Phosphodiesterase Inhibitor and SSRI Combination Therapy Versus SSRI Monotherapy for the Treatment of Major Depressive Disorder: a Systematic Review and Meta-Analysis

Abstract

Background Selective serotonin reuptake inhibitors (SSRI) are the gold standard treatment for major depressive disorder (MDD). However, the use of phosphodiesterase (PDE) inhibitors in treatment of MDD remains unclear. The aim of our study was to compare the effect of PDE inhibitor + SSRI combination therapy to SSRI monotherapy for the treatment of MDD. Methods We performed a comprehensive literature search using PubMed, EMBASE, and Web of Science databases from inception to 07/08/2022, for studies that assess the impact of PDE inhibitor therapy on MDD patients. The primary outcome of our study was treatment response rate (defined as ≥50% reduction in the Hamilton Rating Scale for Depression score) at the end of study time. Secondary outcomes included specific side effect rates. Pooled odds ratio (OR) and corresponding 95% confidence intervals (CIs) were calculated using the random-effects model. A P-value 50% implied the presence of significant heterogeneity). Results A total of four randomized control trials (RCTs), including 270 patients with MDD (mean age: 34.9±8.4 years, 135 patients received PDE inhibitor + SSRI combination therapy and 135 received SSRI monotherapy), were included in the analysis. The follow up period ranged from 6 to 12 weeks. The PDE inhibitor group was associated with a significantly higher treatment response rate (OR:4.77; 95% CI:2.05-11.12; P = 0.0003). Additionally, there was no significant difference in side effect rates between the two treatment modalities. Conclusion Our study supports the use of PDE inhibitor + SSRI combination therapy in patients with MDD, since it is associated with a significantly higher treatment response rate compared to patients receiving SSRI monotherapy (90.4% vs 64.4%, respectively). Further large-scale RCTs with long-term follow-up are necessary to validate our findings. Ultimately, use of PDE inhibitors in MDD patients should be considered on a case-by-case basis to maximize patient benefits.