Schizophrenia and other psychotic disorders are highly debilitating psychiatric conditions that lack a clear etiology and exhibit polygenic inheritance underlain by pleiotropic genes. The prevailing ...explanation points to the interplay between predisposing genes and environmental exposure. Accumulated evidence suggests that epigenetic regulation of the genome may mediate dynamic gene-environment interactions at the molecular level by modulating the expression of psychiatric phenotypes through transcription factors. This systematic review summarizes the current knowledge linking schizophrenia and other psychotic disorders to epigenetics, based on PubMed and Web of Science database searches conducted according to the PRISMA guidelines. Three groups of mechanisms in case-control studies of human tissue (i.e., postmortem brain and bio-fluids) were considered: DNA methylation, histone modifications, and non-coding miRNAs. From the initial pool of 3,204 records, 152 studies met our inclusion criteria (11,815/11,528, 233/219, and 2,091/1,827 cases/controls for each group, respectively). Many of the findings revealed associations with epigenetic modulations of genes regulating neurotransmission, neurodevelopment, and immune function, as well as differential miRNA expression (e.g., upregulated miR-34a, miR-7, and miR-181b). Overall, actual evidence moderately supports an association between epigenetics and schizophrenia and other psychotic disorders. However, heterogeneous results and cross-tissue extrapolations call for future work. Integrating epigenetics into systems biology may critically enhance research on psychosis and thus our understanding of the disorder. This may have implications for psychiatry in risk stratification, early recognition, diagnostics, precision medicine, and other interventional approaches targeting epigenetic fingerprints.
Functional magnetic resonance imaging provides rich spatio-temporal data of human brain activity during task and rest. Many recent efforts have focussed on characterising dynamics of brain activity. ...One notable instance is co-activation pattern (CAP) analysis, a frame-wise analytical approach that disentangles the different functional brain networks interacting with a user-defined seed region. While promising applications in various clinical settings have been demonstrated, there is not yet any centralised, publicly accessible resource to facilitate the deployment of the technique.
Here, we release a working version of TbCAPs, a new toolbox for CAP analysis, which includes all steps of the analytical pipeline, introduces new methodological developments that build on already existing concepts, and enables a facilitated inspection of CAPs and resulting metrics of brain dynamics. The toolbox is available on a public academic repository at https://c4science.ch/source/CAP_Toolbox.git.
In addition, to illustrate the feasibility and usefulness of our pipeline, we describe an application to the study of human cognition. CAPs are constructed from resting-state fMRI using as seed the right dorsolateral prefrontal cortex, and, in a separate sample, we successfully predict a behavioural measure of continuous attentional performance from the metrics of CAP dynamics (R = 0.59).
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•Co-activation pattern (CAP) analysis is a contemporary frame-wise analytical tool.•We provide a toolbox that enables the easy application of all steps of the pipeline.•An intuitive graphical user interface facilitates usage by inexperienced users.•We associate CAP features at rest with performance in a continuous attention task.
In this study, for the first time, we explored a dataset of functional magnetic resonance images collected during focused attention and open monitoring meditation before and after a five-day ...psilocybin-assisted meditation retreat using a recently established approach, based on the Mapper algorithm from topological data analysis. After generating subject-specific maps for two groups (psilocybin vs. placebo, 18 subjects/group) of experienced meditators, organizational principles were uncovered using graph topological tools, including the optimal transport (OT) distance, a geometrically rich measure of similarity between brain activity patterns. This revealed characteristics of the topology (i.e. shape) in space (i.e. abstract space of voxels) and time dimension of whole-brain activity patterns during different styles of meditation and psilocybin-induced alterations. Most interestingly, we found that (psilocybin-induced) positive derealization, which fosters insightfulness specifically when accompanied by enhanced open-monitoring meditation, was linked to the OT distance between open-monitoring and resting state. Our findings suggest that enhanced meta-awareness through meditation practice in experienced meditators combined with potential psilocybin-induced positive alterations in perception mediate insightfulness. Together, these findings provide a novel perspective on meditation and psychedelics that may reveal potential novel brain markers for positive synergistic effects between mindfulness practices and psilocybin.
There is increasing evidence for altered brain resting state functional connectivity in adolescents with disruptive behavior. While a considerable body of behavioral research points to differences ...between reactive and proactive aggression, it remains unknown whether these two subtypes have dissociable effects on connectivity. Additionally, callous-unemotional traits are important specifiers in subtyping aggressive behavior along the affective dimension. Accordingly, we examined associations between two aggression subtypes along with callous-unemotional traits using a seed-to-voxel approach. Six functionally relevant seeds were selected to probe the salience and the default mode network, based on their presumed role in aggression. The resting state sequence was acquired from 207 children and adolescents of both sexes mean age (standard deviation) = 13.30 (2.60); range = 8.02–18.35 as part of a Europe-based multi-center study. One hundred eighteen individuals exhibiting disruptive behavior (conduct disorder/oppositional defiant disorder) with varying comorbid attention-deficit/hyperactivity disorder (ADHD) symptoms were studied, together with 89 healthy controls. Proactive aggression was associated with increased left amygdala–precuneus coupling, while reactive aggression related to hyper-connectivities of the posterior cingulate cortex (PCC) to the parahippocampus, the left amygdala to the precuneus and to hypo-connectivity between the right anterior insula and the nucleus caudate. Callous-unemotional traits were linked to distinct hyper-connectivities to frontal, parietal, and cingulate areas. Additionally, compared to controls, cases demonstrated reduced connectivity of the PCC and left anterior insula to left frontal areas, the latter only when controlling for ADHD scores. Taken together, this study revealed aggression-subtype-specific patterns involving areas associated with emotion, empathy, morality, and cognitive control.
Sertraline is a selective serotonin reuptake inhibitor with specific indications in child and adolescent psychiatry. Notwithstanding its frequent use and clinical benefits, the relationship between ...pharmacokinetics, pharmacodynamics, efficacy, and tolerability of sertraline across indications, particularly in non-adult patients, is not fully understood.
This naturalistic therapeutic drug monitoring (TDM) study was conducted in a transdiagnostic sample of children and adolescents treated with sertraline (n = 78; mean age, 14.22 ± 2.39; range, 7–18 years) within the prospective multicenter “TDM-VIGIL” project. Associations between dose, serum concentration, and medication-specific therapeutic and side effects based on the Clinical Global Impression scale were examined. Tolerability was measured qualitatively with the 56-item Pediatric Adverse Event Rating Scale.
A strong linear positive dose–serum concentration relationship (with dose explaining 45% of the variance in concentration) and significant effects of weight and co-medication were found. Neither dose nor serum concentration were associated with side effects. An overall mild-to-moderate tolerability profile of sertraline was observed. In contrast with the transdiagnostic analysis that did not indicate an effect of concentration, when split into depression (MDD) and obsessive-compulsive disorder (OCD) diagnoses, the probability of clinical improvement significantly increased as both dose and concentration increased for OCD, but not for MDD.
This TDM–flexible-dose study revealed a significant diagnosis-specific effect between sertraline serum concentration and clinical efficacy for pediatric OCD. While TDM already guides clinical decision-making regarding compliance, dose calibration, and drug–drug interactions, combining TDM with other methods, such as pharmacogenetics, may facilitate a personalized medicine approach in psychiatry.
•The dose-, concentration- and age-related effects of SSRIs are not well understood.•The study was conducted in patients aged 7–18 treated with sertraline (25–250 mg/day).•Dose explained 45% of the variance in serum drug concentration across indications.•Clinical improvement was associated with dose and concentration in OCD, but not MDD.•Therapeutic drug monitoring is a promising tool in OCD research and therapy.
Family-based treatment (FBT) is currently the most effective evidence-based treatment approach for adolescents with anorexia nervosa (AN). Home treatment (HT) as an add-on to FBT (FBT-HT) has been ...shown to be acceptable, feasible and effective. The described three-arm randomized clinical trial (RCT) is intended to investigate whether FBT-HT demonstrates higher efficacy compared to standard outpatient FBT with supplemental mindfulness-based stress reduction training (FBT-MBSR).
This RCT compares FBT-HT to standard outpatient FBT and FBT-MBSR as a credible home-based control group in terms of efficacy and delivery. Adolescents with AN or atypical AN disorder (n = 90) and their parent(s)/caregiver(s) are to be randomly assigned to either FBT, FBT-HT or FBT-MBSR groups. Eating disorder diagnosis and symptomatology are to be assessed by eating disorder professionals using standardized questionnaires and diagnostic instruments (Eating Disorder Examination, Eating Disorder Inventory, Body Mass Index). In addition, parents and caregivers independently provide information on eating behavior, intrafamily communication, stress experience and weight. The therapeutic process of the three treatments is to be measured and assessed among both participants and care providers. The feasibility, acceptability and appropriateness can thus also be evaluated.
We hypothesize that FBT-HT will be an acceptable, appropriate and feasible intervention and, importantly, will outperform both established FBT and FBT-MBSR in improving adolescent weight and negative eating habits. Secondary outcome measures include the reduction in the stress experienced by caregivers, as well as the regulation of perceived expressed emotions within the family, while the intrafamily relationships are hypothesized to mediate/moderate the effectiveness of FBT. The proposed study has the potential to enhance the scientific and clinical understanding of the efficacy of FBT for AN, including whether the addition of HT to FBT versus another home-based adjunct intervention improves treatment outcomes. Furthermore, the study aligns with public health priorities to optimize the outcomes of evidence-based treatments and integrate the community setting. Trial registration This study is registered at ClinicalTrials.gov (NCT05418075).
This study capitalizes on individual episodic memories to investigate the question, how dif-ferent environments affect us on a neural level. Instead of using predefined environmental stimuli, this ...study relied on individual representations of beauty and pleasure. Drawing upon episodic memories we conducted two experiments. Healthy subjects imagined pleasant and non-pleasant environments, as well as beautiful and non-beautiful environments while neural activity was measured by using functional Magnetic Resonance Imaging. Although subjects found the different conditions equally simple to visualize, our results revealed more distribut-ed brain activations for non-pleasant and non-beautiful environments than for pleasant and beautiful environments. The additional regions activated in non-pleasant (left lateral prefrontal cortex) and non-beautiful environments (supplementary motor area, anterior cortical midline structures) are involved in self-regulation and top-down cognitive control. Taken together, the results show that perceptual experiences and emotional evaluations of environments within a positive and a negative frame of reference are based on distinct patterns of neural activity. We interpret the data in terms of a different cognitive and processing load placed by exposure to different environments. The results hint at the efficiency of subject-generated representations as stimulus material.
•This DTI cross-sectional study compared UHR, basic symptom & control groups (n = 112).•The splenium of UHR individuals exhibited differences in fractional anisotropy (FA).•Basic symptoms alone were ...not associated with white matter microstructure changes.•Large differences in FA & radial diffusivity were found in converters to psychosis.•Regional FA was inversely correlated with the general psychopathology domain.
Widespread white matter abnormalities are a frequent finding in chronic schizophrenia patients. More inconsistent results have been provided by the sparser literature on at-risk states for psychosis, i.e., emerging subclinical symptoms. However, considering risk as a homogenous construct, an approach of earlier studies, may impede our understanding of neuro-progression into psychosis.
An analysis was conducted of 3-Tesla MRI diffusion and symptom data from 112 individuals (mean age, 21.97 ± 4.19) within two at-risk paradigm subtypes, only basic symptoms (n = 43) and ultra-high risk (n = 37), and controls (n = 32). Between-group comparisons (involving three study groups and further split based on the subsequent transition to schizophrenia) of four diffusion-tensor-imaging-derived scalars were performed using voxelwise tract-based spatial statistics, followed by correlational analyses with Structured Interview for Prodromal Syndromes responses.
Relative to controls, fractional anisotropy was lower in the splenium of the corpus callosum of ultra-high-risk individuals, but only before stringent multiple-testing correction, and negatively correlated with General Symptom severity among at-risk individuals. At-risk participants who transitioned to schizophrenia within 3 years, compared to those that did not transition, had more severe WM differences in fractional anisotropy and radial diffusivity (particularly in the corpus callosum, anterior corona radiata, and motor/sensory tracts), which were even more extensive compared to healthy controls.
These findings align with the subclinical symptom presentation and more extensive disruptions in converters, suggestive of severity-related demyelination or axonal pathology. Fine-grained but detectable differences among ultra-high-risk subjects (i.e., with brief limited intermittent and/or attenuated psychotic symptoms) point to the splenium as a discrete site of emerging psychopathology, while basic symptoms alone were not associated with altered fractional anisotropy.
Fluoxetine is the recommended first-line antidepressant in many therapeutic guidelines for children and adolescents. However, little is known about the relationships between drug dose and serum level ...as well as the therapeutic serum reference range in this age group. Within a large naturalistic observational prospective multicenter clinical trial (“TDM-VIGIL”), a transdiagnostic sample of children and adolescents (n = 138; mean age, 15; range, 7–18 years; 24.6% males) was treated with fluoxetine (10–40 mg/day). Analyses of both the last timepoint and all timepoints (n = 292 observations), utilizing (multiple) linear regressions, linear mixed-effect models, and cumulative link (mixed) models, were used to test the associations between dose, serum concentration, outcome, and potential predictors. The receiver operating curve and first to third interquartile methods, respectively, were used to examine concentration cutoff and reference values for responders. A strong positive relationship was found between dose and serum concentration of fluoxetine and its metabolite. Higher body weight was associated with lower serum concentrations, and female sex was associated with lower therapeutic response. The preliminary reference ranges for the active moiety (fluoxetine+norfluoxetine) were 208–328 ng/mL (transdiagnostically) and 201.5–306 ng/mL (depression). Most patients showed marked (45.6%) or minimal (43.5%) improvements and reported no adverse effects (64.9%). This study demonstrated a clear linear dose–serum level relationship for fluoxetine in youth, with the identified reference range being within that established for adults.
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