Molecular Psychiatry最新文献

Background: The 40-Hz auditory steady-state response (ASSR) is a potential biomarker for schizophrenia (SZ), bipolar disorder (BD), and autism spectrum disorder (ASD). However, the specific differences in ASSR across these disorders remain unclear. Moreover, the neurophysiological characteristics of the stimulation frequency in ASSR have not been fully elucidated. Hence, we conducted meta-analyses to comprehensively analyze 20-Hz, 40-Hz, and 80-Hz ASSR in individuals with SZ, BD, and ASD.

Methods: We included the studies published until January 2025, identified through a literature search in PubMed and the reference lists of relevant studies. We analyzed 52 studies, including 2116 patients with SZ, 271 individuals at clinical high-risk for psychosis (CHR-P), 110 first-degree relatives of patients with SZ (FDR-SZ), 294 patients with BD, 117 patients with ASD, and 2758 healthy controls (HC).

Results: The analyses indicated pronounced reductions in power and inter-trial phase coherence (ITPC) of 40-Hz ASSR in SZ, BD, and power reduction in ASD compared with HC. In addition, reduced power and ITPC were also observed in 40-Hz ASSR in FDR-SZ but not in CHR-P. Power reductions in 80-Hz ASSR were noted in individuals with SZ, while ITPC of 20-Hz ASSR was reduced in the SZ group but not in the BD group.

Conclusions: These findings indicate that 40-Hz ASSR serves as a potential biomarker for psychotic disorders, whereas deficits at 20 Hz and 80 Hz may be specific to schizophrenia, reflecting distinct neural dysfunctions across diagnostic categories. Further studies are warranted to confirm these results.

Mitochondrial DNA copy number (mtDNA-CN) reflects mitochondrial function and has been associated with several psychiatric disorders. However, the shared genetic architecture between mtDNA-CN and psychiatric conditions remains largely unexplored. Utilizing the largest available genome-wide association study (GWAS) summary statistics from individuals of European ancestry, we systematically investigated the shared genetic architecture between mtDNA-CN and five major psychiatric disorders, including attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ). Specifically, we assessed genetic overlap at the global, regional, and variant levels. In addition, gene expression analyses were performed to identify genes whose predicted expression was associated with both mtDNA-CN and psychiatric traits. Functional enrichment analyses were conducted to characterize the biological functions underlying the shared genes. Significant global-level genetic overlap was observed between mtDNA-CN and all five psychiatric disorders. Regional analyses identified four genomic regions with high pleiotropic probability shared between mtDNA-CN and ADHD, BD, and SCZ. At the variant level, 30 lead variants were detected, corresponding to 30 independent loci jointly associated with mtDNA-CN and psychiatric traits. These loci were mapped to 305 unique genes, among which 87 genes exhibited significant associations between their predicted expression levels and both mtDNA-CN and psychiatric disorders. Functional enrichment highlighted neurodevelopmental and ubiquitin-related pathways, with significant downregulation of shared genes in key brain regions. These findings provide comprehensive evidence for shared genetic mechanisms linking mitochondrial function and psychiatric disorders, highlighting mitochondrial dysfunction as a promising target for future therapy.

As psychedelic-assisted psychotherapy gains momentum, clinical investigation of next-generation psychedelics may lead to novel compounds tailored for specific populations. 2,5-dimethoxy-4-bromophenethylamine (2C-B) is a psychedelic phenethylamine reported to produce less dysphoria and subjective impairment than the psychedelic tryptamine psilocybin. Despite its popularity among recreational users and distinct pharmacodynamics, the neural correlates of 2C-B remain unexplored. Using 7 T resting-state functional MRI in 22 healthy volunteers, we mapped out the acute effects of matched doses of 20 mg 2C-B, 15 mg psilocybin and placebo across spatiotemporal benchmarks of functional brain organisation. In a within-subjects, double-blind, placebo-controlled crossover design, we evaluated the neuropharmacological and neurobehavioural correlates of an array of connectivity measures - including static (sFC) and global connectivity (gFC), dynamic connectivity variability (dFC), and spontaneous brain complexity. Compared to placebo, 2C-B and psilocybin selectively reduced intranetwork sFC, while broadly increasing between-network and subcortical-cortical connectivity. Compared to psilocybin, 2C-B exhibited less pronounced reductions in between-network dFC but elicited elevations in transmodal sFC. Both compounds yielded spatially divergent increases in gFC yet produced similar increases in brain complexity. Using PET density modelling, the spatial distribution of neural effects aligned with documented differences in monoaminergic transporter and serotonergic receptor binding affinity beyond 5-HT_2A, highlighting the role of pharmacology in shaping functional dynamics. Lastly, we show behavioural markers of psychedelic effects are reflected by the decoupling of the transmodal axis of functional brain organisation. Together, our findings highlight 2C-B as a useful new addition to the study of psychedelic neuroscience and may motivate new pharmacotherapy strategies.

Selective serotonin reuptake inhibitors (SSRIs) exhibit delayed therapeutic effects despite rapid serotonin elevation, suggesting their dependence on slow neuroplastic adaptations. Here, we demonstrate that antidepressant actions require cell type-specific translational regulation of the peptidergic signaling in the dentate gyrus (DG). Chronic, but not acute, treatment with an SSRI fluoxetine (FLX) selectively enhances translational activity in hilar mossy cells (MCs), with no detectable changes in neighboring granule cells (GCs). Combining Translating Ribosome Affinity Purification (TRAP) with RNA sequencing revealed distinct baseline translatomes between these two glutamatergic neurons and identified FLX-induced remodeling of peptidergic pathways in the DG. Crucially, we discovered MC-specific enrichment of the neuropeptide PACAP, which undergoes translation-dependent upregulation by chronic FLX treatment. This PACAP induction mediates neuroadaptive plasticity in PAC1 receptor-expressing GCs and drives behavioral responses prominently in female mice during prolonged FLX administration. Our findings establish cell type-specific translational reprogramming as a novel mechanistic framework for antidepressant action.

The recent decade has seen an increasing recognition of the importance of sleep in substance use disorders (SUD) in both research and clinical settings. Not only is sleep disturbance a common comorbidity in SUD, but it may provide a causal link and druggable targets for complementary treatment. The interpersonal variation in sleep also provides opportunities for developing biomarkers and individualized medicine. This review is focused on the key neurotransmitter and neuromodulator systems through which sleep loss may bias reward seeking, increasing the risks for initial drug exposure as well as relapse after drug withdrawal. The review summarizes sleep changes following acute or long-term drug exposure and withdrawal, and current understanding of sleep-mediated regulation of glutamatergic, dopaminergic, and peptidergic transmissions importantly indicated in SUD research.

Phelan-McDermid Syndrome (PMS), primarily linked to SHANK3 haploinsufficiency, presents with complex neurodevelopmental features, including developmental regression, whose underlying mechanisms are poorly understood. This study investigated the impact of SHANK3 disruption across multiple levels, from gene expression in patient-derived iPSC neurons to in vivo brain network activity. RNA-sequencing of iPSC-derived neurons from PMS patients with SHANK3 disruption only (n = 9) and controls (n = 7) revealed dysregulation in differential gene expression and co-expression modules linked to cell cycle, RNA metabolism, and metabolic pathways in SHANK3-mutated neurons. All modules were correlated with PMS regression and enriched for genes implicated in neurodevelopmental or neurodegenerative disorders, such as autism, ADHD, and Alzheimer's disease. At the cellular level, SHANK3-mutated cultures exhibited increased proliferation of neural progenitors and intermediate progenitor markers. Differentiated neurons showed reduced morphological complexity, specific changes in postsynaptic marker density and puncta size, and electrophysiological characteristics suggestive of neuronal hyperexcitability. Electroencephalography (EEG) in a PMS patient cohort (n = 20) compared to controls (n = 30) demonstrated hyperconnectivity and excessive high-frequency oscillations, suggesting altered neural network dynamics. In summary, the use of different analytical approaches suggested that SHANK3 haploinsufficiency disrupts neurodevelopmental trajectories and revealed that regression in PMS may share common genes and pathways with neurodegeneration. We also characterized molecular and neurophysiological markers that can be useful in therapeutic protocols for PMS.

The genetic relationship between schizophrenia, IQ, and educational attainment (EA) is complex. Schizophrenia polygenic scores (PGS) are linked to lower IQ, whilst higher IQ-PGS correlates with reduced schizophrenia risk. Paradoxically, genetic predisposition to higher EA has been associated with increased schizophrenia risk, a relationship potentially confounded by genetic overlap between schizophrenia and bipolar disorder. Using a latent-variable Genomic Structural Equation Modelling approach to GWAS summary statistics for schizophrenia and bipolar disorder, we dissected the genetic contribution to schizophrenia, identifying 63 SNPs specifically associated with schizophrenia (SZ_specific) and 78 shared with bipolar disorder (PSY_shared). Both schizophrenia (rg = -0.22) and SZ_specific (rg = -0.24) were genetically negatively correlated with IQ; correlations between bipolar disorder and PSY_shared with IQ were less pronounced (both rg = -0.07). Schizophrenia exhibited no correlation with EA, yet the latent variables demonstrated divergent relationships; PSY_shared was positively correlated (rg = 0.11), whereas SZ_specific was negatively correlated (rg = -0.06). PGS analyses in the UK Biobank (n = 381,688), corroborated these divergent relationships, SZ_specific-PGS was negatively associated with EA (β = -0.13, p < 2e-16), whereas the PSY_shared-PGS was positively associated (β = 0.14, p < 2e-16). Mendelian randomisation provided additional support but also confirmed the presence of genetic pleiotropy. These findings underscore the utility of genetic methods in dissecting the heterogeneity of neuropsychiatric disorders, supporting the existence of two possible pathways to schizophrenia: one shared with bipolar disorder and another with greater neurocognitive impact.

Schizophrenia, a chronic psychiatric disorder, has prompted extensive research into its immunological aspects. Studies in genetics, epidemiology, and treatment have revealed immune changes associated with schizophrenia, including shifts in cytokine levels and microglial reactivity within the central nervous system (CNS). However, the term "neuroinflammation" has been used to describe these findings despite inconsistent classical markers, potentially oversimplifying the complex role of immune mediators in neurodevelopment and brain homeostasis. In this paper, we critically examine the limitations of applying "neuroinflammation" to describe immune changes in schizophrenia, focusing on its four classical hallmarks: elevated cytokines, microglial reactivity, peripheral immune cell infiltration, and neurodegeneration. While some alterations in these markers are reported, many findings fall within clinical norms or likely contribute to neurodevelopment, suggesting that the term "neuroinflammation" may misrepresent their role. Instead, we propose using alternative terminology that reflects the broader spectrum of CNS immune responses, both inflammatory and non-inflammatory, and invite the scientific community to join this dialogue to refine terminology. By reframing immune alterations in schizophrenia, we aim to promote accuracy and consistency across medical disciplines, ensuring terminology that accurately represents the underlying biology. This, in turn, will improve communication among researchers and clinicians.