Progress in Neuro-Psychopharmacology & Biological Psychiatry最新文献

Schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD) are among the most prevalent severe mental illnesses worldwide. These disorders are associated with substantial disability and premature mortality, primarily attributed to chronic somatic comorbidities and adverse effects of pharmacological treatments. Excess mortality and multiple medical age-related comorbidities are indicators of accelerated biological aging. The epigenetic clock, a biomarker of biological aging, and its derivative measure, epigenetic age acceleration (EAA), hold promise as emerging tools for investigating disorder-specific aging patterns and exploring underlying mechanisms and are being actively explored in this context. However, inconsistencies in findings arise from methodological heterogeneity across studies, and the biological validity of existing epigenetic clocks remains to be fully established. This review synthesizes recent advances in epigenetic aging research about these psychiatric disorders. It further examines associated molecular mechanisms, considers their relevance for clinical prediction, and explores implications for therapeutic interventions, thereby aiming to advance the mechanistic understanding within precision psychiatry.

Neurodevelopmental disorders (NDDs) are debilitating conditions that impose significant burdens on individuals, families, and society. Despite evidence demonstrated altered brain structure in NDDs, definitive conclusions remain elusive. Using two-sample mendelian randomization (MR) and the latest GWAS findings, the current study aimed to elucidate the causal relationships between grey matter (GM), white matter (WM), subcortical regions, and two prevalent NDDs: attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Our findings identified two frontal regions as key neural substrates in NDDs. Specifically, an increased surface area (SA) of the superior frontal gyrus (SFG) was significantly associated with an enhanced risk of ADHD (P = 2.04E-13, β = 4.28E-02, SE = 5.82E-03), while a larger SA of the orbital frontal gyrus (OFG) was associated with a reduced risk of ASD (P = 1.98E-42, β = -9.8E-02; SE = 0.007). Regarding WM tracts, the mode of anisotropy (MO) in the inferior fronto-occipital fasciculus (IFO) emerged as a causal factor for ADHD (P = 3.36E-70, β = -18.35; SE = 1.04), whereas the MO in the retro-lenticular part of the internal capsule (RLIC) was implicated in ASD (P = 1.37E-04, β = -12.73, SE = 3.34). No reverse causal link, i.e., brain alteration caused by NDDs was identified. Further mediation analyses using functional MRI (fMRI) GWAS data revealed that brain functional activities mediated the relationship between structural brain changes and NDDs risk. In conclusion, our findings underscored the critical role of the frontal lobe and association and projection fibers in the pathophysiology of NDDs, provide novel insights into the neural mechanisms underlying ADHD and ASD.

People with schizophrenia can experience a range of symptoms, typically classified as positive (such as hallucinations, delusions), negative (such as avolition, anhedonia) or cognitive (such as attentional or working memory impairments). The accumulation of evidence from EEG, and structural and functional imaging, combined with post-mortem neurochemistry and pathology, has gradually focussed attention on altered function in a core neural circuitry as underlying the aetiology of schizophrenia. The principal circuits apparently fundamental to positive symptoms (e.g. auditory pathway, including auditory cortex) overlap with those apparently fundamental to negative/cognitive symptoms (e.g. ventral striatum, ventral tegmental area) at prefrontal cortex and reticular thalamus. This review summarises the various strands of evidence that lead to these conclusions, considers how this circuitry might be selectively affected according to our understanding of the causes of the disease, and then highlights how the knowledge of regionally-specific electrophysiological, imaging and neurochemical endophenotypes could be better exploited for translational purposes.

Background: Recent advancements in psychedelic research have highlighted psilocybin's potential therapeutic benefits for various mental disorders. Understanding its effects on brain function and identifying predictors of individual responses are essential for developing effective treatments.

Methods: This double-blind, randomized, crossover, and placebo-controlled study enrolled 25 healthy individuals (18 males, 7 females, average age 24.44 years). Participants underwent two sessions involving administration of either psilocybin (oral dose of 10-20 mg) or placebo. Ten-minute resting EEG recordings were taken at baseline and post-administration peaks, focusing on EEG power and connectivity in the default-mode network (DMN) and localized cortical networks in the frontal and parietal cortices. Additionally, we investigated whether baseline EEG features could predict subjective experiences during the psilocybin condition.

Results: Psilocybin significantly decreased EEG power in slow frequency bands (theta and alpha) and increased power in fast frequency bands (beta, gamma1, gamma2) compared to placebo. Connectivity analyses revealed increased connectivity in the DMN and localized parietal network under psilocybin. Subjective experiences, as measured by the Altered States of Consciousness Questionnaire, showed positive correlations with changes in EEG power and connectivity.

Conclusions: Psilocybin induces significant changes in brain function, characterized by altered EEG power and connectivity. These changes correlate strongly with subjective experiences, supporting psilocybin's potential for treating mental disorders. The predictive value of baseline EEG features for subjective alterations suggests that specific brain activity patterns may serve as biomarkers for tailoring psilocybin therapy in clinical settings. This study enhances our understanding of psilocybin's neurophysiological impacts and informs future therapeutic applications.

Clinical trials registration: https://clinicaltrials.gov/study/NCT03853577?cond=NCT03853577&rank=1 Registration number: NCT03853577.

Major depressive disorder (MDD) is a debilitating neuropsychiatric condition that affects individuals worldwide. While neuronal deficits have long been recognized in depression pathogenesis, astroglia are increasingly gaining attention. Astroglia are essential for maintaining brain homeostasis, and regulate neurotransmission, neuroinflammation, and metabolic processes that are disrupted in MDD. This review synthesizes findings from current rodent models of depression, which, despite variations in protocols and etiologies, reveal consistent disruptions related to astroglial function. Structural astroglial abnormalities, including atrophy in the prefrontal cortex and hippocampus along with a reduction in the number of cells expressing the astroglial marker, glial fibrillary acidic protein, are commonly observed. Additional intracellular and intercellular disturbances include impaired glutamate homeostasis, reduced neurotrophic factor production, disrupted gap junction communication with decreased connexin 43 expression, diminished lactate release, increased neuroinflammation, and synaptic deficits. Clinical studies corroborate these findings through postmortem brain analyses and serum biomarkers revealing astroglial dysfunction in the cortical regions of patients with MDD. Importantly, standard and atypical antidepressants, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, and serotonin modulators, as well as rapid-acting antidepressants such as ketamine and esketamine, exert their therapeutic effects at least partially by restoring astroglial homeostasis, highlighting astroglia as critical mediators of treatment response. These converging lines of evidence position astroglial dysfunction as a fundamental component of the pathophysiology of depression and a promising target for effective, personalized antidepressant strategies that move beyond exclusively neuron-centric approaches.

Aberrant dopaminergic signaling is implicated in the core symptoms of attention deficit hyperactivity disorder (ADHD), including dysregulated attention, impulsivity, and hyperactivity. In a mouse model with disrupted scaffolding motif of the dopamine transporter (DAT-AAA), we previously reported extensive loss of DAT expression in striatum, resulting in locomotor hyperactivity, dysfunctional reward-driven motivation, and attenuated behavioral response to amphetamine compared to wildtype (WT) controls. Here, we investigated attention and impulsivity in DAT-AAA mice using the 5-choice serial reaction time task (5-CSRTT). Baseline task acquisition was established using a 2-s stimulus duration (SD) and fixed 5-s intertrial interval (ITI). A variable SD probe (0.2-1.8 s with fixed 5-s ITI) was then used to challenge attentional performance and enable Theory of visual attention (TVA)-based modeling. Finally, a variable ITI schedule randomized to 5-, 10-, or 15-s ITI with fixed 2-s SD for 15 consecutive training days probed impulsive action. Training revealed higher rates of premature responding (p < 0.05) in DAT-AAA mice, a finding confirmed in the variable ITI challenge (p < 0.05). DAT-AAA mice demonstrated inattention (p < 0.001) in the variable SD test, and TVA-based modeling revealed a specific deficit in visual processing speed (p < 0.01). Finally, increased anxiety-related behavior was seen in the open field test. These preliminary findings suggest that reduced DAT expression in striatal terminals is associated with inattentive and excessive impulsive behaviors, supplementing our previously reported locomotor hyperactivity finding. The DAT-AAA mouse therefore shows face validity in terms of inattention, impulsivity, and hyperactivity, and may be a new model to study the neurobiology of ADHD.