This Report involves work collected under protocols 08-M-0196 (NCT00759395); 08-M-0150 (NCT00697268); 14-M-0085 (NCT02122562); 07-M-0021 (NCT00397111); 14-M-0041 (NCT02049385); and 07-M-0152 (NCT00472576), 15-M-0151 (NCT 02484456). Results this past year: 1) The prodrug 4-chlorokynurenine (AV-101) causes ketamine-like antidepressant, but not side effects, by NMDA/glycineB-site inhibition. In preclinical studies, we found 4-Cl-KYN administration resulted in rapid, dose-dependent and persistent antidepressant-like effects following a single treatment. These effects were distinct from our findings with fluoxetine, and similar to ketamine. The antidepressant effects of 4-Cl-KYN were prevented by pre-treatment with glycine or the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzofquinoxaline-2,3-dione (NBQX). 4-Cl-KYN administration was not associated with the rewarding and psychotomimetic effects of ketamine, and did not induce locomotor sensitization or stereotypic behaviors. Our results provide further support for antagonism of the glycineB site for the rapid treatment of treatment-resistant depression. We are now studying this compound in our patients with treatment-resistant major depression in the hopes that it produces rapid antidepressant effects, but without the negative side effects seen with ketamine or other channel blocking NMDA receptor antagonists. 2) We assessed measures of suicidal ideation in clinical trials with rapid-acting antidepressants. This work is important as we need to have rating scales that are able to pick up the effects of rapid acting agents. 3) We demonstrated the reliability of 7T 1 H-MRS measured human prefrontal cortex glutamate, glutamine, and glutathione signals using an adapted echo time optimized PRESS sequence: A between- and within-sessions investigation. Within-session measurements of glutamate, glutamine, and glutathione were on average reliable (ICCs ≥0.7). As anticipated, ICCs for between-session values of glutamate, glutamine, and glutathione were slightly lower but nevertheless reliable (ICC >0.62). The adapted sequence provides good reliability to measure glutamate, glutamine, and glutathione signals. This work is important because it gives us the tools to measure in vivo glutamate changes that should occur with the novel glutamatergic modulators. 4) We found baseline working memory activation deficits in dimensional anxious depression as detected by magnetoencephalography (MEG). Compared to healthy volunteers, patients with anxious depression had significantly reduced desynchronisation (less activation) in the left precuneus, right cuneus, and left insula extending into the inferior and middle frontal cortex during the 2-back condition compared with the 1-back condition of the N-back working memory task, indicating less activation of these neural networks in patients with anxious depression during the condition with the highest level of task demands. This preliminary study suggests that a subset of patients--those with anxious depression--may be driving observed group differences between patients with major depressive disorder and healthy volunteers.
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