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?
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
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;
Crossover
Lorazepam
Drug1mg of Lorazepam will be prepared by pharmacy (Barnes, Tulsa) in capsule form
Placebo
Other interventionplacebo will be prepared by pharmacy (Barnes, Tulsa) in capsule form
Eyeblink startle magnitude under threat in AD-MDD compared to MDD.
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.
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
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.
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Laureate Institute for Brain Research, Inc.
Lead sponsor
National Institute of Mental Health (NIMH)
Collaborator
California Institute of Technology
Collaborator
