A Study of the Neurobiology of Depression

Phase 4

Completed

Conditions: Healthy Participants
Major Depressive Disorder

Interventions: Drug: Duloxetine

Registration Number: NCT01051466

Lead Sponsor: Eli Lilly and Company

Brief Summary: 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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 60

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Duloxetine	Duloxetine	-

Primary Outcome Measures

Name	Time	Method
Change From Baseline to 12-Week Endpoint in the Functional Magnetic Resonance Imaging (fMRI) Mean Blood Oxygenation-Level-Dependent (BOLD) Response in the Amygdalae	Baseline, Week 12	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

Name	Time	Method
Change From Baseline to 12-Week Endpoint in Proinflammatory Cytokines [Tumor Necrosis Factor Alpha (TNFα), Interleukin 1 (IL-1), and Interleukin 6 (IL-6)]	Baseline, Week 12	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.
Gs Alpha (Gsα)-Activated Adenylyl Cyclase	Baseline and Weeks 1, 8, and 12	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) Receptors	Baseline, Week 12	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.
Hamilton Anxiety Rating Scale (HAMA)	Baseline and up to Week 12	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).
Percentage of Participants With 17-Item Hamilton Depression Rating Scale (HAMD17) Response	Baseline, up to Week 12	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	Baseline, up to Week 12	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)	Baseline and up to Week 12	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.
Change From Baseline to 12-Week Endpoint in Brain-Derived Neurotrophic Factor (BDNF) and the Precursor of BDNF (proBDNF)	Baseline, Week 12	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 Activation [Blood Oxygenation-Level-Dependent (BOLD) Response to Implicit Processing of Sad Faces] for Each of the 3 Brain Regions	Baseline, Week 12	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	Baseline, Week 12	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	Baseline, Weeks 1, 8, and 12	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.
17-Item Hamilton Depression Rating Scale (HAMD17)	Baseline and up to Week 12	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).
Clinical Global Impressions of Severity Scale (CGI-S)	Baseline and up to Week 12	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	Baseline, up to Week 12	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).
Incidence of Suicidal Behavior and Suicidal Ideation as Measured by the Columbia Suicide Severity Rating Scale (C-SSRS)	Baseline through Week 12	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.

Trial Locations

Locations (1): 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.
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London, United Kingdom