NCT06004115 Processes and Circuitry Underlying Threat Sensitivity as a Treatment Target for Co-morbid Anxiety and Depression

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What to Expect as a Participant

You will actively receive the study intervention — which may be a drug, biologic, device, or procedure.

Phase 4 studies follow an already-approved treatment in real-world conditions to monitor long-term safety and effectiveness.

This trial targets 165 participants in total. It began in 2023-11-08 with a primary completion date of 2027-12-31.

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 \~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 1.5 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?

Eligibility Criteria

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

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