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

Inclusion criteria

• All subjects:
• Female or male sex assigned at birth;
• 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