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Abstract The glutamatergic modulator ketamine is associated with changes in sleep, depression, and suicidal ideation (SI). This study sought to evaluate differences in arousal-related sleep metrics between 36 individuals with treatment-resistant major depression (TRD) and 25 healthy volunteers (HVs). It also sought to determine whether ketamine normalizes arousal in individuals with TRD and whether ketamine’s effects on arousal mediate its antidepressant and anti-SI effects. This was a secondary analysis of a biomarker-focused, randomized, double-blind, crossover trial of ketamine (0.5 mg/kg) compared to saline placebo. Polysomnography (PSG) studies were conducted one day before and one day after ketamine/placebo infusions. Sleep arousal was measured using spectral power functions over time including alpha (quiet wakefulness), beta (alert wakefulness), and delta (deep sleep) power, as well as macroarchitecture variables, including wakefulness after sleep onset (WASO), total sleep time (TST), rapid eye movement (REM) latency, and Post-Sleep Onset Sleep Efficiency (PSOSE). At baseline, diagnostic differences in sleep macroarchitecture included lower TST (p = 0.006) and shorter REM latency (p = 0.04) in the TRD versus HV group. Ketamine’s temporal dynamic effects (relative to placebo) in TRD included increased delta power earlier in the night and increased alpha and delta power later in the night. However, there were no significant diagnostic differences in temporal patterns of alpha, beta, or delta power, no ketamine effects on sleep macroarchitecture arousal metrics, and no mediation effects of sleep variables on ketamine’s antidepressant or anti-SI effects. These results highlight the role of sleep-related variables as part of the systemic neurobiological changes initiated after ketamine administration. Clinical Trials Identifier: NCT00088699.

Abstract The hippocampus and amygdala have been implicated in the pathophysiology and treatment of major depressive disorder (MDD). Preclinical models suggest that stress-related changes in these regions can be reversed by antidepressants, including ketamine. Clinical studies have identified reduced volumes in MDD that are thought to be potentiated by early life stress and worsened by repeated depressive episodes. This study used 3T and 7T structural magnetic resonance imaging data to examine longitudinal changes in hippocampal and amygdalar subfield volumes associated with ketamine treatment. Data were drawn from a previous double-blind, placebo-controlled, crossover trial of healthy volunteers (HVs) unmedicated individuals with treatment-resistant depression (TRD) (3T: 18 HV, 26 TRD, 7T: 17 HV, 30 TRD) who were scanned at baseline and twice following either a 40 min IV ketamine (0.5 mg/kg) or saline infusion (acute: 1–2 days, interim: 9–10 days post infusion). No baseline differences were noted between the two groups. At 10 days post-infusion, a slight increase was observed between ketamine and placebo scans in whole left amygdalar volume in individuals with TRD. No other differences were found between individuals with TRD and HVs at either field strength. These findings shed light on the timing of ketamine’s effects on cortical structures.

Abstract Activity changes within the anterior cingulate cortex (ACC) are implicated in the antidepressant effects of ketamine, but the ACC is cytoarchitectonically and functionally heterogeneous and ketamine’s effects may be subregion specific. In the context of a double-blind randomized placebo-controlled crossover trial investigating the clinical and resting-state fMRI effects of intravenous ketamine vs. placebo in patients with treatment resistant depression (TRD) vs. healthy volunteers (HV), we used seed-based resting-state functional connectivity (rsFC) analyses to determine differential changes in subgenual ACC (sgACC), perigenual ACC (pgACC) and dorsal ACC (dACC) rsFC two days post-infusion. Across cingulate subregions, ketamine differentially modulated rsFC to the right insula and anterior ventromedial prefrontal cortex, compared to placebo, in TRD vs. HV; changes to pgACC-insula connectivity correlated with improvements in depression scores. Post-hoc analysis of each cingulate subregion separately revealed differential modulation of sgACC-hippocampal, sgACC-vmPFC, pgACC-posterior cingulate, and dACC-supramarginal gyrus connectivity. By comparing rsFC changes following ketamine vs. placebo in the TRD group alone, we found that sgACC rsFC was most substantially modulated by ketamine vs. placebo. Changes to sgACC-pgACC, sgACC-ventral striatal, and sgACC-dACC connectivity correlated with improvements in anhedonia symptoms. This preliminary evidence suggests that accurate segmentation of the ACC is needed to understand the precise effects of ketamine’s antidepressant and anti-anhedonic action.

Abstract Objectives This study explored the potential of non‐parametric and complexity analysis metrics to detect changes in activity post‐ketamine and their association with depressive symptomatology. Methods Individuals with treatment‐resistant depression (TRD: n = 27, 16F, 35.9 ± 10.8 years) and healthy volunteers (HVs: n = 9, 4F, 36.4 ± 9.59 years) had their activity monitored during an inpatient, double‐blind, crossover study where they received an infusion of ketamine or saline placebo. All participants were 18–65 years old, medication‐free, and had a MADRS score ≥20. Non‐parametric metrics averaged over each study day, metrics derived from complexity analysis, and traditionally calculated non‐parametric metrics averaged over two weeks were calculated from the actigraphy time series. A separate analysis was conducted for a subsample (n = 17) to assess the utility of these metrics in a hospital setting. Results In HVs, lower intradaily variability was observed within daily rest/activity patterns post‐ketamine versus post‐placebo (F = 5.16(1,15), p = 0.04). No other significant effects of drug or drug‐by‐time or correlations between depressive symptomatology and activity were detected. Conclusions Weak associations between non‐parametric variables and ketamine were found but were not consistent across actigraphy measures. Clinical Trial registration ClinicalTrials.gov, NCT00088699.

Abstract Treatment-resistant depression (TRD) is a severe form of major depressive disorder (MDD) with substantial public health impact and poor treatment outcome. Treatment outcome in MDD is significantly heritable, but genome-wide association studies have failed to identify replicable common marker alleles, suggesting a potential role for uncommon variants. Here we investigated the hypothesis that uncommon, putatively functional genetic variants are associated with TRD. Whole-exome sequencing data was obtained from 182 TRD cases and 2021 psychiatrically healthy controls. After quality control, the remaining 149 TRD cases and 1976 controls were analyzed with tests designed to detect excess burdens of uncommon variants. At the gene level, 5 genes, ZNF248, PRKRA, PYHIN1, SLC7A8, and STK19 each carried exome-wide significant excess burdens of variants in TRD cases (q

Summary: Ketamine is a treatment for both refractory depression and chronic pain syndromes. In order to explore ketamine’s potential mechanism of action and whether ketamine or its metabolites cross the blood brain barrier, we examined the pharmacokinetics of ketamine and its metabolites—norketamine (NK), dehydronorketamine (DHNK), and hydroxynorketamines (HNKs)—in cerebrospinal fluid (CSF) and plasma, as well as in an exploratory proteomic analysis in the CSF of nine healthy volunteers who received ketamine intravenously (0.5 mg/kg IV). We found that ketamine, NK, and (2R,6R;2S,6S)-HNK readily crossed the blood brain barrier. Additionally, 354 proteins were altered in the CSF in at least two consecutive timepoints (p

Bipolar disorder (BD) is characterized by extreme mood swings ranging from manic/hypomanic to depressive episodes. The severity, duration, and frequency of these episodes can vary widely between individuals, significantly impacting quality of life. Individuals with BD spend almost half their lives experiencing mood symptoms, especially depression, as well as associated clinical dimensions such as anhedonia, fatigue, suicidality, anxiety, and neurovegetative symptoms. Persistent mood symptoms have been associated with premature mortality, accelerated aging, and elevated prevalence of treatment-resistant depression. Recent efforts have expanded our understanding of the neurobiology of BD and the downstream targets that may help track clinical outcomes and drug development. However, as a polygenic disorder, the neurobiology of BD is complex and involves biological changes in several organelles and downstream targets (pre-, post-, and extra-synaptic), including mitochondrial dysfunction, oxidative stress, altered monoaminergic and glutamatergic systems, lower neurotrophic factor levels, and changes in immune-inflammatory systems. The field has thus moved toward identifying more precise neurobiological targets that, in turn, may help develop personalized approaches and more reliable biomarkers for treatment prediction. Diverse pharmacological and non-pharmacological approaches targeting neurobiological pathways other than neurotransmission have also been tested in mood disorders. This article reviews different neurobiological targets and pathophysiological findings in non-canonical pathways in BD that may offer opportunities to support drug development and identify new, clinically relevant biological mechanisms. These include: neuroinflammation; mitochondrial function; calcium channels; oxidative stress; the glycogen synthase kinase-3 (GSK3) pathway; protein kinase C (PKC); brain-derived neurotrophic factor (BDNF); histone deacetylase (HDAC); and the purinergic signaling pathway.

Functional magnetic resonance imaging (fMRI) is a non-invasive technique that can be used to examine neural responses with and without the use of a functional task. Indeed, fMRI has been used in clinical trials and pharmacological research studies. In mental health, it has been used to identify brain areas linked to specific symptoms but also has the potential to help identify possible treatment targets. Despite fMRI's many advantages, such findings are rarely the primary outcome measure in clinical trials or research studies. This article reviews fMRI studies in depression that sought to assess the efficacy and mechanism of action of compounds with antidepressant effects. Our search results focused on selective serotonin reuptake inhibitors (SSRIs), the most commonly prescribed treatments for depression and ketamine, a fast-acting antidepressant treatment. Normalization of amygdala hyperactivity in response to negative emotional stimuli was found to underlie successful treatment response to SSRIs as well as ketamine, indicating a potential common pathway for both conventional and fast-acting antidepressants. Ketamine's rapid antidepressant effects make it a particularly useful compound for studying depression with fMRI; its effects on brain activity and connectivity trended toward normalizing the increases and decreases in brain activity and connectivity associated with depression. These findings highlight the considerable promise of fMRI as a tool for identifying treatment targets in depression. However, additional studies with improved methodology and study design are needed before fMRI findings can be translated into meaningful clinical trial outcomes.

Abstract Background This study sought to examine the association between prospective suicidal behavior and variability, intensity, and persistence of suicidal ideation (SI) in bipolar disorder (BD). Methods Data were drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), a naturalistic study of 4360 outpatients 15 years or older with BD. In separate models, logistic regressions with suicidal behavior (first attempt or death by suicide) as the outcome variable and SI variability (fluctuating levels of SI over time, measured as ordinal dispersion of SI score), intensity (median SI score over time in study), or persistence (number of visits with reported SI) as the explanatory variables were used to examine the relationship between SI characteristics and odds of future suicidal behavior events. Results After adjusting for possible confounders, the odds of prospective suicidal behavior were 1.2 times greater per 10% increase in SI variability. SI persistence was not associated with suicidal behavior. For SI intensity, a median SI score of ‘rare/fleeting’ or ‘several days’ of SI was not associated with suicidal behavior, but the odds of prospective suicidal behavior were nearly five times greater for participants with the highest observed median SI intensity score of ‘nearly every day’. Conclusions The findings suggest that, in BD participants, monitoring SI variability may be clinically useful for assessing suicide risk.

Abstract Subanesthetic-dose racemic (R,S)-ketamine (ketamine) produces rapid, robust, and sustained antidepressant effects in major depressive disorder (MDD) and bipolar disorder (BD) and has also been shown to effectively treat neuropathic pain, complex regional pain syndrome, and post-traumatic stress disorder (PTSD). However, to date, its mechanism of action remains unclear. Preclinical studies found that (2 R,6 R;2 S,6 S)-hydroxynorketamine (HNK), a major circulating metabolite of ketamine, elicits antidepressant effects similar to those of ketamine. To help determine how (2 R,6 R)-HNK contributes to ketamine’s mechanism of action, an exploratory, targeted, metabolomic analysis was carried out on plasma and CSF of nine healthy volunteers receiving a 40-minute ketamine infusion (0.5 mg/kg). A parallel targeted metabolomic analysis in plasma, hippocampus, and hypothalamus was carried out in mice receiving either 10 mg/kg of ketamine, 10 mg/kg of (2 R,6 R)-HNK, or saline. Ketamine and (2 R,6 R)-HNK both affected multiple pathways associated with inflammatory conditions. In addition, several changes were unique to either the healthy human volunteers and/or the mouse arm of the study, indicating that different pathways may be differentially involved in ketamine’s effects in mice and humans. Mechanisms of action found to consistently underlie the effects of ketamine and/or (2 R,6 R)-HNK across both the human metabolome in plasma and CSF and the mouse arm of the study included LAT1, IDO1, NAD+, the nitric oxide (NO) signaling pathway, and sphingolipid rheostat.

Background: Nocturnal wakefulness has emerged as a potential predictor of short-term suicide risk. This analysis used dynamic temporal patterns in alpha and beta power and global sleep metrics to explore the possible link between next-day suicidal ideation (NDSI) and wakefulness measures in unmedicated participants with treatment-resistant depression. Methods: Thirty-three medication-free participants with treatment-resistant depression completed overnight polysomnography. Alpha and beta spectral power as functions over time were used to represent arousal-related components of the dynamic sleep process. A functional data analytic approach (multilevel functional principal component analysis [MFPCA]) was used to preserve the oscillatory nature of the data; MFPCA PC scores were then associated with NDSI. Associations between NDSI and polysomnography-defined wakefulness after sleep onset, sleep efficiency, and total sleep time were also evaluated. Results: NDSI had the strongest relationship with the second beta PC score (slope = 0.09 [90% credible interval, 0.03 to 0.14]), which represented an oscillating pattern that reflected disturbed sleep. The first PCs from both alpha and beta MFPCAs represented the overall magnitude of power and were most closely associated with traditional polysomnography metrics but were not related to NDSI. Results were equivocal for wakefulness after sleep onset with NDSI and did not support a relationship between NDSI and either sleep efficiency or total sleep time, highlighting the value of information contained in oscillating electroencephalogram patterns for identifying physiological links between nocturnal wakefulness and NDSI. Conclusions: This study leveraged the dynamic nature of wakefulness-related electroencephalogram frequencies and provides a potential electrophysiological link between suicidal ideation and wakefulness during sleep in individuals with treatment-resistant depression.

For the H4 protons of glutamate (Glu), glutamine (Gln), and the glutamyl moiety of glutathione (GSH), the effect of the internal strong scalar coupling between the two nonequivalent H4 protons is far greater than that of the external couplings between the H3 and H4 protons. In this work, the roles of the internal and external scalar coupling terms in the dependence of Glu, Gln, and glutamyl GSH H4 peak amplitudes on the placement of the refocusing pulses of the point resolved spectroscopy sequence were investigated by full density matrix simulations. These strong coupling effects allowed practical and approximately simultaneous maximization of the sensitivity of the spectrally resolved Glu, Gln, and glutamyl GSH H4 pseudo singlets for spatially localized in vivo detection of Glu, Gln, and GSH in the human brain using magnetic resonance spectroscopy at the magnetic field strength of 7 Tesla.

Abstract The glutamatergic modulator ketamine has been shown to rapidly reduce depressive symptoms in patients with treatment-resistant major depressive disorder (TRD). Although its mechanisms of action are not fully understood, changes in cortical excitation/inhibition (E/I) following ketamine administration are well documented in animal models and could represent a potential biomarker of treatment response. Here, we analyse neuromagnetic virtual electrode time series collected from the primary somatosensory cortex in 18 unmedicated patients with TRD and in an equal number of age-matched healthy controls during a somatosensory ‘airpuff’ stimulation task. These two groups were scanned as part of a clinical trial of ketamine efficacy under three conditions: (a) baseline; (b) 6–9 h following subanesthetic ketamine infusion; and (c) 6–9 h following placebo-saline infusion. We obtained estimates of E/I interaction strengths by using dynamic causal modelling (DCM) on the time series, thereby allowing us to pinpoint, under each scanning condition, where each subject’s dynamics lie within the Poincaré diagram—as defined in dynamical systems theory. We demonstrate that the Poincaré diagram offers classification capability for TRD patients, in that the further the patients’ coordinates were shifted (by virtue of ketamine) toward the stable (top-left) quadrant of the Poincaré diagram, the more their depressive symptoms improved. The same relationship was not observed by virtue of a placebo effect—thereby verifying the drug-specific nature of the results. We show that the shift in neural dynamics required for symptom improvement necessitates an increase in both excitatory and inhibitory coupling. We present accompanying MATLAB code made available in a public repository, thereby allowing for future studies to assess individually tailored treatments of TRD.

Abstract Antidepressant doses of ketamine rapidly facilitate synaptic plasticity and modify neuronal function within prefrontal and hippocampal circuits. However, most studies have demonstrated these effects in animal models and translational studies in humans are scarce. A recent animal study showed that ketamine restored dendritic spines in the hippocampal CA1 region within 1 h of administration. To translate these results to humans, this randomized, double-blind, placebo-controlled, crossover magnetic resonance imaging (MRI) study assessed ketamine’s rapid neuroplastic effects on hippocampal subfield measurements in healthy volunteers. S-Ketamine vs. placebo data were analyzed, and data were also grouped by brain-derived neurotrophic factor (BDNF) genotype. Linear mixed models showed that overall hippocampal subfield volumes were significantly larger (p = 0.009) post ketamine than post placebo (LS means difference=0.008, standard error=0.003). Post-hoc tests did not attribute effects to specific subfields (all p > 0.05). Trend-wise volumetric increases were observed within the left hippocampal CA1 region (p = 0.076), and trend-wise volumetric reductions were obtained in the right hippocampal—amygdaloid transition region (HATA) (p = 0.067). Neither genotype nor a genotype–drug interaction significantly affected the results (all p > 0.7). The study provides evidence that ketamine has short-term effects on hippocampal subfield volumes in humans. The results translate previous findings from animal models of depression showing that ketamine has pro-neuroplastic effects on hippocampal structures and underscore the importance of the hippocampus as a key region in ketamine’s mechanism of action.

Ketamine is associated with rapid antidepressant effects and temporary dissociative experiences, and this review examines whether these dissociative symptoms are necessary for antidepressant efficacy. Although the current literature does not support this relationship, further work is needed to explore possible associations at the molecular, biomarker, and psychological levels.

Suicide is a leading cause of death and morbidity worldwide, yet few interventions are available to mitigate its risk. Barriers to effective treatments involve a limited understanding of factors that predict the onset of suicidal thoughts and behaviors. In the context of suicide risk, stress is a precipitating factor that is largely overlooked in the literature. Indeed, the pathophysiology of stress and suicide are heavily interconnected, underscoring the need to target the stress system in suicide prevention. In this review, we integrate findings from the preclinical and clinical literature that links stress and suicide. We focus specifically on the effects of stress on underlying biological functions and processes associated with suicide, allowing for the review of research using animal models. Owing to the rapid anti-suicidal effects of (R,S)-ketamine, we discuss its ability to modulate various stress-related endophenotypes of suicide, as well as its potential role in preventing suicide in those with a history of chronic life stress (e.g., early life adversity). We highlight future research directions that could advance our understanding of stress-related effects on suicide risk, advocating a dimensional, endophenotype approach to suicide research.

Ketamine, an N-methyl-D-aspartate (NMDA)-receptor antagonist, is a recently revitalized treatment for pain and depression, yet its actions at the molecular level remain incompletely defined. In this molecular-pharmacological investigation in the rat, we used short- and longer-term infusions of high dose ketamine to stimulate neuronal transcription processes. We hypothesized that a progressively stronger modulation of neuronal gene networks would occur over time in cortical and limbic pathways. A continuous intravenous administration paradigm for ketamine was developed in rat consisting of short (1 h) and long duration (10 h, and 10 h + 24 h recovery) infusions of anesthetic concentrations to activate or inhibit gene transcription in a pharmacokinetically controlled fashion. Transcription was measured by RNA-Seq in three brain regions: frontal cortex, hippocampus, and amygdala. Cellular level gene localization was performed with multiplex fluorescent in situ hybridization. Induction of a shared transcriptional regulatory network occurred within 1 h in all three brain regions consisting of (a) genes involved in stimulus-transcription factor coupling that are induced during altered synaptic activity (immediate early genes, IEGs, such as c-Fos, 9–12 significant genes per brain region, p < 0.01 per gene) and (b) the Nrf2 oxidative stress-antioxidant response pathway downstream from glutamate signaling (Nuclear Factor Erythroid-Derived 2-Like 2) containing 12–25 increasing genes (p < 0.01) per brain region. By 10 h of infusion, the acute results were further reinforced and consisted of more and stronger gene alterations reflecting a sustained and accentuated ketamine modulation of regional excitation and plasticity. At the cellular level, in situ hybridization localized up-regulation of the plasticity-associated gene Bdnf, and the transcription factors Nr4a1 and Fos, in cortical layers III and V. After 24 h recovery, we observed overshoot of transcriptional processes rather than a smooth return to homeostasis suggesting an oscillation of plasticity occurs during the transition to a new phase of neuronal regulation. These data elucidate critical molecular regulatory actions during and downstream of ketamine administration that may contribute to the unique drug actions of this anesthetic agent. These molecular investigations point to pathways linked to therapeutically useful attributes of ketamine.

Predictive coding models of brain processing propose that top-down cortical signals promote efficient neural signaling by carrying predictions about incoming sensory information. These “priors” serve to constrain bottom-up signal propagation where prediction errors are carried via feedforward mechanisms. Depression, traditionally viewed as a disorder characterized by negative cognitive biases, is associated with disrupted reward prediction error encoding and signaling. Accumulating evidence also suggests that depression is characterized by impaired local and long-range prediction signaling across multiple sensory domains. This review highlights the electrophysiological and neuroimaging evidence for disrupted predictive processing in depression. The discussion is framed around the manner in which disrupted generative predictions about the sensorium could lead to depressive symptomatology, including anhedonia and negative bias. In particular, the review focuses on studies of sensory deviance detection and reward processing, highlighting research evidence for both disrupted generative predictions and prediction error signaling in depression. The role of the monoaminergic and glutamatergic systems in predictive coding processes is also discussed. This review provides a novel framework for understanding depression using predictive coding principles and establishes a foundational roadmap for potential future research.

The glutamatergic modulator ketamine rapidly reduces depressive symptoms in individuals with treatment-resistant major depressive disorder (TRD) and bipolar disorder. While its underlying mechanism of antidepressant action is not fully understood, modulating glutamatergically-mediated connectivity appears to be a critical component moderating antidepressant response. This double-blind, crossover, placebo-controlled study analyzed data from 19 drug-free individuals with TRD and 15 healthy volunteers who received a single intravenous infusion of ketamine hydrochloride (0.5 mg/kg) as well as an intravenous infusion of saline placebo. Magnetoencephalographic recordings were collected prior to the first infusion and 6–9 h after both drug and placebo infusions. During scanning, participants completed an attentional dot probe task that included emotional faces. Antidepressant response was measured across time points using the Montgomery-Asberg Depression Rating Scale (MADRS). Dynamic causal modeling (DCM) was used to measure changes in parameter estimates of connectivity via a biophysical model that included realistic local neuronal architecture and receptor channel signaling, modeling connectivity between the early visual cortex, fusiform cortex, amygdala, and inferior frontal gyrus. Clinically, ketamine administration significantly reduced depressive symptoms in TRD participants. Within the model, ketamine administration led to faster gamma aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) transmission in the early visual cortex, faster NMDA transmission in the fusiform cortex, and slower NMDA transmission in the amygdala. Ketamine administration also led to direct and indirect changes in local inhibition in the early visual cortex and inferior frontal gyrus and to indirect increases in cortical excitability within the amygdala. Finally, reductions in depressive symptoms in TRD participants post-ketamine were associated with faster α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) transmission and increases in gain control of spiny stellate cells in the early visual cortex. These findings provide additional support for the GABA and NMDA inhibition and disinhibition hypotheses of depression and support the role of AMPA throughput in ketamine's antidepressant effects.Clinical Trial Registration:https://clinicaltrials.gov/ct2/show/NCT00088699?term=NCT00088699&draw=2&rank=1, identifier NCT00088699.

Abstract Background Despite decades of research, the rate of death from suicide is rising in the United States. Suicide is a complex and multifactorial phenomenon and, to date, no validated biomarkers that predict suicidal behavior have been identified. Only one FDA-approved drug to prevent suicide exists, and it is approved only for patients with schizophrenia. Although anti-suicide psychotherapeutic techniques exist, treatment takes time, and only preliminary data exist for rapid-acting therapies. Discussion While more research into suicidal ideation and acute suicidal behavior is clearly needed, this research is fraught with both practical and ethical concerns. As a result, many investigators and bioethicists have called for restrictions on the types of research that individuals with suicidal behavior can participate in, despite the fact that the available empirical evidence suggests that this research can be done safely. This manuscript presents background information on the phenomenology of suicide, discusses the current state of treatment and prevention strategies, and reviews the practical and ethical issues surrounding suicide research in the context of available empirical data. Summary Currently, the causes of suicide are poorly understood, in part due to the fact that very few studies have investigated the acute suicidal crisis. Although some biomarkers for predicting risk have been developed, none have been sufficiently validated. The most successful current interventions involve means restriction. However, while numerous hurdles face researchers, these are not insurmountable. The available evidence suggests that research into suicide can be conducted both safely and ethically.

Rapid-acting interventions for the suicide crisis have the potential to transform treatment. In addition, recent innovations in suicide research methods may similarly expand our understanding of the psychological and neurobiological correlates of suicidal thoughts and behaviors. This review discusses the limitations and challenges associated with current methods of suicide risk assessment and presents new techniques currently being developed to measure rapid changes in suicidal thoughts and behavior. These novel assessment strategies include ecological momentary assessment, digital phenotyping, cognitive and implicit bias metrics, and neuroimaging paradigms and analysis methodologies to identify neural circuits associated with suicide risk. This review is intended to both describe the current state of our ability to assess rapid changes in suicide risk as well as to explore future directions for clinical, neurobiological, and computational markers research in suicide-focused clinical trials.

Limited knowledge exists regarding the neurobiology of suicidal thoughts, given that there are currently no direct probes of the suicidal state. This pilot study used magnetoencephalography (MEG) to evaluate correlates of the implicit association between the self and death compared to the self and life as objective markers of suicide risk. Healthy volunteers (HVs; n=21) completed a modified version of the Suicide Implicit Association Task (S-IAT) during MEG scanning. Gamma power—which is considered a proxy measure of excitation-inhibition balance—was directly compared in the self-death/self-life contrast. As a proof-of-concept, the ability of dynamic causal modeling to categorize HVs versus four individuals with recent suicide crisis (SC) was evaluated. In HVs, enhanced gamma power in both amygdala and anterior insula were found for the self-death compared with self-life contrast. In addition, connectivity estimates between early visual cortex, anterior insula, and amygdala correctly categorized SC participants with 77% to 82% sensitivity and 80% to 85% specificity. These findings, which implicate network-level changes in salience network and amygdala connectivity in mediating suicidal associations, require further replication in larger samples. Direct probing of suicidal thoughts with the S-IAT may provide foundational markers of neural circuits associated with suicide risk.

Major depressive disorder (MDD) is highly prevalent and 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 α-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 (MEG) recordings after both ketamine and placebo infusions and investigated functional connectivity using a multilayer amplitude-amplitude correlation technique spanning the canonical frequency bands. Twenty-four 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. Order of infusion was randomized, and participants crossed over to receive the second infusion after two weeks. 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 also suggest that neural responses to ketamine are fundamentally different between responders and non-responders.

Major depressive disorder (MDD) is highly heterogeneous in its clinical presentation. The present exploratory study used magnetoencephalography (MEG) to investigate electrophysiological intrinsic connectivity differences between healthy volunteers and unmedicated participants with treatment-resistant MDD. The study examined canonical frequency bands from delta through gamma. In addition to group comparisons, correlational studies were conducted to determine whether connectivity was related to five symptom factors: depressed mood, tension, negative cognition, suicidal thoughts, and amotivation. The MDD and healthy volunteer groups did not differ significantly at baseline when corrected across all frequencies and clusters, although evidence of generalized slowing in MDD was observed. Notably, however, electrophysiological connectivity was strongly related to suicidal thoughts, particularly as coupling of low frequency power fluctuations (delta and theta) with alpha and beta power. This analysis revealed hub areas underlying this symptom cluster, including left hippocampus, left anterior insula, and bilateral dorsolateral prefrontal cortex. No other symptom cluster demonstrated a relationship with neurophysiological connectivity, suggesting a specificity to these results as markers of suicidal ideation.

Abstract Background Inflammation is associated with major depressive disorder (MDD). Translocator protein 18 kDa (TSPO), a putative biomarker of neuroinflammation, is quantified using positron emission tomography (PET) and 11C-PBR28, a TSPO tracer. We sought to (1) investigate TSPO binding in MDD subjects currently experiencing a major depressive episode, (2) investigate the effects of antidepressants on TSPO binding, and (3) determine the relationship of peripheral and central inflammatory markers to cerebral TSPO binding. Twenty-eight depressed MDD subjects (unmedicated (n = 12) or medicated (n = 16)) and 20 healthy controls (HC) underwent PET imaging using 11C-PBR28. Total distribution volume (V T, proportional to Bmax/Kd) was measured and corrected with the free fraction in plasma (fp). The subgenual prefrontal cortex (sgPFC) and anterior cingulate cortex (ACC) were the primary regions of interest. Peripheral blood samples and cerebrospinal fluid were analyzed to investigate the relationship between TSPO binding and peripheral and central inflammatory markers, including interleukins and neurotrophic factors previously linked to depression. Results TSPO binding was higher in MDD versus HC in the sgPFC (Cohen’s d = 0.64, p = .038, 95% CI 0.04–1.24) and ACC (d = 0.60, p = .049, 95% CI 0.001–1.21), though these comparisons missed the corrected threshold for statistical significance (α = .025). Exploratory analyses demonstrated that unmedicated MDD subjects had the highest level of TSPO binding, followed by medicated MDD subjects, who did not differ from HC. TSPO binding correlated with interleukin-5 in cerebrospinal fluid but with no other central inflammatory markers. Conclusions This study found a trend towards increased TSPO binding in the brains of MDD subjects, and post hoc analysis extended these findings by demonstrating that this abnormality is significant in unmedicated (but not medicated) MDD subjects.

Background: An urgent need exists for faster-acting pharmacological treatments in major depressive disorder (MDD). The glutamatergic modulator ketamine has been shown to have rapid antidepressant effects, but much remains unknown about its mechanism of action. Functional MRI (fMRI) can be used to investigate how ketamine impacts brain activity during cognitive and emotional processing. Methods: This double-blind, placebo-controlled, crossover study of 33 unmedicated participants with MDD and 26 healthy controls (HCs) examined how ketamine affected fMRI activation during an attentional bias dot probe task with emotional face stimuli across multiple time points. A whole brain analysis was conducted to find regions with differential activation associated with group, drug session, or dot probe task-specific factors (emotional valence and congruency of stimuli). Results: A drug session by group interaction was observed in several brain regions, such that ketamine had opposite effects on brain activation in MDD versus HC participants. Additionally, there was a similar finding related to emotional valence (a drug session by group by emotion interaction) in a large cluster in the anterior cingulate and medial frontal cortex. Conclusions: The findings show a pattern of brain activity in MDD participants following ketamine infusion that is similar to activity observed in HCs after placebo. This suggests that ketamine may act as an antidepressant by normalizing brain function during emotionally valenced attentional processing. Clinical trial: NCT#00088699: https://www.clinicaltrials.gov/ct2/show/NCT00088699 Keywords: Depression, Functional magnetic resonance imaging (fMRI), Ketamine, Emotion, Attentional processing, Dot probe

Studies investigating human brain response to emotional stimuli—particularly high-arousing versus neutral stimuli—have obtained inconsistent results. The present study was the first to combine magnetoencephalography (MEG) with the bootstrapping method to examine the whole brain and identify the cortical regions involved in this differential response. Seventeen healthy participants (11 females, aged 19 to 33 years; mean age, 26.9 years) were presented with high-arousing emotional (pleasant and unpleasant) and neutral pictures, and their brain responses were measured using MEG. When random resampling bootstrapping was performed for each participant, the greatest differences between high-arousing emotional and neutral stimuli during M300 (270–320 ms) were found to occur in the right temporo-parietal region. This finding was observed in response to both pleasant and unpleasant stimuli. The results, which may be more robust than previous studies because of bootstrapping and examination of the whole brain, reinforce the essential role of the right hemisphere in emotion processing.

Existing pharmacological treatments for bipolar disorder (BPD) and major depressive disorder (MDD) are often insufficient for many patients. Here we describe a number of targets/compounds that clinical and preclinical studies suggest could result in putative novel treatments for mood disorders. These include: (1) glycogen synthase kinase-3 (GSK-3) and protein kinase C (PKC), (2) the purinergic system, (3) histone deacetylases (HDACs), (4) the melatonergic system, (5) the tachykinin neuropeptides system, (6) the glutamatergic system, and (7) oxidative stress and bioenergetics. The paper reviews data on new compounds that have shown antimanic or antidepressant effects in subjects with mood disorders, or similar effects in preclinical animal models. Overall, an improved understanding of the neurobiological underpinnings of mood disorders is critical in order to develop targeted treatments that are more effective, act more rapidly, and are better tolerated than currently available therapies.

Currently available antidepressants used to treat major depressive disorder (MDD) unfortunately often take weeks to months to achieve their full effects, commonly resulting in considerable morbidity and increased risk for suicidal behavior. Our lack of understanding of the precise cellular underpinnings of this illness and of the mechanism of action of existing effective pharmacological treatments is a large part of the reason that therapies with a more rapid onset of antidepressant action (ROAA) have not been developed. Other issues that need to be addressed include heterogeneous clinical concepts and statistical models to measure rapid antidepressant effects. This review describes the timing of onset of antidepressant effects for various therapies used to treat MDD. While several agents produce earlier improvement of depressive symptoms (defined as occurring within one week), the response rate associated with such agents can be quite variable. These agents include both currently available antidepressants as well as other pharmacological and non-pharmacological interventions. Considerably fewer treatments are associated with ROAA, defined as occurring within several hours or one day. Treatment strategies for MDD whose sustained antidepressant effects manifest within hours or even a few days would have an enormous impact on public health.

Ketamine and lithium both inhibit glycogen synthase kinase 3. In addition, lithium and ketamine have synergistic antidepressant-like effects at individually subeffective doses in rodents. We hypothesized that ketamine’s antidepressant effects would be improved by therapeutic doses of lithium versus valproate and that serum lithium levels would positively correlate with ketamine’s antidepressant efficacy. Thirty-six patients with treatment-resistant bipolar depression maintained on therapeutic-dose lithium (n=23, 0.79 ± 0.15 mEq/L) or valproate (n=13, 79.6 ± 12.4 mg/mL) received 0.5 mg/kg ketamine infusion in a randomized, double-blind, placebo-controlled, crossover trial. The primary depression outcome measure—the Montgomery-Åsberg Depression Rating Scale (MADRS)—was assessed before infusion and at numerous postinfusion time points. Both lithium (F1,118 = 152.08, p

Anhedonia, a diminished or lack of ability to experience and anticipate pleasure represents a core psychiatric symptom in depression. Current clinician assessment of anhedonia is generally limited to one or two all-purpose questions and most well-known psychometric scales of anhedonia are relatively long, self-administered, typically not state sensitive, and are unsuitable for use in clinical settings. A user-friendly tool for a more in-depth clinician assessment of hedonic capacity is needed. The present study assessed the validity and reliability of a clinician administered version of the Snaith-Hamilton Pleasure Scale, the SHAPS-C, in 34 depressed subjects. We compared total and specific item scores on the SHAPS-C, SHAPS (self-report version), Montgomery-Åsberg Depression Rating Scale (MADRS), and the Inventory of Depressive Symptomatology-Self Rating version (IDS-SR). We also examined construct, content, concurrent, convergent, and discriminant validity, internal consistency, and split-half reliability of the SHAPS-C. The SHAPS-C was found to be valid and reliable. The SHAPS and the SHAPS-C were positively correlated with one another, with levels of depression severity, as measured by the MADRS, and the IDS-SR total scores, and with specific items of the MADRS and IDS-SR sensitive to measuring hedonic capacity. Our investigation indicates that the SHAPS-C is a user friendly, reliable, and valid tool for clinician assessment of hedonic capacity in depressed bipolar and unipolar patients.