Augmentation therapies for treatment-resistant depression: systematic review and meta-analysis

Abstract

BackgroundDepression is considered to have the highest disability burden of all conditions. Although treatment-resistant depression (TRD) is a key contributor to that burden, there is little understanding of the best treatment approaches for it and specifically the effectiveness of available augmentation approaches.AimsWe conducted a systematic review and meta-analysis to search and quantify the evidence of psychological and pharmacological augmentation interventions for TRD.MethodParticipants with TRD (defined as insufficient response to at least two antidepressants) were randomised to at least one augmentation treatment in the trial. Pre-post analysis assessed treatment effectiveness, providing an effect size (ES) independent of comparator interventions.ResultsOf 28 trials, 3 investigated psychological treatments and 25 examined pharmacological interventions. Pre-post analyses demonstrated N-methyl-d-aspartate-targeting drugs to have the highest ES (ES = 1.48, 95% CI 1.25–1.71). Other than aripiprazole (four studies, ES = 1.33, 95% CI 1.23–1.44) and lithium (three studies, ES = 1.00, 95% CI 0.81–1.20), treatments were each investigated in less than three studies. Overall, pharmacological (ES = 1.19, 95% CI 1.08–1.30) and psychological (ES = 1.43, 95% CI 0.50–2.36) therapies yielded higher ESs than pill placebo (ES = 0.78, 95% CI 0.66–0.91) and psychological control (ES = 0.94, 95% CI 0.36–1.52).ConclusionsDespite being used widely in clinical practice, the evidence for augmentation treatments in TRD is sparse. Although pre-post meta-analyses are limited by the absence of direct comparison, this work finds promising evidence across treatment modalities.Declaration of interestIn the past 3 years, A.H.Y. received honoraria for speaking from AstraZeneca, Lundbeck, Eli Lilly and Sunovion; honoraria for consulting from Allergan, Livanova and Lundbeck, Sunovion and Janssen; and research grant support from Janssen. In the past 3 years, A.J.C. received honoraria for speaking from AstraZeneca and Lundbeck; honoraria for consulting with Allergan, Janssen, Livanova, Lundbeck and Sandoz; support for conference attendance from Janssen; and research grant support from Lundbeck. B.B. has recently been (soon to be) on the speakers/advisory board for Hexal, Lilly, Lundbeck, Mundipharma, Pfizer, and Servier. No other conflicts of interest.

The 2020 Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders

“…Lithium and second/third generation antipsychotics remain preferred options for augmentation in treatment-resistant depression (Bassett et al, 2019; Mulder et al, 2018; Strawbridge et al, 2019).…”

Cost-effectiveness of genetic and clinical predictors for choosing combined psychotherapy and pharmacotherapy in major depression

“…A treatment strategy that our study did not explore was the use of pharmacological augmentation to antidepressants instead of augmentation with psychotherapy. However, there is no meta-analysis estimating the effect size of pharmacological augmentation vs. antidepressant only as first line treatment in MDD and in TRD the effect size of this treatment on symptom improvement is similar to that reported for augmentation with psychotherapy (Cuijpers et al, 2014;Ijaz et al, 2018;Zhou et al, 2015;Strawbridge et al, 2019). However, if a drug with very good tolerability profile is demonstrated to have similar or better efficacy than psychotherapy for augmenting treatment in MDD, combined treatment with this drug would be cost-effective compared to combined treatment with psychotherapy.…”

<p>Management of Treatment-Resistant Depression in Real-World Clinical Practice Settings Across Asia</p>

“…The direct evidence estimated a pooled ES = 0.29 (95% CI 0.21-0.37; p<0.001; I 2 = 99%) for antipsychotics vs placebo (13 studies), ES = 0.07 (95% CI −0.18-0.33; p<0.57; I 2 = 22%) for mood stabilisers vs placebo (3 studies), ES = 0.91 (95% CI 0.67-1.16; p<0.001; I 2 =77%) for N-methyl-D-aspartate (NMDA) antagonists vs placebo (5 studies). 28 The authors of this NMA suggested NMDA therapies as having the "highest chance of being an effective treatment 29 In this second meta-analysis, the ES across classes appears more similar with overlapping confidence intervals. Three lithium studies included in this second meta-analysis contributed to an estimated ES = 1.00 (95% CI 0.81-1.20; I 2 =0%).…”

“…16,23,66,67,87 A recent systematic review and meta-analysis assessed the effectiveness, expressed as effect size (ES), of psychological and pharmacological augmentation interventions for TRD. 29…”

“…The above meta-analysis estimated the effect sizes for aripiprazole (4 studies), brexpiprazole (2 studies), ziprasidone (1 study), risperidone (1 study), quetiapine (1 study) and olanzapine (1 study). 29 28 Based on another systematic review and meta-analysis, evidence on the use of aripiprazole and quetiapine, as augmentation therapy in TRD patients, was considered the most robust among various treatment options. 38…”