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Pica in Childhood: Concurrent and Sequential Psychiatric Comorbidity.

OBJECTIVE: Pica is the persistent eating of nonnutritive, nonfood substances, and is associated with serious medical consequences. There has been a lack of research into the psychiatric comorbidities of pica, despite being important for informing clinical care. The current study examines psychiatric comorbidities of pica in childhood and the longitudinal relationship between childhood pica and adolescent eating disorders. METHOD: We analyzed data from the Avon Longitudinal Study of Parents and Children study. Pica and psychopathology, assessed with the Development and Well-Being Assessment and the Strengths and Difficulties Questionnaire, were assessed at about 7- and 10-years of age, and reported eating disorders (EDs) at 14-, 16-, and 18-years of age. We conducted linear and logistic regression models, adjusting for covariates, to identify concurrent psychiatric comorbidities, as well as risk for later EDs. We conducted the Benjamini-Hochberg correction procedure to correct for multiple testing. RESULTS: Pica (prevalence ranged from 0.33% to 2.33% dependent on age) was associated with increased odds of any psychiatric disorder and behavioral disorders in early childhood (OR&#x2009;=&#x2009;7.30, q&#x2009;<&#x2009;0.001, and OR&#x2009;=&#x2009;5.65, q&#x2009;<&#x2009;0.001, respectively) and mid-childhood (OR&#x2009;=&#x2009;5.75, q&#x2009;<&#x2009;0.001, and OR&#x2009;=&#x2009;10.66, q&#x2009;<&#x2009;0.001, respectively), and greater concurrent hyperactivity, conduct problems, peer problems, prosocial difficulties, and emotional difficulties (q&#x2009;<&#x2009;0.01 across analyses). We did not find evidence that pica presence increased odds for concurrent emotional disorders nor for later ED risk. DISCUSSION: The association between pica and psychiatric and behavioral disorders indicates a likely shared etiology. Our findings provide insight into the psychiatric characteristics of children with pica and highlight they may require complex behavioral support beyond their eating difficulties.

Humans

Executive function in alcohol use disorder with low psychiatric comorbidity: Comparison with a non-clinical sample and predictive value for treatment outcome.

BACKGROUND: Executive functions (EF) encompass abilities such as planning, decision-making, and inhibitory control, critical for learning, establishing and maintaining behavioral change. The association between alcohol use disorder (AUD) and impairments in EF are well established. However, prior research is dominated by studies on convenience samples including individuals with severe AUD with high levels of psychiatric comorbidity, which limits generalizability. The present study therefore aimed to investigate the degree of impairment and predictive ability of EF, on alcohol consumption, among individuals with moderate AUD with low levels of psychiatric comorbidity. METHODS: Adults with moderate AUD (n&#x2009;=&#x2009;147) were recruited at three specialized addiction outpatient clinics in Stockholm, to a randomized controlled trial investigating the efficacy of two psychological treatments. Participants underwent neuropsychological testing before treatment. Eight tests from the CANTAB&#xae; battery were administered at baseline, assessing mental flexibility, sustained attention, visuospatial working memory, response inhibition, and delay discounting. Assessments of alcohol use and related symptoms were conducted at baseline, the 12- and 26-weeks follow-up. A non-clinical reference sample (n&#x2009;=&#x2009;72) completed corresponding CANTAB&#xae; tests. The two groups were compared regarding EF using descriptive statistics and t-tests, and the predictive value of EF for reduction in alcohol consumption, was investigated using multiple regression models. RESULTS: Individuals with AUD did not perform worse on any of the tests on executive function (CANTAB&#xae;) as compared to the non-clinical reference sample. Measures of EF were not significant predictors for reduction in alcohol use for the 12-week, or the 26-week follow-up. CONCLUSIONS: EFs were not impaired and were not a clinically relevant predictor of treatment outcomes in this population with AUD. Future research on EF as a predictor in AUD treatment, needs to corroborate the present findings, and include other populations, e.g., with different socio-economic backgrounds and by including other methodologies for measuring EF.

Humans

X-linked ichthyosis with seizures, ADHD, and autism spectrum disorder: a case report with an uncommon clinical presentation.

INTRODUCTION AND IMPORTANCE: X-linked ichthyosis (XLI) is a genetic condition characterized by scaly skin due to steroid sulfatase (STS) deficiency, often associated with additional neurodevelopmental issues. CASE PRESENTATION: A 10-year-old male child was admitted to the dermatology department. The child had been born prematurely at 26&#xa0;weeks' gestation with a low birth weight of 1.6 kg. He presented with seizures characterized by abnormal upper-limb movements and was diagnosed with congenital ichthyosis. The child exhibited delayed language and motor development, learning difficulties, microcephaly, and dry, scaly skin, which he habitually peeled and ingested. Genetic analysis (single-nucleotide polymorphism and combined comparative genomic hybridization) revealed a 1.65 Mb deletion on chromosome Xp22.31 affecting the STS gene and other adjacent genes. The patient had low STS enzyme activity (3.5&#xa0;nmol/hour/protein) in adipose tissue. Neuroimaging showed no structural abnormalities, though an electroencephalogram indicated mild slowing. CLINICAL DISCUSSION: Given the established association between STS deletions and neurodevelopmental as well as psychiatric comorbidities, early recognition of emerging psychiatric features is essential. Given the established association between STS deletions and neurodevelopmental as well as psychiatric comorbidities, early recognition of emerging psychiatric manifestations is essential. Management should follow evidence-based recommendations for first-episode or early psychotic symptoms, emphasizing careful assessment, individualized pharmacological treatment when indicated, and multidisciplinary psychosocial support. Such an approach may improve clinical stabilization while avoiding premature diagnostic labeling. CONCLUSION: This case highlights the importance of early genetic diagnosis and personalized treatment approaches, integrating dermatological, neurological, and psychiatric care to optimize outcomes in XLI.

X-linked ichthyosis

Schizophrenia and bipolar disorder: a comparative analysis of genetic and brain network connectivity.

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.

Humans

Add-on treatment with vinpocetine reduces seizure frequency and improves comorbidities in patients with loss-of-function &#x3b3;-aminobutyric acid type A receptor variants.

OBJECTIVE: The semisynthetic compound vinpocetine has gained attention as a potential precision medicine for developmental and epileptic encephalopathies caused by loss-of-function (LoF) variants in &#x3b3;-aminobutyric acid type A (GABAA) receptor genes. As a positive allosteric modulator of GABAA receptors, case reports suggest that vinpocetine can reduce epileptiform activity and seizure frequency, while improving cognitive function in patients with GABAA receptor-related epilepsies. Here, we extend these observations with a retrospective observational study evaluating the response to vinpocetine in an additional seven patients. METHODS: Patients initiated treatment with vinpocetine between 2018 and 2025 at the Danish Epilepsy Centre or abroad. Clinical data were collected from medical records, seizure diaries, and neuropsychological assessments. The modulatory efficacy of vinpocetine was investigated using electrophysiological studies. RESULTS: Nine patients harboring eight GABAA receptor LoF variants were given add-on vinpocetine treatment. Electrophysiological analyses confirmed dose-dependent positive modulation by vinpocetine across tested variants. Six patients with a median age of 15.5&#x2009;years (range&#x2009;=&#x2009;6-29) continued treatment for a median of 24&#x2009;months (range&#x2009;=&#x2009;12-90), whereas three discontinued due to adverse effects (AEs) or lack of efficacy. The patients' level of function ranged from normal to moderate intellectual disability, psychiatric comorbidities, and behavioral disturbances. Four patients initiated vinpocetine due to uncontrolled seizures. One became seizure-free, and two experienced a 50%-55% reduction. Electroencephalograms demonstrated improved spike-wave indexes in four patients. Six showed improvement in nonseizure factors, and caregivers reported reduced aggressivity and better vocabulary in one. Vinpocetine was well tolerated, with only mild and reversible AEs reported. SIGNIFICANCE: Adjunctive vinpocetine shows promise as a targeted therapy for patients with GABAA receptor LoF variants, decreasing seizure frequency and positively impacting nonseizure factors, with only mild AEs reported. Vinpocetine may be a safe and effective therapy for patients with GABAA receptor-related epilepsies, which should be investigated further in future N-of-1 trials.

Humans

Psychiatric Diagnoses and Psychotropic Medications Among Military-Affiliated Adolescents and Young Adults With Polycystic Ovary Syndrome.

PURPOSE: To study rates of psychiatric diagnoses and psychotropic medication prescription among U.S. military-affiliated adolescents and young adults (AYA) with polycystic ovary syndrome (PCOS). METHODS: This retrospective matched cohort study included U.S. military-affiliated AYA (aged 15-21 years) enrolled in TRICARE Prime for at least 6 months during the surveillance period (January 2016 to October 2023). Military-affiliated AYA were grouped into three categories: individuals diagnosed with PCOS (N = 6,911), age-matched individuals with no diagnosed PCOS symptoms (N = 35,814), and individuals with diagnosed symptoms suggestive of PCOS (N = 2,136). The presence of a psychiatric diagnoses and prescriptions for psychotropic medications were obtained via the International Classification of Diseases, 10th Revision, Clinical Modification codes and National Drug codes, respectively. RESULTS: AYA with diagnosed PCOS had higher odds of having a psychiatric diagnosis and being prescribed a psychotropic medication compared to an age-matched comparison group (psychiatric diagnosis odds ratio [OR] = 2.48 [2.35-2.62], medication OR = 2.14 [2.03-2.25]) and individuals with symptoms suggestive of PCOS (psychiatric diagnosis OR = 1.11 [1.003-1.23], medication OR = 1.16 [1.05-1.28]). DISCUSSION: The odds of psychiatric comorbidities and psychotropic medication prescription were more than twice as high as among U.S. military-affiliated AYA with PCOS. More research is needed to determine whether health-care utilization and military-related factors impact mental health outcomes among AYA with PCOS. Additionally, tailored, multidisciplinary mental health services for AYA with PCOS are needed.

Humans

Prader-Willi syndrome as a neurogenetic model for psychosis and obsessive-compulsive disorder: A review of clinical, behavioral, and biological insights.

Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder classically defined by hyperphagia and obesity. However, its profound psychiatric phenotype offers a unique genetic framework for understanding major mental illnesses. This review positions PWS as a potentially informative biological model for psychosis and obsessive-compulsive disorder (OCD), bridging the gap between 15q11-q13 imprinting defects and neural circuit dysfunction. We synthesize evidence demonstrating that psychosis in PWS is not a uniform trait but is disproportionately linked to the maternal uniparental disomy (mUPD) subtype. This genotype-phenotype correlation suggests that overexpression of maternally imprinted genes and loss of paternal expression disrupt cortical excitatory-inhibitory balance, resembling the "schizophrenia-bipolar" genomic architecture. Furthermore, synthesized evidence characterizes the repetitive, ritualistic behaviors in PWS not merely as behavioral challenges, but as a developmentally arrested OCD-spectrum phenotype driven by distinct serotonergic-oxytocinergic imbalances and hypothalamic-limbic dysconnectivity. Mechanistic insights from preclinical models of MAGEL2, SNORD116, and NDN deficiency are integrated with clinical findings to highlight shared neurobiological substrates. Finally, we outline a roadmap for precision psychiatry in PWS, emphasizing the necessity of pharmacogenomics in antipsychotic management and the potential of targeted circuit-based therapeutics. By deconstructing the psychiatric comorbidities of PWS, we provide a framework for translating genomic architecture into mechanistic understanding and targeted treatment for complex neuropsychiatric disorders.

15q11-q13

Increased somatic mosaicism in autosomal and X chromosomes for suicide death.

Mosaic chromosomal alterations (mCAs) are classified as mosaic deletions (loss), copy-neutral loss of heterozygosity (CN-LOH), and duplications (gain), attracting special attention as biological aging-related acquired genetic alterations. While these mCAs have been linked with aging and various diseases, no study has investigated their association with suicide risk which is associated with abnormal biological aging. Here, we examined the association between suicide deaths and mCAs, including mosaic loss of the X (mLOX) and Y chromosomes, by leveraging blood-derived single nucleotide polymorphism-array data. The first (410 suicide decedents and 88,870 controls) and the second (363 suicide decedents and 88,870 controls) cohorts were analyzed and integrated using meta-analyses (773 suicide decedents and 177,740 controls). Total mCAs in autosomal chromosomes were significantly increased in suicide (p&#x2009;=&#x2009;1.28 &#xd7; 10-6, odds ratio [OR] = 1.78), mostly driven by loss (p&#x2009;=&#x2009;4.05 &#xd7; 10-9, OR&#x2009;=&#x2009;2.70) and gain (p&#x2009;=&#x2009;1.08 &#xd7; 10-3, OR&#x2009;=&#x2009;2.23). mLOX were significantly increased in female suicide (p&#x2009;=&#x2009;2.66 &#xd7; 10-21, OR&#x2009;=&#x2009;4.00). The directions of effects of all mCAs in autosomal and sex chromosomes on suicide were the same in the first and second sets. Subgroup analyses suggest that our findings were mostly driven by suicide itself, and not confounded by comorbid psychiatric disorders or physical diseases, smoking status, sample location, or postmortem sample status. In conclusion, we provide the first evidence for aberrant mCAs in somatic autosomal and X chromosomes in suicide, which may contribute to an improved understanding of the genomic pathophysiology underlying suicide.

Humans

Sex Differences in Health Conditions Associated with Sexual Assault in a Large Hospital Population.

INTRODUCTION: Sexual assault is an urgent public health concern with both immediate and long-lasting health consequences, affecting 44% of women and 25% of men during their lifetimes. Large studies are needed to understand the unique healthcare needs of this patient population. METHODS: We mined clinical notes to identify patients with a history of sexual assault in the electronic health record (EHR) at Vanderbilt University Medical Center (VUMC), a large university hospital in the Southeastern USA, from 1989 to 2021 (N = 3,376,424). Using a phenome-wide case-control study, we identified diagnoses co-occurring with disclosures of sexual assault. We performed interaction tests to examine whether sex modified any of these associations. Association analyses were restricted to a subset of patients receiving regular care at VUMC (N = 833,185). RESULTS: The phenotyping approach identified 14,496 individuals (0.43%) across the VUMC-EHR with documentation of sexual assault and achieved a positive predictive value of 93.0% (95% confidence interval = 85.6-97.0%), determined by manual patient chart review. Out of 1,703 clinical diagnoses tested across all subgroup analyses, 465 were associated with sexual assault. Sex-by-trauma interaction analysis revealed 55 sex-differential associations and demonstrated increased odds of psychiatric diagnoses in male survivors. DISCUSSION: This case-control study identified associations between disclosures of sexual assault and hundreds of health conditions, many of which demonstrated sex-differential effects. The findings of this study suggest that patients who have experienced sexual assault are at risk for developing wide-ranging medical and psychiatric comorbidities and that male survivors may be particularly vulnerable to developing mental illness.

Clinical informatics

Proteomic signatures and predictive modeling of cadmium-associated anxiety in middle-aged and elderly populations: an environmental exposure association study.

BACKGROUND: Emerging evidence implicates environmental contaminants such as cadmium (Cd) as modifiable risk factors for anxiety. Despite growing recognition of heavy metal toxicity in neuropsychiatric disorders, the molecular mechanisms linking environmental exposure to anxiety pathogenesis remain poorly understood. METHODS: Based on the established cohort of individuals with cognitive impairment in cadmium-contaminated areas, this cross-sectional association study enrolled 50 middle-aged and elderly hospitalized patients from these regions, adhering to the STROBE guidelines. Blood concentrations of cadmium (Cd), lead (Pb), and mercury (Hg) were analyzed in relation to anxiety severity assessed via the Hamilton Anxiety Rating Scale (HAMA). Plasma proteomic profiling was performed using data-independent acquisition (DIA) quantitative technology with an LC-MS/MS platform (timsTOF Pro, Bruker Daltonics), systematically characterizing 2,531 proteins across all samples. Machine learning techniques, specifically XGBoost and LASSO, were employed to identify biomarkers that were subsequently validated through mediation analysis and animal experiments, allowing for the screening of key protein signatures. Finally, clinical variables were integrated to construct a comprehensive model, which was then thoroughly evaluated. RESULTS: Anxious individuals exhibited significantly higher blood Cd levels than controls (&#x3b2;&#x2009;=&#x2009;0.50, 95% CI: 0.07-0.93, p&#x2009;<&#x2009;0.01), with anxiety positively correlating with depression (r&#x2009;=&#x2009;0.62, p&#x2009;=&#x2009;0.003) and inversely with ApoE3 genotype prevalence. Proteomics identified 120 differentially expressed proteins in anxious patients, enriched in oxidative phosphorylation and neurodegenerative pathways. CCDC126 emerged as a cadmium-associated biomarker, validated in rat models exposed to Cd. Combining CCDC126, blood Cd, Pb, and hypertension, a clinical prediction model achieved robust discrimination (AUC&#x2009;=&#x2009;0.80, validation cohort). CONCLUSIONS: This first integrative environmental-proteomic study highlights cadmium's synergistic role in anxiety pathophysiology and psychiatric comorbidity. The predictive model offers translatable potential for early risk stratification, while CCDC126 provides mechanistic insights for targeted interventions in populations exposed to environmental pollutants.

Cadmium

[Tics and Tourette Syndrome].

Tics disorders and Tourette syndrome (TS) are neurodevelopmental conditions characterized by motor and/or vocal tics with onset in childhood. Their clinical presentation is heterogeneous and fluctuating over time, with exacerbations related to emotional, environmental, and medical factors. Diagnosis is clinical and based on medical history and neurological examination, following DSM-5-TR criteria, with ancillary testing rarely required. The prevalence of TS is estimated at 0.7%, while transient tic disorders affect up to 10% of children. The natural history is generally favorable, with symptom improvement during adolescence, although a subset of patients continues to experience tics into adulthood. Most individuals with TS present psychiatric comorbidities, particularly attention-deficit/hyperactivity disorder and obsessive-compulsive disorder, which significantly impact quality of life and should be prioritized in management decisions. Treatment is recommended only when tics cause functional impairment and follows a stepwise approach including psychoeducation, behavioral interventions, and individualized pharmacological therapy. Comprehensive behavioral intervention for tics is considered first-line treatment when available. Alpha-2 adrenergic agonists and dopamine antagonists are the most commonly used pharmacological options. Neuromodulation therapies are reserved for severe, refractory cases. These recommendations from the Ibero-American Academy of Pediatric Neurology summarize current evidence and provide a practical, updated framework for the diagnosis and management of tic disorders and Tourette syndrome in pediatric patients.

Humans

A genome-wide cross-trait analysis characterizes the shared genetic architecture between rheumatoid arthritis and psychiatric disorders.

OBJECTIVES: Patients with RA have a 2- to 3-fold elevated risk of psychiatric disorders, suggesting an underlying genetic link between these phenotypes. However, the shared genetic architectures and pathological mechanisms driving RA-psychiatric disorder comorbidity remain to be fully elucidated. Herein, we performed cross-trait analysis to investigate the shared genetic architecture between RA and psychiatric disorders. METHODS: Leveraging European-ancestry genome-wide association studies (GWASs) datasets of RA (n&#x2009;=&#x2009;1&#x2009;026&#x2009;690) and 10 major psychiatric disorders (n&#x2009;=&#x2009;14&#x2009;307-1&#x2009;222&#x2009;882), we performed cross-trait pleiotropic analysis to identify the shared pleiotropic loci and genes between RA and psychiatric disorders, followed by functional annotation and Mendelian randomization analysis to explore the pathological mechanisms underlying RA-psychiatric disorder comorbidity. RESULTS: Our analysis revealed significant positive genetic correlations between RA and seven psychiatric disorders, such as major depressive disorder. From these correlations, we identified 61 pleiotropic loci jointly influencing RA and psychiatric disorder risk, along with 208 pleiotropic genes predominantly involved in immune and inflammatory response biological processes. Druggable target exploration identified 21 drug-gene interactions involving pleiotropic genes, with two genes (RHOA and TRAF3) classified in the clinically actionable category, representing potential therapeutic targets for both RA and psychiatric disorders. Mendelian randomization further demonstrated a bidirectional causal relationship between RA and schizophrenia, while supporting the causal roles of attention-deficit/hyperactivity disorder, major depressive disorder and post-traumatic stress disorder in increasing RA risk. CONCLUSION: Our findings elucidate the shared genetic architecture between RA and psychiatric disorders, providing novel insights into the pathological mechanisms underlying their comorbidity and laying the groundwork for improved comorbidity management.

Arthritis, Rheumatoid

Association of Genetic Liability to Psychiatric Disorders with Peripheral Metabolic Dysregulation.

IMPORTANCE: Individuals with psychiatric disorders face elevated cardiometabolic risk which is linked to increased mortality. The extent to which this reflects shared pathogenesis or the downstream effects of illness and treatment remains poorly understood. OBJECTIVE: To characterize the direct pleiotropic effects of psychiatric genetic liability on circulating metabolites and aggregate cardiometabolic risk, independent of psychiatric diagnosis and psychotropic medication use. DESIGN SETTING AND PARTICIPANTS: Cross-sectional analysis of Mass General Brigham Biobank participants with metabolomic profiling, genomic data, and linked electronic health records. EXPOSURES: Genetic liability to nine psychiatric disorders quantified using polygenic risk scores (PRS): attention deficit/hyperactivity disorder (ADHD), anorexia nervosa (ANO), anxiety disorder (ANX), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), PTSD, schizophrenia (SCZ), and substance use disorder (SUD). MAIN OUTCOMES AND MEASURES: 249 circulating metabolites and four metabolomic risk scores (MRS) for type 2 diabetes, myocardial infarction, ischemic stroke, and vascular dementia. PRS-metabolite associations were estimated using nested models adjusting for lifetime psychiatric diagnosis and psychotropic medication use. RESULTS: Across 25,290 participants, we identified 604 significant PRS-metabolite associations (Bonferroni p< 1.36 x 10-4), of which 89% persisted after adjustment for lifetime diagnosis and medication use, suggesting that the direct genetic effects on metabolism are largely independent of illness or treatment. PRS for MDD, PTSD, and ADHD showed the most extensive dysregulation, with a transdiagnostic pattern of elevated lipids and systemic inflammation, specifically triglycerides (&#x3b2; = 0.04 to 0.05, all p< 4.4 x10-13) and glycoprotein acetyls (&#x3b2; = 0.05, all p< 2.2 x10-16). Notably, PRS for SCZ and BD showed minimal metabolite dysregulation despite having the strongest association with their target diagnoses. PRS for MDD, PTSD, ADHD, and SUD were associated with increased MRS across cardiometabolic conditions (&#x3b2; = 0.03 to 0.08, all p< 2.1 x10-4). Sensitivity analyses controlling for BMI or excluding participants without any psychiatric history (N: 21,305 and 11,150, respectively) showed a similar pattern. CONCLUSIONS AND RELEVANCE: Psychiatric genetic liability is associated with systemic metabolic dysregulation independent of illness onset or treatment, supporting a partially pleiotropic basis for psychiatric-cardiometabolic comorbidity.

Journal Article

Stratifying the risk of transition to adult-onset psychiatric disorders in adolescents with anxiety.

BACKGROUND: Escalating mental health service demands have created a need to better identify young people most likely to require continued support from mental health services at the transition between childhood and adulthood. Anxiety is the most common adolescent mental health condition, yet its clinical significance and prognosis are not well understood. We aimed to examine the risk of young adult-onset psychiatric disorders in individuals with an adolescent anxiety disorder, and identify stratifiers of risk of subsequent psychiatric disorders in this group. METHODS: Individuals from the Norwegian Mother, Father, and Child Cohort Study (MoBa) with linked health records and aged 18 or over as of the 31st December 2023 were included. Those diagnosed with any ICD-10 anxiety disorder when aged 10-17 years were defined as having an adolescent anxiety disorder (n=2107, controls n=47,582). Polygenic scores (PGS) for psychiatric and neurodevelopmental conditions were calculated using LDpred2. Anxiety, comorbidities, and parental psychiatric history were defined through linked ICD-10 diagnoses. Sex was defined through linked records. Individuals were defined as having a young adult-onset psychiatric disorder if they first received any new psychiatric diagnosis aged 18-24. RESULTS: Adolescent anxiety diagnosis was associated with increased risk of all adult-onset psychiatric disorders (HR= 2.33-8.65). Post-traumatic stress disorder PGS, parental history of severe mental illness, and female sex were associated with increased risk of transition to a young adult-onset psychiatric disorder in people with an adolescent anxiety disorder. CONCLUSIONS: Adolescent anxiety greatly increases the risk of a psychiatric disorder during the transition to adult life. Clinicians should consider female sex and parental psychiatric history when prioritising young people with anxiety for adult mental health service support. Future research needs to further consider whether polygenic scores would aid risk stratification in clinical practice.

Norwegian Mother Father and Child Cohort Study

Psychiatric and neurological predictors of early ADHD medication discontinuation across the lifespan: a multinational study.

BACKGROUND: Early discontinuation of attention-deficit/hyperactivity disorder (ADHD) medication is common and linked to worse outcomes. Identifying clinical predictors could aid personalised treatment yet evidence is inconsistent across ages and countries/regions. OBJECTIVE: Investigate psychiatric and neurological comorbidity as predictors of early ADHD medication discontinuation in new ADHD medication users across age groups, sex and countries/regions. METHODS: Using health records from eight countries/regions, we identified 1 000 411 (44% female) new ADHD medication users (2011-2020). Discontinuation was defined as a &#x2265;180&#x2009;day gap between dispensations. We examined 23 indicators of psychiatric or neurological comorbidity, severity and psychotropic medication use. Associations were estimated using Cox regression, pooled with random-effects meta-analyses and stratified by age-at-initiation and sex. FINDINGS: Discontinuation rates varied widely (children 19%-61%, adolescents 37%-68%, young adults 52-67%, adults 38%-68%). In pooled analyses, earlier discontinuation in children was predicted by intellectual disability, autism and use of psychotropic medications (HR range 1.32-1.51), while conduct/oppositional defiant disorder (CD/ODD) was protective (HR 0.83, 95%&#x2009;CI 0.73 to 0.94). In adolescents, no indicators remained statistically significant after multiple-testing control. In young adults, CD/ODD (HR 1.42, 95%&#x2009;CI 1.30 to 1.55), and in adults, schizophrenia (HR 1.25, 95%&#x2009;CI 1.09 to 1.44)&#x2009;and tic disorders (HR 1.27, 95%&#x2009;CI 1.11 to 1.46) predicted earlier discontinuation. Statistical heterogeneity was substantial, largely driven by US estimates. In meta-analyses excluding the USA, additional associations emerged. For example, in children, OCD and anxiety disorders predicted earlier discontinuation, while eating disorders and antidepressants/anxiolytics were protective in adults. Associations with schizophrenia, tic disorders and CD/ODD were no longer significant. Country-specific analyses showed similar association patterns, except in the USA, Hong Kong and the UK. Sex differences were limited. CONCLUSIONS: Children with neuropsychiatric comorbidity and related comedication are more likely to discontinue ADHD medication early, whereas few consistent predictors were seen from adolescence onwards. Marked cross-country variation, particularly in the USA, points to system-level influences on treatment patterns. CLINICAL IMPLICATIONS: Improving ADHD medication persistence will require consideration of healthcare context and age-specific strategies, including close monitoring for children with complex neuropsychiatric profiles, and consideration of broader factors in adolescents and adults, where clinical predictors were limited.

Humans

Clinical impact of obsessive-compulsive disorder comorbidity in bipolar disorder: a systematic review and meta-analysis.

BACKGROUND: Bipolar disorder (BD) is commonly comorbid with other psychiatric conditions, such as obsessive-compulsive disorder (OCD). Despite increasing interest in this comorbidity, quantitative data on its clinical characteristics remain limited. This systematic review and meta-analysis aimed to evaluate the clinical impact of OCD comorbidity in BD by comparing individuals with BD and OCD (BD-OCD) to those with BD without OCD. METHODS: We systematically searched the PubMed/MEDLINE, Scopus, PsycINFO, and Web of Science databases up to April 15, 2024. Meta-analyses were conducted to compare BD-OCD and BD without OCD groups across multiple clinical domains. RESULTS: From 11,959 initial records screened, 26 studies were included in the qualitative synthesis, with 22 eligible for meta-analysis. Individuals with BD-OCD showed higher odds of experiencing chronic mood episodes (OR&#xa0;=&#xa0;9.42; 95%CI&#xa0;=&#xa0;2.23, 39.9), rapid cycling (OR&#xa0;=&#xa0;1.92; 95%CI&#xa0;=&#xa0;1.04, 3.53), comorbid eating disorders (OR&#xa0;=&#xa0;3.37; 95%CI&#xa0;=&#xa0;1.99, 5.7), panic disorder (OR&#xa0;=&#xa0;3.3; 95%CI&#xa0;=&#xa0;2.11, 5.2), substance use disorders (OR&#xa0;=&#xa0;1.39; 95%CI&#xa0;=&#xa0;1.02, 1.89), and lifetime suicide attempts (OR&#xa0;=&#xa0;1.85; 95%CI&#xa0;=&#xa0;1.21, 2.84). Additionally, they presented earlier onset of BD (SMD&#xa0;=&#xa0;-0.27; 95%CI&#xa0;=&#xa0;-0.52, -0.01) and reduced functioning (SMD&#xa0;=&#xa0;-0.42; 95%CI&#xa0;=&#xa0;-0.59, -0.24). Most data were derived from adult populations, limiting the evidence available for children and adolescents. CONCLUSIONS: BD-OCD presents a more severe and complex clinical profile, requiring specialized assessment and integrated treatment approaches. Identifying these features may support earlier recognition and inform personalized interventions for this population.

Humans

Are Adverse Childhood Experiences Associated with Metabolic Syndrome in Patients with Severe Mental Illness?

BACKGROUND: Patients with severe mental disorders (SMD) are at substantially elevated risk for metabolic syndrome (MetS), contributing to excess cardiovascular morbidity and premature mortality. Adverse childhood experiences (ACEs) have been associated with dysregulation of metabolic pathways, yet their contribution to MetS risk in SMD remains poorly understood. OBJECTIVE: This study aimed to investigate the association between ACEs and MetS in outpatients with bipolar disorder (BD) and schizophrenia (SZ) in clinical remission and to identify independent and incremental predictors of MetS using a hierarchical analytical framework. METHODS: This cross-sectional study included 140 outpatients with SMD (96 with BD and 44 with SZ) in clinical remission, recruited from a university hospital in Eastern Turkey. MetS was defined according to NCEP-ATP III criteria, and ACEs were assessed using the Turkish version of the Adverse Childhood Experiences Scale (ACE-TR). Hierarchical and multivariable logistic regression analyses were performed to examine factors associated with MetS. RESULTS: MetS was highly prevalent in this sample (46.4%). ACE-TR total score was independently and consistently associated with MetS across all hierarchical models (odds ratio [OR] range: 1.68-1.77), with each one-unit increase conferring approximately 71% higher odds in the fully adjusted model (OR = 1.71; 95% confidence interval [CI] 1.26-2.32; P = 0.001). The number of hospitalizations was the only other independently associated variable (OR = 1.19; 95% CI 1.02-1.39). Sexual abuse (16.9% vs. 2.7%; P = 0.004), emotional neglect (63.1% vs. 30.7%; P < 0.001), and physical neglect (30.8% vs. 14.7%; P = 0.022) were significantly more prevalent in the MetS group. ACE-TR total score was positively correlated with waist circumference and triglyceride levels. CONCLUSION: The strong and consistent association between ACEs and MetS underscores the importance of trauma-informed care models in psychiatric practice, where metabolic comorbidity remains a leading cause of premature mortality.

Humans

The role of the brain-bone axis in skeletal degenerative diseases and psychiatric disorders, A genome-wide pleiotropic analysis.

INTRODUCTION: Skeletal degenerative diseases and psychiatric disorders often coexist clinically. However, the genetic correlations and underlying biological mechanisms between these two types of diseases remain unclear. OBJECTIVES: To investigate the genetic correlations between skeletal degenerative diseases and psychiatric disorders and to identify shared genomic loci, genes, and pathways. METHODS: This comprehensive genome-wide pleiotropic association study utilized summary statistics from publicly available genome-wide association data. Various statistical genetic correlation methods were employed, including LDSC, HDL, PLACO, Coloc, Hyprcoloc, and Mendelian randomization (MR) analysis, along with immune cell colocalization analysis. The study aimed to identify potential shared genetic factors among three skeletal degenerative diseases (osteoarthritis, intervertebral disc degeneration, and osteoporosis) and three psychiatric disorders (schizophrenia, anxiety disorder, and major depressive disorder). RESULTS: Analyses using LDSC, HDL, and Bonferroni corrections revealed significant genetic correlations between intervertebral disc degeneration (IVDD) and anxiety disorder (ANX); fractures, IVDD, and arthritis with major depressive disorder (MDD); and arthritis with schizophrenia (SCZ). Significant genetic correlations were also observed between VDD and ANX, fractures, IVDD, hip osteoarthritis (HipOA), knee osteoarthritis (KneeOA) and MDD, and KneeOA and SCZ. Pleiotropy analysis using PLACO, MAGMA, and multitrait colocalization Hyprcoloc identified 65 pleiotropic loci, 27 shared causal loci, and 9 shared risk loci involving immune cells related to both psychiatric and bone-related diseases. Additionally, tissue-specific enrichment analysis showed that genes mapped to these loci were enriched in brain, cardiovascular, pancreatic, and other tissues. The IVW method demonstrated that MDD increased the risk of IVDD and KneeOA, while IVDD increased the risk of ANX and MDD. Conversely, SCZ was associated with a reduced risk of KneeOA. Multiple sensitivity analyses further supported a positive causal effect of IVDD on MDD. CONCLUSION: These findings suggest significant genetic correlations between skeletal degenerative diseases and psychiatric disorders, highlighting multiple shared comorbid genes and key immune cell types. Importantly, the study supports the role of the brain-bone axis in the regulation of skeletal degenerative diseases and psychiatric disorders, which could provide valuable insights for potential therapeutic targets and interventions for these conditions.

Humans