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PubMed2025

Psychiatric Polygenic Risk Scores and Week-by-Week Symptomatic Status in Youth with Bipolar Disorder: An Exploratory Study.

Introduction: Prior studies have demonstrated that, in both adults and youth, bipolar disorder (BD) is a polygenic illness. However, no studies have examined polygenic risk scores (PRSs) in relation to the longitudinal course of mood symptoms in youth with BD. Methods: This study included 246 youth of European ancestry with BD (7-20 years old at intake) from the Course and Outcome of Bipolar Youth study and Centre for Youth Bipolar Disorder. Mood symptom severity was assessed at intake and, for 168 participants, prospectively for a median of 8.7 years. PRSs for BD, schizophrenia (SCZ), major depressive disorder (MDD), and attention-deficit/hyperactivity disorder (ADHD) were constructed using genome-wide summary statistics from independent adult cohorts. Results: Higher BD-PRS was significantly associated with lower most severe lifetime depression score at intake (β = -0.14, p = 0.03). Higher SCZ-PRS and MDD-PRS were associated with significantly less time spent in euthymia (SCZ-PRS: β = -0.21, p = 0.02; MDD-PRS: β = -0.22, p = 0.01) and more time with any subsyndromal mood symptoms (i.e., any mania, mixed, or depression symptoms; SCZ-PRS: β = 0.15, p = 0.04; MDD-PRS: β = 0.17, p = 0.01) during follow-up. PRSs for BD and ADHD were not significantly associated with any longitudinal mood variable. Conclusions: This exploratory analysis was the first to examine psychiatric PRSs in relation to the prospective course of mood symptoms among youth with BD. Results from the current study can serve to guide future youth BD studies with larger sample sizes on this topic.

Humans↗

PubMed2025

The relationship between major depression, attention-deficit hyperactivity disorder and coronary artery disease: A two-sample Mendelian randomization analysis.

Coronary artery disease (CAD) constitutes a principal cause of global morbidity and mortality. Studies imply a connection between mental health disorders, especially major depression (MD) and attention-deficit hyperactivity disorder (ADHD), and the risk of CAD. To investigate the causal influence of genetic susceptibility to MD and attention-deficit/hyperactivity disorder (ADHD) on the risk of CAD, summary-level data from genome-wide association studies involving individuals of European descent were utilized. This analysis identified 11 single-nucleotide polymorphisms (SNPs) associated with MD, 60 SNPs linked to ADHD, and 10 SNPs related to CAD as instrumental variables. The inverse variance weighted method was employed for causal estimation, complemented by sensitivity analyses using MR-Egger regression and the weighted median estimator. A positive causal relationship was identified between MD, attention-deficit/hyperactivity disorder (ADHD), and the risk of CAD [MD: Odds Ratio (OR): 42.66, 95% Confidence Interval (CI): 7.55-241.2; ADHD: OR: 1.055, 95% CI: 1.006-1.106]. No significant causal association was observed between obesity and ADHD. In the multivariable Mendelian randomization (MVMR) analysis, the causal effect of ADHD on CAD was found to be diminished (OR: 1.005, 95% CI: 0.998-1.020), while the impact of body mass index on CAD remained stable (OR: 1.557, 95% CI: 1.459-1.661). This Mendelian randomization study reveals the lack of a consistent association among MD, ADHD, and CAD, suggesting a causal relationship and bidirectional effects between ADHD and obesity.

Humans↗

PubMed1995

Comparison of diagnostic criteria for attention deficit disorders in a German elementary school sample.

OBJECTIVE: This study compares teacher-reported prevalence rates for disruptive behavior disorders using DSM-IV, DSM-III-R, and DSM-III criteria within the same population of elementary school students and examines the relationships between DSM "subtypes" and academic performance, perceived behavior problems, and demographic variables. METHOD: Teacher rating scales were obtained on 1,077 students in five rural and five urban public schools in Regensburg, Germany. Rating scales included DSM-III-R items (attention-deficit hyperactivity disorder, oppositional defiant disorder, conduct disorder), DSM-IV items (attention-deficit/hyperactivity disorders [AD/HDs], oppositional defiant disorder), and DSM-III items (attention deficit disorder, with and without hyperactivity). Factor analyses of significance were performed. RESULTS: Overall prevalence for attention deficit disorders increased from 9.6% (DSM-III) to 17.8% (DSM-IV) primarily because of new cases identified as AD/HD-AD (inattentive type) and to a lesser degree, AD/HD-HI (hyperactive-impulsive type). Inattention in any subtype was associated with academic problems, and perceived behavior problems were associated with more than 80% of the cases that included hyperactivity-impulsivity. DSM-IV AD/HD subtypes showed significant behavioral, academic, and demographic differences. CONCLUSION: Application of DSM-IV criteria increased total AD/HD prevalence rates by 64% and identified the majority of children with academic and/or behavioral dysfunction. The data show significant heterogeneity between the subtypes and imply that many children screened into these subtypes require further evaluation to ensure appropriate management.

Achievement↗

PubMed2026

Causal Relationship of Polyunsaturated Fatty Acids With Mental Disorders: A Systematic Review and Meta-analysis.

CONTEXT: Mental disorders (MDs) pose a important global health challenge, with a complex pathogenesis complicating treatment development. Nutritional interventions, particularly polyunsaturated fatty acids (PUFAs), have gained attention as potential therapeutic options. OBJECTIVE: This Mendelian randomization (MR) meta-analysis aimed to evaluate the potential causal relationship between PUFAs and MDs. DATA SOURCES: Genome-wide association study data were utilized to analyze the association between PUFAs (including omega-3, omega-3 percentage [omega-3%], omega-6, omega-6 percentage [omega-6%], and omega-6 to omega-3 ratio) and 12 major MDs. DATA EXTRACTION: Two-sample MR technology was used to assess the role of PUFAs in MDs. DATA ANALYSIS: The MR analysis revealed that genetically predicted omega-3 was causally linked to MDs, such as obsessive-compulsive disorder, bipolar disorder, schizophrenia, and major depressive disorder. Omega-3% exhibited protective effects against emotional personality disorder. Conversely, omega-6 was inversely correlated with attention-deficit/hyperactivity disorder risk, while a high omega-6 to omega-3 ratio was associated with an increased risk of depression and other mood disorders. CONCLUSION: High omega-3 levels and omega-3% may reduce the risk of MDs, whereas a high omega-6:omega-3 ratio may elevate the risk. These findings highlight the potential of PUFAs, particularly omega-3, in MD prevention and treatment, while underscoring the need for further research into the complex interactions between omega-3 and omega-6. The study provides a scientific foundation for future clinical trials and dietary intervention strategies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO no. CRD42024598472.

Humans↗

PubMed1995

Attention-deficit hyperactivity disorder: a longitudinal case study of handwriting characteristics.

This longitudinal case study focuses on handwriting samples of a female diagnosed with Attention-Deficit/Hyperactivity Disorder from 12 years of age to 21 years of age. Diaries and journals produced for class assignments and later for this research yielded 293 handwriting samples. 15 characteristics of handwriting were measured and statistically analyzed to follow changes in handwriting across time. At seven years of age while in elementary school the subject was diagnosed with ADHD and placed on Ritalin (methylphenidate). At puberty the drug was discontinued. During two summers she visited grandparents, once alone and once with two sisters with whom she was in conflict. Her handwriting deviated from its pattern of general decrease in size and increase in uniformity during these visits. The changes over time of three handwriting characteristics (slant of "l," heights and areas of the lower loop of the "g," and area of the left loop of the "I") also deviated from the general pattern of her handwriting change.

Adult↗

PubMed2026

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 = 1 026 690) and 10 major psychiatric disorders (n = 14 307-1 222 882), 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↗

PubMed2026

Metabolomic ageing across mental and behavioural disorders.

BACKGROUND: Individuals with mental disorders face excess morbidity and premature mortality. Accelerated ageing has been proposed as a contributing mechanism but population-scale evidence across diverse diagnoses is limited. OBJECTIVE: To examine whether metabolomic ageing differs across mental disorders and whether associations vary by sex, age group and genetic liability. METHODS: Using plasma metabolomic profiles from UK Biobank participants, we applied a metabolomic ageing clock (MileAge) to estimate disorder-specific differences between metabolite-predicted and chronological age. Mental disorders were ascertained from health records and self-reported physician diagnoses. We analysed nine diagnostic groups and 45 individual disorders and assessed sex and age group differences and associations with polygenic scores. FINDINGS: Among 225 212 participants (54% female; mean age 56.97), 38 524 had a diagnosis preceding baseline. Substance use, psychotic, affective and neurotic disorders were associated with a metabolite-predicted age older than chronological age, largest for psychosis (β=0.556, 95% CI 0.250 to 0.861, p<0.001). Obsessive-compulsive and eating disorders were associated with a metabolite-predicted age younger than chronological age. Several associations were stronger in males and in individuals aged <65 years. Higher genetic liability to depression, autism and attention-deficit/hyperactivity disorder predicted an older metabolomic age (β range=0.020 to 0.047), whereas polygenic scores for psychosis and tobacco use disorder predicted a younger metabolomic age (β range=-0.023 to -0.040). For obsessive-compulsive disorder and anorexia nervosa, clinical and genetic associations indicated younger metabolomic ageing. CONCLUSIONS: Metabolomic ageing in mental disorders is heterogeneous. While many disorders are associated with an older biological age, some are linked to a younger biological age. Divergence between genetic liability and clinical phenotypes suggests that non-genetic factors shape biological ageing differences. CLINICAL IMPLICATIONS: Biological age should not be assumed to uniformly exceed chronological age across mental disorders. Sex and age-specific approaches could improve understanding of biological ageing processes in psychiatry.

Humans↗

PubMed2026

[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↗

PubMed2026

Atomoxetine Versus Placebo for Cognitive Deficits in Stimulant Use Disorder: A Systematic Review.

BACKGROUND: Stimulant use disorder (StUD), particularly involving cocaine and amphetamines, is associated with significant cognitive impairments that impede recovery and increase relapse risk. Atomoxetine, a selective norepinephrine reuptake inhibitor, has been proposed as a potential treatment given its role in enhancing executive function and its established efficacy in attention-deficit/hyperactivity disorder (ADHD). This systematic review aimed to evaluate the efficacy, cognitive, and mood effects of atomoxetine compared with placebo in individuals with StUD. METHODS: A comprehensive literature search of PubMed, Cochrane CENTRAL, and Embase databases was conducted to identify randomized controlled trials (RCTs) evaluating atomoxetine for StUD. Eligible studies compared atomoxetine with placebo and assessed outcomes related to cognition (attention and response inhibition), stimulant use or abstinence, mood symptoms, and safety. Data were extracted and synthesized qualitatively due to methodological heterogeneity across studies. RESULTS: Nine RCTs met the inclusion criteria. Findings on cognitive outcomes were inconsistent: Some studies reported improvements in attentional bias and inhibitory control, while others showed no significant effects. Atomoxetine did not significantly reduce stimulant use, craving, or sustain abstinence compared with placebo. Limited mood-related benefits were observed, particularly among male participants, although results were variable. Across studies, atomoxetine was well tolerated, with most adverse events mild and transient. CONCLUSION: Despite a compelling neurobiological rationale and evidence of modest cognitive and mood benefits, atomoxetine has not demonstrated consistent efficacy as a monotherapy for StUD. Its favorable safety profile may warrant further investigation in carefully defined populations, such as individuals with comorbid ADHD or in combination with behavioral interventions.

Atomoxetine Hydrochloride↗

PubMed1996

The relationship of HIV status, type of coagulation disorder, and school absenteeism to cognition, educational performance, mood, and behavior of boys with hemophilia.

Psychological and educational data were analyzed for all school-aged males with hemophilia at the Hemophilia Center of Central Pennsylvania (N = 66). Mean IQ (113.5) was higher than normal, and 2.4 times as many boys with hemophilia were enrolled in gifted programming than is the state average for boys. However, there was a disproportionately high prevalence of attention-deficit/hyperactivity disorder (ADHD; 28.3%), learning disability (LD; 15.8%), and graphomotor weakness. These were not significantly associated with HIV status or type and severity of coagulation disorder. School absenteeism was high but was not significantly related to academic achievement, IQ/achievement discrepancy, need for educational intervention, or diagnosis of ADHD or LD.

Absenteeism↗

PubMed2025

Associations of Genetic Liability to Six Psychiatric Disorders With Cardiometabolic Diseases.

IMPORTANCE: Individuals with psychiatric disorders have increased risk of cardiometabolic diseases (CMDs). Evaluating how psychiatric genetic liability relates to CMD may clarify mechanisms. OBJECTIVE: Identify genetic overlap between psychiatric disorders and CMDs independent of cross-disorder pleiotropy, BMI, and smoking. DESIGN SETTING AND PARTICIPANTS: Three Northern European cohorts (the Swedish Twin Registry, the Estonian Biobank, and the Norwegian Mother, Father and Child Cohort Study [MoBa]) totaling 355,159 individuals. Associations with CMDs were estimated as adjusted odds ratios (AORs) from logistic models mutually adjusted for all psychiatric PRSs and in models additionally adjusting for body mass index (BMI) and smoking. Cohort-specific AORs were pooled by inverse-variance weighting. MAIN OUTCOMES AND MEASURES: Exposures were PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), anxiety disorder, posttraumatic stress disorder (PTSD), bipolar disorder, and schizophrenia. Outcomes were diagnoses of CMDs (hyperlipidemia, obesity, type 2 diabetes, hypertensive diseases, arteriosclerosis, ischemic heart disease, heart failure, thromboembolic disease, cerebrovascular disease, and arrhythmias), ascertained from electronic health records. RESULTS: The MDD PRS was associated with increased risk of all CMDs across analyses (AORs ranged from 1.13 [95% CI, 1.10-1.15] for heart failure to 1.02 [95% CI, 1.00-1.05] for arrhythmias). The ADHD PRS was associated with increased risk of all CMDs (AOR ranged from 1.11 [95% CI, 1.09-1.12] for obesity to 1.02 [95% CI, 1.01-1.03] for hyperlipidemia), however associations where attenuated when adjusting for BMI and smoking (lifestyle adjusted AOR for obesity: 1.03 [95% CI, 1.02-1.05]). When not mutually adjusting for all psychiatric PRSs, anxiety disorder and PTSD PRSs were associated with all CMDs; these associations diminished after adjustment. The bipolar and schizophrenia PRSs were inversely associated with most CMDs (AOR for schizophrenia PRS and obesity, 0.93 [95% CI, 0.92-0.94]). CONCLUSIONS AND RELEVANCE: Associations between psychiatric PRSs and CMDs diverged: ADHD, MDD, anxiety disorder, and PTSD PRSs were positively associated with CMDs, whereas bipolar and schizophrenia PRSs were inversely associated. Genetic liability to MDD showed robust associations with CMDs independent of cross-disorder pleiotropy, BMI, and smoking status, whereas associations between the ADHD PRS and CMDs were largely attenuated after adjustment for BMI and smoking.

Journal Article↗

PubMed2026

Unravelling sex differences in the genetic architecture of anxiety.

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.

Female↗

PubMed2025

Polygenic and developmental profiles of autism differ by age at diagnosis.

Although autism has been historically conceptualised as a condition that emerges in early childhood, many autistic people are diagnosed later in life. It is unknown whether earlier and later diagnosed autism have different developmental trajectories and genetic profiles. Using longitudinal data from four independent birth cohorts, we demonstrate that two different socioemotional and behavioural trajectories are associated with age at diagnosis. In independent cohorts of autistic individuals, common genetic variants account for approximately 11% of the variance in age at autism diagnosis, comparable to the contribution of individual sociodemographic and clinical factors, which typically explain less than 15% of this variance. We further demonstrate that the polygenic architecture of autism can be decomposed into two modestly genetically correlated (rg = 0.38, SE = 0.07) autism polygenic factors. One of these factors is associated with earlier autism diagnosis, and lower social and communication abilities in early childhood but is only modestly genetically correlated with ADHD and mental health conditions. Conversely, the second factor is associated with later autism diagnosis, increased socioemotional and behavioural difficulties in adolescence, and has moderate to high positive genetic correlations with Attention-Deficit/Hyperactivity Disorder and mental health conditions. These findings indicate that earlier and later diagnosed autism have different developmental trajectories and genetic profiles. Our findings have important implications for how we conceptualise autism and provide one model to explain some of the diversity within autism.

Journal Article↗

PubMed2026

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 ≥180 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% 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% CI 1.30 to 1.55), and in adults, schizophrenia (HR 1.25, 95% CI 1.09 to 1.44) and tic disorders (HR 1.27, 95% 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↗

PubMed1996

The effects of auditory stimulation on the arithmetic performance of children with ADHD and nondisabled children.

This study evaluated the impact of extra-task stimulation on the academic task performance of children with attention-deficit/hyperactivity disorder (ADHD). Twenty boys with ADHD and 20 nondisabled boys worked on an arithmetic task during high stimulation (music), low stimulation (speech), and no stimulation (silence). The music "distractors" were individualized for each child, and the arithmetic problems were at each child's ability level. A significant Group x Condition interaction was found for number of correct answers. Specifically, the nondisabled youngsters performed similarly under all three auditory conditions. In contrast, the children with ADHD did significantly better under the music condition than speech or silence conditions. However, a significant Group x Order interaction indicated that arithmetic performance was enhanced only for those children with ADHD who received music as the first condition. The facilitative effects of salient auditory stimulation on the arithmetic performance of the children with ADHD provide some support for the underarousal/optimal stimulation theory of ADHD.

Acoustic Stimulation↗

PubMed2026

Shared genetic architecture between ADHD and intelligence varies across ADHD subtypes.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental condition frequently accompanied by cognitive difficulties. Although previous genetic studies have demonstrated substantial overlap between ADHD and intelligence, most have treated ADHD as a single phenotype. However, whether this shared genetic architecture differs across ADHD subtypes remains unclear. METHODS: We conducted a genome-wide cross-trait analysis integrating large-scale genome-wide association study (GWAS) datasets of overall ADHD, its subtypes-childhood ADHD, persistent ADHD, and late-diagnosed ADHD-and intelligence (total N > 300,000). Genome-wide genetic correlations, polygenic overlap, local genetic correlations, and variant-level associations between ADHD phenotypes and intelligence were evaluated to characterize their shared genetic architecture. Shared variants were identified through cross-trait enrichment analyses and subsequently mapped to genes for functional annotation and gene-set enrichment. Bidirectional associations were evaluated using two-sample Mendelian randomization with sensitivity analyses. Additional GWAS datasets were used to validate the robustness of shared loci by assessing the consistency of effect directions. RESULTS: All ADHD phenotypes showed significant negative genetic correlations with intelligence (rg ranging from -0.3442 to -0.4205). Despite these modest genome-wide correlations, cross-trait analyses revealed substantial genetic overlap, including polygenic overlap, local genetic correlations, and variant-level associations. We identified 184 loci jointly associated with ADHD traits and intelligence, including 64 novel loci, whereas no shared loci were detected for persistent ADHD under the current analysis. Functional annotation revealed biologically distinct enrichment patterns across subtypes: childhood ADHD loci were linked to early neurodevelopmental processes, while late-diagnosed ADHD loci were enriched in synapse-related and neuronal signaling pathways. Mendelian randomization analyses suggested bidirectional associations, with stronger evidence supporting a directional association from intelligence to ADHD risk. Furthermore, these shared loci showed largely consistent effect directions across additional GWAS datasets, providing support for the robustness of the findings. CONCLUSIONS: The shared genetic architecture between ADHD and intelligence varies across ADHD subtypes, highlighting distinct biological pathways underlying cognitive heterogeneity in ADHD. These findings suggest that the relationship between ADHD liability and general cognitive ability is not uniform across ADHD subtypes and may inform future research on risk stratification and early identification in child and adolescent psychiatry.

Humans↗

PubMed1995

Developmental right-hemisphere syndrome: clinical spectrum of the nonverbal learning disability.

We report the clinical characteristics of the developmental right-hemisphere syndrome (DRHS), a nonverbal learning disability, in 20 children (9 girls and 11 boys; mean age = 9.5 years) who also manifested attention-deficit/hyperactivity disorder (ADHD), severe graphomotor problems, and marked slowness of performance. Diagnostic criteria for this study included (a) emotional and interpersonal difficulties; (b) paralinguistic communication problems; (c) impaired visuospatial skills, verbal IQ > performance IQ, and verbal IQ > or = 85; and either (d) dyscalculia or (e) neurological signs on the left side of the body. In this group, verbal IQ was significantly higher than performance IQ (106.6 +/- 13.0 vs. 85.1 +/- 13.1, respectively, p < .01). Arithmetic was the lowest score among the verbal subtests (7.8 +/- 3.5, p < .01) and Geometrical Design was the lowest score among the performance subtests (5.8 +/- 1.7). Thirteen children had soft neurological signs on the left side of the body. ADHD was seen in all 20 children, marked slowness of performance in 16, and severe graphomotor problems in 18. The latter two features have not been previously described as part of DRHS.

Adolescent↗

PubMed1996

Methylphenidate augmentation of serotonin selective reuptake inhibitors: a case series.

BACKGROUND: The serotonin selective reuptake inhibitors (SSRIs) are effective in treating major depressive episodes. However, for the subgroups of patients who remain refractory to therapy, augmentation strategies can improve the efficacy of these agents. METHOD: We report the results of an open trial of methylphenidate to augment SSRIs in the treatment of five consecutive cases of DSM-III- R diagnosed major depression. RESULTS: Self-reported symptom reduction was achieved rapidly in all cases, with methylphenidate dosages ranging from 10 to 40 mg/day. Symptom remission was independent of the presence of attention-deficit/hyperactivity disorder. Also, the beneficial effects of the methylphenidate-SSRI combination appeared to be robust and sustained. No patients abused or misused methylphenidate. CONCLUSION: The empirical use of methylphenidate added to ineffective or only partially effective SSRI treatment appeared to be a rapid, safe, and efficacious alternative to existing augmentation strategies for the treatment of major depression. Prospective controlled studies are required to confirm or refute these findings.

Adult↗