Processes and Circuitry Underlying Threat Sensitivity as a Treatment Target for Co-morbid Anxiety and Depression

Depression Clinical Trial

Official title: Processes and Circuitry Underlying Threat Sensitivity as a Treatment Target for Co-morbid Anxiety and Depression

Status Recruiting

Clinical Trial 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 ~2.5 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 10.5 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?

Clinical Trial 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 reward/salience responding. Thus, AD-MDD may differ from AD through blunted AT/salience (periaqueductal grey/insula 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 (N=50), MDD (N=50), and AD (N=50). After the ~2.5 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 10.5 hours. In a double-blind placebo crossover design, participants will receive a single 1mg dose of Lorazepam/Placebo and complete threat tasks that delineate PT/AT 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-MDD/AD will exhibit higher PT sensitivity (greater APS) than MDD (NPU APS: AD-MDD > MDD; AD > MDD).

Hypothesis 1 B (H1B): AD-MDD/MDD 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 grey/insula 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 (e.g. for neuromodulation treatments) for AD-MDD, which is a large but under-served treatment resistant group. ;

Related Conditions & MeSH terms

• Anxiety and Fear
• Anxiety Disorders
• Anxious Depression
• Depression
• Depression, Anxiety
• Depressive Disorder
• Fear
• Hypersensitivity

• NCT number: NCT06004115
• Study type: Interventional
• Source: Laureate Institute for Brain Research, Inc.
• Contact: Maria Ironside, DPhil
• Phone: 16174175065
• Email: mironside@laureateinstitute.org
• Status: Recruiting
• Phase: Phase 4
• Start date: November 8, 2023
• Completion date: April 30, 2027