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

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 1.5 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.

An individual must meet the following criteria to be considered eligible to participate in the study:

Inclusion criteria

All subjects:

• Female or male sex assigned at birth;
• Age 18-65;
• Normal or corrected to normal vision/hearing, as protocol elements may not be valid otherwise;
• Fluent English speaker, capable of providing written informed consent

MDD and AD-MDD subjects:

• Current major depressive episode assessed by clinician with guidance from the MINI;
• Minimum score of 55 on PROMIS Depression scale

AD and AD-MDD subjects:

• Current anxiety disorder (generalized anxiety disorder, panic disorder, agoraphobia and social phobia) assessed by clinician with guidance from the MINI;
• Minimum score of 55 on PROMIS Anxiety Scale

Exclusion criteria

All subjects:

• Has uncontrolled, clinically significant neurologic (including seizure disorders): cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, immunologic, endocrine disease, or psychiatric disorder, or other abnormality, which may impact the ability of the subject to participate or potentially confound the study results;
• Reported body mass index (BMI) > 40;
• History of moderate or severe traumatic brain injury, as assessed by a TBI questionnaire;
• History of eating disorder or obsessive-compulsive disorder, schizophrenia, schizo-affective disorder, bipolar disorder or any sign of psychosis;
• Current post-traumatic stress disorder (PTSD) diagnosis (although history of trauma is allowed);
• Current use of medications with major effects on brain function or the fMRI hemodynamic response (e.g., methylphenidate, acetazolamide, excessive caffeine intake > 1000 mg/day) following an initial list compiled by LIBR but also assessed on a case-by-case basis. Individuals who are currently on medication (antidepressants such as SSRIs, TCAs, SNRIs, and Bupropion) and who have not undergone dose or medication changes over the past 6 weeks will be allowed to participate;
• Current benzodiazepine or opiate use;
• Moderate to severe current substance use disorder, defined as 5 or more symptoms of the criteria for Substance Use Disorder according to DSM 5;
• Drug or alcohol intoxication (based on positive UTOX or breathalyzer test at screening or study session) or reported alcohol/drug withdrawal, last cannabis use must be >48 hours prior to study session;
• Has a risk of suicide according to the Investigator's clinical judgement or per Columbia-Suicide Severity Rating Scale (C-SSRS) or equivalent PhenX instrument, the subject scores "yes" on items 4 or 5 in the Suicidal Ideation section with referent to a 30-day period prior to Screening/Baseline or the subject has had one or more suicidal attempts with reference to a 2-year period prior to Screening;
• MRI contraindications;
• Is pregnant or lactating or intending to become pregnant before, during, or within 12 weeks after participating in this study; or intending to donate ova during this time-period;
• Any subject judged by the Investigator to be inappropriate for the study.

MDD subjects:

• Current (assessed by clinician with guidance from the MINI) anxiety disorder;
• Score of > 60 on PROMIS Anxiety Scale

AD subjects:

• Current or past recurrent major depressive episodes assessed by clinician with guidance from the MINI;
• Score of > 60 on PROMIS Depression scale