International Journal of Neuropsychopharmacology最新文献

Background: Fetal alcohol spectrum disorders (FASD) show a myriad of cognitive and neurological deficits, with the prevalence estimated to be 1% to 5 % in children. To date, there are no effective treatments for these deficits in FASD. In a mouse model of FASD, daily intraperitoneal administration of a potassium calcium-activated channel subfamily N member 2 (KCNN2) blocking peptide has been shown to improve motor learning deficits due to upregulation of KCNN2 channels. This study investigates whether intranasal administration of a KCNN2 blocking peptide, Leiurotoxin-1 Dab7 (Lei-Dab7), can improve cognitive flexibility, specifically reversal learning deficits, in these mice.

Methods: We utilized a mouse model of prenatal alcohol exposure. Cognitive flexibility was assessed using the water T-maze test at postnatal day 40. Lei-Dab7's specificity and cytotoxicity were evaluated in vitro, and intranasal delivery efficiency was confirmed through immunohistochemistry, quantifying its distribution and binding to neurons with elevated KCNN2 expression in the prefrontal cortex.

Results: Lei-Dab7 showed high specificity and negligible cytotoxicity in vitro. Intranasal administration efficiently delivered Lei-Dab7 to the prefrontal cortex, where it specifically bound to neurons expressing increased KCNN2 channels. Behavioral tests demonstrated that Lei-Dab7 significantly improved cognitive flexibility, reversing the deficits in the water T-maze test seen in ethanol-exposed mice, without apparent acute physiological adverse effects.

Conclusions: Intranasal administration of KCNN2 blockers, such as Lei-Dab7, represents a promising, non-invasive therapeutic approach for treating cognitive inflexibility and possibly other cognitive dysfunctions associated with FASD.

Background: Ulotaront is an experimental antipsychotic for schizophrenia, but its optimal dose is unclear. This study aimed to evaluate dose-response relationships for efficacy and safety in people with schizophrenia.

Methods: A systematic review of four databases (until January 22, 2025; INPLASY202510091) identified randomized clinical trials assessing ulotaront. Outcomes included efficacy, measured by changes in the Positive and Negative Syndrome Scale (PANSS) total score (primary outcome), positive and negative subdomains, and the Clinical Global Impression Scale-Severity, and safety, assessed by all-cause dropout (co-primary outcome, dropout due to adverse event, serious, non-serious, and specific adverse events). We employed one-stage dose-response meta-analysis (random-effects model) calculating standardized mean differences (SMDs) and risk ratios (RRs) with 95% confidence intervals (CIs).

Results: Analysis of three randomized clinical trials (n = 1144) indicated that the 100 mg dose of ulotaront provided the greatest improvement in PANSS total score (standardized mean difference = -0.23 [95% CI: -0.43, -0.02]), PANSS positive symptom score (-0.30 [-0.70, 0.10]), and PANSS negative symptom score (-0.28 [-0.48, -0.08]). However, Clinical Global Impression Scale-Severity scores did not exhibit a clear dose-response relationship. Regarding safety, all-cause dropout (RR at 100 mg = 1.10 [95% CI: 0.57, 2.12]), adverse event-related dropout, serious, non-serious, and most specific adverse events showed no significant dose-response relationship. The risk of anxiety-related adverse events was significantly higher than placebo at 50 and 75 mg doses (RR at 75 mg = 2.06 [95% CI: 1.11, 3.80]).

Conclusion: Ulotaront 100 mg appears greatest efficacy with favorable safety for acute schizophrenia. However, effect sizes were small, and higher ulotaront doses should be tested. Significance Statement Ulotaront is a new medication being tested for treating schizophrenia. Unlike most existing antipsychotic drugs that block dopamine receptors in the brain, ulotaront works through a different mechanism by activating trace amine-associated receptor 1 and serotonin 1A receptors. These novel targets may help reduce both hallucinations and negative symptoms like social withdrawal and lack of motivation, with fewer side effects. In this study, we analyzed data from several clinical trials to understand how different doses of ulotaront affect patients. We found that higher doses-especially around 100 mg-can improve schizophrenia symptoms without increasing safety concerns. These findings are important because they suggest that ulotaront may offer a new and safer treatment option for people with schizophrenia, and they help guide doctors toward the most effective dose.

Objective: To investigate the differences in executive functions, specifically cognitive flexibility and inhibitory control, between schizophrenia (SCH) patients with predominantly positive symptoms (PSD) and those with predominantly negative symptoms (NSD), compared to healthy controls, using functional near-infrared spectroscopy (fNIRS).

Methods: Fifty-two patients with SCH and 29 control subjects were recruited in the study. We employed fNIRS to measure brain activation while participants performed 2 tasks: a cognitive flexibility-switching task and the Stroop task, which assesses inhibitory control. Performance metrics included accuracy and reaction time. The study included 3 groups: SCH patients with PSD, SCH patients with NSD, and healthy controls.

Results: Patients with SCH exhibited lower accuracy and longer reaction times compared to healthy controls. In terms of brain activation, the PSD group showed the highest levels of prefrontal activation, followed by healthy controls, while the NSD group had the lowest activation levels. Patients had lower accuracy and longer reaction times than healthy controls. The PSD group showed excessive activation in both prefrontal cortex and the dorsolateral prefrontal cortex during both the congruent condition and incongruent condition of the Stroop task. In contrast, the NSD group exhibited higher prefrontal activation under congruent conditions but significantly reduced activation under incongruent conditions.

Conclusion: Our findings highlight distinct patterns of executive function deficits and brain activation in SCH patients with PSD and NSD. These results suggest that symptom profiles may influence the nature and severity of cognitive impairments and associated neural mechanisms. Future research should further explore these differences to inform targeted interventions and improve clinical outcomes for individuals with SCH.

Background: Ethanol use is frequently initiated during adolescence, a vulnerable developmental period with a great deal of neuro-remodeling, specially affecting hippocampal integrity, and with a unique sensitivity to drug abuse. Previous data evaluated the neurochemical effects exerted by either ethanol or cocaine alone in the adolescent brain, but few studies measured the combined negative impact of both drugs immediate during adolescence and later following withdrawal and drug re-exposure in adulthood and therefore will be the aim of this study.

Methods: Male and female Sprague-Dawley rats were treated in adolescence with non-contingent paradigms of ethanol, cocaine, their combination, or vehicle. Hippocampal samples were collected in adolescence, during forced withdrawal and following voluntary exposure to ethanol in adulthood to evaluate signs of neurotoxicity by western blot (Fas-Associated protein with Death Domain [FADD], and the ratio between Neurofilament light chain protein, NF-L, and Brain-Derived Neurotrophic Factor, BDNF) or neurogenesis by immunohistochemistry (Ki-67, NeuroD).

Results: Adolescent ethanol induced hippocampal neurotoxicity by decreasing FADD and increasing NF-L/BDNF ratio, paired with decreased neuronal differentiation as labeled by NeuroD. These effects reverted to normal in adulthood during withdrawal. NeuroD was decreased after adult voluntary ethanol consumption, but exclusively in rats previously exposed to adolescent ethanol. Adolescent cocaine alone did not induce any changes at any time-points examined. The neurochemical effects were observed independently of sex. Interestingly, NeuroD emerged as a biomarker of ethanol toxicity both in adolescence and adulthood.

Conclusions: Ethanol is a neurotoxic agent, and its toxicity is exacerbated by an early initiation during adolescence. Our conclusions reinforce the recommendation of avoiding and/or delaying the age of initial ethanol exposure, since it poses a prior vulnerability to its later impact in life.

Background: Personality traits play crucial roles in the onset, manifestation, and course of schizophrenia and bipolar disorder (BD). Previous meta-analyses focusing on NEO personality traits in patients with schizophrenia and BD revealed distinct differences in specific personality traits between patients with schizophrenia and healthy controls and between patients with BD and healthy controls. However, direct comparisons of personality profiles between schizophrenia patients and BD patients have been limited, with existing studies often limited by relatively small sample sizes.

Methods: Two online databases (PubMed and Scopus) were searched systematically to identify relevant articles, including publications up to April 2024. A meta-analysis of five personality traits, namely, neuroticism (N), extraversion (E), openness (O), agreeableness (A), and conscientiousness (C), assessed by the NEO five-factor inventory, was performed in seven cohorts, including our patient samples, consisting of 768 patients with schizophrenia and 555 patients with BD.

Results: There was no significant heterogeneity in the five personality traits among the seven studies (I2 = 0-53.8, P > .05), except for C (I2 = 77.1, P = 5.65 × 10-4). Our meta-analyses revealed significant differences in three personality traits (E, O, and A) between patients with schizophrenia and patients with BD (E: Hedges' g = -0.40, P = 1.34 × 10-11; O: g = -0.22, P = 1.76 × 10-4; and A: g = -0.24, P = 3.73 × 10-5). Patients with schizophrenia had lower scores on E, O, and A than those with BD did. No significant differences in the other two traits, N and C, were observed between the groups (P > .05).

Conclusions: Our findings suggest that schizophrenia patients and BD patients have distinct personality profiles and that schizophrenia patients have more pronounced personality profiles than BD do, despite their overlapping symptoms and genetic predispositions.

Background: Mitochondria play a pivotal role in energy production, and their dysfunction not only hampers cells' ability to meet energy requirements but also contributes to the impairment of neural plasticity, a critical feature of depressive disorders. In this study, mitochondrial cross-omics analysis was carried out in the hippocampus of restraint rats to understand the role of mitochondria in depression pathophysiology.

Methods: The expression profiles of hippocampal mitochondrial and nuclear-encoded genes in mitochondrial fractions from restraint and handled control rats were obtained using high-throughput RNA sequencing. Weighted gene co-expression network analysis (WGCNA) was used to identify the gene co-expression and pathways associated with the restraint phenotype. Mutual Information Network algorithm tools Arance, CLR, and MRNET were additionally used to screen the functional modules and hub genes and their similarity with the WGCNA-based network analysis. Finally, cross-species homology followed by gene association analysis was conducted to obtain SNPs and haplotypes related to depression phenotype.

Results: A significant proportion of mitochondrial and nuclear-encoded genes showed differential regulation in the hippocampus of restraint rats. WGCNA and Mutual Information Network analysis yielded distinct functional modules significantly related to restraint phenotype. Further network analysis revealed distinct co-expression patterns associated with differentially expressed genes associated with these modules. Cross-species analysis showed 39 significantly associated SNPs with the depression phenotype, where the most significant SNP, rs10899570, was located within the TENM4 gene. Further, rs1573529 and rs10899570 were distributed into the linkage disequilibrium block where SNPs were highly correlated. Subsequent haplotype analysis showed that rs1573529 and rs10899570 were significantly associated with depressive behavior.

Conclusions: The study demonstrates a significant impact of restraint stress on mitochondrial functions and genetic association, suggesting their critical role in depression pathophysiology.

Background: It is well established that peroxisome proliferator-activated receptor α (PPARα) plays a crucial role in the pathogenesis of depression. Several PPARα agonists, including WY14643, fenofibrate, and gemfibrozil, have been reported to produce antidepressant-like effects in mouse models through PPARα-mediated enhancement of hippocampal brain-derived neurotrophic factor (BDNF) signaling and neurogenesis. Pemafibrate is a novel and highly selective modulator of PPARα; we therefore hypothesized that it might also exhibit antidepressant-like efficacy.

Methods: We employed 2 established mouse models of depression, chronic unpredictable mild stress (CUMS) and chronic restraint stress (CRS), to evaluate the potential antidepressant effects of pemafibrate. Western blotting and immunofluorescence were used to assess whether pemafibrate treatment counteracts chronic stress-induced suppression of hippocampal PPARα, BDNF signaling, and neurogenesis. To investigate the mechanism of action, we utilized pharmacological inhibitors (GW6471 for PPARα and K252a for BDNF signaling) combined with adeno-associated virus-mediated genetic knockdown approaches.

Results: Repeated pemafibrate administration significantly ameliorated chronic stress-induced depressive-like behaviors and restored hippocampal PPARα levels, BDNF signaling, and neurogenesis in both models. These antidepressant effects were markedly attenuated by co-administration of GW6471 or K252a. Similarly, genetic knockdown of either hippocampal PPARα or BDNF abolished pemafibrate's antidepressant-like actions.

Conclusions: Pemafibrate exerts antidepressant-like effects in both CUMS and CRS mouse models by promoting hippocampal PPARα and BDNF signaling.

Studying psychiatric illness has often been limited by difficulties in connecting symptoms and behavior to neurobiology. Computational psychiatry approaches promise to bridge this gap by providing formal accounts of the latent information processing changes that underlie the development and maintenance of psychiatric phenomena. Models based on these theories generate individual-level parameter estimates which can then be tested for relationships to neurobiology. In this review, we explore computational modelling approaches to one key aspect of health and illness: affect. We discuss strengths and limitations of key approaches to modelling affect, with a focus on reinforcement learning, active inference, the hierarchical gaussian filter, and drift-diffusion models. We find that, in this literature, affect is an important source of modulation in decision making, and has a bidirectional influence on how individuals infer both internal and external states. Highlighting the potential role of affect in information processing changes underlying symptom development, we extend an existing model of psychosis, where affective changes are influenced by increasing cortical noise and consequent increases in either perceived environmental instability or expected noise in sensory input, becoming part of a self-reinforcing process generating negatively valenced, over-weighted priors underlying positive symptom development. We then provide testable predictions from this model at computational, neurobiological, and phenomenological levels of description.

Importance: The comorbidity of major depressive disorder (MDD) and alcohol use disorder (AUD) is often treated inadequately. This study evaluated the impact of adding the opioid receptor blocker, naltrexone, to the NMDA glutamate receptor antagonist, ketamine, for the treatment of MDD comorbid with AUD. In so doing, it also attempted to shed light on the contribution of opioid receptor stimulation to the antidepressant effects of ketamine in this population.

Objective: To compare the efficacy of ketamine plus naltrexone to ketamine plus saline and midazolam plus saline for reducing depression and decreasing alcohol consumption in outpatients with comorbid MDD and AUD.

Design, setting, and participants: A 3-arm, randomized, double-blind, parallel-group study was conducted. Participants were 65 adults with current MDD and AUD, with Montgomery-Åsberg Depression Rating Scale (MADRS) total score of 20 or higher and heavy drinking at least 4 times in the month prior to randomization.

Interventions: Randomized (1:1:1) to receive (1) intravenous (IV) ketamine (0.5 mg/kg) once a week for 4 weeks (a total of 4 infusions) plus intramuscular (IM) naltrexone (380 mg), (2) IV ketamine plus IM saline, or (3) IV midazolam (0.045 mg/kg) plus IM saline.

Main outcomes and measures: Co-primary: MADRS; complete alcohol abstinence. Secondary: alcohol craving, anxiety, quality of life, safety.

Results: Of 65 participants, 58 received at least 1 ketamine/midazolam infusion: 20 in ketamine-naltrexone, 19 in ketamine-saline, 19 in midazolam-saline. All groups improved significantly (>80% depression remission). No group differences were observed in MADRS changes during treatment (primary outcome), although antidepressant effects persisted longer in ketamine groups compared to midazolam. There were no significant group differences in alcohol-related outcomes. Ketamine groups showed greater improvement in anxiety and quality of life (secondary outcomes) than midazolam, with the ketamine-naltrexone group showing greater improvement in anxiety than ketamine-saline. No study-related serious adverse events.

Conclusions and relevance: This study found similar antidepressant and anti-alcohol effects across 3 groups. Compared to midazolam, the ketamine groups showed longer-lasting antidepressant effects and greater improvements in anxiety and quality of life. Comparable outcomes between the 2 ketamine groups suggest opioid receptor antagonism did not alter ketamine's therapeutic effects.

Clinical trial registration: The study was registered at ClinicalTrials.gov (Identifier: NCT02461927).