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

Effect of severity of depression on augmentation of antidepressant medication in young adults with depression

“…All these atypical antipsychotics have been found effective as augmentors also in the literature and regarded as first-line augmentation in several guidelines. 33,34 Quetiapine was the most used AP, and its use was twice as common as the second most common option (risperidone). In the study by Zhou et al 17 quetiapine was also the most commonly used AP (43.4%), followed by olanzapine (38.8%).…”

The Downstaging Concept in Treatment-Resistant Depression: Spotlight on Ketamine

“…Other factors such as spontaneous evolution, the placebo effect, and patients’ personal beliefs also need to be considered when treatment outcome is analyzed [ 14 ]. A recent systematic review and meta-analysis of studies on concomitant treatment used the term ‘early-stage’ TRD, which describes non-response to one adequate pharmacological or psychological therapy [ 15 ]. This perspective allowed the authors to include more studies for analysis.…”

“…The first attempt at describing resistant depression derived from oncology and laid the ground for developing staging TRD models [ 22 ]. The above-mentioned definition of early-stage TRD corresponds with Stage I TRD according to Thase and Rush’s model [ 15 ]. It has been suggested that, unlike in oncology, where the absence of the disease is defined by the lack of neoplastic cells, depression has no categorical indicator of disease activity.…”

Identifying the neuropsychiatric health effects of low-dose lithium interventions: A systematic review

“…For continuous outcome measures, we planned to use a standardised effect size (Cohen's d or Hedges' g) and for dichotomous outcomes, a relative risk/odds ratio. Where sufficient data from homogenous studies were available (>3 comparisons per outcome), a random effects within-subjects meta-analysis was planned (for methodology, see (Scott et al, 2022)); where not appropriate or not available, a systematic narrative synthesis was planned according to the Synthesis Without Meta-analysis (SWiM) approach (Campbell et al, 2020).…”