Major depressive disorder (MDD) is a leading cause of disability worldwide, and currently available antidepressants remain limited by delayed onset of action, incomplete response, and adverse effects. Ketamine is a rapid-acting antidepressant, whereas xanomeline, an M1/M4 muscarinic receptor agonist, may represent a mechanistically distinct non-monoaminergic strategy. However, the molecular...
To determine whether antibiotic-induced microbiome depletion influences baseline or 3,4-methylenedioxymethamphetamine (MDMA)-induced oxytocin signaling in rats. Male Wistar rats received broad-spectrum antibiotics (ABX) or water for 7 days, followed by a single oral administration of MDMA (30 mg/kg). Plasma oxytocin levels were measured by ELISA, and oxytocin-immunoreactivity in the...
), a combination of the muscarinic M1/M4 receptor agonist xanomeline and the peripherally restricted antagonist trospium, effectively reduces psychosis but is associated with gastrointestinal adverse effects. Here, we tested whether KarXT reverses phencyclidine (PCP)-induced cognitive deficits through microbiota-associated mechanisms in adult male mice. Mice received saline or PCP (10...
Ketamine, a potent N-methyl-D-aspartate receptor (NMDAR) antagonist, is widely used for anesthesia and analgesia and, because of its rapid antidepressant effects, in psychiatry. Increasing evidence suggests that ketamine and its enantiomers-(R)-ketamine (arketamine) and (S)-ketamine (esketamine)-also modulate systemic immunity and provide organ protection, partly through interactions with the...
Major depressive disorder remains a leading cause of disability worldwide, and current antidepressants are limited by delayed onset and incomplete response. Building on advances driven by ketamine research, renewed interest has focused on classical serotonergic psychedelics—particularly psilocybin, N,N-dimethyltryptamine (DMT), 5-methoxy-DMT, and lysergic acid diethylamide (LSD)—which, under...
Treatment-resistant depression (TRD) affects about one-third of people with major depression and leads to higher suicide rates, impaired functioning, and increased healthcare use. Originally defined as nonresponse to tricyclic antidepressants, TRD now encompasses inadequate response to multiple antidepressant classes, psychotherapy, and neuromodulation. Inconsistent criteria-varying by agency,...
Objective: To investigate neurobiological mechanisms through which esketamine produces rapid antidepressant effects in adolescents with major depressive disorder (MDD), focusing on structural changes in the rostral anterior cingulate cortex (rACC) and associated molecular pathways. Method: A total of 49 adolescents (13-18 years of age) with DSM-5 MDD were randomized to receive intravenous...
Chronic stress precipitates depression, yet how gut-immune-brain interactions translate stress into mood pathology remains unclear. We tested the hypothesis that stress-primed small intestinal γδ T cells drive hippocampal mitochondrial dysfunction and depression-like behavior via interleukin-17A (IL-1A). In mice exposed to chronic restraint stress (CRS), we combined behavioral assays...
3,4-Methylenedioxymethamphetamine (MDMA) is widely used recreationally but also modulates serotonergic signaling in the gut, potentially influencing the microbiota. Because low bone mineral density (BMD) is common in depression and other psychiatric disorders, we tested whether repeated, intermittent MDMA attenuates BMD loss in ovariectomized (OVX) mice. OVX mice received MDMA (10 mg/kg) three...
Patients with preexisting sleep disorders face a significantly increased risk of postoperative sleep disturbance (PSD) due to heightened sensitivity to surgical stress, anesthesia, and hospital-related environmental factors. There is a critical unmet need for effective prophylactic medications to prevent PSD, as current treatment options are limited and often inadequate. This study investigated...
MDMA, 3,4-methylenedioxymethamphetamine (“ecstasy,” “molly”), is a distinctive entactogen that reverses the serotonin (5-HT) transporter to increase synaptic 5-HT, while also engaging catecholaminergic and oxytocinergic pathways. In clinical trials, MDMA-assisted psychotherapy has yielded substantial improvements in treatment-resistant posttraumatic stress disorder (PTSD), although regulatory...
Arketamine, the (R)-enantiomer of (R,S)-ketamine, shows even greater rapid and sustained antidepressant-like effects in rodent models compared to esketamine, yet the underlying mechanisms remain unclear. In this study, we used the chronic social defeat stress (CSDS) model to investigate how arketamine exerts its antidepressant-like effects. We found that activating cAMP response element-binding...
Demyelination, defined as the loss of myelin sheaths around neuronal axons, is increasingly recognized as a key factor in a broad range of psychiatric and neurological disorders, including schizophrenia, major depressive disorder, bipolar disorder, post-traumatic stress disorder, autism spectrum disorder, substance use disorders, Alzheimer's disease, Parkinson's disease, and multiple sclerosis....
3,4-Methylenedioxymethamphetamine (MDMA) is a widely recognized entactogen frequently used recreationally. It is known for its interaction with the serotonin and oxytocin systems, which underlie its entactogenic effects in humans. Recently, we demonstrated that the gut-brain axis, mediated by the subdiaphragmatic vagus nerve, contributes to MDMA-induced resilience enhancement in rodents. This...
3,4-Methylenedioxymethamphetamine (MDMA), commonly known as a recreational drug, may also offer therapeutic benefits for mental health. Population-based studies suggest that MDMA users have a lower risk of demyelinating diseases, such as depression. Given the role of the gut microbiota in mediating MDMA's effects, we hypothesized that MDMA might confer mental health benefits via the gut-brain...
Depression is a prevalent mental disorder, affecting approximately 300 million people worldwide. Despite decades of research into the underlying mechanisms of depression, a consensus remains elusive. Recent studies have implicated changes in oligodendrocytes and myelin in the pathogenesis of depression. Conventional antidepressants may alleviate symptoms within weeks of use, but approximately...
Postoperative cognitive dysfunction (POCD) is characterized by a decline in cognitive functions, including memory, attention, and executive abilities, following surgery, with no effective therapeutic drugs currently available. Arketamine, the (R)-enantiomer of ketamine, has shown promise in mitigating cognitive deficits in animal models. In this study, we investigated whether arketamine could...
3,4-Methylenedioxymethamphetamine (MDMA; Ecstasy) is a widely abused recreational drug that has also gained interest for potential clinical applications in mental health. With the growing recognition of gut microbiota's role in mental health, this study examined whether repeated oral MDMA administration could affect gut microbiota in the small intestine, cecum, and colon of male rats. Repeated...
Chronic restrain stress (CRS) induces depression-like behaviors and demyelination in the brain; however, the relationship between these depression-like behaviors and demyelination remains unclear. Arketamine, the (R)-enantiomer of ketamine, has shown rapid antidepressant-like effects in CRS-exposed mice. We examined whether arketamine can improve both depression-like behaviors and demyelination...
The novel antidepressant arketamine, the (R)-enantiomer of ketamine, has been shown to ameliorate demyelination and facilitate remyelination in the brains of cuprizone (CPZ)-treated mice. However, the mechanisms behind its effects remain unclear. Given the role of transforming growth factor β1 (TGF-β1) in arketamine's antidepressant-like effects, we examined whether TGF-β1 also plays a role in...
Arketamine, the (R)-enantiomer of ketamine, exhibits both therapeutic and sustained prophylactic effects in an inflammation-driven model of depression, although the precise mechanisms remain elusive. Given the involvement of γδ T cells in inflammatory processes, this study explored their role in the effects of arketamine. To assess therapeutic outcomes, mice received lipopolysaccharide (LPS:1.0...
Acute kidney injury (AKI) is a serious condition characterized by decreased urine output, often accompanied by psychiatric symptoms like depression. However, there are limited pharmacological treatments available for AKI and its associated depressive symptoms. In this study, we investigated whether cisplatin-induced AKI in mice leads to depression-like behaviors and whether ketamine could...
Arketamine, the (R)-enantiomer of ketamine, exhibits antidepressant-like effects in mice, though the precise molecular mechanisms remain elusive. It has been shown to reduce splenomegaly and depression-like behaviors in the chronic social defeat stress (CSDS) model of depression. This study investigated whether the spleen contributes to the antidepressant-like effects of arketamine in the CSDS...
Ketamine, a dissociative anesthetic, is widely utilized in both human and veterinary anesthesia. Its (S)-enantiomer, esketamine, is similarly employed for anesthesia and analgesia. The anesthetic effects of both ketamine and esketamine arise from their antagonism of the N-methyl-D-aspartate receptor (NMDAR). In field of psychiatry, the rapid-acting antidepressant properties of ketamine for...