Abstract
Objectives: Since the introduction of newer antidepressants, there have been great advances in treatments for major depression. However, many patients with major depression have inadequate responses to standard therapy. To date, many studies that investigated the efficacy of various treatment strategies for treatment resistant depression have been conducted. We investigate whether there are differences in the effect size of various augmentation strategies according to the degree of treatment resistance.
Methods: A comprehensive literature search was performed using multiple databases. We performed this meta-analysis using Cochrane review methods. The primary outcome variable of this meta-analysis was response rate in patients with treatment resistant depression who were treated with alternative augmentation strategies in addition to standard antidepressant therapy.
Results: A comprehensive literature search identified 20 randomized controlled trials. The nineteen studies, which included 3,628 participants, were pooled using a random-effects model to compare the effect sizes among various treatment strategies. We conducted subgroup analyses according to the degree of treatment resistance defined as the number of failed trials during current index episode (TRD 1 and TRD 2 or higher). The seven studies, which included 638 participants, were pooled to compare the effect sizes among various strategies in the TRD 1 trials. Various augmentation strategies for treatment resistant depression included lithium augmentation, antidepressant combination, augmentation with thyroid hormone, pindolol augmentation, augmentation with atypical antipsychotics, augmentation with stimulants. The 8 studies, which included 696 participants, were pooled to compare the effect sizes in the TRD 2 or higher trials. Overall, there was no significant difference in the effect sizes among various strategies in treatment resistant depression in terms of response rates (Response, risk ratio (RR)= 1.45 (95% confidence interval (CI) 1.25 to 1.67); Test for subgroup differences, Chi2=2.57, df=5, P=0.77, I2=0%). For TRD 1 trials, there was no significant difference in the effect sizes among various strategies (Response, risk ratio (RR)= 1.43 (95% confidence interval (CI) 1.10 to 1.85); Test for subgroup differences, Chi2=3.69, df=3, P=0.30, I2=18.7%). For TRD 2 or higher trials, there seemed to be a significant difference in the effect sizes among strategies. The efficacy for atypical antipsychotics has well-founded evidence (RR=1.52 (95% CI= 1.33 to 1.74), n=2052) The evidence regarding the efficacy of other strategies were insufficient. Among them, lithium augmentation showed relatively small effect size (RR=0.63 (95% CI= 0.12 to 3.32)), while augmentation with thyroid hormone (RR= 3.14 (95% CI= 1.05 to 9.38)) or pindolol (RR=10.80 (95% CI = 0.75 to 155.93)) showed large effect sizes.
Conclusion: Overall, there seemed to be no significant differences in effect sizes among different augmentation strategies for treatment resistant depression. However, according to the degree of treatment resistance, despite insufficient evidence, there seemed to be a meaningful difference in effect sizes among various strategies. Further studies to investigate the comparative efficacy of various alternative strategies for treatment resistant depression are needed to draw a more definitive conclusion regarding their efficacy.
Key Words: major depressive disorder, treatment resistance, augmentation
Corresponding author: Won-Myong Bahk, MD, PhD.
The Catholic University of Korea
Table 1.
Overall relative risk ratios of response rates for various augmentation strategies in treatment-resistant depression
Table 2.
Relative risk ratios of response rates for various augmentation strategies in TRD 1 trials TRD 1, treatment resistant depression, defined by history of a treatment failure to standard antidepressant therapy within the current depressive episode.
TRD 2 or higher, treatment resistant depression, defined by history of two or more treatment failures to standard antidepressant therapy within the current depressive episode.