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The Antidiabetic Metformin as a Novel Adjunct to Antidepressants in Major Depressive Disorder Patients

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04088448
Recruitment Status : Recruiting
First Posted : September 12, 2019
Last Update Posted : September 12, 2019
Information provided by (Responsible Party):
Mahmoud Samy Abdallah, Sadat City University

Brief Summary:
The aim of our study was to test whether the combined administration of the SSRI fluoxetine and metformin, a drug improving metabolic profile and therefore potentially able to mimic the influence of supportive living conditions on treatment outcome, results in an improved antidepressant efficacy compared with fluoxetine alone.

Condition or disease Intervention/treatment Phase
Major Depressive Disorder Drug: Placebo oral tablet Drug: Metformin Phase 1 Phase 2

Detailed Description:

Selective Serotonin Reuptake Inhibitors (SSRIs) represent the standard treatment for Major Depressive Disorder (MDD). However, their efficacy is variable and incomplete. In order to explain, at least in part, such variable efficacy, we have shown that SSRI administration does not affect mood per se but, by enhancing neural plasticity, amplifies the influence of the living conditions on mood. Consequently, in a favorable environment, SSRI treatment leads to a reduction of symptoms while, in stressful conditions, it could lead to a worse prognosis. Here, we test the hypothesis that, given the clear association between living conditions and metabolic profile, the modulation of the latter may mimic the effect of the environment on SSRI outcome, determining treatment efficacy.

Metformin is widely used as a first line treatment for patients with type 2 diabetes mellitus for more than 60 years for the reduction of hepatic glucose output and increase of the insulin mediated utilization of glucose. Previous studies demonstrated that metformin can rapidly cross the blood brain barrier and has several beneficial effects in the brain such as anti-inflammatory and neuroprotective effects. Furthermore, metformin, along with its anti-glycemic effects, has been documented to possess anti-depression effects in patients with type 2 diabetes. In Guo's study, 58 participants diagnosed with depression and type 2 diabetes were divided into two groups: one treated with metformin and the other with a placebo for 24 weeks. Analysis of MADRS and HRSD-17 scores showed that metformin significantly reduced MADRS scores and HRSD-17 scores. Metformin administration improves depressive symptoms in type 2 diabetes mellitus.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: The Antidiabetic Metformin as a Novel Adjunct to Antidepressants in Major Depressive Disorder Patients: A Proof-of-Concept, Randomized, Double-Blind, Placebo-Controlled Trial
Actual Study Start Date : January 1, 2019
Estimated Primary Completion Date : January 31, 2020
Estimated Study Completion Date : June 30, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Antidepressants

Arm Intervention/treatment
Placebo Comparator: Control group
Fluoxetine 20 mg capsule once daily for 12 week plus placebo tablet once daily for 12 weeks
Drug: Placebo oral tablet
Fluoxetine 20 mg capsule plus Placebo tablet administered once daily after food

Experimental: Metformin group
Fluoxetine 20 mg capsule once daily for 12 week plus Metformin 1000 mg XR tablet once daily for 12 weeks
Drug: Metformin
Fluoxetine 20 mg capsule plus Metformin 1000 mg extended release tablet administered once daily after food

Primary Outcome Measures :
  1. Effect on Hamilton Depression rating scale score (HAM-D score) [ Time Frame: Baseline to week 12 ]
    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.

  2. Change From Baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score at Week 12 [ Time Frame: Baseline to week 12 ]
    The MADRS is a clinician-rated scale for assessing depressive symptomatology that had occurred in participants during the week preceding each interview. Patients were rated on 10 items to assess feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty concentrating, and lack of interest. Each item was scored on a 7-point scale from 0 (no symptoms) to 6 (symptoms of maximum severity). The total score was the sum of the scores on the 10 items and ranged from 0 to 60. A higher score indicated more depressive symptomatology. A negative change score indicated improvement.

Secondary Outcome Measures :
  1. TNF-α [ Time Frame: Baseline to week 12 ]
    Serum level of tumor necrosis factor alpha (TNF-α)

  2. BDNF [ Time Frame: Baseline to week 12 ]
    Serum level of brain derived neurotrophic factor (BDNF),

  3. CRP [ Time Frame: Baseline to week 12 ]
    Serum level of C-Reactive Protein

  4. IGF‑1 [ Time Frame: Baseline to week 12 ]
    Serum level of Insulin-Like Growth Factor

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 18 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 diabetes and other inflammatory disorders
  • Patients with allergy or contraindications to the used medications
  • Patients with finally pregnant or lactating females

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04088448

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Contact: Mahmoud S Abdallah 00201063340887

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Faculty of Medicine Recruiting
Tanta, Egypt
Contact: Mahmoud S Abdallah, PhD         
Sponsors and Collaborators
Sadat City University

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Responsible Party: Mahmoud Samy Abdallah, Lecturer of Clinical Pharmacy, PhD., Sadat City University Identifier: NCT04088448     History of Changes
Other Study ID Numbers: 0056/2018
First Posted: September 12, 2019    Key Record Dates
Last Update Posted: September 12, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Depressive Disorder
Depressive Disorder, Major
Pathologic Processes
Mood Disorders
Mental Disorders
Behavioral Symptoms
Antidepressive Agents
Hypoglycemic Agents
Physiological Effects of Drugs
Psychotropic Drugs
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Serotonin Agents
Antidepressive Agents, Second-Generation
Cytochrome P-450 CYP2D6 Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors