Although numerous studies have suggested that chronic stress is a major risk factor for major depressive disorder, the process by which stress causes depression is still not fully understood. Previously, we investigated glucocorticoids, which are stress response hormones that activate a synapse-weakening pathway. Therefore, we hypothesized that chronic stress may cause synaptic depression, which could reduce excitability related to emotions. Animals underwent chronic restraint stress (CRS), followed by basal synaptic transmission measurement in hippocampal slices to assess synaptic function. Drugs were infused into the ventral hippocampus via cannulation before behavioral tests, including forced swimming, tail suspension, and sucrose intake tests, which evaluated depressive-like behaviors and anhedonia. The field excitatory postsynaptic potentials (fEPSPs) are reduced by chronic restraint stress (CRS) in the ventral hippocampus. The ventral hippocampi of mice treated with CRS showed low levels of fEPSP after the forced swim test (FST). In the FST and tail suspension test, CRS-induced increases in immobility time were prevented by the acute inhibition of AMPAR internalization by Tat-GluA23y, which also prevented fEPSP reduction. Mice lacking caspase-3 exhibited resilience to CRS-induced increases in immobility time in the FST, as well as changes in the functionality of synaptic AMPAR. Finally, the caspase-3 inhibitor Z-DEVD-FMK rapidly blocked the CRS-induced increase in immobility time in the FST and the CRS-induced decrease in sucrose preference. These findings suggest that chronic stress-related behavioral changes may require caspase-3-dependent alterations in ventral hippocampal synapses.

Addiction is a chronic condition that poses a serious public health challenge, particularly highlighted by the global opioid crisis involving drugs such as morphine (MORPH). One of the major obstacles in effective detoxification is the high relapse rate, with many individuals resuming drug use after withdrawal. Pharmacological treatments developed so far have generally shown limited efficacy in addressing substance use disorder. In this context, esketamine (ESK), the S-ketamine isomer, has been used in cases of treatment-resistant recurrent depression and depression with suicide risk. In our study, rats were treated with two doses of ESK every five days (acute - A-ESK) or daily (sub-chronic - SC-ESK) during MORPH-conditioned place preference (CPP) extinction. After 10 days, the animals were re-exposed to MORPH to assess preference reacquisition in the CPP paradigm. Our findings showed that both acute and sub-chronic ESK (A-ESK and SC-ESK) effectively prevented MORPH-CPP reestablishment. To our knowledge, this is the first experimental study to demonstrate the potential of ESK as a promising treatment for opioid abuse disorder. Clinical studies are needed to confirm its efficacy in human rehabilitation centers.

Postpartum depression (PPD) is an increasingly prevalent but still poorly characterized disorder. Causal and modulating factors include hormones fluctuations, such as estrogen, progesterone, and allopregnolone, pathways imbalances, such as oxytocin and kynurenine, chronobiological factors, and brain imaging alterations. Treatment may differ from the traditional major depression management, while selective serotonin reuptake inhibitors such as sertraline are commonly used and suggested by guidelines, neurosteroids such as brexanolone and the more convenient zuranolone have been recently approved. Newer neurosteroids such as ganaxolone, valaxanolone, and lysaxanolone are currently under development, but also esketamine and psychedelics are promising potential treatments. Other somatic treatments including brain stimulation techniques and light therapy also showed benefit. PPD is therefore increasingly understood as, at least partially, independent from major depressive disorder. Specific and individualized treatments including pharmacological and non-pharmacological therapies are progressively being introduced in the routine clinical practice.

The pharmacologically active (R,S)-ketamine (ketamine) metabolite (2 R,6 R)-hydroxynorketamine (HNK) maintains ketamine's preclinical antidepressant profile without adverse effects. While hypotheses have been proposed to explain how ketamine and its metabolites initiate their antidepressant-relevant effects, it remains unclear how sustained therapeutic actions arise following drug elimination. To distinguish the physiological mechanisms involved in the rapid from sustained actions of HNK, we utilized extracellular electrophysiology combined with pharmacology to develop an in vitro hippocampal slice incubation model that exhibited pharmacological fidelity to the 1) rapid synaptic potentiation induced by HNK at the Schaffer collateral-CA1 (SC-CA1) synapse during bath-application to slices collected from mice, and 2) maintenance of metaplastic (priming) activity that enhanced N-methyl-D-aspartate receptor (NMDAR) activation-dependent long-term potentiation (LTP) hours after in vivo dosing. We used this model to reveal novel mechanisms engaged in HNK's temporally-sensitive antidepressant-relevant synaptic actions, finding that the induction of synaptic potentiation by HNK did not require NMDAR activity, but NMDAR activity was necessary to maintain synaptic priming. HNK required protein kinase A (PKA) activity to rapidly potentiate SC-CA1 neurotransmission to facilitate synaptic priming that persistently promoted LTP formation. HNK's rapid actions were blocked by inhibitors of adenylyl cyclase 1 (AC1), but not an AC5 inhibitor. We conclude that HNK rapidly potentiates SC-CA1 synaptic efficacy, which then stimulates priming mechanisms that persistently favor plasticity. Targeting such priming mechanisms may be an effective antidepressant strategy, and our incubation model may aid in revealing novel pharmacological targets.

Ketamine's use in treating bipolar depression must account for risks, such as switching to manic episodes or worsening symptoms. This study examines ketamine's impact on depressive symptoms, focusing on 'inner tension,' 'sleep reduction,' and 'suicidal ideation' over four weeks in treatment-resistant bipolar disorder (TR-BD) patients. Fifty-nine patients with TR-BD were treated consecutively with ketamine (avg dose 0.8 mg/kg). Results showed significant reductions in MADRS scores without manic switches. Ketamine was well-tolerated despite polypharmacy. Antidepressant treatment of bipolar depression requires great caution because of the risk of switching to manic-mixed episodes and worsening of symptoms such as internal tension, psychomotor agitation, and suicide risk. The aim of this study was to evaluate the efficiency and tolerability of intravenous ketamine in patients with bipolar I or bipolar II disorder and a current treatment-resistant depressive episode (TR-BD), with the aim of examining: 1) the risk of manic switches; 2) the effect on global depressive symptoms as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS); and 3) the specific effects on the MADRS items of internal tension, sleep disturbance, and suicidal ideation over a four-week period. Fiftynine patients with TR-BD (51.4 ± 12.3 years; 30 % female) treated consecutively with intravenous ketamine (mean dose 0.8 mg/kg) were included in this study. No ketamine-treated patient experienced a manic switch during the observation period. A statistically significant decrease (i.e., improvement) in MADRS global score and scores on the Internal Tension, Reduced Sleep, and Suicidal Ideation items was observed from the second week, with no evidence of worsening of the above symptoms. Patient-reported adverse events were generally mild to moderate.

Expression of the N-methyl-D-aspartate receptor, particularly when containing the GluN2B subunit (NMDAR-GluN2B), varies across the prefrontal cortex (PFC). In humans, the subgenual cingulate cortex (SGC) contains among the highest levels of NMDAR-GluN2B expression, while the dorsolateral prefrontal cortex (dlPFC) exhibits a more moderate level of NMDAR-GluN2B expression. NMDAR-GluN2B are commonly associated with ionotropic synaptic function and plasticity and are essential to the neurotransmission underlying working memory in the macaque dlPFC in the layer III circuits, which in humans are afflicted in schizophrenia. However, NMDAR-GluN2B can also be found at extrasynaptic sites, where they may trigger distinct events, including some linked to neurodegenerative processes. The SGC is an early site of tau pathology in sporadic Alzheimer's disease (sAD), which mirrors its high NMDAR-GluN2B expression. Additionally, the SGC is hyperactive in depression, which can be treated with NMDAR antagonists. Given the clinical relevance of NMDAR in the SGC and dlPFC, the current study used immunoelectron microscopy (immunoEM) to quantitatively compare the synaptic and extrasynaptic expression patterns of NMDAR-GluN2B across excitatory and inhibitory neuron dendrites in rhesus macaque layer III SGC and dlPFC. We found a larger population of extrasynaptic NMDAR-GluN2B in dendrites of putative pyramidal neurons in SGC as compared to the dlPFC, while the dlPFC had a higher proportion of synaptic NMDAR-GluN2B. In contrast, in putative inhibitory dendrites from both areas, extrasynaptic expression of NMDAR-GluN2B was far more frequently observed over synaptic expression. These findings may provide insight into varying cortical vulnerability to alterations in excitability and neurodegenerative forces.

Depression is predicted to be the leading burden of disease worldwide by 2030 with a prevalence of 10% to 60% in the surgical population. Depressive symptoms in the perioperative population are associated with a myriad of grave complications, including higher morbidity and mortality. This systematic review aims to determine whether a single dose of intravenous ketamine can be used prophylactically as a routine resilience-enhancing agent in all high-risk adult patients undergoing surgery to mitigate depressive symptoms postoperatively by appraising evidence of existing literature.

An evidence-based systematic review.

The databases PubMed, CINAHL, and Scopus were searched, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Search and Medical Subject Headings (MeSH) terms used: "ketamine," "surgical procedures," "surgical," "surgery," "depression," and "depressive disorder."

In 9 randomized controlled trials (RCTs), bolus ketamine doses of 0.1 mg/kg to 1 mg/kg were administered intraoperatively or in the postanesthesia care unit. The primary outcome was the subjective feelings of depression as evaluated by different validated depression screening tools and seven RCTs observed statistically significant findings between the control and intervention (ketamine) groups with postoperative depression scores. Two RCTs did not find a significant change in depression scores.

Research on the use of prophylactic ketamine as an antidepressant in the perioperative population offers insight into changing routine practices and can shape how mental health is viewed in hospitals. Further research is warranted on the safety profile of ketamine, and risk stratification with careful consideration of baseline depressive symptoms, timing, and its use across a wider variety of surgical subspecialties.

Opioid use disorder (OUD) is a pressing public health concern marked by frequent relapse during periods of abstinence, perpetuated by negative affective states. Classical antidepressants or the currently prescribed opioid pharmacotherapies have limited efficacy to reverse the negative affect or prevent relapse.

Using mouse models, we investigated the effects of ketamine's metabolite (2R,6R)-hydroxynorketamine (HNK) on reversing conditioning to sub-effective doses of morphine in stress-susceptible mice, preventing conditioned-place aversion and alleviating acute somatic abstinence symptoms in opioid-dependent mice. Additionally, we evaluated its effects on anhedonia, anxiety-like behaviours and cognitive impairment during protracted opioid abstinence, while mechanistic studies examined cortical EEG oscillations and synaptic plasticity markers.

(2R,6R)-HNK reversed conditioning to sub-effective doses of morphine in stress-susceptible mice and prevented conditioned-place aversion and acute somatic abstinence symptoms in opioid-dependent mice. In addition, (2R,6R)-HNK reversed anhedonia, anxiety-like behaviours and cognitive impairment emerging during protracted opioid abstinence plausibly via a restoration of impaired cortical high-frequency EEG oscillations, through a GluN2A-NMDA receptor-dependent mechanism. Notably, (2R,6R)-HNK facilitated the extinction of opioid conditioning, prevented stress-induced reinstatement of opioid-seeking behaviours and reduced the propensity for enhanced morphine self-consumption in mice previously exposed to opioids.

These findings emphasize the therapeutic potential of (2R,6R)-HNK, which is currently in Phase II clinical trials, in addressing stress-related opioid responses. Reducing the time and cost required for development of new medications for the treatment of OUDs via drug repurposing is critical due to the opioid crisis we currently face.

Patients with breast cancer experience varying degrees of pain, depression, and anxiety after surgery, which affect their postoperative recovery. Although ketamine/esketamine exhibit potential for opioid-sparing and controlling postoperative pain and depression, their effects on postoperative pain and depression remain unclear. This meta-analysis aimed to evaluate whether perioperative administration of ketamine/esketamine could reduce postoperative pain and depression, improve postoperative recovery, and reduce the incidence of adverse events in patients after breast cancer surgery.

PubMed, Embase, Web of Science, Cochrane Library, and Clinical Trials were searched from inception until June 2, 2024 for randomized controlled trials in English language on the effect of perioperative ketamine/esketamine on postoperative pain in patients undergoing breast cancer surgery. The primary outcome was the postoperative pain score, and the secondary outcomes were the postoperative depression score, quality of postoperative recovery, incidence of adverse events, and extubation time. The standardized mean difference and 95% confidence interval (CI) were calculated for continuous outcomes, and the risk ratio and 95% CI were calculated for binary variables.

Seven studies involving 748 patients were included in this meta-analysis. No significant differences were found in postoperative pain scores at 2 h, 4 h, 1 day, 3 days, 7 days, and 3 months after surgery. Postoperative depression scores at 3 and 7 days after surgery were lower in the ketamine/esketamine group. The incidence of dizziness was lower in ketamine/esketamine group. No statistically significant differences were observed in postoperative depression scores at 30 days after surgery, quality of postoperative recovery at 1 and 3 days after surgery, extubation time, or the incidence of nausea, vomiting, and nightmares.

Perioperative ketamine/esketamine administration did not significantly reduce postoperative pain in patients undergoing breast cancer surgery; however, it may reduce depression within a short period after the surgery.

https://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42024572414, identifier CRD42024572414.

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and oxidative stress represent important mechanisms that have been implicated in etiopathology of depression. Although first antidepressants were introduced in clinical practice more than six decades ago, approximately 30 % of patients with a diagnosis of depression show treatment resistance. A noncompetitive N-methyl-d-aspartate receptor antagonist ketamine has shown promising rapid antidepressant effects and has been approved for treatment-resistant depression (TRD). In the present study, we investigated antioxidant and antidepressant-like activity of a single subanesthetic dose of ketamine (10 mg/kg, ip) in a rodent model of TRD induced by adrenocorticotropic hormone (10 μg ACTH/day, sc, 21 days). Behavioral assessment was performed, and plasma biomarkers of oxidative stress and DNA damage in peripheral blood lymphocytes (PBLs) were determined. We observed that ACTH produced depressive-like behavior and significant increase in superoxide anion (O2·-), advanced oxidation protein products (AOPP), malondialdehyde (MDA) and total oxidant status (TOS) in male Wistar rats. This effect was accompanied by reduced activity of antioxidant enzymes - superoxide dismutase (SOD) and paraoxonase1 (PON1) in plasma and increase in DNA damage in PBLs. In the described model of TRD, we have demonstrated antidepressant effects of ketamine for the first time. Our results reveal that ketamine was effective in reducing O2.-, AOPP, MDA and TOS, while enhancing SOD and PON1 activity in ACTH-rats. Collectively, our study sheds light on molecular mechanisms implicated in antioxidant activity of ketamine, thus incentivizing further investigation of its effects on ROS metabolism and antioxidant defenses in clinical trials, particularly in depression.

Low-dose ketamine is an N-methyl-D-aspartate receptor antagonist that exerts an antidepressant effect on patients with treatment-resistant depression (TRD). This antidepressant effect may extend beyond the glutamatergic hypothesis. Nevertheless, the roles of genes encoding other monoamine neurotransmitters (i.e., serotonin and dopamine) in the neuromechanism of low-dose ketamine remain unknown.

In this clinical trial, which involved 65 patients with TRD, 21 patients received 0.5 mg/kg ketamine, 20 received 0.2 mg/kg ketamine, and 24 received normal saline. All patients were genotyped for 684,616 single-nucleotide polymorphisms (SNPs). A total of 50 monoamine neurotransmitter-related candidate genes, including HTR2A and HTR2C from the serotoninergic system, CHRM4 and CHRNB1 from the cholinergic system, and DRD2 from the dopaminergic system, were selected to conduct a gene-based genome-wide association study of the antidepressant effects of ketamine.

Gene-set enrichment analysis revealed that the pathway underlying neuroactive ligand-receptor interaction (KEGG) played a pivotal role in the biomechanisms underlying ketamine's antidepressant effect. Specifically, the genes and SNPs related to the cholinergic system (e.g., rs2644247 in CHRM5), μ1 opioid receptor (e.g., rs2473546 in OPRM1), dopaminergic system (e.g., rs2617577 in SLC6A3), serotonergic system (HTR2A), cannabinoid receptor (CNR2), and σ1 receptor (SIGMAR1) were associated with the antidepressant effect of low-dose ketamine.

Low-dose ketamine has an antidepressant effect, which may be associated with multiple monoamine neurotransmitter systems and the σ1 receptor.

Existing studies predominantly focus on the molecular and neurobiological mechanisms underlying Ketamine's acute treatment effects on post-traumatic stress disorder (PTSD). This emphasis has largely overlooked its sustained therapeutic effects, which hold significant potential for the development of targeted interventions.

This systematic review examines the pharmacokinetic and pharmacodynamic effects of ketamine on PTSD, differentiating between immediate and sustained molecular effects.

A comprehensive search across databases (Web of Science, Scopus, Global Health, PubMed) and grey literature yielded 317 articles, where 29 studies met the inclusion criteria. These studies included preclinical models and clinical trials, through neurotransmitter regulation, gene expression, synaptic plasticity, and neural pathways (PROSPERO ID: CRD42024582874).

We found accumulating evidence that the immediate effects of ketamine, which involve changes in GABA, glutamate, and glutamine levels, trigger the re-regulation of BDNF, enhancing synaptic plasticity via pathways such as TrkB and PSD-95. Other molecular influences also include c-Fos, GSK-3, HDAC, HCN1, and the modulation of hormones like CHR and ACTH, alongside immune responses (IL-6, IL-1β, TNF-α). Sustained effects arise from neurotransmitter remodulations and involve prolonged changes in gene expression. These include mTOR-mediated BDNF expression, alterations in GSK-3β, FkBP5, GFAP, ERK phosphorylation, and epigenetic modifications (DNMT3, MeCP2, H3K27me3, mir-132, mir-206, HDAC).

These molecular changes promote long-term synaptic stability and re-regulation in key brain regions, contributing to prolonged therapeutic benefits. Understanding the sustained molecular and epigenetic mechanisms behind ketamine's effects is critical for developing safe and effective personalised treatments, potentially leading to more effective recovery.

Unsuccessful response to several courses of antidepressants is a core feature of treatment-resistant depression (TRD), a severe condition that affects a third of patients with depression treated with conventional pharmacotherapy. However, the molecular mechanisms underlying TRD remain poorly understood. Here, we assessed the successful vs. unsuccessful response to ketamine (KET) in chronically stressed mice that failed to respond to initial treatment with fluoxetine (FLX) as a rodent model of TRD and characterized the associated transcriptional profiles in the nucleus accumbens (NAc) using RNA-sequencing. We observed that failed treatment with FLX exerts a priming effect that promotes behavioral and transcriptional responses to subsequent ketamine treatment. We also identified specific gene networks that are linked to both susceptibility to stress and resistance to antidepressant response. Collectively, these findings offer valuable insights into the molecular mechanisms underlying antidepressant resistance and help address a critical gap in preclinical models of TRD.

Subanesthetic doses of (R,S)-ketamine (ketamine) have demonstrated rapid and robust antidepressant effects in individuals with depression. However, individual variability in response to ketamine exists, and current biomarkers of ketamine treatment response are not entirely understood. Preclinical evidence suggests a link between hypothalamic-pituitary-adrenal (HPA) axis activation, a determinant of the stress response system, and ketamine's efficacy in stressed mice exhibiting enhanced antidepressant responses. Here, we assessed the relationship between HPA axis, major depression features, and antidepressant response to ketamine in humans.

We investigated 42 participants following medication washout with treatment-resistant depression who participated in a randomized, placebo-controlled, crossover trial receiving intravenous ketamine. Plasma levels of corticotropin-releasing factor (CRF), adrenocorticotropic hormone (ACTH), and cortisol were measured at baseline. Ketamine's antidepressant effects were assessed using the Montgomery-Asberg Depression Rating Scale.

We found that baseline HPA axis hormone levels did not significantly moderate the antidepressant effects of ketamine. However, a negative association was observed between ACTH and CRF levels and the overall duration of depressive episodes, suggesting potential biomarker implications. Also, a negative correlation between baseline depressive scores and age of onset was observed, suggesting that the severity of depression might be greater if it develops at a younger age, indicating more enduring stress on the brain and body.

Although we did not find a moderation effect of the plasma HPA axis hormones on the antidepressant effects of ketamine, moderation effects of the brain HPA axis hormones cannot be precluded and warrants further investigation. Importantly, our results implicate HPA axis components as potential biomarkers for the duration of depressive episodes.

Opioid use disorder (OUD) has reached epidemic proportions, with many countries facing high levels of opioid use and related fatalities. Although currently prescribed medications for OUD are considered lifesaving, they inadequately address negative affect and cognitive impairment, resulting in high relapse rates to nonmedical opioid use even years after drug cessation (protracted abstinence). Evidence supports the notion that ketamine, an anesthetic and rapid-acting antidepressant drug, holds promise as a candidate for OUD treatment, including the management of acute withdrawal somatic symptoms, negative affect during protracted opioid abstinence, and prevention of retaking nonmedical opioids. In this review, we comprehensively discuss preclinical and clinical research that has evaluated ketamine and its metabolites as potential novel therapeutic strategies for treating OUD. Furthermore, we examine evidence that supports the relevance of the molecular targets of ketamine and its metabolites in relation to their potential effects and therapeutic outcomes in OUD. Overall, existing evidence demonstrates that ketamine and its metabolites can effectively modulate pathophysiological processes affected in OUD, suggesting a promising therapeutic role in the treatment of OUD and the prevention of return to opioid use during abstinence.

The incidence of anxiety and depression disorders is increasing worldwide. There is an increasing incidence of hard-to-treat depression with various aspects of origin. Almost 80% of people prefer to use natural remedies and supplements as their primary healthcare solution. Not surprisingly, around one-third of drugs were inspired by nature. Over the past three decades, the use of such remedies has increased significantly. Synthetic antidepressants may cause various negative side effects, whereas herbal medicines are favored because of their ability to relieve symptoms with minimal to no side effects and lower financial burden. This review provides an overview of herbs and biologically active compounds used to treat depression.

Targeted covalent inhibitors, primarily targeting cysteine residues, have attracted great attention as potential drug candidates due to good potency and prolonged duration of action. However, their discovery is challenging. In this research, a database-assisted liquid chromatography-tandem mass spectrometry (LC-MS/MS) strategy was developed to quickly discover potential cysteine-targeting compounds. First, compounds with potential reactive groups were selected and incubated with N-acetyl-cysteine in microsomes. And the precursor ions of possible cysteine-adducts were predicted based on covalent binding mechanisms to establish in-house database. Second, substrate-independent product ions produced from N-acetyl-cysteine moiety were selected. Third, multiple reaction monitoring scan was conducted to achieve sensitive screening for cysteine-targeting compounds. This strategy showed broad applicability, and covalent compounds with diverse structures were screened out, offering structural resources for covalent inhibitors development. Moreover, the screened compounds, norketamine and hydroxynorketamine, could modify synaptic transmission-related proteins in vivo, indicating their potential as covalent inhibitors. This experimental-based screening strategy provides a quick and reliable guidance for the design and discovery of covalent inhibitors.

Since its synthesis in 1962, ketamine has been widely used in diverse medical contexts, from anesthesia to treatment-resistant depression. However, interpretations of ketamine's subjective effects remain polarized. Biomedical frameworks typically construe the drug's experiential effects as dissociative or psychotomimetic, while psychedelic paradigms emphasize the potential therapeutic merits of these non-ordinary states.

Ketamine's psychoactive effects have inspired diverse interpretations. In this review, we trace the historical evolution of these perspectives - which we broadly categorize as 'dissociative,' 'dream-like,' and 'psychedelic' - and show how they emerged out of these clinical contexts. We highlight the influence of factors such as language, dose, and environmental context on ketamine's effects and therapeutic outcomes. We discuss potential mechanisms underlying these context-dependent effects and explore the broader clinical and research-related ramifications.

Ketamine's subjective effects are undeniably powerful, yet their therapeutic significance remains debated. A nuanced, interdisciplinary approach is essential for maximizing ketamine's potential. Future research should focus on how explanatory models, treatment environments, and patient preparation can optimize ketamine's benefits while minimizing distress. We suggest that, rather than being a tiger to be tamed as its creator once described, ketamine may best be understood as a chameleon whose color shifts depending on its context.

This study adopts and validates an anesthetic protocol designed for rat whisker stimulation experiments, achieving significant enhancements in the neural response of the barrel field cortex. By combining alpha-chloralose, low-dose Isoflurane (0.5%) and Dexdomitor, the protocol not only maintains a stable anesthetic state but also markedly improves the amplitude and latency of local field potential (LFP) signals. Experimental results reveal that LFP amplitudes in the barrel field under this protocol are twice as high as those achieved with Isoflurane and four times as high as those with Ketamine-Xylazine, with significantly shortened latencies and reduced noise interference. For the first time, power spectral analysis reveals a distinct enhancement of oscillatory power in the alpha (8-13 Hz) and beta (13-30 Hz) bands under alpha-chloralose anesthesia, diverging from the traditional dominance of delta (0.5-4 Hz) oscillations observed with other anesthetics. Mechanistically, this phenomenon may be attributed to alpha-chloralose's unique modulation of GABAergic and glutamatergic pathways, promoting cortical desynchronization and enhanced sensory processing. This protocol offers new insights into optimizing sensory-evoked neural signal acquisition and provides a reference for future studies exploring neural modulation in sensory neuroscience.

Optogenetics and chemogenetics are emerging neuromodulation techniques that have attracted significant attention in recent years. These techniques enable the precise control of specific neuronal types and neural circuits, allowing researchers to investigate the cellular mechanisms underlying depression. The advancement in these techniques has significantly contributed to the understanding of the neural circuits involved in depression; when combined with other emerging technologies, they provide novel therapeutic targets and diagnostic tools for the clinical treatment of depression. Additionally, these techniques have provided theoretical support for the development of novel antidepressants. This review primarily focuses on the application of optogenetics and chemogenetics in several brain regions closely associated with depressive-like behaviors in rodent models, such as the ventral tegmental area, nucleus accumbens, prefrontal cortex, hippocampus, dorsal raphe nucleus, and lateral habenula and discusses the potential and challenges of optogenetics and chemogenetics in future research. Furthermore, this review discusses the potential and challenges these techniques pose for future research and describes the current state of research on sonogenetics and odourgenetics developed based on optogenetics and chemogenetics. Specifically, this study aimed to provide reliable insights and directions for future research on the role of optogenetics and chemogenetics in the neural circuits of depressive rodent models.

The mechanisms underlying esketamine's therapeutic effects remain elusive. The study aimed to explore the impact of single esketamine treatment on LPS-induced adolescent depressive-like behaviors and the role of Nrf2 regulated neuroinflammatory response in esketamine-produced rapid antidepressant efficacy.

Adolescent male C57BL/6J mice were randomly assigned to three groups: control, LPS, and LPS + esketamine (15 mg/kg, i.p.). Depressive-like behaviors were evaluated via the OFT, NFST, and TST. Protein expression of Nrf2 and inflammatory cytokines, including TNF-α, IL-1β, and iNOS in the hippocampus and mPFC, were measured by western blot. Moreover, the Nrf2 inhibitor, ML385, was also applied in the current study. The depressive-like behaviors and the protein expression of Nrf2, TNF-α, IL-1β, and iNOS in mPFC and hippocampus were also measured. Additionally, the plasma's pro-inflammatory cytokines and anti-inflammatory cytokines were assessed using ELISA methods with or without ML385.

A single administration of esketamine treatment alleviated the LPS-induced depressive-like behaviors. Esketamine increased the expression of Nrf2 and reduced the expression of the inflammatory cytokines, including TNF-α, IL-1β, and iNOS, in the mPFC and hippocampus. Notably, pharmacological inhibition of Nrf2 via ML385 administration abrogated the antidepressive-like behaviors and anti-inflammatory effects induced by esketamine. In the periphery, esketamine mitigated the LPS-induced elevation of pro-inflammatory cytokines, and the reduction of anti-inflammatory cytokines, and this effect was reversed by Nrf2 inhibition.

Esketamine treatment exerts rapid antidepressant effects and attenuates neuroinflammation in LPS-induced adolescent depressive-like behaviors, potentially through the activation of Nrf2-mediated anti-inflammatory signaling.

Geniposide (GP) and shanzhiside methyl ester (SM) are the two important bioactive compounds in the classical traditional Chinese herbal medicine Yueju Pill, which is currently used as an over-the-counter (OTC) medicine in China. Yueju has been demonstrated with antidepressant-like effects with the prescriptional dose. As GP and SM both have antidepressant potential, the synergism of them could be crucial to the function of Yueju.

The neuropeptide pituitary adenylyl cyclase-activating polypeptide (PACAP) has been implicated in the onset of antidepressant-like response. Here we investigated the synergism of the chronic treatment with GP and SM, at proportional doses to Yueju, on antidepressant-like effects, and underlying mechanism of PACAP-related signaling in a neuroinflammation-based depression model.

Depression-related behaviors were tested in the lipopolysaccharide (LPS)-induced depression model. The molecular signaling of neuroinflammation and neuroplasticity was investigated using Western blot analysis, immunofluorescence and pharmacological inhibition of mTOR signaling.

Chronic treatment of GP and SM (GS) at the dose which is proportional to the prescriptional dose of Yueju synergistically elicited antidepressant-like effects. Chronic treatment of the GS or the conventional antidepressant fluoxetine (FLX) showed antidepressant-like effects in LPS-injected mice. In vitro analysis indicated the synergism of GS on PACAP expression. In the hippocampus of LPS-injected mice, both GS and FLX enhanced PACAP expression, downregulated the inflammatory signaling of Iba-1/NF-кB/IL-1β and NLRP3, and upregulated the neuroplasticity signaling of mTOR-BDNF/PSD95. Additionally, both treatments reduced microglia activation indicated by Iba-1 immunofluorescent staining. Rapamycin, an mTOR inhibitor, blunted the antidepressant-like effects and the upregulation of BDNF expression induced by chronic GS.

The antidepressant-like effects elicited by chronic fluoxetine or by synergistic doses of GS were involved in the upregulation of hippocampal PACAP levels, in association with ameliorated neuroinflammation and neuroplasticity signaling in LPS-injected mice. GS synergism may play a key part in the antidepressant-like effects of the prescriptional dose of Yueju.

Fuzi-Lizhong pill (FLP) is a well-validated traditional Chinese medicine (TCM) formula that has long been used in China for gastrointestinal disease and adjunctive therapy for depression. In our previous study, we reported that the principal herb of FLP, Aconitum carmichaelii Debx. (Fuzi), exhibits antidepressant-like effects. However, there have been no reports on whether FLP produces antidepressant-like effects and its potential molecular mechanisms.

We aim to demonstrate the antidepressant-like effects of FLP in chronic restraint stress (CRS) mice and to explore the associated molecular mechanisms.

The active components and probable molecular targets of FLP, as well as the targets related to depression, were identified through network pharmacology. A protein-protein interaction (PPI) network was generated using the overlapping targets, followed by the visualization as well as identification of the core targets associated with the antidepressant-like action of FLP. Subsequently, KEGG and GO enrichment analyses were conducted. UHPLC-MS/MS was employed to further detect the active compounds in FLP. Molecular docking was applied to assess the connections between the active components as well as the core targets. The efficacy of FLP in treating depression and its molecular mechanisms were examined using western blotting, ELISA, 16S rRNA sequencing, HE staining, Nissl staining, and Golgi-Cox staining in a CRS-induced mouse model.

Network pharmacology and UHPLC-MS/MS analyses indicated that the active compounds of FLP comprised taraxerol, songorine, neokadsuranic acid B, ginkgetin, hispaglabridin B, quercetin, benzoylmesaconine and liquiritin. KEGG pathway analysis implicated that the PI3K/Akt/mTOR as well as MAPK signaling pathways are closely related to the therapeutic effects of FLP on depression. Molecular docking analysis demonstrated that the main components of FLP bind to PI3K, AKT, mTOR, BDNF and MAPK. FLP significantly decreased immobility in mice that were elevated by CRS in the FST and the TST. FLP also significantly increased sucrose preference in mice after CRS in the SPT. FLP upregulated proteins associated with BDNF-TrkB and PI3K/Akt/mTOR signaling and downregulated proteins associated with MAPK signaling. Serum levels of CORT, IL-6, IL-1β, and TNF-α in CRS mice were significantly decreased following treatment with FLP. In addition, FLP ameliorated CRS-induced gut microbiota dysbiosis as demonstrated by 16S rRNA sequencing analysis. FLP ameliorated CRS-induced intestinal inflammation and neuronal damage. Finally, antidepressant-like effects and concomitant increases in dendritic spine density induced by FLP administration were also reduced after rapamycin treatment.

These results demonstrate that FLP has antidepressant-like effects in mice exposed to CRS that involve activation of the PI3K/Akt/mTOR signaling pathway, increase in spinogenesis, inhibition of the MAPK signaling pathway, decrease in inflammation, and amelioration of gut microbiota dysbiosis. These findings provide novel evidence for the clinical application of FLP on depression.

Expression of the N-methyl-D-aspartate receptor, particularly when containing the GluN2B subunit (NMDAR-GluN2B) varies across the prefrontal cortex (PFC). In humans, the subgenual cingulate cortex (SGC) contains among the highest levels of NMDAR-GluN2B expression, while the dorsolateral prefrontal cortex (dlPFC) exhibits a more moderate level of NMDAR-GluN2B expression. NMDAR-GluN2B are commonly associated with ionotropic synaptic function and plasticity, and are essential to the neurotransmission underlying working memory in the macaque dlPFC in the layer III circuits afflicted in schizophrenia. However, NMDAR-GluN2B can also be found at extrasynaptic sites, where they may trigger distinct events, including some linked to neurodegenerative processes. The SGC is an early site of tau pathology in sporadic Alzheimer's Disease (sAD), which mirrors its high NMDAR-GluN2B expression. Additionally, the SGC is hyperactive in depression, which is treated with NMDAR antagonists. Given the clinical relevance of NMDAR in the SGC and dlPFC, the current study used immunoelectron microscopy (immunoEM) to quantitatively compare the synaptic and extrasynaptic expression patterns of NMDAR-GluN2B across excitatory and inhibitory neuron dendrites in the rhesus macaque SGC and dlPFC. We found a larger population of extrasynaptic NMDAR-GluN2B in dendritic shafts and spines of putative pyramidal neurons in SGC as compared to the dlPFC, while the dlPFC had a higher proportion of synaptic NMDAR-GluN2B. In contrast, in putative inhibitory dendrites from both areas, extrasynaptic expression of NMDAR-GluN2B was far more frequently observed over synaptic expression. These findings may provide insight into varying cortical vulnerability to alterations in excitability and to neurodegenerative forces.

NMDAR are ionotropic receptors that contribute to neurotransmission and second messenger signaling events. NMDAR can induce a diverse array of neuronal events, in part due to variation in subunit composition and subcellular localization of receptor expression. Expression of the GluN2B subunit varies across the prefrontal cortex in humans. This subunit is highly expressed in the subgenual cingulate, an area associated with mood and emotion, and more moderately expressed in the dorsolateral prefrontal cortex, an area associated with cognitive processes. Extrasynaptic NMDAR, which often contain with the GluN2B subunit, have been linked to detrimental cellular events like neurodegeneration. Here, using high resolution electron microscopy in rhesus macaques, we found evidence that extrasynaptic NMDAR-GluN2B expression may be more prominent in subgenual cortex than in the dorsolateral prefrontal cortex. Conversely, synaptic NMDAR-GluN2B may be more prominent in the dorsolateral prefrontal cortex, consistent with their essential contribution to neuronal firing during working memory. These findings may help to illuminate the propensity of the subgenual cortex to tonic hyperactivity in major depression and its vulnerability to neurodegeneration in Alzheimer's disease, and may help to explain how rapid acting antidepressants exert therapeutic action across diverse neural circuits.

Suicide is a global public health problem with few empirically supported treatments.

We conducted a systematic review of clinical trials (CT) since 2020 of racemic ketamine or one of its enantiomers' (R/S) potential to reduce suicidal ideation or behavior (SIB). An initial PubMed search on April 15th, 2024 yielded 2483 results. 104 relevant CTs were identified. An additional search using other search engines on March 19th, 2024 yielded 52 sources. After screening, 14 RCTs met the inclusion criteria which required clinically significant SIB among participants, ketamine or one of its enantiomers as an anti-SIB treatment, and SIB as an outcome. We excluded neuroimaging studies, meta-analyses, reviews, and case reports. Open-label studies were also excluded except in the case of R-ketamine where we included 2 open trials due to limited published data for this enantiomer, yielding a total of 16 CTs. We used the Revised Cochrane risk-of-bias tool for the RCTs. CTs reviewed had suicidal ideation (SI) but none had suicidal behavior as an outcome.

The studies include ketamine augmentation of other treatments such as electroconvulsive therapy (ECT), various routes of administration - intravenous (IV), intramuscular (IM), and intranasal (IN) - and single versus multiple dose designs. Multiple doses of IV ketamine/S-ketamine produced reductions in SI for periods of several days to weeks, while single doses showed shorter, more variable effects. Multiple and single doses of IN ketamine/S-ketamine and single doses of IV ketamine produced less consistent anti-SI results. IN and IV ketamine/S-ketamine administration appears to be well tolerated. R-ketamine appears to produce fewer side effects, but additional clinical research is needed to clarify its antidepressant and anti-SI effects in humans.

This review affirms the time-limited, anti-SI effects of ketamine and the need for personalized treatment. Limitations include study heterogeneity, small samples, and paucity of data for suicidal behavior or R-ketamine.

Postpartum depression (PPD) is categorized by the Disorders-Fifth Edition as depression that begins during pregnancy or within the first month after giving birth. Ketamine and esketamine have shown promising results in the treatment of several depressive disorders, which suggests that they may have a role in the prevention of PPD. This systematic review and meta-analysis aim to update evidence about the efficacy and safety of using ketamine and esketamine to reduce PPD incidence.

We searched four databases, PubMed, Scopus, Web of Science, and Cochrane, to collect relevant studies. We included studies which investigated the preventive effect of ketamine or esketamine on PPD among women after giving birth through caesarean or vaginal delivery. We extracted PPD occurrence rate, PPD score, pain score and side effects. Finally, a meta-analysis was conducted using RevMan software.

Twenty-one eligible studies were incorporated in the current systematic review and meta-analysis involving 4,389 pregnant women. Esketamine was the intervention in 14 studies, and ketamine was used in 7 studies. In subgroup analysis, both ketamine and esketamine were significantly effective in reducing the incidence of short-term PPD (ketamine: RR = 0.72, 95% CI [0.56, 0.93], P = 0.01; esketamine: RR = 0.43, P < 0.0001). Esketamine only significantly reduced the incidence of long-term PPD (RR = 0.44, P < 0.00001). Low doses and high doses were effective in reducing the incidence of both short-term (high dose: RR = 0.48, P = 0.0005; low dose: RR = 0.46, P = 0.002) and long-term PPD (high dose: RR = 0.54, P < 0.0001; low dose: RR = 0.61, P = 0.009). Regarding the risk of side effects, patients in the Ketamine/esketamine group showed statistically significant higher rates of developing dizziness (P = 0.0007), blurred vision (P = 0.02), vomiting (P = 0.004) and hallucinations (P = 0,002) than women in the control group.

Both ketamine and esketamine are effective in lowering the incidence of short-term PPD. On the other hand, only esketamine is effective in reducing the incidence of long-term PPD. It is recommended to use smaller doses for a more tolerable treatment period since doses less than 0.5 mg are significantly effective. Temporary side effects such as dizziness, blurred vision, vomiting and hallucinations were reported.

This study aims to quantitatively evaluate the efficacy and safety of various treatment regimens for treatment-resistant depression (TRD) across oral, intravenous, and intranasal routes to inform clinical guidelines.

A systematic review identified randomized controlled trials on TRD, with efficacy measured by changes in the Montgomery-Åsberg Depression Rating Scale (MADRS). We developed pharmacodynamic and covariate models for different administration routes, using Monte Carlo simulations to estimate efficacy distribution. Dropout and adverse event-related dropout rates were analyzed via single-arm meta-analysis.

Involving 22 studies with 56 treatment arms and 3059 patients, our findings suggest combination therapies outperform monotherapy, achieving an additional 6.5% reduction in MADRS scores over 12 weeks. The most effective combinations were olanzapine with fluoxetine and quetiapine with selective serotonin reuptake inhibitors/ selective serotonin and norepinephrine reuptake inhibitors. Injectable treatments, particularly ayahuasca, produced rapid effects, with a 77% reduction in MADRS scores at 15 days. Intranasal treatments reached efficacy sooner than oral ones, with 28-day efficacy similar to the 12-week efficacy of the olanzapine-fluoxetine combination. Dropout rates due to adverse events were similar across methods (4.5%-5.2%), but total dropouts were highest for oral (17.9%) and lowest for intranasal routes (10.6%). Additionally, there was considerable variation in the incidence of headache, dizziness, and nausea across different administration routes.

The quantitative evaluation of 22 TRD treatments illuminates key pharmacodynamic parameters, bolstering the development of clinical guidelines and aiding the design of clinical trials and medical decision-making.

Ketamine is an N-methyl-D-aspartate receptor antagonist that has shown effectiveness as a rapidly acting treatment for depression. Although advances have been made in understanding ketamine's antidepressant pharmacological and molecular mechanisms of action, the large-scale neurocognitive mechanisms driving its therapeutic effects are less clearly understood. To help provide such a framework, we provide a synthesis of current evidence linking ketamine treatment to the modulation of brain systems supporting reward processing, interoception, and self-related cognition. We suggest that ketamine's antidepressant effects are, at least in part, driven by dynamic multi-level influences across these key functional domains.

A substantial number of patients exhibit treatment-resistant depression (TRD), posing significant challenges to clinicians. The discovery of novel molecules or mechanisms that may underlie TRD pathogenesis and antidepressant actions is highly needed.

Using the PubMed database, the authors searched for emerging evidence of novel approaches for TRD based on experimental and human studies. Herein, the authors discuss the mechanisms underlying glutamatergic antagonists, modulators of the opioid system, and tryptamine-derivate psychedelics as well as the emerging platforms to investigate novel pharmacological targets for TRD. A search for clinical trials investigating novel agents and interventions for TRD was also conducted.

The understanding of the multiple pathophysiological mechanisms involved in TRD may add further value to the effective treatment, contributing to a more personalized approach. Esketamine was approved for the treatment of TRD and novel drugs with rapid antidepressant actions such as psilocybin and buprenorphine have also been investigated as potential therapeutic strategies. Over the past decades, technological advances such as omics approaches have broadened our knowledge regarding molecular and genetic underpinnings of complex conditions like TRD. Omics approaches could open new avenues for investigating glial-mediated mechanisms, including their crosstalk with neurons, as therapeutic targets in TRD.

Bipolar disorder (BD) is characterized by a complex constellation of emotional, cognitive, and psychomotor disturbances, each deeply intertwined with underlying dysfunctions in large-scale brain networks and neurotransmitter systems. This manuscript integrates recent advances in neuroimaging, neuromodulation, and pharmacological research to provide a comprehensive view of BD's pathophysiology, emphasizing the role of network-specific dysfunctions and their clinical manifestations. We explore how dysregulation within the fronto-limbic network, particularly involving the prefrontal cortex (PFC) and amygdala, underpins the emotional instability that defines both manic and depressive episodes. Additionally, impairments in the central executive network (CEN) and default mode network (DMN) are linked to cognitive deficits, with hyperactivity in the DMN driving rumination and cognitive inflexibility, while CEN underactivity contributes to attentional lapses and impaired executive function. Psychomotor symptoms, which oscillate between hyperactivity in mania and retardation in depression, are closely associated with imbalances in neurotransmitter systems, particularly dopamine and serotonin, within the basal ganglia-thalamo-cortical motor pathway. Recent studies indicate that these psychomotor disturbances are further exacerbated by disruptions in network connectivity, leading to impairments in both motor control and emotional regulation. Emerging therapeutic strategies are discussed, with a focus on neuromodulation techniques such as transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS), which show promise in restoring balance within these critical networks. Furthermore, pharmacological interventions that modulate synaptic functioning and neuronal plasticity offer potential for addressing both the emotional and motor symptoms of BD. This manuscript underscores the need for an integrative treatment approach that simultaneously targets neural circuits and neurotransmitter systems to address the full spectrum of symptoms in BD. Drawing on recent advancements in neurobiological models and therapeutic frameworks, this proposal outlines a pathway for the development of precision-tailored interventions. These approaches are designed to optimize cognitive, emotional, and psychomotor outcomes, ultimately striving to elevate the quality of life for individuals living with bipolar disorder (BD), while remaining firmly grounded in the latest empirical evidence and theoretical insights.

Schizophrenia is a mental disorder characterized by positive, negative, and cognitive symptoms which is treated with antipsychotics. However, these drugs present several side effects and, some schizophrenia symptoms, like cognitive, are difficult to treat. The peroxisome proliferator-activated receptors-gamma (PPAR-γ) are expressed in dopaminergic neurons of the midbrain participating in the modulation of dopamine-mediated behavior . We investigated the effects of pioglitazone, an agonist of PPAR-γ, on the behavioral alterations induced by ketamine and, whether alterations in monoamine oxidase (MAO) activity, glutamic acid decarboxylase (GAD67), PPAR-γ or tyrosine hydroxylase (TH) immunoreactivity in brain tissues are involved in these effects. Male mice received ketamine (30 mg/kg), intraperitoneally, for 14 consecutive days, and pioglitazone (3 or 9 mg/kg), by gavage (day 8 up to day 14). Ketamine decreased nail-biting increasing the time exploring the center of the open field on day 8 and the number of rearing evaluated 30 min after its administration on day 14. Furthermore, ketamine decreased the percentage of investigation in the NOR test and the immunoreactivity of GAD67 in the hippocampus. No significant changes were found in other behavioral and biochemical tests. Pioglitazone attenuated the effects of ketamine on rearing and GAD67 immunoreactivity in the hippocampus, recovering the ketamine effects on NOR test. At a dose of 9 mg/kg, pioglitazone alone reduced the immunoreactivity of GAD67 in the hippocampus. Pioglitazone at both doses recovered the cognitive symptoms induced by ketamine an effect that seems to involve the modulation of GAD67 immunoreactivity in the hippocampus. In conclusion, pioglitazone improved the effects of ketamine on the NOR test which was, at least in part, associated with the modulation of GAD67 immunoreactivity in the hippocampus suggesting its beneficial role in cognitive symptoms.

Esketamine, a newly developed antidepressant, is the subject of this research which seeks to explore its impact on depressive symptoms in neuropathic pain mice and the potential molecular mechanisms involved. Through transcriptome sequencing and bioinformatics analysis combined with in vivo studies, it was identified that esketamine markedly boosts the levels of the m6A methyltransferase METTL3 and the AMPA receptor GluA1 subunit. Esketamine activates METTL3, allowing it to bind with GluA1 mRNA, promoting m6A modification, thereby enhancing GluA1 expression at synapses. Through this mechanism, esketamine may reduce depressive-like behavior in neuropathic pain mice, providing new insights into the potential applications of esketamine and novel therapeutic avenues for neuropathic pain and depressive behavior.

Resveratrol, a plant-derived polyphenol, exhibits significant antidepressant effects and notably enhances neuroplasticity in neurological diseases. However, whether the antidepressant function of resveratrol is related to neuroplasticity remains uncertain, and the underlying mechanisms is poorly understood. This study aims to investigate the role and mechanism of resveratrol in neuroplasticity in depression. Here, we adopted the chronic unpredictable mild stress (CUMS) model and resveratrol intervention by oral gavage. Thereafter, behavioral tests confirmed resveratrol's antidepressant effect, and Nissl staining, Golgi staining, and Western blotting (WB) were employed to assess the neuronal plasticity. Moreover, proteomic analysis and WB were used to screen and identify the key proteins. To investigate the downstream target of ELAV-like RNA-binding protein 4 (ELAVL4) (one of candidate genes), the RNA Interactome Database and the National Center for Biotechnology Information databases were utilized to predict the targets of ELAVL4. Finally, Quantitative PCR, WB, and Immunofluorescence were used to verify the prediction. Our results indicate that resveratrol alleviates CUMS-induced depressive-like behaviors accompanied by the restoration of impaired hippocampal neuroplasticity. Then, proteomic analysis shows that 351 differentially expressed proteins (DEPs) decrease after CUMS, while 24 DEPs increase remarkably with the resveratrol treatment. Among which, ELAVL4 is downregulated by CUMS, simultaneously increasing after resveratrol intervention, which acts as a protective protein in this process. Finally, brain-derived neurotrophic factor (Bdnf) mRNA is predicted to be the potential target of ELAVL4 and validated by molecular technologies. In conclusion, our findings demonstrate that resveratrol's antidepressant efficacy is closely associated with ELAVL4, an RNA-binding protein, a mediated neuroplasticity pathway, potentially intersecting with the Bdnf mRNA. Overall, this research sheds light on the role of the ELAVL4-Bdnf mRNA pathway through neuroplasticity in resveratrol's antidepressant action, which provides an mRNA regulation perspective for the development of novel antidepressants and understanding depression pathology.

Ketamine is a dissociative drug used for the treatment of depression. However, the neurofunctional mechanism underlying the antidepressant effect of ketamine remains unknown. According to previous research, low-dose ketamine affects large-scale brain networks, including default-mode and salient networks.

A total of 43 patients with treatment-resistant depression (TRD) and suicidal ideation (SI) were randomly assigned to receive a single infusion of either 0.5 mg/kg ketamine or 0.045 mg/kg midazolam. Depressive and suicidal symptoms were evaluated using the 17-item Hamilton Depression Rating Scale and the Columbia-Suicide Severity Rating Scale: Ideation Severity Subscale. Resting-state functional magnetic resonance imaging was performed at baseline and on day 3 after infusion. Graph theoretic metrics such as degree centrality and clustering coefficient were examined.

Relative to midazolam use, low-dose ketamine infusion reduced depressive (p = 0.001) and suicidal (p = 0.025) symptoms and improved the brain network integrity, including increased degree centrality and clustering coefficient in the angular gyrus and increased degree centrality in the right thalamus.

Neurofunctional changes in the thalamus and default-mode network (angular gyrus) may be associated with the antidepressant effect of ketamine on patients with TRD and SI.

UMIN Clinical Trials Registry (UMIN-CTR): Registration number: UMIN000033916.

Plastogens are a class of therapeutics that function by rapidly promoting changes in neuroplasticity. A notable example, ketamine, is receiving great attention due to its combined rapid and long-term antidepressant effects. Ketamine is an N-methyl-D-aspartate receptor (NMDAR) antagonist, and, in addition to its therapeutic activity, it is associated with psychotomimetic and dissociative side effects. Stinels-rapastinel, apimostinel, and zelquistinel-are also plastogens not only with rapid and long-term antidepressant effects but also with improved safety and tolerability profiles compared to ketamine. Previous descriptions of the mechanism by which stinels modulate NMDAR activity have been inconsistent and, at times, contradictory. The purpose of this review is to clarify the mechanism of action and contextualize stinels within a broader class of NMDAR-targeting therapeutics. In this review, we present the rationale behind targeting NMDARs for treatment-resistant depression and other psychiatric conditions, describe the various mechanisms by which NMDAR activity is regulated by different classes of therapeutics, and present evidence for the stinel mechanism. In contrast with previous descriptions of glycine-like NMDAR partial agonists, we define stinels as positive allosteric modulators of NMDAR activity with a novel regulatory binding site.

Treatment-resistant depression responds quickly to ketamine. As an N-methyl-d-aspartate receptor (NMDAR) antagonist, ketamine may affect prefrontal cortex (PFC) neurons. Recent investigations reveal that the (R)-enantiomer is the most effective and least abuseable antidepressant. The Food and Drug Administration approves only the (S)-enantiomer for medical usage. (2R,6R)-Hydroxynorketamine (HNK) inhibits mGlu2, linked to a Gi, in presynaptic glutamatergic neurons, increasing brain-derived neurotrophic factor (BDNF) release, which autocrinely activates Tropomyosin receptor kinase B (TrkB) and promotes synaptogenesis. Ketamine, originally an anesthetic, has garnered attention for its many pharmacological effects, including its potential as a rapid-acting antidepressant and recreational use. In this Perspective, we explore the synthesis, pharmacology, metabolism, and effects of ketamine and its metabolites in animal and human studies to explain the difference in the biological activity between the enantiomers.

Context: Psychiatric and existential distress are common and difficult-to-treat symptoms that are frequently encountered in the palliative care setting; current treatment options are limited in efficacy and tolerability. Psychedelic-assisted therapies (PAT) have gained public and scientific interest in their potential to induce rapid and effective reductions in psychiatric and existential distress in patients with serious medical illness, but remain available only in the research setting. Ketamine as a pharmacologic agent has a large body of evidence in the treatment of refractory depression. Objectives: To review the evidence that exists for use of ketamine or ketamine-assisted psychotherapy (KAP) for psychiatric and existential distress in patients with serious medical illness, aiming to identify therapeutic signals and gaps in research. Methods: A literature search identified publications of (1) ketamine or KAP, (2) psychiatric or existential distress, and (3) palliative care or patients with serious medical illness. Identified reports were carefully reviewed with attention to population and treatment-related factors, which were described in a narrative and aggregate format. Results: Nine studies and 12 case reports were identified that reported positive results and a good safety profile. There was significant variation in patient population, setting, route of administration, dosing schedule, and concurrent treatments. Most reports were of ketamine as a pharmacologic agent for symptoms of psychiatric distress. Conclusion: Evidence suggests that ketamine may induce rapid and transient improvements in psychiatric symptoms in patients with serious medical illness. A large gap in research exists for KAP and symptoms of existential distress. There is a signal that suggests ketamine could be used in a psychedelic therapy model with potential benefits over classical psychedelics.

Given ketamine's conflicting impacts on the central nervous system, investigating its effects within an inflammatory context becomes crucial. This study aimed to assess the impact of varying ketamine doses on neurotrophin and inflammatory cytokine levels within the brains of rats submitted to the sepsis model. Wistar rats were submitted to the cecal ligation and puncture (CLP) model of sepsis. Intraperitoneal ketamine injections (5, 15, or 25 mg/kg) or saline were administered daily for seven days, thirty days post-CLP. Rats were euthanized thirty minutes following the last injection for analysis of IL-1β, IL-6, IL-10, TNF-α, BDNF, NGF, NT-3, and GDNF levels in the frontal cortex, hippocampus, and striatum. CLP-induced elevated IL-1𝛽, IL-6, IL-10, and TNF-α levels in the frontal cortex and hippocampus of rats, with reduced BDNF levels across all structures examined. Furthermore, reduced NGF and GDNF levels were observed solely in the hippocampus. Ketamine at 5 mg/kg normalized CLP-induced alterations and, in Sham animals, increased BDNF and NGF levels in the frontal cortex and/or hippocampus. At 15 mg/kg, ketamine elevated BDNF and NGF levels in Sham animals, while at 25 mg/kg, it exacerbated the inflammatory response initiated by CLP. These findings suggest variable effects of ketamine within a context of systemic inflammation, emphasizing the importance of considering individual inflammatory backgrounds when utilizing ketamine.

Epilepsy presents a significant global health challenge, impacting millions worldwide. Alarmingly, over half of individuals living with epilepsy (PWE) also face concurrent medical conditions, with psychiatric complications, particularly depression, standing out as prevalent issues. The relationship between epilepsy and depression is complex and bidirectional, with approximately a quarter of adults with epilepsy receiving a diagnosis of depression. This complexity underscores the challenges in diagnosing depression in epilepsy patients, hindered by overlapping symptoms and distinct manifestations of depression in this population. Our review highlights that the use of most antidepressant pharmacotherapies does not increase the risk of seizure occurrences. On the contrary, compelling evidence suggests that such treatments may even decrease seizure frequency, offering hope for patients. In addition to pharmacology, non-pharmacological interventions are emerging as vital alternatives, enriching the therapeutic landscape. However, despite these promising avenues, a significant gap in our understanding persists, characterized by a lack of comprehensive, prospective research. Our review rigorously explores the latest pathophysiological insights linking depression and epilepsy while critically evaluating contemporary treatment paradigms for individuals grappling with these comorbid conditions. By focusing on the most current developments, this review aims to equip clinicians with cutting-edge knowledge, fostering a more nuanced and effective approach to managing the intricate interplay between epilepsy and comorbid depression.

Major depressive disorder (MDD) is characterized by persistent feelings of sadness and loss of interest. Ketamine has been widely used to treat MDD owing to its rapid effect in relieving depressive symptoms. Importantly, not all patients respond to ketamine treatment. Identifying sub-populations who will benefit from ketamine, as well as those who may not, prior to treatment initiation, would significantly advance precision medicine in patients with MDD.

Here, we used mass spectrometry-based plasma proteomics to analyze matched pre- and post-ketamine treatment samples from a cohort of 30 MDD patients whose treatment outcomes and demographic and clinical characteristics were considered.

Ketamine responders and non-responders were identified according to their individual outcomes after two weeks of treatment. We analyzed proteomic alterations in post-treatment samples from responders and non-responders and identified a collection of six proteins pivotal to the antidepressive effect of ketamine. Subsequent co-regulation analysis revealed that pathways related to immune response were involved in ketamine response. By comparing the proteomic profiles of samples from the same individuals at the pre- and post-treatment time points, dynamic proteomic rearrangements induced by ketamine revealed that immune-related processes were activated in association with its antidepressive effect. Furthermore, receiver operating characteristic curve analysis of pre-treatment samples revealed three proteins with strong predictive performance in determining the response of patients to ketamine before receiving treatment.

These findings provide valuable knowledge about ketamine response, which will ultimately lead to more personalized and effective treatments for patients.

The study was registered in the Chinese Clinical Trials Registry (ChiCTR-OOC-17012239) on May 26, 2017.

Diabetes mellitus (DM) has become a public health problem, which is associated with high morbidity and mortality, due to the chronic complications, such as diabetic neuropathy. Current recommendations for the treatment of neuropathic pain achieve a reduction of 30% in only 30% of cases. Therefore, it is necessary to identify new therapeutic approaches to improve the quality of life of diabetic patients.

This work evaluated the antinociceptive effect of intranasal administration of the combination of dextro-ketamine (keta), a non-competitive glutamatergic receptor antagonist, and dexmedetomidine (DEX), a selective alpha2-adrenergic agonist, in rats with neuropathic pain induced by streptozotocin-DM.

The thermal hyperalgesia and mechanical allodynia observed in DM model are reduced with the intranasal administration of the combination of keta and DEX (200 + 0.10 μg/kg) after 3 days of treatment. The antinociceptive action could be due to reduction of Ca2+ influx with lower glutamate release and reduced excitability through the activation of alpha2-adrenergic receptors by DEX and reduction of NMDA receptor activation by glutamate with lower excitability due to the antagonism produced by keta. DM induced increased expression of glial fibrillary acid protein (GFAP) and tumor necrosis factor-alpha (TNF-alpha) detected by immunohistochemistry, indicating greater astrocyte activity and intense inflammatory response. Intranasal administration for 10 days of the combination of low doses of keta and DEX promoted an intense decrease in the expression of both GFAP and TNF-alpha, indicating lower activation of astrocytes in the spinal cord and reduced production and release of TNF-alpha, favoring the reduction of inflammation.

Intranasal administration of low doses of keta with DEX could be a new therapeutic approach to reduce neuropathic pain and consequently improve the quality of life of diabetic patients.