Summary of methods

Clinical evidence

Summary of studies included in the evidence review

The NMAs included 142 RCTs (k=142) representing 20,663 participants (n=20,663).

Of the 142 RCTs included in the NMAs for less severe depression, only 26 studies reported either a HAM-D or MADRS score at baseline, and for these studies the mean depression severity scores were HAM-D=12.99 (SD=7.66; k=23) and MADRS=17.74 (SD=6.87; k=3) respectively. Other commonly reported depression scales at baseline for RCTs within this network included the PHQ-9 (mean severity at baseline=12.78, SD=4.84, k=15), CES-D (mean severity at baseline=23.21, SD=9.30, k=35), BDI (mean severity at baseline=16.73, SD=6.89, k=16), and BDI-II (mean severity at baseline=22.38, SD=7.91, k=45). 10 studies were UK-based RCTs.

According to the interventions assessed and the types of outcomes reported in each RCT, the included RCTs have contributed data to one or more networks of evidence and respective NMAs.

For the SMD of depression symptom change scores outcome, the network of evidence (and the respective NMA) included 127 RCTs, 76 interventions grouped in 34 treatment classes, and 16,829 participants. Of the 127 RCTs, 10 reported change from baseline (CFB) depression symptom score data; 115 reported baseline and endpoint depression symptom score data; and 2 reported dichotomous response data and baseline symptom scores. These data were transformed and synthesised accordingly, allowing estimation of the SMD of depression symptom change scores (see appendix M for details).

For the outcome of response in those randomised, the network of evidence (and the respective NMA) included 75 RCTs, 53 interventions grouped in 26 treatment classes and 12,549 participants. Of the 75 RCTs, 11 reported dichotomous response data, 6 reported CFB depression symptom score data; and 58 reported baseline and endpoint depression symptom score data. These data were transformed and synthesised accordingly, allowing estimation of log-odds ratios of response (see appendix M for details).

For the outcome of remission in those randomised, the network of evidence (and the respective NMA) included 26 RCTs reporting dichotomous remission data, 25 interventions grouped in 16 treatment classes and 3,810 participants.

See the full evidence tables in appendix D.

Relevant information on the networks of evidence and the NMAs that informed the economic analysis are reported in appendix M.

Evidence from the network meta-analysis

Base-case analysis

Below is an overview of the treatment class network plots, numbers of people tested on each treatment class and intervention, and NMA findings at the treatment class level (relative effects versus the reference treatment and rankings), for every critical outcome considered in the clinical base-case analysis of treatments for adults with a new episode of less severe depression. For the outcome of the SMD of depressive symptom scores, relative effects of individual interventions versus the reference treatment are also provided in this section.

For each outcome, we present network plots, which depict all treatments considered in each analysis by nodes, and show which treatments have been directly compared in the RCTs included in each NMA, by connecting them with a direct line. In each network plot presented below, the width of lines is proportional to the number of trials that make each direct comparison; the size of each circle (treatment node) is proportional to the number of participants tested on each treatment class.

Full results of the NMA, including network plots and relative effects of individual interventions, as well as relative effects of all pairs of treatment classes and individual interventions, are reported in appendix M and supplements B5 and B6.

SMD of depression symptom change scores

The network plot at the treatment class level is shown in Figure 1. The numbers of participants tested on each treatment class and each intervention are shown in Table 2. The base-case relative effects (posterior mean SMD with 95% CrI) of all treatment classes versus TAU (reference treatment for less severe depression) are illustrated in Figure 2 (forest plots) and reported in Table 3. The same table also shows the class treatment rankings. Treatment classes in the table have been ordered from lowest to highest ranking (with lower rankings suggesting greater effects).

Figure 1

Network plot of the NMA of standardised mean difference (SMD) of depression symptom change scores in adults with a new episode of less severe depression – treatment class level. The width of lines is proportional to the number of trials that make (more...)

Table 2

Treatment classes, interventions and numbers of participants tested on each in the NMA of standardised mean difference (SMD) of depression symptom change scores in adults with a new episode of less severe depression.

Figure 2

Base-case forest plots of standardised mean difference (SMD) of depression symptom change scores in adults with a new episode of less severe depression: effects of treatment classes versus treatment as usual (TAU, N=815). Values on the left side of the (more...)

Table 3

Base-case results of the NMA of standardised mean difference (SMD) of depression symptom change scores in adults with a new episode of less severe depression: posterior effects (mean SMD, 95%CrI) of all treatment classes versus treatment as usual (TAU) (more...)

The base-case relative effects (posterior mean SMD with 95% CrI) of all individual interventions versus TAU (reference treatment for less severe depression) are reported in Table 4. Interventions have been listed by treatment class.

Table 4

Base-case results of the NMA of standardised mean difference (SMD) of depression symptom change scores in adults with a new episode of less severe depression: posterior effects (mean SMD, 95%CrI) of all interventions versus treatment as usual (TAU). Only (more...)

Response in those randomised

The network plot at the treatment class level is shown in Figure 3. The number of participants tested on each treatment class and each intervention are shown in The width of lines is proportional to the number of trials that make each direct comparison; the size of each circle (treatment node) is proportional to the number of participants tested on each treatment class.

SSRIs: selective serotonin uptake inhibitors; TAU: treatment as usual; TCAs: tricyclic antidepressants

Table 5. The base-case relative effects (posterior mean log-odds ratio [LOR] with 95% CrI) of all treatment classes versus TAU (reference treatment for less severe depression) are illustrated in Figure 4 (forest plots) and reported in Table 6. The same table shows also the class treatment rankings. Treatment classes in the table have been ordered from lowest to highest ranking (with lower rankings suggesting greater effects).

Figure 3

Network plot of the NMA of response in those randomised in adults with a new episode of less severe depression – treatment class level. The width of lines is proportional to the number of trials that make each direct comparison; the size of each (more...)

Table 5

Treatment classes, interventions and numbers of participants tested on each in the NMA of response in those randomised in adults with a new episode of less severe depression.

Figure 4

Forest plots of response in those randomised in adults with a new episode of less severe depression: effects of treatment classes versus treatment as usual (TAU, N=623). Values on the right side of the vertical axis indicate better effect compared with (more...)

Table 6

Base-case results of the NMA of response in those randomised in adults with a new episode of less severe depression: posterior effects (mean log-odds ratio [LOR], 95%CrI) of all treatment classes versus treatment as usual (TAU) and treatment class rankings. (more...)

Remission in those randomised

The network plot at the treatment class level is shown in Figure 5. The number of participants tested on each treatment class and each intervention are shown in The width of lines is proportional to the number of trials that make each direct comparison; the size of each circle (treatment node) is proportional to the number of participants tested on each treatment class.

TAU: treatment as usual

Table 7. The base-case relative effects (posterior mean log-odds ratio [LOR] with 95% CrI) of all treatment classes versus TAU (reference treatment for less severe depression) are illustrated in Figure 6 (forest plots) and reported in Table 8. The same table shows also the class treatment rankings. Treatment classes in the table have been ordered from lowest to highest ranking (with lower rankings suggesting greater effects).

Figure 5

Network plot of the NMA of remission in those randomised in adults with a new episode of less severe depression – treatment class level. The width of lines is proportional to the number of trials that make each direct comparison; the size of each (more...)

Table 7

Treatment classes, interventions and numbers of participants tested on each in the NMA of remission in those randomised in adults with a new episode of less severe depression.

Figure 6

Forest plots of remission in those randomised in adults with a new episode of less severe depression: effects of treatment classes versus treatment as usual (TAU, N=437). Values on the right side of the vertical axis indicate better effect compared with (more...)

Table 8

Base-case results of the NMA of remission in those randomised in adults with a new episode of less severe depression: posterior effects (mean log-odds ratio [LOR], 95%CrI) of all treatment classes versus treatment as usual (TAU) and treatment class rankings. (more...)

Bias-adjusted analysis

Bias models tested on the SMD outcome suggested evidence of bias due to small study size.

Figure 7 shows the bias-adjusted forest plots of relative effects (posterior mean SMD with 95% CrI) of all treatment classes versus TAU (reference treatment for less severe depression). Table 9 shows the relative effects of all treatment classes versus TAU on the SMD and the class treatment rankings. Treatment classes in the table have been ranked from lowest to highest ranking (with lower rankings suggesting greater effects).

Table 10 shows the bias-adjusted relative effects (posterior mean SMD with 95% CrI) of all individual interventions versus TAU (reference treatment for less severe depression). Interventions in this table have been listed by treatment class.

Figure 7

Bias-adjusted forest plots of standardised mean difference (SMD) of depression symptom change scores in adults with a new episode of less severe depression: effects of treatment classes versus treatment as usual (TAU, N=815). Values on the left side of (more...)

Table 9

Bias-adjusted results of the NMA of standardised mean difference (SMD) of depression symptom change scores in adults with a new episode of less severe depression: posterior effects (mean SMD, 95%CrI) of all treatment classes versus treatment as usual (more...)

Table 10

Bias-adjusted results of the NMA of standardised mean difference (SMD) of depression symptom change scores in adults with a new episode of less severe depression: posterior effects (mean SMD, 95%CrI) of all interventions versus treatment as usual (TAU). (more...)

Sensitivity analyses

Effects on the SMD of all treatment classes versus TAU in the post-hoc sensitivity analysis that included only RCTs rated as being at low risk of bias for attrition in the Cochrane Risk of Bias tool are presented in Table 11, alongside the base-case analysis effects, to allow comparison between the two sets of results.

Table 11

Comparison of results following inclusion only of trials at low risk of bias for attrition in the NMA and results of the NMA base-case analysis: standardised mean difference (SMD) of depression symptom scores in adults with a new episode of less severe (more...)

Finally, effects on the SMD of all treatment classes versus TAU in the sensitivity analysis conducted after excluding pharmacological trials are reported in Table 12, presented alongside the base-case analysis effects, to allow comparison between the two sets of results. In each analysis, treatment classes have been ordered from lowest to highest ranking (with lower rankings suggesting higher effects).

Table 12

Comparison of results following exclusion of pharmacological trials from the NMA and results of the NMA base-case analysis: standardised mean difference (SMD) of depression symptom scores in adults with a new episode of less severe depression.

Evidence from the pairwise meta-analyses

Important (but not critical) outcomes

See Table 13 for a summary of the clinically important and statistically significant effects observed for the important (but not critical) outcomes of quality of life and functioning (including personal, social, and occupational functioning and global functioning/functional impairment) at endpoint and longer-term (at least 6 months) follow-up. See supplement B2 for forest plots for all important (but not critical) outcomes.

Table 13

Summary of significant important (but not critical outcomes) at endpoint and longer-term (at least 6 months) follow-up for adults with a new episode of less severe depression.

Follow-up of critical outcomes

See Table 14 for a summary of the clinically important and statistically significant effects observed for critical outcomes at longer-term (at least 6 months) follow-up. See supplement B2 for forest plots for all critical outcomes at all follow-up time points.

Table 14

Summary of significant critical outcomes at longer-term (at least 6 months) follow-up for adults with a new episode of less severe depression.

Comparison of the results of the results of pairwise meta-analysis with the NMA for critical outcomes

See Table 15 for comparisons between pairwise and NMA results (base-case analysis) for critical outcomes where the difference between the pairwise meta-analysis and NMA results is equal to, or larger than, the minimally important difference (MID, defined as SMD −0.5/0.5 or logOR ±0.25 [MID for OR calculated as exp[0.25]=1.28]) and the effect estimate of the NMA is not within the 95% confidence interval of the pairwise effect estimate (considered a significant difference), and see Table 16 for differences between pairwise and NMA results ≥MID but where the NMA effect estimate is within the 95% confidence interval of the pairwise effect estimate (considered a non-significant difference). The full table of pairwise meta-analysis and NMA comparisons is available in supplement B4. Out of a total of 93 comparisons between pairwise and NMA results for less severe depression, 26 differences ≥MID were identified (28% of all comparisons), of these only 11 differences (12% of all comparisons) could be considered significant in that the NMA estimate was not within the 95% confidence interval of the pairwise effect estimate. For most differences identified the difference was in magnitude rather than direction of effect and could probably be accounted for by the smaller evidence base contributing to the pairwise effect estimates. It is important to note that these comparisons have been performed in addition to the NMA inconsistency checks (where direct and indirect evidence is compared). For the NMA inconsistency checks, no evidence of inconsistency was identified in any of the outcomes considered in the clinical analysis.

Table 15

Summary of differences between pairwise and NMA results ≥ MID where NMA effect estimate is not within 95% confidence interval of pairwise effect estimate for adults with a new episode of less severe depression.

Table 16

Summary of differences between pairwise and NMA results ≥ MID where NMA effect estimate is within 95% confidence interval of pairwise effect estimate for adults with a new episode of less severe depression.

Quality assessment of studies included in the evidence review and the evidence

A threshold analysis was originally planned to conduct, to test the robustness of treatment recommendations based on the NMA, to potential biases or sampling variation in the included evidence. Threshold analysis has been developed as an alternative to GRADE for assessing confidence in guideline recommendations based on network meta-analysis (Phillippo 2019). Threshold analysis suggests by how much effects that have been estimated in the NMA need to change before recommendations change, and whether such changes might potentially occur due to bias in the evidence. The NICE Guidelines Technical Support Unit (TSU) attended committee discussions on the rationale for recommendations and noted that, in addition to the results of the NMA, the committee took other pragmatic factors into consideration when making recommendations, including the uncertainty and limitations around the clinical and cost-effectiveness data, and the need to provide a wide range of interventions to take into account individual needs and allow patient choice. The TSU advised that as it was difficult to identify a clear decision rule to link the recommendations directly to the NMA results, it was not feasible or helpful to conduct a threshold analysis. CINeMA was also considered as a method to evaluate the confidence in the results from the NMA (Nikolakopoulou 2020). However, this was not possible to carry out, due to the class models being implemented.

In the absence of undertaking threshold analysis or using CINeMA to evaluate the quality of the evidence and the confidence in the results derived from the NMA that informed this review question, we evaluated and summarise the quality of the evidence narratively, using the domains considered as per a standard GRADE approach (risk of bias, inconsistency, publication bias, indirectness and imprecision).

Risk of bias

The Cochrane risk of bias tool version 1.0 for RCTs (see appendix H in Developing NICE guidelines: the manual) was used to assess potential bias in each study included in the review. Generally the standard of reporting in studies was quite low, as demonstrated by the risk of bias summary diagram (Figure 8). Of the 142 studies included in the NMAs for less severe depression, 56 were at low risk of bias for allocation method and 53 were at low risk of bias for allocation concealment. Trials of psychological therapies were typically considered at high risk of bias for participant and provider blinding, although it is difficult to quantify in risk of bias ratings it is also important to bear in mind that the rate of side effects may also make it difficult to maintain blinding in pharmacological trials. Across interventions, 8 trials were at low risk of bias for blinding participants and providers. Assessor blinding was considered for all trials including those using self-report measures: 14 were at low risk of bias, 127 were unclear, and high risk in 1 trial. For attrition bias, 90 trials were at low risk of bias, unclear risk in 33 trials, and 19 trials were at high risk of bias. Other sources of bias, potential or actual (for instance, potential conflicts of interest associated with funding), were identified in 45 RCTs. See appendix D for full study details, including risk of bias ratings by study.

Figure 8

Risk of bias summary for treatments of a new episode in people with less severe depression.

Economic evidence

Summary of studies included in the economic evidence review

All included economic studies were conducted in the UK and adopted a NHS perspective, with some studies including personal social service (PSS) costs as well; in addition, some studies reported separate analyses that adopted a societal perspective. NHS and PSS cost elements included, in the vast majority of studies, intervention, primary and community care, staff time (such as GPs, nurses, psychiatrists, psychologists), medication, inpatient and outpatient care and other hospital care. All studies used national unit costs; in some studies, intervention costs were based on local prices or prices provided by the manufacturers (for example in the case of computerised CBT packages).

Economic model

A decision-analytic model was developed to assess the relative cost effectiveness of interventions of adults with a new episode of less severe depression. The objective of economic modelling, the methodology adopted, the results and the conclusions from this economic analysis are described in detail in appendix J. This section provides a summary of the methods employed and the results of the economic analysis.

Summary of the evidence

The committee’s discussion of the evidence

Recommendations supported by this evidence review

This evidence review supports recommendations 1.5.2 and 1.5.3 and research recommendations in the NICE guideline.

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Additional references to methodological issues

• Nikolakopoulou A, Higgins JPT, Papakonstantinou T, Chaimani A, Del Giovane C, Egger M, Salanti G (2020). CINeMA: An approach for assessing confidence in the results of a network meta-analysis PLOS Medicine 17:1–19. [PMC free article: PMC7122720] [PubMed: 32243458]
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Clinical evidence

Summary of studies included in the evidence review

The NMAs included 534 RCTs (k=534) representing 89,286 participants (n=89,286).

Of the 534 RCTs included in the NMAs for more severe depression, 426 reported either a HAM-D or MADRS score at baseline, and the mean depression severity scores were HAM-D=24.03 (SD=4.68; k=340) and MADRS=30.01 (SD=5.49; k=86) respectively. 34 were UK-based RCTs.

According to the interventions assessed and the types of outcomes reported in each RCT, the included RCTs have contributed data to one or more networks of evidence and respective NMAs.

For the SMD of depression symptom change scores outcome, the network of evidence (and the respective NMA) included 352 RCTs, 99 interventions grouped in 50 treatment classes, and 59,350 participants. Of the 352 RCTs, 146 reported change from baseline (CFB) depression symptom score data; 172 reported baseline and endpoint depression symptom score data; and 34 reported dichotomous response data and baseline symptom scores. These data were transformed and synthesised accordingly, allowing estimation of the SMD of depression symptom scores (see appendix M for details).

For the outcome of response in those randomised, the network of evidence (and the respective NMA) included 364 RCTs, 83 interventions grouped in 43 treatment classes and 68,073 participants. Of the 364 RCTs, 280 reported dichotomous response data, 31 reported CFB depression symptom score data; and 53 reported baseline and endpoint depression symptom score data. These data were transformed and synthesised accordingly, allowing estimation of log-odds ratios of response (see appendix M for details).

For the outcome of remission in those randomised, the network of evidence (and the respective NMA) included 202 RCTs reporting dichotomous remission data, 64 interventions grouped in 38 treatment classes and 40,066 participants.

See the full evidence tables in appendix D.

Relevant information on the networks of evidence and the NMAs that informed the economic analysis are reported in appendix M.

Evidence from the network meta-analysis

Base-case analysis

Below is an overview of the treatment class network plots, numbers of people tested on each treatment class and intervention, and NMA findings at the treatment class level (relative effects versus the reference treatment and rankings), for every critical outcome considered in the clinical base-case analysis of treatments for adults with a new episode of more severe depression. For the outcome of the SMD of depressive symptom scores, relative effects of individual interventions versus the reference treatment are also provided in this section.

For each outcome, we present network plots, which show which treatments have been directly compared in the RCTs included in the NMA, by connecting them with a direct line. In each network plot presented below, the width of lines is proportional to the number of trials that make each direct comparison; the size of each circle (treatment node) is proportional to the number of participants tested on each treatment class.

Full results of the NMA, including network plots and relative effects of individual interventions, as well as relative effects of all pairs of treatment classes and individual interventions, are reported in appendix M and supplements B5 and B6.

SMD of depression symptom change scores

The network plot at the treatment class level is shown in Figure 9. The number of participants tested on each treatment class and each intervention are shown in Table 17. Treatment classes, interventions and numbers of participants tested on each in the NMA of standardised mean difference (SMD) of depression symptom change scores in adults with a new episode of more severe depression. The base-case relative effects (posterior mean SMD with 95% CrI) of all treatment classes versus pill placebo (reference treatment for more severe depression) are illustrated in Figure 10 (forest plots) and reported in Table 18. The same table also shows the class treatment rankings. Treatment classes in the table have been ordered from lowest to highest ranking (with lower rankings suggesting greater effects).

Figure 9

Network plot of the NMA of standardised mean difference (SMD) of depression symptom change scores in adults with a new episode of more severe depression – treatment class level. The width of lines is proportional to the number of trials that make (more...)

Table 17

Treatment classes, interventions and numbers of participants tested on each in the NMA of standardised mean difference (SMD) of depression symptom change scores in adults with a new episode of more severe depression.

Figure 10

Base-case forest plots of standardised mean difference (SMD) of depression symptom change scores in adults with a new episode of more severe depression: effects of treatment classes versus pill placebo (N=12,554). Values on the left side of the vertical (more...)

Table 18

Base-case results of the NMA of standardised mean difference (SMD) of depression symptom change scores in adults with a new episode of more severe depression: posterior effects (mean SMD, 95%CrI) of all treatment classes versus pill placebo and treatment (more...)

The base-case relative effects (posterior mean SMD with 95% CrI) of all individual interventions versus pill placebo (reference treatment for more severe depression) are reported in Table 19. Interventions have been listed by treatment class.

Table 19

Base-case results of the NMA of standardised mean difference (SMD) of depression symptom change scores in adults with a new episode of more severe depression: posterior effects (mean SMD, 95%CrI) of all interventions versus pill placebo. Only interventions (more...)

Response in those randomised

The network plot at the treatment class level is shown in Figure 11. The number of participants tested on each treatment class and each intervention are shown in Table 20. The base-case relative effects (posterior mean log-odds ratio [LOR] with 95% CrI) of all treatment classes versus pill placebo (reference treatment for more severe depression) are illustrated in Figure 12 (forest plots) and reported in Table 21.

Table 21 The same table shows also the class treatment rankings. Treatment classes in the table have been ordered from lowest to highest ranking (with lower rankings suggesting greater effects).

Figure 11

Network plot of the NMA of response in those randomised in adults with a new episode of more severe depression – treatment class level. The width of lines is proportional to the number of trials that make each direct comparison; the size of each (more...)

Table 20

Treatment classes, interventions and numbers of participants tested on each in the NMA of response in those randomised in adults with a new episode of more severe depression.

Figure 12

Forest plots of response in those randomised in adults with a new episode of more severe depression: effects of treatment classes versus pill placebo (N=15,384). Values on the right side of the vertical axis indicate better effect compared with pill placebo. (more...)

Table 21

Base-case results of the NMA of response in those randomised in adults with a new episode of more severe depression: posterior effects (mean log-odds ratio [LOR], 95%CrI) of all treatment classes versus pill placebo and treatment class rankings.

Remission in those randomised

The network plot at the treatment class level is shown in Figure 13. The number of participants tested on each treatment class and each intervention are shown in Table 22. The base-case relative effects (posterior mean log-odds ratio [LOR] with 95% CrI) of all treatment classes versus pill placebo (reference treatment for more severe depression) are illustrated in Figure 14 (forest plots) and reported in Table 23. The same table shows also the class treatment rankings. Treatment classes in the table have been ordered from lowest to highest ranking (with lower rankings suggesting greater effects).

Figure 13

Network plot of the NMA of remission in those randomised in adults with a new episode of more severe depression – treatment class level. The width of lines is proportional to the number of trials that make each direct comparison; the size of each (more...)

Table 22

Treatment classes, interventions and numbers of participants tested on each in the NMA of remission in those randomised in adults with a new episode of more severe depression.

Figure 14

Forest plots of remission in those randomised in adults with a new episode of more severe depression: effects of treatment classes versus pill placebo (N=8,376). Values on the right side of the vertical axis indicate better effect compared with pill placebo. (more...)

Table 23

Base-case results of the NMA of remission in those randomised in adults with a new episode of more severe depression: posterior effects (mean log-odds ratio [LOR], 95%CrI) of all treatment classes versus pill placebo and treatment class rankings.

Bias-adjusted analysis

Bias models tested on the SMD outcome suggested evidence of bias due to small study size.

Figure 15 shows the bias-adjusted forest plots of relative effects (posterior mean SMD with 95% CrI) of all treatment classes versus pill placebo (reference treatment for more severe depression). Table 24 shows the relative effects of all treatment classes versus pill placebo on the SMD and the class treatment rankings. Treatment classes in the table have been ranked from lowest to highest ranking (with lower rankings suggesting greater effects). Table 25 shows the bias-adjusted relative effects (posterior mean SMD with 95% CrI) of all individual interventions versus pill placebo (reference treatment for more severe depression). Interventions in this table have been listed by treatment class.

Figure 15

Bias-adjusted forest plots of standardised mean difference (SMD) of depression symptom change scores in adults with a new episode of more severe depression: effects of treatment classes versus pill placebo (N=12,554). Values on the left side of the vertical (more...)

Table 24

Bias-adjusted results of the NMA of standardised mean difference (SMD) of depression symptom change scores in adults with a new episode of more severe depression: posterior effects (mean SMD, 95%CrI) of all treatment classes versus pill placebo and treatment (more...)

Table 25

Bias-adjusted results of the NMA of standardised mean difference (SMD) of depression symptom change scores in adults with a new episode of more severe depression: posterior effects (mean SMD, 95%CrI) of all interventions versus pill placebo. Only interventions (more...)

Sensitivity analyses

Effects on the SMD of all treatment classes versus TAU in the post-hoc sensitivity analysis that included only RCTs rated as being at low risk of bias for attrition in the Cochrane Risk of Bias tool are presented in Table 26, alongside the base-case analysis effects, to allow comparison between the two sets of results.

Table 26

Comparison of results following inclusion only of trials at low risk of bias for attrition in the NMA and results of the NMA base-case analysis: standardised mean difference (SMD) of depression symptom scores in adults with a new episode of more severe (more...)

Finally, effects on the SMD of all treatment classes versus pill placebo in the sensitivity analysis conducted after excluding pharmacological trials are reported in Table 27, presented alongside the base-case analysis effects, to allow comparison between the two sets of results. In each analysis, treatment classes have been ordered from lowest to highest ranking (with lower rankings suggesting higher effects).

Table 27

Comparison of results following exclusion of pharmacological trials from the NMA and results of the NMA base-case analysis: standardised mean difference (SMD) of depression symptom change scores in adults with a new episode of more severe depression. (more...)

Evidence from the pairwise meta-analyses

Important (but not critical) outcomes

See Table 28 for a summary of the clinically important and statistically significant effects observed for the important (but not critical) outcomes of quality of life and functioning (including personal, social, and occupational functioning and global functioning/functional impairment) at endpoint and longer-term (at least 6 months) follow-up. See supplement B3 for forest plots for all important (but not critical) outcomes.

Table 28

Summary of significant important (but not critical outcomes) at endpoint and longer-term (at least 6 months) follow-up for adults with a new episode of more severe depression.

Follow-up of critical outcomes

See Table 29 for a summary of the clinically important and statistically significant effects observed for critical outcomes at longer-term (at least 6 months) follow-up. See supplement B3 for forest plots for all critical outcomes at all follow-up time points.

Table 29

Summary of significant critical outcomes at longer-term (at least 6 months) follow-up for adults with a new episode of more severe depression.

Comparison of the results of pairwise meta-analysis with the NMA for critical outcomes

See Table 30 for comparisons between pairwise and NMA results for critical outcomes where the difference between the pairwise meta-analysis and NMA results is equal to, or larger than, the minimally important difference (default MID, defined as SMD −0.5/0.5 and logOR ±0.25 [MID for OR calculated as exp[0.25]=1.28]) and the effect estimate of the NMA is not within the 95% confidence interval of the pairwise effect estimate (considered a significant difference), and see Table 31 for differences between pairwise and NMA results ≥MID but where the NMA effect estimate is within the 95% confidence interval of the pairwise effect estimate (considered a non-significant difference). The full table of pairwise meta-analysis and NMA comparisons is available in supplement B4. Out of a total of 160 comparisons between pairwise and NMA results for more severe depression, 32 differences ≥MID were identified (20% of all comparisons), and of these only 17 differences (11% of all comparisons) could be considered significant in that the NMA estimate was not within the 95% confidence interval of the pairwise effect estimate. For most differences identified the difference was in magnitude rather than direction of effect and could probably be accounted for by the smaller evidence base contributing to the pairwise effect estimates. It is important to note that these comparisons have been performed in addition to the NMA inconsistency checks (where direct and indirect evidence is compared).

Table 30

Summary of differences between pairwise and NMA results ≥ MID where NMA effect estimate is not within 95% confidence interval of pairwise effect estimate for adults with a new episode of more severe depression.

Table 31

Summary of differences between pairwise and NMA results ≥ MID where NMA effect estimate is within 95% confidence interval of pairwise effect estimate for adults with a new episode of more severe depression.

Pairwise meta-analysis of couple interventions

One RCT was included in pairwise meta-analysis of couple interventions for people with depression and problems in the relationship with their partner (Beach 1992).

The included study is summarised in Table 32.

Studies considered but not included in the pairwise meta-analysis of couple interventions are listed, and reasons for their exclusion are provided in appendix K.

Table 32

Summary of included study for couple interventions for adults with a new episode of more severe depression.

See the full evidence tables in appendix D, the forest plots in appendix E, and clinical evidence profiles in appendix F.

Quality assessment of studies included in the evidence review and the evidence

A threshold analysis was originally planned to conduct, to test the robustness of treatment recommendations based on the NMA, to potential biases or sampling variation in the included evidence. Threshold analysis has been developed as an alternative to GRADE for assessing confidence in guideline recommendations based on network meta-analysis (Phillippo 2019). Threshold analysis suggests by how much effects that have been estimated in the NMA need to change before recommendations change, and whether such changes might potentially occur due to bias in the evidence. The NICE Guidelines Technical Support Unit (TSU) attended committee discussions on the rationale for recommendations and noted that, in addition to the results of the NMA, the committee took other pragmatic factors into consideration when making recommendations, including the uncertainty and limitations around the clinical and cost-effectiveness data, and the need to provide a wide range of interventions to take into account individual needs and allow patient choice. The TSU advised that as it was difficult to identify a clear decision rule to link the recommendations directly to the NMA results, it was not feasible or helpful to conduct a threshold analysis. CINeMA was also considered as a method to evaluate the confidence in the results from the NMA (Nikolakopoulou 2020). However, this was not possible to carry out, due to the class models being implemented.

In the absence of undertaking threshold analysis or using CINeMA to evaluate the quality of the evidence and the confidence in the results derived from the NMA that informed this review question, we evaluated and summarise the quality of the evidence narratively, using the domains considered as per a standard GRADE approach (risk of bias, inconsistency, publication bias, indirectness and imprecision).

For outcomes analysed only in pairwise meta-analysis (couple interventions), see the clinical evidence profiles in appendix F.

Risk of bias

The Cochrane risk of bias tool version 1.0 for RCTs (see appendix H in Developing NICE guidelines: the manual; NICE 2014) was used to assess potential bias in each study included in the review. Generally the standard of reporting in studies was quite low, as demonstrated by the risk of bias summary diagram (Figure 16). Of the studies included in the NMAs for more severe depression, 106 were at low risk for allocation method, and 86 were at low risk of bias for allocation concealment. Trials of psychological therapies were typically considered at high risk of bias for participant and provider blinding, although it is difficult to quantify in risk of bias ratings it is also important to bear in mind that the rate of side effects may also make it difficult to maintain blinding in pharmacological trials. Across interventions, 364 trials were at low risk of bias for blinding participants and providers. Most reported outcomes were investigator-rated, and assessor blinding was considered for all trials: 82 were at low risk of bias, 423 were unclear, and high risk in 29 trials. For attrition bias, 330 trials were at low risk of bias, unclear risk in 173 trials, and 31 trials were at high risk of bias. For selective reporting bias, 77 trials were at low risk of bias, unclear risk in 143 trials, and 314 trials were at high risk of bias. Other sources of bias, predominantly potential conflict of interest based on the source of funding, were identified in 455 RCTs. See appendix D for full study details, including risk of bias ratings by study.

Figure 16

Risk of bias summary for treatments of a new episode in people with more severe depression.

Economic evidence

Summary of studies included in the economic evidence review

All included economic studies were conducted in the UK and adopted a NHS perspective, with some studies including personal social service (PSS) costs as well; in addition, some studies reported separate analyses that adopted a societal perspective. NHS and PSS cost elements included, in the vast majority of studies, intervention, primary and community care, staff time (such as GPs, nurses, psychiatrists, psychologists), medication, inpatient and outpatient care and other hospital care. All studies used national unit costs; in some studies, intervention costs were based on local prices or prices provided by the manufacturers (for example, in the case of computerised CBT packages).

Economic model

A decision-analytic model was developed to assess the relative cost effectiveness of interventions of adults with a new episode of more severe depression. The objective of economic modelling, the methodology adopted, the results and the conclusions from this economic analysis are described in detail in appendix J. This section provides a summary of the methods employed and the results of the economic analysis.

Summary of the evidence

The committee’s discussion of the evidence

Recommendations supported by this evidence review

This evidence review supports recommendations 1.6.1 and 1.7.1 and research recommendations in the NICE guideline.

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Additional references discussed by the committee

• Barkham 2021

  Barkham M, Saxon, D, Hardy G, et al (2021). Person-centred experiential therapy versus cognitive behavioural therapy delivered in the English Improving Access to Psychological Therapies service for the treatment of moderate or severe depression (PRaCTICED): a pragmatic randomised, non-inferiority trial. Lancet Psychiatry 8:487–499. [PubMed: 34000240]

• Cuijpers 2021

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Additional references to methodological issues

• Nikolakopoulou A, Higgins JPT, Papakonstantinou T, Chaimani A, Del Giovane C, Egger M, Salanti G (2020). CINeMA: An approach for assessing confidence in the results of a network meta-analysis PLOS Medicine 17:1–19. [PMC free article: PMC7122720] [PubMed: 32243458]
• Phillippo DM, Dias S, Welton NJ, Caldwell DM, Taske N, Ades AE (2019) Threshold Analysis as an Alternative to GRADE for Assessing Confidence in Guideline Recommendations Based on Network Meta-analyses. Annals of Internal Medicine 170:538–46. [PMC free article: PMC6739230] [PubMed: 30909295]

Clinical evidence table for review questions: For adults with a new episode of less severe depression or more severe depression, what are the relative benefits and harms of psychological, psychosocial, pharmacological and physical interventions alone or in combination?

Please refer to supplement B1 - Clinical evidence tables for treatment of a new episode of depression

Forest plots for review questions: For adults with a new episode of less severe depression or more severe depression, what are the relative benefits and harms of psychological, psychosocial, pharmacological and physical interventions alone or in combination?

Please refer to supplements B2 and B3 for forest plots for studies included in the NMA treatment of a new episode of less severe depression and more severe depression, respectively

Forest plots for review questions: For adults with a new episode of less severe depression, what are the relative benefits and harms of psychological, psychosocial, pharmacological and physical interventions alone or in combination?

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Forest plots for review question: For adults with a new episode of more severe depression, what are the relative benefits and harms of psychological, psychosocial, pharmacological and physical interventions alone or in combination?

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Excluded studies for review questions: For adults with a new episode of less severe depression or more severe depression, what are the relative benefits and harms of psychological, psychosocial, pharmacological and physical interventions alone or in combination?

Clinical studies

Please refer to supplement B1 - Clinical evidence tables for treatment of a new episode of depression

Economic studies

Please refer to Supporting documentation - Economic evidence included & excluded studies.

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