International Journal of Neuropsychopharmacology最新文献

Background: Negative symptoms of schizophrenia represent an unmet therapeutic need for many patients in whom pentoxifylline may be effective in terms of its dopaminergic, anti-inflammatory, and cerebral blood flow-increasing properties. This study aimed to evaluate pentoxifylline as a therapeutic agent for improving negative symptoms of schizophrenia.

Methods: Chronic schizophrenia outpatients experiencing significant negative symptoms were randomly allocated to receive pentoxifylline 400 mg or matched placebo every 12 hours for 8 weeks. All patients were clinically stable as they had received risperidone for at least 2 months, which was continued. The participants were assessed using the Positive and Negative Syndrome Scale (PANSS), Hamilton Depression Rating Scale, Extrapyramidal Symptom Rating Scale, and side effect checklist.

Results: The patients' baseline characteristics were comparable between the groups. There was a significant time-treatment interaction effect on PANSS negative subscale scores (ηP2=0.075), with the pentoxifylline group showing significantly greater reductions until weeks 4 (Cohen d = 0.512) and 8 (Cohen d = 0.622). Also, this group showed a significantly better response by week 8. Other PANSS scores, Hamilton Depression Rating Scale scores, Extrapyramidal Symptom Rating Scale scores, and side effect frequencies were comparable between the groups. Pentoxifylline showed a nonsignificant higher remission of 37.1% compared with 14.7% in the placebo group.

Conclusions: Pentoxifylline was safely and tolerably beneficial for the primary negative symptoms of chronic schizophrenia.

Background: Understanding drug addiction as a disorder of maladaptive learning, where drug-associated or environmental cues trigger drug cravings and seeking, is crucial for developing effective treatments. Actin polymerization, a biochemical process, plays a crucial role in drug-related memory formation, particularly evident in conditioned place preference paradigms involving drugs like morphine and methamphetamine. However, the role of actin polymerization in the reconsolidation of heroin-associated memories remains understudied.

Methods: This study employed a rodent model of self-administered heroin to investigate the involvement of actin polymerization in the reconsolidation of heroin-associated memories. Rats underwent ten days of intravenous heroin self-administration paired with conditioned cues. Subsequently, a 10-day extinction phase aimed to reduce heroin-seeking behaviors. Following this, rats participated in a 15-minute retrieval trial with or without cues. Immediately post-retrieval, rats received bilateral injections of the actin polymerization inhibitor Latrunculin A (Lat A) into the nucleus accumbens core (NACc), a critical brain region for memory reconsolidation.

Results: Immediate administration of Lat A into the NACc post-retrieval significantly reduced cue-induced and heroin-primed reinstatement of heroin-seeking behavior for at least 28 days. However, administering Lat A 6-hour post-retrieval or without a retrieval trial, as well as administering Jasplakionlide prior to memory reactivation did not affect heroin-seeking behaviors.

Conclusions: Inhibiting actin polymerization during the reconsolidation window disrupts heroin-associated memory reconsolidation, leading to decreased heroin-seeking behavior and prevention of relapse. These effects are contingent upon the presence of a retrieval trial and exhibit temporal specificity, shedding light on addiction mechanisms and potential therapeutic interventions.

Hypofunction of the N-methyl-D-aspartate receptor (NMDAR) has been proposed to underlie the pathophysiology of schizophrenia, suggesting that promoting NMDAR activity may alleviate the negative or cognitive symptoms associated with schizophrenia. To circumvent excitotoxicity that may accompany direct agonism of the glutamate binding site on the NMDAR, therapeutic trials have focused on targeting the glycine binding site on the NMDAR. Direct administration of either glycine or D-serine, both of which are endogenous coagonists at the NMDAR glycine site, has yielded mixed outcomes across an array of clinical trials investigating different doses or patient populations. Furthermore, directly administering D-serine and glycine is challenging, and thus attention has turned to alternative, indirect methods that increase endogenous D-serine and glycine levels in the brain, such as D-amino acid oxidase (DAAO) inhibitors and glycine transporter 1 inhibitors, respectively. In this review, we provide an overview of the evidence supporting the potential of NMDAR modulators in general, and DAAO inhibitors in particular, as potential adjunctive treatments for schizophrenia. We also discuss the preclinical and clinical data related to luvadaxistat, an investigational highly selective and potent DAAO inhibitor that was under development for the treatment of the cognitive impairment associated with schizophrenia.

Background: Oxytocin is being evaluated as a potential treatment for psychostimulant use disorders. It is unknown what effect oxytocin has on dopamine signaling in response to psychostimulants in brain regions such as the striatum where oxytocin and dopamine interact to process natural rewards. We investigated the effect of oxytocin on striatal dopamine release stimulated by methylphenidate whose mechanism of action is analogous to that of cocaine.

Methods: We conducted an [11C] raclopride positron emission tomography study to assess striatal dopamine release in male rhesus macaques treated with oxytocin (80 IU) (administered via the intranasal [N = 5] and intravenous [N = 6] routes) followed by methylphenidate/[11C] raclopride.

Results: Oxytocin delivered by both routes significantly reduced methylphenidate-stimulated dopamine release in the dorsal striatum (caudate/putamen). These effects were, in part, evidenced by a reduction in dorsal striatal [11C] raclopride binding potential (increased dopamine release) following oxytocin administration.

Conclusions: The results provide translational and mechanistic evidence for the potential role of oxytocin as a treatment for psychostimulant use disorders.

Background: The regulatory neuropeptide Y (NPY) is implicated in anxiety and post-traumatic stress disorder (PTSD)-related behaviors. NPY exerts its effects through 5 receptor subtypes, with Y1 and Y2 receptors being predominantly expressed in the rat brain. Activation of Y1 by full-length NPY1-36 induces anxiolytic effects, whereas Y2 binds truncated peptides, eliciting region-specific anxiogenic responses. Dipeptidyl peptidase-IV (DPP-IV) cleaves NPY, thereby modulating its functionality. Sitagliptin, a DPP-IV inhibitor (DPP-IV-I), inhibits the degradation of various vasoactive peptides, including cerebral NPY. As such, the therapeutic potential of DPP-IV-I following a traumatic event remains inconclusive. We assessed the effects of a highly selective DPP-IV-I, administered either shortly after the stressor or intermittently over 3 days, on behavioral outcomes using the predator scent stress (PSS) model of PTSD.

Methods: Rats exposed to PSS or sham-PSS received a single dose of sitagliptin (10 or 30 mg/kg) or saline 1 hour post-exposure, or repeated doses over 3 days (20 mg/kg). Behavioral outcomes were evaluated using the elevated plus maze and acoustic startle response at 7 days post-exposure. Additionally, rats exposed to PSS or sham-PSS were treated with sitagliptin (30 mg/kg) or saline, and their brains were prepared for immunofluorescence and enzyme-linked immunosorbent assay (ELISA).

Results: Sitagliptin did not attenuate anxiety-related behaviors or PTSD-related behavior prevalence compared to saline. Notably, the 30 mg/kg dose increased NPY levels in several brain regions without affecting NPY-Y1 levels.

Conclusions: The findings suggest that sitagliptin-induced upregulation of NPY levels shortly after PSS is insufficient to prevent the development of post-traumatic responses. The effectiveness of NPY signaling may be influenced by factors beyond peptide concentration alone, potentially limiting its therapeutic efficacy. Activation of NPY-Y1 receptors, rather than merely increasing NPY levels, appears to be crucial for modulating anti-anxiety and post-traumatic responses.

Dengue fever, caused by the dengue virus and transmitted through Aedes mosquitoes, is a growing public health concern, particularly in tropical and subtropical regions. Traditionally associated with febrile and hemorrhagic symptoms, recent research suggests a potential link between dengue and cognitive impairments. This systematic review assessed existing research to understand the association between dengue virus infection and cognitive impairments, including dementia, Alzheimer disease, memory loss, and confusion. This systematic review followed preferred reporting items for systematic reviews and meta-analyses guidelines. A comprehensive literature search was conducted in PubMed, EMBASE, and Web of Science up to January 18, 2024. Studies examining the prevalence and association of cognitive impairments in dengue patients were included. Data extraction and quality assessment were performed using Nested Knowledge software and the Newcastle-Ottawa Scale. Of the 1129 articles identified, 5 were included in the review, covering a total of 200 873 participants from Taiwan, Brazil, and France. Evidence from population-based cohort studies indicated short-term cognitive impairments, including confusion and memory loss, in some dengue patients. Additionally, long-term risks of dementia, including Alzheimer disease and vascular dementia, were observed, particularly among older adults. Although the findings suggest there might be an association between dengue infection and cognitive decline, the mechanisms underlying this link remain unclear. This systematic review suggests that dengue virus infection may affect cognitive function in both acute and long-term contexts. However, the current evidence is not strong enough to establish a conclusive link. Further research with larger sample sizes and longitudinal studies is essential to confirm the impact of dengue virus on cognitive health.

Background: Esketamine nasal spray (ESK) is approved, in conjunction with an oral antidepressant, for the treatment of treatment-resistant depression in adults and for the treatment of depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior. No adverse events (AEs) of respiratory depression were reported in ESK phase 3 clinical trials; however, postmarketing incidents of respiratory depression associated with ESK use have been observed.

Methods: The Janssen Global Medical Safety (GMS) database was reviewed for cases meeting the criteria for respiratory depression with ESK using 47 months of postapproval data, based on the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ) acute central respiratory depression (broad). FDA Adverse Event Reporting System (FAERS), EudraVigilance, and literature searches were performed to identify reports of respiratory depression related to ESK use.

Results: Fifty cases, representing 50 patients, in the GMS database met the case definition for respiratory depression; 8 of these had a stronger association with ESK use. The MedDRA preferred term (PT) hypopnea met the threshold for disproportionality with ESK in FAERS. The MedDRA PTs asphyxia, oxygen saturation decreased, respiratory depression, and apnea met the threshold for disproportionality with ESK in EudraVigilance.

Conclusion: Despite extensive soliciting of AEs for ESK with the US Risk Evaluation and Mitigation Strategy program, respiratory depression is infrequently observed with ESK treatment in the postmarketing setting (estimated incidence: 1 case per 20 000 treatment sessions). Symptoms are manageable and resolve with minor supportive measures. Monitoring for symptoms of respiratory depression, including pulse oximetry, is recommended within the postdose observation period.

Background: Gonadal hormones have been reported to be involved in the molecular mechanisms of schizophrenia (SCH). However, only a few studies have examined the gonadal hormone dysfunctions in first-episode schizophrenia (FES) patients, in particular in young patients with SCH. This study was designed to investigate the sex differences in gonadal hormones in young and antipsychotic-naïve FES patients.

Methods: One hundred and sixty-two patients with SCH and 74 healthy controls were recruited, and blood gonadal hormones, including estradiol (E2), follicular-stimulating hormone (FSH), progesterone (PROG), luteinizing hormone (LH), and testosterone (TESTO), were measured in young FES patients and controls.

Results: We found that both male and female young FES patients showed gonadal hormone disturbances at the onset of psychosis. Male patients exhibited a significantly higher rate of abnormal E2 (25.6% vs 3.9%), while female patients had higher rates of abnormal FSH (0% vs 5.3%), PROG (0% vs 21.1%), LH (3.5% vs 17.1%), and TESTO (3.5% vs 13.2%) (all P < .05). Multivariate logistic regression analysis further identified that specific gonadal hormone indices, including E2, LH, and TESTO, were factors associated with sex differences in young FES patients, after controlling for age, smoking status, and body mass index.

Conclusions: Our study reveals an overall gonadal hormone imbalance in young antipsychotic-naïve FES patients, highlighting sex differences at the onset of psychosis. Our study provides a foundation for further research into the role of gonadal hormones in the pathophysiology of SCH and the potential for personalized medicine approaches based on hormonal balance. Future studies were warranted to explore these differences and their implications for clinical practice to improve the treatment outcomes for individuals suffering from SCH.

Background: Glutamatergic system dysfunction contributes to a full spectrum of schizophrenia-like symptoms, including the cognitive and negative symptoms that are resistant to treatment with antipsychotic drugs (APDs). Aripiprazole, an atypical APD, acts as a dopamine partial agonist, and its combination with haloperidol (a typical APD) has been suggested as a potential strategy to improve schizophrenia. Recently, an analog of aripiprazole, UNC9994, was developed. UNC9994 does not affect dopamine 2 receptor (D2R)-mediated Gi/o protein signaling but acts as a partial agonist for D2R/β-arrestin interactions. Hence, one of our objectives was to probe the behavioral effects of co-administrating haloperidol with UNC9994 in the N-methyl-D-aspartate receptor (NMDAR) mouse models of schizophrenia. The biochemical mechanisms underlying the neurobiological effects of dual haloperidol × UNC9994 action are currently missing. Hence, we aimed to explore D2R- and NMDAR-dependent signaling mechanisms that could underlie the effects of dual drug treatments.

Methods: NMDAR hypofunction was induced pharmacologically by acute injection of MK-801 (NMDAR pore blocker; 0.15 mg/kg) and genetically by knockdown of Grin1 gene expression in mice, which have a 90% reduction in NMDAR levels (Grin1 knockdown [Grin1-KD]). After intraperitoneal injections of vehicle, haloperidol (0.15 mg/kg), UNC9994 (0.25 mg/kg), or their combination, mice were tested in open field, prepulse inhibition (PPI), Y-maze, and Puzzle box. Biochemical effects on the phosphorylation of Akt, glycogen synthase kinase-3 (GSK-3), and CaMKII in the prefrontal cortex (PFC) and striatum of MK-801-treated mice were assessed by western blotting.

Results: Our findings indicate that low dose co-administration of UNC9994 and haloperidol reduces hyperactivity in MK-801-treated animals and in Grin1-KD mice. Furthermore, this dual administration effectively reverses PPI deficits, repetitive/rigid behavior in the Y-maze, and deficient executive function in the Puzzle box in both animal models. Pharmacological inhibition of NMDAR by MK-801 induced the opposite effects in the PFC and striatum on pAkt-S473 and pGSK3β-Ser9. Dual injection of haloperidol with UNC9994 reversed MK-801-induced effects on pAkt-S473 but not on pGSK3β-Ser9 in both brain structures.

Conclusions: The dual administration of haloperidol with UNC9994 at low doses represents a promising approach to ameliorate symptoms of schizophrenia. The combined drug regimen elicits synergistic effects specifically on pAkt-S473, suggesting it as a potential biomarker for antipsychotic actions.

Background: Postoperative cognitive dysfunction (POCD) is a common neurological complication in older patients and correlated with adverse outcomes. 17β-estradiol treatment was reported to provide neuroprotective protection in various neurologic disorders, but whether it attenuated POCD was unknown. The purpose of this study was to explore the effects of 17β-estradiol treatment on POCD and its mechanisms.

Methods: We generated a POCD model in 15-month-old mice via laparotomy, followed by subcutaneous injection of 17β-estradiol, intraperitoneal injection of EX527 (a Sirtuin 1 [SIRT1] inhibitor), or bilateral hippocampal injection of miR-138-5p-agomir. Morris water maze test and open field test were applied to evaluate the cognitive function. The neuronal apoptosis in the hippocampus was detected using the terminal transferase dUTP nick end labeling assay. Meanwhile, the levels of interleukin-1β (IL-1β) and microglia activation were measured by enzymelinked immunosorbent assay and immunofluorescence, respectively. Western blot was utilized to assess the expression of SIRT1 and high mobility group box 1 (HMGB1) protein, and gene expression of miR-138-5p was determined through quantitative real-time polymerase chain reaction.

Results: Behavioral tests showed that 17β-estradiol treatment improved cognitive function in aged POCD mice. In addition, 17β-estradiol attenuated neuronal apoptosis and microglia activation as well as IL-1β expression in the hippocampus. Nonetheless, injection with EX527 abolished the beneficial impacts of 17β-estradiol against POCD. Furthermore, miR-138-5p was verified to bind with SIRT1, which regulated the expression of HMGB1. After treatment with 17β-estradiol, miR-138-5p expression was reduced in the hippocampus, and the neuroprotective influence of 17β-estradiol on aged POCD mice was reversed after administration of miR-138-5p-agomir.

Conclusions: 17β-estradiol treatment exerted neuroprotection effects on POCD in aged mice, which might be relevant to alleviating neuroinflammation via miR-138-5p/SIRT1/HMGB1 pathway.