International Journal of Neuropsychopharmacology最新文献

Background: Schizophrenia shortens the average lifespan by an estimated 15 years. This retrospective study evaluated whether relapse independently increases all-cause mortality risk in patients with stable schizophrenia.

Methods: Eligible adults had ≥2 outpatient claims on separate dates or ≥1 inpatient claim with a schizophrenia diagnosis code, had ≥12 months of continuous pre-index enrollment without a relapse, and received ≥1 antipsychotic medication during the baseline period. Occurrence and number of inpatient and non-inpatient relapses and all-cause mortality were evaluated during follow-up. A marginal structural model adjusting for both baseline and time-varying confounding was used to estimate hazard ratios (HRs) and 95% CIs.

Results: Mean age at index of the 32 071 patients included in the analysis was 57.6 (SD, 15.3) years; 51.0% of patients were male and 55.4% were White. During a mean follow-up of 40 (range, 1-127) months, 3974 (12.4%) patients died. Of the 9170 (28.6%) patients with relapse(s) during follow-up, most experienced 1 (53.4%) or 2 (20.0%) relapses. After adjustment for covariates, the HR for all-cause mortality was significantly higher for patients with 1 relapse vs no relapses (1.20 [95% CI, 1.14-1.26]). For the first 5 relapses, each subsequent relapse increased all-cause mortality hazard by approximately 20%. Estimated 5-year survival was 78% in patients with 1 relapse and 58% in patients with 10 relapses.

Conclusions: The observed increase in all-cause mortality associated with schizophrenia relapse underscores the need for heightened attention to relapse prevention, including greater utilization of effective treatment strategies early in the course of disease.

Background: Preclinical work suggests that chronic nicotine/tobacco use is associated with reductions in serotonin within the hippocampus, yet no research has yet shown an association of smoking behaviors and alterations in brain serotonin in humans in vivo.

Methods: We therefore analyzed existing [11C]DASB PET data from the Cimbi Database to compare the availability of the serotonin transporter (SERT) in the hippocampus, midbrain (including the raphe), and neocortex of 60 healthy non-smokers, 15 ex-smokers, and 11 current smokers who also provided blood samples for determination of plasma tryptophan load. Because SERT availability is considered to be negatively associated with extracellular serotonin levels, we hypothesized that current smokers would exhibit greater SERT availability than ex-smokers and non-smokers.

Results: There was a significant main effect of group on SERT binding (DASB BPND) values in the bilateral and left hippocampus, and a trend toward such in the right hippocampus. Post hoc ANOVAs revealed that current smokers exhibited greater hippocampal DASB BPND than both non-smokers and ex-smokers, while the latter 2 groups did not differ. There were no group effects on DASB BPND within the midbrain or global neocortex. Finally, there was no significant group effect on plasma tryptophan load.

Conclusions: This study provides the first in vivo evidence that current smoking may be associated with elevated hippocampal SERT binding-possibly reflecting lower synaptic serotonin concentrations, and that this change may normalize following smoking cessation.

Importance: Childhood trauma (CT) worse the course of bipolar disorder (BD) and negatively impacts treatment outcomes. Despite the recognized influence of CT on clinical trajectories, limited evidence exists on how it affects specific pharmacological responses in BD.

Objective: This study aimed to investigate the effectiveness of lurasidone in BD type I depression, with a focus on how CT exposure impacts treatment response and remission.

Design: A multisite, observational, prospective, comparative effectiveness study over an 8-week period was conducted.

Setting: A multisite in 4 clinical research sites in Colombia.

Participants: A total of 84 adults with BD type I depression were enrolled (lurasidone = 41, lurasidone with lithium = 43).

Intervention: Over an 8-week period, 41 participants were assigned to the lurasidone arm and 43 to the lurasidone plus lithium arm.

Exposure: Childhood trauma exposure was measured with the Childhood Trauma Questionnaire-Short Form. BD with CT (n = 40) and BD without CT (n = 44) were included.

Main outcome and measures: The primary outcome was changes in Montgomery-Åsberg Depression Rating Scale (MADRS) scores. Secondary outcomes included changes in Clinical Global Impression-Bipolar depression severity scores and responder rates.

Results: Bipolar disorder with CT exposure demonstrated a smaller mean reduction in MADRS scores compared to those without CT exposure for both treatments (monotherapy: Least Square (LS) -3.4, 95% CI, -6.03 to -0.76, P = .013; combination therapy: LS -3.1, 95% CI, -5.36 to -0.63, P = .014). The presence of CT exposure, particularly physical abuse (PA), was associated with poorer response rates. Notably, lurasidone in combination with lithium showed superior outcomes compared to monotherapy, although effectiveness was attenuated in participants with documented CT exposure.

Conclusions: This study provides real-world evidence suggesting that CT exposure may modify treatment response in BD type I depression. Our findings underscore the importance of CT screening to guide personalized treatment strategies.

Relevance: This study provides evidence that CT, particularly PA, attenuates the antidepressant effects of lurasidone in BD type I depression, leading to lower response and remission rates in both monotherapy and combination therapy with lithium. These findings underscore the clinical importance of screening for CT in BD to guide personalized treatment strategies. Identifying trauma history may help clinicians optimize treatment selection, considering the potential need for combination pharmacotherapy and adjunctive trauma-focused psychotherapeutic interventions to improve outcomes in this vulnerable population.

Background: Severe emotional dysregulation (SED) may represent an endophenotype of attention-deficit hyperactivity disorder (ADHD) and major affective disorders. However, the specific effects of SED and related psychiatric disorders, including ADHD, bipolar disorder (BD), and major depressive disorder (MDD), on matrix metalloproteinase-9 (MMP-9), proinflammatory cytokine levels, and inhibitory control function remain unclear.

Methods: This study included 48 adolescents with ADHD, 39 with first-episode BD, 53 with first-episode MDD, and 46 healthy adolescents. SED was defined according to total T scores ≥210 on the Child Behavior Checklist Dysregulation Profile. Levels of MMP-9, interleukin (IL)-6, and C-reactive protein (CRP) were measured. Inhibitory control was assessed using the go/no-go task.

Results: Generalized linear models adjusted for demographic and clinical data revealed significant main effects of diagnoses on MMP-9 (P = .009), CRP (P < .001), and IL-6 (P = .029) levels and on the standard deviation of mean response time on the go/no-go task (P = .004). A significant main effect of SED on MMP-9 levels (P = .048) was also observed. Adolescents with BD exhibited the highest MMP-9 and CRP levels and the poorest performance on the go/no-go task compared with the other groups. Adolescents with SED had significantly elevated MMP-9 levels than did those without SED.

Discussion: Diagnoses of adolescent psychiatric disorder were associated with increased MMP-9, IL-6, and CRP levels and with inhibitory control dysfunction. In particular, SED was associated with elevated MMP-9 levels.

Background: Major depressive disorder (MDD) is a common and debilitating disorder whose molecular neurobiology remains unclear. Extracellular vesicles (EVs) are small vesicles that are released by cells and are involved in intercellular communication. They carry bioactive molecules, such as proteins, that reflect the state of their cell of origin. In this study, we sought to investigate the proteomic cargo of brain EVs from depressed individuals as compared to EVs from matched neurotypical individuals. In addition, we investigated how the EV proteomic cargo compares to the proteomic profile of bulk tissue.

Methods: Using mass spectrometry and label-free quantification, we investigated the EV and bulk tissue protein profile from anterior cingulate cortex samples from 86 individuals. We performed differential expression analysis to compare cases and controls, followed by in silico analysis to determine potential implicated functions of dysregulated proteins.

Results: Extracellular vesicles display distinct proteomic profiles compared to bulk tissue. Differential expression analysis showed that 70 proteins were differentially packaged in EVs in MDD, while there was no significant difference in protein levels between groups in bulk tissue. In silico analysis points to a strong role of these differential EV proteins in synaptic functions.

Conclusion: To our knowledge, this is the first study to profile EV proteins in depression, providing novel information to better understand the pathophysiology of MDD. This work paves the way for discovering new therapeutic targets for MDD and prompts more investigations into EVs in MDD and other psychiatric disorders.

Background: Neuropathic pain (NP) is a chronic and debilitating condition frequently comorbid with insomnia. However, the alterations in sleep architecture under NP conditions and the mechanisms underlying both pain and sleep disturbances remain poorly understood. The reticular thalamic nucleus (RTN) plays a crucial role in non-rapid eye movement sleep (NREMS) and pain processing, but its involvement in NP-related sleep disruptions has not been fully elucidated.

Methods: To investigate sleep-related electrophysiological changes in NP, we performed continuous 24-hour electroencephalogram/electromyogram (EEG/EMG) recordings in rats exhibiting allodynia following L5-L6 spinal nerve lesions. Additionally, we assessed the in vivo neuronal activity of the RTN in both NP and sham-operated control rats. Spectral analyses were conducted to examine alterations in sleep oscillatory dynamics. Reticular thalamic nucleus neuronal responses to nociceptive pinch stimuli were classified as increased, decreased, or unresponsive.

Results: Neuropathic pain rats exhibited a significant reduction in NREMS (-20%, P < .001) and an increase in wakefulness (+ 19.13%, P < .05) compared to controls, whereas rapid eye movement sleep (REMS) remained unchanged. Sleep fragmentation was pronounced in NP animals (P < .0001), with frequent brief awakenings, particularly during the inactive/light phase. Spectral analysis revealed increased delta and theta power during both NREMS and REMS. Reticular thalamic nucleus neurons in NP rats displayed a higher basal tonic firing rate, along with increased phasic activity (number of bursts), although the percentage of spikes in bursts remained unchanged.

Conclusions: Neuropathic pain is characterized by disrupted sleep architecture, reduced NREMS, and heightened RTN neuronal firing activity with partial compensation of burst activity. Given that RTN burst activity is essential for optimal NREMS, its disruption may contribute to NP-induced sleep impairments. These findings suggest that altered EEG/EMG signals, alongside dysregulated RTN neuronal activity, may serve as potential brain markers for NP-related insomnia.

Precision psychiatry aims to improve routine clinical practice by integrating biological, clinical, and environmental data. Many studies have been performed in different areas of research on major depressive disorder, bipolar disorder, and schizophrenia. Neuroimaging and electroencephalography findings have identified potential circuit-level abnormalities predictive of treatment response. Protein biomarkers, including IL-2, S100B, and NfL, and the kynurenine pathway illustrate the role of immune and metabolic dysregulation. Circadian rhythm disturbances and the gut microbiome have also emerged as critical transdiagnostic contributors to psychiatric symptomatology and outcomes. Moreover, advances in genomic research and polygenic scores support the perspective of personalized risk stratification and medication selection. While challenges remain, such as data replication issues, prediction model accuracy, and scalability, the progress so far achieved underscores the potential of precision psychiatry in improving diagnostic accuracy and treatment effectiveness.

Background: Alzheimer's disease (AD) is a neurodegenerative disease characterized by memory deficit and has emerged as a growing global health concern. Phosphodiesterase-8 (PDE8) is a cyclic adenosine monophosphate (cAMP)-specific hydrolase and its correlation with AD pathogenesis remains underexplored. Here, the effects and mechanisms of PF-04957325 (denoted as PF), a PDE8 inhibitor, were investigated in reversing AD both in vitro and in vivo.

Methods: Briefly, BV2 cells were incubated with amyloid-β oligomers (AβO) to construct an AD cell model. Then, 2-month-old male C57BL/6J mice injected with AβO into the hippocampus and 10-month-old male amyloid precursor protein/presenilin-1 (APP/PS1) mice were used to construct AD animal models. Cells and mice were treated with PF to observe the effects of PDE8 on behavior and pathology related to AD. The Y-maze, novel object recognition (NOR), and Morris water maze (MWM) were performed to investigate cognitive function in mice. Western blot and immunofluorescence staining were used to identify the microglial activation state. Lastly, Western blot and ELISA were conducted to determine the levels of inflammatory factors and the proteins of PDE8/cAMP/CREB signaling.

Results: PF-04957325 pretreatment reversed the conversation of proinflammatory microglia in BV2 cells induced by AβO, while also suppressing the levels of inflammatory factors, including interleukin-1β, interleukin-6, tumor necrosis factor-α, inducible nitric oxide synthase , and cyclooxygenase-2. In addition, AβO incubation upregulated the expression of PDE8 and concurrently downregulated that of brain-derived neurotrophic factor (BDNF), cAMP, p-PKA/PKA, and p-CREB/CREB in BV2 cells, all of which were reversed by PF. In vivo experiments evidenced impaired performance in the Y-maze, NOR, and MWM; these effects were reversed by PF. Similarly, PF treatment significantly attenuated microglia activation and the release of the inflammatory factors, and reversed the changes in the expression of BDNF and PDE8/cAMP/CREB signaling in AD mice. Finally, PF reduced the generation of Aβ1-42 by suppressing the expression of APP and PS1 in APP/PS1 mice.

Conclusions: PF alleviated AD-like changes in behavior and pathology through various mechanisms, including attenuating microglia-mediated neuroinflammation, upregulating the expression of BDNF, restoring synaptic dysfunction, and inhibiting Aβ generation, which appear to be involved by PDE8/cAMP/CREB signaling. These results highlight the therapeutic potential of targeting PDE8 inhibition for AD treatment.

Classic psychedelics have shown promise in the treatment of various neuropsychiatric disorders. However, weak blinding integrity has been argued to limit the interpretability of therapeutic effects observed in psychedelic clinical trials, highlighting the need to explore alternative active placebos. Here, we aimed to describe the drawbacks of current placebo conditions used in classic psychedelic studies, propose criteria for suitable active placebos, and review interventions that may putatively fit these criteria. Considerations for the characteristics of ideal active placebos in classic psychedelic studies include (1) acute psychoactive effects, (2) acute physiological effects, (3) onset and duration of acute effects, (4) safety, and (5) lack of therapeutic effects in the target disease. We identified several pharmacological agents that may have potential as active placebos in trials involving moderate-to-high doses of certain short-acting and long-acting classic psychedelics, as well as low-dose administration and microdosing regimes. To accurately assess the safety and efficacy of classic psychedelics as therapeutics, future research should apply a thoughtful process for selecting active placebos and consider ancillary strategies to improve blinding in trials involving these substances.

Background: The global prevalence of dementia is significantly increasing. Early detection and prevention strategies, particularly for mild cognitive impairment (MCI), are crucial but currently hindered by the lack of established biomarkers. Here, we aimed to develop a high-precision screening method for MCI by combining D-amino acid profiles from peripheral blood samples with noninvasive subject information using nonlinear machine learning (ML) algorithms.

Methods: A cross-sectional study was conducted with 200 participants aged 50-89 years, classified into cognitively normal and MCI-suspected groups based on Mini-Mental State Examination scores. High-throughput techniques were used to analyze the D-amino acid profiles, specifically D-alanine (%) and D-proline (%), in peripheral blood. Correlation analysis was performed between D-amino acid levels in venous and fingertip blood. The predictive performance of various ML models, including Logistic Regression, Random Forest, kernel Support Vector Machine (SVM), and Artificial Neural Network (ANN), was compared.

Results: Nonlinear models (kernel SVM and ANN) that combined D-amino acid profiles with subject information achieved the highest area under the curve values of 0.78 and 0.79, respectively, demonstrating that the combination of D-amino acid profiles and noninvasive subject information is effective in detecting MCI.

Conclusions: Combining D-amino acid profiles with noninvasive subject information using nonlinear ML models, particularly kernel SVM and ANN, shows promise as a high-precision screening tool for MCI. This approach could serve as a cost-effective preliminary screening method before more invasive and expensive diagnostic tests and significantly contribute to the early detection and development of intervention strategies for dementia.