Frontal Stimulation to Modulate Threat Sensitivity in Anxious Depression

Completed · Not applicable · Has a placebo group

Conditions studied: Depression, Anxiety and Fear

In brief

Over 50% of patients with major depressive disorder (MDD) do not respond to initial treatment and relapse is common. In particular, comorbid depression and anxiety disorders are associated with more treatment resistance. Thus, there is a great need for novel, more targeted treatments. Transcranial direct current stimulation (tDCS) is a novel intervention that can be used to causally target neural excitability and plasticity in brain regions/circuits implicated in regulating mood and anxiety and emerging evidence suggests that it reduces threat sensitivity. Here the investigators propose to use tDCS to target threat sensitivity as a core symptom of anxious depression to determine if the investigators can engage the neural circuits that are treatment targets. Following the administration of a single dose of anxiolytic or antidepressant treatment, early changes in emotional processing have been observed in healthy people and clinical groups. Among patients, acute cognitive effects - such as a reduction in threat sensitivity - have been shown to predict response to drug and behavioral treatments. Functional magnetic resonance imaging (fMRI) studies have confirmed hyperactive amygdala and/or hypoactive prefrontal activity in patients, indicating an imbalance of activity within this cortico-limbic circuit that sub-serves threat identification (amygdala) and top-down control (prefrontal). Specifically, treatments aiming to remediate prefrontal/ amygdala dysfunction could be a critical target in patients exhibiting these deficits. Several clinical trials have shown that administration of frontal cortex tDCS is a potentially effective treatment for MDD. However, underlying mechanisms of action are unclear. To meet this gap, the investigators propose an experimental medicine study (target identification and initial target engagement paths) where 141 volunteers with anxious MDD will be randomized to receive a single session of active or sham tDCS in a parallel design. Threat sensitivity will be measured using task and resting state fMRI and potentiated startle electrophysiology. Preliminary data suggest reductions in behavioral threat sensitivity from a single session of frontal tDCS. This was followed up with an fMRI study which found that a single session of active vs sham frontal tDCS reduced amygdala response to fearful faces whilst simultaneously increasing frontal attentional control signals. This provides evidence that modulating activity in the frontal cortex inhibits amygdala response to threat, highlighting a potential neural mechanism for the behavioral reduction in threat sensitivity. In addition, this offers initial mechanistic insights into the efficacy of tDCS in clinical trials for the treatment of MDD and anxiety disorders, suggesting that threat sensitivity may be a suitable cognitive target. The current proposal builds on this to establish acute effects of frontal tDCS on amygdala response to threat (primary aim), frontoparietal response to threat (secondary aim), startle response under threat (secondary aim) and approach-avoidance-conflict (exploratory aim). The ultimate aim is to apply these multi-level acute findings to mechanistic clinical trials of tDCS, to test their prediction of treatment response (full model path) and improve patient outcomes.

Key facts

Study ID: NCT04948944
Run by: Laureate Institute for Brain Research, Inc.
People needed: 141
Starts: 2021-04-13
Expected to finish: 2023-10-26
Last updated by the study team: 2023-11-14

Who can join

Age: 18 and older, up to 65. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

Current major depressive episode assessed by clinician administered MINI;
Minimum score of 8 on OASIS anxiety scale;
Normal or corrected to normal vision/hearing, as protocol elements may not be valid otherwise;
Fluent English speaker, capable of providing written informed consent

You may not qualify if…

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 participant to participate or potentially confound the study results;
History of moderate or severe traumatic brain injury, as assessed by the Tulsa Head Injury Screen (THIS) questionnaire;
Family history of psychotic or bipolar disorder;
Current diagnosis of eating disorder or obsessive-compulsive disorder;
Current use of medications with major effects on the fMRI hemodynamic response (e.g., methylphenidate, acetazolamide, excessive caffeine intake > 1000 mg/day);
Moderate or severe current substance use disorder according to DSM 5 criteria, assessed via MINI;
Drug or alcohol intoxication (based on positive urine test or breathalyzer test at screen or baseline) or reported acute alcohol or drug withdrawal;
Has a risk of suicide according to the Investigator's clinical judgment or per Columbia-Suicide Severity Rating Scale (C-SSRS), 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/Baseline;
MRI or tDCS 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;
History of highly irritable skin and/or contact dermatitis that affects skin integrity of the scalp;
Any participant judged by the Investigator to be inappropriate for the study.

Where it is running

Laureate Institute for Brain Research — Tulsa, Oklahoma, United States

Full record on ClinicalTrials.gov

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