International Journal of Neuropsychopharmacology

RationalePsychedelic compounds such as psilocybin have attracted growing interest for their potential therapeutic effects in psychiatric disorders, with improvements in cognitive flexibility proposed as a possible mechanism of action. However, the effects of psychedelics on cognitive flexibility remain poorly understood. ObjectiveThis study aimed to examine the acute and post-acute effects of psilocybin (0.1, 0.3, 1 mg/kg) and lysergic acid diethylamide (LSD, (0.02, 0.04, 0.08 mg/kg) on cognitive flexibility in male rats. MethodsThis was tested using two variants of the probabilistic reversal learning task (PRLT): a touchscreen-based operant task and a more ethological foraging-based task. ResultsIn the touchscreen PRLT, acute psilocybin disrupted task engagement, with animals completing fewer trials and showing increased trial initiation latency, although psilocybin also showed a trend toward faster initial rule acquisition. However, psilocybin did not significantly alter the number of rule changes achieved, a canonical measure of cognitive flexibility, or feedback sensitivity. LSD similarly produced limited acute effects, although the highest dose reduced lose-shift probability, suggesting decreased sensitivity to negative feedback under some conditions. Post-acute effects of psilocybin were minimal in both PRLT variants and, where LSD effects were observed these occurred across different doses and timepoints without a consistent pattern. ConclusionsOverall, these findings suggest that serotonergic psychedelics do not robustly enhance reversal learning in these paradigms and that apparent learning effects may reflect transient disruptions in task engagement rather than improvements in cognitive flexibility. These results also highlight potential limitations of these PRLT paradigms for detecting psychedelic-induced changes in cognitive flexibility in rodents.

Background: Stimulant exposure can induce acute stereotyped behaviors and chronic alterations in brain connectivity and white matter integrity. However, the temporal sequence and molecular changes linking these cocaine-induced phenotypes remain unclear. Methods: We combined LabGym-based behavioral analysis, longitudinal brain imaging, and cross-species molecular analysis in 11 common marmosets (Callithrix jacchus; seven male, four female): four underwent behavioral and imaging studies, six provided molecular data, and one provided immunohistochemical data. Male Cryab knockout and wild-type mice underwent functional studies. Results: Acute cocaine (5 mg/kg, intraperitoneally) induced rapid, repetitive lateral head movements, defined as head shaking. After 1 and 10 months of repeated exposure, resting-state functional connectivity was altered in sensory, parietal, prefrontal, motor, and hippocampal regions. Changes were detected at 1 month, whereas diffusion tensor imaging showed reduced fractional anisotropy and axial diffusivity in the corpus callosum splenium at 10 months, with no significant genu changes. Cross-species transcriptomic and proteomic comparison identified DPYSL2 and DNM3 as shared axon-associated molecules. Western blotting showed reduced DPYSL2 in brain tissue from cocaine-treated marmosets. CRYAB localized to O4-positive callosal oligodendrocytes and increased following chronic cocaine exposure. Cryab knockout mice had reduced corpus callosum thickness, increased forced-swim immobility, and reduced open-field distance traveled, supporting a role for CRYAB in corpus callosum integrity and depression-related behavior. Conclusions: These findings show that acute cocaine-induced stereotyped head shaking precedes functional connectivity changes and later corpus callosum deficits. Reduced DPYSL2 may be associated with axonal dysfunction, whereas increased CRYAB may represent a response to cocaine-induced white matter stress.

Background: Reduced concentrations of the neuropeptide oxytocin can occur in disorders with social dysfunction, notably autism. However, the role of peripheral endogenous oxytocin concentrations and increased ones following exogenous administration in modulating key social behaviors in humans is still unclear. Here we investigated effects of targeting peripheral oxytocin receptors through oromucosal administration of oxytocin and an oxytocin receptor antagonist (atosiban) on social attention. Methods: We carried out a pre-registered, randomized, double-blind, placebo-controlled experiment with 250 adult male subjects in five treatment groups (placebo + placebo, placebo + 24 IU OT, placebo + 48 IU OT, atosiban + placebo, and atosiban + 24 IU OT), each receiving two oromucosal (lingual) administrations separated by 15 minutes. Following treatment, subjects performed an autism-sensitive dynamic social versus geometric pattern eye-tracking paradigm. Pre- and post-treatment blood samples were collected for oxytocin measurement. Results: Results showed that 48IU but not 24IU oxytocin significantly increased preferential viewing of social stimuli relative to placebo, and effects were associated with, and mediated by, increased oxytocin concentrations and negatively correlated with subjects autism quotient scores. On the other hand, atosiban reduced preference for social stimuli relative to placebo even after subsequent administration of 24IU oxytocin. Conclusions: Our findings suggest that both exogenous and endogenous oxytocin can act via peripheral receptors to enhance interest in social relative to non-social stimuli, possibly influencing the brain via acting on G[q]-coupled receptors in the vagal system. This further supports the therapeutic potential of oxytocin for social dysfunction.

Executive functions are a set of cognitive processes that regulate behavior and adapt responses to changing demands. Impairments in these processes are common in various neuropsychiatric conditions, including obsessive-compulsive disorder. Mice overexpressing the neuronal glutamate transporter EAAT3 in the forebrain (EAAT3glo/CaMKII) exhibit increased compulsive behaviors and synaptic alterations relevant to OCD. However, whether EAAT3 overexpression affects executive functioning across multiple cognitive domains has not been studied. Using operant conditioning and visuospatial learning tasks, we evaluated the performance of EAAT3glo/CaMKII mice across three behavioral domains commonly associated with executive function: cognitive flexibility, working memory, and inhibitory control. EAAT3glo/CaMKII mice showed impaired cognitive flexibility in both operant extinction and reversal learning. EAAT3glo/CaMKII mice also failed to acquire the Trial-unique, delayed nonmatching-to-location task, suggesting impaired working memory, and showed increased impulsivity in the five-choice serial reaction time task, as evidenced by elevated premature responses. Perseverative responses, response accuracy, and attentional performance were unaffected in EAAT3glo/CaMKII mice. Collectively, these findings suggest that EAAT3 overexpression in forebrain neurons is associated with a cognitive profile characterized by difficulties in flexibility and task acquisition, alongside increased impulsivity, while attentional performance and motivational measures remain intact in a model of compulsive behavior.

To date, no pharmacotherapy has been approved for cocaine use disorder. Endocannabinoid signaling is closely related to dopamine-dependent reinforcement and may regulate cocaine-related behaviors. In this study, we used common marmosets (Callithrix jacchus) to investigate whether 2-arachidonoylglycerol (2-AG), an endogenous cannabinoid lipid, reduces cocaine reinforcement in a non-restraint oral self-administration model. Marmosets performed oral cocaine self-administration under a fixed-ratio 1 schedule, and cocaine intake was confirmed using plasma benzoylecgonine detection. Dopamine transporter (DAT)-related positron emission tomography (PET) signal, DAT and G protein-coupled receptor 55 (GPR55)-associated fluorescent signals, GPR55/DAT immunofluorescence, and synaptosomal dopamine responses were assessed using 18F-N-(3-fluoropropyl)-2{beta}-carboxymethoxy-3{beta}-(4-iodophenyl) nortropane (18F-FP-CIT) PET imaging, ex vivo fluorescent ligand imaging, confocal microscopy, and dopamine quantification. Marmosets acquired oral cocaine self-administration with preferential active lever responding. Repeated cocaine self-administration reduced striatal DAT-related 18F-FP-CIT PET signal in vivo. In striatal slices, cocaine decreased fluorescent false neurotransmitter (FFN102)-associated DAT signal and increased T1117-associated GPR55 signal. Systemic 2-AG pretreatment reduced cocaine self-administration while restoring diminished circulating 2-AG levels. GPR55 and DAT immunofluorescent signals were colocalized in marmoset brain sections, and 2-AG enhanced cocaine-induced dopamine elevation in synaptosomal preparations. Taken together, these findings suggest that 2-AG attenuates cocaine-taking behavior and may be associated with GPR55/DAT-related dopaminergic responses in common marmosets.

Major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) are prevalent, chronic, and disabling mental health conditions which are difficult to treat. Ketamine has demonstrated effect for improving depression and PTSD symptoms independently but reports often overlook focused comorbid improvement of these symptoms within individuals. To address this, we assessed blood-based biomarker and psychological changes following low-dose oral ketamine treatment for adults with MDD alone (n=14) and comorbid MDD+PTSD (n=21). Before treatment, the MDD clinical group presented with more severe depression, lower serotonin levels and higher kynurenine levels than the MDD+PTSD group. Post-treatment there were no detectable differences in the biological response between clinical groups, with combined analysis revealing common decreases in circulating brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF-A). Additionally, post-treatment, both clinical groups showed improvements in anxiety, stress, social functioning, suicidal ideation, and general well-being measures, as well as individual improvements in depression scores and PTSD symptoms in the MDD- and PTSD-containing groups, respectively. Collectively, this study presents additional evidence that low-dose oral ketamine treatment can be effective for MDD and MDD+PTSD, individually and comorbidly, and that both MDD and PTSD clinical groups responded in the same biological manner.

Importance: Obsessive-Compulsive Disorder (OCD) has a 2% global prevalence, but only about 50% of patients respond to conventional treatment, underscoring the need for additional effective interventions. Objective: To assess the feasibility, safety, and preliminary evidence for efficacy of repeated psilocybin administration in OCD patients who had previously attempted psychotherapy or pharmacotherapy. Design: Waitlist-controlled open label randomized clinical trial. Setting: Data were collected at the Johns Hopkins University School of Medicine. Participants: Data were analyzed from 30 participants (total randomized N=37, by age, sex and OCD severity) with a failed previous attempt at either pharmacotherapy or evidence-based psychotherapies such as exposure response prevention (ERP). Intervention: Participants received two psilocybin doses over two weeks (20 mg followed by 30 mg, if well-tolerated) under supportive conditions. The immediate-treatment arm received the drug within a month following enrollment, and the waitlist-control arm received identical support and dosing after an 8-week waiting period. Main Outcomes: Clinician-administered Y-BOCS scores was collected one week post each drug administration and one month post session 2. Self-assessed reports were collected for acute subjective effects (Mystical Experience Questionnaire (MEQ), Challenging Experience Questionnaire (CEQ), and 11-Dimensional Altered States of Consciousness (11D-ASC)), State-Trait Anxiety Inventory (STAI), Beck Depression Inventory-II (BDI-II), and Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). Results: A total of 37 participants were enrolled in the study (age[SD] years:38.4[11.6] years; 21 [56.75%] female), with 30 [81.08%] completing the 1-month follow-up. We show that two successive doses of psilocybin over two weeks were well-tolerated, leading to improvements in OCD symptoms. Compared with the waitlist group (N=14), the immediate-treatment group (N=16) showed a greater reduction in the Y-BOCS scores (F(2,56)=16.17, p<0.001). After crossover, this improvement persisted one month after the second psilocybin dose for both groups (F(3,84)=29.91, p<0.001). Reductions in Y-BOCS score post sessions were correlated with several acute subjective effects measures, including total scores on MEQ, and individual factors on CEQ and 11D-ASC. Conclusions and Relevance: Repeated psilocybin administration is tolerable and potentially efficacious in reducing OCD symptoms. These results support further investigation of multidose psilocybin protocols as a viable therapeutic approach. Trial Registration: ClinicalTrials.gov Identifier NCT05546658

Alcohol use disorder is associated with persistent neuroadaptations and cognitive impairments, particularly during withdrawal, yet the temporal dynamics and interactions between these processes remain poorly understood. In the present study, we investigated time-dependent alterations in the oxytocin receptor (OTR), -opioid receptor (MOPr), metabotropic glutamate receptor 5 (mGlu5R), and translocator protein (TSPO) following chronic ethanol exposure and withdrawal, and their relationship to behavioral impairments. Male C57BL/6J mice were exposed to a 10-day escalating-dose ethanol liquid diet paradigm followed by 1, 4, or 7 days of withdrawal. Motor coordination and recognition memory were assessed using rotarod and novel object recognition tests, and receptor binding was quantified using autoradiography across multiple brain regions. Chronic ethanol exposure induced motor deficits that persisted during early withdrawal, whereas recognition memory impairments emerged after 7 days of withdrawal. Ethanol exposure and withdrawal produced region- and time-dependent alterations across all systems examined, with increased OTR binding in septal regions and transient reductions in basomedial amygdala OTR binding during intermediate withdrawal that normalized following prolonged withdrawal, transient increases in MOPr binding in striatal regions at 4 days of withdrawal, increased mGlu5R binding in the nucleus accumbens core, basolateral amygdala, and hippocampus, and early transient increases in TSPO binding indicative of neuroimmune activation. Notably, mGlu5R binding in the caudate-putamen and amygdala was associated with recognition memory deficits in a withdrawal stage-dependent manner. Bioinformatic analysis of human postmortem hippocampal transcriptomic datasets from individuals with alcohol use disorder revealed no consistent changes in GRM5 expression, suggesting that mGlu5R dysregulation may be driven by post-transcriptional mechanisms. These findings demonstrate that ethanol withdrawal is characterized by temporally distinct neuroadaptations across multiple systems and identify mGlu5R as a key correlate of withdrawal-associated memory impairment, highlighting its potential as a translational therapeutic target.

Chronic stress elicits widespread, multisystem alterations, among them the increased production of inflammatory mediators by immune cells, that culminate in physiological and psychological disruptions. Microglia are resident macrophages of the CNS that show altered morphology alongside increases in pro-inflammatory cytokine release and phagocytosis in response to chronic stress. Chronic stress-induced behavioural and physiological alterations can be replicated in rats using daily injections of corticosterone (CORT) over a prolonged period. Reelin, a glycoprotein reduced in depression and animal models of chronic stress, rapidly reverses chronic CORT-induced symptoms following a single 3 g injection. However, high levels of reelin may be pro-inflammatory, indicating the need to determine if a dose of reelin that resolves chronic stress-induced impairments exacerbates neuroinflammation as a possible adverse effect of reelin treatment. Using either a single 3 g reelin injection following chronic stress or repeated (3) reelin injections throughout chronic stress in male Long Evans rats, we show that reelin does not promote microglia morphologies indicative of pro-inflammatory function within the context of chronic stress, and that both reelin administration schedules rapidly reverse chronic stress-induced despair-like behaviour. These results offer insight into the effect of peripheral reelin administration on processes underlying neuroinflammation and suggest that restoring reelin following chronic stress does not exacerbate microglia-driven neuroinflammation. This research together with past research from our lab supports the advancement of reelin or reelin peptides towards clinical evaluation as a rapid antidepressant.

Post-traumatic stress disorder (PTSD) is a highly prevalent, debilitating psychiatric condition. Existing treatments are ineffective for many patients. 3,4- methylenedioxymethamphetamine (MDMA)-assisted psychotherapy has demonstrated substantial clinical efficacy but relies on prolonged, resource-intensive therapeutic protocols that limit scalability and accessibility. Here, we investigated whether combining MDMA with exposure-based intervention could enhance therapeutic efficiency in a preclinical model of PTSD-like behavior. Using a learned helplessness paradigm in mice, we identified trauma-susceptible individuals based on persistent escape failures following inescapable stress. Traumatised mice subsequently received brief treatment regimens consisting of MDMA or saline vehicle administered with or without exposure to the traumatic cue. Behavioral outcomes were tracked longitudinally using active avoidance performance as the primary endpoint, complemented by assays of anxiety- like, depressive-like, cognitive, and social behaviors. MDMA treatment markedly reduced trauma-associated behavioral deficits. MDMA combined with exposure produced rapid and sustained recovery compared to control conditions. Statistical analyses revealed significant treatment- and time-dependent effects on avoidance behavior, indicating accelerated resilience acquisition in MDMA-treated groups. Additional behavioral assays demonstrated dose-dependent effects of MDMA on anxiety- and depression-related measures. Together, these findings provide proof-of-principle that pharmacological modulation with MDMA can enhance exposure-driven behavioral recovery, supporting a strategy to integrate MDMA into more efficient and accessible PTSD treatment frameworks. This work establishes a preclinical foundation for clinical studies aimed at optimizing MDMA-assisted interventions to improve scalability and patient access.

Background: Social difficulties in alcohol use disorder (AUD) have been linked to alterations in social cognition, including increased egocentric bias. Psychedelics such as psilocybin have been proposed to modulate self-related processing, but their effects on specific socio-cognitive mechanisms remain unclear. Methods: In this randomized controlled pilot study, recently detoxified individuals with AUD with persistent depressive symptoms completed a visual perspective-taking task before and after a psilocybin session (25 mg dose vs active placebo 1 mg psilocybin). Results: The 25 mg psilocybin group showed a significant reduction in egocentric bias and egocentric superiority on reaction times, with no effect on altercentric bias nor on accuracy. Between-group comparisons confirmed greater reductions in the high-dose relative to the low-dose group. The high-dose group reported more intense subjective psychedelic experiences, and greater subjective intensity was associated with lower egocentric superiority in accuracy. Conclusions: These findings provide preliminary evidence that psilocybin may selectively reduce egocentric interference in individuals with AUD, suggesting a decrease in egocentricity rather than enhanced sensitivity to others. Although replication in larger samples is needed, reduced egocentricity may represent one mechanism through which psilocybin influences social cognition in AUD. Clinical trial registration: ClinicalTrials.gov, https://clinicaltrials.gov/study/NCT06235411, NCT06235411.

Background: ADHD is characterized by inattention and impulsivity. Stimulants such as amphetamine are the first line treatments for ADHD. Amphetamine (AMPH) works by increasing extracellular levels of dopamine and noradrenaline. Such stimulants are used to test predictive validity of animal tasks, where it has been reported that amphetamine improves rat 5-CSRTT accuracy when the session length is increased to 250 trials. This improvement in accuracy was observed later in the session as control performance declined. Proving that amphetamine can improve 5C-CPT task performance adds to the predictive validity of the task. No previous works has demonstrated the pro-attentional effects of amphetamine on sustained attention in rat 5C-CPT. We have previously shown that pharmacological manipulations of dopaminergic system improve waiting impulsivity in a rate dependent manner and the importance of analysing the data using Oldham method. The present study extends this work to investigate the effect of amphetamine on attentional processes. Objective: to investigate effects of amphetamine on attentional processes as measured by 5C-CPT task using correlational analysis and group performance. Methods: Trained female Lister hooded rats were tested with AMPH (0.1, 0.2 and 0.4 mg/kg) under reduced stimulus duration schedule (0.25,0.5,1,1.5 and 2s SD) over normal length session (120 trials). Correlational analysis (Oldham method) was used to understand the relationship between baseline performance measures and the change following administration of AMPH. Results: The highest dose of AMPH impaired attentional performance in the 5C-CPT under reduced SD challenge (0.5s,1s,1.5s and 2s). This impairment was due to increase in FAR. Previous studies in 5-CSRTT suggest that reducing the SD increases attentional demand in the form of reducing accuracy without affecting waiting impulsivity. However, the 5-CSRTT does not include non-target trials, therefore, it cannot be used to measure sustained attention (SI) and responsivity index. The 5C-CPT requires greater attentional resources than the 5-CSRTT.This study is the first to report that reducing the SD changes responsivity index (bias) rather than measures of sustained attention (sensitivity index) in the 5C-CPT. Control sensitivity index did not change until the SD was reduced to less than 0.5s and this change was due to a change in baseline responsivity index (bias). Performance under each reduced SD revealed that the highest dose of AMPH (0.4 mg/kg) showed a tendency toward reducing sensitivity index at 0.5, 1.0 and 1.5s SDs. Under 1.0s SD, the highest dose of AMPH changed sustained attention (SI, HR and FAR) and omission in a rate-dependent manner without changing responsivity index. Performance across the session revealed that the impairment in sustained attention was observed at the beginning of the session. In the third trial block, Oldham method revealed an inverse relationship between baseline accuracy and the change following administration of 0.2 mg/kg AMPH, indicative of a rate-dependent effect. Conclusions: This study successfully demonstrates rate-dependent effects of AMPH on measures of attentional performance in the 5C-CPT. This experiment also demonstrates that responsivity index is sensitive to reduced SD challenge. To our knowledge this is the first study to report the presence of a direct relationship between baseline sustained attention and magnitude of improvement following administration of 0.4 mg/kg AMPH and an inverse relationship between baseline accuracy and the change following administration of 0.2 mg/kg AMPH in 5C-CPT task. Future studies should test lower doses of amphetamine (0.05 and 0.1 mg/kg) over extended session length (250 trials) to reveal the pro-attentional effects of this drug on 5C-CPT performance measures.

Negative emotional bias, including reduced processing of positive information and negative interpretation of ambiguous stimuli, is a core feature of depression. Esketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist with rapid antidepressant effects in treatment-resistant depression (TRD), reduces depressive symptoms, but its effects on distinct components of emotional processing remain unclear. Fifty-three patients with TRD and 53 healthy controls performed an Emotional Facial Expression Morphing task. Patients were assessed at baseline, 24 hours after the first esketamine administration, and after 4 weeks of treatment. Statistical models examined detection thresholds for happy and sad faces, negative categorisation of neutral faces, and signal detection indices separating emotion-neutral discrimination sensitivity (d') from response criterion (c), indexing the evidence required to report the presence of an emotion. At baseline, patients required greater happy-face intensity for emotion detection and were more likely to categorise detected neutral faces as negative. They also showed a more conservative response criterion without group difference in discrimination sensitivity. Responders showed an early increase in d'; and, by week 4, less negative categorisation of neutral faces than non-responders. A lower baseline response criterion was associated with responder status and, in secondary continuous analyses, with greater subsequent MADRS improvement. These findings indicate that TRD involves abnormalities across detection-related, valence-related, and decisional aspects of facial-emotion processing that are differently associated with esketamine response: baseline response criterion emerged as a candidate prognostic marker, whereas negative categorisation of neutral faces tracked clinical response. Assessing these domains may inform clinical evaluation, pending independent replication.

Accelerated 5x5 repetitive Transcranial Magnetic Stimulation (rTMS; five stimulation sessions per day for five days) is an effective treatment for Major Depressive Disorder (MDD), and has efficacy comparable to conventional once-daily rTMS. Considering the heterogeneity of symptoms in patients with MDD, it is critical to determine how accelerated 5x5 and conventional rTMS affect depression symptom domains. We compared symptom change over time in patients treated with either accelerated 5x5 rTMS (25 total sessions, n = 40) or conventional once-daily rTMS administered over six weeks (30 total sessions, n = 135). Accelerated 5x5 patients received either prolonged intermittent theta burst stimulation (piTBS) or personalized "resonant frequency" (RF) stimulation. Mixed-effects linear models were built to compare the two protocols, with the primary outcome variables being the Inventory of Depression Symptomology Self-Report (IDS), the Ruminative Response Scale (RRS), and the Profile of Mood States - Brief (POMS), yielding measures of 14 unique depression symptom domains. Both protocols led to similar improvements in all 14 depression symptom domains (all interaction term p-values > .05). Subsequent exploratory analyses demonstrated that accelerated 5x5 and conventional rTMS may differ in the time courses of their effects on anxiety, rumination, mood, depression, and vigor (p-values < .05, uncorrected). These results suggested that accelerated 5x5 rTMS has a similar efficacy in alleviating 14 depression symptom domains compared to conventional once-daily rTMS, and that either protocol may be appropriate for MDD patients with a variety of symptom profiles.

Background: Management of markedly treatment-resistant depression is characterized by low initial benefit and poor durability. Treatments with sustained benefits are needed. This report summarizes clinical outcomes and durability of both the active treatment arm (Early-Active) and the initially sham treatment arm (Delayed-Active) over the second and third years of the multicenter, prospective, implanted vagus nerve stimulation (VNS) RECOVER trial. Methods: A total of 436 participants (N=221 Early-Active and N=215 Delayed-Active, 65.8% females) were studied. Within each group, analyses of change in benefit (depressive symptoms, clinical impression, quality of life [QoL], daily function, and a composite measure) occurred with assessments at 12, 18, 24, 30, and 36 months. Two within-group methods of benefit appraisal over time were conducted: 1) a comparison of the degree of benefit change, and 2) a comparison of proportions of participants achieving benefit categories. Additionally, the degree of durability of benefit was assessed, comparing 12-24 months, 24-36 months, and 12-36 months. Results: For the Early-Active group: The 12-24-month and 12-36-month periods, but not the 24-36-month period, demonstrated significant improvement in benefit categories for depressive symptoms and clinical impression measures. Similarly, statistically significant increases in the proportions of participants achieving benefit during Year 2 for depressive and clinical impression measures occurred. For the Delayed-Active group: The 12-24-month (first exposure of this group to active VNS) and 12-36-month periods, but not the 24-36-month period, demonstrated statistically significant improvements in benefit categories for depressive symptoms and clinical impression measures. Additionally, statistically significant increases in the proportions of participants achieving benefit during Year 2 for depressive symptoms, clinical impression, QoL, daily function, and the composite measure were observed. Averaged across the depressive symptom and clinical impression measures, the Early-Active group demonstrated continued progression to higher benefit categories during Years 2 and 3, whereas the Delayed-Active group was characterized by the emergence of new benefit during Year 2 followed by further progression to higher benefit categories during Year 3. Durability: Robust durability of response was observed for both groups across all time intervals, with a median of 71.1% and 69.0% maintaining or improving benefit from 12 to 36 months for Early-Active and Delayed-Active, respectively. Conclusions: In a highly chronic and markedly resistant depressed sample, active VNS produced benefits that often emerged gradually, sometimes beyond one year after initiation, continued to improve in degree of benefit over time, and were highly durable. The time-associated benefit patterns observed in the sham group (Delayed-Active) closely resembled those of the initially active group (Early-Active) but were delayed by approximately one year, consistent with the delay in therapy activation.

Tobacco use is the leading preventable cause of death worldwide. Anxiety increases the risk for smoking, and smoking in turn increases the risk for anxiety disorders. There is therefore a need to identify interventions that reduce anxiety, in general and in the context of smoking, without producing sedation. Kava (Piper methysticum), a natural product with a long history of indigenous use, has been shown to have anxiolytic and calming effects and reduce nicotine withdrawal. The current study examined whether kava without the hepatotoxic flavokavains A and B (AB-free) could reduce anxiety-like behavior in mice repeatedly treated with nicotine. Male and female C57BL/6NCrl mice received either a control diet or an AB-free kava-supplemented diet and underwent two blocks of nicotine treatments. Mice underwent a first block of five every-other-day injections of nicotine (0.5 mg/kg) or saline, with open field testing after each injection, followed one week later by a nicotine challenge. A second block of injections was given using the same injection schedule, followed by a second challenge one week later, and two weeks afterward mice received a final challenge in a novel open field. During the first treatment block, AB-free kava significantly increased center time overall, an effect most pronounced in saline-treated animals, and increased locomotor activity, while nicotine decreased both measures. During the second challenge, nicotine reduced center time but not locomotor activity, and AB-free kava increased center time in saline-treated animals only. During the final challenge, nicotine reduced both measures, whereas AB-free kava increased center time regardless of nicotine treatment, and kava-treated animals also showed a near-significant increase in center entries. These results suggest that AB-free kava reduces anxiety-like behavior without inducing sedation but does not prevent nicotine-induced suppression of exploratory behavior.

MK-801, a phencyclidine (PCP) derivative also known as dizocilpine, is a potent noncompetitive antagonist of the N-Methyl-D-aspartate receptor (NMDAr). The NMDAr plays a critical role in mediating excitatory synaptic transmission in the central nervous system (CNS) and is important in regulating synaptic plasticity, learning, and memory. MK-801 is known to induce schizophrenia-like phenotypes in animal models by blocking the NMDAr. Several studies have reported that the cognitive impairment associated with schizophrenia is linked to functional defects of ion channels in parvalbumin-positive GABAergic interneurons. Kv3.1 is a voltage-gated K+ (Kv) channel involved in the rapid repolarization of the action potential in neurons; it is richly expressed in parvalbumin-positive GABAergic interneurons and is associated with fast, repetitive spike generation. A decrease of Kv3.1 in the CNS has been reported to be associated with schizophrenia. In the present study, the effect of MK-801 on Kv3.1 was investigated using the whole-cell patch-clamp technique in Chinese hamster ovary (CHO) cells stably expressing Kv3.1. MK-801 caused a concentration-dependent inhibition of Kv3.1, with an IC50 of 10.81 M and a Hill coefficient of 0.89. The blocking potency was stronger at depolarized potentials, indicating a voltage-dependent block. MK-801 also produced a use-dependent block, inducing progressive inhibition with repeated stimulation at increased frequencies (1 Hz and 2 Hz), consistent with a delay in recovery from inactivation of Kv3.1 in the presence of MK-801. In addition, MK-801 induced a hyperpolarizing shift in the voltage dependence of the steady-state inactivation curve of Kv3.1. Taken together, these results indicate that MK-801 blocks Kv3.1 expressed in CHO cells in a concentration-, voltage-, and state-dependent manner. Given the importance of Kv3.1 in parvalbumin-positive, fast-spiking GABAergic interneurons, these findings suggest that MK-801 may alter the firing patterns of these inhibitory neurons, contributing to the onset and symptoms of schizophrenia.

BackgroundPsilocybin, a classic psychedelic, produces acute alterations in brain function, and has shown sustained therapeutic effects in psychiatric disorders. However, most studies focus on acute brain imaging readouts (e.g., fMRI) and rarely assess longer-term molecular changes. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression, are enriched in the brain, and can be released into blood, potentially indexing brain-relevant molecular processes. We hypothesised that a single psilocybin dose would show acute changes in miRNAs with predicted relevance to neuroplasticity related signalling and immune/inflammatory regulation in healthy adults. MethodsIn a randomised, double-blind, placebo-controlled study (N=62; 31 psilocybin, 31 placebo), volunteers received psilocybin (0.17 mg/kg) or placebo. Blood was collected at baseline, 360 minutes, and 7 days after dosing. Plasma miRNAs were quantified by small RNA sequencing. Elastic net regression was used for feature selection, followed by differential expression analysis and validation with linear mixed models. Pathway enrichment used Reactome and Gene Ontology. ResultsTwo circulating miRNAs (let-7g-5p and miR-150-5p) met criteria for differentially expressed at 360 minutes following psilocybin administration, with no significant differences detected at 7 days or in the placebo condition under the statistical thresholds used. Over representation analysis suggested enrichment of molecular processes involved in neuroplasticity (e.g., TrkA, MAPK), inflammation (e.g., IL-6, TGF-{beta}), and transcriptional regulation (e.g., RNA polymerase II, SMAD2/3/4). ConclusionsA single oral dose of psilocybin was associated with transient alterations in circulating miRNA expression, consistent with an acute shift in circulating gene-regulatory miRNA signals, without sustained miRNA changes at 7 days. These findings provide initial evidence that circulating miRNA changes after psilocybin may reflect acute molecular process responses and support further investigation of circulating miRNAs as potential biomarkers of psychedelic-induced molecular responses.

Background: Major depressive disorder (MDD) is a severe mental illness associated with severe clinical consequences and substantial societal burden. It's characterized by immune-inflammatory dysregulation and immune sensitization. Objective: To determine whether in vitro ketamine attenuates phytohemagglutinin (PHA)/lipopolysaccharide (LPS)-induced immune sensitization in patients with MDD and healthy controls (HCs). Methods: Whole blood from 18 patients with MDD and 18 HCs was stimulated with PHA/LPS and exposed to ketamine (0.3 M, 0.6 M, and 6 M) for 72 hours. Cytokines, chemokines, growth factors, and composite immune profiles, including M1/M2 macrophages, T helper (Th)1/2/17, the immune-inflammatory response system (IRS), and compensatory immunoregulatory system (CIRS), were synthesized and determined. Results: Under PHA and LPS stimulation in vitro, the MDD group exhibited markedly elevated immune profiles, including M1, M2, Th1, Th2, Th17, IRS, CIRS, chemokines, and growth factors, consistent with immune sensitization. Significant group-by-treatment interactions were observed for Th1-Th2, M2, growth factors, IL-12(p70), M1, and chemokines. Ketamine produced minimal changes in HCs but broader suppression in MDD, particularly at the highest concentration, without normalizing the sensitized immune phenotype. Among the immune markers with no notable group-by-treatment interactions, ketamine exerted diagnosis-independent effects, decreasing MIP-1{beta}, IL-1&{beta}, Th1, TNF-{beta} IRS, IFN-{gamma}, and IL-2 compared to the control condition. Conclusions: Ketamine exhibited two distinct immunoregulatory patterns: selective, disease-dependent attenuation of sensitized immune pathways and broader, diagnosis-independent suppression of the stimulated immune response, predominantly at higher concentrations. However, these effects were insufficient to normalize the immune-sensitized phenotype of MDD.

Anhedonia and motivational impairment are central features of major depressive disorder, yet the neural processes linking reward information to sustained goal-directed behaviour remain insufficiently understood. Using functional magnetic resonance imaging, we examined representations of reward levels during sustained effort expenditure (a construct in the RDoc framework) as a distinct component of reward processing in depressive patients under escitalopram treatment. Twenty-eight unmedicated patients with a current depressive episode and forty-three healthy control participants underwent fMRI scanning at two time points three weeks apart; patients started escitalopram immediately after the first measurement. Across participants, sustained effort expenditure engaged midbrain reward circuitry (ventral tegmental area, VTA), even in the absence of immediate reinforcement. A targeted analysis also revealed changes in activity of the dorsal raphe nucleus (DRN) in patients. Increases in VTA activity were associated with improvements in clinician-rated depressive symptoms, whereas self-reported anhedonia remained unchanged. By isolating neural mechanisms supporting sustained goal-directed behaviour, the study identifies novel and clinically relevant imaging phenotypes of reward processing and a potential pathway of escitalopram treatment in depression.