Double-blind, randomized, placebo-controlled pilot study of the phosphodiesterase-3 inhibitor cilostazol as an adjunctive to antidepressants in patients with major depressive disorder

Abstract

Aims: Cilostazol (CLS) has shown antidepressant effect in cardiovascular patients, post-stroke depression, and animal models through its neurotrophic and antiinflammatory activities. Consequently, we aimed to investigate its safety and efficacy in patients with MDD by conducting double-blind, randomized, placebo-controlled pilot study.

Methods: 80 participants with MDD (DSM-IV criteria) and Hamilton Depression Rating Scale (HDRS) score >20 were treated with CLS 50 mg or placebo twice daily plus escitalopram (ESC) 20 mg once daily for six weeks. Patients were evaluated by HDRS scores (weeks 0, 2, 4, and 6). Serum levels of CREB1, BDNF, 5-HT, TNF-α, NF- κB, and FAM19A5 were assessed pre- and post-treatment.

Results: Co-administration of CLS had markedly decreased HDRS score at all-time points compared to the placebo group (p < 0.001). Early improvement, response, and remission rates after 6 weeks were significantly higher in the CLS group (90%, 90%, 80%, respectively) than in the placebo group (25%, 65%, 50% respectively) (p < 0.001). Moreover, the CLS group was superior to the placebo group in modulation of the measured neurotrophic and inflammatory biomarkers.

Conclusion: CLS is safe and effective short-term adjunctive therapy in patients with MDD with no other comorbid conditions. Trial registration ID:NCT04069819.

Keywords: CREB/BDNF; adjunctive therapy; cilostazol; inflammatory markers; major depressive disorder.

FIGURE 1

Flow diagram of study participants

FIGURE 2

Baseline‐to‐Endpoint Changes in Hamilton Depression Rating Scale (HDRS) Total Score. Data presented as mean ± SD. Mixed‐effects model repeated measures (MMRM) analysis of covariance (ANCOVA) was used for comparing the end‐point score in HDRS total score. HDRS, Hamilton Depression Rating Scale (HDRS)