A Study of the Neurobiology of Depression

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company
ClinicalTrials.gov Identifier:
NCT01051466
First received: January 15, 2010
Last updated: February 17, 2014
Last verified: February 2014
  Purpose

Previous research studies have shown that depression is associated with changes in structure and activity in different parts of the brain and that antidepressant medication can affect brain activity in different parts of the brain in individuals suffering from depression. The primary purpose of the study is to find out more about how the antidepressant medication duloxetine affects brain activity and structure in individuals with depression.


Condition Intervention Phase
Major Depressive Disorder
Healthy Participants
Drug: Duloxetine
Phase 4

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Neurobiological Correlates of Antidepressant Response After Duloxetine Hydrochloride Treatment in Subjects With Major Depressive Disorder

Resource links provided by NLM:


Further study details as provided by Eli Lilly and Company:

Primary Outcome Measures:
  • Change From Baseline to 12-Week Endpoint in the Functional Magnetic Resonance Imaging (fMRI) Mean Blood Oxygenation-Level-Dependent (BOLD) Response in the Amygdalae [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
    Functional MRI or fMRI is a functional neuroimaging procedure that uses MRI technology to measure brain activity by detecting associated changes in blood flow. When an area of the brain is in use, blood flow to that region increases. The activation in response to the processing of sad faces was measured by the percentage of signal change in BOLD response from before to after sad faces processing. The percentage of signal change was calculated by taking the difference between BOLD response after sad faces processing and BOLD response before sad faces processing and dividing by BOLD response before sad face processing, then multiplying by 100. BOLD signals were measured using arbitrary magnetic resonance units. Amygdala BOLD activation was calculated as an average between the left amygdala activation and right amygdala activation. Least squares (LS) mean was calculated using mixed-model repeated measures (MMRM) adjusted for group, visit, group-by-visit, and baseline value.


Secondary Outcome Measures:
  • Change From Baseline to 12-Week Endpoint in Activation [Blood Oxygenation-Level-Dependent (BOLD) Response to Implicit Processing of Sad Faces] for Each of the 3 Brain Regions [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
    Functional magnetic resonance imaging (fMRI) is a functional neuroimaging procedure that uses MRI technology to measure brain activity by detecting associated changes in blood flow. When an area of the brain is in use, blood flow to that region increases. The activation in response to the processing of sad faces in each brain region (anterior cingulate, left amygdala and right amygdala) was measured by the percentage of signal change in BOLD response. The percentage of signal change was calculated by taking the difference between BOLD response after sad faces processing and BOLD response before sad faces processing and dividing by BOLD response before sad face processing, then multiplying by 100. BOLD signals were measured using arbitrary magnetic resonance units. Least squares (LS) mean was calculated using mixed-model repeated measures (MMRM) adjusted for group, visit, group-by-visit, and baseline value.

  • Change From Baseline to 12-Week Endpoint in Volume of Subgenual Anterior Cingulate, Amygdalae, and Hippocampus [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
    The volume of specific brain regions is obtained using a structural magnetic resonance imaging (sMRI) procedure in which high-resolution spoiled gradient recall images are acquired in coronal brain slices. Least squares (LS) mean was calculated using mixed-model repeated measures (MMRM) adjusted for group, visit, group-by-visit, and baseline value.

  • Translocation of Gs Alpha (Gsα) From Lipid Rafts in the Cell Membranes of Red Blood Cells (RBCs), White Blood Cells (WBCs) and Platelets Compared With Baseline [ Time Frame: Baseline, Weeks 1, 8, and 12 ] [ Designated as safety issue: No ]
    Gsα is a membrane-associated protein that couples receptors for neurotransmitters like serotonin to allow them to send messages between nerve cells - a process that may be altered during depression and antidepressant treatment. Gsα localization in the cholesterol-rich (lipid rafts) and cholesterol-poor regions of cell membranes of RBCs and platelets was measured with quantitative Western blots and reported as the ratio of Gsα (absorbance units) in Triton X-100 (TX-100) over Triton X-114 (TX-114), 2 detergents that discriminate between lipid raft and non-raft membrane domains. Translocation of Gsα was measured as the change from baseline in Gsα localization. Translocation of Gsα from lipid rafts in the cell membranes of WBCs was not analyzed due to technical laboratory issues. Least squares (LS) mean was calculated using mixed-model repeated measures (MMRM) adjusted for group, visit, group-by-visit, and baseline value.

  • Gs Alpha (Gsα)-Activated Adenylyl Cyclase [ Time Frame: Baseline and Weeks 1, 8, and 12 ] [ Designated as safety issue: No ]
    Gsα is a membrane-associated protein that couples receptors for neurotransmitters like serotonin to allow them to send messages between nerve cells - a process that may be altered during depression and antidepressant treatment. Adenylyl cyclase is activated by Gsα, and when Gsα is translocated from lipid rafts it more effectively activates adenylyl cyclase. Gsα-activated adenylyl cyclase was not analyzed due to technical laboratory issues.

  • Change From Baseline to 12-Week Endpoint in Brain-Derived Neurotrophic Factor (BDNF) and the Precursor of BDNF (proBDNF) [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
    There is evidence that stress may decrease BDNF expression, while antidepressant treatment reverses or blocks these effects. BDNF is a protein that occurs naturally and supports the survival and growth of some nerve cells in the brain. proBDNF is a precursor of BDNF. Least squares (LS) mean was calculated using mixed-model repeated measures (MMRM) adjusted for group, visit, group-by-visit, and baseline value.

  • Change From Baseline to 12-Week Endpoint in Brain-Derived Neurotrophic Factor (BDNF) and the Precursor of BDNF (proBDNF) Receptors [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
    There is evidence that stress may decrease BDNF expression, while antidepressant treatment reverses or blocks these effects. BDNF is a protein that occurs naturally and supports the survival and growth of some nerve cells in the brain. proBDNF is a precursor of BDNF. Tropomyosin receptor kinase B (trkB) is a receptor for BDNF, and pan-neurotrophin receptor p75 (p75NTR) is a receptor for proBDNF. p75NTR was not analyzed due to technical laboratory issues. Least squares (LS) mean was calculated using mixed-model repeated measures (MMRM) adjusted for group, visit, group-by-visit, and baseline value.

  • Change From Baseline to 12-Week Endpoint in Proinflammatory Cytokines [Tumor Necrosis Factor Alpha (TNFα), Interleukin 1 (IL-1), and Interleukin 6 (IL-6)] [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
    Cytokines are naturally produced and regulate responses to inflammation. Proinflammatory cytokines like TNFα, IL-1, and IL-6 increase inflammation in the body. Least squares (LS) mean was calculated using mixed-model repeated measures (MMRM) adjusted for group, visit, group-by-visit, and baseline value.

  • 17-Item Hamilton Depression Rating Scale (HAMD17) [ Time Frame: Baseline and up to Week 12 ] [ Designated as safety issue: No ]
    The HAMD17 is a standardized instrument consisting of 17 items used to measure the severity of major depressive disorder (MDD) and improvements in depression symptoms. Each item was evaluated and scored using either a 5-point scale of 0 (not present/absent) to 4 (very severe) or a 3-point scale of 0 (not present/absent) to 2 (marked). Higher scores indicated greater symptom severity. The total score was the sum of the scores from HAMD17 Items 1 through 17 and could have ranged from 0 (not at all depressed) to 52 (severely depressed).

  • Percentage of Participants With 17-Item Hamilton Depression Rating Scale (HAMD17) Response [ Time Frame: Baseline, up to Week 12 ] [ Designated as safety issue: No ]
    HAMD17 response is defined as a >50% reduction in HAMD17 total score from baseline. The HAMD17 is a standardized instrument consisting of 17 items used to measure the severity of major depressive disorder (MDD) and improvements in depression symptoms. Each item was evaluated and scored using either a 5-point scale of 0 (not present/absent) to 4 (very severe) or a 3-point scale of 0 (not present/absent) to 2 (marked). Higher scores indicated greater symptom severity. The total score was the sum of the scores from HAMD17 Items 1 through 17 and could have ranged from 0 (not at all depressed) to 52 (severely depressed). The percentage of participants with a HAMD17 response was calculated as the number of participants with a >50% reduction in HAMD17 total score from baseline divided by the number of participants who had a HAMD17 observation at Week 12 then multiplied by 100.

  • Percentage of Participants With 17-Item Hamilton Depression Rating Scale (HAMD17) Remission [ Time Frame: Baseline, up to Week 12 ] [ Designated as safety issue: No ]
    HAMD17 remission is defined as a HAMD17 total score of ≤7 at Week 12 (endpoint). The HAMD17 is a standardized instrument consisting of 17 items used to measure the severity of major depressive disorder (MDD) and improvements in depression symptoms. Each item was evaluated and scored using either a 5-point scale of 0 (not present/absent) to 4 (very severe) or a 3-point scale of 0 (not present/absent) to 2 (marked). Higher scores indicated greater symptom severity. The total score was the sum of the scores from HAMD17 Items 1 through 17 and could have ranged from 0 (not at all depressed) to 52 (severely depressed). The percentage of participants with remission was calculated as the number of participants with a HAMD17 total score of ≤7 divided by the number of participants who had a HAMD17 observation at Week 12 then multiplied by 100.

  • Sheehan Disability Scale (SDS) [ Time Frame: Baseline and up to Week 12 ] [ Designated as safety issue: No ]
    The SDS is a participant-rated questionnaire used to assess the effect of the participant's symptoms on work/school (Item 1), social life/leisure activities (Item 2), and family/home management (Item 3). Each item was rated on a visual analog scale (VAS) from 0 (not at all) to 10 (very severely). The SDS Global Functional Impairment Score (SDS Global Score) was the sum of the 3 items and could have ranged from 0 (unimpaired) to 30 (highly impaired). Higher values indicated higher functional impairment in the participant's work/social/family life.

  • Clinical Global Impressions of Severity Scale (CGI-S) [ Time Frame: Baseline and up to Week 12 ] [ Designated as safety issue: No ]
    The CGI-S measures severity of illness at the time of assessment. Scores can range from 1 (normal, not at all ill) to 7 (among the most extremely ill participants).

  • Patient's Global Impressions of Improvement (PGI-I) Scale [ Time Frame: Baseline, up to Week 12 ] [ Designated as safety issue: No ]
    The PGI-I scale measures the participant's perception of improvement at the time of assessment compared with the start of treatment. Scores can range from 1 (very much better) to 7 (very much worse).

  • Hamilton Anxiety Rating Scale (HAMA) [ Time Frame: Baseline and up to Week 12 ] [ Designated as safety issue: No ]
    The 14-item HAMA is used to assess the severity of anxiety. The investigator talked to the participant about their symptoms over the previous week. Each item was scored using a 5-point scale (0 = not present to 4 = very severe). Total HAMA scores could have ranged from 0 (normal) to 56 (severe).

  • Incidence of Suicidal Behavior and Suicidal Ideation as Measured by the Columbia Suicide Severity Rating Scale (C-SSRS) [ Time Frame: Baseline through Week 12 ] [ Designated as safety issue: Yes ]
    The C-SSRS captures the occurrence, severity, and frequency of treatment-emergent suicide-related thoughts and behaviors. Suicidal ideation is defined as a "yes" answer to any 1 of 5 suicidal ideation questions: wish to be dead, and 4 different categories of active suicidal ideation. Suicidal behavior is defined as a "yes" answer to any 1 of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Treatment-emergent outcomes were the worsening or new occurrence of suicidal behaviors or ideation during treatment compared with baseline.


Enrollment: 60
Study Start Date: January 2010
Study Completion Date: March 2013
Primary Completion Date: March 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Duloxetine Drug: Duloxetine
60 milligrams (mg) administered orally daily for 8 weeks then 60-120 mg if non remitter or 60 mg if remitter for 4 additional weeks
Other Name: Cymbalta, LY248686
No Intervention: Healthy Participants

Detailed Description:

This study will evaluate participants with depression before treatment is initiated and during treatment, and compare them to a control group of healthy participants. The aim will be to better understand both the neurobiology of depression and how the neurobiology changes in response to treatment of depression and the outcome of treatment. The study will include a variety of assessments of the neurobiology of depression including: scans of brain areas are involved in depression by looking at structures in the brain and how they work and blood tests and how these change in relation to several measures of depression severity.

  Eligibility

Ages Eligible for Study:   25 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

Major Depressive Disorder (MDD) participants:

  • Are right-handed
  • Meet criteria for single episode or recurrent MDD, without psychotic features, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) and confirmed by Structured Clinical Interview for DSM-IV-TR (SCID-IV), without co-morbid DSM-IV Axis I or II disorder at screening
  • Be free of current antidepressant medication for a minimum of 6 weeks for fluoxetine treatment or of 4 weeks of other antidepressant treatment
  • Have a 17-item Hamilton Depression Rating Scale (HAMD17) total score of ≥18 at screening, and baseline
  • Women of child-bearing potential must have negative urine pregnancy tests prior to enrollment and agree to use a reliable method of birth control during the study

Healthy Participants

  • Are right-handed
  • Have a HAMD17 total score of <7 at screening and baseline and must not meet the criteria for MDD based on the SCID-IV

Exclusion Criteria:

MDD participants and healthy participants:

  • Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an off-label use of an investigational drug or device
  • Treatment within the last 30 days with a drug that has not received regulatory approval
  • Have previously completed or withdrawn from this study or any other study investigating duloxetine
  • Have a history of substance abuse or dependence within the past 6 months
  • A positive urine drug screen for any substances of abuse or dependence
  • Have any current DSM-IV-TR co-morbid Axis I or II disorder as determined by participant's history or investigator assessment
  • Have any history of bipolar disorder, a primary psychotic disorder (schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder), known Alzheimer's disease or mental retardation, or obsessive-compulsive disorder as determined by participant's history or investigator assessment
  • Pregnant women, women who are breast-feeding, or women of childbearing potential who are not using a medically accepted means of contraception when engaging in sexual intercourse or have been surgically sterilized
  • Are judged by the investigator to have serious suicidal risk or risk of self-harm
  • Have a history of recurrent self-mutilation or self-harm
  • Have uncontrolled narrow-angle glaucoma
  • Have been diagnosed with an acute liver injury (such as hepatitis) or severe cirrhosis (Child-Pugh Class C)
  • Have end-stage renal disease, a prior renal transplant, current renal dialysis, or severe renal impairment
  • Have abnormal thyroid-stimulating hormone (TSH) concentration
  • Have had electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), or vagus nerve stimulation (VNS) within the past year
  • Initiating psychotherapy within 6 weeks prior to study entry or during study participation, stopping, or changing psychotherapy after study entry
  • Have frequent and/or severe allergic reactions with multiple medications, or known allergic reactions to the study medication
  • Known hypersensitivity to duloxetine or any of the inactive ingredients
  • Lack of response of the current episode to two or more adequate courses of antidepressant therapy at a clinically appropriate dose for a minimum of 4 weeks or in the judgment of the investigator the participant meets criteria for treatment-resistant depression
  • Known human immunodeficiency virus (HIV) and other medical disorders that are known to affect central nervous system (CNS) structures or function as assessed by the investigator (for example, CNS neoplasms, neurosyphilis)
  • Have a medical illness, a clinically significant laboratory abnormality, or is taking a CNS active medication that, in the opinion of the investigator, might interfere with study participation (for example, is likely to require hospitalization) or that, in the opinion of the investigator, might interfere with the interpretation of the primary endpoint (for example, hypertension or diabetes)
  • Are unwilling or unable to comply with the study procedures
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01051466

Locations
United Kingdom
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
London, United Kingdom, SE5 8AF
Sponsors and Collaborators
Eli Lilly and Company
Investigators
Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST) Eli Lilly and Company
  More Information

No publications provided

Responsible Party: Eli Lilly and Company
ClinicalTrials.gov Identifier: NCT01051466     History of Changes
Other Study ID Numbers: 12875, F1J-US-HMGO
Study First Received: January 15, 2010
Results First Received: February 17, 2014
Last Updated: February 17, 2014
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Additional relevant MeSH terms:
Depressive Disorder
Depression
Depressive Disorder, Major
Mood Disorders
Mental Disorders
Behavioral Symptoms
Duloxetine
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Central Nervous System Agents
Therapeutic Uses
Antidepressive Agents
Psychotropic Drugs
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Serotonin Agents
Adrenergic Uptake Inhibitors
Adrenergic Agents
Dopamine Uptake Inhibitors
Dopamine Agents

ClinicalTrials.gov processed this record on August 01, 2014