Background:Post-COVID chronic fatigue syndromes are frequently associated with depressive episodes and alterations in reward processing. Anhedonia, a core depressive symptom linked to reward-system dysfunction, may be particularly relevant in this context. Objective:To investigate whether depressive symptoms in individuals with post-COVID-like chronic fatigue syndrome display a distinctive configuration of core depressive features, particularly in the balance between depressed mood and anhedonia. Methods:In an exploratory cross-sectional comparative study with a matched historical control group, patients with post-COVID-like chronic fatigue syndrome were compared with matched controls from a pre-COVID community sample. Groups were matched for age, sex, and overall depression severity. Depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9), and item-level scores were analyzed. Results:The post-COVID fatigue group and matched historical controls showed comparable overall depressive symptom severity and similar rates of mild and moderate depressive symptoms. However, depressed mood was significantly less pronounced in the post-COVID fatigue group, while anhedonia did not differ significantly between groups. Consequently, the depressed mood/anhedonia ratio was markedly reduced in the post-COVID fatigue group. Conclusions:Depressive symptoms in post-COVID-like chronic fatigue syndrome may show an altered balance between the two core depressive features assessed by the PHQ-9. In this exploratory comparison, the most robust finding was reduced depressed mood in the post-COVID fatigue group, whereas anhedonia was not significantly increased. These findings should therefore be interpreted as preliminary evidence of a different depressive symptom configuration, rather than as demonstration of an anhedonia-dominant phenotype.

OBJECTIVE:Psychiatric and cardiovascular disorders often co-occur, complicating their assessment and management. No umbrella review(UR) has summarized the meta-analytic evidence on the co-occurrence of psychiatric and cardiovascular disorders and assessed its credibility. METHODS:Meta-analytic systematic reviews of observational studies documenting the prevalence, risk factors, and outcomes associated with the co-occurrence of cardiovascular and psychiatric disorders, indexed from inception through March.16.2026, and meeting established diagnostic criteria, were included. Meta-analytic association and prevalence estimates were recalculated and graded based on established or adapted criteria. The AMSTAR-2 assessed the quality of the meta-analyses, while several subgroup analyses and meta-regressions aimed to explain the heterogeneity. RESULTS:We included 76 meta-analyses yielding 131 meta-analytic estimates. Based on pre-existing meta-analytic evidence, 22/24 prevalence estimates (91.7%) met moderate/strong credibility criteria. Strong credibility emerged for: orthostatic hypotension in Lewy body(58%;95%C.I. = 50-66%) and Alzheimer's dementias(28.0% = 95%C.I. = 17.0-40.0%); pericardial effusion in anorexia nervosa(25.0%;95%C.I. = 17.0-34.0%); in heart failure(HF): major depressive disorder(MDD)(41.9%;95%C.I. = 36.7-47.1%), mild cognitive impairment(MCI)(41.4%;95%C.I. = 38.3-45.6%), anxiety(32.0%;95%C.I. = 26.5-37.6%), MDD + anxiety(24.7%;95%C.I. = 17.9-34.3%), and dementia(19.8%;95%C.I. = 12.9-27.8%); in atrial fibrillation(AF): MCI(26.0%;95%C.I. = 21.0-30.0%), anxiety in patients undergoing pulmonary vein isolation(PVI)(25.0%;95%C.I. = 12.0-46.0%), MDD in PVI patients (20.0%;95%C.I. = 13.0-29.0%); in coronary artery disease: MDD + anxiety(19.8%;95%C.I. = 16.0-24.6%): in schizophrenia spectrum disorders: clozapine-associated-cardiomyopathy(0.6%;95%C.I. = 0.2-2.3%); clozapine-associated-cardiomyopathy absolute death rates (0.0003;95%C.I. = 0.0001-0.0012); clozapine-associated-cardiomyopathy case fatality rate (0.078;95%C.I. = 0.018-0.285). Several additional disorders were multimorbid in>5% of people, yet with a lower credibility rating. No re-pooled risk factors/outcomes reached strong credibility criteria. CONCLUSIONS:The present study provides an atlas of cardiovascular and psychiatric multimorbidity across varying levels of credibility, reinforcing the need for an integrated, multidisciplinary approach to patient care and for more research on actionable risk/protective factors and outcomes.

Importance:Adolescence is a high-risk period for subthreshold depression and a critical window for intervention. While aerobic exercise has shown efficacy in alleviating adult depressive symptoms, its efficacy and neural mechanisms in adolescents remain unclear. Objective:To evaluate the association of aerobic exercise with reduced subthreshold depressive symptoms in adolescents and to identify potential neural mechanisms underpinning symptom improvement. Design, Setting, and Participants:This was a prespecified secondary analysis of a 12-month, multicenter, cluster randomized clinical trial (RCT) conducted October 2021 to October 2022 among students aged 12 to 17 years in China. Data analysis took place between April and August 2024. Interventions:The 12-month aerobic exercise intervention consisted of a 6-month supervised phase followed by a 6-month unsupervised phase. The control group received 6 psychoeducation sessions (once every 2 months) focusing on mood regulation, depression awareness, and stress management. Main Outcomes and Measures:At baseline and postintervention, participants reported depressive symptoms (Patient Health Questionnaire-9 [PHQ-9]) and underwent electroencephalography (EEG) recording. Group differences in symptom change were assessed using linear mixed models. Resting-state EEG data were analyzed for functional connectivity and both global and nodal network topology. Mediation analyses were conducted to test the neural processes mediating the exercise effect. Results:A total of 206 adolescents aged 12 to 17 years (110 males [53%]; median age, 13 years) with subthreshold depressive symptoms were included (111 in the exercise group and 95 in the psychoeducation group). The exercise group showed significantly greater reductions in subthreshold depressive symptoms than the control group (exercise: mean [SE] PHQ-9 score, 9.20 [0.05] points at baseline vs 7.33 [0.03] postintervention; t110, -4.49; P < .001; control: 7.74 [0.04] points at baseline vs 7.28 [0.04] postintervention; t94, -1.03; P = .30). The functional connectivity across 355 alpha-band, 127 beta-band, 30 theta-band, and 9 delta-band connections was reduced (all P < .05 after correction for false discovery rate), and global network efficiency, such as the clustering coefficient, was enhanced across all frequency bands after the exercise intervention (all P < .001 after correction for false discovery rate). Mediation analysis revealed 2 opposing neural pathways that represented depression-reduction (B, -2.28; P < .001) and depression-increase (B, 3.26; P < .001) processes. Conclusions and Relevance:In this secondary analysis of an RCT, the findings suggest that exercise reduced subthreshold depressive symptoms in adolescents by engaging opposing EEG-based neural network processes. These findings support exercise as a potential accessible intervention for adolescent subthreshold depression, highlighting neurophysiologic signatures that may inform individualized intervention strategies and outcome monitoring that need to be replicated in adolescents with clinical depression. Trial Registration:ClinicalTrials.gov Identifier: NCT04816617.

BACKGROUND:Bipolar disorder (BD) is a chronic mental illness that requires lifelong treatment. We investigated the comparative efficacy and safety of pharmacological interventions for bipolar maintenance, considering dose effects across different age groups. METHODS:We conducted a network meta-analysis (NMA) of randomized controlled trials (RCTs) comparing pharmacological interventions against each other or placebo for the maintenance of BD, searching for records indexed in PubMed/MEDLINE, Embase, Web of Science, and Scopus (from inception through 2026.1.12). Co-primary outcomes were the relapse rate (into an acute episode of any mood polarity) and tolerability (discontinuation due to side effects). Relapse into episodes of specific mood polarities (namely, depressive/manic/mixed polarity), acceptability (discontinuation due to any cause), and rate of specific adverse events were secondary outcomes. Confidence-In-Network-Meta-Analysis was likewise appraised. RESULTS:Forty-four RCTs involving 23 distinct treatment combinations encompassed 10,867 participants. Sensitivity analysis retaining only low-risk-of-bias studies and excluding outliers for possible effect modifiers indicated that asenapine 20 mg/day, aripiprazole 20 mg/day, 30 mg/day, quetiapine 300 mg/day, 600 mg/day and 550 mg/day, lithium 800 mg/day, lurasidone 80 mg/day, carbamazepine 400 mg/day and 650 mg/day, valproate 71-125 μg/mL, olanzapine 20 mg/day, long-acting aripiprazole 400 mg/4 weeks, long-acting risperidone 25 mg/2 weeks, aripiprazole 30 mg/day+lamotrigine 200 mg/day outperformed placebo. Several additional drugs might be efficacious, although they either emerged as outliers for the mean age of participants/proportion of females/proportion of BD-I/II patients, baseline severity of mania/depression, and trial duration. CONCLUSIONS:Our findings are consistent with previous NMAs and current guidelines, yet they expand current knowledge by concurrently appraising different drugs, doses, and age groups.

Background:Bipolar Disorder (BD) remains challenging to identify, and the Mood Disorder Questionnaire (MDQ) may capture heterogeneous forms of hyperactivation, including adaptive patterns unrelated to psychopathology. Objectives:To determine whether MDQ-positive individuals include a subgroup with adaptive hyperactivation-characterized by high quality of life (QoL) and minimal psychiatric morbidity-and to examine whether MDQ positivity also identifies diagnoses beyond BD. Methods:Using data from a large Italian community survey with DSM-IV clinical interviews and MDQ screening, we conducted a case-control analysis. MDQ-positive individuals were stratified by SF-12 QoL scores (>40 vs. ≤40), and matched MDQ-negative controls were selected by age and sex. Psychiatric diagnoses were compared using ANOVA and chi-square tests. Results:Among 91 MDQ-positive participants, 33% showed high QoL and exhibited markedly fewer psychiatric diagnoses than those with low QoL (χ²=15.529, p<0.0001). High-QoL MDQ-positive individuals displayed psychiatric morbidity comparable to MDQ-negative controls, whereas low-QoL MDQ-positive individuals showed excess anxiety, obsessive-compulsive, and eating disorders. Conclusions:MDQ positivity identifies a heterogeneous population, including individuals with adaptive hyperactivation and preserved functioning. These findings highlight the need for more refined instruments capable of distinguishing adaptive from pathological hyperactivation and caution against over-pathologizing MDQ positivity in clinical and public health settings.

Anxiety disorders are the most prevalent mental health conditions worldwide. While their burden in terms of excess mortality is known to be high, a quantitative systematic evaluation of all-cause and cause-specific mortality and suicide attempt risks in people with anxiety or stress-related disorders is lacking. We performed a systematic review and random effects meta-analysis, in which co-primary outcomes were risk ratios (RRs) for all-cause and suicide-related mortality, and secondary outcomes were natural-cause mortality, other cause-specific mortality, and risk of suicide attempt. Sensitivity and meta-regression analyses were conducted. Overall, 165 studies encompassing 7,395,722 people with any anxiety or stress-related disorder and 135,059,023 controls, from 27 different countries across all continents, were included. Compared with the general population, a higher risk of all-cause mortality was associated with any anxiety or stress-related disorder (n=42, RR=1.54, 95% CI: 1.14-2.08, p=0.005), generalized anxiety disorder (n=9, RR=1.48, 95% CI: 1.23-1.78, p<0.001), and post-traumatic stress disorder (PTSD) and other stress-related disorders (n=21, RR=1.39, 95% CI: 1.15-1.67, p<0.001), but not with panic disorder, phobias, and mixed anxiety or stress-related disorders. Suicide mortality was increased in people with any anxiety or stress-related disorder (n=39, RR=2.88, 95% CI: 2.13-3.89, p<0.001), panic disorder (n=3, RR=3.58, 95% CI: 1.39-9.25, p<0.008), mixed anxiety or stress-related disorders (n=27, RR=2.77, 95% CI: 1.89-4.07, p<0.001), PTSD and other stress-related disorders (n=11, RR=3.13, 95% CI: 1.85-5.28, p<0.001), and generalized anxiety disorder (n=3, RR=1.93, 95% CI: 1.17-3.17, p<0.01). Suicide attempt risk was higher than in the general population in people with all anxiety or stress-related disorders, ranging from RR=6.33 (95% CI: 4.08-9.82, n=5) in panic disorder to RR=2.74 (95% CI: 1.72-4.35, n=5) in phobias. Natural-cause mortality was increased in any anxiety or stress-related disorder (n=19, RR=1.25, 95% CI: 1.09-1.44, p=0.002), generalized anxiety disorder (n=5, RR=1.55, 95% CI: 1.19-2.02, p=0.001), mixed anxiety or stress-related disorders (n=8, RR=1.26, 95% CI: 1.02-1.56, p=0.033), and PTSD and other stress-related disorders (n=9, RR=1.17, 95% CI: 1.03-1.33, p=0.019), but not in panic disorder. Cardiovascular-related deaths were increased in any and mixed anxiety or stress-related disorders and in generalized anxiety disorder, while cancer mortality was increased only in generalized anxiety disorder. When analyzing people with vs. without anxiety disorders with samples being matched by comorbid physical or mental disorders, results remained significant for all-cause mortality in generalized anxiety disorder and panic disorder, but not in any or mixed anxiety or stress-related disorders, and in PTSD and stress-related disorders. When compared with other mental disorders, no difference in co-primary outcomes emerged from more than two studies. Publication bias was present across several analyses, but sensitivity analyses largely confirmed the main findings. In meta-regression analyses, more recent data collection mitigated all-cause mortality, while schizophrenia-spectrum and bipolar disorder comorbidity mitigated suicide mortality risk, possibly driven by underlying treatment. This meta-analysis documents a higher all-cause, suicide and natural-cause mortality, and a higher risk of suicide attempt, in people with anxiety or stress-related disorders compared to the general population. Given the high prevalence and the recognized global treatment gap for these disorders, this finding is of great public health concern, and calls for appropriate prevention, screening and treatment strategies. More studies are needed to fill the publication bias gap and to identify modifiable risk or mitigating factors.

Mental health disorders frequently co-occur with oncological conditions, prompting an umbrella review(UR) to summarize meta-analytic evidence about the outcomes of pharmacological, psychosocial, and brain-stimulation interventions for psychiatric disorders in oncologic populations. We performed an UR of meta-analyses of randomized controlled trials(RCTs) documenting the efficacy of interventions for mental disorders in people with cancer(November 2, 2025). Re-calculated meta-analytic estimates employed the GRADE criteria for credibility. The AMSTAR-Plus Content Score was used to assess the quality of the meta-analyses. Overall, 82 meta-analyses(Number of records=111,331; primary studies=1,659) yielding 113 meta-analytic estimates were included. Five of 113 estimates were assigned a low level of certainty, and 108/113 were assigned a very low GRADE. Major depressive(55/113=48.67%) and any anxiety disorders(43/113=38.05%) emerged as the most frequently studied mental health diseases among the oncologic population. Mindfulness-based-stress-reduction for anxiety disorders in lung cancer was the only intervention significantly outperforming standard treatment(Hedges‘g=-1.46; 95%C.I.=-1.89;-1.04), whereas psychotherapy for women with breast cancer who underwent surgery was inferior to waiting list(in 80% of studies) in the treatment of anxiety due to women’s body image post-mastectomy(G=0.33; 95%C.I.=0.14; 0.52), with relatively higher credibility compared to other outcomes. Meta-regression suggested that psychotherapies might benefit females more than men, and that age might differentially moderate larger and smaller effects of psychotherapies in advanced cancer and any cancer, respectively. While MBSR shows relatively higher-level evidence for anxiety disorders in the oncological population, the level of evidence is low, underscoring the need for further research on alternative treatment modalities. CBT should be part of anxiety management following mastectomy.

BACKGROUND:"Nutraceuticals" and "phytoceuticals" may have antidepressant activity, prompting an in-depth network meta-analysis of randomized clinical trials (RCTs). METHODS:Systematic review and network meta-analysis (PubMed/MEDLINE/EMBASE/Scopus/PsycINFO/CENTRAL/ClinicalTrials.gov (until 01/07/2025) of RCTs vs. placebo or treatment as usual (TAU = antidepressants) testing nutraceuticals/phytoceuticals in major depressive disorder (MDD). Change in depressive symptomatology (standardized-mean-difference = SMD), treatment response, and all-cause discontinuation (acceptability) (risk ratio = RR) were co-primary outcomes. Secondary outcomes were anxiety symptom changes, adverse event-related discontinuation ("tolerability"), and symptom remission. We conducted subgroup, transitivity, and sensitivity analyses to explore/reduce heterogeneity, and assessed global/local inconsistency, publication bias, risk of bias (RoB), and confidence in the evidence (CINeMA/AMSTAR-Plus). RESULTS:Across 163 studies (n = 15,757, distinct compounds' combinations n = 137), several molecules/classes outperformed placebo with very large effect sizes. Restricting analyses to compounds with ≥2RCTs/non-TAU antidepressants/low RoB/non-sponsored trials/non-outliers, higher-than-expected/unrealistic effect sizes emerged vs. placebo for eicosapentaenoic acid (EPA) (k = 20, n = 8483; SMD = -1.67;95%C.I. = -2.38;-0.97), vitamin D3 (k = 3, n = 344; SMD = -1.59;95%C.I. = -2.71;-0.46), and St. John's-wort-extract-ZE117 (k = 3,n = 207;SMD = -1.02;95%C.I = -1.90;-0.15) regarding depressive symptomatology. Substantial heterogeneity (I2 = 85.3%;95%C.I. = 81.9%;88.0%) and global inconsistency (Q-between-designs = 186.91, p < 0.0001) emerged, explained by subgroup and sensitivity analyses, without publication bias. Additionally, a medium effect size emerged vs. placebo for curcumin (k = 2,n = 89;SMD = -0.58;95%C.I. = -0.99;-0.18) regarding anxiety reduction in low RoB analyses. Shugan granules, EPA, EPA+Docosahexaenoic Acid, ZE117, and fluoxetine+EPA response and St. John's wort extract WS5570/ZE117 remission significantly outperformed placebo. Citicoline was associated with significantly more dropouts than placebo. A meta-regression of efficacy effect sizes against adapted AMSTAR-Plus scores showed that larger SMDs were associated with lower AMSTAR scores, indicating lower study quality. Confidence in the evidence was low to very low. CONCLUSIONS:Upon filtering low-quality evidence, only a few nutraceutical/phytoceuticals showed potential for depressive symptoms, warranting more rigorous trials.

Importance Adolescence is a high-risk period for subthreshold depression and a critical window for intervention. While aerobic exercise has shown efficacy in alleviating adult depressive symptoms, its efficacy and neural mechanisms in adolescents remain unclear. Objective To evaluate the association of aerobic exercise with reduced subthreshold depressive symptoms in adolescents and to identify potential neural mechanisms underpinning symptom improvement. Design, Setting, and Participants This was a prespecified secondary analysis of a 12-month, multicenter, cluster randomized clinical trial (RCT) conducted October 2021 to October 2022 among students aged 12 to 17 years in China. Data analysis took place between April and August 2024. Interventions The 12-month aerobic exercise intervention consisted of a 6-month supervised phase followed by a 6-month unsupervised phase. The control group received 6 psychoeducation sessions (once every 2 months) focusing on mood regulation, depression awareness, and stress management. Main Outcomes and Measures At baseline and postintervention, participants reported depressive symptoms (Patient Health Questionnaire-9 [PHQ-9]) and underwent electroencephalography (EEG) recording. Group differences in symptom change were assessed using linear mixed models. Resting-state EEG data were analyzed for functional connectivity and both global and nodal network topology. Mediation analyses were conducted to test the neural processes mediating the exercise effect. Results A total of 206 adolescents aged 12 to 17 years (110 males [53%]; median age, 13 years) with subthreshold depressive symptoms were included (111 in the exercise group and 95 in the psychoeducation group). The exercise group showed significantly greater reductions in subthreshold depressive symptoms than the control group (exercise: mean [SE] PHQ-9 score, 9.20 [0.05] points at baseline vs 7.33 [0.03] postintervention; t 110 , −4.49; P < .001; control: 7.74 [0.04] points at baseline vs 7.28 [0.04] postintervention; t 94 , −1.03; P = .30). The functional connectivity across 355 alpha-band, 127 beta-band, 30 theta-band, and 9 delta-band connections was reduced (all P < .05 after correction for false discovery rate), and global network efficiency, such as the clustering coefficient, was enhanced across all frequency bands after the exercise intervention (all P < .001 after correction for false discovery rate). Mediation analysis revealed 2 opposing neural pathways that represented depression-reduction (B, –2.28; P < .001) and depression-increase (B, 3.26; P < .001) processes. Conclusions and Relevance In this secondary analysis of an RCT, the findings suggest that exercise reduced subthreshold depressive symptoms in adolescents by engaging opposing EEG-based neural network processes. These findings support exercise as a potential accessible intervention for adolescent subthreshold depression, highlighting neurophysiologic signatures that may inform individualized intervention strategies and outcome monitoring that need to be replicated in adolescents with clinical depression. Trial Registration ClinicalTrials.gov Identifier: NCT04816617

Psychiatric disorders frequently co-occur with endocrine, nutritional, and metabolic disorders, complicating diagnosis, treatment, and prognosis. To date, no umbrella review (UR) has summarized the corresponding evidence. We conducted a UR of meta-analyses of observational studies reporting the prevalence and outcomes of comorbid endocrine, nutritional, metabolic, and psychiatric disorders (DSM/ICD criteria, PubMed/Medline/Scopus/Embase/Web of Science, 13/10/2025). Meta-analytic prevalence and association estimates were recalculated/and graded using quantitative criteria. The methodological quality of the meta-analyses was assessed with AMSTAR-2. Subgroup and meta-regression were conducted. Eighty-one meta-analyses (records=254,154,533, k=1,780) yielded 119 meta-analytic estimates. Among 64 prevalence estimates drafted from the original meta-analyses, 10(6.4%) had strong credibility, namely (among adults unless otherwise specified): obesity in autism spectrum disorder(17.0%, 95%C.I.=13.0-22.0); Vitamin-D deficiency in schizophrenia(65.3%, 95%C.I.=46.4-84.2); major depressive disorder(MDD) in diabetic foot ulcer(47.0%, 95%C.I.=26.0-85.0), in diabetes mellitus(61.8%; 95%C.I.=56.6-66.7%), in metabolic syndrome (30.5%; 95%C.I.=26.3-35.1), and in polycystic ovary syndrome(PCOS)(37.0%; 95%C.I.=29.0-44.0%); anxiety in PCOS(48.0%, 95%C.I.=37.0-59.0), in type-1 diabetes(21.3%, 95%C.I.=17.8-26.7); type-2-diabetes in MDD(8.7%; 95%C.I.=7.3-10.2%); and mild cognitive impairment in type-2-diabetes(45.0%; 95%C.I.=36.0-54.0%). Five of 43(11.7%) outcomes met strong credibility criteria. Comorbid-MDD vs. non-comorbid-MDD posed a higher risk for all-cause mortality (relative risk/RR=1.48, 95%C.I.=1.4-1.6) and dementia (RR=2.1, 95%C.I.=1.7-2.6) among diabetic people. ADHD-comorbidity increased glycate hemoglobin-A1C levels among type-I diabetes children (SMD=0.7, 95%C.I.=0.5-0.9) and type-2 diabetic females (SMD=0.6, 95%CI=0.4-0.7). Diabetes increased the risk of 30-day hospital readmission (RR=1.2, 95%C.I.=1.1-1.3) in people with dementia. This study provides a comprehensive atlas of the prevalence and outcomes associated with multimorbidity across endocrine, nutritional, metabolic, and psychiatric diseases, assessing credibility and prompting integrated, multidisciplinary care.

BACKGROUND:Combinatorial pharmacogenomic (PGx) tests aim to guide antidepressant selection and dosing in adult major depressive disorder (MDD), but available platforms differ in gene content, decision rules, clinical reporting, and implementation. Therefore, indiscriminate pooling across PGx platforms may obscure platform-specific effects. METHODS:We searched MEDLINE (PubMed), Embase, and APA PsycINFO from inception to 31 December 2025, screened reference lists, and conducted a formal update search on 14 April 2026 using the same search concepts and eligibility criteria. We included RCTs enrolling adults with MDD and comparing PGx-guided antidepressant prescribing versus treatment as usual (TAU)/unguided care. Two RCT-only quantitative syntheses were prespecified: (a) a primary platform-specific analysis restricted to GeneSight RCTs and (b) a secondary exploratory cross-platform analysis of other multigene PGx panels. Random-effects models were used; effects are reported as risk ratios (RRs). RESULTS:Eight RCTs were included. In the primary platform-specific GeneSight analysis (three trials), PGx-guided care increased response (RR 1.30, 95% CI 1.09-1.56; I2 = 0%) and remission (RR 1.53, 95% CI 1.19-1.97; I2 = 0%) within the prespecified 8-12-week acute window. In the secondary exploratory cross-platform analysis (five trials for response; four for remission), effects were heterogeneous and imprecise: response RR 1.18 (95% CI 0.91-1.54; I2 = 78%) and remission RR 1.18 (95% CI 0.77-1.80; I2 = 82%). CONCLUSIONS:In adult MDD, GeneSight-guided care was associated with modest short-term increases in response and remission within the available RCT evidence. Pooled effects across other multigene PGx panels were heterogeneous and imprecise. The platform-aware structure reflects differences in data availability, comparability, and internal validity, and it should not be interpreted as evidence of superiority of one commercial PGx platform over others. Evidence was limited by the small number of short-term RCTs, residual risk-of-bias concerns, and heterogeneity/imprecision in the secondary exploratory cross-platform analysis. Future trials should harmonize outcomes, follow-up, implementation reporting, and platform-specific decision-support descriptions to improve cross-platform comparability.

BACKGROUND:Growing evidence supports an association between chronotype and mental health, with evening chronotype (ET) being associated with increased vulnerability to bipolar disorder (BD). METHODS:We conducted a cross-sectional survey of adults recruited between February and September 2022 from community COVID-19 points of care in Padua, Italy. Participants completed validated self-report measures assessing chronotype (rMEQ), affective temperaments (Brief-TEMPS-M), emotion regulation (DERS), and subthreshold bipolarity (MDQ and HCL-32-R2). Group differences across chronotypes were examined using ANOVA. Associations between chronotype and psychopathological traits were assessed using regression models adjusted for age and sex. Logistic regression was used to identify sociodemographic and lifestyle factors associated with ET. RESULTS:A total of 1997 participants (mean age = 31.4 ± 12.35 years; 66.3% female) were enrolled. Overall, 22.68% had ET, 22.33% morning chronotype (MT), and 54.98% neither chronotype (NT). Compared with other chronotypes, ET was associated with higher depressive, anxious, irritable, and cyclothymic temperament, greater emotional dysregulation, and increased bipolar-spectrum scores (all p < 0.001). In logistic regressions, obesity, student status, tobacco and drug use, and lack of religious belief increased the odds of ET, whereas older age, parenthood, living with other people, and good/excellent sleep quality decreased the odds. Cross-sectional design and regional sampling may limit generalizability. CONCLUSIONS:Our findings support an association between ET and greater emotional dysregulation, cyclothymic temperament, and bipolar-spectrum features, suggesting that circadian-related patterns may be linked to mood instability. Chronotype may serve as a marker of bipolar-spectrum traits. Longitudinal studies are warranted to clarify causality and evaluate its integration into existing prediction/assessment tools for BD at-risk.

Psychiatric and neurological disorders often co-occur, complicating their assessment, management, and outcomes. No umbrella review (UR) has summarized the meta-analytic evidence on the co-occurrence of psychiatric and neurological disorders and assessed its credibility. Meta-analytic systematic reviews of observational studies documenting the prevalence and outcomes associated with the co-occurrence of neurological and psychiatric disorders, indexed from inception through August 25, 2025, and meeting established diagnostic criteria, were included. Meta-analytic prevalence and association estimates were recalculated and graded based on quantitative criteria. The AMSTAR-2 assessed the quality of the meta-analyses, while several subgroup analyses and meta-regressions aimed to explain the heterogeneity. We included 81 meta-analyses (N=42,464,788, k=2,273), yielding 166 meta-analytic estimates. Based on pre-existing meta-analytic evidence, among 90 prevalence estimates, 45 (50%) met moderate/strong credibility criteria. Strong credibility emerged in bipolar disorder for comorbid migraine (34.8%,95%CI=25.54-44.69) and chronic pain (28.9%,95%CI=16.4-43.4), in epilepsy for ADHD (22.3%,95%CI=20.3-24.4), depression (23.1%,95%CI=20.6-28.3), autism (11.1%,95%CI=9.8-12.1), and PTSD (7.7%,95%CI=5.2-11.2), in myasthenia gravis for anxiety (33%,95%CI=25.0-42.0 children), in multiple sclerosis for anxiety (36%,95%CI=30.0-42.0) and depression (27.01%,95%CI=22.80-31.68), in neuropathic chronic pain for depression (37.5%,95%CI=28.7-47.1) and anxiety (33.8%,95%CI=28.5-39.6), in neuromyelitis optica for depression (40%,95%CI=32.0-49.0), in stroke for anxiety (29.3%,95%CI=24.8-33.8) and depression (31%,95%CI=24.0-38.0 children), in dementia for depression (25.01%,95%CI=22.1-28.4). Several additional disorders were comorbid in >5%with lower credibility. No outcomes reached strong credibility criteria. The present study provides an atlas of neurological and psychiatric multimorbidity across varying levels of credibility, reinforcing the need for an integrated, multidisciplinary approach to patient care and for more research on actionable risk/protective factors and outcomes.

Introduction:Eating disorders (EDs), particularly Anorexia Nervosa (AN), remain one of the most severe and treatment-resistant eating disorders, with high relapse rates and limited pharmacological options. While second-generation antipsychotics and antidepressants are commonly prescribed as adjuncts to nutritional rehabilitation, their real-world impact on weight restoration and psychopathological symptom severity remains unclear. Methods:We conducted a prospective, naturalistic observational study of 127 inpatients diagnosed with restrictive anorexia nervosa (AN-r), binge-purge anorexia nervosa (AN-bp), or bulimia nervosa (BN). BMI and weekly psychopathological symptom burden were systematically monitored throughout a ten-week inpatient treatment program. Psychopharmacological treatments were recorded in real time, and the Average Morbidity Index (AMI), adapted from the Life Chart Methodology, was computed weekly as a prospective measure of clinical severity. Generalized Linear Models assessed the associations between specific drug classes and changes in BMI and AMI. Results:Patients treated with mood stabilizers (e.g., Carbamazepine, Lithium) showed a smaller BMI increase compared to other groups (Coef. = -0.96 to -1.70; p< 0.05), suggesting a potential weight-stabilizing effect. Diazepam use was associated with greater weight gain (Coef. = +2.06; p = 0.02) but no clear benefit on AMI. Several antidepressants (e.g., Sertraline, Escitalopram) correlated with higher AMI scores, indicating less improvement in psychopathological symptom burden. Atypical antipsychotics (e.g., Olanzapine, Aripiprazole) were linked to greater reductions in AMI. Conclusions:Prospective monitoring of BMI and AMI revealed differential associations between psychopharmacological agents and both nutritional and symptomatic trajectories in an inpatient ED cohort predominantly composed of patients with AN. Mood stabilizers were associated with smaller BMI increases, while several antidepressants corresponded to less improvement in psychopathological symptom burden. Atypical antipsychotics showed the strongest prospective reductions in AMI. These findings highlight the value of prospective, real-world monitoring to inform pharmacological strategies in treatment-resistant eating disorders.

Background The Fusiform Gyrus (FG), a brain region relevant for the interaction between cognitive processes and emotional behavior, especially emotion recognition and interpretation of social cues, has been linked to the pathophysiology of schizophrenia conceptualized as a disorder of aberrant synaptic function and brain connectivity as well as characterized by disruptions in thought processes, perceptions, emotional responsiveness, and Theory of Mind (ToM). Disrupted FG connectivity has been reported in schizophrenia; however, no systematic review has addressed this issue in a comprehensive and critical manner. Methods We conducted a systematic review of PubMed, Embase, and Scopus from database inception to February 2026 following PRISMA guidelines. We included peer-reviewed neuroimaging studies using functional magnetic resonance imaging to assess functional connectivity or task-related activation of the FG in patients with schizophrenia compared with healthy controls. Results We identified 2765 articles from different sources. After duplicate removal, 959 articles were screened at the title-abstract level, 269 articles were reviewed for full-texts, and 86 eligible articles were included. Across fMRI studies, the FG emerged as a central node of dysconnectivity. Drug-naïve patients showed heterogeneous FG alterations, with increased local activity and network centrality reported in some studies and reduced interhemispheric and functional connectivity in others, alongside reduced FG activation on visual, affective, and sensory tasks reported more broadly across schizophrenia samples. First-episode psychosis patients were characterized by FG hypoconnectivity associated with negative symptoms and socio-cognitive impairment. Treatment-responsive patients demonstrated partial normalization or modulation of fusiform connectivity and network centrality following antipsychotic treatment. In contrast, treatment-resistant schizophrenia patients showed persistent hypoactivation and reduced connectivity, correlating with cognitive deficits and negative symptoms. Conclusions The FG appears to function as a dynamic, state-sensitive hub underlying perceptual, emotional, and cognitive disturbances in schizophrenia, in line with impaired ToM.

BACKGROUND:Bipolar disorder (BD) is associated with impairments in facial emotion recognition (FER), affecting social functioning and quality of life. Understanding FER deficits in BD is crucial for tailoring interventions and improving treatment outcomes. This systematic review and meta-analysis aims to evaluate FER differences among individuals with BD, unaffected first-degree relatives (FDRs), and healthy controls (HCs), exploring predictors related to patient and study characteristics. METHODS:We systematically searched PubMed/MEDLINE, Scopus, EMBASE, and PsycINFO databases from inception to March 28, 2024. Random-effects meta-analyses were conducted to explore differences in accuracy and reaction time during FER identification and discrimination tasks. RESULTS:A total of 100 studies were included, comprising 4920 individuals with BD (females = 56%, mean age = 34.1 ± 9.1), 676 FDRs (females = 55%, mean age = 36.1 ± 12), and 4909 HCs (females = 53.2%, mean age = 32.5 ± 9.5). Compared to HCs, adults with BD exhibited significantly lower accuracy (SMD = -0.47; 95% CIs = -0.56, -0.38) and higher reaction time (SMD = 0.57; 95%CIs = 0.33, 0.81) during facial emotion identification tasks. During facial emotion discrimination tasks, adults with BD had significantly lower accuracy than HCs (SMD = -0.59; 95%CIs = -0.78, -0.4), but similar speed. No significant differences were observed between BD and FDRs. Meta-regressions identified several predictors of FER performance, including manic symptom severity, stimulus duration, and presence of practice before task. CONCLUSIONS:FER deficits appear to be a core feature of BD and require specialized, systematic assessment. Identifying these deficits may help guide interventions aimed at improving affective cognition and social outcomes in individuals with BD.

BACKGROUND:Lithium is a core treatment for bipolar disorder (BD), yet clinical response varies across patients. Testing accessible predictors of lithium response is critical for personalization strategies in real-world settings. METHODS:In this cross-sectional study, 179 individuals with BD were assessed using a broad range of standardized clinical instruments and the Brief TEMPS-M to evaluate affective temperaments. Lithium response was retrospectively classified via the Alda Scale. Multivariate linear regressions and three supervised machine learning classifiers (random forest, elastic net, and XGBoost) were applied to identify predictors of treatment response. Class imbalance was addressed by down-sampling during training. RESULTS:Responders (12.3 % of participants) were more likely to be employed, diagnosed with BD-II, had fewer lifetime depressive and hypomanic episodes, fewer suicide attempts, and significantly lower anxious temperament scores. In multivariable models, lifetime psychotic and mixed features, as well as higher counts of hypomanic and manic episodes, were independently associated with poorer lithium response. Machine learning models confirmed the importance of these variables, possibly with remarkably high predictive validity (random forest AUC = 1.00; elastic net and XGBoost F1 = 0.86). Hyperthymic temperament was positively associated with lithium response, whereas cyclothymic and depressive traits were associated with poorer lithium response. CONCLUSIONS:The present exploratory study should be intended as a primer for larger samples and more balanced replication studies employing reliable machine learning techniques, allowing for firm conclusions about suggestive clinical predictors of lithium response in BD, and their complex interaction.

BACKGROUND:Acute bipolar depression poses a significant burden and socioeconomic costs. We investigated the comparative efficacy/response/acceptability of pharmacological interventions for acute bipolar depression, considering dose effects across different age groups. METHODS:We conducted a network meta-analysis (NMA), searching for randomized controlled trials (RCTs) comparing pharmacological interventions against each other/or placebo in patients with acute bipolar depression (Type-I/Type-II/other), indexed in PubMed/MEDLINE, Embase, Web-of-Science/and Scopus (database inception up to 2025.11.25). Co-primary outcomes were change in depressive symptoms/response/and acceptability. Tolerability/remission/change in anxious symptoms/and risk-of-manic/hypomanic switches were secondary outcomes. Confidence-In-Network-Meta-Analysis was likewise appraised. RESULTS:103 RCTs, encompassing 71 distinct treatment combinations, included 20,941 participants. Sensitivity analysis including low-risk-of-bias studies only and excluding outliers for possible effect modifiers indicated that lamotrigine 50 mg/day or 200 mg/day, quetiapine extended-release 150 mg/day and 300 mg/day, and lumateperone 42 mg/day outperformed placebo for depressive symptoms, with estimates ranging from -1.53(95%C.I. = -2.13;-0.93) for lamotrigine 50 mg/day, to -0.36(95%C.I. = -0.68;-0.04) for lumateperone 42 mg/day. Several additional drugs might be efficacious, although they emerged as outliers for either mean age of participants/proportion of females/BD-II participants/psychotic features/rapid cycling/baseline severity of depression/and trial duration. No treatment outperformed placebo for response/remission/acceptability/tolerability/and manic/hypomanic switches. CONCLUSIONS:Our findings are consistent with previous NMAs and current guidelines, thereby expanding knowledge by concurrently appraising different drugs, doses, and age groups.