Glutamatergic Modulators for Rapid and Sustained Antidepressant Effect

National Institute Of Mental Health

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Abstract

Our results indicate that the glutamatergic system is involved in the mechanism of action of rapid antidepressant response. This system may also be a feasible target for developing treatments that have rapid and robust efficacy in individuals with treatment-resistant depression (TRD) and/or suicidal thoughts. Prior studies from our laboratory helped establish that the glutamatergic modulator ketamine results in rapid, robust, and relatively sustained antidepressant, anti-suicidal, and anti-anhedonic effects. Response to ketamine occurs within 2 hours and lasts approximately 1 week. Study: Predictors and neural correlates of antidepressant response to ketamine: protocols 04-M-0222 (NCT00088699), 17-M-0060 (NCT03065335), and 19-M-0107 (NCT03973268). OBJECTIVE: To identify the neural correlates and cellular and molecular targets of rapid antidepressant response to the NMDA receptor antagonist ketamine in individuals with major depressive disorder (MDD). AIMS: 1) to examine ketamine’s anti-suicidal effects; 2) to examine correlates of antidepressant response to ketamine in both MDD and bipolar disorder and include these data/outcome measures: clinical, imaging (MRI/MRS), electrophysiological (MEG, 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 compared to placebo administered over 40 minutes; and 4) to understand the involvement of AMPA receptors in antidepressant response to ketamine. 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: Study 1: Ketamine's influence on magnetoencephalography (MEG) patterns during a working memory task in treatment-resistant depression (TRD) This study explored ketamine's influence on working memory, attention, and concentration and studied MEG patterns during a working memory task in individuals with TRD. Twenty-one individuals with TRD (14 with bipolar disorder, 7 with major depressive disorder) received ketamine and placebo infusions in a crossover trial. Behavioral and MEG data were collected at baseline and 6 to 9 hours after ketamine and placebo (normal saline) infusion. Working memory, attention, and concentration were assessed with the N-back task. We found that ketamine significantly improved depressive symptoms but had no effect on cognitive performance. MEG revealed increased gamma power in the parieto-occipital junction coupled with decreased gamma power in the posterior superior temporal sulcus and inferior frontal gyrus after ketamine administration compared to placebo. Thus, despite robust antidepressant effects, ketamine did not affect working memory, attention, or concentration. Nevertheless, the distinct gamma power changes observed in brain regions linked to attention and working memory highlight the need to further explore the neurobiological mechanisms underlying ketamine's cognitive effects in TRD. Study 2: Rapid eye movement (REM) density predicts rapid antidepressant response to ketamine in individuals with treatment-resistant depression (TRD) Abnormalities during REM sleep contribute to the pathophysiology of major depressive disorder (MDD), but few studies have explored the relationship between REM sleep and TRD. In MDD, REM sleep abnormalities often manifest as alterations in total night REM Density (RD), RD in the first REM period (RD1), and REM Latency (RL). Among these, RD1 is notably considered a potential endophenotype of depression. This study compared REM sleep markers between 63 drug-free individuals with TRD (39F/24M) and 41 healthy volunteers (25F/16M). It also investigated the effects of ketamine on these REM sleep variables. Specifically, the study investigated whether RD1 could predict antidepressant response to ketamine. TRD participants showed higher RD1 and shorter RL at baseline compared to HVs, as assessed via non-parametric tests, but Total Night RD did not differ between the two groups. Ketamine treatment decreased RD1 in TRD participants but did not affect Total Night RD or RL. As assessed via the Support Vector Machine (SVM) algorithm, baseline RD1 level moderately predicted antidepressant response to ketamine versus non-response, wherein TRD participants with higher baseline RD1 were more likely to respond to ketamine. These results underscore the utility of RD1 for identifying individuals most likely to benefit from ketamine treatment, enabling more targeted and effective therapeutic strategies. Study 3: A Phase 1 assessment of the safety, tolerability, pharmacokinetics, and pharmacodynamics of (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) in healthy volunteers Despite ketamine’s substantial antidepressant effects, its dissociative side effects and misuse potential limit its expanded use. In multiple preclinical models, the ketamine metabolite (2R,6R)-HNK was found to maintain antidepressant and analgesic activity but lack anesthetic and dissociative activity. This Phase 1 study (NCT04711005) evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of (2R,6R)-HNK in healthy volunteers. A six-level single-ascending dose (SAD) (0.1-4 mg/kg) and a two-level multiple ascending dose (MAD) (1 and 2 mg/kg) study were performed using a 40-minute IV administration, emulating the common practice for ketamine administration for depression. Safety assessments showed that (2R,6R)-HNK had a minimal adverse event profile, and no serious adverse events were noted at any of the doses examined. Evaluations of dissociation and sedation demonstrated that (2R,6R)-HNK had no anesthetic or dissociative characteristics at the doses examined. Pharmacokinetic parameters were measured in both the SAD and MAD studies and exhibited dose-proportional increases in exposure. Quantitative EEG measurements collected as a pharmacodynamic parameter based on preclinical findings and ketamine's established effect on gamma-power oscillations demonstrated increased gamma power in some participants at the lower/mid-range doses examined. CSF examination confirmed (2R,6R)-HNK exposure within the CNS. Collectively, these data demonstrate that (2R,6R)-HNK was well tolerated, and its acceptable pharmacokinetic profile and promising pharmacodynamic outcomes support progression of (2R,6R)-HNK studies into Phase 2. Study 4: Assessment of complement cascade components in patients with major depressive disorder Recent evidence suggests that ketamine has immune regulatory functions. The complement system is an important component of the innate immune response and plays a key role in synaptic plasticity. An increase in complement component 3 (C3) expression was previously found in the prefrontal cortex of individuals with depression. Given the complement system's role in depression and ketamine's potential anti-inflammatory properties, there is reason to suspect overlap between the complement system and ketamine's mechanism of action. This post-hoc study analyzed data from 39 individuals with MDD and 25 healthy volunteers who previously participated in a randomized, double-blind trial comparing intravenous ketamine (0.5 mg/kg) to placebo. Blood was obtained at baseline, 230 minutes, Day 1, and Day 3. Plasma levels of C3a and C4a, two key complement proteins implicated in synaptic plasticity, were determined by enzyme-linked immunosorbent assay (ELISA). Linear mixed models were used to test baseline sex differences, whether differences varied by diagnosis, and ketamine's effects (versus placebo) on C3a and C4a levels in the MDD group only. A significant diagnosis-by-sex interaction was observed for C3a but not C4a levels. Drug effects on C3a and C4a levels did not vary over time. These results suggest that treatment strategies targeting the complement pathway may yield fruitful insights and/or advances in treatment options for MDD.