Although dopaminergic disturbances are well-known in schizophrenia, the understanding of dopamine-related brain dynamics remains limited. This study investigates the dynamic coactivation patterns (CAPs) associated with the substantia nigra (SN), a key dopaminergic nucleus, in first-episode treatment-naïve patients with schizophrenia (FES).

Resting-state fMRI data were collected from 84 FES and 94 healthy controls (HCs). Frame-wise clustering was implemented to generate CAPs related to SN activation or deactivation. Connectome features of each CAP were derived using an edge-centric method. The occurrence for each CAP and the balance ratio for antagonistic CAPs were calculated and compared between two groups, and correlations between temporal dynamic metrics and symptom burdens were explored.

Functional reconfigurations in CAPs exhibited significant differences between the activation and deactivation states of SN. During SN activation, FES more frequently recruited a CAP characterized by activated default network, language network, control network, and the caudate, compared to HCs (F = 8.54, FDR-p = 0.030). Moreover, FES displayed a tilted balance towards a CAP featuring SN-coactivation with the control network, caudate, and thalamus, as opposed to its antagonistic CAP (F = 7.48, FDR-p = 0.030). During SN deactivation, FES exhibited increased recruitment of a CAP with activated visual and dorsal attention networks but decreased recruitment of its opposing CAP (F = 6.58, FDR-p = 0.034).

Our results suggest that neuroregulatory dysfunction in dopaminergic pathways involving SN potentially mediates aberrant time-varying functional reorganizations in schizophrenia. This finding enriches the dopamine hypothesis of schizophrenia from the perspective of brain dynamics.

There is a compelling need for innovative intervention strategies for patients with affective disorders, given their increasing global prevalence and significant associated disability and impaired functioning. This study aimed to investigate whether a comprehensive multimodule individualized intervention (AWARE), targeting known mediators of functioning, improves functioning in affective disorders.

AWARE was a randomized, controlled, rater-blind clinical trial conducted at two centers in the Capital Region of Denmark (Clinicaltrials.gov, NCT 04701827). Participants were adults with bipolar disorder or major depressive disorder and impaired functioning. Participants were randomized to the six-month AWARE intervention or treatment as usual (TAU). The AWARE intervention is based on the International Classification of Functioning, Disability and Health (ICF) Brief Core Set for Bipolar and Unipolar Disorder.

The primary outcome was observation-based functioning using the Assessment of Motor and Process Skills (AMPS). Secondary outcomes were functioning, QoL, stress, and cognition.

Between February 2021 and January 2023, 103 patients were enrolled; 50 allocated to AWARE treatment and 53 to TAU (96 included in the full analysis set). There was no statistically significant differential change over time between groups in the primary outcome (AMPS), however, both groups showed a statistically significant improvement at endpoint. The AWARE intervention had a statistically significant effect compared with TAU on secondary outcomes of patient-reported functioning, stress and cognition.

Compared with TAU, the AWARE intervention was ineffective at improving overall functioning on the primary outcome, presumably due to the short duration of the intervention. Further development of effective treatments targeting functioning is needed.

Individuals with overweight or obesity are at a high risk for so-called ‘atypical’ or immunometabolic depression, with associated neurovegetative symptoms including overeating, fatigue, weight gain, and a poor metabolic profile evidenced e.g. by dyslipidemia or hyperglycemia. Research has generated preliminary evidence for a low-calorie diet (LCD) in reducing depressive symptoms. The aim of the current systematic review and meta-analysis is to examine this evidence to determine whether a LCD reduces depressive symptoms in people with overweight or obesity.

Eligible studies were identified through PubMed, ISI Web of Science, and PsycINFO until August 2023. Standardized mean differences (SMDs) were derived using random-effects meta-analyses for (1) pre-post LCD comparisons of depression outcomes, and (2) LCD v. no-diet-control group comparisons of depression outcomes.

A total of 25 studies were included in the pre-post meta-analysis, finding that depression scores were significantly lower following a LCD (SMD = −0.47), which was not significantly moderated by the addition of exercise or behavioral therapy as a non-diet adjunct. Meta-regressions indicated that a higher baseline BMI and greater weight reduction were associated with a greater reduction in depression scores. The intervention-control meta-analysis (n = 4) found that overweight or obese participants adhering to a LCD showed a nominally lower depression score compared with those given no intervention (SMD = −0.29).

There is evidence that LCDs may reduce depressive symptoms in people with overweight or obesity in the short term. Future well-controlled intervention studies, including a non-active control group, and longer-term follow-ups, are warranted in order to make more definitive conclusions.

Epigenetic changes are plausible molecular sources of clinical heterogeneity in schizophrenia. A subgroup of schizophrenia patients with elevated inflammatory or immune-dysregulation has been reported by previous studies. However, little is known about epigenetic changes in genes related to immune activation in never-treated first-episode patients with schizophrenia (FES) and its consistency with that in treated long-term ill (LTS) patients.

In this study, epigenome-wide profiling with a DNA methylation array was applied using blood samples of both FES and LTS patients, as well as their corresponding healthy controls. Non-negative matrix factorization (NMF) and k -means clustering were performed to parse heterogeneity of schizophrenia, and the consistency of subtyping results from two cohorts. was tested.

This study identified a subtype of patients in FES participants (47.5%) that exhibited widespread methylation level alterations of genes enriched in immune cell activity and a significantly higher proportion of neutrophils. This clustering of FES patients was validated in LTS patients, with high correspondence in epigenetic and clinical features across two cohorts

In summary, this study demonstrated a subtype of schizophrenia patients across both FES and LTS cohorts, defined by widespread alterations in methylation profile of genes related to immune function and distinguishing clinical features. This finding illustrates the promise of novel treatment strategies targeting immune dysregulation for a subpopulation of schizophrenia patients.

Prenatal and perinatal complications are established risk factors for psychotic disorder, but far less is known about these measures and psychotic experiences (PEs). We investigated the longitudinal effect of prenatal risk factors (maternal behavior, medication complications) and perinatal risk factors (birth weight, medical complications) on frequency of PEs. We also examined the cumulative risk of prenatal/perinatal risk factors, and differences between transient PE, persistent PE, and controls.

The Adolescent Brain Cognitive Development study is a large child cohort (age 9–10 at baseline; n = 11 872 with PE data). PEs were measured longitudinally using the Prodromal Questionnaire-Brief, Child version, and included only if reported as distressing. Mixed-effects models were used for analysis, controlling for random effects, and a substantial number of fixed-effects covariates.

Urinary tract infection (β = 0.11, 95% confidence interval [CI] 0.03–0.19) and severe anemia (β = 0.18, 95% CI 0.07–0.29) increased frequency of distressing PEs in childhood. Number of prenatal complications increased frequency of PEs (β = 0.03, 95% CI 0.01–0.06) and risk of persistent PEs (odds ratio [OR] = 1.08, 95% CI 1.01–1.15). Maternal smoking was associated with an increased frequency of PEs (β = 0.11, 95% CI 0.04–0.18) and persistent PEs (OR = 1.31, 95% CI 1.04–1.66). Maternal substance use was a risk factor for a 48% increased risk of persistent PEs (OR = 1.48, 95% CI 1.08–2.01). Perinatal complications showed no effect on PEs.

This study provides evidence that certain prenatal medical complications (severe nausea, severe anemia), cumulative number of prenatal medical complications, and maternal behaviors (smoking during pregnancy), increased frequency of distressing PEs in childhood. Maternal smoking and substance use, as well as cumulative number of prenatal complications increased risk of persistent PEs.

Cross-sectional studies have identified health risks associated with epigenetic aging. However, it is unclear whether these risks make epigenetic clocks ‘tick faster’ (i.e. accelerate biological aging). The current study examines concurrent and lagged within-person changes of a variety of health risks associated with epigenetic aging.

Individuals from the Great Smoky Mountains Study were followed from age 9 to 35 years. DNA methylation profiles were assessed from blood, at multiple timepoints (i.e. waves) for each individual. Health risks were psychiatric, lifestyle, and adversity factors. Concurrent (N = 539 individuals; 1029 assessments) and lagged (N = 380 individuals; 760 assessments) analyses were used to determine the link between health risks and epigenetic aging.

Concurrent models showed that BMI (r = 0.15, PFDR < 0.01) was significantly correlated to epigenetic aging at the subject-level but not wave-level. Lagged models demonstrated that depressive symptoms (b = 1.67 months per symptom, PFDR = 0.02) in adolescence accelerated epigenetic aging in adulthood, also when models were fully adjusted for BMI, smoking, and cannabis and alcohol use.

Within-persons, changes in health risks were unaccompanied by concurrent changes in epigenetic aging, suggesting that it is unlikely for risks to immediately ‘accelerate’ epigenetic aging. However, time lagged analyses indicated that depressive symptoms in childhood/adolescence predicted epigenetic aging in adulthood. Together, findings suggest that age-related biological embedding of depressive symptoms is not instant but provides prognostic opportunities. Repeated measurements and longer follow-up times are needed to examine stable and dynamic contributions of childhood experiences to epigenetic aging across the lifespan.

Psychostimulants and nonstimulants have partially overlapping pharmacological targets on attention-deficit/hyperactivity disorder (ADHD), but whether their neuroimaging underpinnings differ is elusive. We aimed to identify overlapping and medication-specific brain functional mechanisms of psychostimulants and nonstimulants on ADHD.

After a systematic literature search and database construction, the imputed maps of separate and pooled neuropharmacological mechanisms were meta-analyzed by Seed-based d Mapping toolbox, followed by large-scale network analysis to uncover potential coactivation patterns and meta-regression analysis to examine the modulatory effects of age and sex.

Twenty-eight whole-brain task-based functional MRI studies (396 cases in the medication group and 459 cases in the control group) were included. Possible normalization effects of stimulant and nonstimulant administration converged on increased activation patterns of the left supplementary motor area (Z = 1.21, p < 0.0001, central executive network). Stimulants, relative to nonstimulants, increased brain activations in the left amygdala (Z = 1.30, p = 0.0006), middle cingulate gyrus (Z = 1.22, p = 0.0008), and superior frontal gyrus (Z = 1.27, p = 0.0006), which are within the ventral attention network. Neurodevelopmental trajectories emerged in activation patterns of the right supplementary motor area and left amygdala, with the left amygdala also presenting a sex-related difference.

Convergence in the left supplementary motor area may delineate novel therapeutic targets for effective interventions, and distinct neural substrates could account for different therapeutic responses to stimulants and nonstimulants.

Timely outpatient follow-up and readmission after discharge are common quality indicators in psychiatric care, but their association varies in previous research. We aimed to examine whether the impact of outpatient follow-up and other factors on readmission risk evolves over time in people with non-affective psychotic disorder (NAP).

The Finnish Quality of Care Register includes all people diagnosed with NAP since January 2010. Here, we followed patients with a hospital discharge between 2017 and 2021 until readmission, death, or up to 365 days. Time of the first outpatient follow-up appointment, length of stay (LOS), number of previous hospitalizations, psychosis diagnosis, substance use disorder (SUD), residential status, economic activity, gender, age, year, and region were included. Follow-up time was divided into five periods: week 1, weeks 2–4, weeks 5–13, weeks 14–25, and weeks 26–52, and each period was analyzed separately with Cox regression.

Of the 29 858 discharged individuals, 54.1% had an outpatient follow-up within a week. A total of 10 623 (35.6%) individuals were readmitted. Short LOS increased the readmission risk in the first four weeks, whereas lack of outpatient follow-up raised the risk (adjusted HRs between 1.15 (95% CI 1.04–1.26) and 1.53 (1.37–1.71) in weeks 5–52. The number of previous hospitalizations remained a consistent risk factor throughout the follow-up, while SUD increased risk after 4 weeks and living without family after 13 weeks.

Risk factors of readmission vary over time. These temporal patterns must be considered when developing outpatient treatment programs.

Machine learning (ML) has developed classifiers differentiating patient groups despite concerns regarding diagnostic reliability. An alternative strategy, used here, is to develop a functional classifier (hyperplane) (e.g. distinguishing the neural responses to received reward v. received punishment in typically developing (TD) adolescents) and then determine the functional integrity of the response (reward response distance from the hyperplane) in adolescents with externalizing and internalizing conditions and its associations with symptom clusters.

Two hundred and ninety nine adolescents (mean age = 15.07 ± 2.30 years, 117 females) were divided into three groups: a training sample of TD adolescents where the Support Vector Machine (SVM) algorithm was applied (N = 65; 32 females), and two test groups– an independent sample of TD adolescents (N = 39; 14 females) and adolescents with a psychiatric diagnosis (major depressive disorder (MDD), generalized anxiety disorder (GAD), attention deficit hyperactivity disorder (ADHD) & conduct disorder (CD); N = 195, 71 females).

SVM ML analysis identified a hyperplane with accuracy = 80.77%, sensitivity = 78.38% and specificity = 88.99% that implicated feature neural regions associated with reward v. punishment (e.g. nucleus accumbens v. anterior insula cortices). Adolescents with externalizing diagnoses were significantly less likely to show a normative and significantly more likely to show a deficient reward response than the TD samples. Deficient reward response was associated with elevated CD, MDD, and ADHD symptoms.

Distinguishing the response to reward relative to punishment in TD adolescents via ML indicated notable disruptions in this response in patients with CD and ADHD and associations between reward responsiveness and CD, MDD, and ADHD symptom severity.

Psychotic experiences (PEs) and social isolation (SI) seem related during early stages of psychosis, but the temporal dynamics between the two are not clear. Literature so far suggests a self-perpetuating cycle wherein momentary increases in PEs lead to social withdrawal, which, subsequently, triggers PEs at a next point in time, especially when SI is associated with increased distress. The current study investigated the daily-life temporal associations between SI and PEs, as well as the role of SI-related and general affective distress in individuals at clinical high risk (CHR) for psychosis.

We used experience sampling methodology in a sample of 137 CHR participants. We analyzed the association between SI, PEs, and distress using time-lagged linear mixed-effects models.

SI did not predict next-moment fluctuations in PEs, or vice versa. Furthermore, although SI-related distress was not predictive of subsequent PEs, general affective distress during SI was a robust predictor of next-moment PEs.

Our results suggest that SI and PEs are not directly related on a moment-to-moment level, but a negative emotional state when alone does contribute to the risk of PEs. These findings highlight the role of affective wellbeing during early-stage psychosis development.

This study examined the power of theory-derived models to account for the development of PTSD, Complex PTSD (CPTSD), depression, and anxiety in children and adolescents who had experienced a single-event trauma.

Children (n = 234, aged 8–17 years) recruited from local Emergency Departments were assessed at two and nine weeks post-trauma. Data obtained from self-report questionnaires completed by the child, telephone interviews with parents, and hospital data were used to develop four predictive models of risk factors for PTSD, CPTSD, depression, and Generalized Anxiety Disorder (GAD). ICD-11 proposed diagnostic criteria were used to generate measures for CPTSD and PTSD to assess for risk factors and identify the sample prevalence of these disorders.

At nine weeks post-trauma, 64% did not meet criteria for any disorder, 23.5% met criteria for PTSD, and 5.2% met criteria for CPTSD. 23.9% and 10.7% had developed clinically significant symptoms of depression and GAD, respectively. A cognitive model was the most powerful predictive model, a psychosocial model was weak, and subjective markers of event severity were more powerful than objective measures.

Youth exposed to single-incident trauma may develop different forms of psychopathology, and PTSD and CPTSD are frequently experienced alongside other conditions. The cognitive model of PTSD shows utility in identifying predictors of PTSD, CPTSD, depression, and GAD, particularly the role of trauma-related negative appraisals. This supports the application of cognitive interventions which focus upon re-appraising trauma-related beliefs in youth.

This study evaluated the impact of 2015/2016 prescribing guidance on antidepressant prescribing choices in children.

A retrospective e-cohort study of whole population routine electronic healthcare records was conducted. Poisson regression was undertaken to explore trends over time for depression, antidepressant prescribing, indications and secondary care contacts. Time trend analysis was conducted to assess the impact of guidance.

A total of 643 322 primary care patients in Wales UK, aged 6–17 years from 2010–2019 contributed 3 215 584 person-years of follow-up. Adjusted incidence of depression more than doubled (IRR for 2019 = 2.8 [2.5–3.2]) with similar trends seen for antidepressants. Fluoxetine was the most frequently prescribed first-line antidepressant. Citalopram comprised less than 5% of first prescriptions in younger children but 22.9% (95% CI 22.0–23.8; 95% CI 2533) in 16–17-year-olds. Approximately half of new antidepressant prescribing was associated with depression. Segmented regression analysis showed that prescriptions of ‘all’ antidepressants, Fluoxetine and Sertraline were increasing before the guidance. This upward trend flattened for both ‘all’ antidepressants and Fluoxetine and steepened for Sertraline. Citalopram prescribing was decreasing significantly pre guidance being issued with no significant change afterward.

Targeted intervention is needed to address rising rates of depression in children. Practitioners are partially adhering to local and national guidance. The decision-making process behind prescribing choices is likely to be multi-factorial. Activities to support implementation of guidance should be adopted in relation to safety in prescribing of antidepressants in children including timely availability of talking therapies and specialist mental health services.

There is limited evidence as to whether the immune protein profile is associated with a particular symptomatology pattern across the psychosis continuum.

We estimated two bifactor models of general and specific dimensions of psychotic experiences in unaffected siblings of patients (n = 52) and community controls (n = 200), and of psychotic symptoms in first-episode psychosis (FEP) patients (n = 110). We evaluated associations between these transdiagnostic dimensions and trait (TNF-α, IFN-γ), state (IL-6, IL-1β), and regulatory (TGF-β, IL-10, IL-4) cytokines. We explored whether schizophrenia genetic liability (schizophrenia polygenic risk score; SZ-PRS) modified the associations.

High levels of trait marker IFN-γ were associated with the severity of general psychosis dimension in the unaffected siblings and community controls, expanding to the depressive dimension in siblings and to the manic dimension in FEP. High TNF-α levels were associated with more positive psychotic experiences in unaffected siblings and manic symptoms in FEP. Low levels of state markers IL-6 and IL-1β were observed in unaffected siblings presenting more depressive experiences. Still, high levels of IL-6 and IL-1β were associated with the severity of the depressive and negative symptom dimensions at FEP. The severity of transdiagnostic dimension scores across the three groups was associated with lower regulatory cytokines. Exploratory analysis suggested that a high SZ-PRS contributed mostly to associations with psychotic dimensions.

IFN-γ mapped onto the multidimensional expression of psychosis, reinforcing the trait concept. State markers IL-6 and IL-1β may fluctuate along the spectrum. Dysfunction in the regulatory arm may disinhibit the inflammatory system. Associations with psychotic dimensions may be more prone to SZ-PRS susceptibility.