International Journal of Neuropsychopharmacology最新文献

Background: Anhedonic features within major depressive disorder (MDD) have been associated with worse course and outcome and may predict non-response to treatment. However a detailed clinical profile of anhedonia in MDD is still lacking.

Materials and methods: One thousand two hundred ninety-four patients with MDD were selected from the cross-sectional European multicenter Group for the Study of Resistant Depression (GSRD) study. Anhedonia was assessed through the Montgomery-Åsberg Depression Rating Scale anhedonia item "inability to feel". Clinical and demographic features were then analyzed.

Results: The presence of anhedonia related to a distinct demographical (living alone) and clinical profile (thyroid diseases, diabetes, suicide risk, high number of previous depressive episodes, more severe MDD and more frequent inpatients status). Furthermore, anhedonia was associated with non-response to treatment and treatment resistance, even after adjusting for confounding variables.

Conclusion: Our findings support the role of anhedonia as a modulating feature of MDD, being associated with a more severe depression profile. Moreover, anhedonic features are independent predictors of poor treatment response.

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 the 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 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 hippocampus was detected using TUNEL assay. Meanwhile, the levels of IL-1β and microglia activation were measured by ELISA and immunofluorescence, respectively. Western blot was utilized to assess the expression of SIRT1 and HMGB1 protein, and gene expression of miR-138-5p was determined through qRT-PCR.

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 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 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.

Background: While esketamine is effective in treatment-resistant depression (TRD), detailed information about the effect of esketamine on cognition is relatively scarce. This analysis assessed the effect of short-term (three double-blind [DB] studies; DB1, DB2, and DB4) or long-term maintenance treatment (DB3) with esketamine nasal spray (ESK) compared to an active-comparator+placebo (PBO), on cognition in patients with TRD.

Methods: Patients (DB1/DB2/DB3: [18-64years, n=747]; DB4: [≥65years, n=137]) with TRD received ESK (DB1/DB2/DB3:56/84mg; DB4:28/56/84mg) or PBO+newly initiated oral antidepressant (OAD) as per treatment schedules. Cognitive assessments- Cogstate battery and Hopkins Verbal Learning Test-Revised, were administered at baseline, Day-28/early withdrawal, and follow-up visits in DB1/DB2/DB4 and at 12-week intervals in DB3 maintenance phase. Descriptive statistics were used to analyze ESK effects on cognition with effect sizes and 95% confidence intervals (CIs) used to express the nature/magnitude of treatment effects relative to active-comparator+PBO. Correlation between depression severity (MADRS scores) and cognition was assessed at baseline and endpoint(s).

Results: At baseline, mild-to-moderate impairment in psychomotor function, attention, and memory (working/episodic) were evident. For each DB1/DB2/DB4, group mean performance in z-scores for ESK+OAD and OAD+PBO groups on all cognitive tests remained similar/slightly improved from, baseline at endpoint (Day-28) and follow-up assessments. Similarly, in DB3(limited to participants ≥65years), both groups generally showed improvement in cognitive performance at endpoint(s). Correlations between MADRS scores and performance on the cognitive test battery were small at baseline and endpoint(s).

Conclusion: This analysis did not identify evidence of negative effects on cognition following short-term or long-term maintenance treatment with ESK+OAD in patients with TRD.

Background: 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's disease, memory loss, and confusion.

Methods: This systematic review followed PRISMA 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.

Results: Of the 1,129 articles identified, five 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's 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.

Conclusion: 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.

Objective: This study aimed to evaluate the efficacy and safety of lumateperone in treating bipolar disorder and schizophrenia.

Methods: A comprehensive literature search was conducted across multiple databases and websites from inception to July 16, 2024, to identify both published and unpublished randomized controlled trials (RCTs). Meta-analyses were performed using random-effects or fixed-effects models depending on statistical heterogeneity. Relative risks (RRs) or standardized mean differences (SMDs) with 95% confidence intervals (CIs) were used to summarize the effects.

Results: Out of 931 records screened, seven RCTs (four focusing on bipolar depression and three on schizophrenia) were eligible for inclusion. Lumateperone was efficacious in reducing depressive symptoms in bipolar depression (SMDs = -0.36, 95% CI: -0.59 to -0.13). In treating schizophrenia, lumateperone exhibited a lower combined SMD of -0.14 (95% CI: -0.27 to 0, P = 0.051, I² = 49.6%), showing no significant difference from the placebo group, although the p-value approached significance. The lumateperone group showed significantly higher response rates compared to placebo in both bipolar depression (RRs = 1.27, 95% CI: 1.07 to 1.51) and schizophrenia (RRs = 1.44, 95% CI: 1.12 to 1.86). Common treatment-emergent adverse events included somnolence, dry mouth, dizziness, nausea, and headache (RRs = 1.30 to 3.29). Importantly, lumateperone did not significantly increase extrapyramidal symptoms (EPS, RRs = 1.46, 95% CI: 0.84 to 2.53).

Conclusions: Lumateperone is effective in treating bipolar depression but does not significantly reduce symptom severity in schizophrenia. It has a favorable safety and tolerability profile. However, caution is warranted in interpreting these findings due to the limited number of studies included.

Background: Despite the well-documented efficacy of antidepressant agents for the treatment of major depressive disorder (MDD), initial treatment nonresponse rates are high. Recent years have seen an increase in research into predictive biomarkers toward improving diagnosis and individualized treatment. Among those, epigenetic mechanisms such as DNA methylation constitute promising candidate markers in predicting antidepressant treatment response in MDD. The present study sought to address epigenome-wide DNA methylation as a predictor of antidepressant treatment response in the largest sample to date of patients with MDD.

Methods: Epigenome-wide DNA methylation was analyzed using the Infinium MethylationEPIC BeadChip in peripheral blood of n = 230 Caucasian patients with MDD receiving 6-week antidepressant treatment in a naturalistic in-patient setting as well as in a subsample of n = 107 patients primarily receiving continuous treatment with serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors. Treatment response was assessed by means of the Hamilton Depression Scale.

Results: No genome-wide significant hits were observed. Suggestive (P < 1E-5) epigenome-wide evidence was discerned for altered DNA methylation at 6 CpG sites (LOC102724467, LOC100506023, RSPO2, SAG, IL16, PRKCI) to predict response to naturalistic antidepressant treatment. In patients treated with serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors, differential DNA methylation at 11 CpGs, for example, mapping to the TIMP2, VDAC1, or SORL1 genes, was suggestively associated with treatment response.

Conclusions: The present results provide preliminary evidence for altered DNA methylation patterns to be associated with antidepressant treatment response in MDD. Provided significant replication in independent and larger samples, the present findings might in the future aid in clinical decision-making toward more individualized and thus more efficacious treatments of MDD.

Background: Deficits in cognitive control are implicated in numerous neuropsychiatric disorders. However, relevant pharmacological treatments are limited, likely due to weak translational validity of applicable preclinical models used. Neural indices derived from electroencephalography may prove useful in comparing and translating the effects of cognition-enhancing drugs between species. In the current study, we aimed to extend our previous cross-species results by examining if methylphenidate (MPH) modulates behavioral and neural indices of cognitive control in independent cohorts of humans and rats.

Methods: We measured continuous electroencephalography data from healthy adults (n = 25; 14 female) and Long Evans rats (n = 22; 8 female) and compared both stimulus- and response-locked event-related potentials and spectral power measures across species, and their MPH-related moderation following treatment with vehicle (placebo) or 1 of 2 doses of MPH.

Results: Across both species, linear mixed effects modeling confirmed the expected Flanker interference effect on behavior (eg, accuracy) and response-related event-related potentials. Unexpectedly, in contrast to past work, we did not observe any task-related effects on the spectral power of rodents. Moreover, MPH generally did not modulate cognitive control of either species, although some species-specific patterns offer insight for future research.

Conclusions: Collectively, these findings in independent human and rodent subjects replicate some of our previously reported behavioral and neurophysiological patterns partly consistent with the notion that similar neural mechanisms may regulate cognitive control in both species. Nonetheless, these results showcase an approach to accelerate translation using a coordinated between-species platform to evaluate pro-cognitive treatments.

Background: Phosphodiesterases (PDEs) are enzymes that catalyze the hydrolysis of cyclic adenosine monophosphate AMP (cAMP) and/or cyclic guanosine monophosphate (cGMP). PDE inhibitors can mitigate chronic pain and depression when these disorders occur individually; however, there is limited understanding of their role in concurrent chronic pain and depression. We aimed to evaluate the mechanisms of action of PDE using 2 mouse models of concurrent chronic pain and depression.

Methods: C57BL/6J mice were subjected to partial sciatic nerve ligation (PSNL) to induce chronic neuropathic pain or injected with complete Freund's adjuvant (CFA) to induce inflammatory pain, and both animals showed depression-like behavior. First, we determined the change in PDE expression in both animal models. Next, we determined the effect of PDE7 inhibitor BRL50481 or hippocampal PDE7A knockdown on PSNL- or CFA-induced chronic pain and depression-like behavior. We also investigated the role of cAMP-protein kinase A (PKA)-cAMP response element binding protein (CREB)-brain-derived neurotrophic factor (BDNF) signaling and neuroinflammation in the effect of PDE7A inhibition on PSNL- or CFA-induced chronic pain and depression-like behavior.

Results: This induction of chronic pain and depression in the 2 animal models upregulated hippocampal PDE7A. Oral administration of PDE7 inhibitor, BRL50481, or hippocampal PDE7A knockdown significantly reduced mechanical hypersensitivity and depression-like behavior. Hippocampal PDE7 inhibition reversed PSNL- or CFA-induced downregulation of cAMP and BDNF and the phosphorylation of PKA, CREB, and p65. cAMP agonist forskolin reversed these changes and caused milder behavioral symptoms of pain and depression. BRL50481 reversed neuroinflammation in the hippocampus in PSNL mice.

Conclusions: Hippocampal PDE7A mediated concurrent chronic pain and depression in both mouse models by inhibiting cAMP-PKA-CREB-BDNF signaling. Inhibiting PDE7A or activating cAMP-PKA-CREB-BDNF signaling are potential strategies to treat concurrent chronic pain and depression.

Background: Cognitive deficits reflecting impaired executive function are commonly associated with psychiatric disorders, including substance use. Cognitive training is proposed to improve treatment outcomes for these disorders by promoting neuroplasticity within the prefrontal cortex, enhancing executive control, and mitigating cognitive decline due to drug use. Additionally, brain derived neurotrophic factor (BDNF) can facilitate plasticity in the prefrontal cortex and reduce drug-seeking behaviors. We investigated whether working memory training could elevate BDNF levels in the prefrontal cortex and if this training would predict or protect against cocaine or cannabinoid seeking.

Methods: Adult male rats were trained to perform a "simple" or "complex" version of a delayed-match-to-sample working memory task. Rats then self-administered cocaine or the synthetic cannabinoid WIN55,212-2 and were tested for cued drug seeking during abstinence. Tissue from the prefrontal cortex and dorsal hippocampus was analyzed for BDNF protein expression.

Results: Training on the working memory task enhanced endogenous BDNF protein levels in the prelimbic prefrontal cortex but not the dorsal hippocampus. Working memory training did not impact self-administration of either drug but predicted the extent of WIN self-administration and cocaine seeking during abstinence.

Conclusions: These results suggest that working memory training promotes endogenous BDNF but does not alter drug-seeking or drug-taking behavior. However, individual differences in cognitive performance before drug exposure may predict vulnerability to future drug use.