Molecular Psychiatry最新文献

Maternal infections during pregnancy may impact offspring brain development and increase the risk of mental disorders, but their impact on suicidal behavior remains unclear. In this study, we investigated associations between maternal infections before, during, and after pregnancy and offspring suicide attempt later in life to understand the mechanisms explaining these associations. Furthermore, paternal infections during these same periods were examined to pinpoint the possible specific role of intra-uterine exposure vs. genetic and socioeconomic confounding factors. A cohort design was applied to individual-level register-based data including all persons aged 10+ years and living in Denmark in 1987-2021. Information on maternal infection (bacterial, viral, and other, as well as at different body sites) was obtained from the Medical Birth Register based of diagnoses received during hospital contacts. The main outcome was hospital presentations for suicide attempt in the offspring. Adjusted Incidence Rate Ratios (IRR) were estimated to quantify the association between exposure to maternal infections and offspring suicide attempt. Of 2,157,641 individuals (35,047,803 person-years), 38,840 (1.8%), 26,158 (1.2%), and 34,853 (1.6%), had been exposed to maternal infection during, before, and after pregnancy, respectively, while 32,275 attempted suicide. Rates among those exposed to maternal infection during pregnancy and those non-exposed were 141.2 and 90.0 per 100,000 person-years, respectively. After adjustment, individuals exposed to maternal infections during pregnancy had higher risk of suicide attempt when compared to non-exposed (IRR 1.46 [1.36-1.56]), particularly those exposed in the second and third trimesters. Elevated risks were also observed among individuals whose mothers with infections prior (incidence rate: 144.3 per 100,000; IRR 1.45 [1.33-1.57]) and after pregnancy (incidence rate: 128.3 per 100,000; IRR 1.31 [1.21-1.42]). However, no associations were found for paternal infections during, before, or after pregnancy and offspring suicide attempt. These findings show that maternal, but not paternal, infections were associated with later risk of suicide attempt in the offspring, pointing out to a possible role of the intra-uterine environment. The similar estimates obtained for exposure to maternal infections before and after pregnancy suggests that part of this risk may stem from an underlying susceptibility to infections or socioeconomic confounding factors, as well as to possible measurement errors in the onset of infections.

Ferroptosis is a regulated cell death driven by iron-dependent lipid peroxidation and has been implicated in major neurological diseases. The brain is enriched in polyunsaturated fatty acids (PUFAs) and iron, which makes it particularly susceptible to lipid peroxidation, leading to ferroptosis. In neurological diseases such as Alzheimer's disease (AD) and stroke, such mechanisms are dysregulated and contribute to neuronal loss. Physiologically, the lipid peroxidation resistance systems in the brain, including defenses (such as SOD, CAT, Prxs, GPxs) and repair systems (such as GPx4, FSP1), prevent ferroptosis and repair damaged phospholipid membranes. However, the efficacy of endogenous resistance systems is often compromised in pathological states, positioning exogenous antioxidants as promising therapeutic candidates. Future research could optimize the delivery of these compounds and explore new candidates that specifically target the ferroptosis signaling pathway to prevent neurodegeneration occurring in neurological diseases.

Stress-related psychiatric disorders impact the quality of life of half a billion people around the world. However, our understanding of the molecular mechanisms responsible for stress-response regulation remain unclear. Here, we report the largest and most comprehensive characterization of the adult male mouse hippocampus, under baseline and acute stress condition, using single-cell RNA sequencing. We further used genetically modified knockout lines for the glucocorticoid and mineralocorticoid receptors (GR and MR); two transcription factors which are pivotal regulators of the central stress-response. We found previously unknown, cell-type specific, molecular signatures of a single prolonged social defeat stress response and identified Nrgn and SgK1 as key regulators in stress-responsive glutamatergic neurons, oligodendrocytes, astrocytes, and endothelial cells. Intriguingly, GR or MR deletion, specifically in glutamatergic or GABAergic neurons, led to distinct and cell-type specific transcriptional signatures after stress exposure. This study significantly advances our understanding of the molecular and cellular network underlying the central response to stressful stimuli.

MRI studies in bipolar disorder (BD) have yielded inconsistent findings, partly due to the varied use of psychotropic medications. This study utilised a mega-analysis approach, accounting for concurrent medication status (syndrome-based and Neuroscience-based Nomenclature (NbN) classifications), in order to assess the association of medication status with subcortical brain volumes in BD. Data from 2,664 BD patients and 4,065 controls (CN) were pooled from 34 research groups as part of the ENIGMA Bipolar Disorder Working Group. Standardized ENIGMA protocols were used to measure subcortical brain volumes. Linear-mixed-effects regression evaluated the association between psychotropic medications and subcortical volumes, and moderation analyses explored interactions. Medication-free patients (n = 410) showed mild ventricular enlargement (d = 0.07) and increased putamen volume (d = 0.06) compared to CN. Patients taking psychotropic medications exhibited smaller subcortical volumes (d = -0.06 to -0.11) and larger ventricles (d = 0.11 to 0.19). Use of antiepileptic and antipsychotic medications was associated with smaller hippocampal and thalamic volumes (d = -0.07 to -0.14), while NbN classification indicated that the categories of 'valproate' and 'dopamine and other monoamine receptor antagonists' are key variables when considering volume differences between BD and CN. Concurrent lithium use weakened the negative association between antiepileptic use and hippocampal volume (β = 0.19, q = 0.038) in patients. Medication status is associated with altered subcortical brain volumes in BD. The NbN classification provides a useful framework for future studies, emphasizing the need for comprehensive longitudinal research to further unravel complex clinical-pharmacological-neurobiological interactions in BD.

Mosaic chromosomal alterations (mCAs) accumulate in the brain tissues and are associated with psychiatric disorders. The association between mCAs in circulating blood and schizophrenia (SCZ) and bipolar disorders (BD) has not been fully evaluated. We detected mCAs from blood samples in 2470 SCZ, 3732 BD, and 177,773 control subjects. The associations between mCAs and SCZ or BD were evaluated using age-adjusted logistic regression models, further evaluated in age subgroups. We analyzed the associations between high cell fraction (CF) mosaic events (CF-mCAs >5% or CF-mCAs >10%) and SCZ or BD in the same way. Furthermore, we assessed the interaction between mCAs and genetic risk scores for SCZ or BD. Autosomal mCAs, especially mosaic loss events, increased in both SCZ and BD (SCZ; OR = 1.78, P = 4.9×10^-6, BD; OR = 1.41, P = 0.0025). These associations were highlighted in the young-age subgroup (SCZ; OR = 7.01, P = 1.7×10^-16, BD; OR = 4.01, P = 2.9×10^-8). In addition, the effect sizes of losses increased in a CF-dependent manner in both SCZ and BD. Loss events with high cell fraction interacted with polygenic risk score in SCZ (P = 0.0098). SCZ or BD were characterized by the presence of a high burden of mosaic losses in blood, especially in young age, suggesting the common somatic pathophysiological mechanisms between these psychiatric diseases. The possible interaction between losses and PRS for SCZ supports the genetic and environmental cross-talk in SCZ.

Neuroanatomical findings on panic disorder (PD) are typically difficult to replicate, with inconsistent effects. These concerns prompted a paradigm shift towards large-scale collaborations, focused on harmonized data extraction and processing for robust examination of PD brain correlates. Hence, leveraging the largest-ever multi-site neuroimaging database on PD (Age: 10-66 years; global sites: 28), compiled by the ENIGMA-Anxiety Working Group, we report on cortical and subcortical differences in individuals with PD (N = 1146) versus healthy controls (HC: N = 3778). The analyses revealed lower thickness and smaller cortical surface area within fronto-temporo-parietal regions in PD (Cohen's ds: -0.08-0.13), along with lower thalamic and caudate volumes (Cohen's ds: -0.07-0.12). Diagnosis-by-age² interactions (Cohen's ds: 0.07-0.12) revealed lower thickness in individuals with PD compared to HC in certain regions during adulthood (25-55 years), with relative absence of such differences during youth (<25 years) or late adulthood (>55 years). Finally, patient subgroup analyses showed that early disease onset (≤21 years) in PD was associated with larger lateral ventricles (Cohen's ds: 0.31-0.38), whilst no medication, comorbidity, or severity effects were found. These findings lend support to neurocircuitry models of PD, which postulate differences within fronto-striato-limbic circuits and temporo-parietal regions. Moreover, findings highlight the potential importance of abnormal development and aging in neuroanatomical differences related to PD. Given its unprecedented scale, the current study is an important milestone towards identifying the structural brain correlates of PD.

While general procrastination is common, psychopathological procrastination, a debilitating phenotype often indicative of subclinical psychiatric conditions, remains poorly understood in terms of its neurobiological underpinning. Challenging its traditional conceptualization as a mere behavioral deficit, we investigated the neurogenetic architecture of psychopathological procrastination. Leveraging a prospective adolescent twin cohort (N = 71 twin pairs) with neuroanatomical imaging (baseline) and psychopathological procrastination phenotyping in young adulthood (8-year follow-up), we first established moderate heritability for psychopathological procrastination (h² = 0.47, 95% CI: 0.14 - 0.71). Employing normative modeling of brain morphology, we found that adolescent neurodevelopmental deviations, specifically within the nucleus accumbens (NAcc), predicted adult psychopathological procrastination. Crucially, these predictive adolescent NAcc deviations exhibited a strong shared genetic basis with adult psychopathological procrastination (r_g = 0.89, 95% CI: 0.89 - 1.00). Beyond regional effects, psychopathological-procrastination-specific whole-brain deviation patterns were identified, which showed neurobiological enrichment with cortical functional gradient and key dopaminergic (DAT/D1) and serotonergic (5-HT receptors) neurotransmitter systems. Both cross-sectional and longitudinal transcriptomic integration of these neuroimaging signatures with human brain gene expression data pinpointed significant associations with molecular transport, neuroimmune responses, and neuroinflammation, further implicating dysregulation within serotonergic and dopaminergic pathways. Collectively, our findings delineate a multisystem neurogenetic architecture of psychopathological procrastination, providing supportive evidence that recontextualizes this debilitating phenotype from a simple behavioral issue to a condition with neurodevelopmental antecedents, potentially suggesting its conceptualization as a subclinical brain disorder.

Approximately one third of people with Major Depressive Disorder (MDD) experience a relapse within six months of discontinuing antidepressant medication (ADM), however, reliable predictors of relapse following ADM discontinuation are currently lacking. A putative behavioural predictor is delay discounting, which measures a person's impatience to receive reward. Previous studies have linked delay discounting to both MDD and reduced serotonergic function, rendering it a plausible candidate predictor. In this multi-site study we measured delay discounting in participants with remitted MDD (N = 97), before and within six months after discontinuation of ADM, and in matched controls without a lifetime history of MDD (N = 54). Using predictive models, we tested whether either baseline discounting, or an early change in discounting following ADM discontinuation, predicted depressive relapse over a six month follow up period. We also tested differences between remitted MDD and control groups in delay discounting at baseline, and associations between discounting and depressive symptoms. We found that the remitted MDD group, compared to the control group, showed significantly higher (p < 0.05; Cohen's d = 0.34) discounting at baseline. In addition, baseline discounting was positively correlated with depression rating scores (Spearman ρ = 0.24). However, delay discounting did not increase following ADM discontinuation. Neither baseline discounting, nor a change in discounting following ADM discontinuation, predicted subsequent depressive relapse. We conclude that delay discounting is elevated in remitted MDD treated with antidepressant medication. However, delay discounting neither increases following ADM discontinuation, nor does it prospectively predict depressive relapse. These results suggest that delay discounting in Major Depressive Disorder has little relationship with illness trajectory following ADM discontinuation.

Objective: To conduct a network meta-analysis to compare the efficacy and safety of various surgical strategies for refractory obsessive-compulsive disorder (OCD), including ablative surgery (ABL) and deep brain stimulation (DBS), with the aim to guide clinical treatment.

Methods: We searched major electronic databases for different surgical interventions of OCD. The primary outcomes were changes in the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) at 1 year and at the longest follow-up (LFU); the secondary outcomes included responder rates of Y-BOCS (≥35% reduction) and changes in global function, depression, and anxiety; and the safety outcomes included surgery-related adverse events (SRAEs) and serious adverse events (SAEs).

Results: A total of 75 studies involving 1259 patients and 20 surgical strategies were enrolled. Most interventions resulted in significant improvements in Y-BOCS scores, with a reduction of around 10-15 points. Among them, radiofrequency capsulotomy (RF-Cap, mean difference [MD]: 17.251 at 1 year; MD: 17.458 at LFU) and inferior thalamic peduncle DBS (ITP-DBS, MD: 18.126 at 1 year; MD: 20.209 at LFU) were associated with the greatest improvements. Subthalamic nucleus + ventral capsule/ventral striatum DBS (STN + VC/VS-DBS) also exhibited good efficacy at the LFU (MD: 20.780), although data were lacking at 1 year. In terms of safety, ABL was associated with a higher rate of SRAEs than DBS (26 VS. 22%, p = 0.0325), with mechanical-Cap exhibiting the highest SRAE rate (47.5%). However, both DBS and ABL showed good acceptability, with no significant difference in SAEs.

Conclusion: Based on the current analysis, RF-Cap and ITP-DBS were associated with the largest improvements; however, the evidence for ITP-DBS is based on a small sample size, and should therefore be interpreted with caution. More head-to-head studies are needed to directly compare different surgical techniques and identify individual treatment options.