Psychological Medicine[JOURNAL]
Sun
200 papers
Distinct and common subcortical functional connectivity revealed across three major psychiatric disorders - CORRIGENDUM.
Chang WC, Hung DP, Chen MH … +4 more , Su TP, Bai YM, Chen YY, Tu PC
Psychol Med · 2026 Jul · PMID 42394605 · Publisher ↗
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Adversity as the key feature: neuroimaging profiles of subtypes from multiple depression risk factors.
Zhou J, Sun Y, Zhao G … +9 more , Sun J, Lu Z, Kang Z, Zhu Y, Yuan R, Guo J, Zhang Y, Bi W, Yue W
Psychol Med · 2026 Jun · PMID 42339646 · Full text
BACKGROUND: Depression arises from diverse environmental and psychosocial risk factors, yet how these factors co-occur within individuals remains unclear. This study identifies profiles of multiple depression risk factor...
BACKGROUND: Depression arises from diverse environmental and psychosocial risk factors, yet how these factors co-occur within individuals remains unclear. This study identifies profiles of multiple depression risk factors and examines their clinical and neuroimaging correlates. METHODS: Among 157,317 UK Biobank participants completing the mental health questionnaire, 24 psychological, environmental, and lifestyle factors were assessed using latent class analysis. Logistic regression evaluated associations between profiles and depression outcomes; linear models examined neuroimaging differences. Imaging transcriptomics and gene-set enrichment analyses contextualized neural findings. RESULTS: Three latent profiles emerged: low risk profile (81.09%), childhood adversity-related profile (CA; 10.95%), and adulthood adversity-related profile (AA; 7.97%). Both the CA profile and AA profile show significantly higher depression risk than the low risk profile. Compared with the low risk profile, the AA profile shows a 2.7-fold increase in depression risk (OR = 3.701, 95%CI: 3.532~3.881), with appetite change and psychomotor symptoms being more prominent. The CA profile shows a 2.5-fold increase in depression risk (OR = 3.507, 95%CI: 3.353~3.607), with worthlessness, sleep problems, and suicidal ideation being more prominent. Both adversity profiles showed lower white-matter FA in cerebellar-thalamic and associative pathways. The CA profile additionally showed reduced FA in occipital tracts, whereas the AA profile showed greater reductions in prefrontal pathways and lower GMV in insula, amygdala, and cerebellar lobules VIIIb/IX, alongside higher occipital pole GMV. The most pronounced nominally significant difference between CA and AA centered on the right amygdala. Genes overlapping subcortical GMV differences were enriched for psychiatric disorders. CONCLUSIONS: Life-course adversity may be a key feature associated with distinct clinical and neural signatures, helping identify subgroups with co-occurring vulnerabilities. These patterns warrant further investigation in future studies.
Sorting the mind: cognitive enhancement through transcutaneous auricular vagus nerve stimulation: a systematic review and meta-analysis.
Liu F, Li Y
Psychol Med · 2026 Jun · PMID 42339645 · Full text
Transcutaneous auricular vagus nerve stimulation (taVNS) is a noninvasive technique engaging vagal afferents that may enhance cognition, but results vary across domains and samples. Following PRISMA, seven databases (inc...
Transcutaneous auricular vagus nerve stimulation (taVNS) is a noninvasive technique engaging vagal afferents that may enhance cognition, but results vary across domains and samples. Following PRISMA, seven databases (inception-October 2025) plus registries and gray literature were searched. Random-effects meta-analyses (REML; Hedges' ) were complemented by Bayesian hierarchical models and sensitivity analyses. Fifty-three studies were included; 30 contributed quantitative data (>1,500 participants). taVNS was associated with improved cognitive performance overall ( = 0.41, 95% CI: 0.30-0.53; = 51.4%). Effects were moderate for executive functions ( = 0.46, 95% CI: 0.27-0.65; = 9.5%) and cognitive flexibility/learning ( = 0.53, 95% CI: 0.32-0.75; = 52.9%), and small for working memory/attention ( = 0.19, 95% CI: 0.04-0.33; = 14.9%). Social cognition/emotion regulation showed larger but imprecise effects ( = 3; = 0.80, 95% CI: 0.07-1.52; = 82.1%). Clinical samples benefited similarly ( = 7; = 0.55, 95% CI: 0.31-0.79; = 29.5%), with no difference from healthy cohorts ( = -0.001, = .994). High-intensity protocols (>1.0 mA) yielded larger effects; mode, duration, and site were not moderators. Bayesian models supported effects ( [ > 0] ≥ 0.93). taVNS is associated with statistically significant improvements in cognitive performance, strongest for executive control and adaptive learning. We propose a Vagal Neurocognitive Integration Model linking LC-NE arousal modulation to prefrontal control. Future diagnosis-specific, adequately powered trials with multimodal neuroimaging should refine mechanisms and dose-response.
Depression and aging: insights from brain age prediction models.
Mitchell O, Connaughton M, Kelly JR … +3 more , Harkin A, Roddy DW, Aas M
Psychol Med · 2026 Jun · PMID 42333537 · Full text
BACKGROUND: The impact of depression on brain aging remains unclear, but both have been linked to stressful life events. Shared biological pathways may underlie structural brain changes. Clarifying these relationships co...
BACKGROUND: The impact of depression on brain aging remains unclear, but both have been linked to stressful life events. Shared biological pathways may underlie structural brain changes. Clarifying these relationships could advance understanding of underlying mechanisms and inform treatment approaches. METHODS: Structural MRI scans of 190 participants (controls, = 110, clinically diagnosed with major depressive disorder [MDD], = 80), from the REDEEM dataset, were input into three pretrained brain age prediction models: brainageR, DeepBrainNet, and pyment. Prediction accuracy was compared in controls to identify the optimal model. DeepBrainNet demonstrated the highest accuracy and was selected for subsequent analysis. Brain-predicted age difference (brain-PAD) was calculated as predicted age minus chronological age. Linear regression examined the effects of MDD diagnosis, childhood maltreatment, and cortisol awakening response on brain-PAD. RESULTS: Depressed participants reported greater childhood maltreatment but a similar cortisol awakening response. An Age × Group interaction ( = 0.34, 95% CI: 0.15-0.53, < 0.001) indicated older adults with MDD exhibited greater positive deviations from normative brain age predictions, suggesting nonuniform brain aging across the lifespan. Cortisol awakening response showed a negative association with brain-PAD ( = -0.01, 95% CI: -0.01 to -0.00, = 0.041), indicating higher HPA-axis reactivity was linked to younger-appearing brains. Females showed lower brain-PAD than males, reflecting younger-appearing brains. CONCLUSIONS: MDD was associated with age-dependent differences in brain-PAD. The protective association between cortisol awakening response and brain age highlights the importance of integrating stress biomarkers to better understand neural aging mechanisms in depression.
An integrative NLP framework identifies multilevel linguistic phenotypes of schizophrenia across tasks.
Nakamura H, Kano Y, Sugihara G … +10 more , Takemura R, Yamaguchi Y, Shimizu M, Takagi S, Iizuka M, Tashiro S, Kitazawa M, Sento A, Takahashi H, Taishiro K
Psychol Med · 2026 Jun · PMID 42333390 · Full text
BACKGROUND: Linguistic abnormalities in schizophrenia (SCZ) span morphological, syntactic, semantic, and discourse levels. Converging cross-linguistic evidence suggests that SCZ may involve semantic narrowing alongside r...
BACKGROUND: Linguistic abnormalities in schizophrenia (SCZ) span morphological, syntactic, semantic, and discourse levels. Converging cross-linguistic evidence suggests that SCZ may involve semantic narrowing alongside reduced syntactic differentiation, yet how these changes co-occur across linguistic domains and whether they represent core, task-general disturbances remains unclear. We applied a multilevel NLP framework to a large Japanese dataset to identify structurally related linguistic markers of SCZ across elicitation contexts. METHODS: Speech from 104 patients with SCZ and 101 healthy controls was collected through semi-structured interviews. Transcripts from free conversation, storytelling, and picture description were analyzed using GiNZA, Word2Vec, TF-IDF, and SentenceBERT to extract 76 morphosyntactic, semantic, and discourse features. Factor analysis identified representative features independent of diagnosis, which were tested using generalized estimating equations and validated with bootstrap and permutation procedures. Cross-task stability was examined to determine core linguistic markers. RESULTS: In free conversation, reduced Case-particle (Kakujoshi) and Adverb use and increased Mean Pairwise Word Similarity were strongly associated with SCZ (AUC = 0.87, 95% CI: 0.74-0.97). Adverbial, case-particle, and semantic-network measures functioned as cross-task markers. CONCLUSIONS: SCZ involves multidimensional language disturbances characterized by a tripartite linguistic phenotype of diminished morphosyntactic explicitness, semantic narrowing, and reduced modification-based contextual modulation in spontaneous discourse. Extending cross-linguistic evidence, our results indicate that lexical-semantic contraction co-occurs with reduced overt marking of argument relations in Japanese, alongside weakened adverbial elaboration and framing - suggesting convergent, largely task-general dimensions of SCZ language pathology, most evident in free conversation.
Predicting functional remission after antipsychotic discontinuation: a real-world study in schizophrenia - ERRATUM.
Lu C, Dong Y, Zhai Z … +12 more , Gao T, Luo M, Chang D, Chen J, Xue J, Zhao Y, Xiang Q, Li X, Ma X, Wei Z, Feng T, Liu D
Psychol Med · 2026 Jun · PMID 42325016 · Full text
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Genetic heterogeneity affects the risk of incident depression, comorbidity, and response to environment: A prospective trajectory study.
Pan C, Cheng S, Qi X … +9 more , Cheng B, Feng J, Kang M, Liu L, Yang X, Wen Y, Jia Y, Liu H, Zhang F
Psychol Med · 2026 Jun · PMID 42324796 · Full text
BACKGROUND: Depression exhibits significant heterogeneity in its genetic underpinnings. The role of genetic components in the development of depression and its comorbidities remains insufficiently explored. METHODS: Firs...
BACKGROUND: Depression exhibits significant heterogeneity in its genetic underpinnings. The role of genetic components in the development of depression and its comorbidities remains insufficiently explored. METHODS: First, depression risk loci from a large-scale genome-wide meta-analysis were annotated to Gene Ontology (GO) terms by functional enrichment. GO-based polygenic risk scores (GO-PRS) were then calculated for individuals in the UK Biobank. Principal component analysis (PCA) was applied for dimensionality reduction, followed by cluster analysis to identify genetic subtypes of depression. Multistate models were applied to assess the impact of genetic patterns on the trajectory from healthy status to incident depression, and depression to 26 subsequent diseases, as well as the associations between environmental factors and disease trajectories across genetic subtypes. RESULTS: Participants were categorized into three genetic subtypes: immune-dominant, neuro-dominant, and comprehensive-risk. Significant differences in risk of depression and subsequent diseases, and susceptibility to environmental factors were observed across subtypes. Comprehensive-risk subtype showed higher risks of depression compared to immune-dominant (HR: 1.10, 95% CI: 1.05-1.15) and neuro-dominant subtype (HR: 1.12, 95% CI: 1.08-1.16). Comprehensive-risk subtype exhibited higher risks of transition from depression to subsequent diseases, such as anemia compared to immune-dominant subtype, and diseases of the digestive system compared to neuro-dominant subtype. Environmental factors were more strongly associated with the transition from depression to subsequent diseases in immune-dominant and comprehensive-risk subtypes, including cardiovascular, respiratory, and metabolic diseases. CONCLUSIONS: Our findings highlight the genetic heterogeneity of depression and comorbidities, and shed light on how genetic components modulate responses to environmental factors.
DTI-ALPS and subcortical structural-functional coupling mediate the impact of sleep quality on working memory in insomnia disorder.
Lv Z, Zhang H, Yang Y … +2 more , Wei Y, Lei X
Psychol Med · 2026 Jun · PMID 42317112 · Full text
BACKGROUND: Working memory (WM) deficits are frequently observed in patients with insomnia disorder (ID), but their neural basis is unclear. Glymphatic dysfunction and disrupted structural-functional coupling have been i...
BACKGROUND: Working memory (WM) deficits are frequently observed in patients with insomnia disorder (ID), but their neural basis is unclear. Glymphatic dysfunction and disrupted structural-functional coupling have been implicated, yet they have rarely been examined together, particularly in clinical populations. METHODS: We conducted a multimodal MRI study in 391 ID patients. Glymphatic function was estimated using the diffusion tensor image analysis along the perivascular space (DTI-ALPS). The SFC was derived by correlating structural connectivity and functional connectivity. WM was measured by the longest span on the digit span backward task. Partial correlations and mediation analyses were performed to examine associations among sleep quality (Pittsburgh Sleep Quality Index, PSQI), DTI-ALPS, SFC, and WM performance. RESULTS: DTI-ALPS was negatively correlated with PSQI ( = -0.17, = 0.006), indicating reduced glymphatic clearance with poorer sleep quality. Global SFC was positively associated with DTI-ALPS ( = 0.32, pFDR < 0.001), but not with WM ( = 0.01, = 0.84). At the network level, SFC within the subcortical network (Sub-SFC) correlated with both DTI-ALPS ( = 0.29, pFDR < 0.001) and WM performance ( = 0.28, pFDR < 0.001). Mediation analysis revealed that DTI-ALPS and Sub-SFC jointly mediated the association between PSQI and WM performance, with a significant indirect effect (indirect effect = -0.074). CONCLUSIONS: This study provides novel evidence that impaired glymphatic clearance and reduced Sub-SFC form key neural pathways linking poor sleep quality to working-memory deficits in ID, and that DTI-ALPS and Sub-SFC may serve as useful biomarkers of cognitive vulnerability.
Schizophrenia and bipolar disorder: a comparative analysis of genetic and brain network connectivity.
Ren H, Liu Y, Huang Y … +12 more , Tang Y, Xiao L, Wu Y, Liu S, Yin Y, Ma Q, Dai M, Tao S, Xie M, Li M, Li T, Wang Q
Psychol Med · 2026 Jun · PMID 42317101 · Full text
BACKGROUND: Schizophrenia (SCZ) and bipolar disorder (BD) are severe psychiatric conditions with overlapping clinical presentations, genetic risk factors, and brain network dysfunction. Whether alterations in large-scale...
BACKGROUND: Schizophrenia (SCZ) and bipolar disorder (BD) are severe psychiatric conditions with overlapping clinical presentations, genetic risk factors, and brain network dysfunction. Whether alterations in large-scale intrinsic brain networks reflect shared or disorder-specific genetic influences remains poorly understood. Clarifying this distinction is essential for refining etiological models and improving diagnostic precision. METHODS: Genome-wide inferred statistics (GWIS) were applied to decompose the genetic architecture of SCZ and BD into shared and unique components. Using resting-state network (RSN) data from the UK Biobank, functional connectivity (FC) and structural connectivity (SC) were extracted as neuroimaging phenotypes. Causal inference approaches were subsequently employed to infer potential directional relationships between brain network connectivity and each disorder. RESULTS: Analyses revealed both common and distinct patterns of brain network connectivity associated with SCZ and BD. Notably, SC within the default mode network (DMN) exhibited opposing effects across the two disorders, suggesting divergent structural underpinnings despite clinical overlap. Additionally, SC within the limbic network (LN) and frontotemporal control network demonstrated potential causal relationships with both conditions, implicating these circuits astransdiagnostic neural substrates. CONCLUSION: These findings illuminate the shared and disorder-specific genetic and neural architecture underlying SCZ and BD. Integrating genome-wide genetic methods with large-scale neuroimaging data offers a powerful framework for disentangling psychiatric comorbidity and may inform more targeted diagnostic criteria and individualized treatment strategies.
The developmental shift in aperiodic activity and its link to the default mode network in attention-deficit hyperactivity disorder.
Li H, Wu GS, Zhu Y … +6 more , Dang C, Zhong SG, Zhao XX, Luo XS, Wang YF, Sun L
Psychol Med · 2026 Jun · PMID 42312350 · Full text
BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) involves altered neurodevelopment, yet the underlying mechanisms remain elusive. Aperiodic EEG components may reflect neural functions like excitatory/inhibitor...
BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) involves altered neurodevelopment, yet the underlying mechanisms remain elusive. Aperiodic EEG components may reflect neural functions like excitatory/inhibitory balance, but their age-related differences in ADHD and link to default mode network (DMN) dysfunction are unexplored. METHODS: We included 110 medication-naïve children/adolescents with ADHD and 100 matched typically developing peers aged 6-14 years. Aperiodic parameters (exponent, offset) were derived, and source-localized alpha-band DMN coherence was computed. The sample was stratified into middle childhood (6-9 years) and early adolescence (10-14 years) subgroups to delineate age-dependent patterns. RESULTS: ADHD showed globally increased exponent and offset versus controls. Normative age-related decreases were significantly attenuated in ADHD, indicating divergence from typical development. Age-stratified analyses revealed distinct patterns: in middle childhood, increased frontal offset correlated positively with inattention (right hemisphere) and hyperactivity/impulsivity (left hemisphere); in early adolescence, it associated with reduced coherence in two DMN pathways (right mSFG-left hippocampus and left mSFG-right MTG). CONCLUSIONS: Aperiodic activity differences in ADHD are age-dependent. Younger children exhibit focal, symptom-linked frontal abnormalities, whereas adolescents show pervasive network-level dysregulation. Aperiodic measures may capture age-varying ADHD pathophysiology, informing developmentally targeted biomarkers.
Variations of structural-functional coupling in post-traumatic stress disorder are associated with underlying molecular and transcriptional features.
Song Y, Huang B, Wu J … +6 more , Lin J, Xin K, Gao B, Kemp GJ, Guo B, Gong Q
Psychol Med · 2026 Jun · PMID 42312348 · Full text
BACKGROUND: Post-traumatic stress disorder (PTSD) is a growing health problem whose neurobiology remains incompletely understood. Neuroimaging is useful in probing PTSD-related brain dysfunction, and techniques continue...
BACKGROUND: Post-traumatic stress disorder (PTSD) is a growing health problem whose neurobiology remains incompletely understood. Neuroimaging is useful in probing PTSD-related brain dysfunction, and techniques continue to evolve. Structural-functional coupling (SFC) offers a novel integrated perspective on PTSD neurobiology. We sought to define unique SFC alterations in PTSD and explore their associations with clinical symptoms, brain molecular architecture, and gene expression. METHODS: We studied 61 PTSD patients and 62 trauma-exposed non-PTSD controls (TENC) recruited from earthquake survivors. We compared SFC constructed from multimodal MRI data by an eigendecomposition method between the two groups. We explored the spatial correlation of SFC with molecular maps, used partial least squares (PLS) regression to associate them with Allen Human Brain Atlas gene data, and conducted enrichment analysis on the identified genes. RESULTS: PTSD patients showed significant regional SFC alterations in multiple regions: lower SFC in PTSD versus TENC in the default mode network (DMN), frontoparietal network (FPN), dorsal attention network, sensorimotor network, visual network, and thalamus, and higher SFC in PTSD versus TENC in the DMN, FPN, and ventral attention network. Some changes were correlated with clinical symptom severity. In both groups, the spatial distribution of SFC was similarly correlated with molecular architectures. The second component of the PLS regression genes were linked to PTSD-specific SFC variations, enriched mainly in molecular functions and pathways related to synapses and neurotransmitter signaling. CONCLUSIONS: This study yields new insights into PTSD pathophysiology by connecting macroscale SFC changes with their microscale molecular and transcriptional basis.
The role of metabolic health in neurostructural and cognitive alterations in bipolar disorders.
Selitser M, McWhinney SR, Wu L … +8 more , Fraiha-Pegado J, Dietze L, Corkum E, Selitser L, Nunes A, Alda M, Franke K, Hajek T
Psychol Med · 2026 Jun · PMID 42312342 · Full text
BACKGROUND: Bipolar disorders (BD) rank among the most disabling conditions, affecting millions worldwide. Cognitive impairment in BD is linked with brain changes and worse functional outcomes. Obesity and metabolic synd...
BACKGROUND: Bipolar disorders (BD) rank among the most disabling conditions, affecting millions worldwide. Cognitive impairment in BD is linked with brain changes and worse functional outcomes. Obesity and metabolic syndrome (MetSy) are overrepresented in BD and are associated with more pronounced brain structural and cognitive alterations in the general population. Here, we studied for the first time the contribution of metabolic dysfunction to both brain and cognitive alterations in BD. METHODS: We recruited 163 participants (76 individuals with BD, 87 controls). We used principal component analysis (PCA) to derive a composite measure of metabolic health from WHR, BMI, HOMA-IR, HbA1c, TGC, HDL, LDL, systolic, diastolic BP, and to derive a composite cognitive measure from the California Verbal Learning Test and Digit Span. Brain structure was indexed using machine-learning-predicted BrainAGE derived from T1-weighted MRI. RESULTS: Obesity, hypertension, insulin resistance, and dyslipidemia contributed most strongly to variance in metabolic health in this sample. This MetSy-associated risk cluster predicted higher BrainAGE ( = 0.75 ± 0.29, = 0.011) and lower cognitive performance ( = -0.19 ± 0.09, = 0.037), accounting for 30% of the association between BD and higher BrainAGE and 25% of the association between BD and worse cognitive performance. These effects were independent of symptoms, medications, illness course, and duration. CONCLUSIONS: MetSy, particularly obesity, was closely linked with brain/cognitive impairments in BD. While the need for metabolic monitoring should be informed by the diagnosis of BD, screening for MetSy can also help track brain health and cognitive functioning.
Transdiagnostic Biomarkers and Mechanistic Heterogeneity in Cognitive Fatigue: A Response to Rudroff.
Linnhoff S, Cohen Kadosh R, Zaehle T
Psychol Med · 2026 Jun · PMID 42312336 · Full text
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Pharmacological principles for safe benzodiazepine and Z-drug dose reduction.
Horowitz M, Lamberson N, Brandt J … +6 more , Framer A, Shapiro B, Sørensen A, Cadogan C, Ritvo A, Taylor D
Psychol Med · 2026 Jun · PMID 42312333 · Full text
Many guidelines recommend deprescribing benzodiazepines and z-drugs in most long-term users. Due to physical dependence in those using medication as prescribed (distinct from addiction), discontinuation can be difficult...
Many guidelines recommend deprescribing benzodiazepines and z-drugs in most long-term users. Due to physical dependence in those using medication as prescribed (distinct from addiction), discontinuation can be difficult and is often unsuccessful, as withdrawal symptoms can be severe and long-lasting, especially after long-term use. There is a lack of clarity on how to taper patients in a tolerable manner that minimizes discomfort. Current guidelines vary with some suggesting linear reductions (e.g. 1 mg every 1-4 weeks) and some proportionate reductions (e.g. 5%-10% of the most recent dose per month, with smaller reductions as the dose decreases). The shape of the relationship between dose of benzodiazepine and activity at gamma-aminobutyric acid-A (GABA-A) receptors is hyperbolic: steeply inclining at low doses, flattening at higher doses. Consequently, linear dose reductions produce increasingly large changes in receptor occupancy, predicting escalating withdrawal effects, while hyperbolic or proportionate dose reductions produce linear reductions in pharmacological effect. Slower tapering (over months and years) may be more successful than tapering over days or weeks. In practice, rate of tapering should be adjusted according to severity of withdrawal effects. Final doses for some people will need to be very small (equivalent to as little as 0.2 mg of diazepam, or less) so that the last 'step down' to zero is not larger than prior tolerated reductions in terms of pharmacological effects. Liquids or compounded formulations of medication can be helpful at low doses to make small reductions. Guidelines should recommend hyperbolic tapering while awaiting randomized trials comparing linear with hyperbolic tapering.
Real-world effectiveness of antipsychotic treatment of functional outcomes over 10 years: A national cohort of patients in Denmark with schizophrenia.
Twumasi R, Gronemann FH, Hjorthøj C … +4 more , Howes O, Lange M, Nordentoft M, Osler M
Psychol Med · 2026 Jun · PMID 42307260 · Full text
BACKGROUND: Antipsychotic medications are recommended for schizophrenia spectrum disorders, yet their long-term effects on functional recovery remain unclear, with conflicting evidence often derived from between-subject...
BACKGROUND: Antipsychotic medications are recommended for schizophrenia spectrum disorders, yet their long-term effects on functional recovery remain unclear, with conflicting evidence often derived from between-subject comparisons vulnerable to confounding by indication. METHODS: We conducted a nationwide register-based cohort study of 65,630 individuals with incident schizophrenia spectrum disorders in Denmark (1998-2023). We modeled antipsychotic exposure against 'productive engagement' (employment or education). We used two analytical approaches: (1) within-subject stratified Cox models with time-varying covariates to eliminate time-invariant confounding; and (2) Fine-Gray competing risks models with baseline exposure, accounting for mortality and emigration. RESULTS: Over 26.9 million person-weeks, the overall productive engagement rate was 48.2%. Integration of hospital pharmacy data revealed 6.1% exposure misclassification in studies relying solely on community records. The primary within-subject analysis revealed significant temporal heterogeneity: medication use was associated with reduced engagement rates in the acute (0-2 years; HR = 0.908) and consolidation phases (2-5 years; HR = 0.946), but reversed to a small positive association in the maintenance phase (5+ years; HR = 1.019). The between-subject Fine-Gray model, which estimates cumulative engagement probabilities, yielded an SHR of 1.002 (95% CI = 0.988-1.015), a population-level average that obscured these phase-specific dynamics. CONCLUSIONS: Antipsychotic pharmacotherapy exerts a time-dependent, biphasic impact on vocational recovery. We identified a window of vulnerability during the post-acute 'consolidation' phase (years 2-5) where treatment is associated with a transient reduction in productive engagement, before becoming protective after 5 years. These findings challenge the assumption that symptomatic stability automatically facilitates functional reintegration.
Economic evaluations of preventive interventions for self-harm and suicide: a systematic review.
Le LK, Le DQ, Le PH … +6 more , Tan EJ, Neil A, Andriessen K, Pirkis J, Mihalopoulos C, Reifels L
Psychol Med · 2026 Jun · PMID 42306973 · Full text
Self-harm and suicide are major public health concerns and leading causes of mortality worldwide, highlighting a pressing need for policymakers to identify and implement cost-effective interventions. This systematic revi...
Self-harm and suicide are major public health concerns and leading causes of mortality worldwide, highlighting a pressing need for policymakers to identify and implement cost-effective interventions. This systematic review (PROSPERO registration #CRD42023460339) followed the PRISMA guidelines and aimed to synthesize the available cost-effectiveness evidence for the prevention of self-harm and suicide. Systematic searches were performed in MEDLINE, Embase, PsycINFO, CINAHL, Econlit, and ProQuest to identify full economic evaluations and return-on-investment studies on preventive interventions for self-harm and suicide published up to January 15, 2026. Methodological quality was assessed using Drummond's 10-item checklist, and findings were synthesized narratively. A total of 69 eligible studies evaluated 22 types of interventions: three universal, five selective, five indicated, and nine multi-level. Most studies were rated as high-quality ( = 61/69) and conducted in high-income countries (HICs) ( = 63/69), primarily assessing the cost-effectiveness of universal interventions like means restriction ( = 6), selective and indicated interventions like psychotherapy ( = 30), support services ( = 15), and medication ( = 5). Evidence consistently found that interventions for self-harm and suicide prevention were generally cost-effective or cost-saving. Strong evidence supported the cost-effectiveness of several universal (e.g. awareness training), selective (e.g. psychotherapy, support services), indicated (e.g. suicide risk screening, support services, psychotherapy for adults in HICs like Australia, US, Canada), and multi-level interventions. However, more economic evaluations are needed for interventions targeting older adults and children in all countries, especially in low- and middle-income countries, where evidence is lacking.
Does gestational vitamin D attenuate the negative effects of prenatal depression on offspring emotional and behavioral problems? Findings in the ECHO cohort.
Hipwell AE, Tung I, Palmore M … +11 more , Melough MM, Bodnar LM, Croen LA, Hill AV, Bekelman TA, Brennan PA, Carroll KN, Schmidt RJ, Zimmerman E, McGrath M, ECHO Cohort Consortium
Psychol Med · 2026 Jun · PMID 42299714 · Full text
BACKGROUND: Prenatal depression is associated with offspring behavioral problems, but heterogeneity in the strength of this association is not well understood. Maternal vitamin D concentration during pregnancy is importa...
BACKGROUND: Prenatal depression is associated with offspring behavioral problems, but heterogeneity in the strength of this association is not well understood. Maternal vitamin D concentration during pregnancy is important for fetal brain development and may help explain this variability, with potential differences by timing of exposure and maternal race. METHODS: Using data from 1,451 mother-child pairs in the Environmental influences on Child Health Outcomes cohort, linear mixed-effects models examined associations between prenatal depressive symptom severity, gestational 25-hydroxy-vitamin D (25[OH]D) concentrations, and internalizing and externalizing behaviors in preschool-aged children. Analyses were stratified by common 25(OH)D deficiency thresholds, prenatal timing, and race. RESULTS: Prenatal depressive symptom severity was associated with greater child internalizing ( = 0.18, 95% CI = 0.11, 0.25) and externalizing ( = 0.21, 95% CI = 0.14, 0.28) behaviors. Gestational 25(OH)D concentration did not moderate depression effect estimates in adjusted models. In stratified analyses, the association between prenatal depressive symptoms and child externalizing behaviors persisted regardless of 25(OH)D threshold levels, but the association with internalizing behaviors attenuated at 25(OH)D < 20 ng/mL. Timing of 25(OH)D measurement (early/late pregnancy) did not modify relationships. Higher gestational 25(OH)D was associated with fewer externalizing problems among offspring of Black mothers only. CONCLUSIONS: Prenatal depressive symptoms showed robust associations with child behavioral problems, largely independent of gestational 25(OH)D. However, attenuated risk for internalizing behaviors with low vitamin D levels warrants investigation of social-environmental factors.
Plasma neurofilament light chain and regional brain atrophy mediate the association of neuropsychiatric symptoms with cognition in Alzheimer's disease: evidence from two population-based studies.
Wang YY, Zhu HY, Miao W … +9 more , Wang ZX, Qin JJ, Song XH, Wang YH, Sun ZW, Zhou X, Yu XF, Zhu XQ, Alzheimer’s Disease Neuroimaging Initiative
Psychol Med · 2026 Jun · PMID 42294788 · Full text
BACKGROUND: Neuropsychiatric symptoms (NPSs) are prevalent in Alzheimer's disease (AD), yet their neurobiological etiology remains elusive. We investigated relationships between NPS subsyndromes, plasma neurofilament lig...
BACKGROUND: Neuropsychiatric symptoms (NPSs) are prevalent in Alzheimer's disease (AD), yet their neurobiological etiology remains elusive. We investigated relationships between NPS subsyndromes, plasma neurofilament light chain (NFL), AD-vulnerable brain atrophy, and cognition. METHODS: We included 146 participants from a Chinese cohort. NPSs were assessed using the Neuropsychiatric Inventory Questionnaire and clustered into four subsyndromes (hyperactivity, psychosis, affective, apathy), each graded by severity (none, mild, severe). Sequential mediation analyses examined whether NPSs influence cognition through NFL and atrophy. Additionally, 1534 ADNI participants were enrolled to (1) replicate mediation effects; (2) examine longitudinal relationships of NPSs with incident cognitive decline; and (3) evaluate cognitive discrimination of NPSs and NFL and onset hazards of NPS subsyndromes. RESULTS: In the discovery cohort, global NPSs burden and three subsyndromes (hyperactivity, affective, apathy) were associated with elevated plasma NFL, poorer global cognition and memory, and reduced brain volumes (all < 0.05). Sequential mediation revealed that plasma NFL and atrophy mediated the cross-sectional NPSs-cognition relationship, replicated in ADNI. Adding NPSs and NFL improved cognitive discrimination (AUC: 0.6754 to 0.8210, < 0.001). Additionally, apathy and psychosis showed lower onset hazards than affective and hyperactivity (both < 0.001). CONCLUSIONS: Baseline NPSs were cross-sectionally associated with elevated NFL, brain atrophy, and poorer cognition. Sequential mediation models supported a pathway linking NPSs to cognition via NFL and atrophy, though longitudinal evidence did not fully confirm temporal directionality. These hypothesis-generating findings require prospective validation.
Pro-cognitive effects of 5-HT4 receptor agonism in individuals with remitted depression.
de Cates AN, Hamilton S, Guru A … +7 more , Blandhol M, Colwell M, Cowen PJ, Simmons M, Jones B, Harmer CJ, Murphy SE
Psychol Med · 2026 Jun · PMID 42290157 · Full text
BACKGROUND: Cognitive impairment is a common and persistent feature of depression, yet it remains poorly understood and inadequately treated. Preclinical and human studies suggest that stimulating 5-HT receptors (5-HTR)...
BACKGROUND: Cognitive impairment is a common and persistent feature of depression, yet it remains poorly understood and inadequately treated. Preclinical and human studies suggest that stimulating 5-HT receptors (5-HTR) enhances neuroplasticity and improves cognition. This novel study examines the cognitive effects of 5-HTR agonism in adults with a history of recurrent depression. METHODS: Fifty participants who were not currently depressed but had experienced at least two previous episodes of depression were randomized in a double-blind design either to prucalopride (2 mg daily, titrated from 1 mg) or to placebo for 7-10 days. Participants completed self-report questionnaires and a task battery at baseline and post-intervention assessing declarative memory, working memory, emotional processing, and executive function. RESULTS: Compared to placebo, prucalopride significantly improved word recall on an auditory verbal learning task and was associated with faster response times on a complex working memory task without loss of accuracy. It also improved the accurate recognition of rapidly presented facial expressions. Composite analysis of non-emotional tasks identified that the prucalopride group participants post-intervention were faster and more accurate than at baseline compared to those receiving placebo. Prucalopride had minimal effects on affective cognition, consistent with previous findings. Cognitive improvements were independent of baseline mood symptoms or self-reported cognitive difficulties. CONCLUSIONS: Short-term 5-HTR agonism improved performance on multiple objective cognitive measures in individuals with remitted depression. These findings replicate our previous results in healthy volunteers showing a pro-cognitive effect of prucalopride and support a role for 5-HTRs as a promising target for cognitive enhancement in mood disorders.
Unravelling sex differences in the genetic architecture of anxiety.
Hu J, Lupton MK, Byrne EM … +7 more , Martin NG, Whiteman DC, Olsen CM, Thomas JT, Medland SE, Grasby KL, Mitchell BL
Psychol Med · 2026 Jun · PMID 42272362 · Full text
BACKGROUND: Anxiety disorders show striking sex differences in prevalence, symptoms, and clinical characteristics, shaping how they manifest and are experienced. METHODS: Here, we report the first sex-specific meta-analy...
BACKGROUND: Anxiety disorders show striking sex differences in prevalence, symptoms, and clinical characteristics, shaping how they manifest and are experienced. METHODS: Here, we report the first sex-specific meta-analysis of genome-wide association studies (GWAS) of anxiety, leveraging two of the largest biobank datasets, UK Biobank and All of Us, comprising 85,042 female cases with 196,789 controls and 36,732 male cases with 136,924 controls. Functional annotation, sex-specific polygenic scores (PGS), and genetic correlations were performed to assess genetic differences and functional implications. RESULTS: In females, 21 lead SNPs were significantly associated with anxiety, compared to five in males. Although the genetic correlation between sexes was high, it was significantly different from one, indicating partially distinct genetic architectures. In addition, both the SNP-based observed and liability-scale heritabilities (assuming a 2:1 female-to-male prevalence ratio) were significantly higher in females. Gene-based tests and functional prioritization identified different genes associated with anxiety in females and males. Moreover, genetic correlation analyses revealed stronger associations of female anxiety with attention-deficit/hyperactivity disorder (ADHD) and body mass index (BMI), whereas male anxiety showed stronger correlations with waist-hip-ratio-adjusted BMI. CONCLUSIONS: While the overall genetic architecture of anxiety is largely shared, our findings reveal distinct sex-specific genetic associations and correlations, highlighting the value of analyzing the sexes separately to uncover genetic signals that may be masked in sex-combined samples.
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