Publications by authors named "Stephen V Faraone"

825 Publications

Alcohol use disorders and ADHD.

Neurosci Biobehav Rev 2021 Jul 12;128:648-660. Epub 2021 Jul 12.

Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Frankfurt, Frankfurt am Main, Germany.

Despite a growing literature on the complex bidirectional relationship of ADHD and substance use, reviews specifically focusing on alcohol are scarce. ADHD and AUD show a significant genetic overlap, including genes involved in gluatamatergic and catecholaminergic neurotransmission. ADHD drives risky behavior and negative experiences throughout the lifespan that subsequently enhance a genetically increased risk for Alcohol Use Disorders (AUD). Impulsive decisions and a maladaptive reward system make individuals with ADHD vulnerable for alcohol use and up to 43 % develop an AUD; in adults with AUD, ADHD occurs in about 20 %, but is vastly under-recognized and under-treated. Thus, routine screening and treatment procedures need to be implemented in AUD treatment. Long-acting stimulants or non-stimulants can be used to treat ADHD in individuals with AUD. However, it is crucial to combine medical treatment for ADHD with pharmacotherapy and psychotherapy for AUD, and other comorbid disorders. Identification of individuals at risk for AUD, especially those with ADHD and conduct disorder or oppositional defiant disorder, is a key factor to prevent negative outcomes.
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http://dx.doi.org/10.1016/j.neubiorev.2021.07.010DOI Listing
July 2021

Mapping phenotypic and aetiological associations between ADHD and physical conditions in adulthood in Sweden: a genetically informed register study.

Lancet Psychiatry 2021 Jul 6. Epub 2021 Jul 6.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; School of Medical Sciences, Örebro University, Örebro, Sweden.

Background: Emerging evidence suggests increased risk of several physical health conditions in people with ADHD. Only a few physical conditions have been thoroughly studied in relation to ADHD, and there is little knowledge on associations in older adults in particular. We aimed to investigate the phenotypic and aetiological associations between ADHD and a wide range of physical health conditions across adulthood.

Methods: We did a register study in Sweden and identified full-sibling and maternal half-sibling pairs born between Jan 1, 1932, and Dec 31, 1995, through the Population and Multi-Generation Registers. We excluded individuals who died or emigrated before Jan 1, 2005, and included full-siblings who were not twins and did not have half-siblings. ICD diagnoses were obtained from the National Patient Register. We extracted ICD diagnoses for physical conditions, when participants were aged 18 years or older, from inpatient (recorded 1973-2013) and outpatient (recorded 2001-13) services. Diagnoses were regarded as lifetime presence or absence. Logistic regression models were used to estimate the associations between ADHD (exposure) and 35 physical conditions (outcomes) in individuals and across sibling pairs. Quantitative genetic modelling was used to estimate the extent to which genetic and environmental factors accounted for the associations with ADHD.

Findings: 4 789 799 individuals were identified (2 449 146 [51%] men and 2 340 653 [49%] women), who formed 4 288 451 unique sibling pairs (3 819 207 full-sibling pairs and 469 244 maternal half-sibling pairs) and 1 841 303 family clusters (siblings, parents, cousins, spouses). The mean age at end of follow-up was 47 years (range 18-81; mean birth year 1966); ethnicity data were not available. Adults with ADHD had increased risk for most physical conditions (34 [97%] of 35) compared with adults without ADHD; the strongest associations were with nervous system disorders (eg, sleep disorders, epilepsy, dementia; odds ratios [ORs] 1·50-4·62) and respiratory diseases (eg, asthma, chronic obstructive pulmonary disease; ORs 2·42-3·24). Sex-stratified analyses showed similar patterns of results in men and women. Stronger cross-disorder associations were found between full-siblings than between half-siblings for nervous system, respiratory, musculoskeletal, and metabolic diseases (p<0·007). Quantitative genetic modelling showed that these associations were largely explained by shared genetic factors (60-69% of correlations), except for associations with nervous system disorders, which were mainly explained by non-shared environmental factors.

Interpretation: This mapping of aetiological sources of cross-disorder overlap can guide future research aiming to identify specific mechanisms contributing to risk of physical conditions in people with ADHD, which could ultimately inform preventive and lifestyle intervention efforts. Our findings highlight the importance of assessing the presence of physical conditions in patients with ADHD.

Funding: Swedish Research Council; Swedish Brain Foundation; Swedish Research Council for Health, Working Life, and Welfare; Stockholm County Council; StratNeuro; EU Horizon 2020 research and innovation programme; National Institute of Mental Health.
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http://dx.doi.org/10.1016/S2215-0366(21)00171-1DOI Listing
July 2021

A Placebo-Controlled Trial of Lisdexamfetamine in the Treatment of Comorbid Sluggish Cognitive Tempo and Adult ADHD.

J Clin Psychiatry 2021 Jun 29;82(4). Epub 2021 Jun 29.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York.

To examine the efficacy of lisdexamfetamine (LDX) versus placebo on behavioral attributes of sluggish cognitive tempo (SCT) in adults with attention-deficit/hyperactivity disorder (ADHD) and SCT.

In a randomized crossover trial conducted January 2016-April 2018, 38 adults with ADHD (via the Adult ADHD Clinical Diagnostic Scale v1.2) and SCT were recruited at 2 academic medical centers and assessed for symptoms of ADHD, SCT, executive function deficits, and functional impairment at baseline and weekly during treatment. Participants received 4 weeks of treatment with either LDX (30-70 mg/d; mean = 59.1 ± 14.8 mg/d) or matching placebo (mean = 66.6 ± 9.1 mg/d) with a 2-week washout before switching to the other arm. The ADHD Rating Scale and Barkley Adult ADHD Rating Scale-IV SCT subscale were coprimary outcome measures.

There were moderately large treatment effects of LDX vs placebo on SCT ratings in both treatment periods (block 1 effect size = 0.68; block 2 effect size = 0.61), which reached significance only in block 1 owing to carryover effects of the first treatment epoch into the second. Significant effects were also seen for LDX over placebo in ADHD, executive function deficit, and functional impairment ratings, without order effects; no site differences were seen except on the Global Executive Complex score of the Behavior Rating Inventory of Executive Function-Adult Version. No moderating effects of sex, age, race, and ethnicity were seen.

Adults with ADHD and comorbid SCT had significant improvement after LDX vs placebo in ratings of SCT, ADHD, executive function deficits, and functional impairment. This is the first study to show improvement in SCT after stimulant therapy in adults with ADHD.

ClinicalTrials.gov identifier: NCT02635035.
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http://dx.doi.org/10.4088/JCP.20m13687DOI Listing
June 2021

Prescription Stimulant Misuse and Abuse: Characterization of Exposures Managed by United States (US) Poison Centers.

CNS Spectr 2021 04;26(2):166

Syracuse University, Syracuse, NY, USA.

The National Poison Data System (NPDS), is the data warehouse for the 55 US regional poison centers. While the primary role of a poison center is to provide medical management to the public and healthcare providers, a standardized database is used to collect case data. These data are routinely used to evaluate drug safety, including characterization of prescription medication misuse and abuse. While an effective therapy for attention deficit/hyperactivity disorder (ADHD), prescription stimulant medications (RxStim) may be misused and abused, a behavior that has been noted as an emerging public health concern particularly in relation to polysubstance abuse. The objective of this study was to characterize intentional exposures to RxStim in patients age >12 y of age as managed by US poison centers from Jan 2015- 31 Dec 2019.NPDS cases of intentional exposure to a RxStim in a patient >12 y managed from Jan 2015-Dec 2019 were included for analysis. Intentional exposures are defined in the NPDS manual as exposures that involve a purposeful action. These include intentional misuse, intentional abuse and intentional unknown cases. Intentional suspected suicide cases were excluded.A total of 12,972 cases met inclusion criteria, of which 62.5% involved a male patient. Most patients were aged 13-19 y (34.7%) or 20-39 y (50.5%). Over one-half (53.3%) of cases were intentional abuse, 29.1% intentional misuse, and 17.6% intentional unknown. While most exposures were via oral route of administration (90.7%), 9.5% were via inhalation/intranasal and 2.4% via injection (multiple routes may be reported). Other substances in addition to a RxStim were involved in 48.2% of cases, including benzodiazepines (11.2%), alcohol (8.8%), marijuana (5.1%), cocaine (3.7%), methamphetamine (3.0%) and atypical antipsychotics (2.5%). The majority of cases resulted in significant medical outcome (60.3%). This included 39.3% with a moderate effect (medical attention indicated, not life-threatening), 6.1% major effect (life-threatening), 1.0% death and 14.0% lost to follow-up but judged as a potentially toxic exposure. Another 22.4% reported minimally bothersome effects. Admission to a healthcare facility was reported for 1 out of 3 cases and another 36.3% were treated/evaluated/released from a healthcare service. An average of 2.3 clinical effects were reported per exposure, the most common being neurological effects (53.2%; examples include agitation, drowsiness/lethargy, confusion, hallucinations/delusions, tremor), cardiovascular effects (50.8%; examples include tachycardia, hypertension), and gastrointestinal effects (9.4%; examples include vomiting, nausea).RxStim misuse and abuse cases managed by US poison centers most often leads to significant medical outcomes which require medical attention. The role of these medications in polysubstance abuse is concerning and suggestive of needed strategies to address this increasingly important public health concern.Funding: Arbor Pharmaceuticals, LLC.
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http://dx.doi.org/10.1017/S1092852920002680DOI Listing
April 2021

Substance Use Trajectories: Nonmedical Use (NMU) of Prescription Stimulants via Non-Oral Routes of Administration Among Adults Recruited from Reddit.

CNS Spectr 2021 04;26(2):166-167

Syracuse University, Syracuse, NY, USA.

NMU of prescription stimulant medications (RxStim) intended for treatment of attention deficit/hyperactivity disorder (ADHD) is a growing public health concern, particularly when used via non-oral routes of administration. However, the role of non-oral routes of administration for RxStim NMU in the larger substance abuse pathway is less well studied. The purpose of this study was to characterize RxStim NMU and investigate substance use trajectories among adults who reported non-oral RxStim NMU recruited from Reddit.Eligible participants must have been located in the US, English speaking, age 18 y, and have reported RxStim NMU via a non-oral route (any route other than ingestion) within the past 5 y. Participants were recruited from Feb-Sep 2019 using banner ads on Reddit, the 5th most visited website in the US. Participants completed an online survey which captured demographics, lifetime RxStim NMU and illicit substance use; they were compensated for their time. For purposes of this study, NMU included ANY of the following: (1) use for any reason, even once, without their own prescription, (2) use in ways other than prescribed, and (3) use for the feeling or experience the medication caused.Respondents (n=225) were primarily male (86.2%), 18-24 (48.0%) or 25-34 (43.1%) years of age, and Caucasian (78.2%), Black (7.1%) or Hispanic (5.3%). Lifetime diagnosis of ADHD was reported by 27.6%, with 53.2% diagnosed at age 11-19 and 35.5% at age 20+ years. RxStim NMU via snorting was reported by 99.1%, smoking 3.6% and injecting 6.2% (multiple routes could be reported). Almost all (n=222; 98.7%) also reported lifetime illicit drug use, among whom 182 (82.0%) initiated substance use by using an illicit drug (77.9% marijuana, 1.8% cocaine/crack, 0.9% inhalants, 0.9% hallucinogens, 0.5% methamphetamine/amphetamines) prior to RxStim NMU. Forty (18.0%) respondents initiated with RxStim NMU; 14.4% then initiated marijuana use, 0.9% initiated cocaine/crack use, 0.9% initiated barbiturate use, and 0.5% initiated heroin, inhalant, methamphetamine/amphetamine, and hallucinogen use. Average age of initial RxStim NMU was 18.7 (SD 3.7) years and most often was via swallowing (89.1%) followed by snorting (10.9%). Respondents began using marijuana at age 15.9 (SD 2.5), cocaine or crack at 19.7 (SD 3.3), and heroin at 20.9 (SD 5.5).Engagement in RxStim NMU via a non-oral route of administration is most often preceded by marijuana use. Among this Reddit-recruited population of non-oral RxStim nonmedical users, only 1 in 4 reported an ADHD diagnosis and <1 in 5 reported RxStim NMU as their first substance use experience; most of these then added marijuana and few moved toward cocaine/crack or methamphetamine. RxStim NMU via non-oral routes is associated with a larger pattern of risky substance use behaviors. Nearly all non-oral RxStim NMU is associated with concomitant drug use, especially marijuana.Funding. Arbor Pharmaceuticals, LLC.
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http://dx.doi.org/10.1017/S1092852920002692DOI Listing
April 2021

Clinically Meaningful Improvements in Early Morning and Late Afternoon/Evening Functional Impairment in Children with ADHD Treated with Delayed-Release and Extended-Release Methylphenidate.

J Atten Disord 2021 Jun 4:10870547211020073. Epub 2021 Jun 4.

Mount Sinai Medical Center, New York, NY, USA.

Objective: The Before School Functioning Questionnaire and Parent Rating of Evening and Morning Behavior-Revised assess early morning (BSFQ, PREMB-R AM subscale) and late afternoon/evening (PREMB-R PM subscale) functional impairment in children with ADHD. Clinically meaningful improvements were identified and applied to a trial of delayed-release and extended-release methylphenidate (DR/ER-MPH) in children with ADHD (NCT02520388) to determine if the statistically-determined improvements in functional impairment were also clinically meaningful.

Method: Clinically meaningful improvements in BSFQ/PREMB-R were established post hoc by receiver operating characteristics curves, using anchors of Clinical Global Impression-Improvement (CGI-I) = 1 and CGI-I ≤ 2. Percentages of participants achieving these thresholds were calculated.

Results: Thresholds for CGI-I = 1/CGI-I ≤ 2, respectively, were 27/20 (BSFQ), 5/3 (PREMB-R AM), and 9/5 (PREMB-R PM)-point decreases. More children achieved clinically meaningful improvements with DR/ER-MPH versus placebo (all  < .05).

Conclusion: DR/ER-MPH increased proportions of children achieving clinically meaningful improvements in BSFQ and PREMB-R.
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http://dx.doi.org/10.1177/10870547211020073DOI Listing
June 2021

A seq2seq model to forecast the COVID-19 cases, deaths and reproductive R numbers in US counties.

Res Sq 2021 Apr 26. Epub 2021 Apr 26.

The global pandemic of coronavirus disease 2019 (COVID-19) has killed almost two million people worldwide and over 400 thousand in the United States (US). As the pandemic evolves, informed policy-making and strategic resource allocation relies on accurate forecasts. To predict the spread of the virus within US counties, we curated an array of county-level demographic and COVID-19-relevant health risk factors. In combination with the county-level case and death numbers curated by John Hopkins university, we developed a forecasting model using deep learning (DL). We implemented an autoencoder-based Seq2Seq model with gated recurrent units (GRUs) in the deep recurrent layers. We trained the model to predict future incident cases, deaths and the reproductive number, . For most counties, it makes accurate predictions of new incident cases, deaths and R values, up to 30 days in the future. Our framework can also be used to predict other targets that are useful indices for policymaking, for example hospitalization or the occupancy of intensive care units. Our DL framework is publicly available on GitHub and can be adapted for other indices of the COVID-19 spread. We hope that our forecasts and model can help local governments in the continued fight against COVID-19.
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http://dx.doi.org/10.21203/rs.3.rs-456641/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132245PMC
April 2021

Placebo and nocebo responses in randomised, controlled trials of medications for ADHD: a systematic review and meta-analysis.

Mol Psychiatry 2021 May 10. Epub 2021 May 10.

Centre for Innovation in Mental Health, School of Psychology, Faculty of Environmental and Life sciences & Clinical and Experimental Sciences (CNS and Psychiatry), Faculty of Medicine, University of Southampton, Southampton, UK.

The nature and magnitude of placebo and nocebo responses to ADHD medications and the extent to which response to active medications and placebo are inter-correlated is unclear. To assess the magnitude of placebo and nocebo responses to ADHD and their association with active treatment response. We searched literature until June 26, 2019, for published/unpublished double-blind, randomised placebo-controlled trials (RCTs) of ADHD medication. Authors were contacted for additional data. We assessed placebo effects on efficacy and nocebo effects on tolerability using random effects meta-analysis. We assessed the association of study design and patient features with placebo/nocebo response. We analysed 128 RCTs (10,578 children/adolescents and 9175 adults) and found significant and heterogenous placebo effects for all efficacy outcomes, with no publication bias. The placebo effect was greatest for clinician compared with other raters. We found nocebo effects on tolerability outcomes. Efficacy outcomes from most raters showed significant positive correlations between the baseline to endpoint placebo effects and the baseline to endpoint drug effects. Placebo and nocebo effects did not differ among drugs. Baseline severity and type of rating scale influenced the findings. Shared non-specific factors influence response to both placebo and active medication. Although ADHD medications are superior to placebo, and placebo treatment in clinical practice is not feasible, clinicians should attempt to incorporate factors associated with placebo effects into clinical care. Future studies should explore how such effects influence response to medication treatment. Upon publication, data will be available in Mendeley Data: PROSPERO (CRD42019130292).
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http://dx.doi.org/10.1038/s41380-021-01134-wDOI Listing
May 2021

The child behavior checklist can aid in characterizing suspected comorbid psychopathology in clinically referred youth with ADHD.

J Psychiatr Res 2021 06 30;138:477-484. Epub 2021 Apr 30.

Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD, Massachusetts General Hospital, Boston, MA, USA; Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA.

Objective: To examine the utility of the Child Behavior Checklist (CBCL) to aid in the identification of comorbid psychopathological conditions affecting referred youth with suspected ADHD prior to the evaluation. The CBCL is an easy-to-use assessment tool that may provide invaluable information regarding the severity and characteristics of the presenting complaints.

Methods: The sample included 332 youths consecutively referred to an ADHD program for the assessment of suspected ADHD. Parents completed the CBCL, parent-rated ADHD Self-Report Scale (ASRS), Social Responsiveness Scale (SRS), and Behavior Rating Inventory of Executive Function (BRIEF). Because of the established association between the CBCL Attention Problems scale and a structured diagnostic interview of ADHD, all youths analyzed had abnormal Attention Problems T-scores (≥60).

Results: Seventy-six percent of youths with elevated Attention Problems T-scores had ≥3 additional abnormal CBCL scales, suggesting they were likely affected with multiple comorbid psychopathological conditions. Moreover, 44% had ≥1 CBCL clinical scale with a T-score more severe than their Attention Problems T-score, suggesting the putative comorbid condition was more severe than the ADHD symptoms. Additional CBCL scale elevations were associated with more severe functional impairments as assessed by the ASRS, SRS, BRIEF, and CBCL competence scales.

Conclusion: The CBCL obtained before the clinical assessment identified high rates of comorbid psychopathology in youths referred for the assessment of ADHD. It provided detailed information about the types and severity of suspected psychopathological conditions impacting a particular youth, which is critical to guide the assessing clinician on likely differing needs of the affected child.
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http://dx.doi.org/10.1016/j.jpsychires.2021.04.028DOI Listing
June 2021

A seq2seq model to forecast the COVID-19 cases, deaths and reproductive numbers in US counties.

medRxiv 2021 Apr 20. Epub 2021 Apr 20.

The global pandemic of coronavirus disease 2019 (COVID-19) has killed almost two million people worldwide and over 400 thousand in the United States (US). As the pandemic evolves, informed policy-making and strategic resource allocation relies on accurate forecasts. To predict the spread of the virus within US counties, we curated an array of county-level demographic and COVID-19-relevant health risk factors. In combination with the county-level case and death numbers curated by John Hopkins university, we developed a forecasting model using deep learning (DL). We implemented an autoencoder-based Seq2Seq model with gated recurrent units (GRUs) in the deep recurrent layers. We trained the model to predict future incident cases, deaths and the reproductive number, . For most counties, it makes accurate predictions of new incident cases, deaths and R values, up to 30 days in the future. Our framework can also be used to predict other targets that are useful indices for policymaking, for example hospitalization or the occupancy of intensive care units. Our DL framework is publicly available on GitHub and can be adapted for other indices of the COVID-19 spread. We hope that our forecasts and model can help local governments in the continued fight against COVID-19.
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http://dx.doi.org/10.1101/2021.04.14.21255507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077584PMC
April 2021

Long-Term Treatment With Extended-Release Methylphenidate Treatment in Children Aged 4 to <6 Years.

J Am Acad Child Adolesc Psychiatry 2021 Apr 20. Epub 2021 Apr 20.

Drs. Levinson and Adjei are currently retired. At the time of the study, Drs. Levinson and Adjei were with Rhodes Pharmaceuticals, Coventry, Rhode Island. Electronic address:

Objective: To investigate long-term (12-month) safety and symptom control of extended-release methylphenidate (MPH-MLR) in children aged 4 to <6 years after treatment optimization.

Method: A total of 90 children aged 4 to <6 years with attention-deficit/hyperactivity disorder (ADHD) were enrolled from 2 MPH-MLR studies. Treatment-emergent adverse events (TEAEs) and ADHD symptom control were assessed in the safety population (n = 89) and modeled with mixed model analyses.

Results: Most TEAEs (89.9%) were rated by investigators as of mild or moderate severity. One serious AE was reported (unrelated to study drug). Ten children discontinued because of TEAEs. Two discontinued because of weight loss; no significant increase in the rate of underweight children from baseline to endpoint was observed. Overall, 18% lost weight and 18% reported decreased appetite. Weight and height z scores and obesity rates decreased significantly from baseline to endpoint. Insomnia was reported (9%); none of these children discontinued. Sleep quality did not change significantly. Hypertension was reported (6.7%); none of these children dropped out. Diastolic, but not systolic, blood pressure increased significantly during the follow-up. Control of ADHD symptoms was maintained throughout follow-up.

Conclusion: These data contribute to the understanding of the long-term safety of an extended-release stimulant in children 4 to <6 years of age. The observed risk of a TEAE-related discontinuation was ∼11%. TEAEs were not dose related, and most were of mild to moderate severity. Symptom control was maintained through the year-long study.

Clinical Trial Registration Information: A 12-Month Open Label Safety Study of Aptensio XR® in Children Ages 4-5 Years Diagnosed With ADHD (EF004); https://clinicaltrials.gov; NCT02677519.
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http://dx.doi.org/10.1016/j.jaac.2021.03.019DOI Listing
April 2021

Characterizing the heterogeneous course of inattention and hyperactivity-impulsivity from childhood to young adulthood.

Eur Child Adolesc Psychiatry 2021 Apr 3. Epub 2021 Apr 3.

Department of Psychiatry, Interdisciplinary Center Psychopathology and Emotion Regulation (ICPE), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

To advance understanding of the heterogeneity in the course of ADHD, joint symptom trajectories of inattention and hyperactivity-impulsivity from childhood to young adulthood were modelled and associated with genetic, demographic, and clinical characteristics. Data were obtained from the NeuroIMAGE cohort which includes 485 individuals with ADHD, their 665 siblings, and 399 typically developing children. Trajectories were based on scores of the Conners Parent Rating Scale Revised and estimated over seven homogeneous age bins (from 5 to 28 years) using parallel process latent class growth analysis on data collected across 2-4 time points. Multilevel multinomial logistic regression was used to identify characteristics that differentiated between the derived classes. A seven-class solution revealed "severe combined stable" (4.8%), "severe combined decreasing" (13%), "severe inattentive stable" (4.8%), "moderate combined increasing" (7.5%), "moderate combined decreasing" (12.7%), "stable mild" (12.9%), and "stable low" (44.3%) classes. Polygenic risk for depression, ADHD diagnosis, ADHD medication use, IQ, comorbid symptom levels (foremost oppositional behaviour), and functional impairment levels differentiated classes with similar ADHD symptom levels in childhood but a diverging course thereafter. The course of ADHD is highly heterogeneous, with stable, decreasing, and increasing trajectories. Overall, severe symptom levels in childhood are associated with elevated-to-severe symptom levels in adolescence and young adulthood, despite substantial symptom reductions. Beyond symptom severity in childhood, genetic, demographic, and clinical characteristics distinguish the heterogeneous course.
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http://dx.doi.org/10.1007/s00787-021-01764-zDOI Listing
April 2021

Effect of Delayed-Release and Extended-Release Methylphenidate on Caregiver Strain and Validation of Psychometric Properties of the Caregiver Strain Questionnaire: Results from a Phase 3 Trial in Children with Attention-Deficit/Hyperactivity Disorder.

J Child Adolesc Psychopharmacol 2021 Apr 1;31(3):179-186. Epub 2021 Apr 1.

Ironshore Pharmaceuticals & Development, Inc., Camana Bay, Grand Cayman, Cayman Islands.

Inadequately controlled symptoms and associated impaired functioning have a significant negative impact on caregivers of children with attention-deficit/hyperactivity disorder (ADHD). This study aimed to assess the impact of evening-dosed, delayed-release and extended-release methylphenidate (DR/ER-MPH) treatment on caregiver strain, measured by the Caregiver Strain Questionnaire (CGSQ), and present psychometric analyses assessing the reliability and validity of the CGSQ, its ability to detect change (responsiveness), and to derive responder definitions. The CGSQ was an exploratory efficacy endpoint in a phase 3, 3-week, randomized, double-blind, multicenter, placebo-controlled, forced-dose titration trial of DR/ER-MPH in children aged 6-12 years with ADHD (NCT02520388). Psychometric properties of the CGSQ evaluated included internal consistency using Cronbach's alpha; test/retest reliability using intraclass correlation coefficients (ICCs); construct validity (known groups and convergent/divergent validity); responsiveness to changes in assessments of ADHD severity (ADHD Rating Scale-IV [ADHD-RS-IV], Conners' Global Index-Parent [CGI-P], and Clinical Global Impression-Severity [CGI-S]/CGI-Improvement [CGI-I]); and meaningful change threshold (MCT) using receiver operating characteristic curves, which were used to compare response between DR/ER-MPH and placebo groups. Randomized DR/ER-MPH (54.5) and placebo (54.9) groups had similar mean CGSQ scores at screening. Caregivers of children on DR/ER-MPH reported significant reductions in CGSQ scores after 3 weeks of DR/ER-MPH treatment versus placebo (least-squares mean: 41.2 vs. 49.1;  < 0.001). The CGSQ demonstrated strong internal consistency (Cronbach's alpha = 0.93) and good test/retest reliability (ICC = 0.72). Known groups, convergent/divergent validity, and responsiveness were demonstrated from relationships between the CGSQ and the CGI-S, ADHD-RS-IV, and CGI-P. The mean anchor-based MCT for CGSQ total score was estimated as -9.0 (DR/ER-MPH vs. placebo: 53.2% vs. 29.9%  = 0.003). CGSQ scores significantly decreased after 3 weeks of DR/ER-MPH treatment versus placebo, and the CGSQ was found to be a valid and reliable measure of strain in caregivers of children with ADHD. Clinical trial registration identification number: NCT02520388.
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http://dx.doi.org/10.1089/cap.2020.0159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066344PMC
April 2021

Analysis of structural brain asymmetries in attention-deficit/hyperactivity disorder in 39 datasets.

J Child Psychol Psychiatry 2021 Mar 22. Epub 2021 Mar 22.

Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA.

Objective: Some studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium.

Methods: We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries.

Results: There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t = 2.1, p = .04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t = 2.7, p = .01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen's d from -0.18 to 0.18) and would not survive study-wide correction for multiple testing.

Conclusion: Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.
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http://dx.doi.org/10.1111/jcpp.13396DOI Listing
March 2021

Intermediate lengths of the hexanucleotide repeat expansion may synergistically contribute to attention deficit hyperactivity disorder in child and his father: case report.

Neurocase 2021 Apr 18;27(2):138-146. Epub 2021 Mar 18.

Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni Di Dio Fatebenefratelli, Brescia, Italy.

We have summarized the abstract section as follows: "We report a son and his father affected by Attention Deficit Hyperactivity Disorder (ADHD). They belonged to a larger cohort (116 ADHD children, 20 related parents, 77 controls) wholly genotyped forexpansion. Ten ADHD susceptibility genes were further investigated in the family. We revealed that son and father shared an intermediateexpansion and common variants in, and . Bioinformatics highlighted a-interaction. This case-report underlines that in relatives with ADHD, carrying variants in ADHD susceptibility genes, the intermediaterepeats might have a potentially pathogenetic synergistic effect, supporting the multifactorial polygenic aetiopathogenetic profile of disease".
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http://dx.doi.org/10.1080/13554794.2021.1887275DOI Listing
April 2021

Can polygenic risk scores help identify pediatric bipolar spectrum and related disorders?: A systematic review.

Psychiatry Res 2021 May 3;299:113843. Epub 2021 Mar 3.

Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA.

The genetic basis of mood disorders can, theoretically, provide diagnostic information in scenarios of clinical uncertainty. Therefore, we examined the available body of knowledge on the association between polygenic risk scores for bipolar disorder (BP-PRSs) and pediatric bipolar spectrum and related disorders. We performed a literature search through PubMed in March of 2020. The following variables were extracted from relevant studies: population age, study sample size, source of polygenic risk scores, source of data, the primary goal of the study, the assessments used during the course of the study, and the main findings/outcomes of each study. BP-PRSs were associated with deficits in executive functioning and the diagnosis of attention deficit/hyperactivity disorder (ADHD). Three studies included in our analysis directly compared major depressive disorder (MDD)-PRSs to BP-PRSs in youth. Results showed that MDD-PRSs, and not BP-PRSs, were associated with ADHD symptoms, internalizing problems, and social problems. ADHD-PRSs were associated with conduct problems, depressive symptomatology, and externalizing disorders symptoms. Findings revealed that ADHD-PRSs were more clearly associated with emotional reactivity, emotional dysregulation, and irritability-frequent correlates of pediatric BP disorder. These findings suggest that ADHD-PRSs may have an important contribution to the development of mood related problems in youth.
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http://dx.doi.org/10.1016/j.psychres.2021.113843DOI Listing
May 2021

Investigating Shared Genetic Basis Across Tourette Syndrome and Comorbid Neurodevelopmental Disorders Along the Impulsivity-Compulsivity Spectrum.

Biol Psychiatry 2021 Jan 8. Epub 2021 Jan 8.

Department of Biological Sciences, Purdue University, West Lafayette, Indiana. Electronic address:

Background: Tourette syndrome (TS) is often found comorbid with other neurodevelopmental disorders across the impulsivity-compulsivity spectrum, with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) as most prevalent. This points to the possibility of a common etiological thread along an impulsivity-compulsivity continuum.

Methods: Investigating the shared genetic basis across TS, ADHD, ASD, and OCD, we undertook an evaluation of cross-disorder genetic architecture and systematic meta-analysis, integrating summary statistics from the latest genome-wide association studies (93,294 individuals, 6,788,510 markers).

Results: As previously identified, a common unifying factor connects TS, ADHD, and ASD, while TS and OCD show the highest genetic correlation in pairwise testing among these disorders. Thanks to a more homogeneous set of disorders and a targeted approach that is guided by genetic correlations, we were able to identify multiple novel hits and regions that seem to play a pleiotropic role for the specific disorders analyzed here and could not be identified through previous studies. In the TS-ADHD-ASD genome-wide association study single nucleotide polymorphism-based and gene-based meta-analysis, we uncovered 13 genome-wide significant regions that host single nucleotide polymorphisms with a high posterior probability for association with all three studied disorders (m-value > 0.9), 11 of which were not identified in previous cross-disorder analysis. In contrast, we also identified two additional pleiotropic regions in the TS-OCD meta-analysis. Through conditional analysis, we highlighted genes and genetic regions that play a specific role in a TS-ADHD-ASD genetic factor versus TS-OCD. Cross-disorder tissue specificity analysis implicated the hypothalamus-pituitary-adrenal gland axis in TS-ADHD-ASD.

Conclusions: Our work underlines the value of redefining the framework for research across traditional diagnostic categories.
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http://dx.doi.org/10.1016/j.biopsych.2020.12.028DOI Listing
January 2021

How Frequent Is Switching From an Initial Stimulant Family to the Alternative One in the Clinical Setting?: A Pilot Study of 49 Consecutively Referred Medication-Naive Adults With Attention-Deficit/Hyperactivity Disorder.

J Clin Psychopharmacol 2021 May-Jun 01;41(3):310-314

MIT Integrated Learning Initiative, Department of Brain and Cognitive Sciences, and McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA.

Purpose/background: This study aimed to evaluate the frequency of needing to switch the initial treatment of a stimulant to the alternative family in newly referred, medication-naive adults with attention-deficit/hyperactivity disorder (ADHD) initiating treatment with stimulants.

Methods/procedures: Subjects were 49 unmedicated adults (18-45 years old) with Diagnostic and Statistical Manual of Disorders (Fifth Edition) ADHD who initiated treatment with a stimulant. Before the clinical assessment with an expert clinician, participants completed the Adult Self-Report, Behavior Rating Inventory of Executive Function-Adult Version, Emotional Dysregulation Subscale of the Barkley Current Behavior Scale-Self-report, and Mind Wandering Questionnaire. The rate of switching was examined using information from the electronic medical record for up to three clinical follow-up visits. Comparisons were made between those who did and did not need to switch on baseline demographic and clinical characteristics.

Findings/results: Sixty-seven percent of ADHD patients were initially prescribed a methylphenidate product, and 33%, an amphetamine product. Forty-one percent of ADHD patients needed to switch from their initially prescribed stimulant family within 90 days of initiating treatment because of poor tolerability. Whereas the rate of switching was significantly higher in those initially prescribed methylphenidate, the rate of patients who required changes in formulation (long- to short-acting and vice versa) or additional antianxiety or antidepressant treatment ("strugglers") was higher in those taking amphetamine. Switchers were more impaired on the Adult Self-Report Intrusive scale, whereas nonswitchers were more impaired on the Behavior Rating Inventory of Executive Function Inhibit and Task Monitor scales. However, these findings were small and of unclear clinical significance.

Implications/conclusions: Forty-one percent of medication-naive adults with ADHD initiating stimulant treatment required a switch from the initially prescribed stimulant family to the alternative one because of poor tolerability. Switching could not be adequately predicted by baseline demographic or clinical characteristics. These findings call for improved efforts to help identify predictors of response to stimulant treatment in adults with ADHD to avoid unnecessary delays in identifying a safe and effective treatment for these patients.
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http://dx.doi.org/10.1097/JCP.0000000000001374DOI Listing
March 2021

Examining Sex-Differentiated Genetic Effects Across Neuropsychiatric and Behavioral Traits.

Biol Psychiatry 2021 06 9;89(12):1127-1137. Epub 2021 Jan 9.

Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Background: The origin of sex differences in prevalence and presentation of neuropsychiatric and behavioral traits is largely unknown. Given established genetic contributions and correlations, we tested for a sex-differentiated genetic architecture within and between traits.

Methods: Using European ancestry genome-wide association summary statistics for 20 neuropsychiatric and behavioral traits, we tested for sex differences in single nucleotide polymorphism (SNP)-based heritability and genetic correlation (r < 1). For each trait, we computed per-SNP z scores from sex-stratified regression coefficients and identified genes with sex-differentiated effects using a gene-based approach. We calculated correlation coefficients between z scores to test for shared sex-differentiated effects. Finally, we tested for sex differences in across-trait genetic correlations.

Results: We observed no consistent sex differences in SNP-based heritability. Between-sex, within-trait genetic correlations were high, although <1 for educational attainment and risk-taking behavior. We identified 4 genes with significant sex-differentiated effects across 3 traits. Several trait pairs shared sex-differentiated effects. The top genes with sex-differentiated effects were enriched for multiple gene sets, including neuron- and synapse-related sets. Most between-trait genetic correlation estimates were not significantly different between sexes, with exceptions (educational attainment and risk-taking behavior).

Conclusions: Sex differences in the common autosomal genetic architecture of neuropsychiatric and behavioral phenotypes are small and polygenic and unlikely to fully account for observed sex-differentiated attributes. Larger sample sizes are needed to identify sex-differentiated effects for most traits. For well-powered studies, we identified genes with sex-differentiated effects that were enriched for neuron-related and other biological functions. This work motivates further investigation of genetic and environmental influences on sex differences.
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http://dx.doi.org/10.1016/j.biopsych.2020.12.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163257PMC
June 2021

Translating Attention-Deficit/Hyperactivity Disorder Rating Scale-5 and Weiss Functional Impairment Rating Scale-Parent Effectiveness Scores into Clinical Global Impressions Clinical Significance Levels in Four Randomized Clinical Trials of SPN-812 (Viloxazine Extended-Release) in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder.

J Child Adolesc Psychopharmacol 2021 Apr 17;31(3):214-226. Epub 2021 Feb 17.

Supernus Pharmaceuticals, Inc., Rockville, Maryland, USA.

Clinical trials in psychiatry frequently report results from lengthy, comprehensive assessments to characterize a subject emotionally, cognitively, and behaviorally before and after treatment. However, the potential treatment implications of these results and how they translate into clinical practice remain unclear. Conversely, the Clinical Global Impressions (CGI) scales are quick, intuitive assessments used to assess the functional impact of a treatment in clinically relevant terms. The objectives of the present analyses are to translate scores from comprehensive assessments of symptom severity and functional impairment into clinically meaningful CGI levels. These analyses use data integrated from four pivotal Phase 3 trials in attention-deficit/hyperactivity disorder (ADHD) in children and adolescents treated with the novel nonstimulant SPN-812 (Viloxazine Extended-Release). In this study, we evaluated the ADHD Rating Scale-5 (ADHD-RS-5) and Weiss Functional Impairment Rating Scale-Parent (WFIRS-P), assessments of symptom severity and functional impairment, respectively, by linking these scales with the CGI scales at baseline and end of study. For participants that improved, a one-level change on the CGI-Improvement (CGI-I) was associated with a 10-15-point change on the ADHD-RS-5, and a 0.2-0.5-point change on the WFIRS-P. On the CGI-I, ratings of much improved and very much improved were associated with a percent score decrease (i.e., improvement) of ∼55% and 80% on the ADHD-RS-5 and ∼40% and 70% on the WFIRS-P, respectively. Differences between children and adolescents were minor and are unlikely to be clinically meaningful. These analyses provide clinically meaningful benchmarks for the interpretation of scores on the ADHD-RS-5 and WFIRS-P in terms of CGI evaluations in subjects with ADHD. These results may be useful for physicians seeking to understand a treatment's potential impact on their ADHD patients or for researchers looking to define their study results within a clinically relevant context. Data are from clinical trials NCT03247530, NCT03247543, NCT03247517, and NCT03247556.
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http://dx.doi.org/10.1089/cap.2020.0148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066343PMC
April 2021

Characterizing Pathways of Non-oral Prescription Stimulant Non-medical Use Among Adults Recruited From Reddit.

Front Psychiatry 2020 25;11:631792. Epub 2021 Jan 25.

Inflexxion, An IBH Company, Costa Mesa, CA, United States.

Prescription stimulant non-medical use (NMU) is a national predicament. While the risks of prescription stimulant NMU have been considered, less is known about non-oral use. To focus on this gap, a sample of adults with non-oral prescription stimulant NMU within the last 5-years was recruited. The purpose of the present study was to characterize the pathways and substance transitions associated with prescription stimulant NMU and non-oral prescription stimulant NMU in this unique sample of adults. Adults ( = 225) reporting non-oral prescription stimulant NMU within the last 5 years were recruited to complete an online survey by banner ads placed on the Reddit website between February and September 2019. After completion of the survey, a second study consisting of an in-depth telephone interview was conducted with 23 participants: interviews took place between July and September 2019. Data reported here include substance, route of administration and class transitions, as well as qualitative data from the interviews. Approximately 1 in 5 began their substance use trajectory with prescription stimulants (19.1%). Other than marijuana, most exposures to illicit substances occurred after both initial prescription stimulant NMU and initial non-oral prescription stimulant NMU. The most frequently reported route of administration transition was from oral use to snorting ( = 158, 70.2%), however, other route of administration transitions included oral use to injection drug use ( = 14, 6%). In-depth interviews elaborated upon these transitions and indicated that prescription stimulant NMU was consequential to substance use pathways. Oral prescription stimulant NMU was a precursor to non-oral prescription stimulant NMU. Non-oral prescription stimulant NMU was a precursor to illicit substance use, suggesting that prescription stimulant NMU impacts substance use pathways and revealing opportunities for intervention.
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http://dx.doi.org/10.3389/fpsyt.2020.631792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883730PMC
January 2021

Can the Child Behavior Checklist (CBCL) help characterize the types of psychopathologic conditions driving child psychiatry referrals?

Scand J Child Adolesc Psychiatr Psychol 2020 31;8:157-165. Epub 2020 Oct 31.

Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA.

Background: Little is known about the scope of problems driving referrals to child and adolescent psychiatry services. Identifying the full range of mental disorders affecting a particular child can help triage the child to a clinician with the appropriate level of expertise. The Child Behavior Checklist (CBCL) is an easy-to-use assessment tool that may provide invaluable information regarding the severity of the presenting complaints and also aid in the referral process.

Objective: To assess the utility of the CBCL to gain insights into the type of clinical problems driving referrals of youth to an outpatient pediatric psychiatry clinic.

Method: The sample consisted of 418 newly referred youth 4-18 years of age of both sexes. Parents completed the CBCL assessing psychopathology and competence. Rates of patients with elevated T-scores on each scale were calculated for the whole group and stratified by sex and age (≤12 versus >12).

Results: The CBCL identified high rates of psychopathology affecting referred youth. It also provided information on the type of suspected disorders affecting a particular child as well as their severity, critical information to guide likely differing clinical needs and therapeutic approaches. It also helped identify a high number of youth affected with multiple psychopathological conditions, likely to require a high level of clinical attention. Overall, males were significantly more impaired than females but there were no major differences between children and adolescents.

Conclusions: The CBCL can aid in the identification of individual and comorbid mental disorders affecting youth seeking mental health services by providing specific information about the presence and the severity of specific suspected disorder. These findings have implications for prioritizing scarce resources in child mental health and for improved consideration of the complexity of clinical presentations to pediatric psychiatry programs of any type.
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http://dx.doi.org/10.21307/sjcapp-2020-016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866779PMC
October 2020

The World Federation of ADHD International Consensus Statement: 208 Evidence-based conclusions about the disorder.

Neurosci Biobehav Rev 2021 Feb 4. Epub 2021 Feb 4.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Wuerzburg, Wuerzburg, Germany. Electronic address:

Background: Misconceptions about ADHD stigmatize affected people, reduce credibility of providers, and prevent/delay treatment. To challenge misconceptions, we curated findings with strong evidence base.

Methods: We reviewed studies with more than 2000 participants or meta-analyses from five or more studies or 2000 or more participants. We excluded meta-analyses that did not assess publication bias, except for meta-analyses of prevalence. For network meta-analyses we required comparison adjusted funnel plots. We excluded treatment studies with waiting-list or treatment as usual controls. From this literature, we extracted evidence-based assertions about the disorder.

Results: We generated 208 empirically supported statements about ADHD. The status of the included statements as empirically supported is approved by 80 authors from 27 countries and 6 continents. The contents of the manuscript are endorsed by 366 people who have read this document and agree with its contents.

Conclusions: Many findings in ADHD are supported by meta-analysis. These allow for firm statements about the nature, course, outcome causes, and treatments for disorders that are useful for reducing misconceptions and stigma.
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http://dx.doi.org/10.1016/j.neubiorev.2021.01.022DOI Listing
February 2021

Polygenic association between attention-deficit/hyperactivity disorder liability and cognitive impairments.

Psychol Med 2021 Feb 3:1-9. Epub 2021 Feb 3.

Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Background: A recent genome-wide association study (GWAS) identified 12 independent loci significantly associated with attention-deficit/hyperactivity disorder (ADHD). Polygenic risk scores (PRS), derived from the GWAS, can be used to assess genetic overlap between ADHD and other traits. Using ADHD samples from several international sites, we derived PRS for ADHD from the recent GWAS to test whether genetic variants that contribute to ADHD also influence two cognitive functions that show strong association with ADHD: attention regulation and response inhibition, captured by reaction time variability (RTV) and commission errors (CE).

Methods: The discovery GWAS included 19 099 ADHD cases and 34 194 control participants. The combined target sample included 845 people with ADHD (age: 8-40 years). RTV and CE were available from reaction time and response inhibition tasks. ADHD PRS were calculated from the GWAS using a leave-one-study-out approach. Regression analyses were run to investigate whether ADHD PRS were associated with CE and RTV. Results across sites were combined via random effect meta-analyses.

Results: When combining the studies in meta-analyses, results were significant for RTV (R2 = 0.011, β = 0.088, p = 0.02) but not for CE (R2 = 0.011, β = 0.013, p = 0.732). No significant association was found between ADHD PRS and RTV or CE in any sample individually (p > 0.10).

Conclusions: We detected a significant association between PRS for ADHD and RTV (but not CE) in individuals with ADHD, suggesting that common genetic risk variants for ADHD influence attention regulation.
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http://dx.doi.org/10.1017/S0033291720005218DOI Listing
February 2021

Evidence for similar structural brain anomalies in youth and adult attention-deficit/hyperactivity disorder: a machine learning analysis.

Transl Psychiatry 2021 02 1;11(1):82. Epub 2021 Feb 1.

Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA.

Attention-deficit/hyperactivity disorder (ADHD) affects 5% of children world-wide. Of these, two-thirds continue to have impairing symptoms of ADHD into adulthood. Although a large literature implicates structural brain differences of the disorder, it is not clear if adults with ADHD have similar neuroanatomical differences as those seen in children with recent reports from the large ENIGMA-ADHD consortium finding structural differences for children but not for adults. This paper uses deep learning neural network classification models to determine if there are neuroanatomical changes in the brains of children with ADHD that are also observed for adult ADHD, and vice versa. We found that structural MRI data can significantly separate ADHD from control participants for both children and adults. Consistent with the prior reports from ENIGMA-ADHD, prediction performance and effect sizes were better for the child than the adult samples. The model trained on adult samples significantly predicted ADHD in the child sample, suggesting that our model learned anatomical features that are common to ADHD in childhood and adulthood. These results support the continuity of ADHD's brain differences from childhood to adulthood. In addition, our work demonstrates a novel use of neural network classification models to test hypotheses about developmental continuity.
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http://dx.doi.org/10.1038/s41398-021-01201-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851168PMC
February 2021

Comorbidity of ADHD and adult bipolar disorder: A systematic review and meta-analysis.

Neurosci Biobehav Rev 2021 05 27;124:100-123. Epub 2021 Jan 27.

Department for Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt- Goethe University, Germany.

Attention-deficit / hyperactivity disorder (ADHD) and Bipolar Disorder (BD) are common mental disorders with a high degree of comorbidity. However, no systematic review with meta-analysis has aimed to quantify the degree of comorbidity between both disorders. To this end we performed a systematic search of the literature in October 2020. In a meta-analysis of 71 studies with 646,766 participants from 18 countries, it was found that about one in thirteen adults with ADHD was also diagnosed with BD (7.95 %; 95 % CI: 5.31-11.06), and nearly one in six adults with BD had ADHD (17.11 %; 95 % CI: 13.05-21.59 %). Substantial heterogeneity of comorbidity rates was present, highlighting the importance of contextual factors: Heterogeneity could partially be explained by diagnostic system, sample size and geographical location. Age of BD onset occurred earlier in patients with comorbid ADHD (3.96 years; 95 % CI: 2.65-5.26, p < 0.001). Cultural and methodological differences deserve attention for evaluating diagnostic criteria and clinicians should be aware of the high comorbidity rates to prevent misdiagnosis and provide optimal care for both disorders.
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http://dx.doi.org/10.1016/j.neubiorev.2021.01.017DOI Listing
May 2021

Risk variants and polygenic architecture of disruptive behavior disorders in the context of attention-deficit/hyperactivity disorder.

Nat Commun 2021 01 25;12(1):576. Epub 2021 Jan 25.

The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder often comorbid with disruptive behavior disorders (DBDs). Here, we report a GWAS meta-analysis of ADHD comorbid with DBDs (ADHD + DBDs) including 3802 cases and 31,305 controls. We identify three genome-wide significant loci on chromosomes 1, 7, and 11. A meta-analysis including a Chinese cohort supports that the locus on chromosome 11 is a strong risk locus for ADHD + DBDs across European and Chinese ancestries (rs7118422, P = 3.15×10, OR = 1.17). We find a higher SNP heritability for ADHD + DBDs (h = 0.34) when compared to ADHD without DBDs (h = 0.20), high genetic correlations between ADHD + DBDs and aggressive (r = 0.81) and anti-social behaviors (r = 0.82), and an increased burden (polygenic score) of variants associated with ADHD and aggression in ADHD + DBDs compared to ADHD without DBDs. Our results suggest an increased load of common risk variants in ADHD + DBDs compared to ADHD without DBDs, which in part can be explained by variants associated with aggressive behavior.
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http://dx.doi.org/10.1038/s41467-020-20443-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835232PMC
January 2021

Structural brain imaging studies offer clues about the effects of the shared genetic etiology among neuropsychiatric disorders.

Mol Psychiatry 2021 Jan 17. Epub 2021 Jan 17.

Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA.

Genomewide association studies have found significant genetic correlations among many neuropsychiatric disorders. In contrast, we know much less about the degree to which structural brain alterations are similar among disorders and, if so, the degree to which such similarities have a genetic etiology. From the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium, we acquired standardized mean differences (SMDs) in regional brain volume and cortical thickness between cases and controls. We had data on 41 brain regions for: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), epilepsy, major depressive disorder (MDD), obsessive compulsive disorder (OCD), and schizophrenia (SCZ). These data had been derived from 24,360 patients and 37,425 controls. The SMDs were significantly correlated between SCZ and BD, OCD, MDD, and ASD. MDD was positively correlated with BD and OCD. BD was positively correlated with OCD and negatively correlated with ADHD. These pairwise correlations among disorders were correlated with the corresponding pairwise correlations among disorders derived from genomewide association studies (r = 0.494). Our results show substantial similarities in sMRI phenotypes among neuropsychiatric disorders and suggest that these similarities are accounted for, in part, by corresponding similarities in common genetic variant architectures.
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http://dx.doi.org/10.1038/s41380-020-01002-zDOI Listing
January 2021