Translational Psychiatry最新文献

Guideline-conform treatment of mental disorders is compromised in immigrant populations, but longitudinal pharmacoepidemiologic patterns in bipolar disorder (BD) remain unknown. We aimed to close this knowledge gap by applying state sequence analysis (SSA) to comprehensively assess individual-level medication use. Psychopharmacological medication use was assessed among Swedish-born, second-generation, non-refugee and refugee first-generation immigrants with incident BD diagnosed in Sweden 2006-2015 (n = 24,578, 16-65 years). Three years of medication-use were conceptualized with SSA as consecutive sequences of three-month periods. Anticonvulsant mood-stabilizer, lithium and antipsychotic use was considered adequate treatment. Typologies were identified by clustering and associated with population groups and covariates applying multinomial logistic regression, yielding odds ratios (OR) for comparison to the majority typology as well as estimated probabilities for each typology. Immigrant populations discontinued medication within 6 months more frequently than Swedish-born (42.1-45.7% vs 36.8%). Transitions from periods lacking medication to adequate treatment showed low likelihood across population groups (8.9-10.1%). Treatment failure (48.3% of refugees, 32.3% of Swedish-born), representing lack of adequate and antidepressant medication, predominated among seven identified typologies. Compared to Swedish-born and treatment failure, adjusted OR for other typologies were lower for refugees (0.3-0.5) and other immigrant groups (0.5-0.8). Adjusting for covariates, highest probabilities for treatment failure were computed for non-refugee (44%) and refugee first-generation immigrants (51%), followed by individuals with low education level (42%) and psychiatric comorbidities (attention-deficit/hyperactivity disorder 38%, substance-use disorder 37%). In conclusion, immigrant groups, particularly refugees, with incident BD are less likely to receive adequate treatment, requiring special emphasis on guideline-conformance.

Cognitive performance has been found to be associated with the complex structure of human cerebral cortex. However, due to the limitations of previous cortical parcellation atlases, the cortical genetic patterns determining cognitive performance remain unknown. Here, we utilized the latest Human Connectome Project Multi-Modal Parcellation (HCP-MMP) atlas to divide the cerebral cortex into 180 regions per hemisphere. We investigated the shared genetic architecture between four types of magnetic resonance imaging (MRI)-derived cortical phenotypes and cognitive performance using large-scale genome-wide association studies (N for cortical phenotypes = 36,843; N for cognitive performance = 257,828). We observed extensive genetic overlap between cortical surface area, volume, and local gyrification index (LGI) with cognitive performance, particularly the subregions in the insula, cingulate cortex, and ventromedial prefrontal cortex, many of which were novel findings. However, the thickness of some prefrontal regions was negatively correlated with cognitive performance. We identified 18 and 312 shared genetic loci for global and regional cortical phenotypes with cognitive performance, respectively. These genetic loci were involved in a substantial number of biological processes related to neuronal development, cell growth, and neuronal death or apoptosis. The cortical patterns defined by these shared loci were established entirely along the sensorimotor-association (S-A) axis. These findings provide new insights into the genetic relationship between cognitive performance and the human cerebral cortex under a more refined multimodal cortical parcellation scheme.

Alcohol use disorder (AUD) is a serious mental health condition and a risk factor for morbidity and preterm death. The drug acamprosate (Campral® - calcium-bis[N-acetylhomotaurinate]) is one of few pharmacological treatments available for AUD. Recent research suggests that the properties of acamprosate may be attributed to calcium, but the acute and long-term effects by calcium supplementation on ethanol-induced dopamine release and relapse-like drinking is not fully known. We used in vivo microdialysis and the alcohol deprivation model, to further define the interaction of local or systemic calcium and ethanol on accumbal dopamine and taurine levels, and to outline the impact of acute and repeated calcium treatment on dopamine and the alcohol deprivation effect (ADE) in male Wistar rats. The role of calcium was further studied by local administration of an L-type Ca²⁺ channel (LTCC) blocker. The results demonstrate that acute local administration of calcium in naïve rats increased nucleus accumbens extracellular dopamine levels, and prevented ethanol from further increasing dopamine. In addition, the ethanol-induced elevation of taurine was delayed in animals receiving calcium. Following sub-chronic systemic calcium administration, the dopamine-elevating property of calcium was lost. The LTCC inhibitor nicardipine decreased accumbal dopamine levels and prevented both calcium and ethanol from altering dopamine output. Acute systemic calcium administration abolished the ADE in treatment-naïve rats, but not in rats pretreated with sub-chronic calcium. Taken together, the results suggest that acute properties of calcium abolish ethanol-induced effects within the mesolimbic dopamine system, while there is an indication of tolerance development to both the dopaminergic and behavioral ethanol-related effects of calcium, thus mimicking the outcomes previously observed with acamprosate.

Psychopharmacotherapy is often used to treat anxiety- and stress-associated psychiatric disorders, including post-traumatic stress disorder (PTSD). Adjunctive therapy is most typically used with medications that influence serotonin balance, such as selective serotonin reuptake inhibitors (SSRIs). Contrary to expectations, SSRIs show an anxiety-increasing effect during the initial treatment phase. Among the 14 different serotonin receptor subtypes, pharmacological studies have demonstrated that 5-HT2C receptors (5-HT2CRs) in the bed nucleus of the stria terminalis (BNST) play a significant role in the anxiogenic effect of acute SSRI treatment. Although numerous studies have confirmed the role of the 5-HT2CR in anxiety behavior, little is known about its involvement in learned fear and fear extinction. In particular, fear extinction is considered a central neural mechanism in the treatment of PTSD patients. Recent results from 5-HT2CR knockout mice (2CKO) revealed that global loss of 5-HT2CRs enhances fear extinction, without affecting fear acquisition. Here, we implemented a chemogenetic approach to examine the neuronal substrate which underlies this extinction-enhancing effect in 2CKO mice. DREADD-activation of BNST^CRF neurons promotes fear extinction in 5-HT2CR WT mice, whereas DREADD-inactivation of BNST^CRF neurons impairs fear extinction in 2CKO mice. Thus, using activating and inactivating DREADDs, we were able to bidirectionally modulate fear extinction. These findings provide a possible explanation for the fear extinction-enhancing effect in 2CKO mice with relevance for the treatment of PTSD patients.

Neuropsychiatric symptoms (NPS) are early indicators of cognitive decline due to neurodegenerative diseases, and their timely detection is of the utmost importance. We aimed to develop and validate methods for large-scale NPS screening among elderly individuals and explore underlying metabolic mechanisms. This observational, cross-section study involved 138 and 200 participants in the modeling and external validation cohorts, respectively, chosen from community healthcare centers in Chongqing, China. Data collection involved demographic questionnaires, saliva samples for oral microbiome analysis, and assays for other biomarkers (IL-6, IL-1β, TNF-α, Cath-B and cortisol). EXtreme gradient boosting(XGBoost), support vector machine(SVM), and logistic regression(LR) were developed with RFE and LASSO. The models were primarily evaluated using AUROC and F1 scores. The best model was interpreted using SHAP values, while the LR model was transformed into a nomogram. Additionally, BioCyc function pathway analysis was used to predict the functional shift of biomarkers. The genus-augmented XGBoost model achieved the highest performance, with an AUROC of 0.936 and an F1 score of 0.864, outperforming other models. The LR model was converted into a nomogram to facilitate NPS-risk assessment in community settings. The external validation confirmed the strong predictive power (AUROC = 0.986, F1 score = 0.944). Enrichment and correlation analyses revealed cortisol and microbial interactions with pathways such as the pentose phosphate pathway and enterobacterial common antigen biosynthesis. The XGBoost-augmented model and nomogram offer promising tools for community-based NPS screening, while enrichment analysis provides insights into biological mechanisms.

Opioid use disorder (OUD) poses significant global health and socioeconomic burden. While epigenetic mechanisms, particularly DNA methylation (5mC), have been implicated in OUD, recent work from our group has revealed an important role of DNA hydroxymethylation (5hmC). Building on prior work, we aimed to construct epigenetic risk scores as tools to help predict OUD. Methylation and hydroxymethylation risk scores (MRS/hMRS) were calculated and evaluated for their predictive ability, variance explained, and functional significance. Our results revealed that hMRS outperforms MRS in predicting OUD, with a variance explained of 33.5%. The combined MRS and hMRS explained 34.5% of the variance in OUD. Functional analysis revealed enrichment for Wnt signaling and embryonic development. Gene interaction networks implicated genes involved in opioid signaling pathway and unveiled potential novel gene candidates. This study further supports the importance of distinguishing between 5mC and 5hmC to further understand the epigenetic landscape of OUD. The higher predictive accuracy of hMRS along with hMRS's functional pathways and networks provide valuable insights into the molecular underpinnings of OUD.

Translating findings from preclinical assessments of cognitive function relevant to synucleinopathies into successful clinical trials poses significant challenges. In this study, we examined the effectiveness of human-relevant touchscreen cognitive assessments in detecting the impact of α-synuclein pathology in a mouse model of synucleinopathy on the emergence of stimulus-response learning impairments as a potential cognitive biomarker. We generated two types of α-synuclein pre-formed fibrils, each displaying distinct biophysical characteristics in vitro and biochemical properties when stereotaxically injected in vivo. These two types of fibrils were capable of triggering impairments in stimulus-response learning in pre-motor, prodromal disease stages, akin to what is observed in humans with synucleinopathy. This work supports the use of touchscreen cognitive assessments in conjunction with robust preclinical rodent models for identifying targets and testing therapeutic strategies for synucleinopathic diseases.

Pre-Pulse Inhibition (PPI) is a neural process where suppression of a startle response is elicited by preceding the startling stimulus (Pulse) with a weak, non-startling one (Pre-Pulse). Defective PPI is widely employed as a behavioural endophenotype in humans and mammalian disorder-relevant models for neuropsychiatric disorders. We have developed a user-friendly, semi-automated, high-throughput-compatible Drosophila light-off jump response PPI paradigm, with which we demonstrate that PPI, with similar parameters measured in mammals, exists in adults of this model organism. We report that Drosophila PPI is affected by reduced expression of Dysbindin and both reduced and increased expression of Nmdar1 (N-methyl-D-aspartate receptor 1), perturbations associated with schizophrenia. Studying the biology of PPI in an organism that offers an abundance of genetic tools and a complex and well characterized connectome will greatly facilitate our efforts to gain deeper insight into the aetiology of human mental disorders, while reducing the need for mammalian models.

Serum cytokine alterations are associated with the usage of antipsychotic medications (AP). However, few studies have been designed to longitudinally measure cytokine changes during AP exposure in individuals at clinical high risk (CHR) for psychosis. This study aimed to assess changes in levels of cytokines after initiating AP in the prodromal phase. This longitudinal study involved individuals with CHR who completed the 1-year follow-up reassessment. Individuals with CHR were grouped into those treated with AP (AP + group) and those without (AP- group). Levels of vascular endothelial growth factor (VEGF), granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, 2, 6, 8, and 10 were measured at baseline and 1 year after completion of the clinical assessment. This study included 88 CHR individuals (median age, 18 years and 40.9% [n = 36] women; AP- group: n = 28, AP + group: n = 60). The baseline serum levels of IL-6 were higher in the AP- group than in the AP + group (z = -2.577, p = 0.010). Self-controlled comparisons showed that VEGF (z = 3.826, p < 0.001), TNF-α (z = 2.642, p = 0.008), IL-8 (z = 2.300, p = 0.021), and GM-CSF (z = 2.346, p = 0.019) levels were significantly increased in the AP- group. In the AP + group, IL-6 (z = 3.512, p < 0.001) was significantly increased, IL-1β (z = 2.563, p = 0.010), and GM-CSF (z = 2.095, p = 0.036) were significantly decreased. Repeated-measures analysis of variance revealed a significant group × visit effect on VEGF (F = 20.348, p < 0.001), GM-CSF (F = 7.042, p = 0.013), and IL-1β(F = 4.670, p = 0.040). The findings revealed significant differences in trajectories between individuals with CHR who were and were not taking AP. There is an association between AP use in CHR individuals and differences in inflammatory and neurotrophic factor trajectories.

Neural oscillations have emerged as critical markers of cognitive and emotional states, offering valuable insights into psychiatric disorders. Given the potential suicide risk in patients with major depressive disorders (MDD), its underlying neurophysiological associations need to be further elucidated. This review aimed to comprehensively examine the complex relationships between neural oscillations and suicide risk in MDD. We performed a detailed analysis of electrophysiological phenomena reported in studies investigating suicide risk within depressive populations, consisting of event-related potentials (ERPs) and neuronal oscillations across theta, delta, alpha, beta, and gamma frequency bands. Notably, reduced P300 amplitude, associated with cognitive dysfunction, was observed with elevated theta and delta activity in brain regions implicated in emotional processing, correlating with heightened susceptibility to suicidal behavior. Altered alpha and beta oscillations were associated with emotional dysregulation and cognitive deficits. Importantly, gamma oscillations exhibited increased activity in individuals with suicidal tendencies, reflecting disruptions in the balance between excitatory and inhibitory neuronal circuits. Despite these findings, current research was limited by heterogeneity among study populations, small sample sizes, challenges in establishing causality, and an incomplete understanding of the biological associations underpinning these oscillations. Future research should focus on integrating multi-dimensional oscillatory features to improve individual risk prediction, employing longitudinal designs to track dynamic changes over time, and developing targeted interventions. Addressing these challenges will be critical for advancing reliable biomarkers and innovative strategies for suicide prevention in depression.