Jessica R. Gilbert

Background: Like ketamine, group II metabotropic glutamate receptor (mGluR2/3) antagonists increase glutamate release and monoaminergic signaling, promote synaptic plasticity, and show antidepressant-related activity in preclinical models. A recent phase I trial of the orthosteric mGluR2/3 antagonist prodrug TS-161 established its safety, tolerability, and pharmacokinetic profile. Methods: This phase IIa randomized, placebo-controlled, double-blind, crossover, proof-of-concept, single-site trial was designed to evaluate the antidepressant effects of TS-161. Eleven unmedicated adults with treatment-resistant depression received either oral TS-161 (50 to 100 mg daily) or a placebo for 3 weeks before crossing over to the other condition. The study was halted early due to low recruitment. Results: Adverse events were mild and consistent with the prior phase I study. Linear mixed models using drug×time interaction to estimate mean Montgomery-Åsberg Depression Rating Scale scores per treatment identified no significant difference between treatment conditions at any timepoint, including the primary endpoint, day 21 ( P =0.91). One of the 11 participants responded to TS-161 by day 7 (vs. 0/9 receiving placebo); no participants achieved remission. Magnetic resonance spectroscopy suggested a qualitative trend for increased glutamate metabolite values, and TS-161 increased gamma power during magnetoencephalography relative to baseline and placebo (p _FDR P =0.055). No advantages were seen in secondary clinical or cognitive outcomes. Conclusions: The findings suggest potential central nervous system engagement through proxy biomarkers and increased glutamatergic tone, but this did not translate to clinical improvement.

Depression and treatment-resistant depression (TRD) are significant public health issues, but the associated network-level neurobiological mechanisms remain poorly understood. This study used magnetoencephalography (MEG) to identify altered resting-state connectivity within the default mode (DMN), executive control (ECN), salience (SN), dorsal attention (DAN), motor (MN), and visual (VN) networks as potential biomarkers of depression and treatment resistance. The study recruited 168 participants (80 healthy volunteers (HVs) and 88 currently experiencing a major depressive episode (74 with TRD and 14 without TRD (noTRD))). Data Integration Analysis for Biomarker Discovery using Latent Variable Approaches for Omics Studies (DIABLO) was used to differentiate the depression, TRD, and HV subgroups and identify neural markers of depression and treatment resistance. For differentiating the depression and HV groups, the triple network model (area under the receiver operating curve (AUROC): 0.759- 0.787)—which includes the DMN, ECN, and SN—outperformed the six-network model (AUROC: 0.747-0.762) across different bandwidths. For differentiating the TRD and HV groups, the triple network model demonstrated reasonable prediction across different bandwidths (AUROC: 0.737-0.807); potential within-network connectivity differences distinguished those with TRD from HVs, especially DMN within-network connectivity between the inferior parietal lobule and precuneus in the beta band ( FDR-corrected p <.05). Hyperconnectivity within the SN (superior parietal lobule and frontal operculum in the alpha band) and DMN (inferior parietal lobule and lateral prefrontal cortex in the beta band) was associated with number of treatment failures (ps<.05). These findings highlight key brain regions and connectivity patterns, advancing our understanding of neural mechanisms underlying depression and treatment resistance.

Despite distinct receptor targets, both ketamine and serotonergic psychedelics produce a rapid clinical response and share biological signatures that suggest convergence on common downstream molecular mediators. To identify shared biomarkers of rapid antidepressant response, this study integrated CSF proteomics from healthy volunteers (HVs) who received intravenous ketamine with transcriptomic analyses from induced pluripotent stem cells (iPSCs) derived from participants with treatment-resistant depression (TRD) and HVs; iPSCs were treated with ketamine, its metabolite (2 R ,6 R )-hydroxynorketamine, lysergic acid diethylamide (LSD), or psilocybin. Multimodal clinical characterization (transcriptomics ( n = 16 TRD; 11 HV), magnetoencephalography (MEG) ( n = 30 TRD; 25 HV), and plasma cytokines ( n = 39 TRD; 25 HV) were also performed on TRD and HV participants who received a single dose of intravenous ketamine (0.5 mg/kg) or placebo. Conserved immune pathways were identified across CSF and iPSC neurons with interleukin-15 (IL)-15 and monocyte chemoattractant protein-1 (MCP-1) emerging as key regulatory hubs. Transcriptomically, in whole blood, ketamine responders exhibited decreased IL-15 and elevated B-cell signaling pathways at baseline that were reversed post-treatment. At the protein level, plasma IL-7 levels (primary B-cell driver) correlated with baseline MEG gamma power, reaching brain-wide significance across all participants (main effect p _FDR < 0.05). The association was most pronounced in the TRD participants across subcortical regions (diagnosis x IL-7 p _FDR < 10 ^-14 ). Post-ketamine, the TRD IL-7–gamma relationship inverted, paralleling widespread gamma power reductions throughout default-mode network regions (session x IL-7 p _clc < 0.05). In mixed-effects models, cytokine ratios linked to IL-7/IL-15 signaling predicted antidepressant response (IL-4/interferon gamma (IFN-γ) p _FDR < 0.041) and non-response (MCP-1/IL-7 p _FDR < 0.009), suggesting that rebalancing within the IL-7/IL-15 axis may contribute to therapeutic efficacy. Clinicaltrials.gov identifier: NCT00088699; NCT02484456.

A core function of episodic memory is to distinguish between overlapping experiences by converting similar inputs into distinct, non-overlapping representations, a process termed pattern separation. While anatomical models emphasize the role of specific hippocampal subfields, particularly the dentate gyrus, CA3, and CA1, less is known about how these computations unfold over time and influence memory-based decisions. Here, we use source-localized magnetoencephalography and computational modeling to examine how theta oscillations from the hippocampus as a whole are related to evidence accumulation during mnemonic discrimination. Participants performed the Mnemonic Similarity Task, in which they classified Repeat, Lure, and Foil images as “Old,” “Similar,” or “New.” Event-related spectral and source activity confirmed reliable hippocampal engagement during the task despite its anatomical depth. We fit a hierarchical Linear Ballistic Accumulator model to behavioral data, estimating trial-by-trial drift rates as a latent index of mnemonic evidence accumulation, and examined whether hippocampal theta power predicted these dynamics. Left hippocampal theta was negatively associated with drift toward “New” responses on lure trials, while right hippocampal theta was positively associated with drift toward “Similar” responses on foil trials. These effects suggest that hippocampal theta selectively indexes partial-match sensitivity, with consequences that are beneficial or costly depending on whether the stimulus has a encoded memory counterpart. However, direct comparisons between hemispheres did not yield credible differences. These findings offer preliminary evidence that trial-level hippocampal theta fluctuations are related to the dynamics of memory-guided decision-making, and demonstrate the feasibility of linking deep-source MEG recordings to computational models of evidence accumulation.

Introduction: Treatment‐resistant depression (TRD) remains a challenge, necessitating novel interventions that address associated cognitive deficits. The glutamatergic modulator ketamine exerts rapid antidepressant effects, prompting investigators to assess its impact on cognitive function, specifically working memory. This study explored ketamine's influence on working memory and magnetoencephalography (MEG) patterns during a working memory task in individuals with TRD.Objectives: To examine the effects of ketamine on working memory, attention, and concentration, and to study MEG patterns during a working memory task in individuals with TRD.Methods: 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 h after ketamine and placebo (normal saline) infusion. Working memory, attention, and concentration were assessed with the N‐back task.Results: 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.Conclusions: Despite robust antidepressant effects, ketamine did not affect working memory, attention, or concentration. However, distinct gamma power changes 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. Future research with larger samples, broader cognitive batteries, and repeated ketamine infusions are needed to fully elucidate ketamine's cognitive effects in individuals with TRD.

(R,S)‐Ketamine (ketamine) is a dissociative anesthetic that also possesses analgesic and antidepressant activity. Undesirable dissociative side effects and misuse potential limit expanded use of ketamine in several mental health disorders despite promising clinical activity and intensifying medical need. (2R,6R)‐Hydroxynorketamine (RR‐HNK) is a metabolite of ketamine that lacks anesthetic and dissociative activity but maintains antidepressant and analgesic activity in multiple preclinical models. To enable future assessments in selected human indications, we report the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of RR‐HNK in a Phase 1 study in healthy volunteers (NCT04711005). 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 was performed using a 40‐minute IV administration emulating the common practice for ketamine administration for depression. Safety assessments showed RR‐HNK possessed a minimal adverse event profile and no serious adverse events at all doses examined. Evaluations of dissociation and sedation demonstrated that RR‐HNK did not possess anesthetic or dissociative characteristics in the doses examined. RR‐HNK PK parameters were measured in both the SAD and MAD studies and exhibited dose‐proportional increases in exposure. Quantitative electroencephalography (EEG) measurements collected as a PD parameter based on preclinical findings and ketamine's established effect on gamma‐power oscillations demonstrated increases of gamma power in some participants at the lower/mid‐range doses examined. Cerebrospinal fluid examination confirmed RR‐HNK exposure within the central nervous system (CNS). Collectively, these data demonstrate RR‐HNK is well tolerated with an acceptable PK profile and promising PD outcomes to support the progression into Phase 2.

Aggression and impulsivity are linked to suicidal behaviors, but their relationship to the suicidal crisis remains unclear. This magnetoencephalography (MEG) study investigated the link between aggression, impulsivity, and resting-state MEG power and connectivity. Four risk groups were enrolled: high-risk (HR; n = 14), who had a recent suicidal crisis; lower-risk (LR; n = 41), who had a history of suicide attempts but no suicide attempt or ideation in the past year; clinical control (CC; n = 38), who had anxiety/mood disorders but no suicidal history; and minimal risk (MR; n = 28), who had no psychiatric/suicidal history. No difference in resting-state MEG power was observed between the groups. Individuals in the HR group with high self-reported aggression and impulsivity scores had reduced MEG power in regions responsible for sensory/emotion regulation vs. those in the HR group with low scores. The HR group also showed downregulated bidirectional glutamatergic feedback between the precuneus (PRE) and insula (INS) compared to the LR, CC, and MR groups. High self-reported impulsivity was linked to reduced PRE to INS feedback, whereas high risk-taking impulsivity was linked to upregulated INS to postcentral gyrus (PCG) and PCG to INS feedback. These preliminary findings suggest that glutamatergic-mediated sensory and emotion-regulation processes may function as potential suicide risk markers.