A Study of the Neurobiology of Depression

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.

Time frame: Baseline, Week 12

Population: Enrolled participants who had baseline and at least 1 post-baseline activation (BOLD response) observation.

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).

Time frame: Baseline and up to Week 12

Population: Enrolled participants who had a baseline and at least 1 post-baseline HAMD17 observation. Last observation carried forward (LOCF) was utilized when calculating the Week 12 endpoint outcome.

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.

Time frame: Baseline, Week 12

Population: Enrolled participants who had baseline and at least 1 post-baseline activation (BOLD response) observation, excluding 3 healthy participants who did not meet entry criteria.

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.

Time frame: Baseline, Week 12

Population: Enrolled participants who had baseline and at least 1 post-baseline BDNF or proBDNF observation, excluding 3 healthy participants who did not meet entry criteria.

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.

Time frame: Baseline, Week 12

Population: Enrolled participants who had baseline and at least 1 post-baseline trkB observation, excluding 3 healthy participants who did not meet entry criteria. No participant was analyzed for the change from baseline in p75NTR receptors.

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.

Time frame: Baseline, Week 12

Population: Enrolled participants who had baseline and at least 1 post-baseline cytokine observation (TNFα, IL-1, or IL-6), excluding 3 healthy participants who did not meet entry criteria.

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.

Time frame: Baseline, Week 12

Population: Enrolled participants who had baseline and at least 1 post-baseline observation for the volume of specific brain regions, excluding 3 healthy participants who did not meet entry criteria.

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).

Time frame: Baseline and up to Week 12

Population: Enrolled participants who had baseline and at least 1 post-baseline CGI-S observation. Last observation carried forward (LOCF) was utilized when calculating the Week 12 endpoint outcome.

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.

Time frame: Baseline and Weeks 1, 8, and 12

Population: No participants were analyzed.

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).

Time frame: Baseline and up to Week 12

Population: Enrolled participants who had a baseline and at least 1 post-baseline HAMA observation. Last observation carried forward (LOCF) was utilized when calculating the Week 12 endpoint outcome.

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.

Time frame: Baseline through Week 12

Population: Participants with MDD who had a baseline and at least 1 post-baseline C-SSRS assessment. Healthy participants did not have a C-SSRS assessment post baseline.

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).

Time frame: Baseline, up to Week 12

Population: Enrolled MDD participants who had at least 1 post-baseline PGI-I observation. Last observation carried forward (LOCF) was utilized when calculating the Week 12 endpoint outcome. PGI-I observations were not completed for healthy participants.

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.

Time frame: Baseline, up to Week 12

Population: Enrolled MDD participants who had a baseline and at least 1 post-baseline HAMD17 observation. Last observation carried forward (LOCF) was utilized when calculating the Week 12 endpoint outcome.

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.

Time frame: Baseline, up to Week 12

Population: Enrolled MDD participants who had a baseline and at least 1 post-baseline HAMD17 observation. Last observation carried forward (LOCF) was utilized when calculating the Week 12 endpoint outcome.

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.

Time frame: Baseline and up to Week 12

Population: Enrolled participants who had baseline and at least 1 post-baseline SDS observation. Last observation carried forward (LOCF) was utilized when calculating the Week 12 endpoint outcome.

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.

Time frame: Baseline, Weeks 1, 8, and 12

Population: Enrolled participants who had a baseline and at least 1 post-baseline Gsα localization observation, excluding 3 healthy participants who did not meet entry criteria. No participants were analyzed for the translocation of Gsα from lipid rafts in the cell membranes of WBCs.