Further-line treatment

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Further-line treatment

Depression in adults

Evidence review D

NICE Guideline, No. 222

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

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

Further-line treatment

Review question

What are the relative benefits and harms of further-line psychological, psychosocial, pharmacological and physical interventions (alone or in combination), for adults with depression showing an inadequate response to at least one previous intervention for the current episode?

Introduction

This review was concerned with further-line treatment for those with depression, and included people with coexisting personality disorders, psychotic depression, and chronic depression. The committee recognised that these were overlapping populations in the context of further-line treatment, and agreed that a broader evidence base would more accurately reflect the complexities that may be associated with non-response to initial treatment.

Further-line treatments for depression may be required when people with depression have not responded to first-line treatments or are unable to tolerate them, and an alternative treatment is required, or in cases where people have not responded to multiple treatments.

Failure or intolerance of first-line treatment

First-line treatments for depression do not lead to remission in approximately two-thirds of people and therefore the choice of further-line treatment is a common clinical dilemma for patients and professionals. In addition, there will be people who cannot tolerate the original choice of first-line treatment, and these people will also require selection of an appropriate second-line option.

Further-line treatment strategies can include switching to a different medication or psychological therapy, switching from medication to a psychological therapy, or vice versa, using dose escalation, or using combinations of treatments. In addition, choice of second-line therapy may be informed by personal preference, although patient characteristics including previous history of treatment response, type of depressive syndrome and comorbidities can be helpful in guiding the choice.

For the people who remain depressed despite second-line treatment, the terms ‘treatment resistance’ or ‘treatment resistant depression’ (TRD) are often used.

Treatment resistant depression

Treatment resistant depression (TRD) is usually defined as a failure to respond to 2 adequate courses of antidepressants within a specified episode of depression. There does not appear to be a similarly accepted definition of failure to 2 adequate courses of psychological therapy.

Recent models of TRD (such as the Massachusetts General Hospital and the Maudsley Staging Method) consider the duration of depression, the severity of the illness and the number and types of treatments. A systematic review of all of these approaches identified that the Maudsley Staging Method had the best predictive utility in assessing resistance. However, all of these staging methods remain limited through their focus on assessing resistance to treatments within the current episode.

Recent clinical trials and functional neuroimaging studies have suggested that some types of psychotherapy may have an important place in overcoming treatment resistance, and further clarifying this role, particularly at later stages of treatment failure, may help in developing fuller models of treatment resistance and likelihood of future remission.

Alongside efforts to more clearly delineate treatment resistance there has been greater acknowledgement of so-called ‘pseudo-resistance’, where lack of response relates to misdiagnosis (for example, of bipolar depression) or under-treatment (for example, through inadequate dosage or length of treatment), rather than true treatment resistance. Understanding this problem of ‘pseudo-resistance’ (and avoiding incorrectly labelling an individual as genuinely treatment resistant) should remain a significant concern in day-to-day clinical practice in order to improve treatment outcomes.

Genuine treatment resistance has been linked to a number of demographic and illness characteristics, including: living alone; lower income; unemployment; male gender; lower education; higher complexity through associated physical or psychiatric disorder; and a longer, more severe current episode.

Several approaches to overcoming treatment resistant depression have been evaluated, including pharmacology, physical interventions and psychological therapy. Pharmacological next-step options include switching within a class of antidepressants (for example, different SSRIs); switching between different classes of antidepressants (for example, from an SSRI to a SNRI); combining different antidepressants together (for example, SSRI plus mirtazapine); or augmenting an antidepressant with an agent that is not antidepressant in its own right (for example, lithium). Given the lack of convincing superiority of one agent over another at group level, part of the therapeutic advantage of switching between antidepressants may come through ‘pharmacogenomics’, indicating the genetic factors that may make people differentially liable to the beneficial or adverse effects of particular pharmacological agents.

Evidence indicates that people continue to achieve remission when further treatment steps are used but that even with this approach around one third of people will remain treatment resistant at one year. After a period of treatment resistance there is some evidence that remission is less stable, associated with higher subsequent relapse and shorter average time to relapse, indicating over the longer term that those people who find it difficult to get well may also then find it more difficult to stay well.

The aim of this review is to identify the most effective interventions for people who have had no or limited response to previous treatment(s) for the current episode of depression, have not tolerated previous treatment(s) for the current episode of depression, or who have treatment-resistant 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 processes

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

125 RCTs were included in this review (Appelberg 2001; Baert 2010_study 2; Barbee 2011; Bauer 2009; Bauer 2013; Bauer 2019; Baumann 1996; Berman 2007; Berman 2009; Bose 2012; Carpenter 2002; Chan 2012; Cheon 2017; Chiesa 2015; Corya 2006; Dai 2019; Danielsson 2014; Doree 2007; Dornseif 1989; Dozois 2009; Dunn 1979; Dunner 2007; Durgam 2016; Earley 2018; Eisendrath 2016; El-Khalili 2010; Embling 2002; Fang 2010; Fang 2011; Fava 1994a; Fava 2002; Fava 2012/Mischoulon 2012 [1 study reported across 2 papers]; Fava 2018; Fava 2019; Ferreri 2001; Folkerts 1997; Fonagy 2015; Girlanda 2014; GlaxoSmithKline 2009; Gulrez 2012; Haghighi 2013; Ho 2014; Hobart 2018a; Hobart 2018b; Jahangard 2018; Joffe 1993; Kamijima 2013; Kamijima 2018; Kato 2018; Keitner 2009; Kennedy 2003; Kessler 2018a/2018b; Kim 2019; Kocsis 2009/Klein 2011 [1 study reported across 2 papers]; Kornstein 2008; Lavretsky 2011; Lenox-Smith 2008; Lenze 2015; Li 2009; Li 2013; Li 2015; Licht 2002; Lynch 2007_study 2; Mahmoud 2007; Mantani 2017; Marcus 2008; Mather 2002; McIntyre 2007; Mohamed 2017; Moica 2018; Mota-Pereira 2011; Mowla 2011; Mozaffari-Khosravi 2013; Murray 2010; Nakagawa 2017; Nakajima 2011; Nakao 2018; Nan 2017; Navarro 2019a; Navarro 2019b; Nemets 2002; Nierenberg 2003a; Nierenberg 2006; Ostacoli 2018; Otsuka Pharmaceutical 2015; Otsuka Pharmaceutical 2016; Papakostas 2015; Patkar 2006; Paykel 1999/Scott 2000 [1 study reported across 2 papers]; Peet 2002; Poirier 1999; Ravindran 2008a; Reeves 2008; Reynolds 2010; Rocca 2002b; Ruhe 2009; Rush 2006; Salehi 2016; Santos 2008; Schindler 2007; Schlogelhofer 2014; Schramm 2007; Schweizer 1990; Schweizer 2001; Sharma 2017; Shelton 2005; Song 2007; Souery 2011a; Souza 2016; Stein 1993; Strauss 2012; Thase 2007; Thase 2015a; Thase 2015b; Town 2017/2020; Trivedi 2006; Uebelacker 2017; Wang 2012a; Watkins 2011a; Wiles 2008; Wiles 2013/2016; Xiao 2020; Yang 2016; Yoshimura 2014; Zhang 2016). There was evidence for 67 comparisons.

The included studies are summarised in Table 2 to Table 68.

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

Excluded studies

Studies not included in this review are listed, and reasons for their exclusion are provided in appendix K.

Summary of studies included in the evidence review

Summaries of the studies that were included in this review are presented in Table 2 to Table 68.

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

Quality assessment of studies included in the evidence review

See the 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 economic literature identified 3 UK studies that assessed the cost-effectiveness of psychological interventions (Hollinghurst 2014, Phillips 2014, Scott 2003), 3 UK studies that assessed the cost-effectiveness of pharmacological interventions (Benedict 2010, Edwards 2013, Kessler 2018a/2018b) and 1 UK study that assessed the cost-effectiveness of ECT (Greenhalgh 2005) for adults with depression showing an inadequate response to at least one previous intervention for the current episode. Following the hierarchy of inclusion criteria regarding country settings, one Canadian study (Town 2017/2020) that assessed the cost-effectiveness of short term psychodynamic psychotherapy, one Swedish study (Nordström 2010), one Finnish study (Soini 2017) and 6 US studies (Malone 2007, Taneja 2012, Olgiati 2013, Singh 2017, Sussman 2017, Yoon 2018) that assessed the cost effectiveness of pharmacological interventions, and 1 US study (Ross 2018) that assessed the cost-effectiveness of ECT in adults with depression that failed to respond to previous treatment were also included in the review, because they assessed interventions or made comparisons that had not been covered in UK studies.

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

Computerised cognitive behavioural therapy with support following inadequate response to antidepressants

Phillips 2014 undertook an economic analysis alongside a RCT (N=637; for the clinical analysis, completion was 56% at 6 weeks and 36% at 12 weeks; for the cost analysis, completion rates were not reported) to estimate the cost effectiveness of computerised CBT with support (the freely available package of MoodGYM) versus attention control in adults with depression, who were already under psychotropic medication, in the UK. The perspective of the analysis was that of the NHS. Costs included hospital services (inpatient and outpatient care), community services, staff time (GP, psychiatrist, district nurse, counsellor, occupational health providers, other providers) and medication. The outcome measures were the change in Work and Social Adjustment Scale (WSAS) scores and the QALY, estimated based on EQ-5D (UK tariff). The time horizon of the analysis was 12 weeks for the outcomes and 6 weeks for costs.

The time horizon of the analysis was very short and different for costs and outcomes, with very low completion rates for outcome data both at 6 and 12 weeks. Attention control was shown to be more costly and more effective than computerised CBT. The study is characterised by inadequate reporting of results; no incremental analysis was conducted (although it is possible to conduct from reported data) and no uncertainty results were presented. Finally, it is unclear if the intervention cost (in terms of equipment and overheads required) has been considered in the analysis. Therefore, although the study is directly applicable to the UK context, it is characterised by very serious limitations and therefore was not further considered when formulating recommendations.

Cognitive therapy or cognitive behavioural therapy in addition to antidepressants versus antidepressants alone

Scott 2003 conducted a cost effectiveness analysis alongside a RCT (Paykel1999/Scott 2000; N=158) that compared cognitive therapy in addition to antidepressant therapy and clinical management versus antidepressant therapy and clinical management alone, in adults who were in an episode of major depression within the past 18 months but not in the past 2 months, and who had residual symptoms over at least 8 weeks (HAMD ≥ 8 and BDI ≥ 9). The perspective of the analysis was that of the NHS and personal social services (PSS). Healthcare cost elements consisted of interventions (cognitive therapy, medication, clinical management), inpatient care, day hospital, staff time (GP, social worker, community psychiatric nurse, therapist/counsellor), group therapy and marital therapy. National and local inpatient unit costs were used. The outcome measure was the percentage of relapses prevented. The duration of the analysis was 17 months.

Cognitive therapy in addition to antidepressants and clinical management was significantly more effective and more costly than antidepressant therapy and clinical management alone, with an Incremental Cost Effectiveness Ratio (ICER) of £7,621/additional relapse prevented (2020 prices). This figure was higher depending on the method of imputation of missing data and reached £12,425 when a complete case analysis, using 65% of participants, was conducted. The probability of cognitive therapy in addition to antidepressant being cost-effective was 0.60 and 0.80 at a willingness to pay (WTP) of £10,500 and £15,000 per relapse prevented, respectively. This probability was sensitive to the method of missing data imputation. The study is partially applicable to the NICE decision-making context as it does not use the QALY as the measure of outcome and interpretation of the results requires judgement as to whether the additional unit of benefit (prevention of one relapse) is worth the additional cost of £7,621. The study is characterised by minor limitations.

Hollinghurst 2014 conducted a cost consequence and cost-utility analysis alongside a RCT (Wiles 2013/2016; N=469) to assess the cost effectiveness of cognitive behavioural therapy (CBT) in addition to TAU versus TAU alone, in adults with major depression who had adhered to antidepressant medication for at least 6 weeks in primary care, but who continued to have significant depressive symptoms (BDI-II score ≥14 and ICD-10 diagnosis of depression), in the UK; TAU comprised GP care, including antidepressant treatment as judged appropriate by the person’s GP or a referral, as required. The time horizon of the analysis was 12 months; 3-5 year follow up data were also reported. The perspective of the cost-utility analysis was that of the NHS and PSS, with cost elements comprising intervention (CBT), medication, primary and community mental and general health care, and specialist (secondary) mental health care. National unit costs were used. A number of outcomes were assessed, such as the change in BDI-II score, response and remission rates, and the SF-12 mental and physical subscales. QALYs were estimated using the EQ-5D (UK tariff), with SF-6D ratings being used for the estimation of QALYs in a sensitivity analysis.

CBT was found to be associated with a significant increase in total NHS and PSS costs and was also significantly better than control in a number of outcomes including response, the SF-12 mental sub-scale score and the QALY, both at 12 months and at the 3-5 year follow up. At 12 months, the ICER of CBT plus TAU versus TAU alone was £17,639/QALY (2020 prices). The probability of CBT being cost-effective was 0.74 and 0.91 at the NICE lower and upper cost effectiveness threshold of £20,000 and £30,000/QALY, respectively. Results were not sensitive to a change in psychologist unit costs and to the exclusion of hospitalisation costs; in contrast, results were sensitive to estimation of QALYs using the SF-6D instead of EQ-5D, with the ICER rising at £35,045/QALY. Analysis of participants with full complete data (instead of imputation of missing data) resulted in ICER of £21,720/QALY. At the 3-5 year follow up, the ICER of CBT versus TAU dropped at £5,943/QALY (2020 prices) with the probability of CBT being cost-effective rising at 0.92 and 0.95, at the NICE lower and upper cost effectiveness threshold of £20,000 and £30,000/QALY, respectively. The study is directly applicable to the NICE decision-making context and is characterised by minor limitations.

Intensive short-term psychodynamic psychotherapy

Town 2017/2020 assessed the cost-utility of intensive short-term psychodynamic psychotherapy versus secondary care TAU, comprising community mental health teams delivering pharmacotherapy and clinical management, supportive or structured activities focused around symptom management and in some cases individual or group psychotherapy, in adults with depression who were non-remitting following at least one antidepressant treatment course, over 18 months, in Canada. The study was undertaken alongside a RCT (Town 2017/2020, N=60) and adopted a mental health payer perspective. Costs included intervention costs and other healthcare costs relating to mental health care (physician visits, inpatient and outpatient care, medication, A & D, out of pocket expenses). Two measures of outcome were used for the economic analysis: the QALY (primary measure) estimated using the SF-6D (UK tariff) and the HAMD score at 18 months (secondary measure).

Short-term psychodynamic psychotherapy was found to be dominant compared with secondary care TAU, i.e. it was both more effective (using either outcome measure) and overall less costly than its comparator. However, probabilistic analysis suggested that costs were highly skewed as short-term psychodynamic psychotherapy was found to be cost-saving only in 2.5% of iterations. The probability of short-term psychodynamic psychotherapy being cost-effective was 0.65 at a cost-effectiveness threshold of £15,000/QALY (2020 prices). When high volume service users (who apparently had been predominantly randomised to the TAU group) were removed from the analysis, short-term psychodynamic psychotherapy became more costly than its comparator, with an ICER versus TAU of £11,369/QALY. The study is partially applicable to the UK setting as it was conducted in Canada, and it was considered to have potentially serious limitations, mainly the small study sample, the narrow perspective and the highly skewed costs reported in particular for the TAU arm, which appeared to have a significant impact on the results.

Mirtazapine as an adjunct treatment to SSRIs or SNRIs

Kessler 2018a/2018b undertook a cost-utility analysis alongside a RCT (Kessler 2018a/2018b; N=480, with 75% of cost and effectiveness data available for the economic analysis) to assess the cost effectiveness of mirtazapine added to a SSRI or SNRs versus pill placebo added to a SSRI or SNRI, in adults with major depression who had used an SSRI or SNRI for at least six weeks but were still depressed, in the UK. The time horizon of the analysis was 12 months. The perspective of the cost-utility analysis was that of the NHS and PSS. Costs included mirtazapine, other medication, hospital care related to depression or mental health (inpatient care, A&E attendances, outpatient care), primary and community care (e.g. GP or nurse contacts, CBT, counselling or other talking therapies, mental health clinic, prescribed exercise programmes, NHS Direct, NHS walk-in centres), personal social services (mental health nurse home visits, occupational therapy, social worker, day centre use, etc.) National unit costs were used. The primary measure of outcome was the QALY, estimating using the 5-level EQ-5D (UK tariff).

Mirtazapine was found to be more costly and more effective than pill placebo, with an incremental net monetary benefit (INMB) of £430 (-£987 to £1,846) [completer analysis] and £99 (-£115 to £313) [imputed data analysis] in 2020 prices. The probability of mirtazapine being cost-effective was 0.69 and 0.71 at the NICE lower and upper cost effectiveness threshold of £20,000 and £30,000/QALY, respectively. The study is partially applicable to the NICE decision-making context as it used the EQ-5D-5L (and not the 3-level one) and is characterised by minor limitations.

Continuation of current pharmacological treatment (citalopram) versus switching to another antidepressant (venlafaxine, sertraline) or augmentation with bupropion

Olgiati 2013 compared the cost-effectiveness of different strategies for adults with depression that did not remit following pharmacological treatment (citalopram), comprising continuation of current treatment (citalopram), switching to sertraline or venlafaxine, or augmentation of citalopram with bupropion in the US. The study reported that both switching and augmentation strategies were more cost-effective than continuation of current treatment with citalopram. However, efficacy data for the 3 strategies were taken from different studies without using a common comparator, thus breaking randomisation rules. The study is partially applicable to the UK context and is characterised by very serious limitations; therefore, it has not been considered further when formulating recommendations.

Sertraline versus venlafaxine versus bupropion following inadequate response to previous SSRI treatment

Soini 2017 assessed the relative cost-effectiveness of a number of antidepressants (sertraline, venlafaxine, bupriopion, as well as agomelatine and votrioxetine that were not part of this review question) for adults with depression that required further treatment after inadequate response to previous treatment with SSRIs. The study was based on decision-analytic modelling and was conducted from the perspective of the Finnish health service payer. Costs included medication, GP visits, psychiatrist, psychotherapist or counsellor’s time, and hospital (psychiatric ward, outpatient visit). National unit costs were used. The source of efficacy data for the 3 interventions of interest was a RCT (Rush 2006; n=727 at level 2). The measure of outcome was the QALY, based on Finish EQ-5D ratings on the VAS scale. The time horizon of the analysis was 12 months.

According to the results, sertraline was dominated by both venlafaxine and bupropion. Bupropion was more effective and more costly than venlafaxine, with an ICER of £2,249/QALY in 2020 prices. The study is partially applicable to the UK as it was conducted in Finland, and is characterised by potentially serious limitations, including the bias introduced in the analysis, as it was funded by industry. Moreover, the analysis included two further interventions (agomelatine, vortioxertine) that were not part of the review question for this guideline (and thus were not of interest) and assessed uncertainty, in the form of probability of cost-effectiveness, after making pairwise comparisons (so that vortioxetine was compared with one intervention at a time); therefore, it was not possible to extract the uncertainty associated with the 3 interventions of interest (in terms of probability of cost-effectiveness of each intervention out of the 3) from the study.

Singh 2017 assessed the relative cost-effectiveness of sertraline, venlafaxine and bupriopion for adults with depression that required further treatment after inadequate response to previous treatment with SSRIs. The study was conducted alongside a RCT (Rush 2006; n=727) and was conducted from the perspective of the US government as a payer. Costs included medication, outpatient and A&E visits, as well as hospitalisation. National unit costs were used. Two measures of outcome were used: response and remission. The time horizon of the analysis was 9 weeks.

According to the results, there were no statistically significant differences in costs or in effects among the 3 interventions. At a cost-effectiveness threshold of £23,000 per unit of effectiveness, venlafaxine had the highest net health benefit in terms of response and a probability of being the most cost-effective option around 40%, while sertraline had the highest net health benefit in terms of remission and a probability of being the most cost-effective option of approximately 45%. The study is partially applicable to the NICE decision making-context as it was carried out in the US and did not use the QALY as the outcome measure and is characterised by potentially serious limitations, mainly due to its short time horizon.

Duloxetine versus venlafaxine versus mirtazapine following inadequate response to previous SSRI treatment

Benedict 2010 constructed an economic model to evaluate the cost effectiveness of duloxetine, venlafaxine and mirtazapine in adults with severe major depression who failed previous SSRI treatment and were referred to mental health specialists in secondary care in the UK. The duration of the analysis was 48 weeks. The analysis adopted the perspective of the Scottish NHS, with costs including medication, A&E visits, staff time (GPs, psychiatrists) and hospitalisation. Resource use estimates were based on expert opinion; national unit costs were used. The outcome measure was the QALY, based on EQ-5D ratings (UK tariff). Efficacy data were obtained from meta-analyses of RCTs, with randomisation rules possibly being broken. Duloxetine was found to dominate both venlafaxine and mirtazapine and to have a probability of being cost-effective of 0.80 at the NICE lower cost effectiveness threshold of £20,000/QALY. Although the study is directly applicable to the NICE decision-making context, it is characterised by potentially serious limitations, including the methods for meta-analysis and evidence synthesis (selective use of RCTs and synthesis that appears to have potentially broken randomisation) and the fact that it was funded by industry, which may have introduced bias in the analysis.

Escitalopram versus duloxetine versus venlafaxine following inadequate response to previous antidepressant treatment

Nordström 2010 developed an economic model to evaluate the cost effectiveness of escitalopram, duloxetine and venlafaxine in adults with major depression treated in primary care, who had had a history of treatment with another antidepressant within the previous 6 months, in Sweden. The time horizon of the analysis was 6 months. The analysis adopted a societal perspective but healthcare costs were reported separately and included medication, staff time (GP, psychiatrist, other doctors e.g. neurologist, cardiologist, psychotherapist, counsellor, psychologist, nurse), hospitalisation and treatment of side effects. Resource use estimates were based on a cohort study conducted in 56 primary care centres in Sweden over 6 months; national unit costs were used. The outcome measure was the probability of remission (defined as a MADRS total score ≤ 12) achieved after 8 weeks of treatment and sustained until the end of 6 months; and the QALY estimated based on EQ-5D ratings (UK tariff). Efficacy data were derived from pooled analysis of trial data, including only participants who had already received antidepressant therapy prior to randomisation; data for duloxetine and venlafaxine were pooled together. Considering only healthcare costs, escitalopram was found to dominate both duloxetine and venlafaxine and to have a probability of being cost-effective of more than 0.98 at the NICE lower cost effectiveness threshold of £20,000/QALY. The study is only partially applicable to the NICE decision-making context and is characterised by potentially serious limitations, including the methods for evidence synthesis (selective use of RCTs and data pooling for two of the assessed interventions) and the fact that it was funded by industry, which may have introduced bias in the analysis.

Generic SSRIs (citalopram, fluoxetine, paroxetine) versus escitalopram versus paroxetine controlled release versus sertraline versus venlafaxine following inadequate response to previous SSRI treatment

Malone 2007 compared different SSRIs (including escitalopram, paroxetine controlled release, sertraline and venlafaxine) in adults with major depression who failed to achieve remission with previous treatment with SSRIs in the US. Efficacy estimates were based on a review of published trial data and further assumptions; evidence synthesis was done by naïve addition of efficacy data, leading to breaking of randomisation rules. Paroxetine controlled release and sertraline were found to be dominated by other SSRIs. Results for other SSRIs and ICERs are difficult to interpret, as the measure of outcome was the probability of response and not the QALY. The study was funded by industry, which may have introduced further bias to the analysis. The study is partially applicable to the UK context and is characterised by very serious limitations. Therefore, it has not been considered further when formulating recommendations.

Atypical antipsychotics adjunct to a SSRI versus lithium adjunct to a SSRI

Edwards 2013 developed an economic model to assess the cost-utility of atypical antipsychotics versus lithium, both as adjuncts to an SSRI, for the treatment of adults with treatment-resistant depression (defined as failure to respond to at least 2 previous antidepressants in the current episode of depression) in the UK. The study adopted a NHS and PSS perspective and considered medication costs, healthcare professional time (GP, community mental health teams, crisis resolution and home treatment teams), hospitalisation and monitoring (laboratory testing) costs. Efficacy data were taken from a systematic review and network meta-analysis that enabled an indirect comparison between the two interventions, using 6 RCTs comparing olanzapine plus fluoxetine versus fluoxetine alone in people with treatment-resistant depression and 1 RCT comparing lithium plus fluoxetine versus fluoxetine alone in people who had failed at least one antidepressant; a common class effect was assumed for SSRIs and also for antipsychotics. Data on lithium as adjunct to an SSRI were taken from a population that had failed to respond to one previous SSRI (and not from people with treatment-resistant depression) due to lack of more relevant data. In order to estimate the effect of each intervention, a fixed baseline MADRS score was assumed for both arms; the change in MADRS scores at endpoint was assumed to have a normal distribution, which was used to estimate proportions of people in the remission, response and no response states.

Resource use estimates were mainly based on clinical expert opinion, with the exception of the length of hospitalisation, which was based on national hospital episode statistics. In order to estimate medication costs in each arm of the model, it was assumed, based on expert advice, that antipsychotic use comprised 30% aripiprazole, 30% olanzapine, 20% quetiapine, and 20% risperidone; and SSRI use comprised 20% citalopram, 20% escitalopram, 30% fluoxetine, and 30% sertraline. The study utilised national unit costs. The outcome measure was the QALY estimated based on EQ-5D ratings (UK tariff). The time horizon of the analysis was 12 months.

Augmentation of SSRIs with lithium was found to dominate augmentation of SSRIs with an atypical antipsychotic; the probability of lithium being dominant versus antipsychotics (both as adjuncts to an SSRI) was 1. Results were sensitive to the efficacy of augmentation strategies and discontinuation rates; they were robust under different assumptions regarding resource use, as well as under changes in remission and relapse risk at follow-up. The study is directly applicable to the UK context and is characterised by potentially serious limitations, comprising mainly the source of efficacy data (i.e. the lack of evidence on treatment-resistant depression treated with lithium as an adjunct on a SSRI), the assumptions made around baseline and endpoint MADRS scores, and the fact that all resource use was based on expert opinion.

Aripiprazole adjunct to an antidepressant versus bupropion adjunct to antidepressant versus switching to bupropion

Yoon 2018 assessed the cost-effectiveness of aripiprazole adjunct to an antidepressant versus bupropion adjunct to an antidepressant versus switching to bupropion in adult veterans with treatment-resistant depression defined as failure to respond to at least 2 previous antidepressants in the current episode of depression. The economic study was conducted alongside a RCT (Mohamed 2017; N=1522, completers n=1131). The study used a healthcare perspective and included medication and mental health (inpatient, outpatient) costs. Unit costs were based on national sources. The outcome measures were remission, defined as QIDS-C score of ≤5 in 2 consecutive follow-up visits; and the QALY, estimated using EQ-5D. No further details on the use of EQ-5D were reported (e.g. whether the VAS value or a utility value was used; if the latter, which country’s tariff was used). The time horizon of the analysis was 12 weeks.

Aripiprazole was found to be the most effective in terms of remission and the most costly among the 3 options; QALYs were very similar across the 3 options. Using the remission outcome, switching to bupropion was dominated by bupropion adjunct. The ICER of aripiprazole adjunct vs bupropion adjunct was £3,791/ remission (2020 prices). Using the QALY as the outcome, the ICER of aripiprazole adjunct vs bupropion switch was £348,428/QALY; the ICER of bupropion switch vs bupropion adjunct was £21,614/QALY. At a cost-effectiveness threshold of £15,000/remission, the probability of cost-effectiveness was 76% for aripiprazole adjunct, 23% for bupropion adjunct and only 1% for bupropion switch. The study is partially applicable to the UK context as it was conducted in the UK and is characterised by potentially serious limitations, including its short time horizon, the unclear method of estimation of QALYs from EQ-5D, and the potential conflicts of interest due to relations with pharmaceutical industry.

Various antipsychotics adjunct to antidepressants versus antidepressant treatment alone

Taneja 2012 compared the cost-effectiveness of different antipsychotics (aripiprazole, quetiapine and olanzapine) as adjuncts to antidepressants versus antidepressant treatment alone, in adults with major depression who had responded inadequately to previous antidepressant therapy in the US, from a healthcare perspective, using decision-analytic modellling. The measure of outcome was response. Efficacy data were derived from a meta-analysis of published phase III clinical trials and indirect comparison using placebo as baseline comparator. The time horizon was too short (only 6 weeks) to allow assessment of the cost effectiveness of interventions over the duration of the depressive episode; moreover, the study was funded by industry, which may have introduced additional bias in the analysis. The study is partially applicable to the UK context and is characterised by very serious limitations (as the time horizon was not adequate to measure effects) and was therefore not considered further.

Sussman 2017 also compared the cost-effectiveness of different antipsychotics (brexpiprazole, quetiapine 150 and 300mg/day, olanzapine/fluoxetine) as adjuncts to antidepressants versus antidepressant treatment alone, in adults with major depression who had responded inadequately to previous antidepressant therapy in the US, from a payer’s perspective, using decision-analytic modelling. The measures of outcome were response and remission. Efficacy data were derived from various trials and meta-analyses, using indirect comparisons for evidence synthesis. The time horizon was 48 weeks. The study found that quetiapine was dominated by olanzapine/fluoxetine. Brexpiprazole was the most effective and most costly intervention. Its ICER versus olanzapine/fluoxetine was £36,619/responder and £53,969/remitter. The ICER of olanzapine/fluoxetine versus antidepressants alone was £8,053/responder and £9,986/remitter (2020 prices). The study is partially applicable to the UK context and is characterised by potentially serious limitations, mainly that is was funded by industry, which may have introduced bias in the analysis.

ECT versus TCAs, SSRIs, SNRIs and lithium augmentation

Greenhalgh 2005 developed an economic model to assess the cost effectiveness of electroconvulsive therapy (ECT) compared with various pharmacological treatments such as TCAs, SSRIs, SNRIs and lithium augmentation in adults with major depressive disorder who require hospitalisation. The interventions assessed in the analysis were combined in 8 strategies of 3 lines of therapy and maintenance therapy following ECT, which mostly comprised SSRIs. Efficacy data were taken from a systematic literature review of RCTs and published meta-analyses, and further assumptions. No harms were modelled for any of the modelled interventions (in terms of costs or outcomes), although early treatment discontinuation (for any reason) was considered in the model structure (however, this was not assumed to have any effect on health-related quality of life).

The perspective of the analysis was that of the NHS. Costs included intervention (ECT, medication), hospitalisation, continued care for non-responders (nursing home placement with psychiatric provision), and maintenance treatment (laboratory testing, contacts with GP, psychiatrist and psychiatric nurse). Resource use data were based on published literature and expert opinion. The outcome measure was the QALY, estimated based on preferences for vignettes using the McSad health state classification system valued by service users with previous depression in Canada. The time horizon of the analysis was 12 months.

The most effective and cost-effective strategy appeared to be a sequence of ECT – SSRI – lithium augmentation, which had an ICER versus a sequence of SNRI – ECT – lithium augmentation of £10,082/QALY (2020 prices). All other strategies were dominated. Results were modestly sensitive to use of alternative utility values and robust to small changes in costs and suicide rates. The study is partially applicable to the NICE decision-making context as the method of generation of QALYs was not consistent with NICE recommendations and is characterised by potentially serious limitations, including the assumptions made in clinical and cost input parameters and the lack of consideration of any intervention harms.

Ross 2018 also constructed an economic model to assess the cost effectiveness of ECT being used as 1^st-6^th line treatment following 0-5 lines of pharmacological and/or psychological treatment, compared with no ECT (antidepressants and/or psychological treatment alone) in people with treatment-resistant depression in the UK. Efficacy data were taken from meta-analyses, RCTs, observational studies and further assumptions. No comparative data between ECT and pharmacotherapy/psychotherapy were utilised in the analysis and no evidence synthesis of available data was undertaken. The perspective of the analysis was that of the healthcare system. Costs included ECT, medication, outpatient and inpatient care, and laboratory testing. Resource use data were based on published literature. The outcome measure was the QALY, estimated using published utility data that had, in turn, been estimated using the EQ-5D (UK tariff). The time horizon of the analysis was 4 years. The study is partially applicable to the NICE decision-making context as the method of generation of QALYs was not consistent with NICE recommendations and is characterised by very serious limitations, as no comparative data between ECT and pharmacotherapy/psychotherapy seem to have been utilised in the analysis and no evidence synthesis of available data was undertaken. Therefore this study was not considered further.

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. Augmenting with cognitive and cognitive behavioural therapies versus continuing with antidepressant (+/ waitlist or attention-placebo)

Critical outcomes

Depression symptomatology

Very low quality evidence from 13 RCTs (N=1224) shows a clinically important and statistically significant benefit of augmenting antidepressants with cognitive and cognitive behavioural therapies, relative to continuing with antidepressants-only or augmenting with waitlist or attention-placebo, on depression symptomatology at endpoint for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Very low quality evidence from 10 RCTs (N=524) shows a clinically important and statistically significant benefit of augmenting antidepressants with cognitive and cognitive behavioural therapies, relative to continuing with antidepressants-only or augmenting with waitlist or attention-placebo, on depression symptomatology change from baseline to endpoint for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Moderate quality evidence from 2 RCTs (N=123) shows a clinically important and statistically significant benefit of augmenting antidepressants with cognitive and cognitive behavioural therapies, relative to continuing with antidepressants-only or augmenting with attention-placebo, on depression symptomatology at 2-3 month follow-up for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Low quality evidence from 5 RCTs (N=696) shows a clinically important and statistically significant benefit of augmenting antidepressants with cognitive and cognitive behavioural therapies, relative to continuing with antidepressants-only or augmenting with waitlist or attention-placebo, on depression symptomatology at 4-6 month follow-up for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Very low quality evidence from 2 RCTs (N=238) shows neither a clinically important nor statistically significant effect of augmenting antidepressants with individual CBT, relative to continuing with antidepressants-only, on depression symptomatology at 11-12 month follow-up for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Low quality evidence from 1 RCT (N=248) shows a statistically significant but not clinically important benefit of augmenting antidepressants with individual CBT, relative to continuing with antidepressants-only, on depression symptomatology at 40-month follow-up for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Remission

Moderate quality evidence from 8 RCTs (N=1293) shows a clinically important and statistically significant benefit of augmenting antidepressants with cognitive and cognitive behavioural therapies, relative to continuing with antidepressants-only or augmenting with waitlist or attention-placebo, on the rate of remission for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Moderate quality evidence from 1 RCT (N=80) shows a clinically important but not statistically significant benefit of augmenting antidepressants with individual CBT, relative to continuing with antidepressants-only, on the rate of remission at 3-month follow-up for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Moderate quality evidence from 2 RCTs (N=549) shows a clinically important and statistically significant benefit of augmenting antidepressants with individual CBT relative to continuing with antidepressants-only on the rate of remission at 6-month follow-up for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Moderate quality evidence from 1 RCT (N=80) shows a clinically important and statistically significant benefit of augmenting antidepressants with individual CBT, relative to continuing with antidepressants-only, on the rate of remission at 12-month follow-up for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Low quality evidence from 1 RCT (N=469) shows a clinically important and statistically significant benefit of augmenting antidepressants with individual CBT, relative to continuing with antidepressants-only, on the rate of remission at 40-month follow-up for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Response

Moderate quality evidence from 6 RCTs (N=829) shows a clinically important and statistically significant benefit of augmenting antidepressants with cognitive and cognitive behavioural therapies, relative to continuing with antidepressants-only or augmenting with waitlist or attention-placebo, on the rate of response for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Moderate quality evidence from 1 RCT (N=80) shows a clinically important and statistically significant benefit of augmenting antidepressants with individual CBT, relative to continuing with antidepressants-only, on the rate of response at 3-month follow-up for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Moderate quality evidence from 2 RCTs (N=549) shows a clinically important and statistically significant benefit of augmenting antidepressants with individual CBT relative to continuing with antidepressants-only on the rate of response at 6-month follow-up for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Moderate quality evidence from 1 RCT (N=80) shows a clinically important and statistically significant benefit of augmenting antidepressants with individual CBT, relative to continuing with antidepressants-only, on the rate of response at 12-month follow-up for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Moderate quality evidence from 1 RCT (N=469) shows a clinically important and statistically significant benefit of augmenting antidepressants with individual CBT, relative to continuing with antidepressants-only, on the rate of response at 40-month follow-up for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to any reason

Moderate quality evidence from 13 RCTs (N=1494) shows neither a clinically important nor statistically significant effect on the number of participants who discontinued for any reason of augmenting antidepressants with cognitive and cognitive behavioural therapies, relative to continuing with antidepressants-only or augmenting with waitlist or attention-placebo, for the further-line treatment of depression

Discontinuation due to side effects

Low quality evidence from 1 RCT (N=296) shows lower discontinuation due to side effects for participants receiving combined cognitive behavioural analysis system of psychotherapy (CBASP) and antidepressant treatment relative to antidepressants-only for the further-line treatment of depression, however this effect is not statistically significant

Important outcomes

Quality of life

Low quality evidence from 1 RCT (N=40) shows neither a clinically important nor statistically significant effect of augmenting antidepressants with a blended computerised and face-to-face CBT intervention, relative to waitlist and antidepressants, on quality of life at endpoint for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Moderate to low quality evidence from 3 RCTs (N=530) shows neither clinically important nor statistically significant effects of augmenting antidepressants with cognitive and cognitive behavioural therapies, relative to continuing with antidepressants-only or antidepressants and waitlist, on quality of life physical and mental component scores for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
High to moderate quality evidence from 1 RCT (N=80) shows neither clinically important nor statistically significant effects of augmenting antidepressants with individual CBT, relative to continuing with antidepressants-only, on quality of life physical and mental component scores at 3-month follow-up and 12-month follow-up for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Very low quality evidence from 2 RCTs (N=469) shows neither clinically important nor statistically significant effects of augmenting antidepressants with individual CBT, relative to continuing with antidepressants-only, on quality of life physical and mental component scores at 6-month follow-up for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Moderate quality evidence from 1 RCT (N=242) shows neither a clinically important nor statistically significant effect of augmenting antidepressants with individual CBT, relative to continuing with antidepressants-only, on quality of life physical component score at 40-month follow-up for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Low quality evidence from 1 RCT (N=242) shows a statistically significant but not clinically important benefit of augmenting antidepressants with individual CBT, relative to continuing with antidepressants-only, on quality of life mental component score at 40-month follow-up for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Personal, social, and occupational functioning

Low quality evidence from 2 RCTs (N=405) shows a statistically significant but not clinically important benefit of augmenting antidepressants with cognitive and cognitive behavioural therapies, relative to continuing with antidepressants-only, on functional impairment for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Moderate quality evidence from 1 RCT (N=158) shows neither a clinically important nor statistically significant effect of augmenting antidepressants with individual CBT, relative to continuing with antidepressants-only, on functional impairment at 11-month follow-up for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Comparison 2. Augmenting with cognitive and cognitive behavioural therapies versus augmenting with counselling

Critical outcomes

Depression symptomatology

High quality evidence from 1 RCT (N=342) shows neither a clinically important nor statistically significant difference between augmenting antidepressant treatment with cognitive behavioural analysis system of psychotherapy (CBASP) relative to brief supportive psychotherapy, on depression symptomatology at endpoint for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Remission

Moderate quality evidence from 1 RCT (N=395) shows a clinically important but not statistically significant benefit of augmenting antidepressant treatment with cognitive behavioural analysis system of psychotherapy (CBASP), relative to brief supportive psychotherapy, on the rate of remission for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Response

No evidence was identified for this outcome.

Discontinuation due to any reason

Low quality evidence from 1 RCT (N=395) shows neither a clinically important nor statistically significant difference between augmenting antidepressant treatment with cognitive behavioural analysis system of psychotherapy (CBASP) relative to brief supportive psychotherapy, on the rate of discontinuation for any reason, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to side effects

Low quality evidence from 1 RCT (N=395) shows a clinically important but not statistically significant benefit of augmenting antidepressant treatment with brief supportive psychotherapy, relative to cognitive behavioural analysis system of psychotherapy (CBASP), on the rate of discontinuation due to side effects for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

High quality evidence from 1 RCT (N=334) shows neither a clinically important nor statistically significant difference between augmenting antidepressant treatment with cognitive behavioural analysis system of psychotherapy (CBASP) relative to brief supportive psychotherapy, on functional impairment for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Comparison 3. Augmenting with counselling versus continuing with antidepressant

Critical outcomes

Depression symptomatology

High quality evidence from 1 RCT (N=244) shows neither a clinically important nor statistically significant effect of augmenting antidepressant treatment with brief supportive psychotherapy, relative to continuing with antidepressants-only, on depression symptomatology at endpoint for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Remission

Moderate quality evidence from 1 RCT (N=291) shows neither a clinically important nor statistically significant effect of augmenting antidepressant treatment with brief supportive psychotherapy, relative to continuing with antidepressants-only, on the rate of remission for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Response

No evidence was identified for this outcome.

Discontinuation due to any reason

Low quality evidence from 1 RCT (N=291) shows neither a clinically important nor statistically significant effect of augmenting antidepressant treatment with brief supportive psychotherapy, relative to continuing with antidepressants-only, on the rate of discontinuation due to any reason for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to side effects

Low quality evidence from 1 RCT (N=291) shows a clinically important but not statistically significant benefit of augmenting antidepressant treatment with brief supportive psychotherapy, relative to continuing with antidepressants-only, on the rate of discontinuation due to side effects for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

High quality evidence from 1 RCT (N=237) shows neither a clinically important nor statistically significant effect of augmenting antidepressant treatment with brief supportive psychotherapy, relative to continuing with antidepressants-only, on functional impairment for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Comparison 4. Augmenting with IPT versus continuing with antidepressant

Critical outcomes

Depression symptomatology

Low quality evidence from 2 RCTs (N=158) shows a statistically significant but not clinically important benefit of augmenting antidepressant treatment with IPT, relative to continuing with antidepressants-only, on depression symptomatology at endpoint for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Low quality evidence from 3 RCTs (N=212) shows a clinically important and statistically significant benefit of augmenting antidepressant treatment with IPT, relative to continuing with antidepressants-only, on depression symptomatology change from baseline to endpoint for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Low quality evidence from 2 RCTs (N=131) shows neither a clinically important nor statistically significant effect of augmenting antidepressant treatment with IPT, relative to continuing with antidepressants-only, on depression symptomatology at 1-3 month follow-up for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Low quality evidence from 1 RCT (N=97) shows a clinically important and statistically significant benefit of augmenting antidepressant treatment with IPT, relative to continuing with antidepressants-only, on depression symptomatology at 12-month follow-up for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Remission

Low quality evidence from 4 RCTs (N=358) shows a clinically important and statistically significant benefit of augmenting antidepressant treatment with IPT, relative to continuing with antidepressants-only, on the rate of remission for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Response

Low quality evidence from 3 RCTs (N=234) shows a clinically important and statistically significant benefit of augmenting antidepressant treatment with IPT, relative to continuing with antidepressants-only, on the rate of response for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to any reason

Low quality evidence from 4 RCTs (N=358) shows higher discontinuation due to any reason with combined IPT and antidepressant treatment relative to continuing with antidepressants-only for the further-line treatment of depression, however this effect is not statistically significant

Discontinuation due to side effects

No evidence was identified for this outcome.

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

Low quality evidence from 1 RCT (N=124) shows neither a clinically important nor statistically significant effect of augmenting antidepressant treatment with IPT, relative to continuing with antidepressants-only, on global functioning for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Low quality evidence from 1 RCT (N=97) shows statistically significant but not clinically important benefits of augmenting antidepressant treatment with IPT, relative to continuing with antidepressants-only, on global functioning at 3-month and 12-month follow-up for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Comparison 5. Augmenting with short-term psychodynamic psychotherapy versus continuing with antidepressant

Critical outcomes

Depression symptomatology

Moderate quality evidence from 1 RCT (N=60) shows a clinically important and statistically significant benefit of augmenting antidepressant treatment with intensive short-term dynamic psychotherapy, relative to continuing with antidepressants-only, on depression symptomatology at endpoint, and on change from baseline to endpoint, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Moderate quality evidence from 1 RCT (N=60) shows a clinically important and statistically significant benefit of augmenting antidepressant treatment with intensive short-term dynamic psychotherapy, relative to continuing with antidepressants-only, on depression symptomatology at 3-month, 6-month and 12-month follow-up for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Remission

High quality evidence from 1 RCT (N=60) shows a clinically important and statistically significant benefit of augmenting antidepressant treatment with intensive short-term dynamic psychotherapy, relative to continuing with antidepressants-only, on the rate of remission for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Low quality evidence from 1 RCT (N=60) shows a clinically important but not statistically significant benefit of augmenting antidepressant treatment with intensive short-term dynamic psychotherapy, relative to continuing with antidepressants-only, on the rate of remission at 12-month follow-up for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Response

Low quality evidence from 1 RCT (N=60) shows a clinically important but not statistically significant benefit of augmenting antidepressant treatment with intensive short-term dynamic psychotherapy, relative to continuing with antidepressants-only, on the rate of response at 12-month follow-up for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to any reason

Low quality evidence from 1 RCT (N=60) shows higher discontinuation due to any reason with combined intensive short-term dynamic psychotherapy and antidepressant treatment relative to continuing with antidepressants-only for the further-line treatment of depression, however this effect is not statistically significant

Discontinuation due to side effects

No evidence was identified for this outcome.

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 6. Augmenting with long-term psychodynamic psychotherapy versus continuing with antidepressant

Critical outcomes

Depression symptomatology

Very low quality evidence from 1 RCT (N=99) shows neither a clinically important nor statistically significant effect of augmenting antidepressant treatment with long-term psychodynamic psychotherapy, relative to continuing with antidepressants-only, on depression symptomatology at endpoint for adults with depression who have shown an inadequate response to at least 2 previous treatments for the current episode
Very low quality evidence from 1 RCT (N=96-98) shows neither a clinically important nor statistically significant effect of augmenting antidepressant treatment with long-term psychodynamic psychotherapy, relative to continuing with antidepressants-only, on depression symptomatology at 6-month or 12-month follow-up for adults with depression who have shown an inadequate response to at least 2 previous treatments for the current episode
Very low quality evidence from 1 RCT (N=92) shows a clinically important and statistically significant benefit of augmenting antidepressant treatment with long-term psychodynamic psychotherapy, relative to continuing with antidepressants-only, on depression symptomatology at 2-year follow-up for adults with depression who have shown an inadequate response to at least 2 previous treatments for the current episode

Remission

Very low quality evidence from 1 RCT (N=129) shows a clinically important but not statistically significant benefit of augmenting antidepressant treatment with long-term psychodynamic psychotherapy, relative to continuing with antidepressants-only, on the rate of remission for adults with depression who have shown an inadequate response to at least 2 previous treatments for the current episode
Very low quality evidence from 1 RCT (N=129) shows a clinically important but not statistically significant benefit of augmenting antidepressant treatment with long-term psychodynamic psychotherapy, relative to continuing with antidepressants-only, on the rate of remission at 2-year follow-up for adults with depression who have shown an inadequate response to at least 2 previous treatments for the current episode

Response

No evidence was identified for this outcome.

Discontinuation due to any reason

Very low quality evidence from 1 RCT (N=129) shows neither a clinically important nor statistically significant effect of augmenting antidepressant treatment with long-term psychodynamic psychotherapy, relative to continuing with antidepressants-only, on the rate of discontinuation due to any reason for adults with depression who have shown an inadequate response to at least 2 previous treatments for the current episode

Discontinuation due to side effects

No evidence was identified for this outcome.

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 7. Augmenting with self-help versus continuing with the antidepressant (+/− attention-placebo)

Critical outcomes

Depression symptomatology

Moderate quality evidence from 3 RCTs (N=157) shows neither a clinically important nor statistically significant effect of augmenting antidepressants with a self-help intervention, relative to continuing with antidepressants-only or augmenting with attention-placebo, on depression symptomatology at endpoint for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Moderate quality evidence from 3 RCTs (N=157) shows a statistically significant but not clinically important benefit of augmenting antidepressants with a self-help intervention, relative to continuing with antidepressants-only or augmenting with attention-placebo, on depression symptomatology change from baseline to endpoint for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Moderate quality evidence from 1 RCT (N=32) shows a clinically important and statistically significant benefit of augmenting antidepressants with attentional bias training, relative to augmenting with attention-placebo, on depression symptomatology at 1-month follow-up for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Remission

No evidence was identified for this outcome.

Response

No evidence was identified for this outcome.

Discontinuation due to any reason

Low quality evidence from 2 RCTs (N=130) shows higher discontinuation due to any reason with combined self-help and antidepressant treatment, relative to continuing with antidepressants-only or combined attention-placebo and antidepressant treatment for the further-line treatment of depression, however this effect is not statistically significant

Discontinuation due to side effects

No evidence was identified for this outcome.

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 8. Augmenting with self-help and switching to SSRI versus switching to SSRI-only

Critical outcomes

Depression symptomatology

Low to very low quality evidence from 1 RCT (N=164) shows a clinically important and statistically significant benefit of switching to SSRI and augmenting with computerised CBT, relative to switching to SSRI-only, on depression symptomatology at endpoint, and change from baseline to endpoint, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Remission

Very low quality evidence from 1 RCT (N=164) shows a clinically important but not statistically significant benefit of switching to SSRI and augmenting with computerised CBT, relative to switching to SSRI-only, on the rate of remission for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Response

Very low quality evidence from 1 RCT (N=164) shows a clinically important and statistically significant benefit of switching to SSRI and augmenting with computerised CBT, relative to switching to SSRI-only, on the rate of response for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to any reason

Very low quality evidence from 1 RCT (N=164) shows higher discontinuation due to any reason with combined SSRI switch and computerised CBT augmentation relative to switch to SSRI-only for the further-line treatment of depression, however this effect is not statistically significant

Discontinuation due to side effects

No evidence was identified for this outcome.

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 9. Augmenting with art therapy versus attention-placebo

Critical outcomes

Depression symptomatology

Moderate to low quality evidence from 1 RCT (N=100) shows a clinically important and statistically significant benefit of augmenting antidepressant treatment with clay art therapy, relative to augmenting with attention-placebo, on depression symptomatology (at endpoint, and change from baseline to endpoint) for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Remission

No evidence was identified for this outcome.

Response

No evidence was identified for this outcome.

Discontinuation due to any reason

Very low quality evidence from 1 RCT (N=106) shows lower discontinuation due to any reason with combined clay art therapy and antidepressant treatment relative to attention-placebo augmentation for the further-line treatment of depression, however this effect is not statistically significant

Discontinuation due to side effects

No evidence was identified for this outcome.

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 10. Augmenting with eye movement desensitization reprocessing (EMDR) versus augmenting with cognitive behavioural therapy

Critical outcomes

Depression symptomatology

Very low quality evidence from 1 RCT (N=66) shows a clinically important and statistically significant benefit of augmenting antidepressant treatment with eye movement desensitization reprocessing (EMDR), relative to augmenting with individual CBT, on depression symptomatology at endpoint for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Remission

Very low quality evidence from 1 RCT (N=82) shows a clinically important but not statistically significant benefit of augmenting antidepressant treatment with eye movement desensitization reprocessing (EMDR), relative to augmenting with individual CBT, on the rate of remission for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Very low quality evidence from 1 RCT (N=82) shows neither a clinically important nor statistically significant difference between augmenting antidepressant treatment with eye movement desensitization reprocessing (EMDR) relative to individual CBT, on the rate of remission at 6-month follow-up for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Response

No evidence was identified for this outcome.

Discontinuation due to any reason

Very low quality evidence from 1 RCT (N=82) shows higher discontinuation due to any reason with combined eye movement desensitization reprocessing (EMDR) and antidepressant treatment relative to individual CBT augmentation for the further-line treatment of depression, however this effect is not statistically significant

Discontinuation due to side effects

No evidence was identified for this outcome.

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

Very low quality evidence from 1 RCT (N=66) shows neither a clinically important nor statistically significant difference between augmenting antidepressant treatment with eye movement desensitization reprocessing (EMDR) relative to individual CBT, on global functioning at endpoint and 6-month follow-up for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Comparison 11. Increasing the dose of SSRI versus continuing SSRI at the same dose

Critical outcomes

Depression symptomatology

Moderate quality evidence from 1 RCT (N=57) shows a clinically important and statistically significant benefit of remaining on the same dose of paroxetine for an additional 6 weeks, relative to an increased dose, on depression symptomatology at endpoint for adults with depression who have failed to respond to 6 weeks of treatment with paroxetine
Very low quality evidence from 2 RCTs (N=416) shows neither a clinically important nor statistically significant difference between increasing the dose of the SSRI relative to continuing at the same dose for an additional 5-6 weeks, on depression symptomatology change from baseline to endpoint for adults with depression who have failed to respond to 3-4 weeks of treatment with a SSRI

Remission

Very low quality evidence from 5 RCTs (N=753) shows neither a clinically important nor statistically significant difference between increasing the dose of the SSRI relative to continuing at the same dose for an additional 5-6 weeks, on the rate of remission for adults with depression who have failed to respond to 3-6 weeks of treatment with a SSRI

Response

Very low quality evidence from 6 RCTs (N=830) shows neither a clinically important nor statistically significant difference between increasing the dose of the SSRI relative to continuing at the same dose for an additional 5-6 weeks, on the rate of response for adults with depression who have failed to respond to 3-6 weeks of treatment with a SSRI

Discontinuation due to any reason

Very low quality evidence from 5 RCTs (N=753) shows lower discontinuation due to any reason with an increased dose of the SSRI relative to the same dose for the further-line treatment of depression, however this effect is not statistically significant

Discontinuation due to side effects

Very low quality evidence from 4 RCTs (N=558) shows higher discontinuation due to side effects with an increased dose of the SSRI relative to the same dose for the further-line treatment of depression, however this effect is not statistically significant

Important outcomes

Quality of life

Moderate quality evidence from 1 RCT (N=57) shows a clinically important and statistically significant benefit of remaining on the same dose of paroxetine for an additional 6 weeks, relative to an increased dose, on quality of life physical component score for adults with depression who have failed to respond to 6 weeks of treatment with paroxetine
High quality evidence from 1 RCT (N=57) shows a clinically important and statistically significant benefit of increasing the dose of paroxetine relative to continuing at the same dose for an additional 6 weeks, on quality of life mental component score for adults with depression who have failed to respond to 6 weeks of treatment with paroxetine

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 12. Increasing the dose of SSRI versus switching to SNRI

Critical outcomes

Depression symptomatology

Low quality evidence from 1 RCT (N=472) shows a statistically significant but not clinically important benefit of increasing the dose of escitalopram, relative to switching to duloxetine, on depression symptomatology at endpoint for adults with depression who have failed to respond to 2 weeks of treatment with escitalopram
Low quality evidence from 1 RCT (N=472) shows neither a clinically important nor statistically significant difference between increasing the dose of escitalopram relative to switching to duloxetine on depression symptomatology change from baseline to endpoint, for adults who had failed to respond to 2 weeks of treatment with escitalopram

Remission

Very low quality evidence from 1 RCT (N=484) shows a clinically important and statistically significant benefit of increasing the dose of escitalopram, relative to switching to duloxetine, on the rate of remission for adults with depression who have failed to respond to 2 weeks of treatment with escitalopram

Response

Low quality evidence from 1 RCT (N=484) shows neither a clinically important nor statistically significant difference between increasing the dose of escitalopram relative to switching to duloxetine on the rate of response, for adults who had failed to respond to 2 weeks of treatment with escitalopram

Discontinuation due to any reason

Very low quality evidence from 1 RCT (N=484) shows neither a clinically important nor statistically significant difference between increasing the dose of escitalopram relative to switching to duloxetine on the rate of discontinuation for any reason, for adults who had failed to respond to 2 weeks of treatment with escitalopram

Discontinuation due to side effects

Very low quality evidence from 1 RCT (N=484) shows neither a clinically important nor statistically significant difference between increasing the dose of escitalopram relative to switching to duloxetine on the rate of discontinuation due to side effects, for adults who had failed to respond to 2 weeks of treatment with escitalopram

Important outcomes

Quality of life

Low quality evidence from 1 RCT (N=472) shows neither a clinically important nor statistically significant difference between increasing the dose of escitalopram relative to switching to duloxetine on quality of life, for adults who had failed to respond to 2 weeks of treatment with escitalopram

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 13. Increasing the dose of SSRI versus augmenting with TCA

Critical outcomes

Depression symptomatology

Low quality evidence from 2 RCTs (N=94) shows a clinically important and statistically significant benefit of increasing the dose of fluoxetine, relative to augmenting the same dose of fluoxetine with desipramine, on depression symptomatology at endpoint for adults with depression who have failed to respond to 8 weeks of treatment with fluoxetine
Low quality evidence from 2 RCTs (N=94) shows neither a clinically important nor statistically significant difference between increasing the dose of fluoxetine, relative to augmenting the same dose of fluoxetine with desipramine on depression symptomatology change from baseline to endpoint, for adults with depression who have failed to respond to 8 weeks of treatment with fluoxetine

Remission

Low quality evidence from 2 RCTs (N=94) shows a clinically important but not statistically significant benefit of increasing the dose of fluoxetine, relative to augmenting the same dose of fluoxetine with desipramine, on the rate of remission for adults with depression who have failed to respond to 8 weeks of treatment with fluoxetine

Response

No evidence was identified for this outcome.

Discontinuation due to any reason

Low quality evidence from 2 RCTs (N=94) shows lower discontinuation due to any reason with an increased dose of fluoxetine relative to augmenting the same dose of fluoxetine with desipramine for the further-line treatment of depression, however this effect is not statistically significant

Discontinuation due to side effects

Very low quality evidence from 1 RCT (N=27) shows lower discontinuation due to side effects with an increased dose of fluoxetine relative to augmenting the same dose of fluoxetine with desipramine for the further-line treatment of depression, however this effect is not statistically significant

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 14. Increasing the dose of SSRI versus augmenting with antipsychotic

Critical outcomes

Depression symptomatology

Moderate quality evidence from 1 RCT (N=60) shows neither a clinically important nor statistically significant difference between increasing the dose of paroxetine, relative to augmenting the same dose of paroxetine with amisulpride on depression symptomatology at endpoint and change from baseline to endpoint, for adults with depression who have failed to respond to 3 months of treatment with paroxetine

Remission

Low quality evidence from 1 RCT (N=60) shows a clinically important but not statistically significant benefit of augmenting paroxetine with amisulpride, relative to increasing the dose of paroxetine, on the rate of remission for adults with depression who have failed to respond to 3 months of treatment with paroxetine

Response

Low quality evidence from 1 RCT (N=60) shows neither a clinically important nor statistically significant difference between increasing the dose of paroxetine, relative to augmenting the same dose of paroxetine with amisulpride, on the rate of response for adults with depression who have failed to respond to 3 months of treatment with paroxetine

Discontinuation due to any reason

Low quality evidence from 1 RCT (N=60) shows neither a clinically important nor statistically significant difference between increasing the dose of paroxetine, relative to augmenting the same dose of paroxetine with amisulpride, on the rate of discontinuation for any reason for adults with depression who have failed to respond to 3 months of treatment with paroxetine

Discontinuation due to side effects

Low quality evidence from 1 RCT (N=60) shows neither a clinically important nor statistically significant difference between increasing the dose of paroxetine, relative to augmenting the same dose of paroxetine with amisulpride, on the rate of discontinuation due to side effects for adults with depression who have failed to respond to 3 months of treatment with paroxetine

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

Moderate quality evidence from 1 RCT (N=60) shows a clinically important and statistically significant benefit of augmenting paroxetine with amisulpride, relative to increasing the dose of paroxetine, on the rate of functional remission for adults with depression who have failed to respond to 3 months of treatment with paroxetine
Moderate quality evidence from 1 RCT (N=60) shows a clinically important and statistically significant benefit of augmenting paroxetine with amisulpride, relative to increasing the dose of paroxetine, on global functioning for adults with depression who have failed to respond to 3 months of treatment with paroxetine

Comparison 15. Increasing the dose of SSRI versus augmenting with lithium

Critical outcomes

Depression symptomatology

Low quality evidence from 2 RCTs (N=96) shows neither a clinically important nor statistically significant difference between increasing the dose of fluoxetine, relative to augmenting the same dose of fluoxetine with lithium on depression symptomatology at endpoint and change from baseline to endpoint, for adults with depression who have failed to respond to 8 weeks of treatment with fluoxetine

Remission

Low quality evidence from 2 RCTs (N=96) shows a clinically important and statistically significant benefit of increasing the dose of fluoxetine, relative to augmenting the same dose of fluoxetine with lithium, on the rate of remission for adults with depression who have failed to respond to 8 weeks of treatment with fluoxetine

Response

No evidence was identified for this outcome.

Discontinuation due to any reason

Low quality evidence from 2 RCTs (N=96) shows lower discontinuation due to any reason with an increased dose of fluoxetine relative to augmenting the same dose of fluoxetine with lithium for the further-line treatment of depression, however this effect is not statistically significant

Discontinuation due to side effects

Very low quality evidence from 1 RCT (N=29) shows lower discontinuation due to side effects with an increased dose of fluoxetine relative to augmenting the same dose of fluoxetine with lithium for the further-line treatment of depression, however this effect is not statistically significant

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 16. Switching to SSRI versus continuing with antidepressant

Critical outcomes

Depression symptomatology

Very low quality evidence from 2 RCTs (N=324) shows neither a clinically important nor statistically significant difference between switching to a SSRI, relative to continuing with the antidepressant, on depression symptomatology change from baseline to endpoint for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Remission

Very low quality evidence from 2 RCTs (N=329) shows a higher rate of remission for continuing with the antidepressant for an additional 8-12 weeks, relative to switching to a SSRI, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode, however this effect is not statistically significant

Response

Very low quality evidence from 2 RCTs (N=329) shows a higher rate of response for continuing with the antidepressant for an additional 8-12 weeks, relative to switching to a SSRI, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode, however this effect is not statistically significant

Discontinuation due to any reason

Very low quality evidence from 2 RCTs (N=329) shows neither a clinically important nor statistically significant difference between switching to a SSRI relative to continuing with the antidepressant on the rate of discontinuation due to any reason, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Discontinuation due to side effects

Very low quality evidence from 2 RCTs (N=329) shows a higher rate of discontinuation due to side effects for those switching to a SSRI relative to continuing with the antidepressant for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode, however this effect is not statistically significant

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 17. Switching to a different SSRI versus continuing same SSRI

Critical outcomes

Depression symptomatology

No evidence was identified for this outcome.

Remission

Very low quality evidence from 1 RCT (N=41) shows a clinically important and statistically significant benefit of switching to a different SSRI, relative to continuing with the same SSRI for an additional 6 weeks, on the rate of remission for adults with depression who have failed to respond to 2 weeks of treatment with sertraline

Response

Very low quality evidence from 1 RCT (N=41) shows a clinically important and statistically significant benefit of switching to a different SSRI, relative to continuing with the same SSRI for an additional 6 weeks, on the rate of response for adults with depression who have failed to respond to 2 weeks of treatment with sertraline

Discontinuation due to any reason

Very low quality evidence from 1 RCT (N=41) shows a lower rate of discontinuation due to any reason with a switch to a different SSRI relative to continuing with the same SSRI for the further-line treatment of depression, however this effect is not statistically significant

Discontinuation due to side effects

Low quality evidence from 1 RCT (N=41) shows neither a clinically important nor statistically significant difference between switching to a different SSRI relative to continuing with the same SSRI on the rate of discontinuation due to side effects, for adults with depression who have failed to respond to 2 weeks of treatment with sertraline

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 18. Switching to SSRI versus antipsychotic

Critical outcomes

Depression symptomatology

Very low quality evidence from 2 RCTs (N=401) shows a statistically significant but not clinically important benefit of switching to a SSRI, relative to switching to an antipsychotic, on depression symptomatology change from baseline to endpoint for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Remission

Very low quality evidence from 2 RCTs (N=408) shows neither a clinically important nor statistically significant difference between switching to a SSRI relative to switching to an antipsychotic on the rate of remission, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Response

Very low quality evidence from 2 RCTs (N=408) shows a clinically important and statistically significant benefit of switching to a SSRI, relative to switching to an antipsychotic, on the rate of response for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Discontinuation due to any reason

Low quality evidence from 2 RCTs (N=408) shows neither a clinically important nor statistically significant difference between switching to a SSRI relative to switching to an antipsychotic on the rate of discontinuation due to any reason, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Discontinuation due to side effects

Low quality evidence from 2 RCTs (N=408) shows significantly lower discontinuation due to side effects with switching to a SSRI, relative to switching to an antipsychotic, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 19. Switching to combined SSRI + antipsychotic versus switching to antipsychotic-only

Critical outcomes

Depression symptomatology

Very low quality evidence from 2 RCTs (N=595) shows neither a clinically important nor statistically significant difference between switching to a combined SSRI and antipsychotic treatment, relative to switching to an antipsychotic-only, on depression symptomatology change from baseline to endpoint for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Remission

Very low quality evidence from 2 RCTs (N=595) shows a clinically important but not statistically significant benefit of switching to a combined SSRI and antipsychotic treatment, relative to switching to an antipsychotic-only, on the rate of remission for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Response

Very low quality evidence from 2 RCTs (N=595) shows a clinically important and statistically significant benefit of switching to a combined SSRI and antipsychotic treatment, relative to switching to an antipsychotic-only, on the rate of response for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Discontinuation due to any reason

Low quality evidence from 2 RCTs (N=595) shows neither a clinically important nor statistically significant difference between switching to a combined SSRI and antipsychotic treatment, relative to switching to an antipsychotic-only, on discontinuation due to any reason for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Discontinuation due to side effects

Very low quality evidence from 2 RCTs (N=595) shows neither a clinically important nor statistically significant difference between switching to a combined SSRI and antipsychotic treatment, relative to switching to an antipsychotic-only, on discontinuation due to side effects for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 20. Augmenting with SSRI versus augmenting with lithium

Critical outcomes

Depression symptomatology

Low quality evidence from 1 RCT (N=104) shows a clinically important and statistically significant benefit of augmenting imipramine treatment with citalopram, relative to augmenting with lithium, on depression symptomatology change from baseline to endpoint for adults with depression who have failed to respond to 10 weeks of treatment with imipramine

Remission

Low quality evidence from 1 RCT (N=104) shows a clinically important and statistically significant benefit of augmenting imipramine treatment with citalopram, relative to augmenting with lithium, on the rate of remission for adults with depression who have failed to respond to 10 weeks of treatment with imipramine

Response

No evidence was identified for this outcome.

Discontinuation due to any reason

No evidence was identified for this outcome.

Discontinuation due to side effects

No evidence was identified for this outcome.

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 21. Switching to TCA versus SSRI

Critical outcomes

Depression symptomatology

Very low quality evidence from 1 RCT (N=152) shows neither a clinically important nor statistically significant difference between switching to desipramine relative to switching to citalopram on depression symptomatology, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Remission

Very low quality evidence from 1 RCT (N=189) shows a clinically important but not statistically significant benefit of switching to desipramine relative to switching to citalopram on the rate of remission, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Response

Very low quality evidence from 1 RCT (N=189) shows neither a clinically important nor statistically significant difference between switching to desipramine relative to switching to citalopram on the rate of response, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to any reason

Very low quality evidence from 1 RCT (N=189) shows neither a clinically important nor statistically significant difference between switching to desipramine relative to switching to citalopram on the rate of discontinuation due to any reason, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to side effects

No evidence was identified for this outcome.

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 22. Switching to TCA versus augmenting with mirtazapine

Critical outcomes

Depression symptomatology

Low quality evidence from 1 RCT (N=112) shows a clinically important and statistically significant benefit of switching to imipramine, relative to augmenting venlafaxine with mirtazapine, on depression symptomatology (at endpoint and change from baseline to endpoint) for adults with depression who have failed to respond to 10 weeks of treatment with venlafaxine

Remission

Low quality evidence from 1 RCT (N=112) shows a clinically important and statistically significant benefit of switching to imipramine, relative to augmenting venlafaxine with mirtazapine, on the rate of remission for adults with depression who have failed to respond to 10 weeks of treatment with venlafaxine

Response

No evidence was identified for this outcome.

Discontinuation due to any reason

Very low quality evidence from 1 RCT (N=112) shows a higher rate of discontinuation due to any reason with a switch to imipramine relative to augmenting venlafaxine with mirtazapine for the further-line treatment of depression, however this effect is not statistically significant

Discontinuation due to side effects

No evidence was identified for this outcome.

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 23. Switching to mianserin versus continuing with antidepressant

Critical outcomes

Depression symptomatology

Very low quality evidence from 1 RCT (N=71) shows neither a clinically important nor statistically significant difference between switching to mianserin, relative to continuing with fluoxetine for an additional 6 weeks, on depression symptomatology change from baseline to endpoint for adults with depression who have failed to respond to 6 weeks of treatment with fluoxetine

Remission

Very low quality evidence from 1 RCT (N=72) shows a clinically important but not statistically significant benefit of switching to mianserin, relative to continuing with fluoxetine for an additional 6 weeks, on the rate of remission for adults with depression who have failed to respond to 6 weeks of treatment with fluoxetine

Response

Very low quality evidence from 1 RCT (N=72) shows a clinically important but not statistically significant benefit of switching to mianserin, relative to continuing with fluoxetine for an additional 6 weeks, on the rate of response for adults with depression who have failed to respond to 6 weeks of treatment with fluoxetine

Discontinuation due to any reason

Very low quality evidence from 1 RCT (N=72) shows higher discontinuation due to any reason associated with switching to mianserin relative to continuing with fluoxetine for an additional 6 weeks, for adults with depression who have failed to respond to 6 weeks of treatment with fluoxetine, however this effect is not statistically significant

Discontinuation due to side effects

Very low quality evidence from 1 RCT (N=72) shows significantly higher discontinuation due to side effects associated with switching to mianserin, relative to continuing with fluoxetine for an additional 6 weeks, for adults with depression who have failed to respond to 6 weeks of treatment with fluoxetine

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 24. Augmenting with mianserin versus continuing with antidepressant (+/− placebo)

Critical outcomes

Depression symptomatology

Very low quality evidence from 1 RCT (N=70) shows a clinically important and statistically significant benefit of augmenting fluoxetine with mianserin, relative to continuing with fluoxetine-only, on depression symptomatology change from baseline to endpoint for adults with depression who had failed to respond to at least 6 weeks of treatment with fluoxetine

Remission

Very low quality evidence from 2 RCTs (N=267) shows a clinically important but not statistically significant benefit of augmenting a SSRI with mianserin, relative to continuing with SSRI-only, on the rate of remission for adults with depression who had failed to respond to at least 6 weeks of SSRI treatment

Response

Very low quality evidence from 2 RCTs (N=267) shows neither a clinically important nor statistically significant difference between augmenting a SSRI with mianserin relative to continuing with SSRI-only, on the rate of response for adults with depression who had failed to respond to at least 6 weeks of SSRI treatment

Discontinuation due to any reason

Very low quality evidence from 2 RCTs (N=267) shows higher discontinuation due to any reason associated with augmenting a SSRI with mianserin relative to continuing with SSRI-only, for adults with depression who have failed to respond to at least 6 weeks of SSRI treatment, however this effect is not statistically significant

Discontinuation due to side effects

Very low quality evidence from 1 RCT (N=70) shows higher discontinuation due to side effects associated with augmenting fluoxetine with mianserin relative to continuing with fluoxetine-only, for adults with depression who have failed to respond to at least 6 weeks of treatment with fluoxetine, however this effect is not statistically significant

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 25. Augmenting with mianserin versus increasing dose of antidepressant

Critical outcomes

Depression symptomatology

No evidence was identified for this outcome.

Remission

Very low quality evidence from 1 RCT (N=196) shows a clinically important and statistically significant benefit of augmenting sertraline with mianserin, relative to increasing the dose of sertraline, on the rate of remission for adults with depression who have failed to respond to 6 weeks of treatment with sertraline

Response

Very low quality evidence from 1 RCT (N=196) shows neither a clinically important nor statistically significant difference between augmenting sertraline with mianserin relative to increasing the dose of sertraline, on the rate of response for adults with depression who have failed to respond to 6 weeks of treatment with sertraline

Discontinuation due to any reason

Very low quality evidence from 1 RCT (N=196) shows neither a clinically important nor statistically significant difference between augmenting sertraline with mianserin relative to increasing the dose of sertraline, on the rate of discontinuation due to any reason for adults with depression who have failed to respond to 6 weeks of treatment with sertraline

Discontinuation due to side effects

No evidence was identified for this outcome.

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 26. Augmenting with mianserin versus switch to mianserin

Critical outcomes

Depression symptomatology

Very low quality evidence from 1 RCT (N=65) shows neither a clinically important nor statistically significant difference between augmenting fluoxetine with mianserin relative to switching to mianserin (and discontinuing fluoxetine), on depression symptomatology change from baseline to endpoint, for adults with depression who have failed to respond to at least 6 weeks of fluoxetine treatment

Remission

Very low quality evidence from 1 RCT (N=66) shows neither a clinically important nor statistically significant difference between augmenting fluoxetine with mianserin relative to switching to mianserin (and discontinuing fluoxetine), on the rate of remission, for adults with depression who have failed to respond to at least 6 weeks of fluoxetine treatment

Response

Very low quality evidence from 1 RCT (N=66) shows a clinically important but not statistically significant benefit of augmenting fluoxetine with mianserin, relative to switching to mianserin (and discontinuing fluoxetine), on the rate of response for adults with depression who have failed to respond to at least 6 weeks of fluoxetine treatment

Discontinuation due to any reason

Very low quality evidence from 1 RCT (N=66) shows lower discontinuation due to any reason associated with augmenting fluoxetine with mianserin relative to switching to mianserin (and discontinuing fluoxetine), for adults with depression who have failed to respond to at least 6 weeks of treatment with fluoxetine, however this effect is not statistically significant

Discontinuation due to side effects

Low quality evidence from 1 RCT (N=66) shows lower discontinuation due to side effects associated with augmenting fluoxetine with mianserin relative to switching to mianserin (and discontinuing fluoxetine), for adults with depression who have failed to respond to at least 6 weeks of treatment with fluoxetine, however this effect is not statistically significant

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 27. Increasing the dose of SNRI versus continuing SNRI at the same dose

Critical outcomes

Depression symptomatology

Very low quality evidence from 1 RCT (N=248) shows neither a clinically important nor statistically significant difference between increasing the dose and continuing on the same dose of duloxetine on depression symptomatology change from baseline to endpoint, for adults with depression who have failed to respond to 5 weeks of treatment with duloxetine

Remission

Very low quality evidence from 1 RCT (N=255) shows neither a clinically important nor statistically significant difference between increasing the dose and continuing on the same dose of duloxetine on the rate of remission, for adults with depression who have failed to respond to 5 weeks of treatment with duloxetine

Response

Very low quality evidence from 1 RCT (N=255) shows neither a clinically important nor statistically significant difference between increasing the dose and continuing on the same dose of duloxetine on the rate of response, for adults with depression who have failed to respond to 5 weeks of treatment with duloxetine

Discontinuation due to any reason

Very low quality evidence from 1 RCT (N=255) shows higher discontinuation due to any reason associated with increasing the dose of duloxetine relative to continuing on the same dose, for adults with depression who have failed to respond to at 5 weeks of treatment with duloxetine, however this effect is not statistically significant

Discontinuation due to side effects

Very low quality evidence from 1 RCT (N=255) shows neither a clinically important nor statistically significant difference between increasing the dose and continuing on the same dose of duloxetine on the rate of discontinuation due to side effects, for adults with depression who have failed to respond to 5 weeks of treatment with duloxetine

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 28. Switching to SNRI versus continuing with antidepressant

Critical outcomes

Depression symptomatology

No evidence was identified for this outcome.

Remission

Very low quality evidence from 1 RCT (N=95) shows neither a clinically important nor statistically significant difference between switching to venlafaxine and continuing with paroxetine on the rate of remission, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Response

Very low quality evidence from 1 RCT (N=95) shows neither a clinically important nor statistically significant difference between switching to venlafaxine and continuing with paroxetine on the rate of response, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Discontinuation due to any reason

Very low quality evidence from 1 RCT (N=95) shows neither a clinically important nor statistically significant difference between switching to venlafaxine and continuing with paroxetine on the rate of discontinuation due to any reason, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Discontinuation due to side effects

Very low quality evidence from 1 RCT (N=95) shows lower discontinuation due to side effects associated with switching to venlafaxine relative to continuing with paroxetine, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode, however this effect is not statistically significant

Important outcomes

Quality of life

Low to very low quality evidence from 1 RCT (N=95) shows neither a clinically important nor statistically significant difference between switching to venlafaxine and continuing with paroxetine on quality of life physical and mental component scores, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 29. Switching to SNRI versus switching to another antidepressant from same class

Critical outcomes

Depression symptomatology

Moderate quality evidence from 2 RCTs (N=595) shows neither a clinically important nor statistically significant difference between switching to venlafaxine and a within-class switch to a SSRI, on depression symptomatology change from baseline to endpoint for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Remission

Very low quality evidence from 3 RCTs (N=1017) shows a clinically important but not statistically significant benefit of switching to venlafaxine, relative to a within-class switch to a SSRI, on the rate of remission for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Response

Low quality evidence from 2 RCTs (N=611) shows neither a clinically important nor statistically significant difference between switching to venlafaxine and a within-class switch to a SSRI, on the rate of response for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to any reason

Low quality evidence from 2 RCTs (N=529) shows neither a clinically important nor statistically significant difference between switching to venlafaxine and a within-class switch to a SSRI, on the rate of discontinuation due to any reason for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to side effects

Low quality evidence from 3 RCTs (N=1017) shows neither a clinically important nor statistically significant difference between switching to venlafaxine and a within-class switch to a SSRI, on the rate of discontinuation due to side effects for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 30. Switching to SNRI versus switching to bupropion

Critical outcomes

Depression symptomatology

Low quality evidence from 1 RCT (N=489) shows neither a clinically important nor statistically significant difference between switching to venlafaxine and switching to bupropion on depression symptomatology change from baseline to endpoint, for adults with depression who have failed to respond to treatment with citalopram

Remission

Very low quality evidence from 1 RCT (N=489) shows neither a clinically important nor statistically significant difference between switching to venlafaxine and switching to bupropion on the rate of remission, for adults with depression who have failed to respond to treatment with citalopram

Response

Very low quality evidence from 1 RCT (N=489) shows neither a clinically important nor statistically significant difference between switching to venlafaxine and switching to bupropion on the rate of response, for adults with depression who have failed to respond to treatment with citalopram

Discontinuation due to any reason

No evidence was identified for this outcome.

Discontinuation due to side effects

Low quality evidence from 1 RCT (N=489) shows lower discontinuation due to side effects associated with switching to venlafaxine relative to switching to bupropion for adults with depression who have failed to respond to treatment with citalopram, however this effect is not statistically significant

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 31. Switching to SNRI versus switching to mirtazapine

Critical outcomes

Depression symptomatology

No evidence was identified for this outcome.

Remission

Very low quality evidence from 1 RCT (N=105) shows neither a clinically important nor statistically significant difference between switching to venlafaxine and switching to mirtazapine on the rate of remission, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Response

Very low quality evidence from 1 RCT (N=105) shows neither a clinically important nor statistically significant difference between switching to venlafaxine and switching to mirtazapine on the rate of response, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Discontinuation due to any reason

Very low quality evidence from 1 RCT (N=105) shows neither a clinically important nor statistically significant difference between switching to venlafaxine and switching to mirtazapine on the rate of discontinuation due to any reason, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Discontinuation due to side effects

Moderate quality evidence from 1 RCT (N=105) shows neither a clinically important nor statistically significant difference between switching to venlafaxine and switching to mirtazapine on the rate of discontinuation due to side effects, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Important outcomes

Quality of life

Very low quality evidence from 1 RCT (N=105) shows neither a clinically important nor statistically significant difference between switching to venlafaxine and switching to mirtazapine on quality of life physical and mental component scores, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 32. Switching to bupropion versus placebo

Critical outcomes

Depression symptomatology

Low quality evidence from 1 RCT (N=322) shows neither a clinically important nor statistically significant difference between switching to bupropion and placebo on depression symptomatology change from baseline to endpoint, for adults with depression who have failed to respond to 4 weeks of treatment with paroxetine

Remission

Very low quality evidence from 1 RCT (N=325) shows neither a clinically important nor statistically significant difference between switching to bupropion and placebo on the rate of remission, for adults with depression who have failed to respond to 4 weeks of treatment with paroxetine

Response

Very low quality evidence from 1 RCT (N=325) shows neither a clinically important nor statistically significant difference between switching to bupropion and placebo on the rate of response, for adults with depression who have failed to respond to 4 weeks of treatment with paroxetine

Discontinuation due to any reason

Very low quality evidence from 1 RCT (N=325) shows significantly higher discontinuation due to any reason with switching to bupropion relative to placebo, for adults with depression who have failed to respond to 4 weeks of treatment with paroxetine

Discontinuation due to side effects

Very low quality evidence from 1 RCT (N=325) shows neither a clinically important nor statistically significant difference between switching to bupropion and placebo on the rate of discontinuation due to side effects, for adults with depression who have failed to respond to 4 weeks of treatment with paroxetine

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 33. Switching to bupropion versus switching to another antidepressant from same class

Critical outcomes

Depression symptomatology

Low quality evidence from 1 RCT (N=477) shows neither a clinically important nor statistically significant difference between switching to bupropion and switching to sertraline on depression symptomatology change from baseline to endpoint, for adults with depression who have failed to respond to treatment with citalopram

Remission

Very low quality evidence from 1 RCT (N=477) shows neither a clinically important nor statistically significant difference between switching to bupropion and switching to sertraline on the rate of remission, for adults with depression who have failed to respond to treatment with citalopram

Response

Very low quality evidence from 1 RCT (N=477) shows neither a clinically important nor statistically significant difference between switching to bupropion and switching to sertraline on the rate of response, for adults with depression who have failed to respond to treatment with citalopram

Discontinuation due to any reason

No evidence was identified for this outcome.

Discontinuation due to side effects

Low quality evidence from 1 RCT (N=477) shows higher discontinuation due to side effects with switching to bupropion relative to switching to sertraline for adults with depression who have failed to respond to treatment with citalopram, however this effect is not statistically significant

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 34. Augmenting with bupropion versus placebo

Critical outcomes

Depression symptomatology

No evidence was identified for this outcome.

Remission

Moderate quality evidence from 1 RCT (N=60) shows a clinically important and statistically significant benefit of augmenting with bupropion relative to placebo for adults with depression who have failed to respond to 4 weeks of SSRI treatment

Response

No evidence was identified for this outcome.

Discontinuation due to any reason

No evidence was identified for this outcome.

Discontinuation due to side effects

No evidence was identified for this outcome.

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 35. Augmenting with bupropion versus switching to bupropion

Critical outcomes

Depression symptomatology

No evidence was identified for this outcome.

Remission

Moderate quality evidence from 1 RCT (N=1017) shows neither a clinically important nor statistically significant difference between augmenting with bupropion and switching to bupropion on the rate of remission, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Response

High quality evidence from 1 RCT (N=1017) shows neither a clinically important nor statistically significant difference between augmenting with bupropion and switching to bupropion on the rate of response, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to any reason

Moderate quality evidence from 1 RCT (N=1017) shows neither a clinically important nor statistically significant difference between augmenting with bupropion and switching to bupropion on the rate of discontinuation due to any reason, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to side effects

Moderate quality evidence from 1 RCT (N=1017) shows higher discontinuation due to side effects with switching to bupropion relative to augmenting with bupropion for the further-line treatment of depression, however this effect is not statistically significant

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 36. Switching to mirtazapine versus continuing with antidepressant

Critical outcomes

Depression symptomatology

Low quality evidence from 2 RCTs (N=1223) shows neither a clinically important nor statistically significant difference between switching to mirtazapine and continuing with the antidepressant on depression symptomatology at endpoint, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Very low quality evidence from 1 RCT (N=136) shows neither a clinically important nor statistically significant difference between switching to mirtazapine and continuing with paroxetine (for an additional 6 weeks) on depression symptomatology change from baseline to endpoint, for adults with depression who have failed to respond to 2 weeks of treatment with paroxetine
High quality evidence from 1 RCT (N=1078) shows neither a clinically important nor statistically significant difference between switching to mirtazapine and continuing with sertraline (for an additional 6 weeks) on depression symptomatology at 4-month follow-up, for adults with depression who have failed to respond to 2 weeks of treatment with sertraline

Remission

Low quality evidence from 3 RCTs (N=1345) shows a statistically significant but not clinically important benefit of switching to mirtazapine relative to continuing with the antidepressant on the rate of remission, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
High quality evidence from 1 RCT (N=1109) shows neither a clinically important nor statistically significant difference between switching to mirtazapine and continuing with sertraline (for an additional 6 weeks) on the rate of remission at 4-month follow-up, for adults with depression who have failed to respond to 2 weeks of treatment with sertraline

Response

Moderate quality evidence from 3 RCTs (N=1345) shows neither a clinically important nor statistically significant difference between switching to mirtazapine and continuing with the antidepressant on the rate of response, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to any reason

Very low quality evidence from 3 RCTs (N=1345) shows neither a clinically important nor statistically significant difference between switching to mirtazapine and continuing with the antidepressant on the rate of discontinuation due to any reason, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to side effects

Very low quality evidence from 2 RCTs (N=236) shows neither a clinically important nor statistically significant difference between switching to mirtazapine and continuing with the antidepressant on the rate of discontinuation due to side effects, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Important outcomes

Quality of life

Very low quality evidence from 1 RCT (N=100) shows neither a clinically important nor statistically significant difference between switching to mirtazapine and continuing with paroxetine on quality of life physical and mental component scores, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 37. Augmenting with mirtazapine versus continuing with antidepressant (+/− placebo)

Critical outcomes

Depression symptomatology

Low quality evidence from 4 RCTs (N=1657) shows a statistically significant but not clinically important benefit of augmenting SSRI/SNRI treatment with mirtazapine, relative to augmentation with placebo or continuing with SSRI/SNRI-only, on depression symptomatology at endpoint for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Very low quality evidence from 2 RCTs (N=162) shows a clinically important but not statistically significant benefit of augmenting SSRI/SNRI treatment with mirtazapine, relative to augmentation with placebo, on depression symptomatology change from baseline to endpoint for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
High quality evidence from 1 RCT (N=1058) shows neither a clinically important nor statistically significant difference between augmenting sertraline treatment with mirtazapine, relative to continuing with sertraline-only (for an additional 6 weeks), on depression symptomatology at 4-months follow-up for adults with depression who have failed to respond to 2 weeks of treatment with sertraline

Remission

Low quality evidence from 4 RCTs (N=1730) shows a clinically important and statistically significant benefit of augmenting SSRI/SNRI treatment with mirtazapine, relative to augmentation with placebo or continuing with SSRI/SNRI-only, on the rate of remission for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Moderate quality evidence from 1 RCT (N=1088) shows neither a clinically important nor statistically significant difference between augmenting sertraline treatment with mirtazapine, relative to continuing with sertraline-only (for an additional 6 weeks), on the rate of remission at 4-months follow-up for adults with depression who have failed to respond to 2 weeks of treatment with sertraline

Response

Low quality evidence from 4 RCTs (N=1730) shows a statistically significant but not clinically important benefit of augmenting SSRI/SNRI treatment with mirtazapine, relative to augmentation with placebo or continuing with SSRI/SNRI-only, on the rate of response for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to any reason

Very low quality evidence from 4 RCTs (N=1730) shows neither a clinically important nor statistically significant difference between augmenting SSRI/SNRI treatment with mirtazapine and augmentation with placebo or continuing with SSRI/SNRI-only, on the rate of discontinuation due to any reason for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to side effects

Very low quality evidence from 2 RCTs (N=162) shows higher discontinuation due to side effects with mirtazapine augmentation of SSRI/SNRI treatment relative to augmentation with placebo for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode, however this effect is not statistically significant

Important outcomes

Quality of life

Low quality evidence from 1 RCT (N=429) shows neither a clinically important nor statistically significant difference between augmenting SSRI/SNRI treatment with mirtazapine, relative to augmentation with placebo, on quality of life for adults with depression who have failed to respond to 6 weeks of treatment with a SSRI/SNRI
Low quality evidence from 1 RCT (N=418) shows neither a clinically important nor statistically significant difference between augmenting SSRI/SNRI treatment with mirtazapine, relative to augmentation with placebo, on quality of life physical component score for adults with depression who have failed to respond to 6 weeks of treatment with a SSRI/SNRI
Low quality evidence from 1 RCT (N=418) shows a statistically significant but not clinically important benefit of augmenting SSRI/SNRI treatment with mirtazapine, relative to augmentation with placebo, on quality of life mental component score for adults with depression who have failed to respond to 6 weeks of treatment with a SSRI/SNRI

Personal, social, and occupational functioning

Very low quality evidence from 1 RCT (N=26) shows a clinically important and statistically significant benefit of augmenting SSRI/SNRI treatment with mirtazapine, relative to augmentation with placebo, on global functioning for adults with depression who have failed to respond to at least 4 weeks of standard antidepressant monotherapy

Comparison 38. Augmenting with mirtazapine versus switching to mirtazapine

Critical outcomes

Depression symptomatology

High quality evidence from 2 RCTs (N=1213) shows neither a clinically important nor statistically significant difference between augmenting SSRI treatment with mirtazapine, relative to switching to mirtazapine, on depression symptomatology at endpoint for adults with depression who have failed to respond to 2 weeks of SSRI treatment
Very low quality evidence from 1 RCT (N=136) shows neither a clinically important nor statistically significant difference between augmenting paroxetine with mirtazapine, relative to switching to mirtazapine, on depression symptomatology change from baseline to endpoint for adults with depression who have failed to respond to 2 weeks of treatment with paroxetine
High quality evidence from 1 RCT (N=1060) shows neither a clinically important nor statistically significant difference between augmenting sertraline with mirtazapine, relative to switching to mirtazapine, on depression symptomatology at 4-month follow-up for adults with depression who have failed to respond to 2 weeks of treatment with sertraline

Remission

Moderate quality evidence from 2 RCTs (N=1213) shows neither a clinically important nor statistically significant difference between augmenting SSRI treatment with mirtazapine, relative to switching to mirtazapine, on the rate of remission for adults with depression who have failed to respond to 2 weeks of SSRI treatment
High quality evidence from 1 RCT (N=1095) shows neither a clinically important nor statistically significant difference between augmenting sertraline with mirtazapine, relative to switching to mirtazapine, on the rate of remission at 4-month follow-up for adults with depression who have failed to respond to 2 weeks of treatment with sertraline

Response

High quality evidence from 2 RCTs (N=1213) shows neither a clinically important nor statistically significant difference between augmenting SSRI treatment with mirtazapine, relative to switching to mirtazapine, on the rate of response for adults with depression who have failed to respond to 2 weeks of SSRI treatment

Discontinuation due to any reason

Low quality evidence from 2 RCTs (N=1213) shows neither a clinically important nor statistically significant difference between augmenting SSRI treatment with mirtazapine, relative to switching to mirtazapine, on the rate of discontinuation due to any reason for adults with depression who have failed to respond to 2 weeks of SSRI treatment

Discontinuation due to side effects

Very low quality evidence from 1 RCT (N=136) shows higher discontinuation due to side effects associated with switching to mirtazapine relative to augmenting paroxetine with mirtazapine for adults with depression who have failed to respond to 2 weeks of treatment with paroxetine, however this effect is not statistically significant

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 39. Augmenting with trazodone versus continuing with antidepressant

Critical outcomes

Depression symptomatology

No evidence was identified for this outcome.

Remission

Very low quality evidence from 1 RCT (N=92) shows neither a clinically important nor statistically significant difference between augmenting paroxetine with trazodone and continuing with paroxetine-only on the rate of remission, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Response

Very low quality evidence from 1 RCT (N=92) shows neither a clinically important nor statistically significant difference between augmenting paroxetine with trazodone and continuing with paroxetine-only on the rate of response, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Discontinuation due to any reason

No evidence was identified for this outcome.

Discontinuation due to side effects

No evidence was identified for this outcome.

Important outcomes

Quality of life

Low quality evidence from 1 RCT (N=92) shows neither a clinically important nor statistically significant difference between augmenting paroxetine with trazodone and continuing with paroxetine-only on quality of life physical and mental component scores, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 40. Augmenting with anticonvulsant versus continuing with antidepressant (+/− placebo)

Critical outcomes

Depression symptomatology

Very low quality evidence from 8 RCTs (N=599) shows a clinically important and statistically significant benefit of augmenting antidepressant treatment with lamotrigine or topiramate, relative to continuing with antidepressant-only or augmentation with placebo, on depression symptomatology (at endpoint and change from baseline to endpoint) for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Remission

Very low quality evidence from 1 RCT (N=84) shows neither a clinically important nor statistically significant difference between augmenting paroxetine with sodium valproate and continuing with paroxetine-only on the rate of remission for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Response

Very low quality evidence from 8 RCTs (N=641) shows a clinically important but not statistically significant benefit of augmenting antidepressant treatment with lamotrigine or sodium valproate, relative to continuing with antidepressant-only or augmentation with placebo, on the rate of response for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Discontinuation due to any reason

Very low quality evidence from 3 RCTs (N=183) shows neither a clinically important nor statistically significant difference between augmenting antidepressant treatment with lamotrigine or topiramate, relative to augmentation with placebo, on the rate of discontinuation due to any reason for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to side effects

Very low quality evidence from 2 RCTs (N=130) shows neither a clinically important nor statistically significant difference between augmenting antidepressant treatment with lamotrigine and augmentation with placebo on the rate of discontinuation due to side effects, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Important outcomes

Quality of life

Low quality evidence from 1 RCT (N=84) shows neither a clinically important nor statistically significant difference between augmenting paroxetine with lamotrigine and continuing with paroxetine-only on quality of life physical and mental component scores, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 41. Augmenting with anticonvulsant versus lithium

Critical outcomes

Depression symptomatology

Low quality evidence from 1 RCT (N=34) shows neither a clinically important nor statistically significant difference between augmenting antidepressant treatment with lamotrigine and augmenting with lithium on depression symptomatology at endpoint, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode
Low quality evidence from 1 RCT (N=34) shows a clinically important and statistically significant benefit of augmenting antidepressant treatment with lamotrigine, relative to augmenting with lithium, on depression symptomatology change from baseline to endpoint for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Remission

Very low quality evidence from 1 RCT (N=34) shows a clinically important but not statistically significant benefit of augmenting antidepressant treatment with lamotrigine, relative to augmenting with lithium, on the rate of remission for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Response

Very low quality evidence from 1 RCT (N=34) shows a clinically important but not statistically significant benefit of augmenting antidepressant treatment with lamotrigine, relative to augmenting with lithium, on the rate of response for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Discontinuation due to any reason

Low quality evidence from 1 RCT (N=34) shows neither a clinically important nor statistically significant difference between augmenting antidepressant treatment with lamotrigine and augmenting with lithium on discontinuation due to any reason, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Discontinuation due to side effects

High quality evidence from 1 RCT (N=34) shows neither a clinically important nor statistically significant difference between augmenting antidepressant treatment with lamotrigine and augmenting with lithium on discontinuation due to side effects, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 42. Switching to antipsychotic versus continuing with antidepressant

Critical outcomes

Depression symptomatology

Very low quality evidence from 3 RCTs (N=729) shows neither a clinically important nor statistically significant difference between switching to olanzapine and continuing with antidepressant treatment on depression symptomatology at endpoint, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Remission

Very low quality evidence from 3 RCTs (N=738) shows a higher rate of remission associated with continuing with antidepressant treatment relative to switching to olanzapine for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode, however this effect is not statistically significant

Response

Very low quality evidence from 3 RCTs (N=738) shows a significantly higher rate of response associated with continuing with antidepressant treatment relative to switching to olanzapine for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Discontinuation due to any reason

Moderate quality evidence from 3 RCTs (N=738) shows a significantly higher rate of discontinuation due to any reason with switching to olanzapine, relative to continuing with antidepressant treatment, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Discontinuation due to side effects

Moderate quality evidence from 3 RCTs (N=738) shows a significantly higher rate of discontinuation due to side effects with switching to olanzapine, relative to continuing with antidepressant treatment, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Important outcomes

Quality of life

Low quality evidence from 1 RCT (N=400) shows neither a clinically important nor statistically significant difference between switching to olanzapine and continuing with fluoxetine on quality of life physical and mental component scores, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 43. Switching to combined antipsychotic + SSRI versus continuing with antidepressant

Critical outcomes

Depression symptomatology

Low quality evidence from 2 RCTs (N=502) shows neither a clinically important nor statistically significant difference between switching to combined olanzapine and fluoxetine, and continuing with venlafaxine or nortriptyline, on depression symptomatology change from baseline to endpoint for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Remission

Very low quality evidence from 2 RCTs (N=516) shows neither a clinically important nor statistically significant difference between switching to combined olanzapine and fluoxetine, and continuing with venlafaxine or nortriptyline, on the rate of remission for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Response

Very low quality evidence from 2 RCTs (N=516) shows neither a clinically important nor statistically significant difference between switching to combined olanzapine and fluoxetine, and continuing with venlafaxine or nortriptyline, on the rate of response for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Discontinuation due to any reason

Very low quality evidence from 2 RCTs (N=516) shows neither a clinically important nor statistically significant difference between switching to combined olanzapine and fluoxetine, and continuing with venlafaxine or nortriptyline, on the rate of discontinuation due to any reason for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Discontinuation due to side effects

Low quality evidence from 2 RCTs (N=516) shows a significantly higher rate of discontinuation due to side effects associated with switching to combined olanzapine and fluoxetine, relative to continuing with venlafaxine or nortriptyline, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 44. Switching to combined antipsychotic + SSRI versus switch to SSRI-only

Critical outcomes

Depression symptomatology

Low quality evidence from 2 RCTs (N=574) shows neither a clinically important nor statistically significant difference between switching to combined olanzapine and fluoxetine, and switching to fluoxetine-only, on depression symptomatology change from baseline to endpoint for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Remission

Very low quality evidence from 2 RCTs (N=591) shows a clinically important but not statistically significant benefit of switching to combined olanzapine and fluoxetine, relative to switching to fluoxetine-only, on the rate of remission for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Response

Very low quality evidence from 2 RCTs (N=591) shows neither a clinically important nor statistically significant difference between switching to combined olanzapine and fluoxetine, and switching to fluoxetine-only, on the rate of response for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Discontinuation due to any reason

Very low quality evidence from 2 RCTs (N=591) shows neither a clinically important nor statistically significant difference between switching to combined olanzapine and fluoxetine, and switching to fluoxetine-only, on the rate of discontinuation due to any reason for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Discontinuation due to side effects

Low quality evidence from 2 RCTs (N=591) shows a significantly higher rate of discontinuation due to side effects associated with switching to combined olanzapine and fluoxetine, relative to switching to fluoxetine-only, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 45. Augmenting with antipsychotic versus antidepressant-only or antidepressant + placebo

Critical outcomes

Depression symptomatology

Very low quality evidence from 5 RCTs (N=706) shows a clinically important and statistically significant benefit of augmenting antidepressant treatment with an antipsychotic, relative to augmentation with placebo or continuing with antidepressant-only, on depression symptomatology at endpoint for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Very low quality evidence from 20 RCTs (N=6716) shows a statistically significant but not clinically important benefit of augmenting antidepressant treatment with an antipsychotic, relative to augmentation with placebo or continuing with antidepressant-only, on depression symptomatology change from baseline to endpoint for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Remission

Very low quality evidence from 28 RCTs (N=10,078) shows a clinically important and statistically significant benefit of augmenting antidepressant treatment with an antipsychotic, relative to augmentation with placebo or continuing with antidepressant-only, on the rate of remission for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Response

Low quality evidence from 28 RCTs (N=9154) shows a clinically important and statistically significant benefit of augmenting antidepressant treatment with an antipsychotic, relative to augmentation with placebo or continuing with antidepressant-only, on the rate of response for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to any reason

Low quality evidence from 28 RCTs (N=10,012) shows a significantly higher rate of discontinuation due to any reason associated with augmenting antidepressant treatment with an antipsychotic, relative to augmentation with placebo or continuing with antidepressant-only, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to side effects

Moderate quality evidence from 27 RCTs (N=9989) shows a significantly higher rate of discontinuation due to side effects associated with augmenting antidepressant treatment with an antipsychotic, relative to augmentation with placebo or continuing with antidepressant-only, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Important outcomes

Quality of life

Very low quality evidence from 1 RCT (N=202) shows a statistically significant but not clinically important benefit of augmenting SSRI/SNRI treatment with risperidone, relative to augmentation with placebo, on quality of life at endpoint for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Moderate quality evidence from 2 RCTs (N=727) shows neither a clinically important nor statistically significant difference between augmenting SSRI/SNRI treatment with an antipsychotic and augmentation with placebo on quality of life change from baseline to endpoint, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode
Low to very low quality evidence from 2 RCTs (N=491) shows neither a clinically important nor statistically significant difference between augmenting SSRI treatment with an antipsychotic and continuing with the SSRI-only on quality of life physical and mental component scores, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Personal, social, and occupational functioning

Low quality evidence from 1 RCT (N=313) shows a clinically important and statistically significant benefit of augmenting sertraline with aripiprazole, relative to augmentation with placebo, on global functioning change from baseline to endpoint for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode
Very low quality evidence from 1 RCT (N=886) shows neither a clinically important nor statistically significant difference between augmenting SSRI/SNRI treatment with brexpiprazole and placebo augmentation on functional remission, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Very low quality evidence from 1 RCT (N=201) shows a clinically important and statistically significant benefit of augmenting SSRI/SNRI treatment with risperidone, relative to placebo augmentation, on functional impairment at endpoint for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Low quality evidence from 10 RCTs (N=4554) shows a statistically significant but not clinically important benefit of augmenting antidepressant treatment with an antipsychotic, relative to placebo augmentation, on functional impairment change from baseline to endpoint for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Comparison 46. Augmenting with antipsychotic versus bupropion

Critical outcomes

Depression symptomatology

Very low quality evidence from 1 RCT (N=103) shows a statistically significant but not clinically important benefit of augmenting SSRI treatment with aripiprazole, relative to bupropion augmentation, on depression symptomatology change from baseline to endpoint for adults with depression who have shown an inadequate response to at least 4 weeks of SSRI treatment

Remission

Low quality evidence from 2 RCTs (N=1114) shows a clinically important but not statistically significant benefit of augmenting SSRI/SNRI treatment with aripiprazole, relative to bupropion augmentation, on the rate of remission for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Response

Moderate quality evidence from 2 RCTs (N=1114) shows neither a clinically important nor statistically significant difference between augmenting SSRI/SNRI treatment with aripiprazole and augmentation with bupropion on the rate of response, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to any reason

Moderate quality evidence from 2 RCTs (N=1114) shows neither a clinically important nor statistically significant difference between augmenting SSRI/SNRI treatment with aripiprazole and augmentation with bupropion on the rate of discontinuation due to any reason, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to side effects

Moderate quality evidence from 2 RCTs (N=1114) shows a higher rate of discontinuation due to side effects associated with augmenting SSRI/SNRI treatment with bupropion relative to augmentation with aripiprazole for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode, however this effect is not statistically significant

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 47. Augmenting with antipsychotic versus lithium

Critical outcomes

Depression symptomatology

No evidence was identified for this outcome.

Remission

Low quality evidence from 3 RCTs (N=510) shows a higher rate of remission associated with augmenting antidepressant treatment with an antipsychotic relative to augmentation with lithium for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode, however this effect is not statistically significant

Response

Low quality evidence from 3 RCTs (N=510) shows neither a clinically important nor statistically significant difference between augmenting antidepressant treatment with an antipsychotic and lithium augmentation on the rate of response, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to any reason

Low quality evidence from 3 RCTs (N=510) shows a higher rate of discontinuation due to any reason associated with augmenting antidepressant treatment with lithium relative to augmentation with an antipsychotic for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode, however this effect is not statistically significant

Discontinuation due to side effects

Very low quality evidence from 3 RCTs (N=510) shows neither a clinically important nor statistically significant difference between augmenting antidepressant treatment with an antipsychotic and lithium augmentation on the rate of discontinuation due to side effects, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 48. Augmenting with antipsychotic versus switch to antipsychotic

Critical outcomes

Depression symptomatology

Very low quality evidence from 1 RCT (N=395) shows a statistically significant but not clinically important benefit of augmenting fluoxetine treatment with olanzapine, relative to switching to olanzapine monotherapy, on depression symptomatology change from baseline to endpoint for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Remission

Low quality evidence from 2 RCTs (N=858) shows a clinically important and statistically significant benefit of augmenting SSRI/venlafaxine treatment with an antipsychotic, relative to switching to antipsychotic monotherapy, on the rate of remission for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Response

Very low quality evidence from 2 RCTs (N=858) shows a higher rate of response associated with augmenting SSRI/venlafaxine treatment with an antipsychotic, relative to switching to antipsychotic monotherapy for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode, however this effect is not statistically significant

Discontinuation due to any reason

Low quality evidence from 2 RCTs (N=858) shows a significantly higher rate of discontinuation due to any reason associated with switching to antipsychotic monotherapy, relative to augmenting SSRI/venlafaxine treatment with an antipsychotic, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to side effects

Low quality evidence from 2 RCTs (N=858) shows neither a clinically important nor statistically significant difference between augmenting SSRI/venlafaxine treatment with an antipsychotic and switching to antipsychotic monotherapy on the rate of discontinuation due to side effects, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Important outcomes

Quality of life

Very low quality evidence from 1 RCT (N=395) shows a statistically significant but not clinically important benefit of augmenting fluoxetine treatment with olanzapine, relative to switching to olanzapine monotherapy, on quality of life physical component score for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode
Low quality evidence from 1 RCT (N=395) shows neither a clinically important nor statistically significant difference between augmenting fluoxetine treatment with olanzapine and switching to olanzapine monotherapy on quality of life mental component score, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 49. Augmenting with antipsychotic versus switch to bupropion

Critical outcomes

Depression symptomatology

No evidence was identified for this outcome.

Remission

Moderate quality evidence from 1 RCT (N=1016) shows a clinically important and statistically significant benefit of augmenting SSRI/SNRI treatment with aripiprazole, relative to switching to bupropion monotherapy, on the rate of remission for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Response

Moderate quality evidence from 1 RCT (N=1016) shows a statistically significant but not clinically important benefit of augmenting SSRI/SNRI treatment with aripiprazole, relative to switching to bupropion monotherapy, on the rate of response for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to any reason

High quality evidence from 1 RCT (N=1016) shows a significantly higher rate of discontinuation due to any reason associated with switching to bupropion monotherapy, relative to augmenting SSRI/SNRI treatment with aripiprazole, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to side effects

Moderate quality evidence from 1 RCT (N=1016) shows a significantly higher rate of discontinuation due to side effects associated with switching to bupropion monotherapy, relative to augmenting SSRI/SNRI treatment with aripiprazole, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 50. Augmenting with buspirone versus continuing with antidepressant (+/− placebo)

Critical outcomes

Depression symptomatology

No evidence was identified for this outcome.

Remission

Low quality evidence from 1 RCT (N=91) shows a higher rate of remission associated with continuing paroxetine-only treatment relative to augmenting paroxetine with buspirone on the rate of remission for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode, however this effect is not statistically significant

Response

Low quality evidence from 2 RCTs (N=193) shows neither a clinically important nor statistically significant difference between augmenting SSRI treatment with buspirone, relative to placebo augmentation or continuing with the SSRI-only, on the rate of response for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to any reason

No evidence was identified for this outcome.

Discontinuation due to side effects

No evidence was identified for this outcome.

Important outcomes

Quality of life

Moderate quality evidence from 1 RCT (N=91) shows neither a clinically important nor statistically significant difference between augmenting paroxetine with buspirone, relative to continuing with paroxetine-only, on quality of life physical and mental component scores for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 51. Augmenting with buspirone versus bupropion

Critical outcomes

Depression symptomatology

Moderate quality evidence from 1 RCT (N=565) shows a statistically significant but not clinically important benefit of augmenting citalopram with bupropion, relative to buspirone augmentation, on depression symptomatology (at endpoint, and change from baseline to endpoint) for adults with depression who have failed to respond to citalopram monotherapy

Remission

Low quality evidence from 1 RCT (N=565) shows neither a clinically important nor statistically significant difference between bupropion and buspirone augmentation of citalopram on the rate of remission, for adults with depression who have failed to respond to citalopram monotherapy

Response

Moderate quality evidence from 1 RCT (N=565) shows neither a clinically important nor statistically significant difference between bupropion and buspirone augmentation of citalopram on the rate of response, for adults with depression who have failed to respond to citalopram monotherapy

Discontinuation due to any reason

No evidence was identified for this outcome.

Discontinuation due to side effects

Moderate quality evidence from 1 RCT (N=565) shows a higher rate of discontinuation due to side effects associated with buspirone augmentation of citalopram, relative to bupropion augmentation, for adults with depression who have failed to respond to citalopram monotherapy

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 52. Augmenting with methylphenidate versus placebo

Critical outcomes

Depression symptomatology

Very low quality evidence from 1 RCT (N=144) shows neither a clinically important nor statistically significant difference between augmentation of antidepressant treatment with methylphenidate or placebo on depression symptomatology change from baseline to endpoint, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Remission

Very low quality evidence from 1 RCT (N=60) shows a clinically important but not statistically significant benefit of augmentation of antidepressant treatment with methylphenidate, relative to placebo augmentation, on the rate of remission for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Response

Very low quality evidence from 2 RCTs (N=205) shows neither a clinically important nor statistically significant difference between augmentation of antidepressant treatment with methylphenidate or placebo on the rate of response, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to any reason

Very low quality evidence from 1 RCT (N=145) shows higher discontinuation due to any reason associated with augmentation of antidepressant treatment with methylphenidate relative to placebo for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode, however this effect is not statistically significant

Discontinuation due to side effects

Very low quality evidence from 2 RCTs (N=205) shows higher discontinuation due to side effects associated with augmentation of antidepressant treatment with methylphenidate relative to placebo for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode, however this effect is not statistically significant

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 53. Augmenting with lithium versus continuing with antidepressant (+/− placebo)

Critical outcomes

Depression symptomatology

Low quality evidence from 2 RCTs (N=67) shows neither a clinically important nor statistically significant difference between augmentation of TCA treatment with lithium or placebo on depression symptomatology at endpoint, for adults with depression who have failed to respond to TCA monotherapy
Low quality evidence from 3 RCTs (N=116) shows neither a clinically important nor statistically significant difference between augmentation of antidepressant treatment with lithium or placebo on depression symptomatology change from baseline to endpoint, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Remission

Low quality evidence from 1 RCT (N=34) shows a clinically important but not statistically significant benefit of augmenting TCA treatment with lithium, relative to placebo augmentation, on the rate of remission for adults with depression who have failed to respond to TCA monotherapy

Response

Very low quality evidence from 2 RCTs (N=59) shows a clinically important but not statistically significant benefit of augmenting SSRI/TCA treatment with lithium, relative to placebo augmentation, on the rate of response for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to any reason

Low quality evidence from 4 RCTs (N=159) shows a lower rate of discontinuation due to any reason associated with augmenting antidepressant treatment with lithium relative to placebo augmentation for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode, however this effect is not statistically significant

Discontinuation due to side effects

Low quality evidence from 2 RCTs (N=68) shows a higher rate of discontinuation due to side effects associated with augmenting TCA treatment with lithium relative to placebo augmentation for adults with depression who have failed to respond to TCA monotherapy, however this effect is not statistically significant

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 54. Augmenting with lithium versus switch to antipsychotic

Critical outcomes

Depression symptomatology

No evidence was identified for this outcome.

Remission

Very low quality evidence from 1 RCT (N=457) shows neither a clinically important nor statistically significant difference between augmenting SSRI/venlafaxine treatment with lithium and switching to quetiapine monotherapy on the rate of remission, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Response

Very low quality evidence from 1 RCT (N=457) shows neither a clinically important nor statistically significant difference between augmenting SSRI/venlafaxine treatment with lithium and switching to quetiapine monotherapy on the rate of response, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to any reason

Very low quality evidence from 1 RCT (N=457) shows neither a clinically important nor statistically significant difference between augmenting SSRI/venlafaxine treatment with lithium and switching to quetiapine monotherapy on the rate of discontinuation due to any reason, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to side effects

Very low quality evidence from 1 RCT (N=457) shows a higher rate of discontinuation due to side effects associated with switching to quetiapine monotherapy relative to augmenting SSRI/venlafaxine treatment with lithium for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode, however this effect is not statistically significant

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 55. Augmenting with lithium versus augmenting with a psychological intervention

Critical outcomes

Depression symptomatology

Moderate quality evidence from 1 RCT (N=39) shows neither a clinically important nor statistically significant difference between augmenting antidepressant treatment with lithium and augmenting with individual CBT on depression symptomatology (at endpoint, and change from baseline to endpoint), for adults with depression who have shown a partial response to 8-14 weeks of antidepressant treatment
Moderate quality evidence from 1 RCT (N=39) shows a clinically important but not statistically significant benefit of augmenting antidepressant treatment with lithium, relative to augmenting with individual CBT, on depression symptomatology at 1-month follow-up for adults with depression who have shown a partial response to 8-14 weeks of antidepressant treatment

Remission

Low quality evidence from 1 RCT (N=44) shows a clinically important but not statistically significant benefit of augmenting antidepressant treatment with lithium, relative to augmenting with individual CBT, on the rate of remission for adults with depression who have shown a partial response to 8-14 weeks of antidepressant treatment

Response

No evidence was identified for this outcome.

Discontinuation due to any reason

Low quality evidence from 1 RCT (N=44) shows neither a clinically important nor statistically significant difference between augmenting antidepressant treatment with lithium and augmenting with individual CBT on discontinuation due to any reason, for adults with depression who have shown a partial response to 8-14 weeks of antidepressant treatment

Discontinuation due to side effects

Low quality evidence from 1 RCT (N=44) shows a higher rate of discontinuation due to side effects associated with augmenting antidepressant treatment with lithium relative to augmenting with individual CBT for adults with depression who have shown a partial response to 8-14 weeks of antidepressant treatment, however this effect is not statistically significant

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 56. Augmenting with lithium versus augmenting with TCA

Critical outcomes

Depression symptomatology

Low quality evidence from 2 RCTs (N=94) shows neither a clinically important nor statistically significant difference between augmenting fluoxetine with lithium or desipramine on depression symptomatology (at endpoint, and change from baseline to endpoint), for adults with depression who have failed to respond to 8 weeks of treatment with fluoxetine

Remission

Very low quality evidence from 2 RCTs (N=94) shows neither a clinically important nor statistically significant difference between augmenting fluoxetine with lithium or desipramine on the rate of remission, for adults with depression who have failed to respond to 8 weeks of treatment with fluoxetine

Response

No evidence was identified for this outcome.

Discontinuation due to any reason

Low quality evidence from 2 RCTs (N=94) shows neither a clinically important nor statistically significant difference between augmenting fluoxetine with lithium or desipramine on the rate of discontinuation due to any reason, for adults with depression who have failed to respond to 8 weeks of treatment with fluoxetine

Discontinuation due to side effects

Very low quality evidence from 1 RCT (N=26) shows a higher rate of discontinuation due to side effects associated with augmenting fluoxetine with desipramine relative to lithium for adults with depression who have failed to respond to 8 weeks of treatment with fluoxetine, however this effect is not statistically significant

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 57. Augmenting with omega-3 fatty acids versus placebo

Critical outcomes

Depression symptomatology

Very low quality evidence from 3 RCTs (N=132) shows a clinically important but not statistically significant benefit of augmenting antidepressant treatment with omega-3 fatty acids, relative to placebo augmentation, on depression symptomatology at endpoint for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Very low quality evidence from 3 RCTs (N=132) shows a clinically important and statistically significant benefit of augmenting antidepressant treatment with omega-3 fatty acids, relative to placebo augmentation, on depression symptomatology change from baseline to endpoint for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Remission

Very low quality evidence from 1 RCT (N=81) shows a clinically important but not statistically significant benefit of augmenting antidepressant treatment with omega-3 fatty acids, relative to placebo augmentation, on the rate of remission for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Response

Very low quality evidence from 3 RCTs (N=170) shows a clinically important but not statistically significant benefit of augmenting antidepressant treatment with omega-3 fatty acids, relative to placebo augmentation, on the rate of response for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to any reason

Low quality evidence from 4 RCTs (N=221) shows neither a clinically important nor statistically significant difference between augmenting antidepressant treatment with omega-3 fatty acids and placebo augmentation on discontinuation due to any reason, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to side effects

Low quality evidence from 4 RCTs (N=221) shows a lower rate of discontinuation due to side effects associated with augmenting antidepressant treatment with omega-3 fatty acids relative to placebo augmentation for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode, however this effect is not statistically significant

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

High quality evidence from 1 RCT (N=50) shows a clinically important and statistically significant benefit of augmenting sertraline with omega-3 fatty acids, relative to placebo augmentation, on sleeping difficulties at endpoint for adults with depression who have failed to respond to 8 weeks of treatment with sertraline

Comparison 58. Augmenting with thyroid hormone versus continuing with antidepressant (+/− placebo)

Critical outcomes

Depression symptomatology

Moderate quality evidence from 1 RCT (N=33) shows a clinically important but not statistically significant benefit of augmenting desipramine or imipramine with triiodothyronine (T3), relative to placebo augmentation, on depression symptomatology at endpoint for adults with depression who have failed to respond to at least 5 weeks of treatment with desipramine/imipramine
Moderate quality evidence from 1 RCT (N=33) shows a clinically important and statistically significant benefit of augmenting desipramine or imipramine with triiodothyronine (T3), relative to placebo augmentation, on depression symptomatology change from baseline to endpoint for adults with depression who have failed to respond to at least 5 weeks of treatment with desipramine/imipramine

Remission

Very low quality evidence from 2 RCTs (N=126) shows a clinically important but not statistically significant benefit of augmenting SSRI/TCA treatment with thyroid hormone, relative to placebo augmentation or continuing with the antidepressant-only, on the rate of remission for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Response

Low quality evidence from 1 RCT (N=93) shows neither a clinically important nor statistically significant difference between augmenting paroxetine with thyroid hormone and continuing with paroxetine-only, on the rate of response for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Discontinuation due to any reason

High quality evidence from 1 RCT (N=33) shows neither a clinically important nor statistically significant difference between augmenting desipramine or imipramine with triiodothyronine (T3) and placebo augmentation on the rate of discontinuation due to any reason, for adults with depression who have failed to respond to at least 5 weeks of treatment with desipramine/imipramine

Discontinuation due to side effects

High quality evidence from 1 RCT (N=33) shows neither a clinically important nor statistically significant difference between augmenting desipramine or imipramine with triiodothyronine (T3) and placebo augmentation on the rate of discontinuation due to side effects, for adults with depression who have failed to respond to at least 5 weeks of treatment with desipramine/imipramine

Important outcomes

Quality of life

Moderate to low quality evidence from 1 RCT (N=93) shows neither a clinically important nor statistically significant difference between augmenting paroxetine with thyroid hormone and continuing with paroxetine-only on quality of life physical and mental component scores, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 59. Augmenting with thyroid hormone versus augmenting with lithium

Critical outcomes

Depression symptomatology

Very low quality evidence from 2 RCTs (N=176) shows a statistically significant but not clinically important benefit of augmenting antidepressant treatment with triiodothyronine (T3), relative to lithium augmentation, on depression symptomatology at endpoint for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Low quality evidence from 2 RCTs (N=176) shows neither a clinically important nor statistically significant difference between augmenting antidepressant treatment with thyroid hormone and augmenting with lithium on depression symptomatology change from baseline to endpoint, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Remission

Very low quality evidence from 2 RCTs (N=177) shows a clinically important but not statistically significant benefit of augmenting antidepressant treatment with triiodothyronine (T3), relative to lithium augmentation, on the rate of remission for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Response

Very low quality evidence from 1 RCT (N=142) shows a clinically important but not statistically significant benefit of augmenting antidepressant treatment with triiodothyronine (T3), relative to lithium augmentation, on the rate of response for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Discontinuation due to any reason

Low quality evidence from 1 RCT (N=142) shows a higher rate of discontinuation due to any reason associated with augmenting desipramine or imipramine with lithium relative to triiodothyronine (T3) augmentation for adults with depression who have failed to respond to at least 5 weeks of treatment with desipramine/imipramine, however this effect is not statistically significant

Discontinuation due to side effects

Low quality evidence from 2 RCT (N=177) shows a significantly higher rate of discontinuation due to side effects associated with augmenting antidepressant treatment with lithium, relative to triiodothyronine (T3) augmentation, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 60. Switching to ECT versus switching to paroxetine

Critical outcomes

Depression symptomatology

Low quality evidence from 1 RCT (N=39) shows a clinically important and statistically significant benefit of switching to ECT, relative switching to paroxetine, on depression symptomatology (at endpoint, and change from baseline to endpoint) for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Remission

No evidence was identified for this outcome.

Response

Very low quality evidence from 1 RCT (N=40) shows a clinically important and statistically significant benefit of switching to ECT, relative switching to paroxetine, on the rate of response for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Discontinuation due to any reason

Low quality evidence from 1 RCT (N=40) shows a higher rate of discontinuation due to any reason associated with switching to paroxetine relative to switching to ECT for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode, however this effect is not statistically significant

Discontinuation due to side effects

High quality evidence from 1 RCT (N=40) shows neither a clinically important nor statistically significant difference between switching to ECT and switching to paroxetine on discontinuation due to side effects, for adults with depression who have shown an inadequate response to at least 2 previous courses of antidepressant treatment for the current episode

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 61. Augmenting with ECT versus continuing with antidepressant

Critical outcomes

Depression symptomatology

Very low quality evidence from 1 RCT (N=40) shows neither a clinically important nor statistically significant difference between augmenting citalopram with ECT and continuing with citalopram-only on depression symptomatology at endpoint, for adults with depression who have failed to respond to 2 weeks of treatment with citalopram
Low quality evidence from 1 RCT (N=40) shows a clinically important but not statistically significant benefit of augmenting citalopram with ECT, relative to continuing with citalopram-only, on depression symptomatology change from baseline to endpoint for adults with depression who have failed to respond to 2 weeks of treatment with citalopram

Remission

No evidence was identified for this outcome.

Response

No evidence was identified for this outcome.

Discontinuation due to any reason

No evidence was identified for this outcome.

Discontinuation due to side effects

No evidence was identified for this outcome.

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 62. Augmenting with ECT versus augmenting with exercise

Critical outcomes

Depression symptomatology

Moderate to low quality evidence from 1 RCT (N=40) shows neither a clinically important nor statistically significant difference between augmenting citalopram with ECT and augmenting with exercise on depression symptomatology (at endpoint, and change from baseline to endpoint), for adults with depression who have failed to respond to 2 weeks of treatment with citalopram

Remission

Low quality evidence from 1 RCT (N=40) shows neither a clinically important nor statistically significant difference between augmenting citalopram with ECT and augmenting with exercise on the rate of remission, for adults with depression who have failed to respond to 2 weeks of treatment with citalopram

Response

No evidence was identified for this outcome.

Discontinuation due to any reason

No evidence was identified for this outcome.

Discontinuation due to side effects

No evidence was identified for this outcome.

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 63. Augmenting with ECT + exercise versus augmenting with exercise

Critical outcomes

Depression symptomatology

High to moderate quality evidence from 1 RCT (N=40) shows a clinically important and statistically significant benefit of augmenting citalopram with both ECT and exercise, relative to augmenting with exercise-only, on depression symptomatology (at endpoint, and change from baseline to endpoint) for adults with depression who have failed to respond to 2 weeks of treatment with citalopram

Remission

High quality evidence from 1 RCT (N=40) shows a clinically important and statistically significant benefit of augmenting citalopram with both ECT and exercise, relative to augmenting with exercise-only, on the rate of remission for adults with depression who have failed to respond to 2 weeks of treatment with citalopram

Response

No evidence was identified for this outcome.

Discontinuation due to any reason

No evidence was identified for this outcome.

Discontinuation due to side effects

No evidence was identified for this outcome.

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 64. Augmenting with exercise versus TAU

Critical outcomes

Depression symptomatology

Moderate quality evidence from 1 RCT (N=52) shows a clinically important and statistically significant benefit of augmenting antidepressant treatment with aerobic exercise, relative to continuing with antidepressant treatment, on depression symptomatology at endpoint for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Moderate quality evidence from 2 RCTs (N=94) shows a clinically important and statistically significant benefit of augmenting antidepressant treatment with aerobic exercise, relative to continuing with antidepressant treatment, on depression symptomatology change from baseline to endpoint for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Remission

Moderate quality evidence from 2 RCTs (N=94) shows a clinically important and statistically significant benefit of augmenting antidepressant treatment with aerobic exercise, relative to continuing with antidepressant treatment, on the rate of remission for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Response

Low quality evidence from 1 RCT (N=42) shows a clinically important but not statistically significant benefit of augmenting SSRI/SNRI treatment with aerobic exercise, relative to enhanced TAU and continuing with SSRI/SNRI treatment, on the rate of response for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to any reason

Low quality evidence from 2 RCTs (N=94) shows neither a clinically important nor statistically significant difference between augmenting antidepressant treatment with aerobic exercise and continuing with antidepressant treatment on discontinuation due to any reason, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to side effects

No evidence was identified for this outcome.

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 65. Augmenting with exercise versus attention-placebo

Critical outcomes

Depression symptomatology

Moderate quality evidence from 1 RCT (N=68) shows neither a clinically important nor statistically significant difference between augmenting escitalopram with a Tai Chi group and augmenting with attention-placebo on depression symptomatology at endpoint, for adults with depression who have failed to respond to 4 weeks of treatment with escitalopram
Low quality evidence from 1 RCT (N=29) shows a clinically important and statistically significant benefit of augmenting antidepressant treatment with aerobic exercise, relative to augmenting with attention-placebo, on depression symptomatology change from baseline to endpoint for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Remission

Low quality evidence from 2 RCTs (N=106) shows a clinically important but not statistically significant benefit of augmenting antidepressant treatment with exercise, relative to augmenting with attention-placebo, on the rate of remission for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Response

Low quality evidence from 2 RCTs (N=119) shows a clinically important and statistically significant benefit of augmenting antidepressant treatment with exercise, relative to augmenting with attention-placebo, on the rate of response for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to any reason

Low quality evidence from 3 RCTs (N=192) shows a higher rate of discontinuation due to any reason associated with augmenting antidepressant treatment with exercise relative to augmenting with attention-placebo for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode, however this effect is not statistically significant

Discontinuation due to side effects

No evidence was identified for this outcome.

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

Low quality evidence from 1 RCT (N=29) shows a clinically important and statistically significant benefit of augmenting antidepressant treatment with aerobic exercise, relative to augmenting with attention-placebo, on global functioning change from baseline to endpoint for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Moderate quality evidence from 1 RCT (N=68) shows neither a clinically important nor statistically significant difference between augmenting escitalopram with a Tai Chi group and augmenting with attention-placebo on sleeping difficulties at endpoint, for adults with depression who have failed to respond to 4 weeks of treatment with escitalopram

Comparison 66. Augmenting with exercise + ECT versus augmenting with ECT

Critical outcomes

Depression symptomatology

High to moderate quality evidence from 1 RCT (N=40) shows a clinically important and statistically significant benefit of augmenting citalopram with both exercise and ECT, relative to augmenting with ECT-only, on depression symptomatology (at endpoint, and change from baseline to endpoint) for adults with depression who have failed to respond to 2 weeks of treatment with citalopram

Remission

High quality evidence from 1 RCT (N=40) shows a clinically important and statistically significant benefit of augmenting citalopram with both exercise and ECT, relative to augmenting with ECT-only, on the rate of remission for adults with depression who have failed to respond to 2 weeks of treatment with citalopram

Response

No evidence was identified for this outcome.

Discontinuation due to any reason

No evidence was identified for this outcome.

Discontinuation due to side effects

No evidence was identified for this outcome.

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Comparison 67. Augmenting with yoga versus continuing with antidepressant (+/− waitlist or attention-placebo)

Critical outcomes

Depression symptomatology

High quality evidence from 1 RCT (N=25) shows a clinically important and statistically significant benefit of augmenting antidepressant treatment with a yoga group intervention, relative to continuing with antidepressant treatment (and being placed on a waitlist for yoga), on depression symptomatology change from baseline to endpoint for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Remission

Low quality evidence from 2 RCTs (N=147) shows a clinically important but not statistically significant benefit of augmenting antidepressant treatment with a yoga group intervention, relative to continuing with antidepressant treatment (in addition to attention-placebo or waitlist), on the rate of remission for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Low to very low quality evidence from 1 RCT (N=122) shows a clinically important but not statistically significant benefit of augmenting antidepressant treatment with a yoga group intervention, relative to augmenting with attention-placebo, on the rate of remission at 3-month and 6-month follow-up for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Response

Very low quality evidence from 2 RCTs (N=147) shows a clinically important but not statistically significant benefit of augmenting antidepressant treatment with a yoga group intervention, relative to continuing with antidepressant treatment (in addition to attention-placebo or waitlist), on the rate of response for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode
Low quality evidence from 1 RCT (N=122) shows a clinically important but not statistically significant benefit of augmenting antidepressant treatment with a yoga group intervention, relative to augmenting with attention-placebo, on the rate of response at 3-month and 6-month follow-up for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to any reason

Very low quality evidence from 2 RCTs (N=147) shows neither a clinically important nor statistically significant difference between augmenting antidepressant treatment with a yoga group intervention and continuing with antidepressant treatment (in addition to attention-placebo or waitlist) on the rate of discontinuation due to any reason, for adults with depression who have shown an inadequate response to at least 1 previous course of antidepressant treatment for the current episode

Discontinuation due to side effects

No evidence was identified for this outcome.

Important outcomes

Quality of life

No evidence was identified for this outcome.

Personal, social, and occupational functioning

No evidence was identified for this outcome.

Economic evidence statements

Evidence from 1 single UK study conducted alongside a RCT (N=637) indicates that computerised CBT with support is unlikely to be cost-effective compared with attention control in people with depression that have had limited response to previous pharmacological treatment. The evidence is directly applicable to the UK context but is characterised by very serious limitations and therefore was not considered further.
Evidence from 1 single UK study conducted alongside a RCT (N=158) is inconclusive regarding the cost effectiveness of cognitive therapy added to treatment as usual in people with depression who have responded inadequately to previous treatment and have residual depressive symptoms, as the outcome measure was not the QALY and interpretation of the results depends on the willingness to pay in order to avoid an additional relapse. This evidence, although it was conducted in the UK, is only partially applicable to the NICE decision-making context (due to lack of QALY estimation) and it characterised by minor limitations.
Evidence from 1 single UK study conducted alongside a RCT (N = 469) suggests that CBT added to treatment as usual is a cost-effective treatment option in people with depression who have responded inadequately to previous treatment. This evidence is directly applicable to the NICE decision-making context and is characterised by minor limitations.
Evidence from 1 single Canadian study conducted alongside a RCT (N=60) suggests that intensive short-term psychodynamic psychotherapy is cost-effective compared with TAU in people with depression who have responded inadequately to previous treatment. The evidence is partially applicable to the UK context and is characterised by potentially serious limitations.
Evidence from 1 single UK study conducted alongside a RCT (N=480) suggests that mirtazapine may be cost-effective when added to a SSRI or SNRI in people who have responded inadequately to previous treatment with a SSRI or SNRI. This evidence, although it was conducted in the UK, is only partially applicable to the NICE decision-making context (due to EQ-5D-5L being used for the estimation of QALYs) and it characterised by minor limitations.
Evidence from 1 US model-based economic study suggests that switching (to venlafaxine or sertraline) or augmentation (with bupropion) pharmacological strategies are more cost-effective than continuation of current antidepressant treatment (citalopram) in adults with major depression that failed to respond to previous treatment. The study is partially applicable to the UK context and is characterised by very serious limitations.
Evidence from 1 US model-based economic study suggests that switching (to venlafaxine or sertraline) or augmentation (with bupropion) pharmacological strategies are more cost-effective than continuation of current antidepressant treatment (citalopram) in adults with major depression that failed to respond to previous treatment with a SSRI. The study is partially applicable to the UK context and is characterised by very serious limitations.
Evidence from 1 Finnish model-based economic study suggests that switching to bupropion is more cost-effective that switching to venlafaxine or sertraline in adults with depression that failed to respond to previous treatment with a SSRI. The study is partially applicable to the UK context and is characterised by potentially serious limitations. Evidence from 1 US study that made the same comparison was difficult to interpret, as the study did not use the QALY as the measure of outcome; nevertheless, the study suggested that the relative cost-effectiveness of the 3 treatment options was characterised by uncertainty. The US study is partially applicable to the UK context and is characterised by minor limitations.
Evidence from 1 UK model-based economic study suggests that duloxetine is more cost-effective than venlafaxine and mirtazapine in people with depression who have responded inadequately to previous antidepressant treatment with SSRIs. The study is directly applicable to the UK context but is characterised by potentially serious limitations.
Evidence from 1 Swedish model-based economic study suggests that escitalopram is more cost-effective than duloxetine and venlafaxine in adults with major depression treated in primary care, who had had a history of treatment with another antidepressant within the previous 6 months. The study is partially applicable to the UK context and is characterised by potentially serious limitations.
Evidence from 1 US model-based economic study suggests that paroxetine controlled release and sertraline are less cost-effective compared with other SSRIs in adults with major depression who failed to achieve remission with previous treatment with SSRIs. The study is partially applicable to the UK context and is characterised by very serious limitations.
Evidence from 1 UK model-based study suggests that lithium dominates antipsychotics as an adjunct to SSRIs in the treatment of adults with treatment-resistant depression. The study is directly applicable to the NICE decision-making context and is characterised by potentially serious limitations.
Evidence from 1 US study conducted alongside a RCT (N=1522) is inconclusive regarding the cost-effectiveness of aripiprazole adjunct to antidepressants versus bupropion adjunct to antidepressants versus switching to bupropion in adults with treatment-resistant depression. The study is partially applicable to the UK and is characterised by potentially serious limitations.
Evidence from 2 US model-based economic study was inconclusive as to whether antipsychotics used as adjuncts to antidepressant therapy were cost-effective compared with antidepressant therapy alone in adults with major depression who had responded inadequately to previous antidepressant therapy, as the studies did not use the QALY as the measure of outcome. The studies are partially applicable to the UK context; one is characterised by very serious limitations and the other by potentially serious limitations.
Evidence from 1 model-based UK study suggests that ECT may be cost-effective as part of a sequence of treatments that includes ECT – SSRI – lithium augmentation in adults with major depression that requires hospitalisation. The evidence is partially applicable to the NICE decision-making context and is characterised by potentially serious limitations.
Evidence from 1 model-based US study suggests that ECT may be cost-effective as part of a sequence of antidepressant, psychological and ECT treatments. The evidence is partially applicable to the UK and is characterised by very serious limitations.

The committee’s discussion of the evidence

Interpreting the evidence

The outcomes that matter most

The aim of this review was to identify the most effective treatments for depression that has not responded to previous therapies, so the committee prioritised depression symptomatology, remission and response as critical outcomes. As a treatment can only be effective if it is utilised by the person with depression, discontinuation due to any reason, and due to side effects, were also prioritised by the committee as critical outcomes.

The aim of treating depression is to improve people’s life and so health-related quality of life and personal, social and occupational functioning were chosen as important outcomes. The committee were cognisant that for people with depression, quality of life may be the most valued outcome, however, it was not prioritised as a critical outcome as the committee were aware that the data for this outcome was very limited and so it would have less of an impact on decision-making.

The quality of the evidence

The quality of evidence was assessed using GRADE and was generally rated as low to very low, reflecting the high risk of bias associated with the studies. This included high risk of bias associated with randomisation method (as reflected by significant group differences at baseline), and lack of (or unclear) blinding of outcome assessment. There were also a limited number of studies for each comparator, small numbers of participants in most trials and imprecision in most of the results.

Benefits and harms

In developing recommendations for people with depression that has not responded or where there has been a limited response to treatment, the committee drew on their knowledge and experience that a significant number of people with depression may not adhere to the prescribed treatment regimen and their personal or social factors could have a significant impact on their response to treatment, and so should be identified and addressed if possible. They therefore agreed that a review of these factors should be considered before initiating any additional treatment options. Based on the expert opinion of the committee, it was noted that coexisting conditions or alternative diagnoses could also limit response to treatment, and it was agreed that the diagnosis should be reviewed if adherence and lifestyle factors had been addressed and a limited response continued.

The committee recognised that people with depression may experience a loss of confidence when the initial treatment has not worked, and may need reassurance that alternative or additional treatments can be tried, and that this can include a discussion about the rationale for switching to an alternative approach, acknowledging that some treatments have not worked and providing some explanation about how the further-line treatment works differently.

When developing the recommendations for further-line treatment, the committee considered a number of factors including the relative strength of the evidence, the preference that service users may have for medication or psychological interventions and the adverse effects of medication, in particular when combinations of medications are used. The committee were aware, from established data on response curves to antidepressant treatment that most people who respond to pharmacological interventions will have have shown some response within 4 weeks of initiation of treatment. Response curves are similar for psychological interventions but response to psychological interventions may initially be slower than to medication with people typically responding to treatment within 4 to 6 weeks.

In developing their recommendations, the committee considered three main scenarios: first where a person had not responded to initial psychological therapy, secondly where a person had not responded to initial antidepressant medication, and thirdly where a person had not responded to initial treatment with a combination of antidepressant medication and psychological therapy.

Where there was limited or no response to initial psychological therapy, the committee drew on their expert knowledge, and evidence for other review questions in this guideline, as there was no evidence identified that was specific to this population. Based on this limited evidence base, the committee also made a research recommendation. The committee agreed that switching to an alternative psychological intervention may align with clinical needs and preferences, particularly for people who may not want to take antidepressant medication, and that this option should be discussed and considered. The committee also recommended a combination of a psychological intervention with antidepressant medication (adding an SSRI) as an option for those who have shown a limited response to initial psychological therapy alone and who were willing to try an antidepressant. In developing this recommendation, the committee drew on the evidence for first-line treatments particularly in more severe depression where combination treatment was more clinically and cost-effective than medication alone. The committee also recognised that those who had shown limited response to an initial psychological intervention may wish to switch to an antidepressant treatment and so, drawing on their expert knowledge and experience and the data on first-line treatments developed a recommendation that a person should have the option of switching to an SSRI alone.

Where there was limited or no response to an initial antidepressant monotherapy the committee recommended that, based on the evidence, either a group exercise programme or a psychological therapy should be used to augment the antidepressant. Alternatively, individuals could switch to a psychological intervention, or antidepressant medication could be continued but with an alternative drug or an increased dose. There was some evidence from randomised controlled trials for clinical benefits associated with augmenting antidepressant treatment with group exercise programmes, in particular aerobic exercise groups, and the committee agreed that this option should be discussed with the person and offered. However, the committee took into account that this option may not suit everyone, and may be difficult for some people to engage with. There was evidence from multiple trials in the review of the benefit of augmenting antidepressant medication with cognitive-behavioural therapies. The committee were also aware of a number of important, often pragmatic, trials of cognitive-behavioural therapies (including CBASP and rumination-focused CBT) as further-line treatment or treatment for residual depression, which replicated the findings in the meta-analysis but were excluded, typically because patients were not randomised at the point of non-response (including Clarke 2002; Fava 1994; Hollon 2014; Hvenegaard 2020; Moore and Blackburn 1997; Segal 2020; Teissman 2014). The committee agreed that an alternative further-line treatment option for those who have not responded to initial antidepressant treatment could be switching to a psychological intervention. There was no evidence that specifically examined switching to a psychological intervention for those who have not responded to initial antidepressant treatment, however, the committee drew on the evidence for first-line treatments in more severe depression. The committee agreed that the psychological interventions that had been identified as effective and cost-effective for first-line treatment of more severe depression could be used for people who had not responded to antidepressants and wished to try a psychological therapy instead. The committee also considered options for continuing antidepressant treatment. The committee were aware that currently, a common approach to a limited or non-response to pharmacological interventions is to either increase the dose or switch to an alternative medication. The committee noted that the evidence reviewed in this guideline did not provide significant support for either of these two strategies as being effective. However, the committee were aware that in a number of the trials which were reviewed, the absence of benefit may have been due to improvement in the continued antidepressant/dose arm. The committee were also aware that some people would not want to try an exercise programme or a psychological intervention, nor be willing to accept the increased side effect burden of combined drug treatment. Given this, the committee agreed to make a recommendation for switching to another antidepressant or increasing the dose. However, the committee were concerned about the limited evidence for these strategies and so also recommended close monitoring and a review of the treatment strategy. They also recommended that discussion of other treatment options should take place and consideration be given to referral for specialist advice.

Where there was limited or no response to combined antidepressant medication and psychological therapy, the committee considered that the options used in those who had failed to respond to psychological intervention alone or antidepressant medication monotherapy, namely switching to another psychological therapy and/or continuing with antidepressant medication using an alternative drug or increased dose, should be used. Combinations with an antidepressant of a different class, antipsychotics (aripiprazole, risperidone, quetiapine, olanzapine) and lithium were all identified in the reviews undertaken for this guideline as effective: there was evidence for improved depression symptomatology and higher rates of remission or response in the treatment of people with no or limited response to initial antidepressant treatment and so the committee decided to recommend these options. There was also some evidence for clinical benefits associated with augmenting antidepressant treatment with ECT, lamotrigine or triiodothyronine, however, the committee agreed that these further-line treatment strategies may require increased monitoring, and that use of all combination medications would require advice from specialist mental health services. There was also some evidence for the use of augmentation with omega-3 but the committee noted that the studies used a number of different preparations and that there was uncertainty about the dose and preparation and so they did not recommend this combination. The committee were aware that for all combinations of medication, there was a risk of a significant increase in side effect burden and therefore recommended that people should be informed about this so that they can decide if this increased burden is acceptable to them.

The committee were aware that there was already NICE guidance on the use of vortioxetine in people who had had no or limited response to at least 2 previous antidepressants and so they included a reference to this as part of their recommendations.

There was some very limited evidence that ECT may be beneficial as a further-line treatment, either alone or in combination with exercise. The committee used this evidence to recommend that ECT may be considered for use as further-line treatment when other treatments have been unsuccessful. However, the committee were aware that there may be other situations where ECT could be considered: when a rapid response is needed (and the committee provided an example of when this might be the case), or if a person with severe depression had received successful ECT in the past and expressed a preference for it. The committee discussed the care and considerations that needed to be taken into account when delivering ECT, such as informing people of the risks and benefits, obtaining consent, monitoring cognitive function and stopping ECT. The committee amended the existing recommendations on these topics but agreed that there are now recognised up to date standards produced by the Royal College of Psychiatrists which provide guidance on how a safe and effective ECT service should be delivered. This is in the contect of an ECT accreditation service (ECTAS), and so the committee added a recommendation to advise that clinics providing ECT should be accredited, and Trusts should ensure compliance with ECTAS standards.

The committee were aware that, since the publication of the previous guideline, there had been much further research into refining the administration of ECT, comparing different modalities of ECT treatment, comparing ECT with other neuromodulatory therapies, and into possible adverse effects. However the remit of the original review of ECT for the guideline did not include other neuromodulatory techniques (and/or rapidly acting treatments) or within-class comparisons, and so had not taken account of this wider evidence base and so the committee agreed that further work would be necessary to allow incorporation of this evidence into the recommendations on ECT.

The committee considered the short-term and long-term harms associated with medication, for example, side effects associated with SSRIs include drowsiness, nausea, insomnia, agitation, restlessness and sexual problems. For the TCAs there is the potential for cardiotoxicity and associated increased risk in overdose, although this is much greater for some TCAs such as amitriptyline and dosulepin and so the committee included a warning about this. They also added, based on their knowledge and the BNF guidance that ‘lofepramine has a lower incidence of side-effects and is less dangerous in overdose [than other tricyclic antidepressants]’ the fact that lofepramine has the best safety profile.. For lithium there were concerns about renal toxicity and thyroid and parathyroid function. For the antipsychotics concerns with weight gain and hyperlipidaemia and raised blood glucose were also considered. The committee took these factors into consideration and in particular the increased burden of harms that may arise with the use of a combination of medications. In developing the recommendations, the committee were mindful of the negative consequences of prolonged depressive episodes including not only the impact on the mental health of the individual and their family but also on an individual’s physical health (depression is associated with poorer physical health outcomes) and the impact on employment. The committee agreed that the benefits of improving the outcome of a depressive episode outweighed the potential harms. The committee were also aware that a number of prescribers, including GPs, would not feel competent to initiate such combination treatment and therefore also recommended that combination therapy should be initiated in specialist settings or after consulting a specialist.

Longer-term follow-up

The committee noted that very few studies of further-line treatment reported any follow-up data, and this data was particularly sparse for the pharmacological trials. A small number of studies could be combined in meta-analyses for outcomes up to 6 months after endpoint, however, beyond this point it was predominantly single-study analyses. The committee considered this limited evidence, and noted that a small number of studies showed evidence for sustained benefits on depression outcomes associated with augmenting antidepressants with CBT (up to 40 months), IPT (up to 12 months), short-term psychodynamic psychotherapy (up to 12 months), and long-term psychodynamic psychotherapy (up to 2 years). The committee agreed that the effects on depression outcomes at follow-up were generally in line with the effects observed at endpoint, and this strengthened their confidence in the recommendations.

Quality of life and functioning outcomes

The committee also noted that there was very little data for quality of life or functioning outcomes. The committee considered the evidence for clinically important and statistically significant effects, and noted single-study analyses showing equivocal benefits on quality of life associated with increasing the dose of an SSRI (versus same dose), some evidence for a benefit on global functioning or functional impairment of antipsychotic augmentation (relative to increasing SSRI dose, or continuing with the antidepressant at the same dose) or augmenting antidepressants with exercise, and of omega-3 augmentation on sleeping difficulties. However, given the sparsity of this evidence, and that it is broadly consistent with the findings observed for the critical outcomes, the committee did not consider it necessary to make any changes to recommendations based on effects observed for quality of life and functioning outcomes.

Cost effectiveness and resource use

The committee considered the high healthcare costs and outcomes to the person associated with depression showing an inadequate response to treatment, and expressed the view that successful treatment, as expressed by full response to treatment and eventual remission, would lead to the optimal outcome to the person but also considerable cost-savings to the healthcare system.

The committee considered the available economic evidence on treatments for people with depression who have responded inadequately to previous treatment. They noted that UK evidence suggests that CBT may be a cost-effective treatment option in this population when added to TAU (including pharmacological treatment) compared with TAU alone. Also, there was limited non-UK evidence suggesting that short-term psychodynamic psychotherapy may be cost-effective in this population when added to secondary care TAU. Regarding drugs, evidence from the UK suggests that mirtazapine is likely to be cost-effective when added to a SSRI or SNRI in people who have responded inadequately to previous treatment with a SSRI or SNRI; other UK evidence suggests that duloxetine is more cost-effective than venlafaxine and mirtazapine in people with depression that has responded inadequately to previous treatment with SSRIs. Evidence from Sweden suggests that escitalopram is more cost-effective than duloxetine and venlafaxine in people whose depression responded inadequately to previous antidepressant treatment. Evidence from Finland suggests that switching to bupropion is more cost-effective that switching to venlafaxine or sertraline in adults with depression that failed to respond to previous treatment with a SSRI. Other evidence from the UK suggests that lithium dominates antipsychotics as an adjunct to SSRIs in the treatment of adults with depression that has not responded to treatment. The committee noted that economic evidence on psychological interventions is overall characterised by minor limitations, whereas evidence on pharmacological interventions is characterised by minor to potentially serious limitations. Other available non-UK evidence was not considered as it was characterised by very serious limitations and/or high uncertainty. Finally, there was some UK evidence that ECT may be cost-effective as part of a sequence of treatments that includes ECT – SSRI – lithium augmentation in adults with major depression that requires hospitalisation. The committee considered this evidence when formulating separate ECT recommendations in the guideline.

The committee acknowledged that the economic evidence in this area is rather sparse and has limitations, and decided to draw additional information from the economic analysis of treatments of a new depressive episode that was undertaken for the guideline (See Evidence report B, Appendix J). According to the guideline economic analysis, group psychological therapies (such as group CBT and group behavioural activation), pharmacological treatment, and other low-intensity psychological and physical interventions were the most cost-effective options for the treatment of new episodes of less severe depression in adults. For populations with more severe depression, the combination of individual CBT with an antidepressant was likely to be the most cost-effective option for the treatment of new episodes, followed by pharmacological treatments, group exercise and individual psychological interventions (such as CBT, BA and IPT). All these options were found to be more cost-effective than GP care.

Considering the available economic evidence, the committee decided to recommend further-line treatment options among those that were found to be cost-effective versus TAU (which might include GP care, referral to specialist care, and/or active pharmacological treatment), according to the type of treatment to which there was no or inadequate response, following a shared decision and based on the person’s clinical need and preferences. They therefore recommended, as one cost-effective option, the combination of medication and psychological treatment for people who have responded inadequately to medication alone or to psychological intervention alone, and the possibility of changing the components of combination therapy in people who are already on a combination of medication and a psychological therapy.

The committee considered that offering an SSRI or mirtazapine as an alternative or as an adjunct to psychological treatment to people whose symptoms have not adequately responded to an initial psychological intervention would have minor resource implications as the intervention cost of providing antidepressant treatment is overall lower than that of an individual psychological intervention. Moreover, the committee noted that switching from a psychological therapy that led to inadequate response to a different type of psychological therapy or a different type of treatment, such as pharmacological or combined therapy, would potentially result in better outcomes for the person and, therefore, anticipated reduction in further care costs.

The committee considered that increasing the dose of a well-tolerated drug, switching between antidepressants within the same or different class, or adding an antidepressant to existing medication (for example, adding a SSRI or mirtazapine) would have negligible resource implications in terms of the drug acquisition cost, as these drugs are available in generic form, although there are costs associated with the necessary clinical review of dose escalations or switching. Switching from a drug that is causing side effects to another drug of the same or different class may lead to cost-savings and better outcomes for the person, if the new drug is better tolerated.

The committee noted that, according to existing evidence, offering psychological therapy to people who have limited response to previous pharmacological treatment may be cost-effective. They also considered that adding a group exercise intervention to people with inadequate response to previous antidepressant treatment has been shown to be beneficial to the person and is likely to have minor resource implications.

The committee acknowledged the additional costs associated with combined medication therapy, for example combined antidepressant treatment or provision of lithium or antipsychotics in addition to antidepressant treatment, which should take place in specialist settings or after consultation with a specialist. These costs relate to specialist staff time but also to monitoring costs and costs associated with side effects. The committee considered the available UK evidence according to which adding mirtazapine to SSRI treatment is cost-effective. They also noted that lithium dominates antipsychotics as an adjunct to SSRIs in the treatment of adults with depression that has not responded to treatment, but noted that this evidence was characterised by potentially serious limitations. Based on the above considerations, the committee recommended combining different antidepressants (for example mirtazapine with a SSRI) or combining antidepressants with an antipsychotic or lithium in specialist settings, or after consultation with a specialist, as an option if a person has had no response or a limited response to antidepressant medication, does not want to try a psychological therapy, and wants to try a combination of medications and is willing to accept the possibility of an increased side-effect burden. In this population, alternative effective treatment options are limited and the committee expressed the view that the benefits of combined medication treatment are likely to outweigh costs associated with its provision to this group.

Other factors the committee took into account

When reviewing the evidence for further line treatment the committee had originally decided to separately examine the evidence base for treatment resistant depression (usually defined as no or limited response to two adequate courses of an antidepressant) from no or limited response to treatment. However, after carefully reviewing the trial populations and the variation in the criteria used to identify both no or limited response and treatment resistance the committee came to the view that there were considerable similarities and overlaps between the two populations and therefore decided to use the same data sets for both questions to inform the development of recommendations for no or limited response.

The review of further-line treatment included those with chronic depression, but the committee also took into consideration the evidence base for the first-line treatment of chronic depression that was reviewed in Evidence report E. When reviewing the evidence for further-line treatment, the committee were aware that a number of pragmatic trials were excluded, typically because they recruited in usual clinical settings and participants were not randomised at the point of no/inadequate/limited response. The committee used their knowledge of these studies in the round when interpreting the evidence from the systematic review and making recommendations.

Recommendations supported by this evidence review

This evidence review supports recommendations 1.9.1 to 1.9.9, 1.13.1 to 1.3.9 and research recommendations in the NICE guideline.

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Appendices

Appendix D. Clinical evidence tables

Evidence tables for review question: What are the relative benefits and harms of further-line psychological, psychosocial, pharmacological and physical interventions (alone or in combination), for adults with depression showing an inadequate response to at least one previous intervention for the current episode?

Please refer to the clinical evidence tables in supplement D – Clinical evidence tables for Evidence review D Further-line treatment.

Appendix E. Forest plots

Forest plots for review question: What are the relative benefits and harms of further-line psychological, psychosocial, pharmacological and physical interventions (alone or in combination), for adults with depression showing an inadequate response to at least one previous intervention for the current episode? (PDF, 5.2M)

Appendix F. GRADE tables

GRADE tables for review question: What are the relative benefits and harms of further-line psychological, psychosocial, pharmacological and physical interventions (alone or in combination), for adults with depression showing an inadequate response to at least one previous intervention for the current episode? (PDF, 2.5M)

Appendix G. Economic evidence study selection

Economic evidence study selection for review question: What are the relative benefits and harms of further-line psychological, psychosocial, pharmacological and physical interventions (alone or in combination), for adults with depression showing an inadequate response to at least one previous intervention for the current episode? (PDF, 221K)

Appendix H. Economic evidence tables

Economic evidence tables for review question: What are the relative benefits and harms of further-line psychological, psychosocial, pharmacological and physical interventions (alone or in combination), for adults with depression showing an inadequate response to at least one previous intervention for the current episode? (PDF, 368K)

Appendix I. Economic evidence profiles

Economic evidence profiles for review question: What are the relative benefits and harms of further-line psychological, psychosocial, pharmacological and physical interventions (alone or in combination), for adults with depression showing an inadequate response to at least one previous intervention for the current episode? (PDF, 287K)

Appendix J. Economic analysis

Economic analysis for review question: What are the relative benefits and harms of further-line psychological, psychosocial, pharmacological and physical interventions (alone or in combination), for adults with depression showing an inadequate response to at least one previous intervention for the current episode?

No economic analysis was conducted for this review question.

Appendix K. Excluded studies

Excluded studies for review question: What are the relative benefits and harms of further-line psychological, psychosocial, pharmacological and physical interventions (alone or in combination), for adults with depression showing an inadequate response to at least one previous intervention for the current episode?

Clinical studies

Please refer to the excluded studies in supplement D – Clinical evidence tables for Evidence Review D Further-line treatment.

Economic studies

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

Appendix L. Research recommendations

Research recommendations for review question: What are the relative benefits and harms of further-line psychological, psychosocial, pharmacological and physical interventions (alone or in combination), for adults with depression showing an inadequate response to at least one previous intervention for the current episode? (PDF, 224K)

Supplemental Data

d1: Clinical evidence tables for review question 2.42.5 (Excel)

Tables

Table 1Summary of the protocol (PICO table)

Population	Adults in a depressive episode whose depression has not responded or there has been limited response to previous treatment(s) (for the current episode) according to DSM, ICD or similar criteria, or (residual) depressive symptoms as indicated by depression scale score, or who have not tolerated previous treatment (for the current episode), or who are defined as meeting criteria for treatment-resistant depression, and who have been randomised to the further-line interventions at the point at which they had no/inadequate/limited response If some, but not all, of a study’s participants are eligible for the review, then we will include a study if at least 80% of its participants are eligible for this review.
Intervention	Psychological interventions: Behavioural therapies Cognitive and cognitive behavioural therapies Counselling Interpersonal psychotherapy Psychodynamic psychotherapies Psychoeducational interventions Self-help with or without support Art therapy Music therapy Eye movement desensitization and reprocessing (EMDR) (for depression, not PTSD) Psychosocial interventions: Peer support Mindfulness, meditation or relaxation Pharmacological interventions: SSRIs, including: Citalopram Escitalopram Fluoxetine Fluvoxamine Paroxetine Sertraline TCAs, including: Amineptine Amitriptyline Clomipramine Desipramine Imipramine Lofepramine Nortriptyline TeCAs Mianserin SNRIs, including: Duloxetine Venlafaxine Other antidepressant drugs Bupropion Mirtazapine Anticonvulsants, including: Lamotrigine Antipsychotics, including: Amisulpride Aripiprazole Olanzapine Quetiapine Risperidone Ziprasidone Anxiolytics Buspirone Stimulants Methylphenidate Other agents Lithium Omega-3 fatty acids Thyroid hormones Physical interventions: Acupuncture ECT Exercise Yoga Light therapy (for depression, not SAD) Interventions will be categorised into the following strategies: Dose escalation strategies Switching strategies Augmentation strategies
Comparison	Other active intervention (must also meet inclusion criteria above) Treatment as usual Waitlist No treatment Placebo
Outcome	Critical: Depression symptomatology Remission Response Discontinuation due to any reason Discontinuation due to side effects Important: Quality of life Personal, social, and occupational functioning

: DSM: Diagnostic and statistical manual of mental disorders; ECT: electroconvulsive therapy; ICD: international classification of diseases; PTSD: post-traumatic stress disorder; SAD: seasonal affective disorder; SNRIs: serotonin noradrenaline reuptake inhibitor SSRIs: selective serotonin reuptake inhibitor; TCA: tricyclic antidepressant; TeCA: tetracyclic antidepressant

Table 2Summary of included studies. Comparison 1. Augmenting with cognitive and cognitive behavioural therapies versus continuing with antidepressant (+/ waitlist or attention-placebo)

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Chan 2012

RCT

China

N=50

Mean age (years): 46.2

Gender (% female): 76

Ethnicity (% BME): NR

Baseline severity: HAMD 11.91 (less severe)

CBT group + any antidepressant

Intensity: 10x 90-min sessions

Waitlist + any antidepressant

Inadequate response: participants met inclusion criteria despite all receiving antidepressants at baseline

Treatment length (weeks): 10

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score
Discontinuation due to any reason

Chiesa 2015

RCT

Italy

N=50

Mean age (years): 49.0

Gender (% female): 72

Ethnicity (% BME): NR

Baseline severity: HAMD 16.4 (more severe)

Mindfulness-based cognitive therapy (MBCT) group + any antidepressant

Intensity: 8x 2-hour weekly sessions

Attention-placebo (psychoeducational control group) + any antidepressant

Intensity: 8x 2-hour weekly sessions

Inadequate response (failure to achieve remission, HAMD score≥8) to treatment with antidepressants at adequate dosages for at least 8 weeks before study beginning

Treatment length (weeks): 8

Outcomes:

Depression symptomatology at:
- Endpoint
- 2-month follow-up
- 4-month follow-up
Depression symptomatology change score
Discontinuation due to any reason

Dozois 2009

RCT

Canada

N=48

Mean age (years): 46.5

Gender (% female): 74

Ethnicity (% BME): 2

Baseline severity: HAMD 19.72 (more severe)

CBT individual + any antidepressant

Intensity: 15x 1-hour sessions

Waitlist + any antidepressant

Inadequate response: participants met inclusion criteria despite all receiving antidepressants at baseline

Treatment length (weeks): 15

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score
Discontinuation due to any reason

Dunn 1979

RCT

Canada

N=24

Mean age (years): NR

Gender (% female): 70

Ethnicity (% BME): NR

Baseline severity: BDI 22.5 (more severe)

CBT individual + TCA

Intensity: 16x twice-weekly sessions

Waitlist + TCA

Inadequate response to current TCA treatment

Treatment length (weeks): 8

Outcomes:

Depression symptomatology at:
- Endpoint
- 6-month follow-up
Depression symptomatology change score

Eisendrath 2016

RCT

N=173

Mean age (years): 46.2

Gender (% female): 76

Ethnicity (% BME): 20

Baseline severity: HAMD 17.9 (more severe)

Mindfulness-based cognitive therapy (MBCT) group + any antidepressant

Intensity: 8x 2.25-hour weekly sessions

Attention-placebo (health enhancement programme) + any AD antidepressant

Intensity: 8x 2.25-hour weekly sessions

TRD: Inadequate response to 2 or more adequate trials prescribed during the current episode assessed with the Antidepressant Treatment History Form (ATHF)

Treatment length (weeks): 8

Outcomes:

Remission
Response
Discontinuation due to any reason

Embling 2002

RCT

N=38

Mean age (years): NR

Gender (% female): NR

Ethnicity (% BME): NR

Baseline severity: BDI-II 31 (more severe)

CBT group + any antidepressant

Intensity: 12x 60-90 min sessions

Waitlist + any antidepressant

Inadequate response: participants met inclusion criteria despite taking antidepressants for at least 1 month prior to study entry

Treatment length (weeks): 8

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score

Kocsis 2009/Klein 2011

RCT

N=296

Mean age (years): 44.6

Gender (% female): 54

Ethnicity (% BME): 11

Baseline severity: HAMD 19.15 (more severe)

Cognitive behavioral analysis system of psychotherapy (CBASP) + any antidepressant

Intensity: 16-20 sessions

Any antidepressant

Inadequate response (≥60% reduction in HAMD score, a HAMD total score<8, and no longer meeting DSM-IV criteria for MDD for 2 consecutive visits during weeks 6-12) to 12 weeks of antidepressant medication according to a pharmacotherapy algorithm

Treatment length (weeks): 12

Outcomes:

Depression symptomatology endpoint
Remission
Discontinuation due ato any reason
Functional impairment endpoint

Lynch 2007_study 2

RCT

N=35

Mean age (years): 61.4

Gender (% female): 46

Ethnicity (% BME): 14

Baseline severity: HAMD 16.53 (more severe)

Dialectical behaviour therapy (DBT) + any antidepressant

Intensity: 24x individual sessions + 24x group sessions

Any antidepressant

Inadequate response (HAMD score>10) to 8 weeks of prospective treatment with physician choice of SSRI

Treatment length (weeks): 24

Outcomes:

Depression symptomatology endpoint
Remission
Discontinuation due ato any reason

Nakagawa 2017

RCT

Japan

N=80

Mean age (years): 40.6

Gender (% female): 36

Ethnicity (% BME): NR

Baseline severity: HAMD 20.9 (more severe)

CBT individual + any antidepressant

Intensity: 16x 50-min sessions (+4 additional sessions if appropriate)

Any antidepressant

Inadequate response: at least a minimal degree of treatment-resistant depression (Maudsley Staging Method for treatment-resistant depression score≥3) and HAMD score≥16 despite having received adequate therapeutic levels of antidepressant medication for at least 8 weeks as part of their routine care

Treatment length (weeks): 16

Outcomes:

Depression symptomatology at:
- Endpoint
- 3-month follow-up
- 6-month follow-up
- 12-month follow-up
Depression symptomatology change score
Remission at:
- Endpoint
- 3-month follow-up
- 6-month follow-up
- 12-month follow-up
Response at:
- Endpoint
- 3-month follow-up
- 6-month follow-up
- 12-month follow-up
Discontinuation due ato any reason
Quality of life physical component score at:
- Endpoint
- 3-month follow-up
- 6-month follow-up
- 12-month follow-up
Quality of life mental component score at:
- Endpoint
- 3-month follow-up
- 6-month follow-up
- 12-month follow-up

Nakao 2018

RCT

Japan

N=40

Mean age (years): 40.2

Gender (% female): 50

Ethnicity (% BME): NR

Baseline severity: HAMD 18.4 (more severe)

Blended computerised CBT and individual face-to-face CBT + any antidepressant

Intensity: 12 online modules + 12x 45-min face-to-face sessions

Waitlist + any antidepressant

Inadequate response: HAMD score ≥14 despite having received adequate therapy with ≥1 antidepressant medications for at least 6 weeks as part of their routine care

Treatment length (weeks): 12

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score
Remission
Response
Discontinuation due ato any reason
Quality of life endpoint
Quality of life physical component score
Quality of life mental component score

Paykel 1999/Scott 2000

RCT

N=158

Mean age (years): 43.4

Gender (% female): 49

Ethnicity (% BME): NR

Baseline severity: HAMD 12.2 (less severe)

CBT individual + any antidepressant

Intensity: 16 sessions

Any antidepressant

Inadequate response (HAMD≥8 and BDI≥9) to antidepressant medication for at least the previous 8 weeks, with at least 4 weeks at an adequate dose

Treatment length (weeks): 20

Outcomes:

Depression symptomatology at:
- Endpoint
- 6-month follow-up
- 11-month follow-up
Depression symptomatology change score
Remission
Discontinuation due ato any reason
Functional impairment at:
- Endpoint
- 11-month follow-up

Strauss 2012

RCT

N=28

Mean age (years): 43

Gender (% female): 71

Ethnicity (% BME): NR

Baseline severity: BDI-II 39.11 (more severe)

Person-based cognitive therapy (PBCT) group + any antidepressant

Intensity: 12x 90-min sessions

Any antidepressant

Inadequate response: met inclusion criteria despite requirement to have been on stable antidepressant treatment for at least 3 months

Treatment length (weeks): 12

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score
Discontinuation due ato any reason

Watkins 2011a

RCT

N=42

Mean age (years): 44.2

Gender (% female): 57

Ethnicity (% BME): 5

Baseline severity: HAMD 12.7 (less severe)

Rumination-focused CBT + SSRI/SNRI

Intensity: 12 sessions

SSRI/SNRI

Inadequate response (HAMD score≥8 and BDI-II score≥9) to antidepressant medication taken at a therapeutic dose as recommended by the BNF and/or equivalent to 125 mg of amitriptyline for at least 8 weeks continuously during the current episode and within the past 2 months

Treatment length (weeks): 26

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score
Remission
Response
Discontinuation due ato any reason

Wiles 2008

RCT

N=25

Mean age (years): 45.3

Gender (% female): 84

Ethnicity (% BME): NR

Baseline severity: BDI-II 29.21 (less severe)

CBT individual + SSRI

Intensity: 12-20 sessions

SSRI

Inadequate response (BDI-II≥15) despite having taken antidepressant medication for at least 6 weeks at recommended (BNF) doses

Treatment length (weeks): 17

Outcomes:

Response
Discontinuation due ato any reason

Wiles 2013/2016

RCT

N=469

Mean age (years): 49.6

Gender (% female): 72

Ethnicity (% BME): 2

Baseline severity: BDI-II 31.8 (more severe)

CBT individual + any antidepressant

Intensity: 12x 50-60min sessions (+6 sessions if judged to be clinically appropriate)

Any antidepressant

Inadequate response (BDI-II≥14) to an adhered to, adequate dose of antidepressant medication (based on BNF and advice from psychopharmacology experts) for at least 6 weeks

Treatment length (weeks): 26

Outcomes:

Depression symptomatology at:
- Endpoint
- 6-month follow-up
- 40-month follow-up
Remission at:
- Endpoint
- 6-month follow-up
- 40-month follow-up
Response at:
- Endpoint
- 6-month follow-up
- 40-month follow-up
Discontinuation due ato any reason
Quality of life physical component score at:
- Endpoint
- 6-month follow-up
- 40-month follow-up
Quality of life mental component score at:
- Endpoint
- 6-month follow-up
- 40-month follow-up

: BDI/BDI-II: Beck depression inventory; BME: black and minority ethnic; BNF: British national formulary; CBT: cognitive behavioural therapy; DSM: diagnostic statistical manual; HAMD: Hamilton depression scale; MDD: major depressive disorder; NR: not reported; RCT: randomised controlled trial; SNRI: serotonin–norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; TCA: tricyclic antidepressant; TRD: treatment-resistant depression

Table 3Summary of included studies. Comparison 2. Augmenting with cognitive and cognitive behavioural therapies versus augmenting with counselling

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Kocsis 2009/Klein 2011

RCT

N=395

Mean age (years): 45.8

Gender (% female): 57

Ethnicity (% BME): 10

Baseline severity: HAMD 19.48 (more severe)

Cognitive behavioral analysis system of psychotherapy (CBASP) + any antidepressant (algorithm-based)

Intensity: 16-20 sessions

Brief Supportive Psychotherapy + any antidepressant (algorithm-based)

Treatment length (weeks): 12

Outcomes:

Depression symptomatology endpoint
Remission
Discontinuation due to any reason
Discontinuation due to side effects
Functional impairment endpoint

: BME: black and minority ethnic; DSM: diagnostic statistical manual; HAMD: Hamilton depression scale; MDD: major depressive disorder; RCT: randomised controlled trial

Table 4Summary of included studies. Comparison 3. Augmenting with counselling versus continuing with antidepressant

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Kocsis 2009/Klein 2011

RCT

N=291

Mean age (years): 45.3

Gender (% female): 55

Ethnicity (% BME): 12

Baseline severity: HAMD 19.08 (more severe)

Brief Supportive Psychotherapy + any antidepressant (algorithm-based)

Intensity: 16-20 sessions

Any antidepressant (algorithm-based)

Treatment length (weeks): 12

Outcomes:

Depression symptomatology endpoint
Remission
Discontinuation due to any reason
Discontinuation due to side effects
Functional impairment endpoint

: BME: black and minority ethnic; DSM: diagnostic statistical manual; HAMD: Hamilton depression scale; MDD: major depressive disorder; RCT: randomised controlled trial

Table 5Summary of included studies. Comparison 4. Augmenting with IPT versus continuing with antidepressant

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Murray 2010

RCT

Canada

N=64

Mean age (years): 45.2

Gender (% female): 72

Ethnicity (% BME): NR

Baseline severity: NR (unclear severity)

IPT group (Re-ChORD) + any antidepressant

Intensity: 16x 90-min sessions

Any antidepressant

TRD: Mean 2.95 (SD=1.1) failed medication trials

Treatment length (weeks): 16

Outcomes:

Depression symptomatology change score
Remission
Response
Discontinuation due to any reason

Reynolds 2010

RCT

N=124

Mean age (years): 72.3

Gender (% female): 68

Ethnicity (% BME): 8

Baseline severity: HAMD 12.5 (less severe)

IPT individual + escitalopram (dose increase; 10-20mg/day)

Intensity: IPT 16x 60-75 min sessions

Escitalopram (dose increase; 10-20mg/day)

Inadequate (partial) response (HAMD score=11-14) to 6 weeks prospective open-label treatment with escitalopram

Treatment length (weeks): 16

Outcomes:

Remission
Discontinuation due to any reason

Schramm 2007

RCT

Germany

N=130

Mean age (years): 41.9

Gender (% female): 65

Ethnicity (% BME): NR

Baseline severity: HAMD 23.53 (more severe)

IPT individual & group (modified for an inpatient setting) + SSRI/TCA (sertraline 50-250mg/day or amitriptyline 75-360mg/day)

Intensity: 15x 50-min individual sessions

SSRI/TCA (sertraline 50-250mg/day or amitriptyline 75-360mg/day)

Inadequate response: met inclusion criteria despite 83% having received outpatient treatment before admission

Treatment length (weeks): 5

Outcomes:

Depression symptomatology at:
- Endpoint
- 3-month follow-up
- 12-month follow-up
Depression symptomatology change score
Remission
Response
Discontinuation due to any reason
Global functioning at:
- Endpoint
- 3-month follow-up
- 12-month follow-up

Souza 2016

RCT

Brazil

N=40

Mean age (years): 49.2

Gender (% female): 85

Ethnicity (% BME): NR

Baseline severity: HAMD 19 (more severe)

IPT individual + any antidepressant

Intensity: 16x 40-min weekly sessions

Any antidepressant

Inadequate response to 1 trial of antidepressant medication in adequate dose (defined as the equivalent of at least 75mg of amitriptyline) and duration (at least 4 weeks)

Treatment length (weeks): 19

Outcomes:

Depression symptomatology at:
- Endpoint
- 1-month follow-up
Depression symptomatology change score
Remission
Response
Discontinuation due to any reason

: BME: black and minority ethnic; HAMD: Hamilton depression scale; IPT: interpersonal therapy; NR: not reported; RCT: randomised controlled trial; SD: standard deviation; SSRI: selective serotonin reuptake inhibitors; TCA: tricyclic antidepressants; TRD: treatment-resistant depression

Table 6Summary of included studies. Comparison 5. Augmenting with short-term psychodynamic psychotherapy versus continuing with antidepressant

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Town 2017/2020

RCT

Canada

N=60

Mean age (years): 41.6

Gender (% female): 63

Ethnicity (% BME): 3

Baseline severity: HAMD 23.77 (more severe)

Intensive short-term dynamic psychotherapy + any antidepressant

Intensity: 20 sessions

Any antidepressant

Inadequate response to treatment (HAMD score ≥16) to at least 1 trial of antidepressants at the adequate recommended therapeutic dose. 34% 2 or more failed antidepressants for current episode

Treatment length (weeks): 26

Outcomes:

Depression symptomatology at:
- Endpoint
- 3-month follow-up
- 6-month follow-up
- 12-month follow-up
Depression symptomatology change score
Remission at:
- Endpoint
- 12-month follow-up
Response
Discontinuation due to any reason

: BME: black and minority ethnic; HAMD: Hamilton depression scale; RCT: randomised controlled trial

Table 7Summary of included studies. Comparison 6. Augmenting with long-term psychodynamic psychotherapy versus continuing with antidepressant

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Fonagy 2015

RCT

N=129

Mean age (years): 44.3

Gender (% female): 66

Ethnicity (% BME): NR

Baseline severity: HAMD 20.1 (more severe)

Long-term psychodynamic psychotherapy (following manual by Taylor 2015) + any antidepressant

Intensity: 60x 50-min weekly sessions

Any antidepressant

TRD: Inadequate response to least 2 different treatments (mean of 3.7 previously failed treatment attempts)

Treatment length (weeks): 78

Outcomes:

Depression symptomatology at:
- Endpoint
- 6-month follow-up
- 12-month follow-up
- 24-month follow-up
Remission at:
- Endpoint
- 24-month follow-up
Discontinuation due to any reason

: BME: black and minority ethnic; HAMD: Hamilton depression scale; NR: not reported; RCT: randomised controlled trial; TRD: treatment-resistant depression

Table 8Summary of included studies. Comparison 7. Augmenting with self-help versus continuing with the antidepressant (+/− attention-placebo)

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Baert 2010_study 2

RCT

Belgium & Netherlands

N=44

Mean age (years): 42.3

Gender (% female): 64

Ethnicity (% BME): NR

Baseline severity: HAMD 23.19 (more severe)

Attentional bias training + any antidepressant

Intensity: 1x pre-training lab session, 10x training sessions at home, & 1 post-training lab session

Attention-placebo + any antidepressant

Intensity: 1x pre-training lab session, 10x training sessions at home, & 1 post-training lab session

Inadequate response: met inclusion criteria despite all participants having received therapy and/or medication at study entry

Treatment length (weeks): 1.4

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score

Dai 2019

RCT

China

N=40

Mean age (years): 38.7

Gender (% female): 45

Ethnicity (% BME): NR

Baseline severity: HAMD 23.01 (more severe)

Attentional bias training + any antidepressant

Intensity: 10 sessions (daily over 10 days)

Attention-placebo + any antidepressant

Intensity: 10 sessions (daily over 10 days)

Inadequate response (HAMD score≥20) despite at least 6 weeks of adequate antidepressant treatment

Treatment length (weeks): 1.4

Outcomes:

Depression symptomatology at:
- Endpoint
- 1-month follow-up
Depression symptomatology change score
Discontinuation due to any reason

Schlogelhofer 2014

RCT

Austria

N=90

Mean age (years): 47.8

Gender (% female): 67

Ethnicity (% BME): NR

Baseline severity: HAMD 12.6 (less severe)

Cognitive bibliotherapy + any antidepressant

Intensity: 1 monitoring session

Any antidepressant

Inadequate response (not achieving full remission, HAMD score 10-19) to at least 1 course of a recommended dose of an antidepressant medication for at least 4 weeks (the median treatment duration with antidepressant medication before screening was 6 months)

Treatment length (weeks): 6

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score
Discontinuation due to any reason

: BME: black and minority ethnic; HAMD: Hamilton depression scale; NR: not reported; RCT: randomised controlled trial

Table 9Summary of included studies. Comparison 8. Augmenting with self-help and switching to SSRI versus switching to SSRI-only

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Mantani 2017

RCT

Japan

N=164

Mean age (years): 40.9

Gender (% female): 53

Ethnicity (% BME): NR

Baseline severity: PHQ-9 13.2 (less severe)

Computerised CBT (CCBT) + switch to escitalopram 5-10 mg/day or sertraline 25-100 mg/day

Intensity: 8 sessions

Switch to escitalopram 5-10 mg/day or sertraline 25-100 mg/day

Inadequate response (BDI-II≥10) after taking 1 or more antidepressants at an adequate dosage for at least 4 weeks

Treatment length (weeks): 9

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score
Remission
Response
Discontinuation due to any reason

: BDI-II: Beck depression inventory; BME: black and minority ethnic; NR: not reported; PHQ-9: patient health questionnaire-9 item; RCT: randomised controlled trial; SSRI: selective serotonin reuptake inhibitors

Table 10Summary of included studies. Comparison 9. Augmenting with art therapy versus attention-placebo

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Nan 2017

RCT

China

N=106

Mean age (years): 45.1

Gender (% female): 89

Ethnicity (% BME): NR

Baseline severity: BDI-II 30.59 (more severe)

Clay art therapy + any antidepressant

Intensity: 6x 2.5-hour sessions

Attention-placebo (non-directive visual art control group) + any antidepressant

Intensity: 6x 2.5-hour sessions

Inadequate response (BDI-II≥10) after taking 1 or more antidepressants at an adequate dosage for at least 4 weeks

Treatment length (weeks): 6

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score
Discontinuation due to any reason

: BDI-II: Beck depression inventory; BME: black and minority ethnic; NR: not reported; RCT: randomised controlled trial

Table 11Summary of included studies. Comparison 10. Augmenting with eye movement desensitization reprocessing (EMDR) versus augmenting with cognitive behavioural therapy

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Ostacoli 2018

RCT

Italy & Spain

N=82

Mean age (years): 47.9

Gender (% female): 84

Ethnicity (% BME): NR

Baseline severity: NR (less severe)

Eye Movement Desensitization Reprocessing (EMDR), following the DeprEnd protocol (Hofmann et al. 2016) + any antidepressant

Intensity: 12-18 sessions

CBT individual (Beck, 1979) + any antidepressant

Intensity: 12-18 sessions

Inadequate response (BDI-II≥10) after taking 1 or more antidepressants at an adequate dosage for at least 4 weeks

Treatment length (weeks): 13-26

Outcomes:

Depression symptomatology endpoint
Remission at:
- Endpoint
- 6-month follow-up
Discontinuation due to any reason
Global functioning at:
- Endpoint
- 6-month follow-up

: BDI-II: Beck depression index; BME: black and minority ethnic; CBT: cognitive behavioural therapy; NR: not reported; RCT: randomised controlled trial

Table 12Summary of included studies. Comparison 11. Increasing the dose of SSRI versus continuing SSRI at the same dose

Study	Population	Intervention	Comparison	Details of inadequate response/treatment resistance	Comments
Dornseif 1989 RCT US	N=371 Mean age (years): 43.4 Gender (% female): 66 Ethnicity (% BME): 6 Baseline severity: HAMD 26.7 (more severe)	Fluoxetine 60mg/day	Fluoxetine 20mg/day	Inadequate response (<50% reduction in HAMD) to 3 weeks of single-blind therapy with fluoxetine 20mg	Treatment length (weeks): 5 Outcomes: Depression symptomatology change score Remission Response Discontinuation due to any reason Discontinuation due to side effects
Kim 2019 RCT Korea	N=50 Mean age (years): 39.5 Gender (% female): 76 Ethnicity (% BME): NR Baseline severity: MADRS 20.2 (less severe)	Escitalopram 30mg/day	Escitalopram 20mg/day	Inadequate response (non-remission defined by MADRS score > 10) after 4 weeks of open-label treatment with 10–20 mg of escitalopram per day	Treatment length (weeks): 6 Outcomes: Depression symptomatology change score Remission Response Discontinuation due to any reason Discontinuation due to side effects
Licht 2002 RCT Denmark & Iceland	N=197 Mean age (years): 40.0 Gender (% female): 59 Ethnicity (% BME): NR Baseline severity: NR (unclear severity)	Sertraline 200mg/day	Sertraline 100mg/day	Inadequate response (<50% improvement on HAMD) to 6 weeks of open-label treatment with sertraline (50-100mg/day)	Treatment length (weeks): 5 Outcomes: Remission Response Discontinuation due to any reason Discontinuation due to side effects
Ruhe 2009 RCT Netherlands	N=60 Mean age (years): 42.4 Gender (% female): 67 Ethnicity (% BME): 40 Baseline severity: HAMD 20.6 (more severe)	Paroxetine 30-50mg/day	Paroxetine 20mg/day	Inadequate response (<50% improvement on HAMD) to 6 weeks, open-label paroxetine treatment (20 mg/day)	Treatment length (weeks): 6 Outcomes: Depressionsy mptomatology endpoint Remission Response Discontinuation due to any reason Discontinuation due to side effects Quality of life physical component score Qulity of life mental component score
Schweizer 1990 RCT US	N=77 Mean age (years): 45.1 Gender (% female): 56 Ethnicity (% BME): NR Baseline severity: HAMD 25 (more severe)	Fluoxetine 60mg/day	Fluoxetine 20mg/day	Inadequate response (<50% improvement on HAMD) to 3-week open-label prospective treatment with fluoxetine 20mg/day. 74% previous antidepressant prescribed	Treatment length (weeks): 5 Outcomes: Response Discontinuation due to any reason Discontinuation due to side effects
Schweizer 2001 RCT US	N=75 Mean age (years): 40.0 Gender (% female): 54 Ethnicity (% BME): NR Baseline severity: NR (unclear severity)	Sertraline 150mg/day	Sertraline 50mg/day	Inadequate response (failure to achieve remission [HAMD>8]) to 3-week open-label prospective treatment phase with sertraline (50mg/day)	Treatment length (weeks): 5 Outcomes: Remission Response Discontinuation due to any reason

: BME: black and minority ethnic; HAMD: Hamilton depression scale; MADRS: Montgomery-Asberg depression rating scale; NR: not reported; RCT: randomised controlled trial; SSRI: selective serotonin reuptake inhibitor

Table 13Summary of included studies. Comparison 12. Increasing the dose of SSRI versus switching to SNRI

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Bose 2012

RCT

N=484

Mean age (years): 42.3

Gender (% female): 59

Ethnicity (% BME): 22

Baseline severity: MADRS 34.8 (more severe)

Escitalopram (dose increase) 20mg/day

Duloxetine 60mg/day

Inadequate response (<50% improvement on MADRS) to 2 weeks of single-blind escitalopram (10mg/day)

Treatment length (weeks): 8

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score
Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects
Quality of life endpoint

: BME: black and minority ethnic; MADRS: Montgomery-Asberg depression rating scale; RCT: randomised controlled trial; SNRI: serotonin-norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor

Table 14Summary of included studies. Comparison 13. Increasing the dose of SSRI versus augmenting with TCA

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Fava 1994a

RCT

N=27

Mean age (years): NR

Gender (% female): NR

Ethnicity (% BME): NR

Baseline severity: HAMD 18.54 (more severe)

Fluoxetine 40-60mg/day

Desipramine 25-50mg/day + fluoxetine 20mg/day

Inadequate response (defined as failure to achieve a 50% or greater reduction in HAMD score and a HAMD score of ≥10) to 8 weeks of open-label treatment with fluoxetine (20mg/day)

Treatment length (weeks): 4

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score
Remission
Discontinuation due to any reason
Discontinuation due to side effects

Fava 2002

RCT

N=67

Mean age (years): NR

Gender (% female): NR

Ethnicity (% BME): NR

Baseline severity: HAMD 16.86 (more severe)

Fluoxetine 40-60mg/day

Desipramine 25-50mg/day + fluoxetine 20mg/day

Inadequate response (defined as failure to achieve a 50% or greater reduction in HAMD score and a HAMD score of ≥10) to 8 weeks of open-label treatment with fluoxetine (20mg/day)

Treatment length (weeks): 4

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score
Remission
Discontinuation due to any reason

: BME: black and minority ethnic; HAMD: Hamilton depression scale; NR: not reported; RCT: randomised controlled trial; SSRI: selective serotonin reuptake inhibitor; TCA: tricyclic antidepressant

Table 15Summary of included studies. Comparison 14. Increasing the dose of SSRI versus augmenting with antipsychotic

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Rocca 2002b

RCT

Italy

N=60

Mean age (years): 40.8

Gender (% female): 68

Ethnicity (% BME): NR

Baseline severity: HAMD 18.3 (more severe)

Paroxetine (dose increase) 40mg/day

Amisulpride 50mg/day + paroxetine 20mg/day

Inadequate response to 3-month treatment with paroxetine 20 mg/day

Treatment length (weeks): 13

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score
Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects
Functional remission
Global functioning endpoint

: BME: black and minority ethnic; HAMD: Hamilton depression scale; NR: not reported; RCT: randomised controlled trial; SSRI: selective serotonin reuptake inhibitor

Table 16Summary of included studies. Comparison 15. Increasing the dose of SSRI versus augmenting with lithium

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Fava 1994a

RCT

N=29

Mean age (years): NR

Gender (% female): NR

Ethnicity (% BME): NR

Baseline severity: HAMD 18.09 (more severe)

Fluoxetine 40-60mg/day

Lithium 300-600mg/day + fluoxetine 20mg/day

Inadequate response (defined as failure to achieve a 50% or greater reduction in HAMD score and a HAMD score of ≥10) to 8 weeks of open-label treatment with fluoxetine (20mg/day)

Treatment length (weeks): 4

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score
Remission
Discontinuation due to any reason
Discontinuation due to side effects

Fava 2002

RCT

N=67

Mean age (years): NR

Gender (% female): NR

Ethnicity (% BME): NR

Baseline severity: HAMD 16.1 (more severe)

Fluoxetine 40-60mg/day

Lithium 300-600mg/day + fluoxetine 20mg/day

Inadequate response (defined as failure to achieve a 50% or greater reduction in HAMD score and a HAMD score of ≥10) to 8 weeks of open-label treatment with fluoxetine (20mg/day)

Treatment length (weeks): 4

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score
Remission
Response
Discontinuation due to any reason

: BME: black and minority ethnic; HAMD: Hamilton depression scale; NR: not reported; RCT: randomised controlled trial; SSRI: selective serotonin reuptake inhibitor

Table 17Summary of included studies. Comparison 16. Switching to SSRI versus continuing with antidepressant

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Corya 2006

RCT

16 countries

N=119

Mean age (years): NR

Gender (% female): NR

Ethnicity (% BME): NR

Baseline severity: NR (more severe)

Fluoxetine 25 or 50mg/day

Venlafaxine 75-375mg/day

TRD: Inadequate response to a SSRI after at least 6 weeks at a therapeutic dose at entry into the trial and inadequate response (<30% improvement in MADRS total score) to an open-label, 7-week lead-in phase of venlafaxine (75–375 mg/day according to the investigator’s clinical judgment)

Treatment length (weeks): 12

Outcomes:

Depression symptomatology change score
Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects

Shelton 2005

RCT

US & Canada

N=210

Mean age (years): 41.6

Gender (% female): 71

Ethnicity (% BME): 10

Baseline severity: MADRS 28.53 (more severe)

Fluoxetine 25-50mg/day

Nortriptyline 25-175mg/day

TRD: History of at least 1 failure to respond to SSRI after at least 4 weeks at a therapeutic dose, and failure to respond (<30% improvement on MADRS) to nortriptyline (25-175mg/day; mean modal dose 104.6mg/day) during a 7-week open-label treatment phase

Treatment length (weeks): 8

Outcomes:

Depression symptomatology change score
Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects

: BME: black and minority ethnic; MADRS: Montgomery-Asberg depression rating scale; NR: not reported; RCT: randomised controlled trial; SSRI: selective serotonin reuptake inhibitor; TRD: treatment-resistant depression

Table 18Summary of included studies. Comparison 17. Switching to a different SSRI versus continuing same SSRI

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Nakajima 2011

RCT

Japan

N=41

Mean age (years): 47.5

Gender (% female): 41

Ethnicity (% BME): NR

Baseline severity: MADRS 30.49 (more severe)

Paroxetine 20-40mg/day

Sertraline 50-100mg/day

Inadequate response (HAMD score improvement <20%) after 2 weeks of treatment with sertraline

Treatment length (weeks): 6

Outcomes:

Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects

: BME: black and minority ethnic; HAMD: Hamilton depression scale; MADRS: Montgomery-Asberg depression rating scale; NR: not reported; RCT: randomised controlled trial; SSRI: selective serotonin reuptake inhibitor

Table 19Summary of included studies. Comparison 18. Switching to SSRI versus antipsychotic

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Corya 2006

RCT

16 countries

N=122

Mean age (years): NR

Gender (% female): NR

Ethnicity (% BME): NR

Baseline severity: NR (more severe)

Fluoxetine 25 or 50mg/day

Olanzapine 6 or 12mg/day

Treatment length (weeks): 12

Outcomes:

Depression symptomatology change score
Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects

Shelton 2005

RCT

US & Canada

N=286

Mean age (years): 42.6

Gender (% female): 69

Ethnicity (% BME): 13

Baseline severity: MADRS 28.4 (more severe)

Fluoxetine 25-50mg/day

Olanzapine 6-12mg/day

Treatment length (weeks): 8

Outcomes:

Depression symptomatology change score
Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects

: BME: black and minority ethnic; MADRS: Montgomery-Asberg depression rating scale; NR: not reported; RCT: randomised controlled trial; SSRI: selective serotonin reuptake inhibitor; TRD: treatment-resistant depression

Table 20Summary of included studies. Comparison 19. Switching to combined SSRI + antipsychotic versus switching to antipsychotic-only

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Corya 2006

RCT

16 countries

N=305

Mean age (years): NR

Gender (% female): NR

Ethnicity (% BME): NR

Baseline severity: NR (more severe)

Fluoxetine 25 or 50mg/day + Olanzapine 6 or 12mg/day

Olanzapine 6 or 12mg/day

Treatment length (weeks): 12

Outcomes:

Depression symptomatology change score
Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects

Shelton 2005

RCT

US & Canada

N=290

Mean age (years): 43.0

Gender (% female): 66

Ethnicity (% BME): 13

Baseline severity: MADRS 28.45 (more severe)

Fluoxetine 25-50mg/day + Olanzapine 6-12mg/day

Olanzapine 6-12mg/day

Treatment length (weeks): 8

Outcomes:

Depression symptomatology change score
Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects

: BME: black and minority ethnic; MADRS: Montgomery-Asberg depression rating scale; NR: not reported; RCT: randomised controlled trial; SSRI: selective serotonin reuptake inhibitor; TRD: treatment-resistant depression

Table 21Summary of included studies. Comparison 20. Augmenting with SSRI versus augmenting with lithium

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Navarro 2019b

RCT

Spain

N=104

Mean age (years): 55.4

Gender (% female): 68

Ethnicity (% BME): NR

Baseline severity: HAMD 28.52 (more severe)

Citalopram 30mg/day + imipramine target plasma level 175-300 ng/mL

Lithium target plasma level 0.6-0.8 mEq/L + imipramine target plasma level 175-300 ng/mL

Inadequate response (HAMD improved ≤50%) following 10-week open-label treatment with imipramine

Treatment length (weeks): 10

Outcomes:

Depression symptomatology change score
Remission

: BME: black and minority ethnic; HAMD: Hamilton depression scale; NR: not reported; RCT: randomised controlled trial; SSRI: selective serotonin reuptake inhibitor

Table 22Summary of included studies. Comparison 21. Switching to TCA versus SSRI

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Souery 2011a

RCT

Austria, Belgium, France & Israel

N=189

Mean age (years): 51.4

Gender (% female): 72

Ethnicity (% BME): 5

Baseline severity: MADRS 31.5 (more severe)

Desipramine minimum dose 150mg/day (mean final dose 169.61mg/day)

Citalopram minimum dose 40mg/day (mean final dose 43.06mg/day)

Inadequate response to treatment with at least 1 antidepressant (except citalopram and desipramine) given at an adequate dose for at least 4 weeks

Treatment length (weeks): 4

Outcomes:

Depression symptomatology endpoint
Remission
Response
Discontinuation due to any reason

: BME: black and minority ethnic; MADRS: Montgomery-Asberg depression rating scale; RCT: randomised controlled trial; SSRI: selective serotonin reuptake inhibitor; TCA: tricyclic antidepressant

Table 23Summary of included studies. Comparison 22. Switching to TCA versus augmenting with mirtazapine

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Navarro 2019a

RCT

Spain

N=112

Mean age (years): 55.5

Gender (% female): 67

Ethnicity (% BME): NR

Baseline severity: HAMD 28.22 (more severe)

Imipramine target plasma level 175-300 ng/mL

Mirtazapine 30mg/day + Venlafaxine 225-300mg/day

Inadequate response (non-remission HAMD>7) to 10 weeks of treatment with venlafaxine

Treatment length (weeks): 10

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score
Remission
Discontinuation due to any reason

: BME: black and minority ethnic; HAMD: Hamilton depression scale; NR: not reported; RCT: randomised controlled trial; TCA: tricyclic antidepressant

Table 24Summary of included studies. Comparison 23. Switching to mianserin versus continuing with antidepressant

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Ferreri 2001

RCT

France

N=72

Mean age (years): 46.4

Gender (% female): 72

Ethnicity (% BME): NR

Baseline severity: HAMD 26.99 (more severe)

Mianserin 60mg/day

Fluoxetine 20mg/day

Inadequate response to previous fluoxetine treatment after at least 6 weeks of treatment with 20 mg/day

Treatment length (weeks): 6

Outcomes:

Depression symptomatology change score
Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects

: BME: black and minority ethnic; HAMD: Hamilton depression scale; NR: not reported; RCT: randomised controlled trial

Table 25Summary of included studies. Comparison 24. Augmenting with mianserin versus continuing with antidepressant (+/− placebo)

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Ferreri 2001

RCT

France

N=70

Mean age (years): 45.9

Gender (% female): 74

Ethnicity (% BME): NR

Baseline severity: HAMD 27.27 (more severe)

Mianserin 60mg/day + Fluoxetine 20mg/day

Fluoxetine 20mg/day

Inadequate response to previous fluoxetine treatment after at least 6 weeks of treatment with 20 mg/day

Treatment length (weeks): 6

Outcomes:

Depression symptomatology change score
Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects

Licht 2002

RCT

Denmark & Iceland

N=197

Mean age (years): 40.0

Gender (% female): 61

Ethnicity (% BME): NR

Baseline severity: NR (unclear severity)

Mianserin 10-30mg/day + Sertraline 100mg/day

Sertraline 100mg/day + placebo

Inadequate response (<50% improvement on HAMD) to 6 weeks of open-label treatment with sertraline (50-100mg/day)

Treatment length (weeks): 5

Outcomes:

Remission
Response
Discontinuation due to any reason

: BME: black and minority ethnic; HAMD: Hamilton depression scale; NR: not reported; RCT: randomised controlled trial

Table 26Summary of included studies. Comparison 25. Augmenting with mianserin versus increasing dose of antidepressant

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Licht 2002

RCT

Denmark & Iceland

N=196

Mean age (years): 41.0

Gender (% female): 65

Ethnicity (% BME): NR

Baseline severity: NR (unclear severity)

Mianserin 10-30mg/day + Sertraline 100mg/day

Sertraline 200mg/day + placebo

Inadequate response (<50% improvement on HAMD) to 6 weeks of open-label treatment with sertraline (50-100mg/day)

Treatment length (weeks): 5

Outcomes:

Remission
Response
Discontinuation due to any reason

: BME: black and minority ethnic; HAMD: Hamilton depression scale; NR: not reported; RCT: randomised controlled trial

Table 27Summary of included studies. Comparison 26. Augmenting with mianserin versus switch to mianserin

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Ferreri 2001

RCT

France

N=66

Mean age (years): 47.5

Gender (% female): 76

Ethnicity (% BME): NR

Baseline severity: HAMD 27.39 (more severe)

Mianserin 60mg/day + Fluoxetine 20mg/day

Mianserin 60mg/day

Inadequate response to previous fluoxetine treatment after at least 6 weeks of treatment with 20 mg/day

Treatment length (weeks): 6

Outcomes:

Depression symptomatology change score
Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects

: BME: black and minority ethnic; HAMD: Hamilton depression scale; NR: not reported; RCT: randomised controlled trial

Table 28Summary of included studies. Comparison 27. Increasing the dose of SNRI versus continuing SNRI at the same dose

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Kornstein 2008

RCT

N=255

Mean age (years): 45.5

Gender (% female): 61

Ethnicity (% BME): 19

Baseline severity: HAMD 14.3 (less severe)

Duloxetine 120mg/day

Duloxetine 60mg/day

Inadequate response (HAMD score >7) to 5-week prospective treatment with duloxetine 60mg/day

Treatment length (weeks): 8

Outcomes:

Depression symptomatology change score
Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects

: BME: black and minority ethnic; HAMD: Hamilton depression scale; RCT: randomised controlled trial; SNRI: serotonin-norepinephrine reuptake inhibitors

Table 29Summary of included studies. Comparison 28. Switching to SNRI versus continuing with antidepressant

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Fang 2010

RCT

China

N=95

Mean age (years): NR

Gender (% female): NR

Ethnicity (% BME): NR

Baseline severity: NR (more severe)

Venlafaxine extended release 225mg/day

Paroxetine 20mg/day

TRD: Inadequate response to 2 or more adequate treatments from different classes of antidepressants in the current depressive episode (adequate dosages of antidepressants with at least 3-month duration) determined through medical records and/or prospective treatment

Treatment length (weeks): 8

Outcomes:

Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects
Quality of life physical component score
Quality of life mental component score

: BME: black and minority ethnic; NR: not reported; RCT: randomised controlled trial; SNRI: serotonin-norepinephrine reuptake inhibitors; TRD: treatment-resistant depression

Table 30Summary of included studies. Comparison 29. Switching to SNRI versus switching to another antidepressant from same class

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Lenox-Smith 2008

RCT

Europe & Australia

N=406

Mean age (years): 42.5

Gender (% female): 67

Ethnicity (% BME): NR

Baseline severity: MADRS 30.9 (more severe)

Venlafaxine extended release 75-300mg/day

Citalopram 20-60mg/day

Inadequate response following 8 weeks of monotherapy with an adequate dosing regimen of an SSRI other than citalopram

Treatment length (weeks): 12

Outcomes:

Remission
Discontinuation due to any reason
Discontinuation due to side effects

Poirier 1999

RCT

France

N=123

Mean age (years): 43.3

Gender (% female): 72

Ethnicity (% BME): NR

Baseline severity: HAMD 24.6 (more severe)

Venlafaxine 65-300mg/day

Paroxetine 20-40mg/day

TRD: History of resistance to 2 previous successive antidepressant treatments for the current episode (except venlafaxine or paroxetine)

Treatment length (weeks): 4

Outcomes:

Depression symptomatology change score
Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects

Rush 2006

RCT

N=488

Mean age (years): 41.8

Gender (% female): 60

Ethnicity (% BME): 24

Baseline severity: QIDS 13.2 (more severe)

Venlafaxine extended release 37.5-375mg/day

Sertraline 50-200mg/day

Inadequate response (not achieved remission or who were intolerant [56%]) to an initial prospective treatment with citalopram

Treatment length (weeks): ≤14

Outcomes:

Depression symptomatology change score
Remission
Response
Discontinuation due to side effects

: BME: black and minority ethnic; HAMD: Hamilton depression scale; MADRS: Montgomery-Asberg depression rating scale; NR: not reported; QIDS: quick inventory of depressive symptomatology; RCT: randomised controlled trial; SNRI: serotonin-norepinephrine reuptake inhibitors; SSRI: selective serotonin reuptake inhibitor; TRD: treatment-resistant depression

Table 31Summary of included studies. Comparison 30. Switching to SNRI versus switching to bupropion

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Rush 2006

RCT

N=489

Mean age (years): 41.5

Gender (% female): 61

Ethnicity (% BME): 25

Baseline severity: QIDS 13.2 (more severe)

Venlafaxine extended release 37.5-375mg/day

Bupropion sustained release 150-400mg/day

Inadequate response (not achieved remission or who were intolerant [56%]) to an initial prospective treatment with citalopram

Treatment length (weeks): ≤14

Outcomes:

Depression symptomatology change score
Remission
Response
Discontinuation due to side effects

: BME: black and minority ethnic; QIDS: quick inventory of depressive symptomatology; RCT: randomised controlled trial; SNRI: serotonin-norepinephrine reuptake inhibitors

Table 32Summary of included studies. Comparison 31. Switching to SNRI versus switching to mirtazapine

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Fang 2010

RCT

China

N=105

Mean age (years): NR

Gender (% female): NR

Ethnicity (% BME): NR

Baseline severity: NR (more severe)

Venlafaxine extended release 225mg/day

Mirtazapine 45mg/day

Treatment length (weeks): 8

Outcomes:

Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects
Quality of life physical component score
Quality of life mental component score

: BME: black and minority ethnic; NR: not reported; RCT: randomised controlled trial; SNRI: serotonin-norepinephrine reuptake inhibitors; TRD: treatment-resistant depression

Table 33Summary of included studies. Comparison 32. Switching to bupropion versus placebo

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

GlaxoSmithKline 2009

RCT

Japan

N=325

Mean age (years): 36.4

Gender (% female): 45

Ethnicity (% BME): NR

Baseline severity: HAMD 19.6 (more severe)

Bupropion hydrochloride sustained release 100-300mg/day

Placebo

Inadequate response to paroxetine (20-40 mg/day) for 4 weeks

Treatment length (weeks): 12

Outcomes:

Depression symptomatology change score
Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects

: BME: black and minority ethnic; HAMD: Hamilton depression scale; NR: not reported; RCT: randomised controlled trial

Table 34Summary of included studies. Comparison 33. Switching to bupropion versus switching to another antidepressant from same class

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Rush 2006

RCT

N=477

Mean age (years): 42.3

Gender (% female): 56

Ethnicity (% BME): 23

Baseline severity: QIDS 13.3 (more severe)

Bupropion sustained release 150-400mg/day

Sertraline 50-200mg/day

Inadequate response (not achieved remission or who were intolerant [56%]) to an initial prospective treatment with citalopram

Treatment length (weeks): ≤14

Outcomes:

Depression symptomatology change score
Remission
Response
Discontinuation due to side effects

: BME: black and minority ethnic; QIDS: quick inventory of depressive symptomatology; RCT: randomised controlled trial

Table 35Summary of included studies. Comparison 34. Augmenting with bupropion versus placebo

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Gulrez 2012

RCT

India

N=60

Mean age (years): 41.2

Gender (% female): 52

Ethnicity (% BME): NR

Baseline severity: HAMD 17.67 (more severe)

Bupropion sustained release 300mg/day (target dose, titrated upwards from 150mg in first week) + SSRI

Placebo + SSRI

Inadequate response (HAMD score ≥16) after 4 weeks of SSRI treatment

Treatment length (weeks): 4

Outcomes:

Remission

: BME: black and minority ethnic; HAMD: Hamilton depression scale; NR: not reported; RCT: randomised controlled trial; SSRI: selective serotonin reuptake inhibitor

Table 36Summary of included studies. Comparison 35. Augmenting with bupropion versus switching to bupropion

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Mohamed 2017

RCT

N=1017

Mean age (years): 54.5

Gender (% female): 15

Ethnicity (% BME): 30

Baseline severity: QIDS 16.6 (more severe)

Bupropion 150-400mg/day + SSRI/SNRI

Bupropion 150-400mg/day

Inadequate response (QIDS score ≥16 after ≥6 weeks of treatment or score≥11 after ≥8 weeks of treatment with the 3 most recent weeks at a stable “optimal” dose) to a treatment course with a SSRI, SNRI, or mirtazapine that met or exceeded minimal standards for dose and duration of treatment

Treatment length (weeks): 12

Outcomes:

Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects

: BME: black and minority ethnic; QIDS: quick inventory of depressive symptomatology; RCT: randomised controlled trial; SNRI: serotonin-norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor

Table 37Summary of included studies. Comparison 36. Switching to mirtazapine versus continuing with antidepressant

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Fang 2010

RCT

China

N=100

Mean age (years): NR

Gender (% female): NR

Ethnicity (% BME): NR

Baseline severity: NR (more severe)

Mirtazapine 45mg/day

Paroxetine 20mg/day

Treatment length (weeks): 8

Outcomes:

Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects
Quality of life physical component score
Quality of life mental component score

Kato 2018

RCT

Japan

N=1109

Mean age (years): 41.5

Gender (% female): 51

Ethnicity (% BME): NR

Baseline severity: PHQ-9 12.8 (less severe)

Mirtazapine 7.5-45mg/day

Sertraline 50mg/day or 100mg/day (mean final dose 71.7mg)

Inadequate response (non-remission as defined by PHQ-9 score>4) to 2 weeks of treatment with sertraline (50mg or 100mg)

Treatment length (weeks): 6

Outcomes:

Depression symptomatology at:
- Endpoint
- 4-month follow-up
Remission
Response
Discontinuation due to any reason

Xiao 2020

RCT

China

N=136

Mean age (years): 39.6

Gender (% female): 66

Ethnicity (% BME): NR

Baseline severity: HAMD 21.9 (more severe)

Mirtazapine 30mg/day

Paroxetine 20mg/day

Inadequate response: early non-response (HAMD score improved by less than 20%) to prospective open-label treatment with paroxetine (10-20mg/day) for 2 weeks

Treatment length (weeks): 6

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score
Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects

: BME: black and minority ethnic; HAMD: Hamilton depression scale; NR: not reported; PHQ-9: patient health questionnaire-9 item; RCT: randomised controlled trial; TRD: treatment-resistant depression

Table 38Summary of included studies. Comparison 37. Augmenting with mirtazapine versus continuing with antidepressant (+/− placebo)

Study	Population	Intervention	Comparison	Details of inadequate response/treatment resistance	Comments
Carpenter 2002 RCT US	N=26 Mean age (years): 46.3 Gender (% female): 62 Ethnicity (% BME): NR Baseline severity: HAMD 22.3 (more severe)	Mirtazapine (final dose: 31% 15mg/69% 30mg) + SSRI/SNRI	Placebo + SSRI/SNRI	Inadequate response (HAMD total score>12) after at least 4 weeks of standard antidepressant monotherapy at maximum recommended or tolerated doses	Treatment length (weeks): 4 Outcomes: Depression symptomatology endpoint Depression symptomatology change score Remission Response Discontinuation due to any reason Discontinuation due to side effects Global functioning endpoint
Kato 2018 RCT Japan	N=1088 Mean age (years): 41.8 Gender (% female): 53 Ethnicity (% BME): NR Baseline severity: PHQ-9 12.7 (less severe)	Mirtazapine 7.5-45mg/day + sertraline 50mg/day or 100mg/day	Sertraline 50mg/day or 100mg/day (mean final dose 71.7mg)	Inadequate response (non-remission as defined by PHQ-9 score>4) to 2 weeks of treatment with sertraline (50mg or 100mg)	Treatment length (weeks): 6 Outcomes: Depression symptomatology at: Endpoint 4-month follow-up Remission at: Endpoint 4-month follow-up Response at endpoint Discontinuation due to any reason
Kessler 2018a/2018b RCT UK	N=480 Mean age (years): 50.2 Gender (% female): 69 Ethnicity (% BME): 3 Baseline severity: BDI-II 31.05 (more severe)	Mirtazapine 30mg/day + SSRI/SNRI	Placebo + SSRI/SNRI	Inadequate response to an SSRI or SNRI antidepressant at an adequate dose for at least 6 weeks	Treatment length (weeks): 12 Outcomes: Depression symptomatology endpoint Remission Response Discontinuation due to any reason Quality of life endpoint Quality of life physical component score Quality of life mental component score
Xiao 2020 RCT China	N=136 Mean age (years): 39.3 Gender (% female): 53 Ethnicity (% BME): NR Baseline severity: HAMD 20.95 (more severe)	Mirtazapine 30mg/day + paroxetine 20mg/day	Paroxetine 20mg/day	Inadequate response: early non-response (HAMD score improved by less than 20%) to prospective open-label treatment with paroxetine (10-20mg/day) for 2 weeks	Treatment length (weeks): 6 Outcomes: Depression symptomatology endpoint Depression symptomatology change score Remission Response Discontinuation due to any reason Discontinuation due to side effects

: BDI-II: Beck depression inventory; BME: black and minority ethnic; HAMD: Hamilton depression scale; NR: not reported; PHQ-9: patient health questionnaire-9 item; RCT: randomised controlled trial; SNRI: serotonin-norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor

Table 39Summary of included studies. Comparison 38. Augmenting with mirtazapine versus switching to mirtazapine

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Kato 2018

RCT

Japan

N=1095

Mean age (years): 41.7

Gender (% female): 52

Ethnicity (% BME): NR

Baseline severity: PHQ-9 12.7 (less severe)

Mirtazapine 7.5-45mg/day + sertraline 50mg/day or 100mg/day

Mirtazapine 7.5-45mg/day

Inadequate response (non-remission as defined by PHQ-9 score>4) to 2 weeks of treatment with sertraline (50mg or 100mg)

Treatment length (weeks): 6

Outcomes:

Depression symptomatology at:
- Endpoint
- 4-month follow-up
Remission at:
- Endpoint
- 4-month follow-up
Response at endpoint
Discontinuation due to any reason

Xiao 2020

RCT

China

N=136

Mean age (years): 38.6

Gender (% female): 57

Ethnicity (% BME): NR

Baseline severity: HAMD 21.74 (more severe)

Mirtazapine 30mg/day + paroxetine 20mg/day

Mirtazapine 30mg/day

Inadequate response: early non-response (HAMD score improved by less than 20%) to prospective open-label treatment with paroxetine (10-20mg/day) for 2 weeks

Treatment length (weeks): 6

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score
Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects

: BME: black and minority ethnic; HAMD: Hamilton depression scale; NR: not reported; PHQ-9: patient health questionnaire-9 item; RCT: randomised controlled trial

Table 40Summary of included studies. Comparison 39. Augmenting with trazodone versus continuing with antidepressant

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Fang 2011

RCT

China

N=92

Mean age (years): NR

Gender (% female): NR

Ethnicity (% BME): NR

Baseline severity: NR (more severe)

Trazodone 100mg/day + paroxetine 20mg/

Paroxetine 20mg/day

Treatment length (weeks): 8

Outcomes:

Remission
Response
Quality of life physical component score
Quality of life mental component score

: BME: black and minority ethnic; NR: not reported; RCT: randomised controlled trial; TRD: treatment-resistant depression

Table 41Summary of included studies. Comparison 40. Augmenting with anticonvulsant versus continuing with antidepressant (+/− placebo)

Study	Population	Intervention	Comparison	Details of inadequate response/treatment resistance	Comments
Barbee 2011 RCT US	N=96 Mean age (years): 45.2 Gender (% female): 69 Ethnicity (% BME): NR Baseline severity: MADRS 27 (more severe)	Lamotrigine 100-400mg/day + paroxetine/paroxetine CR	Placebo + paroxetine/paroxetine CR	TRD: History of failure of ≥1 adequate trial of a US FDA-approved antidepressant within the current episode of MDD, and failure to respond (HAMD≥15) to open-label prospective treatment with paroxetine or paroxetine CR (in flexible doses up to 50/62.5mg/day) after 8 weeks	Treatment length (weeks): 10 Outcomes: Depression symptomatology endpoint Depression symptomatology change score Response Discontinuation due to any reason Discontinuation due to side effects
Fang 2011 RCT China	N=84 Mean age (years): NR Gender (% female): NR Ethnicity (% BME): NR Baseline severity: NR (more severe)	Sodium valproate 600mg/day + paroxetine 20mg/day	Paroxetine 20mg/day	TRD: Inadequate response to ≥2 adequate treatments from different classes of antidepressants in the current depressive episode (adequate dosages of antidepressants with at least 3-month duration) determined through medical records and/or prospective treatment	Treatment length (weeks): 8 Outcomes: Remission Response Quality of life physical component score Quality of life mental component score
Li 2009 RCT China	N=98 Mean age (years): 67.0 Gender (% female): 56 Ethnicity (% BME): NR Baseline severity: HAMD 23.7 (more severe)	Lamotrigine 50-100mg/day + sertraline 100-150mg/day	Sertraline 100-150mg/day	TRD (failure to respond to at least 2 antidepressant treatment trials with adequate dose and duration)	Treatment length (weeks): 4 Outcomes: Depression symptomatology endpoint Depression symptomatology change score Response
Li 2015 RCT China	N=115 Mean age (years): 33.8 Gender (% female): 44 Ethnicity (% BME): NR Baseline severity: HAMD 36.5 (more severe)	Lamotrigine 25-150mg/day + paroxetine 20-40mg/day	Paroxetine 20-40mg/day	TRD (failure to respond to at least 2 antidepressant treatment trials with adequate dose and duration)	Treatment length (weeks): 8 Outcomes: Depression symptomatology endpoint Depression symptomatology change score Response
Mowla 2011 RCT Iran	N=53 Mean age (years): 36.2 Gender (% female): 57 Ethnicity (% BME): NR Baseline severity: HAMD 21.79 (more severe)	Topiramate 100-200mg/day + SSRI	Placebo + SSRI	Inadequate response (HAMD≥18) to at least 8 weeks of treatment with an adequate and stable dose of one of the SSRIs (fluoxetine, citalopram or sertraline)	Treatment length (weeks): 8 Outcomes: Depression symptomatology endpoint Depression symptomatology change score Discontinuation due to any reason
Santos 2008 RCT Brazil	N=34 Mean age (years): 27.5 Gender (% female): 74 Ethnicity (% BME): NR Baseline severity: MADRS 30.4 (more severe)	Lamotrigine 50-200mg/day + any antidepressant	Placebo + any antidepressant	TRD: Inadequate response to treatment with at least 2 antidepressants of different classes at the maximum-tolerated dose for at least 6 weeks	Treatment length (weeks): 8 Outcomes: Depression symptomatology endpoint Depression symptomatology change score Response Discontinuation due to any reason Discontinuation due to side effects
Wang 2012a RCT China	N=60 Mean age (years): 45.3 Gender (% female): 45 Ethnicity (% BME): NR Baseline severity: HAMD 22.75 (more severe)	Lamotrigine 100-200mg/day + venlafaxine 75-225mg/day	Venlafaxine 75-225mg/day	TRD: failed to achieve a response in at least 2 antidepressant treatment trials of adequate dose and duration	Treatment length (weeks): 12 Outcomes: Depression symptomatology endpoint Depression symptomatology change score Response
Yang 2016 RCT China	N=66 Mean age (years): 38.2 Gender (% female): 52 Ethnicity (% BME): NR Baseline severity: HAMD 28.01 (more severe)	Lamotrigine 150mg/day + escitalopram 10-20mg/day	Escitalopram 10-20mg/day	TRD: failed to achieve a response in at least 2 antidepressant treatment trials of adequate dose and duration	Treatment length (weeks): 12 Outcomes: Depression symptomatology endpoint Depression symptomatology change score Response
Zhang 2016 RCT China	N=88 Mean age (years): 47.3 Gender (% female): 72 Ethnicity (% BME): NR Baseline severity: HAMD 31.23 (more severe)	Lamotrigine 50-200mg/day + duloxetine 60mg/day	Duloxetine 60mg/day	TRD: failed to respond to at least 2 antidepressant treatment trials of adequate dose and duration	Treatment length (weeks): 8 Outcomes: Depression symptomatology endpoint Depression symptomatology change score Response

: BME: black and minority ethnic; CR: controlled release; FDA: food and drug administration; HAMD: Hamilton depression scale; MADRS: Montgomery-Asberg depression rating scale; MDD: major depressive disorder; NR: not reported; RCT: randomised controlled trial; SSRI: selective serotonin reuptake inhibitor; TRD: treatment-resistant depression

Table 42Summary of included studies. Comparison 41. Augmenting with anticonvulsant versus lithium

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Schindler 2007

RCT

Germany

N=34

Mean age (years): 47.7

Gender (% female): 50

Ethnicity (% BME): NR

Baseline severity: HAMD 22.1 (More severe)

Lamotrigine 25-250mg/day (mean final dose 152.94 mg/day) + any antidepressant

Lithium target plasma level 0.6–0.8mmol/l (mean final plasma level 0.71mmol/l) + any antidepressant

TRD: Inadequate response (<50% reduction of initial HAMD) to at least 2 trials of different classes of antidepressants for a duration of at least 6 weeks

Treatment length (weeks): 8

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score
Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects

: BME: black and minority ethnic; HAMD: Hamilton depression scale; NR: not reported; RCT: randomised controlled trial; TRD: treatment-resistant depression

Table 43Summary of included studies. Comparison 42. Switching to antipsychotic versus continuing with antidepressant

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Corya 2006

RCT

16 countries

N=121

Mean age (years): NR

Gender (% female): NR

Ethnicity (% BME): NR

Baseline severity: NR (more severe)

Olanzapine 6 or 12mg/day

Venlafaxine 75-375mg/day

TRD: Inadequate response to SSRI after ≥6 weeks at a therapeutic dose at entry into the trial and inadequate response (<30% improvement in MADRS score) to 7 weeks of venlafaxine 75–375mg/day

Treatment length (weeks): 12

Outcomes:

Depression symptomatology change score
Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects

Shelton 2005

RCT

US & Canada

N=212

Mean age (years): 42.2

Gender (% female): 67

Ethnicity (% BME): 16

Baseline severity: MADRS 28.53 (more severe)

Olanzapine 6-12mg/day

Nortriptyline 25-175mg/day

TRD: History of ≥1 failure to respond to SSRI after ≥4 weeks of therapy at a therapeutic dose, and failure to respond (<30% improvement on MADRS) to 7 weeks of nortriptyline 25-175mg/day

Treatment length (weeks): 8

Outcomes:

Depression symptomatology change score
Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects

Thase 2007

RCT

US & Canada

N=405

Mean age (years): 44.5

Gender (% female): 62

Ethnicity (% BME): 16

Baseline severity: MADRS 29.9 (more severe)

Olanzapine 6, 12 or 18mg/day

Fluoxetine 50mg/day

TRD: Documented history of failure to achieve a satisfactory response (based on investigator’s clinical judgement) to an antidepressant (except fluoxetine) after ≥6 weeks of therapy at a therapeutic dose to 8 weeks of fluoxetine 25-50mg/day

Treatment length (weeks): 8

Outcomes:

Depression symptomatology change score
Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects
Quality of life physical component score
Quality of life mental component score

: BME: black and minority ethnic; MADRS: Montgomery-Asberg depression rating scale; NR: not reported; RCT: randomised controlled trial; SSRI: selective serotonin reuptake inhibitor; TRD: treatment-resistant depression

Table 44Summary of included studies. Comparison 43. Switching to combined antipsychotic + SSRI versus continuing with antidepressant

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Corya 2006

RCT

16 countries

N=302

Mean age (years): NR

Gender (% female): NR

Ethnicity (% BME): NR

Baseline severity: NR (more severe)

Olanzapine 6 or 12mg/day + fluoxetine 25 or 50mg/day

Venlafaxine 75-375mg/day

TRD: Inadequate response to SSRI after ≥6 weeks at a therapeutic dose at entry into the trial and inadequate response (<30% improvement in MADRS score) to 7 weeks of venlafaxine 75–375mg/day

Treatment length (weeks): 12

Outcomes:

Depression symptomatology change score
Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects

Shelton 2005

RCT

US & Canada

N=214

Mean age (years): 42.2

Gender (% female): 67

Ethnicity (% BME): 10

Baseline severity: MADRS 28.6 (more severe)

Olanzapine 6-12mg/day + fluoxetine 25-50mg/day

Nortriptyline 25-175mg/day

TRD: History of ≥1 failure to respond to SSRI after ≥4 weeks of therapy at a therapeutic dose, and failure to respond (<30% improvement on MADRS) to 7 weeks of nortriptyline 25-175mg/day

Treatment length (weeks): 8

Outcomes:

Depression symptomatology change score
Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects

: BME: black and minority ethnic; MADRS: Montgomery-Asberg depression rating scale; NR: not reported; RCT: randomised controlled trial; SSRI: selective serotonin reuptake inhibitor; TRD: treatment-resistant depression

Table 45Summary of included studies. Comparison 44. Switching to combined antipsychotic + SSRI versus switch to SSRI-only

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Corya 2006

RCT

16 countries

N=303

Mean age (years): NR

Gender (% female): NR

Ethnicity (% BME): NR

Baseline severity: NR (more severe)

Olanzapine 6 or 12mg/day + fluoxetine 25 or 50mg/day

Fluoxetine 25 or 50mg/day

TRD: Inadequate response to SSRI after ≥6 weeks at a therapeutic dose at entry into the trial and inadequate response (<30% improvement in MADRS score) to 7 weeks of venlafaxine 75–375mg/day

Treatment length (weeks): 12

Outcomes:

Depression symptomatology change score
Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects

Shelton 2005

RCT

US & Canada

N=288

Mean age (years): 42.1

Gender (% female): 70

Ethnicity (% BME): 9

Baseline severity: MADRS 28.45 (more severe)

Olanzapine 6-12mg/day + fluoxetine 25-50mg/day

Fluoxetine 25-50mg/day

TRD: History of ≥1 failure to respond to SSRI after ≥4 weeks of therapy at a therapeutic dose, and failure to respond (<30% improvement on MADRS) to 7 weeks of nortriptyline 25-175mg/day

Treatment length (weeks): 8

Outcomes:

Depression symptomatology change score
Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects

: BME: black and minority ethnic; MADRS: Montgomery-Asberg depression rating scale; NR: not reported; RCT: randomised controlled trial; SSRI: selective serotonin reuptake inhibitor; TRD: treatment-resistant depression

Table 46Summary of included studies. Comparison 45. Augmenting with antipsychotic versus antidepressant-only or antidepressant + placebo

Study	Population	Intervention	Comparison	Details of inadequate response/treatment resistance	Comments
Bauer 2009 RCT Australia, Canada, Europe & South Africa	N=493 Mean age (years): 45.4 Gender (% female): 68 Ethnicity (% BME): 2 Baseline severity: HAMD 24.6 (more severe)	Quetiapine 150mg/day or 300mg/day + SSRI/SNRI	Placebo + SSRI/SNRI	Inadequate response during the current episode to amtitriptyline, bupropion, citalopram, duloxetine, escitalopram, fluoxetine, paroxetine, sertraline or venlafaxine, which were given for ≥6 weeks at adequate doses (minimum effective dose according to label and including at least 1 dose increase as permitted by label)	Treatment length (weeks): 6 Outcomes: Remission Response Discontinuation due to any reason Discontinuation due to side effects
Bauer 2019 RCT 16 countries in Asia, Europe, Latin America, & North America	N=886 Mean age (years): 46.8 Gender (% female): 69 Ethnicity (% BME): 4 Baseline severity: MADRS 25.85 (more severe)	Brexpiprazole 1-3mg/day + SSRI/SNRI	Placebo + SSRI/SNRI	Insufficient response to 1-3 adequate antidepressants (including the treatment a patient was taking at screening) for the current MDE; and insufficient response (defined as <50% improvement in MADRS; MADRS score ≥18; CGI-I score ≥3) to open-label antidepressants and double-blind augmentation during the 8 week prospective treatment phase	Treatment length (weeks): 24 Outcomes: Remission Discontinuation due to any reason Discontinuation due to side effects Functional remission
Berman 2007 RCT US	N=362 Mean age (years): 45.4 Gender (% female): 63 Ethnicity (% BME): 10 Baseline severity: MADRS 26 (more severe)	Aripiprazole 2-20mg/day + SSRI/SNRI	Placebo + SSRI/SNRI	TRD: Inadequate response to 1-3 adequate antidepressant trials (>6 weeks duration at adequate doses) at entry into trial and inadequate response (failing to meet criteria of <50% reduction in symptoms, HAMD≥15 and CGI-I≥3) to prospective treatment phase (8-week treatment with escitalopram [10/20mg/day], fluoxetine [20/40mg/day], paroxetine CR [37.5/50mg/day], sertraline [100/150mg/day] or venlafaxine [150/225mg/day])	Treatment length (weeks): 6 Outcomes: Remission Response Discontinuation due to any reason Discontinuation due to side effects
Berman 2009 RCT US	N=349 Mean age (years): 45.4 Gender (% female): 73 Ethnicity (% BME): 13 Baseline severity: MADRS 26.9 (more severe)	Aripiprazole 2-20mg/day + SSRI/SNRI	Placebo + SSRI/SNRI	TRD: Inadequate response to a previous antidepressant (as defined by <50% reduction in severity of depressive symptoms-determined by the MGH ATRQ) in 1-3 antidepressant trials of at least 6 weeks duration at entry into trial and inadequate response (failing to meet criteria of <50% reduction in HAMD from baseline, HAMD≥14 and CGI-I≥3) to prospective treatment phase (8-week treatment with escitalopram [10/20mg/day], fluoxetine [20/40mg/day], paroxetine CR [37.5/50mg/day; paroxetine 30/40m/day if paroxetine CR unavailable], sertraline [100/150mg/day] or venlafaxine [150/225mg/day])	Treatment length (weeks): 6 Outcomes: Depression symptomatology change score Remission Response Discontinuation due to any reason Discontinuation due to side effects Quality of life change score Functional impairment change score
Dunner 2007 RCT US	N=64 Mean age (years): 44.0 Gender (% female): 52 Ethnicity (% BME): 11 Baseline severity: MADRS 29.95 (more severe)	Ziprasidone 80mg/day or 160mg/day + sertraline 100-200mg/day	Sertraline 100-200mg/day	TRD: Failure to respond to ≥1 previous course of treatment of ≥4 weeks’ duration with a clinically appropriate dose of an SSRI or non-SSRI antidepressant (based on self-report), and failure to respond (<30% improvement in MADRS score and continued to have a CGI-S score ≥4 and meet DSM-IV criteria for MDD) to an initial 6-week open-label prospective treatment phase with sertraline	Treatment length (weeks): 8 Outcomes: Depression symptomatology change score Remission Response Discontinuation due to any reason Discontinuation due to side effects
Durgam 2016 RCT US & Europe	N=819 Mean age (years): 45.7 Gender (% female): 71 Ethnicity (% BME): 13 Baseline severity: MADRS 29.1 (more severe)	Cariprazine 1-2mg/day or 2-4.5mg/day + SSRI/SNRI	Placebo + SSRI/SNRI	Inadequate response during the current episode to antidepressant treatment for at least 6 weeks at recommended doses	Treatment length (weeks): 8 Outcomes: Depression symptomatology change score Remission Response Discontinuation due to any reason Discontinuation due to side effects Functional impairment change score
Earley 2018 RCT US	N=527 Mean age (years): 44.0 Gender (% female): 65 Ethnicity (% BME): 28 Baseline severity: MADRS 25.3 (more severe)	Cariprazine 1.5-4.5mg/day + any antidepressant	Placebo + any antidepressant	TRD: previously failed to respond to 1 or 2 adequate antidepressant trials, and inadequate response (HAMD score improved <50%, HAMD score <15, or CGI-I score <3) to prospective open-label 8 week prospective antidepressant treatment	Treatment length (weeks): 8 Outcomes: Depression symptomatology change score Remission Response Discontinuation due to any reason Discontinuation due to side effects
El-Khalili 2010 RCT US	N=446 Mean age (years): 45.5 Gender (% female): 72 Ethnicity (% BME): 10 Baseline severity: HAMD 24.1 (more severe)	Quetiapine 150mg/day or 300mg/day + SSRI/SNRI	Placebo + SSRI/SNRI	Inadequate response (continuing depressive symptoms) during their current depressive episode to one of the following antidepressants: amitriptyline, bupropion, citalopram, duloxetine, escitalopram, fluoxetine, paroxetine, sertraline, or venlafaxine for at least 6 weeks at adequate doses (minimum effective dose according to US label and including ≥1 dose increase as permitted by label)	Treatment length (weeks): 6 Outcomes: Remission Response Discontinuation due to any reason Discontinuation due to side effects
Fang 2011 RCT China	N=90 Mean age (years): NR Gender (% female): NR Ethnicity (% BME): NR Baseline severity: NR (more severe)	Risperidone 2mg/day + paroxetine 20mg/day	Paroxetine 20mg/day	TRD: Inadequate response to ≥2 adequate treatments from different classes of antidepressants in the current depressive episode (adequate dosages of antidepressants for ≥3-month duration) determined through medical records and/or prospective treatment	Treatment length (weeks): 8 Outcomes: Remission Response Quality of life physical component score Quality of life mental component score
Fava 2012/Mischoulon 2012 RCT US	N=225 Mean age (years): 45 Gender (% female): 68 Ethnicity (% BME): 19 Baseline severity: MADRS 31.1 (more severe)	Aripiprazole 2mg/day + SSRI/SNRI	Placebo + SSRI/SNRI	Inadequate response (< 50% reduction in depressive symptom severity, as assessed by the MGH ATRQ) to 1-3 antidepressant trials with an adequate dose of SSRIs/SNRIs during the current episode for ≥8 weeks	Treatment length (weeks): 4 Outcomes: Depression symptomatology endpoint Depression symptomatology change score Remission Response Discontinuation due to any reason Discontinuation due to side effects
Fava 2018 RCT US	N=231 Mean age (years): 45.4 Gender (% female): 71 Ethnicity (% BME): 81 Baseline severity: MADRS 26.4 (more severe)	Cariprazine 0.1–0.3mg/day or 1–2mg/day + SSRI/SNRI	Placebo + SSRI/SNRI	TRD: failed to respond to 1-2 adequate trials of antidepressants (<50% reduction in depressive symptoms using the MGH ATRQ) and failed to respond (achieved <50% improvement in HAMD, HAMD score >14, or CGI-I score ≥3) to 8-week prospective open-label antidepressant treatment phase	Treatment length (weeks): 8 Outcomes: Depression symptomatology change score Remission Response Discontinuation due to any reason Discontinuation due to side effects
Fava 2019 RCT US	N=207 Mean age (years): NR Gender (% female): 73 Ethnicity (% BME): 28 Baseline severity: HAMD 22.23 (more severe)	Pimavanserin 34mg/day + SSRI/SNRI	Placebo + SSRI/SNRI	Inadequate response to 1 or 2 antidepressant treatments (including SSRI/SNRI) during the current depression episode	Treatment length (weeks): 5 Outcomes: Depression symptomatology change score Remission Response Discontinuation due to any reason Discontinuation due to side effects Functional impairment score
Hobart 2018a RCT US, Germany, Poland, Slovakia, & Hungary	N=394 Mean age (years): 42.9 Gender (% female): 74 Ethnicity (% BME): 15 Baseline severity: MADRS 26.64 (more severe)	Brexpiprazole 2mg/day + SSRI/SNRI	Placebo + SSRI/SNRI	TRD: Inadequate response (<50% improved according to the MGH ATRQ) to 1-3 prior antidepressants (on a therapeutic dose for an adequate duration) during the current episode; and inadequate response (<50% improvement in HAMD and MADRS, HAMD score >14, and CGI-I score ≥3) to 8-week prospective open-label antidepressant treatment	Treatment length (weeks): 6 Outcomes: Depression symptomatology change score Remission Response Discontinuation due to any reason Discontinuation due to side effects Functional impairment score
Hobart 2018b RCT US, Russia, Poland, France, Serbia, Germany, & Canada	N=503 Mean age (years): 43.1 Gender (% female): 68 Ethnicity (% BME): 10 Baseline severity: MADRS 25.44 (more severe)	Brexpiprazole 2-3mg/day or quetiapine 150-300mg/day + SSRI/SNRI	Placebo + SSRI/SNRI	TRD: Inadequate response (defined as <50% improved on the MGH ATRQ) during the current episode to 1-3 antidepressants at a therapeutic dose and for an adequate duration (>6 weeks); inadequate response (<50% reduction in MADRS total score between the start of prospective treatment and each 2-weekly visit; CGI-I score>3 at each 2-weekly visit; and MADRS total score≥ 18) to open-label 8-10 week prospective antidepressant treatment phase	Treatment length (weeks): 6 Outcomes: Response Discontinuation due to any reason Discontinuation due to side effects Functional impairment score
Kamijima 2013 RCT Japan	N=586 Mean age (years): 38.7 Gender (% female): 42 Ethnicity (% BME): NR Baseline severity: MADRS 25.3 (more severe)	Aripiprazole fixed dose 3mg/day or flexible dose 3-15mg/day + SSRI/SNRI	Placebo + SSRI/SNRI	TRD: Previous inadequate response to 1–3 antidepressant trials of at least 6-weeks’ duration (64% 1 trial; 27% 2 trials; 10% 3 trials); and inadequate response (<50% reduction in HAMD from baseline to the end of the screening phase; HAMD score≥14; or CGI-I score≥3) to an 8-week, single-blind, prospective treatment phase	Treatment length (weeks): 6 Outcomes: Depression symptomatology change score Remission Response Discontinuation due to any reason Discontinuation due to side effects Functional impairment score
Kamijima 2018 RCT Japan, Korea, Malaysia, Taiwan, & Australia	N=412 Mean age (years): 38.9 Gender (% female): 37 Ethnicity (% BME): 99 Baseline severity: MADRS 25.05 (more severe)	Aripiprazole 3-12mg/day + sertraline 100mg/day	Placebo + sertraline 100mg/day	TRD: inadequate response to 1-3 previous antidepressant treatments (75% 1 previous adequate antidepressant treatments) and inadequate response (<50% reduction in HAMD from baseline to the end of the prospective treatment period; HAMD score≥14 at the end of the prospective treatment period; and a constant CGI-I score≥3 throughout the prospective treatment period) to 8-week prospective treatment phase with sertraline	Treatment length (weeks): 6 Outcomes: Depression symptomatology change score Remission Response Discontinuation due to any reason Discontinuation due to side effects Global functioning change score
Keitner 2009 RCT US	N=97 Mean age (years): 45.2 Gender (% female): 59 Ethnicity (% BME): 10 Baseline severity: MADRS 25.7 (more severe)	Risperidone 0.5-3mg/day + SSRI/SNRI	Placebo + SSRI/SNRI	Inadequate response to open-label treatment trial with antidepressant monotherapy (the particular antidepressant used was based on clinician choice) lasting for ≥5 weeks	Treatment length (weeks): 4 Outcomes: Remission Response Discontinuation due to any reason Discontinuation due to side effects
Lenze 2015 RCT US & Canada	N=181 Mean age (years): 66.0 Gender (% female): 57 Ethnicity (% BME): 12 Baseline severity: MADRS 23 (more severe)	Aripiprazole 2-15mg/day + venlafaxine 300mg/day	Placebo + venlafaxine 300mg/day	Inadequate response (failure to remit; MADRS>10) to venlafaxine 150-300mg/day (for ≥12 weeks of treatment with ≥4 weeks at the highest tolerated dose). 74% previous history of at least 1 adequate antidepressant trial during the present episode	Treatment length (weeks): 12 Outcomes: Remission Discontinuation due to any reason
Li 2013 RCT China	N=95 Mean age (years): 42.2 Gender (% female): 52 Ethnicity (% BME): NR Baseline severity: HAMD 25.9 (more severe)	Quetiapine 200-400mg/day + venlafaxine 225mg/day (antidepressant switch)	Venlafaxine 225mg/day (antidepressant switch)	TRD: Inadequate response (<50% reduction of initial HAMD and HAMD score ≥20) to ≥2 different antidepressant therapies with clinically-appropriate dosage and time-course	Treatment length (weeks): 8 Outcomes: Depression symptomatology endpoint Depression symptomatology change score Remission Response Discontinuation due to any reason Discontinuation due to side effects
Mahmoud 2007 RCT US	N=274 Mean age (years): 46.1 Gender (% female): 74 Ethnicity (% BME): 24 Baseline severity: HAMD 24.6 (more severe)	Risperidone 0.25-2mg/day + any antidepressant	Placebo + any antidepressant	Inadequate response (defined as CGI-S score≥4 and a Carroll Depression Scale score≥20) to a 4-week prospective open-label run-in period with current antidepressant monotherapy at the dosages recommended in product labelling	Treatment length (weeks): 6 Outcomes: Depression symptomatology endpoint Remission Response Discontinuation due to any reason Discontinuation due to side effects Quality of life endpoint Functional impairment endpoint
Marcus 2008 RCT US	N=381 Mean age (years): 44.5 Gender (% female): 67 Ethnicity (% BME): 11 Baseline severity: MADRS 26.1 (more severe)	Aripiprazole 2-20mg/day + SSRI/SNRI	Placebo + SSRI/SNRI	TRD: Inadequate response to 1-3 previous antidepressant trials of >6 weeks’ duration (>3 weeks for combination treatments) at a minimum acceptable dose as determined by the MGH ATRQ and inadequate response (defined as failure to achieve ≥50% reduction in the HAMD total score from baseline to the end of the prospective treatment phase, a HAMD>14, or a CGI-I score >3) to 8-week single-blind prospective treatment phase with standard antidepressant in accordance with current product labelling	Treatment length (weeks): 6 Outcomes: Remission Response Discontinuation due to any reason Discontinuation due to side effects
McIntyre 2007 RCT Canada	N=58 Mean age (years): 44.5 Gender (% female): 62 Ethnicity (% BME): NR Baseline severity: HAMD 23.3 (more severe)	Quetiapine 50-600mg/day + SSRI/SNRI	Placebo + SSRI/SNRI	Inadequate response to treatment for their current episode with a single SSRI/venlafaxine at a therapeutic dose for ≥6 weeks	Treatment length (weeks): 8 Outcomes: Remission Response Discontinuation due to any reason Discontinuation due to side effects
Moica 2018 RCT Romania	N=72 Mean age (years): 39.8 Gender (% female): 75 Ethnicity (% BME): NR Baseline severity: HAMD 23.39 (more severe)	Quetiapine 150mg/day + duloxetine 60mg/day	Duloxetine 60mg/day	Inadequate response (HAMD≥14) to the antidepressant therapy (the use of minimal doses accepted as effective for a period of at least 4 - 6 weeks), for the current depressive episode	Treatment length (weeks): 8 Outcomes: Depression symptomatology endpoint Depression symptomatology change score
Otsuka Pharmaceutical 2015 RCT US	N=372 Mean age (years): 43.5 Gender (% female): 68 Ethnicity (% BME): NR Baseline severity: NR (unclear severity)	Brexpiprazole 1-3mg/day + any antidepressant	Placebo + any antidepressant	TRD: history for the current depressive episode of an inadequate response to 1-3 adequate antidepressant treatments; incomplete response to prospective open-label treatment with commercially available antidepressant for 8 weeks at maximally tolerated doses	Treatment length (weeks): 6 Outcomes: Depression symptomatology change score Remission Response Discontinuation due to any reason Discontinuation due to side effects Functional impairment change score
Otsuka Pharmaceutical 2016 RCT US	N=429 Mean age (years): 43.7 Gender (% female): 67 Ethnicity (% BME): NR Baseline severity: NR (unclear severity)	Brexpiprazole 1-4mg/day + SSRI/SNRI	Placebo + SSRI/SNRI	TRD: report a history for the current depressive episode of an inadequate response to 1-3 adequate antidepressant treatments; incomplete response to prospective open-label treatment with a commercially available antidepressant for 8 weeks at maximally tolerated doses	Treatment length (weeks): 6 Outcomes: Depression symptomatology change score Remission Response Discontinuation due to any reason Discontinuation due to side effects Quality of life change score Functional impairment change score
Papakostas 2015 RCT US	N=139 Mean age (years): 44.5 Gender (% female): 71 Ethnicity (% BME): NR Baseline severity: HAMD 20 (more severe)	Ziprasidone 40-160mg/day + escitalopram 10-30mg/day	Placebo + escitalopram 10-30mg/day	Inadequate response (continued to meet DSM-IV criteria and had a QIDS-SR score≥10) to 8-week open-label prospective phase of escitalopram treatment. Mean number of past unsuccessful trials of antidepressants during the current major depressive episode was 0.94 (SD=0.76)	Treatment length (weeks): 8 Outcomes: Depression symptomatology change score Remission Response Discontinuation due to any reason Discontinuation due to side effects
Reeves 2008 RCT US	N=23 Mean age (years): 44.0 Gender (% female): 70 Ethnicity (% BME): NR Baseline severity: MADRS 35.5 (more severe)	Risperidone 0.25-2mg/day + any antidepressant	Placebo + any antidepressant	Inadequate response to 1-2 antidepressants for 3 or more weeks	Treatment length (weeks): 8 Outcomes: Depression symptomatology change score Response Discontinuation due to any reason Discontinuation due to side effects
Song 2007 RCT China	N=120 Mean age (years): 44.0 Gender (% female): 50 Ethnicity (% BME): NR Baseline severity: HAMD 28 (more severe)	Risperidone 0.5-2mg/day + venlafaxine 50-250mg/day	Venlafaxine 50-250mg/day	TRD: inadequate response to at least 2 antidepressants at adequate dose	Treatment length (weeks): 6 Outcomes: Depression symptomatology endpoint
Thase 2007 RCT US & Canada	N=406 Mean age (years): 44.5 Gender (% female): 64 Ethnicity (% BME): 13 Baseline severity: MADRS 30 (more severe)	Olanzapine 6, 12 or 18mg/day + fluoxetine 50mg/day	Fluoxetine 50mg/day	TRD: Documented history of failure to achieve a satisfactory response (based on investigator’s clinical judgement) to an antidepressant (except fluoxetine) after ≥6 weeks of therapy at a therapeutic dose, and failure to respond (<25% decrease in HAMD) to an 8-week, open-label prospective fluoxetine (25-50mg/day) therapy lead-in	Treatment length (weeks): 8 Outcomes: Depression symptomatology change score Remission Response Discontinuation due to any reason Discontinuation due to side effects Quality of life physical component score Quality of life mental component score
Thase 2015a RCT US, Poland, France, & Slovakia	N=379 Mean age (years): 44.7 Gender (% female): 70 Ethnicity (% BME): 13 Baseline severity: MADRS 26.85 (more severe)	Brexpiprazole 0.5-2mg/day + SSRI/SNRI	Placebo + SSRI/SNRI	Inadequate response during the current episode, defined as <50% reduction in symptoms via patient self-reports on the MGH ATRQ to an adequate trial of 1-3 antidepressants including the most recent drug treatment. During the current episode, 82% had 1 prior antidepressant failure	Treatment length (weeks): 6 Outcomes: Depression symptomatology change score Remission Response Discontinuation due to any reason Discontinuation due to side effects Functional impairment score
Thase 2015b RCT US, Germany, Ukraine, Russia, Hungary, Canada, & Romania	N=677 Mean age (years): 45.6 Gender (% female): 68 Ethnicity (% BME): 13 Baseline severity: MADRS 26.47 (more severe)	Brexpiprazole 1mg/day or 3mg/day + SSRI/SNRI	Placebo + SSRI/SNRI	Inadequate response during the current episode, defined as <50% reduction in MGH ATRQ score to an adequate trial of 1-3 antidepressants. 78% 1 prior antidepressant treatment	Treatment length (weeks): 6 Outcomes: Depression symptomatology change score Remission Response Discontinuation due to any reason Discontinuation due to side effects Functional impairment score

: BME: black and minority ethnic; CGI-I: clinical global impression-improvement; CGI-S: clinical global impression-severity; CR: controlled release; DSM: diagnostic statistical manual; HAMD: Hamilton depression scale; MADRS: Montgomery-Asberg depression rating scale; MDD: major depressive disorder; MDE: major depressive episode; MGH ATRQ: Massachusetts General Hospital antidepressant treatment response questionnaire; NR: not reported; QIDS-SR: quick inventory of depressive symptomatology-self report; RCT: randomised controlled trial; SD: standard deviation; SNRI: serotonin-norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; TRD: treatment-resistant depression

Table 47Summary of included studies. Comparison 46. Augmenting with antipsychotic versus bupropion

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Cheon 2017

RCT

Korea

N=103

Mean age (years): 45.6

Gender (% female): 65

Ethnicity (% BME): NR

Baseline severity: MADRS 25.54 (more severe)

Aripiprazole 2.5-20mg/day + SSRI

Bupropion 150-300mg/day + SSRI

Inadequate response to 4 or more weeks with SSRIs

Treatment length (weeks): 6

Outcomes:

Depression symptomatology change score
Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects

Mohamed 2017

RCT

N=1011

Mean age (years): 54.3

Gender (% female): 16

Ethnicity (% BME): 30

Baseline severity: QIDS 16.75 (more severe)

Aripiprazole 2-15mg/day + SSRI/SNRI

Bupropion 150-400mg/day + SSRI/SNRI

Treatment length (weeks): 12

Outcomes:

Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects

: BME: black and minority ethnic; MADRS: Montgomery-Asberg depression rating scale; NR: not reported; QIDS: quick inventory of depressive symptomatology; RCT: randomised controlled trial; SNRI: serotonin-norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor

Table 48Summary of included studies. Comparison 47. Augmenting with antipsychotic versus lithium

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Bauer 2013

RCT

Australia, Austria, Belgium, Bulgaria, Germany, Hungary, Italy, Portugal, Romania, Slovakia, Spain & UK

N=460

Mean age (years): NR

Gender (% female): NR

Ethnicity (% BME): NR

Baseline severity: MADRS 33.05 (more severe)

Quetiapine extended-release (XR) 200-300mg/day + SSRI/SNRI

Lithium 450-900mg/day (target plasma level: 0.6–1.2mmol/L) + SSRI/SNRI

Stage I (failure to achieve remission after ≥1 adequate trial of 1 major class of AD) or stage II (failure of adequate trials of 2 different classes of AD) TRD, 50% in each category

Treatment length (weeks): 6

Outcomes:

Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects

Doree 2007

RCT

Canada

N=20

Mean age (years): 50.8

Gender (% female): 60

Ethnicity (% BME): NR

Baseline severity: MADRS 37.95 (more severe)

Quetiapine 400-800mg/day + any antidepressant

Lithium 600mg/day (target plasma levels 0.8–1.2 mmol/L) + any antidepressant

Inadequate response after 4 weeks of treatment with an antidepressant at the maximal recommended dose

Treatment length (weeks): 8

Outcomes:

Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects

Yoshimura 2014

RCT

Japan

N=30

Mean age (years): 40.3

Gender (% female): 60

Ethnicity (% BME): NR

Baseline severity: HAMD 22.7 (more severe)

Olanzapine (mean dose 7mg/day) or Aripiprazole (mean dose 9mg/day) + paroxetine

Lithium (mean dose 458mg/day) + paroxetine

Inadequate response (<50% improvement from baseline on HAMD) to 8-week prospective treatment with paroxetine

Treatment length (weeks): 4

Outcomes:

Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects

: BME: black and minority ethnic; HAMD: Hamilton depression scale; MADRS: Montgomery-Asberg depression rating scale; NR: not reported; RCT: randomised controlled trial; SNRI: serotonin-norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; TRD: treatment-resistant depression

Table 49Summary of included studies. Comparison 48. Augmenting with antipsychotic versus switch to antipsychotic

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Bauer 2013

RCT

Australia, Austria, Belgium, Bulgaria, Germany, Hungary, Italy, Portugal, Romania, Slovakia, Spain & UK

N=459

Mean age (years): NR

Gender (% female): NR

Ethnicity (% BME): NR

Baseline severity: MADRS 33.45 (more severe)

Quetiapine extended-release (XR) 200-300mg/day + SSRI/SNRI

Quetiapine monotherapy 200-300mg/day

Stage I (failure to achieve remission after ≥1 adequate trial of 1 major class of antidepressants) or stage II (failure of adequate trials of 2 different classes of antidepressants) TRD, 50% in each category

Treatment length (weeks): 6

Outcomes:

Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects

Thase 2007

RCT

US & Canada

N=399

Mean age (years): 44.3

Gender (% female): 64

Ethnicity (% BME): 15

Baseline severity: MADRS 30 (more severe)

Olanzapine 6, 12 or 18mg/day + fluoxetine 50mg/day

Olanzapine monotherapy 6, 12 or 18mg/day

TRD: Documented history of failure to achieve a satisfactory response (based on investigator’s clinical judgement) to an antidepressant (except fluoxetine) after at least 6 weeks of therapy at a therapeutic dose, and failure to respond (<25% decrease in HAMD) to 8 weeks of fluoxetine 25-50mg/day

Treatment length (weeks): 8

Outcomes:

Depression symptomatology change score
Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects
Quality of life physical component score
Quality of life mental component score

: BME: black and minority ethnic; HAMD: Hamilton depression scale; MADRS: Montgomery-Asberg depression rating scale; NR: not reported; RCT: randomised controlled trial; SNRI: serotonin-norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; TRD: treatment-resistant depression

Table 50Summary of included studies. Comparison 49. Augmenting with antipsychotic versus switch to bupropion

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Mohamed 2017

RCT

N=1016

Mean age (years): 54.4

Gender (% female): 14

Ethnicity (% BME): 32

Baseline severity: QIDS 16.75 (more severe)

Aripiprazole 2-15mg/day + SSRI/SNRI

Bupropion monotherapy 150-400mg/day

Treatment length (weeks): 12

Outcomes:

Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects

: BME: black and minority ethnic; QIDS: quick inventory of depressive symptomatology; RCT: randomised controlled trial; SNRI: serotonin-norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor

Table 51Summary of included studies. Comparison 50. Augmenting with buspirone versus continuing with antidepressant (+/− placebo)

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Appelberg 2001

RCT

Finland

N=113

Mean age (years): 44

Gender (% female): 63

Ethnicity (% BME): NR

Baseline severity: NR (more severe)

Buspirone 20-60mg/day + citalopram or fluoxetine

Placebo + citalopram or fluoxetine

Inadequate response (as judged by the psychiatrist in charge of treatment) to ≥ 6 weeks of treatment with fluoxetine (at a dose of ≥30mg/day for ≥4 weeks prior to inclusion) or citalopram (at a dose of ≥40mg/day for ≥4 weeks prior to inclusion)

Treatment length (weeks): 6

Outcomes:

Response

Fang 2011

RCT

China

N=91

Mean age (years): NR

Gender (% female): NR

Ethnicity (% BME): NR

Baseline severity: NR (more severe)

Buspirone 30mg/day + paroxetine

Paroxetine 20mg/day

TRD: Inadequate response to ≥2 adequate treatments from different classes of antidepressants in the current depressive episode (adequate dosages of antidepressants with at least 3-month duration) determined through medical records and/or prospective treatment

Treatment length (weeks): 8

Outcomes:

Remission
Response
Quality of life physical component score
Quality of life mental component score

: BME: black and minority ethnic; NR: not reported; RCT: randomised controlled trial; TRD: treatment-resistant depression

Table 52Summary of included studies. Comparison 51. Augmenting with buspirone versus bupropion

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Trivedi 2006

RCT

N=565

Mean age (years): 41.1

Gender (% female): 59

Ethnicity (% BME): 22

Baseline severity: HAMD 15.8 (less severe)

Buspirone 15-60mg/day (mean final dose 40.9 mg/day) + citalopram

Bupropion sustained release 200-400mg/day (mean final dose 267.5 mg/day) + citalopram

Inadequate response (without remission [HAMD>7]) to a mean of 11.9 weeks of citalopram therapy (mean final dose 55mg/day)

Treatment length (weeks): 6

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score
Remission
Response
Discontinuation due to side effects

: BME: black and minority ethnic; HAMD: Hamilton depression scale; RCT: randomised controlled trial

Table 53Summary of included studies. Comparison 52. Augmenting with methylphenidate versus placebo

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Patkar 2006

RCT

N=60

Mean age (years): 48.5

Gender (% female): 63

Ethnicity (% BME): 40

Baseline severity: HAMD 19.4 (more severe)

Methylphenid ate extended release formulation 18-54mg/day + any antidepressant

Placebo + any antidepressant

Inadequate response to ≥1 antidepressant at study entry, defined as ≥ 6-week trial of an antidepressant at an acceptable therapeutic dose. 70% had failed multiple antidepressant trials for the current MDD episode

Treatment length (weeks): 4

Outcomes:

Remission
Response
Discontinuation due to side effects

Ravindran 2008a

RCT

Canada

N=145

Mean age (years): 43.8

Gender (% female): 65

Ethnicity (% BME): 2

Baseline severity: MADRS 26.7 (more severe)

Methylphenid ate extended release formulation 18-54mg/day + any antidepressant

Placebo + any antidepressant

Inadequate response to 1-3 previous antidepressant monotherapies (including current AD antidepressant of adequate dose and duration and at entry were taking an adequate dose of an antidepressant during the current depressive episode for ≥4 weeks

Treatment length (weeks): 5

Outcomes:

Depression symptomatology change score
Response
Discontinuation due to any reason
Discontinuation due to side effects

: BME: black and minority ethnic; HAMD: Hamilton depression scale; MADRS: Montgomery-Asberg depression rating scale; MDD: major depressive disorder; RCT: randomised controlled trial

Table 54Summary of included studies. Comparison 53. Augmenting with lithium versus continuing with antidepressant (+/− placebo)

Study	Population	Intervention	Comparison	Details of inadequate response/treatment resistance	Comments
Baumann 1996 RCT Switzerland	N=25 Mean age (years): 41.8 Gender (% female): 71 Ethnicity (% BME): NR Baseline severity: NR (more severe)	Lithium 800mg/day (target plasma levels 0.5-0.8 mmol/L) + citalopram 20-60mg/day	Placebo + citalopram 20-60mg/day	Inadequate response (improvement<50% on HAMD) to 4-week prospective treatment phase with citalopram (20-60mg/day)	Treatment length (weeks): 1 Outcomes: Response
Girlanda 2014 RCT Italy	N=56 Mean age (years): 46.5 Gender (% female): 63 Ethnicity (% BME): NR Baseline severity: QIDS 18.3 (more severe)	Lithium (planned starting dose 150-300mg and target plasma levels from 0.4 to 1.0 mmol/L; actual mean dose 444 mg & mean blood level of 0.57 mEq/L) + any antidepressant	Any antidepressant	TRD: Inadequate response to ≥2 antidepressants given sequentially at an adequate dose for an adequate time for the current depressive episode	Treatment length (weeks): 52 Outcomes: Depression symptomatology change score Discontinuation due to any reason
Joffe 1993 RCT Canada	N=33 Mean age (years): NR Gender (% female): 55 Ethnicity (% BME): NR Baseline severity: HAMD 19.47 (more severe)	Lithium 900-1200mg/day (target plasma level 0.55 nmol/L; mean dose 935.3mg/day) + desipramine/imipramine	Placebo + desipramine/imipramine	Inadequate response (HAMD score≥16) to a previous adequate trial of desipramine hydrochloride (90%) or imipramine hydrochloride (10%) ≥5 weeks	Treatment length (weeks): 2 Outcomes: Depression symptomatology endpoint Depression symptomatology change score Remission Discontinuation due to any reason Discontinuation due to side effects
Nierenberg 2003a RCT US	N=35 Mean age (years): 38.4 Gender (% female): 46 Ethnicity (% BME): NR Baseline severity: NR (unclear severity)	Lithium (dose NR) + nortriptyline	Placebo + nortriptyline	TRD: Inadequate response to 1-5 adequate trials of antidepressants during the current episode, and failure to respond to 6 weeks of nortriptyline	Treatment length (weeks): 6 Outcomes: Response Discontinuation due to any reason
Stein 1993 RCT UK	N=34 Mean age (years): 47.2 Gender (% female): 79 Ethnicity (% BME): NR Baseline severity: MADRS 29.9 (more severe)	Lithium 250mg/day + TCA	Placebo + TCA	Inadequate response (failure to show improvement) to treatment with ≥3 weeks of TCA at an adequate dose	Treatment length (weeks): 3 Outcomes: Depression symptomatology endpoint Depression symptomatology change score Discontinuation due to any reason Discontinuation due to side effects

: BME: black and minority ethnic; HAMD: Hamilton depression scale; MADRS: Montgomery-Asberg depression rating scale; NR: not reported; QIDS: quick inventory of depressive symptomatology; RCT: randomised controlled trial; TCA: tricyclic antidepressant; TRD: treatment-resistant depression

Table 55Summary of included studies. Comparison 54. Augmenting with lithium versus switch to antipsychotic

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Bauer 2013

RCT

Australia, Austria, Belgium, Bulgaria, Germany, Hungary, Italy, Portugal, Romania, Slovakia, Spain & UK

N=457

Mean age (years): NR

Gender (% female): NR

Ethnicity (% BME): NR

Baseline severity: MADRS 33.3 (more severe)

Lithium 450-900mg/day (target plasma level: 0.6–1.2mmol/L) + SSRI/SNRI

Quetiapine monotherapy 200-300mg/day

Stage I (failure to achieve remission after ≥1 adequate trial of 1 major class of antidepressant) or stage II (failure of adequate trials of 2 different classes of antidepressant) TRD, 50% in each category

Treatment length (weeks): 6

Outcomes:

Remission
Response
Discontinuation due to any reason
Discontinuation due to side effects

: BME: black and minority ethnic; MADRS: Montgomery-Asberg depression rating scale; NR: not reported; RCT: randomised controlled trial; SNRI: serotonin-norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; TRD: treatment-resistant depression

Table 56Summary of included studies. Comparison 55. Augmenting with lithium versus augmenting with a psychological intervention

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Kennedy 2003

RCT

Canada

N=44

Mean age (years): 39.3

Gender (% female): 55

Ethnicity (% BME): NR

Baseline severity: HAMD 11.9 (less severe)

Lithium 600-900mg/day + SSRI/SNRI/moclobemide

CBT individual 12 sessions + SSRI/SNRI/moclobemide

Partial response (score of 8-15 on HAMD-D) to 1 of 4 standard antidepressant medications (moclobemi de, paroxetine, sertraline, or venlafaxine) to maximum tolerated doses for 8-14 weeks

Treatment length (weeks): 8

Outcomes:

Depression symptomatology at:
- Endpoint
- 1-month follow-up
Depression symptomatology change score
Remission
Discontinuation due to any reason
Discontinuation due to side effects

: BME: black and minority ethnic; HAMD: Hamilton depression scale; NR: not reported; RCT: randomised controlled trial; SNRI: serotonin-norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor

Table 57Summary of included studies. Comparison 56. Augmenting with lithium versus augmenting with TCA

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Fava 1994a

RCT

N=26

Mean age (years): NR

Gender (% female): NR

Ethnicity (% BME): NR

Baseline severity: HAMD 19.01 (more severe)

Lithium 300-600mg/day + fluoxetine 20mg/day

Desipramine 25-50mg/day + fluoxetine 20mg/day

Inadequate response (<50% improvement in HAMD score and HAMD≥10) to 8 weeks of fluoxetine 20mg/day

Treatment length (weeks): 4

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score
Remission
Discontinuation due to any reason
Discontinuation due to side effect

Fava 2002

RCT

N=68

Mean age (years): NR

Gender (% female): NR

Ethnicity (% BME): NR

Baseline severity: HAMD 16.75 (more severe)

Lithium 300-600mg/day + fluoxetine 20mg/day

Desipramine 25-50mg/day + fluoxetine 20mg/day

Inadequate response (<50% improvement in HAMD score and HAMD≥10) to 8 weeks of fluoxetine 20mg/day

Treatment length (weeks): 4

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score
Remission
Discontinuation due to any reason

: BME: black and minority ethnic; HAMD: Hamilton depression scale; NR: not reported; RCT: randomised controlled trial; TCA: tricyclic antidepressant

Table 58Summary of included studies. Comparison 57. Augmenting with omega-3 fatty acids versus placebo

Study	Population	Intervention	Comparison	Details of inadequate response/treatment resistance	Comments
Jahangard 2018 RCT Iran	N=50 Mean age (years): 42.5 Gender (% female): 68 Ethnicity (% BME): NR Baseline severity: MADRS 34.9 (more severe)	Omega-3 fatty acid 1000mg/day + sertraline 50-200mg/day	Placebo + sertraline 50-200mg/day	Inadequate response: met inclusion criteria despite receiving sertraline (50–200 mg/day) for 8 weeks	Treatment length (weeks): 12 Outcomes: Depression symptomatology endpoint Depression symptomatology change score Discontinuation due to any reason Discontinuation due to side effects Sleeping difficulties endpoint
Mozaffari-Khosravi 2013 RCT Iran	N=81 Mean age (years): 35.1 Gender (% female): 61 Ethnicity (% BME): NR Baseline severity: HAMD 15.7 (less severe)	Eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) 1 g/day + any antidepressant	Placebo + any antidepressant	Inadequate response to current antidepressant treatment (met DSM-IV criteria for MDD and HAMD>7; mean length of antidepressant treatment: 3.9 months)	Treatment length (weeks): 12 Outcomes: Depression symptomatology endpoint Depression symptomatology change score Remission Response Discontinuation due to any reason Discontinuation due to side effects
Nemets 2002 RCT Israel	N=20 Mean age (years): 53.4 Gender (% female): 85 Ethnicity (% BME): NR Baseline severity: HAMD 23.15 (more severe)	Eicosapentaenoic acid (E-EPA) 2g/day + SSRI	Placebo + SSRI	Inadequate response: met inclusion criteria despite receiving current AD treatment for ≥3 months	Treatment length (weeks): 4 Outcomes: Depression symptomatology endpoint Depression symptomatology change score Response Discontinuation due to any reason Discontinuation due to side effects
Peet 2002 RCT UK	N=70 Mean age (years): 44.7 Gender (% female): 84 Ethnicity (% BME): NR Baseline severity: MADRS 22.7 (more severe)	Ethyl-eicosapemtaenoate 1g/day, 2g/day or 4g/day + any antidepressant	Placebo + any antidepressant	Inadequate response (HAMD≥15) to ongoing treatment with antidepressant at an adequate dose	Treatment length (weeks): 12 Outcomes: Response Discontinuation due to any reason Discontinuation due to side effects

: BME: black and minority ethnic; DSM: diagnostic statistical manual; HAMD: Hamilton depression scale; MADRS: Montgomery-Asberg depression rating scale; MDD: major depressive disorder; NR: not reported; RCT: randomised controlled trial; SSRI: selective serotonin reuptake inhibitor

Table 59Summary of included studies. Comparison 58. Augmenting with thyroid hormone versus continuing with antidepressant (+/− placebo)

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Fang 2011

RCT

China

N=93

Mean age (years): NR

Gender (% female): NR

Ethnicity (% BME): NR

Baseline severity: NR (more severe)

Thyroid hormone 80mg/day + paroxetine

Paroxetine 20mg/day

TRD: Inadequate response to ≥2 adequate treatments from different classes of antidepressants in the current depressive episode (adequate dosages of antidepressants with ≥3-month duration) determined through medical records and/or prospective treatment. Paroxetine 1-week lead-in

Treatment length (weeks): 8

Outcomes:

Remission
Response
Quality of life physical component score
Quality of life mental component score

Joffe 1993

RCT

Canada

N=33

Mean age (years): NR

Gender (% female): 67

Ethnicity (% BME): NR

Baseline severity: HAMD 18.75 (more severe)

Liothyronine sodium (triiodothyronine, T3) 37.5μg + desipramine/imipramine

Placebo + desipramine/imipramine

Inadequate response (HAMD≥16) to a previous adequate trial of desipramine hydrochloride (90%) or imipramine hydrochloride (10%) ≥5 weeks

Treatment length (weeks): 2

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score
Remission
Discontinuation due to any reason
Discontinuation due to side effects

: BME: black and minority ethnic; HAMD: Hamilton depression scale; NR: not reported; RCT: randomised controlled trial; TRD: treatment-resistant depression

Table 60Summary of included studies. Comparison 59. Augmenting with thyroid hormone versus augmenting with lithium

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Joffe 1993

RCT

Canada

N=34

Mean age (years): NR

Gender (% female): 59

Ethnicity (% BME): NR

Baseline severity: HAMD 19.5 (more severe)

Liothyronine sodium (triiodothyronine, T3) 37.5μg + desipramine/imipramine

Lithium 900-1200mg/day (target plasma level 0.55 nmol/L) + desipramine/imipramine

Inadequate response (HAMD≥16) to a previous adequate trial of desipramine hydrochloride (90%) or imipramine hydrochloride (10%) ≥5 weeks

Treatment length (weeks): 2

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score
Remission
Discontinuation due to any reason
Discontinuation due to side effects

Nierenberg 2006

RCT

N=142

Mean age (years): 42.0

Gender (% female): 58

Ethnicity (% BME): 17

Baseline severity: QIDS 12.4 (more severe)

Thyroid hormone (T3) 25-50 μg/day + any antidepressant

Lithium 225-900mg/day + any antidepressant

TRD: Inadequate response (not achieved remission or who were intolerant) to an initial prospective treatment with citalopram and a second switch or augmentation trial

Treatment length (weeks): 14

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score
Remission
Response
Discontinuation due to side effects

: BME: black and minority ethnic; HAMD: Hamilton depression scale; NR: not reported; QIDS: quick inventory of depressive symptomatology; RCT: randomised controlled trial; TRD: treatment-resistant depression

Table 61Summary of included studies. Comparison 60. Switching to ECT versus switching to paroxetine

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Folkerts 1997

RCT

Germany

N=40

Mean age (years): 49.8

Gender (% female): 54

Ethnicity (% BME): NR

Baseline severity: HAMD 31.79 (more severe)

6-9- ECT treatments

Paroxetine 20-50mg/day

TRD: Failure to respond to ≥2 different antidepressants (including ≥1 TCA) over a total period of 8 weeks

Treatment length (weeks): 4

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score
Response
Discontinuation due to any reason
Discontinuation due to side effects

: BME: black and minority ethnic; ECT: electroconvulsive therapy; HAMD: Hamilton depression scale; NR: not reported; RCT: randomised controlled trial; TCA: tricyclic antidepressant; TRD: treatment-resistant depression

Table 62Summary of included studies. Comparison 61. Augmenting with ECT versus continuing with antidepressant

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Haghighi 2013

RCT

Iran

N=40

Mean age (years): 31.5

Gender (% female): 30

Ethnicity (% BME): NR

Baseline severity: HAMD 37.2 (more severe)

12 ECT sessions + citalopram 40mg/day

Citalopram 40mg/day

Inadequate response to 2-weeks of citalopram (40mg/day) and ECT recommended by 2 independent psychiatrists

Treatment length (weeks): 4

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score

: BME: black and minority ethnic; ECT: electroconvulsive therapy; HAMD: Hamilton depression scale; NR: not reported; RCT: randomised controlled trial

Table 63Summary of included studies. Comparison 62. Augmenting with ECT versus augmenting with exercise

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Salehi 2016

RCT

Iran

N=40

Mean age (years): 29.4

Gender (% female): 28

Ethnicity (% BME): NR

Baseline severity: HAMD 41.23 (more severe)

12 ECT sessions + citalopram 40mg/day

12 exercise sessions + citalopram 40mg/day

Inadequate response to 2-weeks of citalopram (40mg/day) and ECT recommended by 2 independent psychiatrists

Treatment length (weeks): 4

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score
Remission

: BME: black and minority ethnic; ECT: electroconvulsive therapy; HAMD: Hamilton depression scale; NR: not reported; RCT: randomised controlled trial

Table 64Summary of included studies. Comparison 63. Augmenting with ECT + exercise versus augmenting with exercise

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Salehi 2016

RCT

Iran

N=40

Mean age (years): 29.7

Gender (% female): 28

Ethnicity (% BME): NR

Baseline severity: HAMD 42.5 (more severe)

12 ECT sessions + 12 exercise sessions + citalopram 40mg/day

12 exercise sessions + citalopram 40mg/day

Inadequate response to 2-weeks of citalopram (40mg/day) and ECT recommended by 2 independent psychiatrists

Treatment length (weeks): 4

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score
Remission

: BME: black and minority ethnic; ECT: electroconvulsive therapy; HAMD: Hamilton depression scale; NR: not reported; RCT: randomised controlled trial

Table 65Summary of included studies. Comparison 64. Augmenting with exercise versus TAU

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Danielsson 2014

RCT

Sweden

N=42

Mean age (years): 45.5

Gender (% female): 76

Ethnicity (% BME): NR

Baseline severity: MADRS 24 (more severe)

Aerobic exercise + SSRI/SNRI

Intensity: 2 individual sessions + 16x twice-weekly 1-hour group training sessions

Enhanced TAU + SSRI/SNRI

Intensity: 1 session

Inadequate response (retained diagnosis) to a course of antidepressants, of at least 6 weeks duration

Treatment length (weeks): 10

Outcomes:

Depression symptomatology change score
Remission
Response
Discontinuation due to any reason

Ho 2014

RCT

China

N=52

Mean age (years): 46.2

Gender (% female): 67

Ethnicity (% BME): NR

Baseline severity: MADRS 19 (less severe)

Aerobic exercise group + any antidepressant

Intensity: 15x thrice-weekly 40-min sessions

Any antidepressant

Inadequate response: met inclusion criteria despite being on antidepressant at baseline

Treatment length (weeks): 3

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score
Remission

: BME: black and minority ethnic; MADRS: Montgomery-Asberg depression rating scale; NR: not reported; RCT: randomised controlled trial; SNRI: serotonin-norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; TAU: treatment as usual

Table 66Summary of included studies. Comparison 65. Augmenting with exercise versus attention-placebo

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Lavretsky 2011

RCT

N=73

Mean age (years): 70.6

Gender (% female): 62

Ethnicity (% BME): NR

Baseline severity: HAMD 9 (less severe)

Tai Chi + escitalopram 10-20mg/day

Intensity: 10x 2-hour sessions

Attention-placebo (health education) + escitalopram 10-20mg/day

Intensity: 10x 2-hour sessions

Inadequate response to 4 weeks prospective treatment with escitalopram

Treatment length (weeks): 10

Outcomes:

Depression symptomatology endpoint
Remission
Discontinuation due to any reason
Sleeping difficulties emdpoint

Mather 2002

RCT

N=86

Mean age (years): 65.0

Gender (% female): 69

Ethnicity (% BME): NR

Baseline severity: HAMD 17.05 (more severe)

Weight training class + any antidepressant

Intensity: 20x twice-weekly 45-min sessions

Attention-placebo (health education talks) + any antidepressant

Intensity: 20x twice-weekly 30-40 min sessions

Inadequate response: all participants had been in receipt of a therapeutic dose of antidepressant therapy for at least 6 weeks without evidence of a sustained response prior to study entry

Treatment length (weeks): 10

Outcomes:

Response
Discontinuation due to any reason

Mota-Pereira 2011

RCT

Portugal

N=33

Mean age (years): 47.5

Gender (% female): 66

Ethnicity (% BME): NR

Baseline severity: HAMD 17 (more severe)

Aerobic exercise + any antidepressant

Intensity: 60 sessions/12x 30-45min sessions supervised

Attention-placebo (social interaction with study staff and peers) + any antidepressant

Intensity: 12x 30-45min sessions

Inadequate response (failure to show clinical remission, HAMD>7) to combined therapy in doses considered adequate for 9-15 months

Treatment length (weeks): 12

Outcomes:

Depression symptomatology change score
Remission
Response
Discontinuation due to any reason
Global functioning change score

: BME: black and minority ethnic; HAMD: Hamilton depression scale; NR: not reported; RCT: randomised controlled trial

Table 67Summary of included studies. Comparison 66. Augmenting with exercise + ECT versus augmenting with ECT

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Salehi 2016

RCT

Iran

N=40

Mean age (years): 30.0

Gender (% female): 35

Ethnicity (% BME): NR

Baseline severity: HAMD 43.38 (more severe)

Exercise + ECT + citalopram 40mg/day

Intensity: Exercise: 12x thrice-weekly sessions; ECT: 12x thrice-weekly sessions

ECT + citalopram 40mg/day

Intensity: 12x thrice-weekly exercise sessions

Inadequate response to 2-weeks of citalopram (40mg/day) and ECT recommended by 2 independent psychiatrists

Treatment length (weeks): 4

Outcomes:

Depression symptomatology endpoint
Depression symptomatology change score
Remission

: BME: black and minority ethnic; ECT: electroconvulsive therapy; HAMD: Hamilton depression scale; NR: not reported; RCT: randomised controlled trial

Table 68Summary of included studies. Comparison 67. Augmenting with yoga versus continuing with antidepressant (+/− waitlist or attention-placebo)

Study

Population

Intervention

Comparison

Details of inadequate response/treatment resistance

Comments

Sharma 2017

RCT

N=25

Mean age (years): 37.2

Gender (% female): 72

Ethnicity (% BME): 8

Baseline severity: HAMD 20.4 (more severe)

Sudarshan Kriya yoga (SKY) group + any antidepressant

Intensity: 12 sessions

Waitlist + any antidepressant

Inadequate response: met inclusion criteria despite having received a stable dose of antidepressant treatment for at least 8 weeks

Treatment length (weeks): 8

Outcomes:

Depression symptomatology change score
Remission
Response
Discontinuation due to any reason

Uebelacker 2017

RCT

N=122

Mean age (years): 46.5

Gender (% female): 84

Ethnicity (% BME): 16

Baseline severity: QIDS 12.87 (more severe)

Hatha yoga group + any antidepressant

Intensity: 10-20x 80-min sessions

Attention-placebo (health living workshop) + any antidepressant

Intensity: 10-20x 60-min sessions

Inadequate response: met inclusion criteria despite currently taking an antidepressant at a dose with demonstrated effectiveness per American Psychiatric Association practice guidelines for at least 8 weeks

Treatment length (weeks): 10

Outcomes:

Remission at:
- Endpoint
- 3-month follow-up
- 6-month follow-up
Response at:
- Endpoint
- 3-month follow-up
- 6-month follow-up
Discontinuation due to any reason

: BME: black and minority ethnic; HAMD: Hamilton depression scale; QIDS: quick inventory of depressive symptomatology; RCT: randomised controlled trial

Final

Evidence review underpinning recommendations 1.9.1 to 1.9.9 and 1.13.1 to 1.13.9, and research recommendations 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: NBK583075PMID: 35977063