Molecular Psychiatry最新文献

Treatment-resistant depression (TRD) is associated with chronic depression, suicidal behaviours, and reduced quality of life. TRD has a demonstrated genetic component, estimated around 8% based on common genetic variation in unrelated individuals. However, only six genome-wide association studies of TRD were published, and no replicated signals at locus or gene level have been identified; furthermore, apparently opposite results were reported in terms of genetic overlap between TRD and other traits. Other than limited power, an important issue of previous studies was the scarce consideration of TRD heterogeneity, as TRD likely comprises different groups and talking about TRDs could be more appropriate. This review points out important issues in the definition of TRD and differences across samples included in previous studies, which can be partly responsible for the inconsistency across results. Different definitions of TRD should not be expected to have similar genetic profiles, and the whole TRD group can partitioned into subgroups, based on clinical and biological features, to increase reproducibility, as exemplified by recent findings. This can be a key factor to develop/repurpose targeted treatments, or simply to aid a more personalised prescription of available medications compared to current clinical practice, that is largely concentrated on the prescription of a limited number of antidepressants compared to those available.

Background

Oxytocin has received considerable research attention for its role in affiliative behaviors, particularly regarding its pro-social effects. More recent evidence has pointed to a broader role of oxytocin signaling, which includes non-social cognitive processes. However, meta-analytic data on oxytocin’s effects on non-social cognition is currently limited.

Methods

We registered plans for a systematic review and meta-analysis on the effects of oxytocin administration on non-social executive functions prior to data collection via a time-stamped protocol. We performed searches in PubMed, Europe PubMed Central, and the Bielefeld Academic Search Engine. We conducted a meta-analysis of 20 effect estimates from 13 eligible studies. Subgroup meta-analyses and a test for publication bias were also performed.

Results

We found no overall significant effect of oxytocin administration on non-social executive functions (p = 0.30; Hedges’ g = 0.07). However, effect sizes across sub-categories of executive function varied, where the effect of oxytocin administration was the largest for cognitive flexibility (p = 0.02; Hedges’ g = 0.2). Publication bias was assessed using Robust Bayesian Meta-Analysis, which yielded moderate support for the absence of publication bias (BF_PB = 0.32).

Conclusion

Our analysis suggests that oxytocin’s effects may extend beyond social cognitive processing as data synthesis provided evidence supporting a role in non-social cognitive flexibility. The data and analysis output from this meta-analysis can be viewed in a point-and-click web application.

Cognitive dysfunction in Alzheimer’s disease (AD) correlates closely with pathology in the neuronal microtubule-associated protein tau. Tau pathology may spread via neural synapses. In a population of cognitively unimpaired elderly at elevated risk of AD, we investigated four cerebrospinal (CSF) markers of synaptic dysfunction and degeneration. Three of these (SYT1, SNAP25, and ADAM23) are derived from pre-synaptic structures, while ADAM22 reflects post-synaptic changes. All four markers correlated strongly with tau protein measures. In statistical models, SYT1 accounted for more than half the total variance in both total- and P(181)-tau levels. Observed correlations with CSF levels of Alzheimer amyloid-β (Aβ42) were somewhat weaker. In longitudinal data, baseline levels of ADAM22 and ADAM23 robustly predicted increase over time in both total- and P-tau. CSF SYT1 levels also correlated with PET image uptake of tau and (at a trend level) Aβ in areas of interest for early AD pathology. CSF SYT1 and SNAP25 levels correlated inversely with a global psychometric score and several of its domain subscales. In quantitative trait loci analyses, all four synaptic markers were associated with at least one AD genetic risk locus. Upon “staging” participants by their evidence of amyloid and tau pathology (A/T/N framework), the CSF synaptic markers were unexpectedly reduced in participants with CSF evidence of amyloid but not tau pathology. They were clearly elevated, however, in the CSF of persons with indications of both tau and amyloid pathology. These observations provide evidence for clear pre-synaptic degeneration in cognitively unimpaired persons with biomarker evidence of early AD pathology.

Schizophrenia is a chronic and severe mental disorder. It is currently treated with antipsychotic drugs (APD). However, APD’s work only in a limited number of patients and may have cognition impairing side effects. A growing body of evidence points out the potential involvement of abnormal sphingolipid metabolism in the pathophysiology of schizophrenia. Here, an analysis of human gene polymorphisms and brain gene expression in schizophrenia patients identified an association of SMPD1 and SMPD3 genes coding for acid- (ASM) and neutral sphingomyelinase-2 (NSM). In a rat model of psychosis using amphetamine hypersensitization, we found a locally restricted increase of ASM activity in the prefrontal cortex (PFC). Short-term haloperidol (HAL) treatment reversed behavioral symptoms and the ASM activity. A sphingolipidomic analysis confirmed an altered ceramide metabolism in the PFC during psychosis. Targeting enhanced ASM activity in a psychotic-like state with the ASM inhibitor KARI201 reversed psychotic like behavior and associated changes in the sphingolipidome. While effective HAL treatment led to locomotor decline and cognitive impairments, KARI201 did not. An RNA sequencing analysis of the PFC suggested a dysregulation of numerous schizophrenia related genes including Olig1, Fgfr1, Gpr17, Gna12, Abca2, Sox1, Dpm2, and Rab2a in the rat model of psychosis. HAL and KARI201 antipsychotic effects were associated with targeting expression of other schizophrenia associated genes like Col6a3, Slc22a8, and Bmal1, or Nr2f6a, respectively, but none affecting expression of sphingolipid regulating genes. Our data provide new insight into a potentially pathogenic mechanism of schizophrenia and suggest a new pharmaco-treatment strategy with reduced side effects.

To understand the neural mechanism of autism spectrum disorder (ASD) and developmental delay/intellectual disability (DD/ID) that can be associated with ASD, it is important to investigate individuals at an early stage with brain, behavioural and also genetic measures, but such research is still lacking. Here, using the cross-sectional sMRI data of 1030 children under 8 years old, we employed developmental normative models to investigate the atypical development of gray matter volume (GMV) asymmetry in individuals with ASD without DD/ID, ASD with DD/ID and individuals with only DD/ID, and their associations with behavioral and clinical measures and transcription profiles. By extracting the individual deviations of patients from the typical controls with normative models, we found a commonly abnormal pattern of GMV asymmetry across all ASD children: more rightward laterality in the inferior parietal lobe and precentral gyrus, and higher individual variability in the temporal pole. Specifically, ASD with DD/ID children showed a severer and more extensive abnormal pattern in GMV asymmetry deviation values, which was linked with both ASD symptoms and verbal IQ. The abnormal pattern of ASD without DD/ID children showed higher and more extensive individual variability, which was linked with ASD symptoms only. DD/ID children showed no significant differences from healthy population in asymmetry. Lastly, the GMV laterality patterns of all patient groups were significantly associated with both shared and unique gene expression profiles. Our findings provide evidence for rightward GMV asymmetry of some cortical regions in young ASD children (1–7 years) in a large sample (1030 cases), show that these asymmetries are related to ASD symptoms, and identify genes that are significantly associated with these differences.

Patients with post-COVID condition (PCC) present with diverse symptoms which persist at long-term after SARS-CoV-2 infection. Among these symptoms, cognitive impairment is one of the most prevalent and has been related to brain structural and functional changes. The underlying mechanisms of these cognitive and brain alterations remain elusive but neuroinflammation and immune mechanisms have been majorly considered. In this sense, the choroid plexus (ChP) volume has been proposed as a marker of neuroinflammation in immune-mediated conditions and the ChP epithelium has been found particularly susceptible to the effects of SARS-CoV-2. The objective was to investigate the ChP in PCC and evaluate its relationships with cognition, brain, and immunological alterations. One-hundred and twenty-nine patients with PCC after a mean of 14.79 ± 7.17 months of evolution since the infection and 36 healthy controls were recruited. Participants underwent a neuropsychological, and neuroimaging assessment and immunological markers evaluation. Results revealed ChP volume enlargement in PCC compared to healthy controls. The ChP enlargement was associated with cognitive dysfunction, grey matter volume reduction in frontal and subcortical areas, white matter integrity and diffusivity changes and functional connectivity changes. These ChP changes were also related to intermediate monocytes levels. Findings suggest that the ChP integrity may play a relevant role in the pathophysiology of cognitive deficits and the observed brain changes in PCC. The previously documented function of the ChP in maintaining brain homeostasis and regulating the entry of immune cells into the brain supports the presence of neuroinflammatory mechanisms in this disorder.

Anxiety disorders are one of the top contributors to psychiatric burden worldwide. Recent years have seen a dramatic rise in the potential anxiolytic properties ascribed to cannabidiol (CBD), a non-intoxicating constituent of the Cannabis Sativa plant. This has led to several clinical trials underway to examine the therapeutic potential of CBD for anxiety disorders. Yet, CBD’s anxiolytic effects are mixed with some studies reporting little to no impact on trait anxiety but significant reductions in pathological anxiety with suggestions that CBD’s effect may relate to triggered or cue-induced behavior. Here, we studied the effects of CBD on cued and non-cued behaviors and related neurobiological underpinnings. To investigate the effect of CBD on cue-induced anxiety, male rats underwent a fear conditioning protocol (odor associated with shock) followed by assessments of avoidance behavior. CBD (10 mg/kg) was administered 1 h prior to anxiety assessments. To understand molecular mechanisms associated with behavior, we investigated the transcriptome and lipid profile of the nucleus accumbens shell (NAcSh), a structure implicated in cue-mediated behaviors and aversion. Administration of CBD significantly reduced avoidance behavior, but only in animals repeatedly exposed to a shock-paired cue. CBD did not affect behavior in animals exposed to neutral cue or encoding of the cue behavioral response. RNA sequencing revealed substantial impact of the shock-paired cue in control animals, recruiting mechanisms ranging from cytoskeletal dynamics to mitochondria dysfunction. The shock-paired cue also resulted in elevated linoleic acid in vehicle animals which correlated with anxiety-like behavior. CBD either reversed or normalized these cue-induced molecular phenotypes. CBD also recruited lipid networks which correlated with transcripts involved in synaptic plasticity, signaling, and epigenetic mechanisms. These results suggest that CBD may specifically alleviate salient, conditioned anxiety and normalize related biological mechanisms in the NAcSh which may guide therapeutic interventions for anxiety disorders.

Ketamine, a dissociative compound, shows promise in treating mood disorders, including treatment-resistant depression (TRD) and bipolar disorder (BD). Despite its therapeutic potential, the neurophysiological mechanisms underlying ketamine’s effects are not fully understood. This study explored acute neurophysiological changes induced by subanesthetic doses of ketamine in BD patients with depression using electroencephalography (EEG) biomarkers. A cohort of 30 BD (F = 12) inpatients with TRD undergoing ketamine treatment was included in the study. EEG recordings were performed during one of the ketamine infusions with doses ranging from 0.5 to 1 mg/kg, and subjective effects were evaluated using the Clinician-Administered Dissociative States Scale (CADSS). Both rhythmic and arrhythmic features were extrapolated from the EEG signal. Patients who exhibited a clinical response to ketamine treatment within one week were classified as early responders (ER), whereas those who responded later were categorized as late responders (LR). Ketamine reduced low-frequency spectral power density while increasing gamma oscillatory power. Additionally, ketamine flattened the slope of the power spectra, indicating altered scale-free dynamics. Ketamine also increased brain signal entropy, particularly in high-frequency bands. Notably, LR exhibited greater EEG changes compared to ER, suggesting endophenotypic differences in treatment sensitivity. These findings provide valuable insights into the neurophysiological effects of ketamine in BD depression, highlighting the utility of EEG biomarkers for assessing ketamine’s therapeutic mechanisms in real-world clinical settings. Understanding the neural correlates of ketamine response may contribute to personalized treatment approaches and improved management of mood disorders.

Suicide is a major public health concern, and the number of deaths by suicide has been increasing in recent years in the US. There are various biological risk factors for suicide, but causal molecular mechanisms remain unknown, suggesting that investigation of novel mechanisms and integrative approaches are necessary. Transfer (t)RNAs and their modifications, including cytosine methylation (m⁵C), have received little attention regarding their role in normal or diseased brain function, though they are dynamic mediators of protein synthesis. tRNA regulation is highly interconnected with proteomic and metabolomic outcomes, suggesting that investigating these multiple levels of molecular regulation together may elucidate more information on neural function and suicide risk. In the current study, we used an integrative ‘omics’ approach to probe tRNA dysregulation, including tRNA expression and tRNA m⁵C, proteomics, and amino acid metabolomics in prefrontal cortex from 98 subjects who died by suicide during an episode of major depressive disorder (MDD) and neurotypical controls. While no changes were detected in amino acid content, results showed increased tRNA^Gly_GCC expression in the suicide brain that is not driven by changes in m⁵C. Proteomics revealed increased expression of proteins with high glycine codon GGC content, demonstrating a strong association between isoacceptor-specific tRNA expression and proteomic outcomes in the suicide brain, which is in line with previous work linking tRNA^Gly with alterations in glycine-rich proteins in a translational rodent model of depression. Further, we confirmed using a rodent model that tRNA^Gly_GCC overexpression was sufficient to increase the expression of proteins with high glycine codon GGC content that were upregulated in the suicide brain. By characterizing the effects of MDD-suicide in human PFC tissue, we now begin to elucidate a novel molecular signature with downstream consequences for psychiatric outcomes.