Neurobiology and Target Validation of Novel Therapeutic Agents in Mood Disorders

National Institute Of Mental Health

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Linked publications, trials & patents

Abstract

This Report involves work collected under protocols 01-M-0254 (NCT00024635); 08-M-0196 (NCT00759395); 08-M-0150 (NCT00697268); 14-M-0085 (NCT02122562); 07-M-0021 (NCT00397111); 14-M-0041 (NCT02049385); 07-M-0152 (NCT00472576), 09-M-N230; 15-M-0151 (NCT 02484456), 15-M-0188 (NCT02543983), 19-M-0107 (NCT03973268), and 000101-M (NCT04821271). Results this past year: 1. Brain Correlates of Suicide Attempt in 18,925 Participants Across 18 International Cohorts. In a data-sharing project, ENIGMA-MDD, pooled data from 18 international cohorts with neuroimaging and clinical measurements in 18,925 participants (12,477 healthy control subjects and 6448 people with depression, of whom 694 had attempted suicide) were analyzed. We identified 25 regions of interest with statistically significant differences between groups. Post hoc examinations identified neuroimaging markers associated with suicide attempt including smaller volumes of the left and right thalamus and the right pallidum and lower surface area of the left inferior parietal lobe. This study addresses the lack of replicability and consistency in several previously published neuroimaging studies of suicide attempt and further demonstrates the need for well-powered samples and collaborative efforts. Our results highlight the potential involvement of the thalamus, a structure viewed historically as a passive gateway in the brain, and the pallidum, a region linked to reward response and positive affect. 2. Network Changes in Insula and Amygdala Connectivity Accompany Implicit Suicidal Associations. Limited knowledge exists regarding the neurobiology of suicidal thoughts, given that there are currently no direct probes of the suicidal state. This pilot study used magnetoencephalography (MEG) to evaluate correlates of the implicit association between the self and death compared to the self and life as objective markers of suicide risk. Healthy volunteers (HVs; n=21) completed a modified version of the Suicide Implicit Association Task (S-IAT) during MEG scanning. Gamma power-which is considered a proxy measure of excitation-inhibition balance-was directly compared in the self-death/self-life contrast. As a proof-of-concept, the ability of dynamic causal modeling to categorize HVs versus four individuals with recent suicide crisis (SC) was evaluated. In HVs, enhanced gamma power in both amygdala and anterior insula were found for the self-death compared with self-life contrast. In addition, connectivity estimates between early visual cortex, anterior insula, and amygdala correctly categorized SC participants with 77% to 82% sensitivity and 80% to 85% specificity. These findings, which implicate network-level changes in salience network and amygdala connectivity in mediating suicidal associations, require further replication in larger samples. 3. Randomized Controlled Trial of Riluzole Augmentation for Posttraumatic Stress Disorder: Efficacy of a Glutamatergic Modulator for Antidepressant-Resistant Symptoms. Current pharmacologic treatments for posttraumatic stress disorder (PTSD) have shown limited efficacy. The current study investigated the efficacy of glutamate modulation with riluzole augmentation for combat-related PTSD symptoms resistant to treatment with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). A randomized, double-blind, placebo-controlled, parallel trial was conducted at Walter Reed National Military Medical Center and Syracuse VA Medical Center. Veterans and active duty service members with combat-related PTSD who were not responsive to SSRI or SNRI pharmacotherapy were randomized to 8-week augmentation with a starting dose of 100 mg/d of riluzole (n = 36) or placebo (n = 38) and assessed weekly for PTSD symptoms, anxiety, depression, disability, and side effects. There was clinically significant within-group improvement in overall PTSD symptoms in both groups, with a greater mean decrease in scores in the riluzole group than in the placebo group. Exploratory analyses of PTSD symptom clusters showed significantly greater improvement on hyperarousal symptoms in the riluzole group. Riluzole augmentation was not superior to placebo on change in depression, anxiety, or disability severity. Additional investigation of the mechanism of the efficacy of riluzole for hyperarousal symptoms is warranted.