Efficacy and safety of olanzapine/fluoxetine combination in the treatment of treatment-resistant depression: a meta-analysis of randomized controlled trials

Background: Whether olanzapine/fluoxetine combination (OFC) is superior to olanzapine or fluoxetine monotherapy in patients with treatment-resistant depression (TRD) remains controversial. Thus, we conducted this meta-analysis of randomized controlled trials (RCTs) to compare the efficacy and safety of OFC with olanzapine or fluoxetine monotherapy for patients with TRD. Materials and methods: RCTs published in PubMed, Embase, Web of Science, and the ClinicalTrials.gov registry were systematically reviewed to assess the efficacy and safety of OFC. Outcomes included mean changes from baseline in Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impression-Severity (CGI-S), Hamilton Rating Scale for Anxiety (HAM-A), Brief Psychiatric Rating Scale (BPRS) scores, response rate, remission rate, and adverse events. Results were expressed with weighted mean difference (WMD) with 95% confidence intervals (CIs) and risk ratio (RR) with 95% CIs. Results: A total of five RCTs with 3,020 patients met the inclusion criteria and were included in this meta-analysis. Compared with olanzapine or fluoxetine monotherapy, OFC was associated with greater changes from baseline in MADRS (WMD=-3.37, 95% CI: -4.76, -1.99; P < 0.001), HAM-A (WMD=-1.82, 95% CI: -2.25, - 1.40; P < 0.001), CGI-S (WMD=-0.37, 95%CI:-0.45,-0.28;P < 0.001), and BPRS scores (WMD=-1.46, 95% CI: -2.16, -0.76; P < 0.001). Moreover, OFC had significantly higher response rate (RR= 1.35, 95% CI: 1.12, 1.63; P=0.001) and remission rate (RR=1.71, 95% CI: 1.31, 2.23; P < 0.001). The incidence of treatment-related adverse events was similar between the OFC and monotherapy groups (RR= 1.01, 95% CI: 0.94, 1.08; P= 0.834). Conclusion: OFC is more effective than olanzapine or fluoxetine monotherapy in the treatment of patients with TRD. Our results provided supporting evidence for the use of OFC in TRD. However, considering the limitations in this study, more large-scale, well-designed RCTs are needed to confirm these findings.