Systematic review and meta-analysis of augmentation and combination treatments for early-stage treatment-resistant depression: Adjunctive therapies for non-responsive depression

Fraser Scott; Elliot Hampsey; Sam Gnanaprgasam; Ben Carter; Lindsey Marwood; Rachael W. Taylor; Cansu Emre; Lora Korotkova; Jonatan Martín-Dombrowski; Anthony J. Cleare; Allan H. Young; Rebecca  Strawbridge

doi:10.1177/02698811221104058

Systematic review and meta-analysis of augmentation and combination treatments for early-stage treatment-resistant depression: Adjunctive therapies for non-responsive depression

Fraser Scott, Elliot Hampsey, Sam Gnanaprgasam, Ben Carter, Lindsey Marwood, Rachael W. Taylor, Cansu Emre, Lora Korotkova, Jonatan Martín-Dombrowski, Anthony J. Cleare, Allan H. Young, Rebecca Strawbridge

SLaM South London and Maudsley NHS Foundation Trust

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

Abstract

BACKGROUND: Major depressive disorder (MDD) is a highly burdensome health condition, for which there are numerous accepted pharmacological and psychological interventions. Adjunctive treatment (augmentation/combination) is recommended for the ~50% of MDD patients who do not adequately respond to first-line treatment. We aimed to evaluate the current evidence for concomitant approaches for people with early-stage treatment-resistant depression (TRD; defined below).

METHODS: We systematically searched Medline and Institute for Scientific Information Web of Science to identify randomised controlled trials of adjunctive treatment of ⩾10 adults with MDD who had not responded to ⩾1 adequate antidepressant. The cochrane risk of bias (RoB) tool was used to assess study quality. Pre-post treatment meta-analyses were performed, allowing for comparison across heterogeneous study designs independent of comparator interventions.

RESULTS: In total, 115 trials investigating 48 treatments were synthesised. The mean intervention duration was 9 weeks (range 5 days to 18 months) with most studies assessed to have low (n = 57) or moderate (n = 51) RoB. The highest effect sizes (ESs) were from cognitive behavioural therapy (ES = 1.58, 95% confidence interval (CI): 1.09-2.07), (es)ketamine (ES = 1.48, 95% CI: 1.23-1.73) and risperidone (ES = 1.42, 95% CI: 1.29-1.61). Only aripiprazole and lithium were examined in ⩾10 studies. Pill placebo (ES = 0.89, 95% CI: 0.81-0.98) had a not inconsiderable ES, and only six treatments' 95% CIs did not overlap with pill placebo's (aripiprazole, (es)ketamine, mirtazapine, olanzapine, quetiapine and risperidone). We report marked heterogeneity between studies for almost all analyses.

CONCLUSIONS: Our findings support cautious optimism for several augmentation strategies; although considering the high prevalence of TRD, evidence remains inadequate for each treatment option.

Original language	English
Pages (from-to)	268-278
Number of pages	11
Journal	Journal of Psychopharmacology
Volume	37
Issue number	3
Early online date	21 Jul 2022
DOIs	https://doi.org/10.1177/02698811221104058
Publication status	Published - Mar 2023

Keywords

Adult
Humans
Aripiprazole
Risperidone/therapeutic use
Depression
Depressive Disorder, Major/drug therapy
Ketamine

Access to Document

10.1177/02698811221104058

Cite this

Scott, F., Hampsey, E., Gnanaprgasam, S., Carter, B., Marwood, L., Taylor, R. W., Emre, C., Korotkova, L., Martín-Dombrowski, J., Cleare, A. J., Young, A. H., & Strawbridge, R. (2023). Systematic review and meta-analysis of augmentation and combination treatments for early-stage treatment-resistant depression: Adjunctive therapies for non-responsive depression. Journal of Psychopharmacology, 37(3), 268-278. https://doi.org/10.1177/02698811221104058

@article{5ba500d5598c45748ad0af76648fe7ad,

title = "Systematic review and meta-analysis of augmentation and combination treatments for early-stage treatment-resistant depression: Adjunctive therapies for non-responsive depression",

abstract = "BACKGROUND: Major depressive disorder (MDD) is a highly burdensome health condition, for which there are numerous accepted pharmacological and psychological interventions. Adjunctive treatment (augmentation/combination) is recommended for the ~50% of MDD patients who do not adequately respond to first-line treatment. We aimed to evaluate the current evidence for concomitant approaches for people with early-stage treatment-resistant depression (TRD; defined below).METHODS: We systematically searched Medline and Institute for Scientific Information Web of Science to identify randomised controlled trials of adjunctive treatment of ⩾10 adults with MDD who had not responded to ⩾1 adequate antidepressant. The cochrane risk of bias (RoB) tool was used to assess study quality. Pre-post treatment meta-analyses were performed, allowing for comparison across heterogeneous study designs independent of comparator interventions.RESULTS: In total, 115 trials investigating 48 treatments were synthesised. The mean intervention duration was 9 weeks (range 5 days to 18 months) with most studies assessed to have low (n = 57) or moderate (n = 51) RoB. The highest effect sizes (ESs) were from cognitive behavioural therapy (ES = 1.58, 95% confidence interval (CI): 1.09-2.07), (es)ketamine (ES = 1.48, 95% CI: 1.23-1.73) and risperidone (ES = 1.42, 95% CI: 1.29-1.61). Only aripiprazole and lithium were examined in ⩾10 studies. Pill placebo (ES = 0.89, 95% CI: 0.81-0.98) had a not inconsiderable ES, and only six treatments' 95% CIs did not overlap with pill placebo's (aripiprazole, (es)ketamine, mirtazapine, olanzapine, quetiapine and risperidone). We report marked heterogeneity between studies for almost all analyses.CONCLUSIONS: Our findings support cautious optimism for several augmentation strategies; although considering the high prevalence of TRD, evidence remains inadequate for each treatment option.",

keywords = "Adult, Humans, Aripiprazole, Risperidone/therapeutic use, Depression, Depressive Disorder, Major/drug therapy, Ketamine",

author = "Fraser Scott and Elliot Hampsey and Sam Gnanaprgasam and Ben Carter and Lindsey Marwood and Taylor, {Rachael W.} and Cansu Emre and Lora Korotkova and Jonatan Mart{\'i}n-Dombrowski and Cleare, {Anthony J.} and Young, {Allan H.} and Rebecca Strawbridge",

note = "Funding Information: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: LM is currently an employee at COMPASS Pathways plc. This work is unrelated to COMPASS Pathways plc. In the last 3 years, AJC has received honoraria for speaking from Janssen, honoraria for consulting from Allergan, Janssen and NICE, and research grant support from the Medical Research Council (UK), Wellcome Trust (UK), the National Institute for Health Research (UK) and Protexin Probiotics International Ltd. RS declares an honorarium from Lundbeck. AHY declares honoraria for speaking from Astra Zeneca, Lundbeck, Eli Lilly, Sunovion; honoraria for consulting from Allergan, Livanova and Lundbeck, Sunovion, Janssen; and research grant support from Janssen. No other conflicts of interest are declared. Funding Information: We would like to sincerely thank Professor Borwin Bandelow for introducing the team to the approach and benefits of within-subjects meta-analyses and the systematic reviewers from the previous related meta-analyses for their input both of which influenced our work. This paper represents independent research funded in part by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King{\textquoteright}s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. The funder had no role in the study design, data collection, data analysis, data interpretation or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Publisher Copyright: {\textcopyright} The Author(s) 2022.",

year = "2023",

month = mar,

doi = "10.1177/02698811221104058",

language = "English",

volume = "37",

pages = "268--278",

journal = "Journal of Psychopharmacology",

issn = "0269-8811",

publisher = "SAGE Publications Ltd STM",

number = "3",

}

Scott, F, Hampsey, E, Gnanaprgasam, S, Carter, B , Marwood, L , Taylor, RW, Emre, C, Korotkova, L, Martín-Dombrowski, J, Cleare, AJ , Young, AH & Strawbridge, R 2023, 'Systematic review and meta-analysis of augmentation and combination treatments for early-stage treatment-resistant depression: Adjunctive therapies for non-responsive depression', Journal of Psychopharmacology, vol. 37, no. 3, pp. 268-278. https://doi.org/10.1177/02698811221104058

Systematic review and meta-analysis of augmentation and combination treatments for early-stage treatment-resistant depression: Adjunctive therapies for non-responsive depression. / Scott, Fraser; Hampsey, Elliot; Gnanaprgasam, Sam et al.
In: Journal of Psychopharmacology, Vol. 37, No. 3, 03.2023, p. 268-278.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Systematic review and meta-analysis of augmentation and combination treatments for early-stage treatment-resistant depression

T2 - Adjunctive therapies for non-responsive depression

AU - Scott, Fraser

AU - Hampsey, Elliot

AU - Gnanaprgasam, Sam

AU - Carter, Ben

AU - Marwood, Lindsey

AU - Taylor, Rachael W.

AU - Emre, Cansu

AU - Korotkova, Lora

AU - Martín-Dombrowski, Jonatan

AU - Cleare, Anthony J.

AU - Young, Allan H.

AU - Strawbridge, Rebecca

N1 - Funding Information: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: LM is currently an employee at COMPASS Pathways plc. This work is unrelated to COMPASS Pathways plc. In the last 3 years, AJC has received honoraria for speaking from Janssen, honoraria for consulting from Allergan, Janssen and NICE, and research grant support from the Medical Research Council (UK), Wellcome Trust (UK), the National Institute for Health Research (UK) and Protexin Probiotics International Ltd. RS declares an honorarium from Lundbeck. AHY declares honoraria for speaking from Astra Zeneca, Lundbeck, Eli Lilly, Sunovion; honoraria for consulting from Allergan, Livanova and Lundbeck, Sunovion, Janssen; and research grant support from Janssen. No other conflicts of interest are declared. Funding Information: We would like to sincerely thank Professor Borwin Bandelow for introducing the team to the approach and benefits of within-subjects meta-analyses and the systematic reviewers from the previous related meta-analyses for their input both of which influenced our work. This paper represents independent research funded in part by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. The funder had no role in the study design, data collection, data analysis, data interpretation or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Publisher Copyright: © The Author(s) 2022.

PY - 2023/3

Y1 - 2023/3

N2 - BACKGROUND: Major depressive disorder (MDD) is a highly burdensome health condition, for which there are numerous accepted pharmacological and psychological interventions. Adjunctive treatment (augmentation/combination) is recommended for the ~50% of MDD patients who do not adequately respond to first-line treatment. We aimed to evaluate the current evidence for concomitant approaches for people with early-stage treatment-resistant depression (TRD; defined below).METHODS: We systematically searched Medline and Institute for Scientific Information Web of Science to identify randomised controlled trials of adjunctive treatment of ⩾10 adults with MDD who had not responded to ⩾1 adequate antidepressant. The cochrane risk of bias (RoB) tool was used to assess study quality. Pre-post treatment meta-analyses were performed, allowing for comparison across heterogeneous study designs independent of comparator interventions.RESULTS: In total, 115 trials investigating 48 treatments were synthesised. The mean intervention duration was 9 weeks (range 5 days to 18 months) with most studies assessed to have low (n = 57) or moderate (n = 51) RoB. The highest effect sizes (ESs) were from cognitive behavioural therapy (ES = 1.58, 95% confidence interval (CI): 1.09-2.07), (es)ketamine (ES = 1.48, 95% CI: 1.23-1.73) and risperidone (ES = 1.42, 95% CI: 1.29-1.61). Only aripiprazole and lithium were examined in ⩾10 studies. Pill placebo (ES = 0.89, 95% CI: 0.81-0.98) had a not inconsiderable ES, and only six treatments' 95% CIs did not overlap with pill placebo's (aripiprazole, (es)ketamine, mirtazapine, olanzapine, quetiapine and risperidone). We report marked heterogeneity between studies for almost all analyses.CONCLUSIONS: Our findings support cautious optimism for several augmentation strategies; although considering the high prevalence of TRD, evidence remains inadequate for each treatment option.

AB - BACKGROUND: Major depressive disorder (MDD) is a highly burdensome health condition, for which there are numerous accepted pharmacological and psychological interventions. Adjunctive treatment (augmentation/combination) is recommended for the ~50% of MDD patients who do not adequately respond to first-line treatment. We aimed to evaluate the current evidence for concomitant approaches for people with early-stage treatment-resistant depression (TRD; defined below).METHODS: We systematically searched Medline and Institute for Scientific Information Web of Science to identify randomised controlled trials of adjunctive treatment of ⩾10 adults with MDD who had not responded to ⩾1 adequate antidepressant. The cochrane risk of bias (RoB) tool was used to assess study quality. Pre-post treatment meta-analyses were performed, allowing for comparison across heterogeneous study designs independent of comparator interventions.RESULTS: In total, 115 trials investigating 48 treatments were synthesised. The mean intervention duration was 9 weeks (range 5 days to 18 months) with most studies assessed to have low (n = 57) or moderate (n = 51) RoB. The highest effect sizes (ESs) were from cognitive behavioural therapy (ES = 1.58, 95% confidence interval (CI): 1.09-2.07), (es)ketamine (ES = 1.48, 95% CI: 1.23-1.73) and risperidone (ES = 1.42, 95% CI: 1.29-1.61). Only aripiprazole and lithium were examined in ⩾10 studies. Pill placebo (ES = 0.89, 95% CI: 0.81-0.98) had a not inconsiderable ES, and only six treatments' 95% CIs did not overlap with pill placebo's (aripiprazole, (es)ketamine, mirtazapine, olanzapine, quetiapine and risperidone). We report marked heterogeneity between studies for almost all analyses.CONCLUSIONS: Our findings support cautious optimism for several augmentation strategies; although considering the high prevalence of TRD, evidence remains inadequate for each treatment option.

KW - Adult

KW - Humans

KW - Aripiprazole

KW - Risperidone/therapeutic use

KW - Depression

KW - Depressive Disorder, Major/drug therapy

KW - Ketamine

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U2 - 10.1177/02698811221104058

DO - 10.1177/02698811221104058

M3 - Article

C2 - 35861202

SN - 0269-8811

VL - 37

SP - 268

EP - 278

JO - Journal of Psychopharmacology

JF - Journal of Psychopharmacology

IS - 3

ER -

Systematic review and meta-analysis of augmentation and combination treatments for early-stage treatment-resistant depression: Adjunctive therapies for non-responsive depression

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