Processes and Circuitry Underlying Threat Sensitivity as a Treatment Target for Co-morbid Anxiety and Depression
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| ClinicalTrials.gov Identifier: NCT06004115 |
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Recruitment Status :
Recruiting
First Posted : August 22, 2023
Last Update Posted : November 15, 2023
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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?
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Depression, Anxiety Fear Depression Anxiety and Fear Anxiety Disorders Anxious Depression | Drug: Lorazepam Other: Placebo | Phase 4 |
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| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 165 participants |
| Allocation: | Randomized |
| Intervention Model: | Crossover Assignment |
| Intervention Model Description: | double blind crossover design |
| Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
| Masking Description: | placebo preparation by the pharmacy |
| Primary Purpose: | Basic Science |
| Official Title: | Processes and Circuitry Underlying Threat Sensitivity as a Treatment Target for Co-morbid Anxiety and Depression |
| Actual Study Start Date : | November 8, 2023 |
| Estimated Primary Completion Date : | April 30, 2027 |
| Estimated Study Completion Date : | April 30, 2027 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Lorazepam
Participants will receive a single 1mg dose of Lorazepam, to be taken orally under registered nurse (RN) supervision
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Drug: Lorazepam
1mg of Lorazepam will be prepared by pharmacy (Barnes, Tulsa) in capsule form
Other Names:
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Placebo Comparator: Placebo
Participants will receive a single dose of placebo, to be taken orally under RN supervision
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Other: Placebo
placebo will be prepared by pharmacy (Barnes, Tulsa) in capsule form |
- Eyeblink startle magnitude under threat in AD-MDD compared to MDD. [ Time Frame: 1-2 hours after single session placebo administration, an average of 1-5 weeks after enrollment (placebo could be session 1 or session 2) ]Difference in magnitude of eyeblink startle response under threat of predictable and unpredictable shock conditions compared to neutral condition in the Neutral, Predictable, Unpredictable (NPU) Threat Task measured with electromyography. Comparing the AD-MDD group to the MDD group.
- Magnitude of blood oxygenated level dependent (BOLD) response to threat in AD-MDD compared to MDD. [ Time Frame: 1-2 hours after single session placebo administration, an average of 1-5 weeks after enrollment (placebo could be session 1 or session 2) ]Magnitude of hippocampal-vmPFC-amygdala and periaqueductal grey/insula blood oxygenated level dependent (BOLD) responses to fast and slow threat compared to a no threat condition in the Flight Initiation Distance (FID) Task, measured with functional magnetic resonance imaging (fMRI). Comparing the AD-MDD group to the MDD group.
- The effect of Lorazepam on eyeblink startle magnitude and BOLD response to threat in AD-MDD compared to MDD [ Time Frame: 1-2 hours after single session drug administration, after both Lorazepam and sessions have been completed, an average of 5 weeks after enrollment ]
Comparing the effects of Lorazepam to placebo (within subject) and AD-MDD to MDD (between subject) on the magnitude of eyeblink startle response under threat of predictable and unpredictable shock conditions compared to neutral condition in the NPU Threat Task measured with EMG.
Comparing the effects of Lorazepam to placebo (within subject) and AD-MDD to MDD (between subject) on the magnitude of hippocampal-vmPFC-amygdala and periaqueductal grey/insula blood oxygenated level dependent (BOLD) responses to fast and slow threat compared to a no threat condition in the Flight Initiation Distance Task, measured with fMRI.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 18 Years to 65 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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 administered MINI;
- Minimum score of 60 on the Patient Recorded Outcomes Measurement Information System (PROMIS) Depression scale
AD and AD-MDD subjects:
- Current anxiety disorder (generalized anxiety disorder, panic disorder, agoraphobia and social phobia) assessed by clinician administered MINI;
- Minimum score of 60 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 (TBI), 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 the Laureate Institute for Brain Research (LIBR) but also assessed on a case-by-case basis. Individuals who are currently on medication [antidepressants such as selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), serotonin and norepinephrine reuptake inhibitors (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 the Diagnostic and Statistical Manual of Mental Disorders (DSM 5);
- Drug or alcohol intoxication [based on positive urine toxicology (UTOX) or breathalyzer test at study session] or reported alcohol/drug withdrawal;
- 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 MINI) or past (self-reported) anxiety disorder;
- Score of > 60 on PROMIS Anxiety Scale
AD subjects:
- Current (assessed by MINI) or past (self-reported) major depressive episode;
- Score of > 55 on PROMIS Depression scale
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT06004115
| Contact: Maria Ironside, DPhil | 16174175065 | mironside@laureateinstitute.org |
| United States, Oklahoma | |
| Laureate Institute for Brain Research | Recruiting |
| Tulsa, Oklahoma, United States, 74136 | |
| Contact: Maria A Ironside, DPhil 617-417-5065 mironside@laureateinstitute.org | |
| Principal Investigator: Maria Ironside, DPhil | |
| Principal Investigator: | Maria Ironside, DPhil | Laureate Institute for Brain Research |
| Responsible Party: | Laureate Institute for Brain Research, Inc. |
| ClinicalTrials.gov Identifier: | NCT06004115 |
| Other Study ID Numbers: |
2022-009 R01MH132565 ( U.S. NIH Grant/Contract ) |
| First Posted: | August 22, 2023 Key Record Dates |
| Last Update Posted: | November 15, 2023 |
| Last Verified: | November 2023 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
| Product Manufactured in and Exported from the U.S.: | Yes |
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depression anxiety fMRI threat sensitivity |
flight initiation distance startle reflex benzodiazepine |
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Hypersensitivity Depression Depressive Disorder Anxiety Disorders Behavioral Symptoms Mood Disorders Mental Disorders Immune System Diseases Lorazepam Anticonvulsants Antiemetics Autonomic Agents |
Peripheral Nervous System Agents Physiological Effects of Drugs Gastrointestinal Agents Hypnotics and Sedatives Central Nervous System Depressants Anti-Anxiety Agents Tranquilizing Agents Psychotropic Drugs GABA Modulators GABA Agents Neurotransmitter Agents Molecular Mechanisms of Pharmacological Action |