Glutamatergic Modulators for Rapid and Sustained Antidepressant Effect

点击翻译按钮获取中文摘要

Our results indicate that the glutamatergic system is involved in the mechanism of action of rapid antidepressant response. In addition, this system may be a feasible target for developing treatments that have rapid and robust efficacy in individuals who have treatment-resistant depression and suicidal thoughts. We found that the glutamatergic modulator ketamine resulted in rapid, robust and relatively sustained antidepressant, antisuicidal, and antianhedonic effects. Response with ketamine occurred within 2 hours and lasted approximately 1 week. Study: (Biomarkers of rapid response in major depressive disorder): protocols 04-M-0222 (NCT00088699), 17-M-0060 (NCT03065335), and 19-M-0107 (NCT 03973268). OBJECTIVE: To identify the neural correlates and cellular and molecular targets of rapid antidepressant response to the NMDA antagonist ketamine in subjects with major depressive disorder. Aims are 1) to examine the antisuicidal effects of ketamine, and 2) to examine correlates of antidepressant response to ketamine in both major depressive disorder and bipolar disorder and include these data/outcome measures: clinical (e.g., family history), imaging (magnetic resonance imaging/spectroscopy), electrophysiological (magnetoencephalography MEG, electroencephalography EEG), neuropsychological, and biochemical (e.g., genetics, microRNA, BDNF, metabolomics), 3) To demonstrate more robust neuropharmacodynamic effects measured by neuropharmacodynamic imaging (fMRI+EEG and MEG) of ketamine 0.5 mg/kg as compared to placebo administered over 40 minutes, and 4) To understand the involvement of AMPA receptors in ketamines antidepressant response. Secondary aims: To determine if increases in synaptic plasticity, using electrophysiological measures in response to TMS and in association with sleep (i.e., slow wave sleep EEG activity) are associated with better antidepressant response. Results in the past year: 1. The Effect of Ketamine on Electrophysiological Connectivity in Major Depressive Disorder: Major depressive disorder (MDD) is frequently disabling. Only about 30% of patients respond to a first-line antidepressant treatment, and around 30% of patients are classified as "treatment-resistant" after failing to respond to multiple adequate trials. While most antidepressants target monoaminergic targets, ketamine is an N-methyl-D-aspartate (NMDA) antagonist that has shown rapid antidepressant effects when delivered intravenously or intranasally. While there is evidence that ketamine exerts its effects via enhanced -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) throughput, its mechanism for relieving depressive symptoms is largely unknown. This study acquired resting-state magnetoencephalography recordings after both ketamine and placebo infusions and investigated functional connectivity using a multilayer amplitude-amplitude correlation technique spanning the canonical frequency bands24 healthy volunteers (HVs) and 27 unmedicated participants with MDD took part in a double-blind, placebo-controlled, crossover trial of 0.5 mg/kg IV ketamine. The results indicated widespread ketamine-induced reductions in connectivity in the alpha and beta bands that did not correlate with magnitude of antidepressant response. In contrast, the magnitude of ketamine's antidepressant effects in MDD participants was associated with cross-frequency connectivity for delta-alpha and delta-gamma bands, with HVs and ketamine non-responders showing connectivity decreases post-ketamine and ketamine responders demonstrating small increases in connectivity. These results may indicate functional subtypes of MDD and suggest that neural responses to ketamine are different between responders and non-responders. 2. Ketamine metabolites, clinical response, and gamma power in a randomized, placebo-controlled, crossover trial for treatment-resistant major depression: A single, subanesthetic dose of (R,S)-ketamine (ketamine) exerts rapid and robust antidepressant effects. We previously reported that (2S,6S;2R,6R)-hydroxynorketamine (HNK) had antidepressant effects in rodents, and that (2R,6R)-HNK increased cortical electroencephalographic gamma power. This study examined the relationship between ketamine metabolites, clinical response, psychotomimetic symptoms, and gamma power changes in 34 individuals (ages 18-65) with treatment-resistant depression who received a single ketamine infusion (0.5 mg/kg) over 40 min. Plasma concentrations of ketamine, norketamine, and HNKs were measured at 40, 80, 120, and 230 min and at 1, 2, and 3 days post-infusion. Linear mixed models evaluated ketamine metabolites as mediators of antidepressant and psychotomimetic effects and their relationship to resting-state whole-brain magnetoencephalography (MEG) gamma power 6-9 h post-infusion. We found that ketamine concentration positively predicted distal antidepressant response at Day 11 post-infusion, and an inverse relationship was observed between (2S,6S;2R,6R)-HNK concentration and antidepressant response at three and seven days post-infusion. Next, ketamine increased (2S,6S;2R,6R)-HNK maximum observed concentration (Cmax) was associated with increased MEG gamma power. 3.Evaluating global brain connectivity as an imaging marker for depression: influence of preprocessing strategies and placebo-controlled ketamine treatment: Major depressive disorder (MDD) is associated with altered global brain connectivity (GBC), as assessed via resting-state functional magnetic resonance imaging (rsfMRI). Previous studies found that antidepressant treatment with ketamine normalized aberrant GBC changes in the prefrontal and cingulate cortices, warranting further investigations of GBC as a putative imaging marker. These results were obtained via global signal regression (GSR). GBC was analyzed in 28 participants with MDD and 22 healthy controls (HCs) at baseline, post-placebo, and post-ketamine. Reduced GBC was observed in individuals with MDD only at baseline in the anterior and medial cingulate cortices, as well as in the prefrontal cortex only after regressing the global signal. Ketamine had no effect compared to baseline or placebo in either group in any pipeline. These results concur with several studies that used GSR to study GBC. Further investigations are warranted into disease-specific components of global fMRI signals that may drive these results and of GBCr as a potential imaging marker in MDD. 4. Ketamine on typical and atypical depressive symptoms: This study examined the effects of a single intravenous dose of ketamine on general depressive symptoms (measured using the Montgomery-Asberg Depression Rating Scale (MADRS), typical/melancholic symptoms (measured using the MADRS5), and atypical symptoms (measured using the Scale for Atypical Symptoms (SAS)). Data were from 68 participants with treatment-resistant major depressive disorder (MDD) or bipolar. Effect sizes were greater for typical/melancholic than atypical symptoms at Day 1 postinfusion. Ketamine appears to effectively treat both the typical/melancholic and atypical symptoms of depression, but may have early preferential effects for the former. 5. The Mental Health Impact of COVID-19 Pandemic on Healthcare Workers Protocol (P205022: PI: Zarate, Carlos) completed initial baseline data collection and one month follow-up, and will re-contact participants for 6 month follow-up ratings later this year. In total, over 900 HCWs completed ratings related to COVID exposure, distress, resilience and mental health symptoms including PTSD. We are currently in the process of writing the first paper, which will examine the role of COVID-19 exposure and distress in HCWs.