Neurobiology and Target Validation of Novel Therapeutic Agents in Mood Disorders

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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); and 07-M-0152 (NCT00472576), 09-M-N230; 15-M-0151 (NCT 02484456), 15-M-0188 (NCT02543983). Results this past year: 1. Antisuicidal response after ketamine infusion is associated with decreased nighttime wakefulness in treatment-resistant depression. In this study, we find a biomarker that predicts who will respond to ketamine and who will not. Here we find that subjects with treatment-resistant depression who have more time awake at later times of the night have more suicidal thinking, and that a single dose of ketamine rapidly eliminates suicidal thinking and restores sleep in depressed patients. The pattern of sleep is no longer different from healthy control subjects. 2. Safety of research into severe and treatment-resistant mood disorders. In this review of 12 years of data of from the intramural program at NIMH, we show that randomized, placebo-controlled drug-free trials in treatment-resistant depression can be performed safely in an inpatient setting. 3. A randomized, placebo-controlled pilot trial of the delta opioid agonist AZD2327 in anxious major depressive disorder. In this double-blind, placebo-controlled pilot study, we show that the delta opioid agonist AZD2327 does not have significant antidepressant property in anxious major depressive disorder. We do find that one of its metabolites appears to have anxiolytic effects. 4. The prodrug 4-chlorokynurenine causes ketamine-like antidepressant, but not side effects, by NMDA/glycineB-site inhibition. This work extends our finding of the rapid antidepressant effects of ketamine. Ketamine modulates the NMDA receptor complex; we believe that such actions are in part responsible for its significant side effects and risk of abuse. We believe that the prodrug 4-chlorokynurenine would more selectively modulate the NMDA receptor complex and thus not result in the liabilities of ketamine (i.e., side effects, risk of abuse). In a series of animal studies we demonstrate the safety of this new compound. A clinical study has begun at the intramural program at NIMH in patients with depression. 5. Reliability of 1H-MRS measured human prefrontal cortex glutamatergic signals at 7 Tesla. We demonstrate the reliability of a new technique for measuring the brain levels of glutamate, believed to be important to rapid antidepressant effects of ketamine. Such technology could help us track the changes in brain glutamate levels before and after ketamine which could help in better understanding antidepressant effects and to develop better treatments. 6. Group differences in MEG-ICA derived resting state networks. We demonstrate using a new technology (magnetoencephalography, MEG), differences in resting state brain networks between patients with depression and healthy controls.