Efficacy, quality of life, and acceptability outcomes of atypical antipsychotic augmentation treatment for treatment-resistant depression: protocol for a systematic review and network meta-analysis

AimsThe placebo response in depression clinical trials is a major contributing factor for failure to establish the efficacy of novel and repurposed treatments. However, it is not clear as to what the placebo response in treatment-resistant depression (TRD) patients is or whether it differs across treatment modalities. Our objective was to conduct a systematic review and meta-analysis of the magnitude of the placebo response in TRD patients across different treatment modalities and its possible moderators.MethodSearches were conducted on MEDLINE and PsychInfo from inception to January 24, 2020. Only studies that recruited TRD patients and randomization to a placebo (or sham) arm in a pharmacotherapy, brain stimulation, or psychotherapy study were included (PROSPERO 2020 CRD42020190465). The primary outcome was the Hedges’ g for the reported depression scale using a random-effects model. Secondary outcomes included moderators assessed via meta-regression and response and remission rate. Heterogeneity was evaluated using the Egger's Test and a funnel plot. Cochrane Risk of Bias Tool was used to estimate risks.Result46 studies met our inclusion criteria involving a total of 3083 participants (mean (SD) age: 45.7 (6.2); female: 52.4%). The pooled placebo effect for all modalities was large (N = 3083, g = 1.08 ,95% CI [0.95-1.20)I 2 = 0.1). The placebo effect in studies of specific treatment modalities did not significantly differ: oral medications g = 1.14 (95%CI:0.99-1.29); parenteral medications g = 1.32 (95%CI:0.59-2.04); ayahuasca g = 0.47 (95%CI:-0.28-1.17); rTMS g = 0.93 (95%CI:0.63-1.23); tDCS g = 1.32 (95%CI:0.52-2.11); invasive brain stimulation g = 1.06 (95%CI:0.64-1.47). There were no psychotherapy trials that met our eligibility criteria. Similarly, response and remission rates were comparable across modalities. Heterogeneity was large. Two variables predicted a lager placebo effect: open-label prospective design (B:0.32, 95%CI: 0.05-0.58; p:0.02) and sponsoring by a pharmaceutical or medical device company (B:0.39, 95%CI:0.13-0.65, p:0.004)). No risk of publication bias was found.ConclusionThe overall placebo effect in TRD studies was large (g = 1.08) and did not differ among treatment modalities. A better understanding of the placebo response in TRD will require: standardizing the definition of TRD, head-to-head comparisons of treatment modalities, an assessment of patient expectations and experiences, and standardized reporting of outcomes.

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Relative effectiveness of augmentation treatments for treatment-resistant depression: a systematic review and network meta-analysis

International Review of Psychiatry ◽

10.1080/09540261.2020.1765748 ◽

2020 ◽

Vol 32 (5-6) ◽

pp. 477-490 ◽

Cited By ~ 1

Author(s):

Ben Carter ◽

Rebecca Strawbridge ◽

Muhammad Ishrat Husain ◽

Brett D. M. Jones ◽

Roxanna Short ◽

...

Keyword(s):

Systematic Review ◽

Meta Analysis ◽

Relative Effectiveness ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Resistant Depression

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

Journal of Affective Disorders ◽

10.1016/j.jad.2018.10.344 ◽

2019 ◽

Vol 254 ◽

pp. 153

Author(s):

Dr Rebecca Strawbridge ◽

Dr Ben Carter ◽

Dr Lindsey Marwood ◽

Professor Borwin Bandelow ◽

Dimosthenis Tsapekos ◽

...

Keyword(s):

Systematic Review ◽

Meta Analysis ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Resistant Depression

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

The British Journal of Psychiatry ◽

10.1192/bjp.2018.233 ◽

2018 ◽

Vol 214 (1) ◽

pp. 42-51 ◽

Cited By ~ 21

Author(s):

Rebecca Strawbridge ◽

Ben Carter ◽

Lindsey Marwood ◽

Borwin Bandelow ◽

Dimosthenis Tsapekos ◽

...

Keyword(s):

Systematic Review ◽

Psychological Control ◽

Meta Analysis ◽

Treatment Modalities ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

The Past ◽

Grant Support ◽

Resistant Depression ◽

Research Grant

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.

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Magnetic seizure therapy in treatment-resistant depression: clinical, neuropsychological and metabolic effects

Psychological Medicine ◽

10.1017/s0033291714002244 ◽

2014 ◽

Vol 45 (5) ◽

pp. 1073-1092 ◽

Cited By ~ 42

Author(s):

S. Kayser ◽

B. H. Bewernick ◽

A. Matusch ◽

R. Hurlemann ◽

M. Soehle ◽

...

Keyword(s):

Quality Of Life ◽

Depressive Symptoms ◽

Fdg Pet ◽

Metabolic Effects ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Magnetic Seizure Therapy ◽

Resistant Depression ◽

Pet Scans

Background.Magnetic seizure therapy (MST), despite being in an early phase of clinical research, has been demonstrated to be associated with antidepressant efficacy. However, safety, tolerability and efficacy data in connection with functional brain activity from larger samples are lacking. The aim of this study was to determine clinical and cognitive effects of MST and the influence of MST on regional brain glucose metabolism.Method.Twenty-six patients suffering from treatment-resistant depression (TRD) underwent MST. Ten patients underwent a randomized trial and 16 patients an open-label study design. The primary outcome criterion was the severity of depressive symptoms assessed with the Hamilton Depression Rating Scale (HAMD). Depressive symptoms, tolerability and cognitive safety, along with social functioning and quality of life parameters, were assessed using various rating scales. A clinical follow-up visit 6 months following the completion of a course of MST and [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) scans of 12 patients were analysed.Results.A significant response to MST was demonstrated by 69% of the patient sample, with 46% meeting remission criteria. Anxiety ratings were significantly reduced in responders and their quality of life was improved. Half of the responders relapsed within 6 months. No cognitive side-effects were observed. FDG-PET scans showed a metabolic increase in the frontal cortex bilaterally and a decrease in the left striatum.Conclusions.Robust antidepressant and anti-anxiety efficacy of MST was demonstrated, and found to be associated with localized metabolic changes in brain areas that are strongly implicated in depression. Thus, MST presents an effective, well-tolerated and safe treatment option for patients unable to respond to other forms of therapy for depression.

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