The Phosphodiesterase-3 Inhibitor Cilostazol as an Adjunctive to Antidepressants in Patients With Major Depressive Disorder.

The Phosphodiesterase-3 Inhibitor Cilostazol as an Adjunctive to Antidepressants in Patients With Major Depressive Disorder.

Double-blind, Randomized, Placebo-Controlled Pilot Study of the Phosphodiesterase-3 Inhibitor Cilostazol as an Adjunctive to Antidepressants in Patients With Major Depressive Disorder

Cilostazol is a PDE 3 inhibitor, which showed as decrease in HAM-D scores in post-stroke depression through inhibition of neurodegeneration in the primary lesion and secondary extrafocal sites and through promotion of neurogenesis. These beneficial effects on post-stroke depression may be involved in activation of CREB/BDNF signaling.The aim of the current study is to evaluate the potential adjunct antidepressant effect of cilostazol in adult patients with MDD. Furthermore, we will assess the relationship between HAM-D score and BDNF as well as their role as a therapeutic targets of MDD.

Cilostazol produces various powerful pleiotropic effects via restoration of intracellular second messenger cyclic adenosine monophosphate (cAMP). Treatment with cilostazol against cerebral ischemic injury ameliorates negative effects of cerebral hypoperfusion through the PDE3- cAMP signaling cascade with subsequent activation of inducible transcription factor cAMP response element-binding protein (CREB), suggesting the importance of the CREB signaling pathway. Activation of CREB promotes the gene expression of neuroprotective molecules that activate subsequent anti-apoptotic pathways with the gene expression of brain-derived neurotrophic factor (BDNF). BDNF also regulates neurogenesis, proliferation, and survival of neural stem or progenitor cells, as well as neuronal survival. In addition, CREB and BDNF signaling play an important role in the pathophysiology of major depressive disorder . Psychopharmacotherapy with antidepressants or mood stabilizers provides an effective treatment for depression after stroke, but alternative therapy by activation of CREB and BDNF signaling may exert beneficial effects on various aspects of negative mood. Drugs that activate CREB and BDNF signaling may provide a potential therapeutic approach for treatment of poststroke depression via neural cell survival and proliferation of neural progenitor cells. The aim of the current study is to evaluate the potential adjunct antidepressant effect of cilostazol in adult patients with MDD. Furthermore, we will assess the relationship between HAM-D score and BDNF as well as their role as a therapeutic targets of MDD.

Escitalopram,Selective serotonin reuptake inhibitor- Cilostazol, a selective phosphodiesterase 3 (PDE3) inhibitor, acts as an antiplatelet agent and has been widely approved for treatment of intermittent claudication with peripheral arterial disease and for secondary prevention of ischemic stroke.

The principal measure of the outcome was the 17-items HAM-D. Scoring is based on the 17-item scale and scores of 0-7 are considered as being normal, 8-13 suggest mild depression, 14-17 moderate depression and scores over 17 are indicative of severe depression. Remission is defined as HAM-D total score ≤ 7 (primary outcome). Treatment response is defined as ≥ 50% drop in the HAM-D total score.

Serum level of brain derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), SEROTONIN, tumor necrosis factor alpha (TNF-α), Interleukin-6 (IL-6), and Nuclear factor kappa were measured at the baseline and after the treatment to evaluate the biological effects of the used medications.

Inclusion Criteria: Eighty adult outpatients with the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) diagnosis of MDD based on a MINI Neuropsychiatric Interview (MINI) (American Psychiatric Association., 2000; Sheehan et al., 1998), without psychotic features and a total 17 item HAM-D score of at least 20 with item 1 (depressed mood) scored 2 or greater were eligible (Hamilton, 1960). Patients were requested to be free of all the psychotropic and anti-inflammatory medications for at least 4 weeks before participating in the study. Exclusion Criteria: Patients with bipolar I or bipolar II disorder Patients with personality disorders Patients with eating disorders Patients with substance dependence or abuse Patients with concurrent active medical condition Patients with history of seizures Patients with history of receiving Electroconvulsive therapy (ECT) Patients with inflammatory disorders Patients with allergy or contraindications to the used medications Patients with finally pregnant or lactating females Cardiovascular disorders Severe renal impairment: creatinine clearance of ≤ 25 ml/min Moderate or severe hepatic impairment

Abdallah MS, Ramadan AN, Omara-Reda H, Mansour NO, Elsokary MA, Elsawah HK, Zaki SA, Abo Mansour HE, Mosalam EM. Double-blind, randomized, placebo-controlled pilot study of the phosphodiesterase-3 inhibitor cilostazol as an adjunctive to antidepressants in patients with major depressive disorder. CNS Neurosci Ther. 2021 Dec;27(12):1540-1548. doi: 10.1111/cns.13731. Epub 2021 Sep 21.