The Phosphodiesterase 4 Inhibitor Roflumilast as an Adjunct to Antidepressants in Major Depressive Disorder Patients

The Phosphodiesterase 4 Inhibitor Roflumilast as an Adjunct to Antidepressants in Major Depressive Disorder Patients. Proof-of-Concept, Randomized, Double-Blind, Placebo-Controlled Trial

n pre-clinical studies and early-stage clinical trials, PDE4 inhibitors such as rolipram have been shown to enhance memory. They also improve depressive-like behaviors induced by chronic unpredictable mild stress, lipopolysaccharide, or ethanol abstinence . Consequently, it is reasonable to believe that PDE4 is a potential target for treatment of the comorbidity of depression and AD.The aim of the current study is to evaluate the potential adjunct antidepressant effect of the Phosphodiesterase-4 Inhibitor Roflumilast in adult patients with MDD.

Study Overview

• Status: Recruiting
• Conditions: Major Depressive Disorder
• Intervention / Treatment: Drug: Placebo; Drug: Roflumilast 500Mcg Tab

Detailed Description

Phosphodiesterase-4 (PDE4), an important member of the PDE superfamily, is a key regulator of intracellular cyclic AMP (cAMP) level. As the second messenger, cAMP activates protein kinase A, which phosphorylates the subsequent downstream cAMP-response element binding (CREB) protein. In the central nervous system, this signaling cascade exerts both pre- and post-synaptic effects and is essential for a variety of cellular functions, including neurotransmitter release and neuroprotection. Inhibition of PDE4 prevents cAMP breakdown, which is well recognized as the mechanism by which PDE4 inhibitors can treat impaired memory linked to several brain disorders. In pre-clinical studies and early-stage clinical trials, PDE4 inhibitors such as rolipram have been shown to enhance memory. They also improve depressive-like behaviors induced by chronic unpredictable mild stress, lipopolysaccharide, or ethanol abstinence . Consequently, it is reasonable to believe that PDE4 is a potential target for treatment of the comorbidity of depression and AD.

The aim of the current study is to evaluate the potential adjunct antidepressant effect of Roflumilast 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.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Egypt
  • Menoufia
    • Shibeen Elkom, Menoufia, Egypt, 13829
      • Recruiting
      • Faculty of Pharmacy
      • Contact: Mahmoud S Abdallah, PhD; Phone Number: 01063340887; Email: Mahmoud.samy@fop.usc.edu.eg
      • Contact: Phone Number: +201063340887; Email: Mahmoud.samy@fop.usc.edu.eg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

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).

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; placebo tablet plus standard therapy	Drug: Placebo; Placebo tablet once daily for 6 weeks plus the standard therapy
Active Comparator: Roflumilast; Roflumilast 500 µg tablet plus standard therapy	Drug: Roflumilast 500Mcg Tab; Roflumilast 500µg tablet once daily for 6 weeks plus the standard therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect on Hamilton Depression rating scale score (HAM-D score)	The principal measure of the outcome was the 17-items Effect on Hamilton Depression rating scale score. 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 Effect on Hamilton Depression rating scale total score ≤ 7 (primary outcome). Treatment response is defined as ≥ 50% drop in the Effect on Hamilton Depression rating scale total score.	6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect on biological markers	Serum level of brain derived neurotrophic factor (BDNF)	6 weeks
Effect on biological markers	Serum level of cAMP response element-binding protein (CREB)	6 weeks
Effect on biological markers	Serum level of SEROTONIN	6 weeks
Effect on biological markers	Serum level of tumor necrosis factor alpha (TNF-α)	6 weeks
Effect on biological markers	Serum level of Interleukin-6 (IL-6)	6 weeks
Effect on biological markers	Serum level of Nuclear factor kappa	6 weeks

Collaborators and Investigators

• Sponsor: Sadat City University

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2021
• Primary Completion (Estimated): October 1, 2024
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: February 3, 2021
• First Submitted That Met QC Criteria: February 10, 2021
• First Posted (Actual): February 11, 2021

Study Record Updates

• Last Update Posted (Estimated): November 21, 2023
• Last Update Submitted That Met QC Criteria: November 20, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Depression; Depressive Disorder; Depressive Disorder, Major
• Other Study ID Numbers: 10/2021NEUR2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No