Molecular Psychiatry最新文献

Psychedelics have shown promising effects in several psychiatric diseases as demonstrated by multiple clinical trials. However, no clinical experiments on patients with schizophrenia have been conducted up to date, except for some old semi-anecdotal studies mainly performed in the time-span ‘50s-‘60s. Notably, these studies reported interesting findings, particularly on the improvement of negative symptoms and social cognition. With no doubts the lack of modern clinical studies is due to the psychomimetic properties of psychedelics, a noteworthy downside that could worsen positive symptoms. However, a rapidly increasing body of evidence has suggested that the mechanisms of action of such compounds partially overlaps with the pathogenic underpinnings of schizophrenia but in an opposite way. These findings suggest that, despite being a controversial issue, the use of psychedelics in the treatment of schizophrenia would be based on a strong biological rationale. Therefore, the aim of our perspective paper is to provide a background on the old experiments with psychedelics performed on patients with schizophrenia, interpreting them in the light of recent molecular findings on their ability to induce neuroplasticity and modulate connectivity, the immune and TAARs systems, neurotransmitters, and neurotropic factors. No systematic approach was adopted in reviewing the evidence given the difficulty to retrieve and interpret old findings. Interestingly, we identified a therapeutic potential of psychedelics in schizophrenia adopting a critical point of view, particularly on negative symptoms and social cognition, and we summarized all the relevant findings. We also identified an eligible subpopulation of chronic patients predominantly burdened by negative symptoms, outlining possible therapeutic strategies which encompass very low doses of psychedelics (microdosing), carefully considering safety and feasibility, to pave the way to future clinical trials.

Individuals diagnosed with autism spectrum disorder (ASD) show difficulty in recognizing emotions in others, a process termed emotion recognition. While human fMRI studies linked multiple brain areas to emotion recognition, the specific mechanisms underlying impaired emotion recognition in ASD are not clear. Here, we employed an emotional state preference (ESP) task to show that Cntnap2-knockout (KO) mice, an established ASD model, do not distinguish between conspecifics according to their emotional state. We assessed brain-wide local-field potential (LFP) signals during various social behavior tasks and found that Cntnap2-KO mice exhibited higher LFP theta and gamma rhythmicity than did C57BL/6J mice, even at rest. Specifically, Cntnap2-KO mice showed increased theta coherence, especially between the prelimbic cortex (PrL) and the hypothalamic paraventricular nucleus, during social behavior. Moreover, we observed significantly increased Granger causality of theta rhythmicity between these two brain areas, across several types of social behavior tasks. Finally, optogenetic stimulation of PrL pyramidal neurons in C57BL/6J mice impaired their social discrimination abilities, including in ESP. Together, these results suggest that increased rhythmicity of PrL pyramidal neuronal activity and its hyper-synchronization with specific brain regions are involved in the impaired emotion recognition exhibited by Cntnap2-KO mice.

Chronic, low-grade inflammation has been associated with motivational deficits in patients with major depression (MD). In turn, impaired motivation has been linked to poor quality of life across psychiatric disorders. We thus determined effects of the anti-inflammatory drug infliximab–a potent tumor necrosis factor (TNF) antagonist–on behavioral and neural measures of motivation in 42 medically stable, unmedicated MD patients with a C-reactive protein >3 mg/L. All patients underwent a double-blind, placebo-controlled, single-dose, randomized clinical trial with infliximab (5 mg/kg) versus placebo. Behavioral performance on an effort-based decision-making task, self-report questionnaires, and neural responses during event-related functional magnetic resonance imaging were assessed at baseline and 2 weeks following infusion. We found that relative to placebo, patients receiving infliximab were more willing to expend effort for rewards. Moreover, increase in effortful choices was associated with reduced TNF signaling as indexed by decreased soluble TNF receptor type 2 (sTNFR2). Changes in effort-based decision-making and sTNFR2 were also associated with changes in task-related activity in a network of brain areas, including dorsomedial prefrontal cortex (dmPFC), ventral striatum, and putamen, as well as the functional connectivity between these regions. Changes in sTNFR2 also mediated the relationships between drug condition and behavioral and neuroimaging measures. Finally, changes in self-reported anhedonia symptoms and effort-discounting behavior were associated with greater responses of an independently validated whole-brain predictive model (aka “neural signature”) sensitive to monetary rewards. Taken together, these data support the use of anti-inflammatory treatment to improve effort-based decision-making and associated brain circuitry in depressed patients with high inflammation.

New-onset psychiatric disorders are frequent after COVID-19. We aim to determine whether acute COVID-19 severity markers can predict post-COVID new-onset psychiatric disorders. We conducted an electronic health records (EHR) cohort study of patients hospitalized for COVID-19 and without any known history of psychiatric disorders. Patients were included between January 2020 and September 2022 in one of the 36 university hospitals of the Assistance Publique - Hôpitaux de Paris. Acute COVID-19 clinical and biological severity markers were recorded during hospitalization for COVID-19. Psychiatric ICD-10 diagnoses were recorded up to 2 years and 9 months after hospitalization for COVID-19. Predictors of post-COVID new-onset psychiatric disorders were identified based on Cox regression models and sensitivity analyses. Predictive scores were built and tested in age- and sex-stratified populations. A total 34,489 patients hospitalized for COVID-19 were included; 3717 patients (10.8%) had at least one post-COVID new-onset psychiatric disorder. Hospital stay >7 days (HR = 1.72, 95%CI [1.59–1.86], p < 0.001), acute delirium (HR = 1.49, 95%CI [1.28–1.74], p < 0.001), elevated monocyte count (HR = 1.14, 95%CI [1.06–1.23], p < 0.001) and elevated plasma CRP (HR = 0.92, 95%CI [0.86–0.99], p = 0.04) independently predicted post-COVID new-onset psychiatric disorders. Sensitivity analyses confirmed hospital stay >7 days, acute delirium, and elevated monocyte count as predictors. Predictive scores based on these variables had good 12-month positive predictive values, up to 7.5 times more accurate than random in women < 65 years. In conclusion, hospital stay >7 days, acute delirium, and elevated monocyte count during acute COVID-19 predict post-COVID new-onset psychiatric disorders.

Prenatal cannabis exposure (PCE) is of increasing concern globally, due to the potential impact on offspring neurodevelopment, and its association with childhood and adolescent brain development and cognitive function. However, there is currently a lack of research addressing the molecular impact of PCE, that may help to clarify the association between PCE and neurodevelopment. To address this knowledge gap, here we present epigenome-wide association study data across multiple time points, examining the effect of PCE and co-exposure with tobacco using two longitudinal studies, the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Christchurch Health and Development Study (CHDS) at birth (0 y), 7 y and 15–17 y (ALSPAC), and ~27 y (CHDS). Our findings reveal genome-wide significant DNA methylation differences in offspring at 0 y, 7 y, 15–17 y, and 27 y associated with PCE alone, and co-exposure with tobacco. Importantly, we identified significantly differentially methylated CpG sites within the genes LZTS2, NPSR1, NT5E, CRIP2, DOCK8, COQ5, and LRP5 that are shared between different time points throughout development in offspring. Notably, functional pathway analysis showed enrichment for differential DNA methylation in neurodevelopment, neurotransmission, and neuronal structure pathways, and this was consistent across all timepoints in both cohorts. Given the increasing volume of epidemiological evidence that suggests a link between PCE and adverse neurodevelopmental outcomes in exposed offspring, this work highlights the need for further investigation into PCE, particularly in larger cohorts.

Abnormalities in cellular metabolism are seen early in Alzheimer’s disease (AD). Astrocyte support for neuronal function has a high metabolic demand, and astrocyte glucose metabolism plays a key role in encoding memory. This indicates that astrocyte metabolic dysfunction might be an early event in the development of AD. In this paper we interrogate glycolytic and mitochondrial functional changes and mitochondrial structural alterations in patients’ astrocytes derived with a highly efficient direct conversion protocol. In astrocytes derived from patients with sporadic (sAD) and familial AD (fAD) we identified reductions in extracellular lactate, total cellular ATP and an increase in mitochondrial reactive oxygen species. sAD and fAD astrocytes displayed significant reductions in mitochondrial spare respiratory capacity, have altered mitochondrial membrane potential and a stressed mitochondrial network. A reduction in glycolytic reserve and glycolytic capacity is seen. Interestingly, glycolytic reserve, mitochondrial spare respiratory capacity and extracellular lactate levels correlated positively with neuropsychological tests of episodic memory affected early in AD. We identified a deficit in the glycolytic enzyme hexokinase 1 (HK1), and correcting this deficit improved the metabolic phenotype in sAD not fAD astrocytes. Importantly, the amount of HK1 at the mitochondria was shown to be reduced in sAD astrocytes, and not in fAD astrocytes. Overexpression of HK1 in sAD astrocytes increases mitochondrial HK1 levels. In fAD astrocytes HK1 levels were unaltered at the mitochondria after overexpression. This study highlights a clear metabolic deficit in AD patient-derived astrocytes and indicates how HK1, with its roles in both oxidative phosphorylation and glycolysis, contributes to this.

Transcriptomic profiles are important indicators for molecular mechanisms and pathways involved in major depressive disorder (MDD) and its different phenotypes, such as immunometabolic depression. We performed whole-transcriptome and pathway analyses on 139 individuals from the observational, case-control, BIOmarkers in DEPression (BIODEP) study, 105 with MDD and 34 controls. We divided MDD participants based on levels of inflammation, as measured by serum high-sensitivity C-reactive protein (CRP), in n = 39 ‘not inflamed’ (CRP < 1 mg/L), n = 31 with ‘elevated CRP’ (1–3 mg/L), and n = 35 with ‘low-grade inflammation’ (>3 mg/L). We performed whole-blood RNA sequencing using Illumina NextSeq 550 and statistical analyses with the Deseq2 package for R statistics (RUV-corrected) and subsequent pathway analyses with Ingenuity Pathway Analysis. Immunometabolic pathways were activated in individuals with CRP > 1 mg/L, although surprisingly the CRP 1–3 group showed stronger immune activation than the CRP > 3 group. The main pathways identified in the comparison between CRP < 1 group and controls were cell-cycle-related, which may be protective against immunometabolic abnormalities in this ‘non-inflamed’ depressed group. We further divided MDD participants based on exposure and response to antidepressants (n = 47 non-responders, n = 37 responders, and n = 22 unmedicated), and identified specific immunomodulatory and neuroprotective pathways in responders (especially vs. non-responders), which could be relevant to treatment response. In further subgroup analyses, we found that the specific transcriptional profile of responders is independent of CRP levels, and that the inhibition of cell-cycle-related pathways in MDD with CRP < 1 mg/L is present only in those who are currently depressed, and not in the responders. The present study demonstrates immunometabolic and cell-cycle-related transcriptomic pathways associated with MDD and different (CRP-based and treatment-based) MDD phenotypes, while shedding light on potential molecular mechanisms that could prevent or facilitate an individual’s trajectory toward immunometabolic depression and/or treatment-non-responsive depression. The recognition and integration of these mechanisms will facilitate a precision-medicine approach in MDD.

The formation of memories is a complex, multi-scale phenomenon, especially when it involves integration of information from various brain systems. We have investigated the differences between a novel and consolidated association of spatial cues and amphetamine administration, using an in situ hybridisation method to track the short-term dynamics during the recall testing. We have found that remote recall group involves smaller, but more consolidated groups of neurons, which is consistent with their specialisation. By employing machine learning analysis, we have shown this pattern is especially pronounced in the VTA; furthermore, we also uncovered significant activity patterns in retrosplenial and prefrontal cortices, as well as in the DG and CA3 subfields of the hippocampus. The behavioural propensity towards the associated localisation appears to be driven by the nucleus accumbens, however, further modulated by a trio of the amygdala, VTA and hippocampus, as the trained association is confronted with test experience. Moreover, chemogenetic analysis revealed central amygdala as critical for linking appetitive emotional states with spatial contexts. These results show that memory mechanisms must be modelled considering individual differences in motivation, as well as covering dynamics of the process.

Varying combinations of genetic and environmental risk factors are thought to underpin phenotypic heterogeneity between individuals in psychiatric conditions such as schizophrenia. While epigenome-wide association studies in schizophrenia have identified extensive alteration of mean DNA methylation levels, less is known about the location and impact of DNA methylation variance, which could contribute to phenotypic and treatment response heterogeneity. To explore this question, we conducted the largest meta-analysis of blood DNA methylation variance in schizophrenia to date, leveraging three cohorts comprising 1036 individuals with schizophrenia and 954 non-psychiatric controls. Surprisingly, only a small proportion (0.1%) of the 213 variably methylated positions (VMPs) associated with schizophrenia (Benjamini-Hochberg FDR < 0.05) were shared with differentially methylated positions (DMPs; sites with mean changes between cases and controls). These blood-derived VMPs were found to be overrepresented in genes previously associated with schizophrenia and amongst brain-enriched genes, with evidence of concordant changes at VMPs in the cerebellum, hippocampus, prefrontal cortex, or striatum. Epigenetic covariance was also observed with respect to clinically significant metrics including age of onset, cognitive deficits, and symptom severity. We also uncovered a significant VMP in individuals with first-episode psychosis (n = 644) from additional cohorts and a non-psychiatric comparison group (n = 633). Collectively, these findings suggest schizophrenia is associated with significant changes in DNA methylation variance, which may contribute to individual-to-individual heterogeneity.

Weighing risks and benefits of the use of psychotropic medications during pregnancy remains a challenge worldwide. We systematically assessed the strength of associations between psychotropic medication use in pregnant people with mental disorders and various adverse health outcomes in both pregnant people and foetuses. Systematic reviews with meta-analyses of observational studies investigating the association between exposure to psychotropic medication in pregnancy and any adverse health outcomes were included. Credibility was graded into convincing, highly suggestive, suggestive, weak or not significant. Quality of the meta-analyses and of individual studies were assessed with A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2) the Newcastle-Ottawa Scale (NOS), respectively. We considered 21 meta-analyses encompassing 17,290,755 participants (AMSTAR 2 high = 1, low = 12, or critically low = 8). Evidence was suggestive for: (1) preterm birth in pregnant people with either any mental disorder (equivalent odds ratio 1.62 (95% confidence interval 1.24–2.12) or depression (1.65 [1.34–2.02]) receiving antidepressants during any trimester of pregnancy; (2) small for gestational age for pregnant people with depression receiving a SSRI during any trimester of pregnancy (1.50 [1.19–1.90]); and (3) major congenital malformation (1.24 [1.09–1.40]) or cardiac malformations (1.28 [1.11–1.47]) in babies for pregnant people with depression or anxiety receiving paroxetine during first trimester of pregnancy. Additional associations were supported by weak evidence, or were not statistically significant. This umbrella review found no convincing or highly suggestive level of evidence of adverse health outcomes associated with psychotropic medication use in pregnant people with mental disorders.