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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); .
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.

Table 1. Summary of the protocol (PICO table).

Table 1

Summary of the protocol (PICO table).

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.

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

Table 2

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

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

Table 3

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

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

Table 4

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

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

Table 5

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

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

Table 6

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

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

Table 7

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

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

Table 8

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

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

Table 9

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

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

Table 10

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

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

Table 11

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

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

Table 12

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

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

Table 13

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

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

Table 14

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

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

Table 15

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

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

Table 16

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

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

Table 17

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

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

Table 18

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

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

Table 19

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

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

Table 20

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

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

Table 21

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

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

Table 22

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

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

Table 23

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

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

Table 24

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

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

Table 25

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

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

Table 26

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

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

Table 27

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

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

Table 28

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

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

Table 29

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

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

Table 30

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

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

Table 31

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

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

Table 32

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

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

Table 33

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

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

Table 34

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

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

Table 35

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

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

Table 36

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

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

Table 37

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

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

Table 38

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

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

Table 39

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

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

Table 40

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

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

Table 41

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

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

Table 42

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

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

Table 43

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

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

Table 44

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

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

Table 45

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

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

Table 46

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

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

Table 47

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

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

Table 48

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

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

Table 49

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

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

Table 50

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

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

Table 51

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

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

Table 52

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

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

Table 53

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

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

Table 54

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

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

Table 55

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

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

Table 56

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

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

Table 57

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

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

Table 58

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

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

Table 59

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

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

Table 60

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

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

Table 61

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

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

Table 62

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

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

Table 63

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

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

Table 64

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

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

Table 65

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

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

Table 66

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

Table 67. Summary of included studies. Comparison 66. Augmenting with exercise + ECT versus augmenting with ECT.

Table 67

Summary of included studies. Comparison 66. Augmenting with exercise + ECT versus augmenting with ECT.

Table 68. Summary of included studies. Comparison 67. Augmenting with yoga versus continuing with antidepressant (+/− waitlist or attention-placebo).

Table 68

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

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 1st-6th 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 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.

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.

Copyright © NICE 2022.
Bookshelf ID: NBK583075PMID: 35977063

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