Ignite Creation Date:
2024-05-06 @ 7:24 PM
Last Modification Date:
2024-10-26 @ 3:06 PM
Study NCT ID:
NCT06004115
Status:
RECRUITING
Last Update Posted:
2023-11-15
First Post:
2023-07-07
Brief Title:
Processes and Circuitry Underlying Threat Sensitivity as a Treatment Target for Co-morbid Anxiety and Depression
Sponsor:
Laureate Institute for Brain Research Inc
Organization:
Laureate Institute for Brain Research Inc
Study Overview
Official Title:
Processes and Circuitry Underlying Threat Sensitivity as a Treatment Target for Co-morbid Anxiety and Depression
Status:
RECRUITING
Status Verified Date:
2023-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This mechanistic study uses an anti anxiety drug and brain imaging to study the threat processing system and associated brain circuits in people with depression anxiety disorders and comorbid depression and anxiety disorders In a double blind placebo controlled crossover design up to 65 individuals will be recruited who will have a diagnosis of major depressive disorder MDD and at least one anxiety disorder AD AD-MDD group up to 65 participants will have a diagnosis of MDD and no diagnosis of an AD and up to 65 participants will have no diagnosis of MDD and a diagnosis of at least one AD will be enrolled to participate in an two session study to obtain 150 completers 50 per group All participants will receive a single dose of Lorazepam and placebo order randomized taken orally After the 25 hr screening session participants will complete two identical 5 hr experimental sessions each of which include a 30 min eyeblink startle session and a 1 hr functional magnetic resonance imaging MRI brain scan session The total time involved in the study is approximately 105 hours
The main questions the study seeks to answer are
are people with comorbid depression and anxiety different than those with depression alone in terms of their eyeblink startle response to threat
are people with comorbid depression and anxiety different than those with depression alone in terms of their brain activation in response to threat
are people with comorbid depression and anxiety different than those with depression alone in terms of their responses to anxiety drugs
The main questions the study seeks to answer are
are people with comorbid depression and anxiety different than those with depression alone in terms of their eyeblink startle response to threat
are people with comorbid depression and anxiety different than those with depression alone in terms of their brain activation in response to threat
are people with comorbid depression and anxiety different than those with depression alone in terms of their responses to anxiety drugs
Detailed Description:
This mechanistic study of major depressive disorder MDD anxiety disorders AD and comorbid anxiety and depression AD-MDD aims to break down threat sensitivity into acute threat AT and potential threat PT A well validated startle task Neutral Predictable Unpredictable or NPU-threat task and a cutting-edge computational functional magnetic resonance imaging fMRI probe of predator escape decisions Flight Initiation Distance or FID task will be used to determine whether AD-MDD show increased PT or AT and how the behavioral dynamics of escape decisions are most impaired in AD-MDD Based on prior studies we hypothesize that AD is associated with exaggerated PT whereas MDD is associated with blunted rewardsalience responding Thus AD-MDD may differ from AD through blunted ATsalience periaqueductal greyinsula circuitry and Fear-Potentiated Startle FPS and may differ from MDD through increased PT hippocampal - ventromedial prefrontal cortex vmPFC - amygdala dependent circuitry and Anxiety-Potentiated Startle APS To causally probe this circuitry we will manipulate gamma-aminobutyric acid GABA to demonstrate different responses in PT between these three groups providing further evidence for PT as a targetable process This mechanistic R01 uses a benzodiazepine within an experimental medicine approach to causally modulate the threat processing system and associated circuits in AD-MDD N50 MDD N50 and AD N50 After the 25 hr screening session participants will complete two identical 5 hr experimental sessions each of which include a 30 min electromyography EMG session and a 1 hr functional magnetic resonance imaging fMRI session The total time involved in the study is approximately 105 hours In a double-blind placebo crossover design participants will receive a single 1mg dose of LorazepamPlacebo and complete threat tasks that delineate PTAT during startle EMG NPU task unpredictable vs predictable shock and fMRI FID task slow vs fast threat
Specific aims of this project are
Aim 1 Determine EMG signatures of dysregulated threat processing in AD-MDD
Hypothesis 1 A H1A AD-MDDAD will exhibit higher PT sensitivity greater APS than MDD NPU APS AD-MDD MDD AD MDD
Hypothesis 1 B H1B AD-MDDMDD will exhibit lower AT sensitivity smaller FPS than AD NPU FPS AD-MDD AD MDD AD
Aim 2 Determine neural computational signatures of dysregulated threat processing in AD-MDD
Hypothesis 2 A H2A AD-MDD and AD will show higher hippocampal-vmPFC-amygdala responses to FID slow threat PT than MDD FID slow AD-MDD MDD AD MDD
Hypothesis 2 B H2B AD-MDD and MDD will show lower periaqueductal greyinsula responses to FID fast threat AT than AD FID fast AD-MDD AD MDD AD
Hypothesis 2 C H2C Utility functions for the FID task will show both blunted reward and exaggerated threat valuation in AD-MDD leading to less optimal choices than both MDD and AD
Aim 3 Determine the relevance of comorbidity to GABAergic manipulation of threat circuitry
Hypothesis 3 A H3A In the NPU task Lorazepam will decrease APS PT but not FPS AT in AD and AD-MDD but not MDD
Hypothesis 3 B H3B In the FID task Lorazepam will decrease neural response to slow PT but not fast AT threat and decrease the computational threat valuation parameter in AD and AD-MDD but not MDD
Significance These aims seek to mechanistically define and pharmacologically probe process dysfunction and associated targetable circuitry unique to AD-MDD and provide evidence that AD-MDD and MDD should be separated in future clinical trials This will also inform intervention strategies with circuit-based targets eg for neuromodulation treatments for AD-MDD which is a large but under-served treatment resistant group
Specific aims of this project are
Aim 1 Determine EMG signatures of dysregulated threat processing in AD-MDD
Hypothesis 1 A H1A AD-MDDAD will exhibit higher PT sensitivity greater APS than MDD NPU APS AD-MDD MDD AD MDD
Hypothesis 1 B H1B AD-MDDMDD will exhibit lower AT sensitivity smaller FPS than AD NPU FPS AD-MDD AD MDD AD
Aim 2 Determine neural computational signatures of dysregulated threat processing in AD-MDD
Hypothesis 2 A H2A AD-MDD and AD will show higher hippocampal-vmPFC-amygdala responses to FID slow threat PT than MDD FID slow AD-MDD MDD AD MDD
Hypothesis 2 B H2B AD-MDD and MDD will show lower periaqueductal greyinsula responses to FID fast threat AT than AD FID fast AD-MDD AD MDD AD
Hypothesis 2 C H2C Utility functions for the FID task will show both blunted reward and exaggerated threat valuation in AD-MDD leading to less optimal choices than both MDD and AD
Aim 3 Determine the relevance of comorbidity to GABAergic manipulation of threat circuitry
Hypothesis 3 A H3A In the NPU task Lorazepam will decrease APS PT but not FPS AT in AD and AD-MDD but not MDD
Hypothesis 3 B H3B In the FID task Lorazepam will decrease neural response to slow PT but not fast AT threat and decrease the computational threat valuation parameter in AD and AD-MDD but not MDD
Significance These aims seek to mechanistically define and pharmacologically probe process dysfunction and associated targetable circuitry unique to AD-MDD and provide evidence that AD-MDD and MDD should be separated in future clinical trials This will also inform intervention strategies with circuit-based targets eg for neuromodulation treatments for AD-MDD which is a large but under-served treatment resistant group
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
True
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| R01MH132565 | NIH | None | httpsreporternihgovquickSearchR01MH132565 |