Molecular Psychiatry最新文献

While a growing number of studies have highlighted the relevance of core and bridge symptoms as potential intervention targets by following the network approach to  psychopathology, their findings have remained primarily descriptive or retrospective. To date, no study has prospectively tested whether interventions tailored to person-specific symptom networks can improve clinical outcomes compared to standard interventions. To address this gap, we conducted an exploratory investigation to examine whether a network-driven, person-specific sequencing of modules yields signals of added benefit compared with a standardized sequence. Accordingly, this proof-of-concept pilot randomized controlled trial recruited participants aged 18-29 years with depressive symptoms, and the Mini International Neuropsychiatric Interview was administered in person to screen for psychiatric conditions. The study compared a digital intervention program, consisting of up to 9 sessions plus one psychoeducation session, sequenced according to core symptoms identified through network analysis using 10-day ecological momentary assessment (EMA) collected beforehand, with a standardized fixed-sequence intervention. Depressive symptoms were measured using the, which includes one item assessing thoughts of self-harm or suicide, at post-intervention, and at 1- and 3-months follow-up. In total, 62 participants were randomly assigned to one of two intervention groups in a 1:1 ratio, with 31 participants in each group. An intent-to-treat analysis revealed significant improvements in depressive symptoms over time in both groups (p_fdr < 0.01). Both groups showed substantial reductions in depression scores from baseline to post-intervention, with large effect sizes (d = 1.24 for the personalized group and d = 1.15 for the standardized group). These improvements were maintained at the 1-month follow-up (d = 0.86 for the personalized group and d = 1.09 for the standardized group) and the 3-month follow-up (d = 1.05 for the personalized group and d = 0.89 for the standardized group). However, the group × time interaction was near zero and imprecisely estimated (β = -0.01, 95% CI - 0.96-0.94; p = 0.987), indicating that, in this pilot, between-arm differences were small and statistically non-significant. Non-significant results are interpreted as inconclusive rather than evidencing equivalence. These findings underscore the need for further trials to identify the specific conditions under which personalized, network-informed approaches might yield advantages over standard interventions. TRIAL REGISTRATION: The study was pre-registered with the Chinese Clinical Trial Registry (ChiCTR2300078568).

Observational studies have reported alteration of circulating metabolites across several psychiatric conditions, but these studies cannot resolve causal relationships. Emerging evidence suggests a genetic relationship exists between these traits requiring further investigation to identify clinically actionable biology. Here, we used the largest genome-wide association studies available to investigate genetic correlation and causal relationships between 10 psychiatric conditions and 249 circulating metabolites. This revealed 1,100 significantly correlated trait pairings, involving fatty acids, lipoproteins and other metabolites, with evidence for causal effects on the liability for major depressive disorder, post-traumatic stress disorder and anorexia nervosa. Notably, the most robust association was a putative causal effect of high-density lipoprotein properties on anorexia nervosa. We also observed significant relationships between metabolic traits and cortical thickness and surface area, as well as evidence of shared gene-level common variant associations amongst 23 metabolite-psychiatric pairings, converging in pathways with metabolic and neuronal function. These findings highlight specific metabolites as potential biomarkers and therapeutic targets in the clinical management of psychiatric disorders.

Angelman syndrome (AS) is a neurodevelopmental disorder caused by UBE3A loss. In humans, UBE3A generates three isoforms that localize to distinct subcellular compartments-one mainly nuclear and two cytoplasmic. The nuclear and most highly expressed cytoplasmic UBE3A isoform are highly conserved in mice, whereas the cytoplasmic human isoform accounting for just ~1% of total UBE3A has no mouse counterpart. Loss of the nuclear-enriched UBE3A isoform causes AS and behavioral deficits in mice; no specific contribution of the predominant cytoplasmic UBE3A isoform has yet been identified. Because the nuclear-enriched isoform constitutes ~80% of total UBE3A protein, it is unclear if its outsized phenotypic impact upon deletion is due to a loss of nuclear UBE3A function or simply a dramatic reduction in overall UBE3A levels. If the former, overexpression of the cytoplasmic UBE3A isoform would be unable to rescue AS phenotypes. To test this, we developed a mouse model that overexpresses the cytoplasmic UBE3A isoform (mIso2-OE) and crossed it with an AS mouse model to yield wildtype (WT), mIso2-OE, AS, and AS/mIso2-OE mice, the latter of which lacked the endogenous nuclear UBE3A isoform (mIso3) in neurons. Unexpectedly, we found that overexpression of the cytoplasmic UBE3A isoform alone rescued most tested AS-related behavioral deficits, except for kindling-induced epileptogenesis or seizure-linked perineuronal net (PNN) accumulation in AS mice. Thus, while many AS phenotypes may be caused by isoform non-selective reductions in UBE3A levels, AS-associated epilepsies appear linked to isoform-selective nuclear UBE3A loss. This information is expected to inform AS gene therapy studies.

China is undergoing a transition from the development of generic drugs to innovative drugs, including those targeting neuropsychiatric disorders. Currently, a total of 273 neuropsychiatric drugs are under development within China's innovative drug pipeline. Although there are still several gaps compared to some developed countries, China is accelerating efforts toward the development of first-in-class products. This article provides an overview of the state of drug development for neuropsychiatric disorders entering the clinical study phase in China, aiming to offer insights into drug development trends in this field.

Bipolar disorder (BD) shows different clinical manifestations according to illness onset (early vs late onset). Its etiology is multifaceted and no reliable biomarkers are available. However, clinical manifestations of BD may stem from disruption in white matter (WM) integrity within brain networks or selective epigenetic alterations, including plasma neural derived extracellular vesicles (NDEVs). In this context, this study further explores the existence of similar epigenetic expression patterns in NDVEs, such as micro-ribonucleic acid (miRNA), and seeks to correlate them with biological markers obtained through Diffusion Tensor Imaging and with clinical data. 23 early onset BD (35% males) (EOBD), 15 late-onset BD (47% males) (LOBD), and 18 healthy controls (44% males) (HC) were recruited. Fractional anisotropy (FA) was investigated through Tract-Based Spatial Statistics. NDEVs were isolated from plasma, and their miRNA content was profiled using real-time polymerase chain reaction. Compared to HC, miR-20a and miR-299-5p were upregulated in EOBD, while miR-323-3p expression was reduced in both EOBD and LOBD patients relative to HC. Moreover, compared to HC, EOBD and LOBD showed decreased FA in the left posterior thalamic radiation and the left anterior corona radiata, respectively. Finally, after Bonferroni correction, EOBD patients showed a negative correlation between miR-323-3p and FA in the left tapetum. Our results shed light on a possible interaction between miRNA expression and WM modifications in BD. However, further research is needed to better characterize the role of miRNA by FA interaction in BD pathophysiology.