duration (weeks): 8

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Remission
Response

Study F1J-MC-HMAQ-Study Group Ba

RCT

Outpatient

N=119

Baseline severity: More severe

Mean age (years): 39.8

Sex (% female): NR

Ethnicity (% BME): NR

Duloxetine 40-120mg/day

Fluoxetine 20mg/day

Treatment duration (weeks): 10

Outcomes (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score
Remission
Response

Tylee 1997

RCT

Outpatient

N=341

Baseline severity: More severe

Mean age (years): 44.5

Sex (% female): 71

Ethnicity (% BME): NR

Venlafaxine 75mg/day

Fluoxetine 20mg/day

Treatment duration (weeks): 12

Outcomes (for inpatient versus outpatient subgroup analysis):

Remission
Response

VEN XR 367 (FDA)^a

RCT

Europe

Outpatient

N=246

Baseline severity: More severe

Mean age (years): NR

Sex (% female): 59

Ethnicity (% BME): NR

Venlafaxine 75mg/day or 150mg/day

Paroxetine 20mg/day

Treatment duration (weeks): 8

Outcome (for inpatient versus outpatient subgroup analysis):

Depression symptoms change score

Wade 2007

RCT

Belgium, Canada, the Czech Republic, France, Germany, Italy, Spain, Sweden & UK

Outpatient

N=295

Baseline severity: More severe

Mean age (years): 43.9

Sex (% female): 72

Ethnicity (% BME): 4

Duloxetine 60mg/day

Escitalopram 20mg/day

Treatment duration (weeks): 24

Outcomes (for inpatient versus outpatient subgroup analysis):

Remission
Response

a: Three-armed trial but where possible the demographics reported here are for only the two relevant arms.
: BME: black, minority, ethnic; mg: milligrams; N: number of participants; NR: not reported; RCT: randomised controlled trial.

Table 22Summary of included studies for inpatient versus outpatient subgroup analysis for comparison 3e Mirtazapine versus TCAs

Study	Population	Intervention	Comparison	Comments
Inpatient setting (K=2, N=425)
Richou 1995 RCT France	Inpatient N=174 Baseline severity: More severe Mean age (years): 50.7 Sex (% female): 67 Ethnicity (% BME): NR	Mirtazapine 20-80mg/day	Clomipramine 50-200mg/day	Treatment duration (weeks): 6 Outcome (for inpatient versus outpatient subgroup analysis): Response
Zivkov 1995 RCT Former Yugoslavia	Inpatient N=251 Baseline severity: More severe Mean age (years): 46.9 Sex (% female): 78 Ethnicity (% BME): NR	Mirtazapine 20-60mg/day	Amitriptyline 75-225mg/day	Treatment duration (weeks): 6 Outcome (for inpatient versus outpatient subgroup analysis): Response
Outpatient setting (K=4, N=387)
Bremner 1995a RCT US	Outpatient N=100 Baseline severity: More severe Mean age (years): 39.0 Sex (% female): 67 Ethnicity (% BME): NR	Mirtazapine 5-35mg/day	Amitriptyline 40-280mg/day	Treatment duration (weeks): 6 Outcome (for inpatient versus outpatient subgroup analysis): Response
MIR 003-020 (FDA)^a RCT US	Outpatient N=87 Baseline severity: More severe Mean age (years): 43.5 Sex (% female): 45 Ethnicity (% BME): NR	Mirtazapine 5-35mg/day	Amitriptyline 40-280mg/day	Treatment duration (weeks): 6 Outcome (for inpatient versus outpatient subgroup analysis): Response
MIR 003-021 (FDA)^a RCT US	Outpatient N=100 Baseline severity: More severe Mean age (years): 44.5 Sex (% female): 55 Ethnicity (% BME): NR	Mirtazapine 5-35mg/day	Amitriptyline 40-280mg/day	Treatment duration (weeks): 6 Outcome (for inpatient versus outpatient subgroup analysis): Response
Smith 1990a RCT US	Outpatient N=100 Baseline severity: More severe Mean age (years): NR Sex (% female): NR Ethnicity (% BME): NR	Mirtazapine 10-35mg/day	Amitriptyline 80-280mg/day	Treatment duration (weeks): 6 Outcome (for inpatient versus outpatient subgroup analysis): Response

a: Three-armed trial but where possible the demographics reported here are for only the two relevant arms.
: BME: black, minority, ethnic; mg: milligrams; N: number of participants; NR: not reported; RCT: randomised controlled trial.

Table 23Summary of included studies for inpatient versus outpatient subgroup analysis for comparison 3f Acupuncture + antidepressants versus antidepressants

Study	Population	Intervention	Comparison	Comments
Inpatient setting (K=2, N=119)
Wang 2014a RCT China	Inpatient N=77 Baseline severity: More severe Mean age (years): NR Sex (% female): 72 Ethnicity (% BME): NR	Traditional acupuncture (30 sessions) + any SSRI (dose NR)	Any SSRI (dose NR)	Treatment duration (weeks): 6 Outcome (for inpatient versus outpatient subgroup analysis): Depression symptoms change score
Zhang 2007a RCT China	Inpatient N=42 Baseline severity: More severe Mean age (years): 36.8 Sex (% female): 50 Ethnicity (% BME): NR	Electroacupunctu re (36x 30-min sessions) + paroxetine 10-40mg/day	Paroxetine 10-40mg/day	Treatment duration (weeks): 6 Outcome (for inpatient versus outpatient subgroup analysis): Depression symptoms change score
Outpatient setting (K=2, N=637)
Qu 2013 RCT China	Outpatient N=160 Baseline severity: More severe Mean age (years): 33.3 Sex (% female): 59 Ethnicity (% BME): NR	Traditional acupuncture or electroacupuncture (18 sessions) + paroxetine 20-40mg/day	Paroxetine 20-40mg/day	Treatment duration (weeks): 6 Outcome (for inpatient versus outpatient subgroup analysis): Depression symptoms change score
Zhao 2019a RCT China	Outpatient N=477 Baseline severity: More severe Mean age (years): 41.5 Sex (% female): 65 Ethnicity (% BME): NR	Traditional acupuncture or electroacupuncture (18x 30-min sessions) + any SSRI (most commonly paroxetine 20mg/day)	Any SSRI (most commonly paroxetine 20mg/day)	Treatment duration (weeks): 6 Outcome (for inpatient versus outpatient subgroup analysis): Depression symptoms change score

: BME: black, minority, ethnic; mg: milligrams; N: number of participants; NR: not reported; RCT: randomised controlled trial; SSRI: selective serotonin reuptake inhibitor.

Table 24Summary of included studies for comparison 4 acute psychiatric day hospital versus inpatient care

Study

Population

Intervention

Comparison

Comments

Creed 1990

RCT

N=102

Non-psychotic severe mental illness

Diagnosis: 27% schizophrenia; 20% depression; 9% mania; 27% neurotic disorder; 9% personality disorder; 8% addiction/organic disorder

Mean age (years): 42.5

Sex (% female): 51

Ethnicity (% BME): NR

Acute day hospital care. Teaching hospital serving small socially deprived inner city area. Day hospital designed to take acute admissions because of few beds (8 nurses, 3 OTs)

Inpatient care (routine inpatient)

Duration of follow-up: 12 months

Outcomes:

Duration of index admission
Readmission at 12 months post-admission
Social functioning response at 12 months post-admission

Creed 1997

RCT

N=187

Non-psychotic severe mental illness

Diagnosis: 43% schizophrenia; 34% depression; 23% neurosis

Mean age (years): 38.0

Sex (% female): 43

Ethnicity (% BME): 18

Acute day hospital care. Teaching hospital serving small socially deprived inner city area. Day hospital designed to take acute admissions because of few beds (CPN out of hours).

Inpatient care (routine inpatient)

Duration of follow-up: 12 months

Outcomes:

Psychiatric symptom severity at 3 months post-admission
Psychiatric symptom severity at 12 months post-admission
Duration of index admission
Readmission at 12 months post-admission
Carer distress at 3 months post-admission
Carer distress at 12 months post-admission

Dick 1985

RCT

N=91

Non-psychotic severe mental illness

Diagnosis: Neurosis (56% depressive neurosis), personality disorder, or adjustment reaction

Mean age (years): ~35

Sex (% female): 68

Ethnicity (% BME): NR

Acute day hospital care. 2 trained staff + OT, patient/staff ratio: 12.5:1, individual counselling, groups, activities and medication

Inpatient care. Mixed sex and female wards

Duration of follow-up: 12 months

Outcomes:

Readmission at 4 months post-admission
Emergency contacts at 4 months post-admission
Outpatient contact at 4 months post-admission
Satisfaction at 4 months post-admission

Dinger 2014

RCT

Germany

N=44

Depression

Diagnosis: 97.7% had a major depressive episode, 2.3% had primary dysthymia

Mean age (years): 35.1

Sex (% female): 50

Ethnicity (% BME): NR

Acute day hospital care. Therapeutic staff were the same for both treatment arms. Both groups received equal amounts of psychotherapeutic interventions. Day-clinic patients attended therapy on 5 weekdays from 8 a.m. to 4 p.m. (8 weeks of treatment)

Inpatient care. Therapeutic staff were the same for both treatment arms. Both groups received equal amounts of psychotherapeutic interventions. Inpatients were free to leave the unit outside of night hours and therapy sessions and spent 6 weekends at home (8 weeks of treatment)

Duration of follow-up: 3 months

Outcomes:

Depression symptomatology at 3 months post-admission
Remission at 3 months post-admission
Response at 3 months post-admission

Kallert 2007

RCT

Germany, UK, Poland, Slovakia and Czech Republic

N=1117

Non-psychotic severe mental illness

Diagnosis: 27% schizophrenia, schizotypal, delusional, and other non-mood psychotic disorders (ICD-10 F20-F29); 41% mood [affective] disorders (ICD-10 F30-F39); 22% anxiety, dissociative, stress-related, somatoform and other non-psychotic mental disorders (ICD-10 F40-F49); 9% disorders of adult personality and behaviour (ICD-10 F60-F69)

Mean age (years): ~38

Sex (% female): 56

Ethnicity (% BME): NR

Acute day hospital care. Provided between 15 and 35 places, mean staff hours per week per treatment place ranged from 8.8 to 16.0. Staff patient ratios not reported

Inpatient care (routine inpatient)

Duration of follow-up: 14 months

Outcomes:

Psychiatric symptom severity at 2 months post-admission
Psychiatric symptom severity at 14 months post-admission
Duration of index admission
Quality of life at 2 months post-admission
Quality of life at 14 months post-admission
Social functioning at 2 months post-admission
Social functioning at 14 months post-admission
Satisfaction at 2 months post-admission

Schene 1993

RCT

Netherlands

N=222

Non-psychotic severe mental illness

Diagnosis: 21% psychosis; 38% mood disorders; 24% anxiety disorders; 10% eating disorders; 8% other

Mean age (years): 31.9

Sex (% female): 58

Ethnicity (% BME): NR

Acute day hospital care. Provided 24 places. For each day treatment patient, a 0.08 full-time equivalent social psychiatric nurse was available

Inpatient care. Open inpatient ward with 20 beds. For each inpatient, a 0.40 full-time equivalent psychiatric nurse was available

Duration of follow-up: 13 months

Outcomes:

Remission at 13 months post-admission
Duration of index admission
Social functioning response at 13 months post-admission

: BME: black, minority, ethnic; CPN: community psychiatric nurse; ICD: International Classification of Diseases; N: number of participants; NR: not reported; OT: occupational therapist; RCT: randomised controlled trial

Table 25Summary of included studies for comparison 5 non-acute day hospital versus outpatient care

Study

Population

Intervention

Comparison

Comments

Dick 1991

RCT

N=96

Depression

Diagnosis: 92% DSM-III major depressive disorder; 8% dysthymic disorder

Mean age (years): NR

Sex (% female): 75

Ethnicity (% BME): NR

Non-acute day hospital care. Places for up to 40 patients. Treatment is eclectic, with a focus on time structuring and socialisation, and a problem-orientated supportive/behavi oural rather than a psychodynamic approach. Staffing comprises three sessions per week of consultant time, three sessions per week of support medical time, three full-time trained nurses, and one full-time occupational therapist. Mean duration of day treatment was 10.7 weeks

Outpatient care. Patients allocated to continued outpatient treatment were seen approximately monthly and given advice on relaxation, anxiety management, and alternative approaches to time structuring and handling relationships

Duration of follow-up: 6 months

Outcomes:

Admission as an inpatient 6 months post-admission
Satisfaction at 6 months post-admission

Glick 1986

RCT

N=79

Non-psychotic severe mental illness

Diagnosis: 47% schizophrenia; 53% major affective disorder

Mean age (years): 35

Sex (% female): 63

Ethnicity (% BME): NR

Non-acute day hospital care. Transitional day care following inpatient admission (about 15 hours/week and limited to 6-12 weeks) involving milieu, family, supportive & group therapy, medication, care management, recreation & dance therapy, and discharge planning

Outpatient care. Outpatient follow-up post-inpatient admission involving 6-12 weeks in outpatient group therapy (90 mins/week), medication management and 24 hour crisis intervention

Duration of follow-up: 12 months

Outcomes:

Psychiatric symptom severity at 6 months post-admission
Psychiatric symptom severity at 12 months post-admission
Admission as an inpatient 12 months post-admission
Social functioning at 6 months post-admission
Social functioning at 12 months post-admission
Global functioning at 6 months post-admission
Global functioning at 12 months post-admission

Tyrer 1979

RCT

N=106

Non-psychotic severe mental illness

Diagnosis: Neurotic disorder (severe enough for day hospital treatment)

Mean age (years): NR

Sex (% female): NR

Ethnicity (% BME): NR

Non-acute day hospital care. Two different types of day hospital: one specialising in neurotic disorders (well-staffed with psychotherapeutic orientation) and the other a standard day hospital (psychiatrists, nurses, occupational & art therapists)

Outpatient care (routine outpatient)

Duration of follow-up: 24 months

Outcomes:

Psychiatric symptom severity at 4 months post-admission
Psychiatric symptom severity at 8 months post-admission
Admission as an inpatient 8 months post-admission
Social functioning at 4 months post-admission
Social functioning at 8 months post-admission
Satisfaction at 4 months post-admission

: BME: black, minority, ethnic; DSM Diagnostic and Statistical Manual of Mental Disorders; N: number of participants; NR: not reported; RCT: randomised controlled trial

Table 26Summary of included studies for comparison 6 community mental health teams versus standard care

Study

Population

Intervention

Comparison

Comments

Merson 1992

RCT

N=100

Non-psychotic severe mental illness

Diagnosis: 38% ICD-10 schizophrenia and related disorders; 32% mood disorder; 25% neurotic and stress-related disorders; 4% substance misuse; 1% personality disorder only

Mean age (years): NR (median 32)

Sex (% female): 60

Ethnicity (% BME): 32

Community mental health team (CMHT). Early intervention from a multidisciplinary community-based team, open referral, in-home assessments, collaboration maintained with already involved agencies, clinical decisions by team consensus

Standard care included conventional hospital-based psychiatric services, usually outpatient clinic assessments with occasional home visits

Duration of follow-up: 3 months

Outcomes:

Psychiatric symptom severity at 3 months post-entry
Admission as an inpatient 3 months post-entry
Admission as an inpatient for >10 days at 3 months post-entry
Satisfaction (number of participants satisfied with their treatment) at 3-months post-entry
Satisfaction (service satisfaction score) at 3-months post-entry

: BME: black, minority, ethnic; ICD: International Classification of Diseases; N: number of participants; NR: not reported; RCT: randomised controlled trial

Final

Evidence reviews underpinning recommendations 1.16.7 to 1.16.14 in the NICE guideline

Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.

Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.

NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.

Bookshelf ID: NBK583072PMID: 35977062