Differences in schizophrenia treatments by race and ethnicity-analysis of electronic health records.

Racial disparities in prescriptions of anti-psychotics have been highlighted before. However, (i) the evidence on other medications, including anti-depressant or mood stabilizing medications is lacking, and (ii) the role of potentially confounding factors and (iii) specificity of such disparities to schizophrenia (SCZ), are still unknown. We used electronic health records (EHRs) from 224,212 adults to estimate the odds ratios of receiving a prescription for different nervous system medications among patients with SCZ of different race/ethnicity, and analogous linear models to investigate differences in prescribed medication doses. To verify specificity of the observed patterns to SCZ, we conducted analogous analyses in depression and bipolar disorder (BD) patients. We found that Black/African American (AA) and Hispanic patients with SCZ were more likely to be prescribed haloperidol (Black/AA: OR = 1.52 (1.33-1.74); Hispanic: OR = 1.32 (1.12-1.55)) or risperidone (Black/AA: OR = 1.27 (1.11-1.45); Hispanic: OR = 1.40 (1.19-1.64)), but less likely to be prescribed clozapine (Black/AA: OR = 0.40 (0.33-0.49); Hispanic: OR = 0.45 (0.35-0.58)), compared to white patients. There were no race/ethnicity-related differences in the prescribed medication doses. These patterns were not specific to SCZ: Asian, Hispanic and Black/AA patients with BD or depression were more likely to be prescribed anti-psychotics, but less likely to be prescribed antidepressants or mood-stabilizers. In conclusion, we found racial/ethnic disparities in the medications prescribed to patients with SCZ and other psychiatric conditions. We discuss the potential implications for the quality of care for patients of diverse races/ethnicities.

Changes in cognitive processes and coping strategies precede changes in symptoms during cognitive therapy for posttraumatic stress disorder.

Theories of posttraumatic stress disorder (PTSD) highlight the role of cognitive and behavioral factors in its development, maintenance, and treatment. This study investigated the relationship between changes in factors specified in Ehlers and Clark's (2000) model of PTSD and PTSD symptom change in 217 patients with PTSD who were treated with cognitive therapy for PTSD (CT-PTSD) in routine clinical care. Bivariate latent change score models (LCSM) of session-by-session changes in self-report measures showed that changes in PTSD symptoms were preceded by changes in negative appraisals, flashback characteristics of unwanted memories, safety behaviours, and unhelpful responses to intrusions, but not vice versa. For changes in trauma memory disorganization and PTSD symptoms we found a bidirectional association. This study provides evidence that cognitive and behavioral processes proposed in theoretical models of PTSD play a key role in driving symptom improvement during CT-PTSD.

Therapist-assisted online psychological therapies differing in trauma focus for post-traumatic stress disorder (STOP-PTSD): a UK-based, single-blind, randomised controlled trial.

BACKGROUND: Many patients are currently unable to access psychological treatments for post-traumatic stress disorder (PTSD), and it is unclear which types of therapist-assisted internet-based treatments work best. We aimed to investigate whether a novel internet-delivered cognitive therapy for PTSD (iCT-PTSD), which implements all procedures of a first-line, trauma-focused intervention recommended by the UK National Institute for Health and Care Excellence (NICE) for PTSD, is superior to internet-delivered stress management therapy for PTSD (iStress-PTSD), a comprehensive cognitive behavioural treatment programme focusing on a wide range of coping skills. METHODS: We did a single-blind, randomised controlled trial in three locations in the UK. Participants (≥18 years) were recruited from UK National Health Service (NHS) Improving Access to Psychological Therapies (IAPT) services or by self-referral and met DSM-5 criteria for PTSD to single or multiple events. Participants were randomly allocated by a computer programme (3:3:1) to iCT-PTSD, iStress-PTSD, or a 3-month waiting list with usual NHS care, after which patients who still met PTSD criteria were randomly allocated (1:1) to iCT-PTSD or iStress-PTSD. Randomisation was stratified by location, duration of PTSD (<18 months or ≥18 months), and severity of PTSD symptoms (high vs low). iCT-PTSD and iStress-PTSD were delivered online with therapist support by messages and short weekly phone calls over the first 12 weeks (weekly treatment phase), and three phone calls over the next 3 months (booster phase). The primary outcome was the severity of PTSD symptoms at 13 weeks after random assignment, measured by self-report on the PTSD Checklist for DSM-5 (PCL-5), and analysed by intention-to-treat. Safety was assessed in all participants who started treatment. Process analyses investigated acceptability and compliance with treatment, and candidate moderators and mediators of outcome. The trial was prospectively registered with the ISRCTN registry, ISRCTN16806208. FINDINGS: Of the 217 participants, 158 (73%) self-reported as female, 57 (26%) as male, and two (1%) as other; 170 (78%) were White British, 20 (9%) were other White, six (3%) were Asian, ten (5%) were Black, eight (4%) had a mixed ethnic background, and three (1%) had other ethnic backgrounds. Mean age was 36·36 years (SD 12·11; range 18-71 years). 52 (24%) participants met self-reported criteria for ICD-11 complex PTSD. Fewer than 10% of participants dropped out of each treatment group. iCT-PTSD was superior to iStress-PTSD in reducing PTSD symptoms, showing an adjusted difference on the PCL-5 of -4·92 (95% CI -8·92 to -0·92; p=0·016; standardised effect size d=0·38 [0·07 to 0·69]) for immediate allocations and -5·82 (-9·59 to -2·04; p=0·0027; d=0·44 [0·15 to 0·72]) for all treatment allocations. Both treatments were superior to the waiting list for PCL-5 at 13 weeks (d=1·67 [1·23 to 2·10] for iCT-PTSD and 1·29 [0·85 to 1·72] for iStress-PTSD). The advantages in outcome for iCT-PTSD were greater for participants with high dissociation or complex PTSD symptoms, and mediation analyses showed both treatments worked by changing negative meanings of the trauma, unhelpful coping, and flashback memories. No serious adverse events were reported. INTERPRETATION: Trauma-focused iCT-PTSD is effective and acceptable to patients with PTSD, and superior to a non-trauma-focused cognitive behavioural stress management therapy, suggesting that iCT-PTSD is an effective way of delivering the contents of CT-PTSD, one of the NICE-recommended first-line treatments for PTSD, while reducing therapist time compared with face-to-face therapy. FUNDING: Wellcome Trust, UK National Institute for Health and Care Research Oxford Health Biomedical Research Centre.

Association Between Mental Health and Reproductive System Disorders in Women: A Systematic Review and Meta-analysis.

Importance: Reproductive system and mental health disorders are commonly comorbid in women. Although the causes of this overlap remain elusive, evidence suggests potential shared environmental and genetic factors associated with risk. Objective: To investigate the comorbidity between psychiatric and reproductive system disorders, both as broad diagnostic categories and among specific pairs of diagnoses. Data Source: PubMed. Study Selection: Observational studies published between January 1980 and December 2019 assessing prevalence of psychiatric disorders in women with reproductive system disorders and prevalence of reproductive system disorders in women with psychiatric disorders were included. The study did not include psychiatric and reproductive disorders triggered by life events (eg, trauma, infection, surgery) to address potential confounding. Data Extraction and Synthesis: A search yielded 1197 records, of which 50 met the inclusion criteria for the qualitative and 31 for the quantitative synthesis in our study. A random-effects model was used for data synthesis and Egger test and I2 to assess study bias and heterogeneity. Data were analyzed from January to December 2022. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline. Main Outcomes and Measures: Psychiatric and reproductive system disorders. Results: A total of 1197 records were identified, of which 50 met the inclusion criteria for qualitative and 31 for quantitative synthesis. Diagnosis of a reproductive system disorder was associated with a 2- to 3-fold increased odds of having a psychiatric disorder (lower bound odds ratio [OR], 2.00; 95% CI, 1.41-2.83; upper bound OR; 2.88; 95% CI, 2.21-3.76). The analysis focused on specific diagnoses described in the literature and found that polycystic ovary syndrome was associated with increased odds of depression (population-based studies OR, 1.71; 95% CI, 1.19-2.45; clinical studies OR, 2.58; 95% CI, 1.57-4.23) and anxiety (population-based studies OR, 1.69; 95% CI, 1.36-2.10; clinical studies OR, 2.85; 95% CI, 1.98-4.09). Chronic pelvic pain was also associated with both depression (OR, 3.91; 95% CI, 1.81-8.46) and anxiety (OR, 2.33; 95% CI, 1.33-4.08). Few studies investigated risk of other reproductive system disorders in women with psychiatric disorders, or reverse associations (risk of reproductive system disorder among women with a psychiatric diagnosis). Conclusions and Relevance: In this systematic review and meta-analysis, a high rate of reported co-occurrence between psychiatric and reproductive disorders overall was observed. However, data for many disorder pairs were limited. The available literature focused overwhelmingly on affective disorders in polycystic ovary syndrome, overlooking a substantial portion of disease overlap. As such, the associations between the majority of mental health outcomes and conditions of the female reproductive system are largely unknown.

Comorbidities in autism spectrum disorder and their etiologies.

Individuals with autism spectrum disorder (ASD), in addition to the core features of the disease, experience a higher burden of co-occurring medical conditions. This study sought to describe the frequency and distribution of comorbidit conditions in individuals with ASD, and systematically evaluate the possibility that pre- and postnatal exposures (e.g., preterm birth, hypoxia at birth, traumatic brain injury, and fetal alcohol syndrome) associated with ASD may also be linked with distinct comorbidities. We used the SPARK study database, launched by the Simons Foundation Autism Research Initiative (SFARI). Comorbidities considered in the study included neurological, cognitive, psychiatric, and physical conditions. The study sample consisted of 42,569 individuals with ASD and their 11,389 non-ASD siblings (full and half siblings). Majority (74%) of individuals with ASD had at least one comorbidity, and had a greater average number of comorbidities than their non-ASD siblings. Preterm birth and hypoxia at birth were the most common peri-natal exposures in the sample. In logistic regression models adjusted for covariates, these exposures were associated with several distinct comorbidities in ASD cases, including attention and behavior problems, psychiatric and neurological disorders, and growth conditions. A similar pattern of association was also observed in non-ASD siblings. Our findings underscore that individuals with ASD experience a greater burden of comorbidities, which could be partly attributable to the higher rates of perinatal exposures compared to their non-ASD siblings. Study findings, if replicated in other samples, can inform the etiology of comorbidity in ASD.

Somatic comorbidities of mental disorders in pregnancy.

BACKGROUND: Mental and physical health conditions are frequently comorbid. Despite the widespread physiological and behavioral changes during pregnancy, the pattern of comorbidities among women in pregnancy is not well studied. This study aimed to systematically examine the associations between mental and somatic disorders before and during pregnancy. METHOD: The study used data from mothers of a nationally representative birth cohort of children born in Israel (1997-2008). We compared the risk of all major somatic disorders (International Classification of Diseases, Ninth Revision) in pregnant women with and without a mental disorder. All analyses were adjusted for maternal age, child's birth year, family socioeconomic status, and the total number of maternal encounters with health services around pregnancy period. RESULTS: The analytical sample included 77,030 mother-child dyads, with 30,083 unique mothers. The mean age at child's birth was 29.8 years. Prevalence of diagnosis of mental disorder around pregnancy in our sample was 4.4%. Comorbidity between mental and somatic disorders was two times higher than the comorbidity between pairs of different somatic disorders. Of the 17 somatic disorder categories, seven were positively associated with mental health disorders. The highly prevalent comorbidities associated with mental disorders in pregnancy included e.g. musculoskeletal (OR = 1.30; 95% CI = 1.20-1.42) and digestive system diseases (OR = 1.23; 95% CI = 1.13-1.34). CONCLUSIONS: We observed that associations between maternal diagnoses and mental health stand out from the general pattern of comorbidity between nonmental health diseases. The study results confirm the need for screening for mental disorders during pregnancy and for potential comorbid conditions associated with mental disorders.

Familial clustering of psychiatric disorders and low IQ.

BACKGROUND: Although the ICD and DSM differentiate between different psychiatric disorders, these often share symptoms, risk factors, and treatments. This was a population-based, case-control, sibling study examining familial clustering of all psychiatric disorders and low IQ, using data from the Israel Draft-Board Registry on all Jewish adolescents assessed between 1998 and 2014. METHODS: We identified all cases with autism spectrum disorder (ASD, N = 2128), severe intellectual disability (ID, N = 9572), attention-deficit hyperactive disorder (ADHD) (N = 3272), psychotic (N = 7902), mood (N = 9704), anxiety (N = 10 606), personality (N = 24 816), or substance/alcohol abuse (N = 791) disorders, and low IQ (⩾2 SDs below the population mean, N = 31 186). Non-CNS control disorders were adolescents with Type-1 diabetes (N = 2427), hernia (N = 29 558) or hematological malignancies (N = 931). Each case was matched with 10 age-matched controls selected at random from the Draft-Board Registry, with replacement, and for each case and matched controls, we ascertained all full siblings. The main outcome measure was the relative recurrence risk (RRR) of the sibling of a case having the same (within-disorder RRR) or a different (across-disorder RRR) disorder. RESULTS: Within-disorder RRRs were increased for all diagnostic categories, ranging from 11.53 [95% confidence interval (CI): 9.23-14.40] for ASD to 2.93 (95% CI: 2.80-3.07) for personality disorders. The median across-disorder RRR between any pair of psychiatric disorders was 2.16 (95% CI: 1.45-2.43); the median RRR between low IQ and any psychiatric disorder was 1.37 (95% CI: 0.93-1.98). There was no consistent increase in across-disorder RRRs between the non-CNS disorders and psychiatric disorders and/or low IQ. CONCLUSION: These large population-based study findings suggest shared etiologies among most psychiatric disorders, and low IQ.

Autistic traits and alcohol use in adolescents within the general population.

It has been suggested that autistic traits are associated with less frequent alcohol use in adolescence. Our study seeks to examine the relationship between autistic traits and alcohol use in a large adolescent population. Leveraging data from the IMAGEN cohort, including 2045 14-year-old adolescents that were followed-up to age 18, we selected items on social preference/skills and rigidity from different questionnaires. We used linear regression models to (1) test the effect of the sum scores on the prevalence of alcohol use (AUDIT-C) over time, (2) explore the relationship between autistic traits and alcohol use patterns, and (3) explore the specific effect of each autistic trait on alcohol use. Higher scores on the selected items were associated with trajectories of less alcohol use from the ages between 14 and 18 (b = - 0.030; CI 95% = - 0.042, - 0.017; p < 0.001). Among adolescents who used alcohol, those who reported more autistic traits were also drinking less per occasion than their peers and were less likely to engage in binge drinking. We found significant associations between alcohol use and social preference (p < 0.001), nervousness for new situations (p = 0.001), and detail orientation (p < 0.001). Autistic traits (social impairment, detail orientation, and anxiety) may buffer against alcohol use in adolescence.

Reprint of: Advanced paternal age and risk of schizophrenia in offspring - Review of epidemiological findings and potential mechanisms.

A large number of studies have examined the association between advanced paternal age (APA) and risk of schizophrenia in offspring. Here we present an overview of epidemiological studies on this subject published since 2000, and systematically summarize their methodologies and results. Next, we discuss evidence to elucidate the potential mechanisms contributing to the association between APA and offspring schizophrenia, considering paternal psychiatric morbidity and genetic liability, maternal factors, and findings from family design studies. We propose that multiple mechanisms, including causal and non-causal pathways, contribute to the observed relationship between APA and schizophrenia in offspring, and conclude by highlighting the need for multi-disciplinary studies in disentangling these complex, non-mutually exclusive mechanisms.

Systematic review and meta-analysis: relationships between attention-deficit/hyperactivity disorder and urinary symptoms in children.

Lower urinary tract symptoms (LUTS), e.g., urinary frequency, pressure, urgency, and overactive bladder syndrome, are commonly reported in children with attention-deficit/hyperactivity disorder (ADHD). Understanding the co-occurrence of these conditions has implications regarding clinical approaches, treatments, and improved quality of life. We conducted a systematic review and meta-analysis to examine the relationships between LUTS and ADHD in children. We searched for articles published between January 1990 and July 2019, in PubMed, CENTRAL, and PsycNet. Two authors independently screened all articles and extracted data. We performed random-effect meta-analyses for ADHD with pooled outcomes for LUTS. We identified 119 relevant articles in the literature and 18 articles fulfilled the inclusion criteria for the systematic review, of which, 5 articles had sufficient data for meta-analysis. Examining ADHD among individuals with LUTS, the odds ratio was 2.99 (95% CI 1.13, 7.88, p < 0.001), compared to controls. In multiple studies, the mean overall score for LUTS, using a standardized measure, was significantly higher in patients with ADHD in comparison to controls, and the severity of ADHD was positively associated with the severity of LUTS. Younger age in children was correlated with a higher LUTS score. Different subtypes of urinary incontinence demonstrated differences in behavioral problems and psychiatric comorbidity. Sex differences in LUTS were not consistent across articles. Our results indicate clinically significant associations between ADHD and LUTS in children. Because LUTS and ADHD are common disorders in children, clinicians should be aware of these associations as they inform optimal assessment and treatment strategies.

Systematic review and meta-analysis identify significant relationships between clinical anxiety and lower urinary tract symptoms.

BACKGROUND: Lower urinary tract symptoms (LUTS), such as voiding symptoms, overactive bladder, and interstitial cystitis, and anxiety disorders are often comorbid conditions in patients. However, the existing evidence regarding the rates and nature of the co-occurrence of these conditions has not been systematically evaluated. The aim of this study was to examine these relationships. METHODS: We conducted a systematic review and meta-analysis to examine the relationship between LUTS and anxiety. We searched for articles published from January 1990 to July 2019 in PubMed, CENTRAL, PsycINFO, and Google Scholar. Outcomes were anxiety-related disorders and symptoms (clinically significant anxiety) and LUTS. We performed random-effects meta-analyses, inspected funnel plots, and applied the Egger's test to evaluate publication bias. We followed PRISMA guidelines and recorded our protocol on PROSPERO (ID = CRD42019118607). RESULTS: We identified 814 articles, of which 94 fulfilled inclusion criteria, and 23 had sufficient data for meta-analysis. The odds ratio (OR) for clinically significant anxiety among individuals with LUTS was 2.87 (95% CI: 2.38,3.46, p < .001). The OR for LUTS among individuals with clinically significant anxiety was 2.87 (95% CI: 1.07,7.74, p < .001), although very few studies examined this relationship. A large value of I2 index suggests high heterogeneity between studies. CONCLUSION: The results demonstrate a significant association between clinically significant anxiety and LUTS in both females and males. There were limited studies on younger individuals and on individuals ascertained for clinically significant anxiety, which should motivate further study in these areas. Understanding the co-occurrence of these conditions will lead to better prevention and interventions to ameliorate the progression of the symptoms and improve the quality of life. A thorough assessment of anxiety may provide more optimal care for LUTS patients.

Advanced paternal age and risk of schizophrenia in offspring - Review of epidemiological findings and potential mechanisms.

A large number of studies have examined the association between advanced paternal age (APA) and risk of schizophrenia in offspring. Here we present an overview of epidemiological studies on this subject published since 2000, and systematically summarize their methodologies and results. Next, we discuss evidence to elucidate the potential mechanisms contributing to the association between APA and offspring schizophrenia, considering paternal psychiatric morbidity and genetic liability, maternal factors, and findings from family design studies. We propose that multiple mechanisms, including causal and non-causal pathways, contribute to the observed relationship between APA and schizophrenia in offspring, and conclude by highlighting the need for multi-disciplinary studies in disentangling these complex, non-mutually exclusive mechanisms.

Maternal health around pregnancy and autism risk: a diagnosis-wide, population-based study.

BACKGROUND: Many studies have reported an increased risk of autism spectrum disorder (ASD) associated with some maternal diagnoses in pregnancy. However, such associations have not been studied systematically, accounting for comorbidity between maternal disorders. Therefore our aim was to comprehensively test the associations between maternal diagnoses around pregnancy and ASD risk in offspring. METHODS: This exploratory case-cohort study included children born in Israel from 1997 to 2008, and followed up until 2015. We used information on all ICD-9 codes received by their mothers during pregnancy and the preceding year. ASD risk associated with each of those conditions was calculated using Cox proportional hazards regression, adjusted for the confounders (birth year, maternal age, socioeconomic status and number of ICD-9 diagnoses during the exposure period). RESULTS: The analytic sample consisted of 80 187 individuals (1132 cases, 79 055 controls), with 822 unique ICD-9 codes recorded in their mothers. After extensive quality control, 22 maternal diagnoses were nominally significantly associated with offspring ASD, with 16 of those surviving subsequent filtering steps (permutation testing, multiple testing correction, multiple regression). Among those, we recorded an increased risk of ASD associated with metabolic [e.g. hypertension; HR = 2.74 (1.92-3.90), p = 2.43 × 10-8], genitourinary [e.g. non-inflammatory disorders of cervix; HR = 1.88 (1.38-2.57), p = 7.06 × 10-5] and psychiatric [depressive disorder; HR = 2.11 (1.32-3.35), p = 1.70 × 10-3] diagnoses. Meanwhile, mothers of children with ASD were less likely to attend prenatal care appointment [HR = 0.62 (0.54-0.71), p = 1.80 × 10-11]. CONCLUSIONS: Sixteen maternal diagnoses were associated with ASD in the offspring, after rigorous filtering of potential false-positive associations. Replication in other cohorts and further research to understand the mechanisms underlying the observed associations with ASD are warranted.

Clinical signs associated with earlier diagnosis of children with autism Spectrum disorder.

BACKGROUND: The objective of this study is to gain new insights into the relationship between clinical signs and age at diagnosis. METHOD: We utilize a new, large, online survey of 1743 parents of children diagnosed with ASD, and use multiple statistical approaches. These include regression analysis, factor analysis, and machine learning (regression tree). RESULTS: We find that clinical signs that most strongly predict early diagnosis are not necessarily specific to autism, but rather those that initiate the process that eventually leads to an ASD diagnosis. Given the high correlations between symptoms, only a few signs are found to be important in predicting early diagnosis. For several clinical signs we find that their presence and intensity are positively correlated with delayed diagnosis (e.g., tantrums and aggression). Even though our data are drawn from parents' retrospective accounts, we provide evidence that parental recall bias and/or hindsight bias did not play a significant role in shaping our results. CONCLUSION: In the subset of children without early deficits in communication, diagnosis is delayed, and this might be improved if more attention will be given to clinical signs that are not necessarily considered as ASD symptoms. Our findings also suggest that careful attention should be paid to children showing excessive tantrums or aggression, as these behaviors may interfere with an early ASD diagnoses.

Parental Age and Differential Estimates of Risk for Neuropsychiatric Disorders: Findings From the Danish Birth Cohort.

OBJECTIVE: Parental age at birth has been shown to affect the rates of a range of neurodevelopmental disorders, but the understanding of the mechanisms through which it mediates different outcomes is still lacking. A population-based cohort was used to assess differential effects of parental age on estimates of risk across pediatric-onset neuropsychiatric disorders: autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), and Tourette's disorder/chronic tic disorder (TD/CT). METHOD: The study cohort included all singleton births in Denmark from 1980 through 2007 with full information on parental ages (N = 1,490,745) and was followed through December 31, 2013. Cases of ASD, ADHD, OCD, and TD/CT were identified in the Danish Psychiatric Central Register and the National Patient Register. Associations with parental age were modeled using a stratified Cox regression, allowing for changes in baseline diagnostic rates across time. RESULTS: Younger parental age was significantly associated with increased estimates of risk for ADHD and TD/CT, whereas older parental age was associated with ASD and OCD. Except for OCD, no evidence for differential effects of parental ages on male versus female offspring was observed. CONCLUSION: This study provides novel evidence for the association between age at parenthood and TD/CT and OCD and for the first time shows in a population-based sample that parental age confers differential risk rates for pediatric-onset psychiatric disorders. These results are consistent with a model of shared and unshared risk architecture for pediatric-onset neuropsychiatric conditions, highlighting unique contributions of maternal and paternal ages.

Association of Autism Spectrum Disorder With Prenatal Exposure to Medication Affecting Neurotransmitter Systems.

Importance: Prenatal exposure to certain medications has been hypothesized to influence the risk of autism spectrum disorders (ASD). However, the underlying effects on the neurotransmitter systems have not been comprehensively assessed. Objective: To investigate the association of early-life interference with different neurotransmitter systems by prenatal medication exposure on the risk of ASD in offspring. Design, Setting, and Participants: This case-control study included children born from January 1, 1997, through December 31, 2007, and followed up for ASD until January 26, 2015, within a single Israeli health maintenance organization. Using publicly available data, 55 groups of medications affecting neurotransmitter systems and prescribed to pregnant women in this sample were identified. Children prenatally exposed to medications were compared with nonexposed children. Data were analyzed from March 1, 2017, through June 20, 2018. Main Outcome and Measures: Hazard ratios (HRs) and 95% CIs of ASD risk associated with exposure to medication groups using Cox proportional hazards regression, adjusted for the relevant confounders (eg, birth year, maternal age, maternal history of psychiatric and neurologic disorders, or maternal number of all medical diagnoses 1 year before pregnancy). Results: The analytic sample consisted of 96 249 individuals (1405 cases; 94 844 controls; mean [SD] age at the end of follow-up, 11.6 [3.1] years; 48.8% female), including 1405 with ASD and 94 844 controls. Of 34 groups of medications, 5 showed nominally statistically significant association with ASD in fully adjusted models. Evidence of confounding effects of the number of maternal diagnoses on the association between offspring exposure to medication and ASD was found. Adjusting for this factor, lower estimates of ASD risk among children exposed to cannabinoid receptor agonists (HR, 0.72; 95% CI, 0.55-0.95; P = .02), muscarinic receptor 2 agonists (HR, 0.49; 95% CI, 0.24-0.98; P = .04), opioid receptor κ and ε agonists (HR, 0.67; 95% CI, 0.45-0.99; P = .045), or α2C-adrenergic receptor agonists (HR, 0.43; 95% CI, 0.19-0.96; P = .04) were observed. Exposure to antagonists of neuronal nicotinic acetylcholine receptor α was associated with higher estimates of ASD risk (HR, 12.94; 95% CI, 1.35-124.25; P = .03). Conclusions and Relevance: Most of the medications affecting neurotransmitter systems in this sample had no association with the estimates of ASD risk. Replication and/or validation using experimental techniques are required.

Transparency about the outcomes of mental health services (IAPT approach): an analysis of public data.

BACKGROUND: Internationally, the clinical outcomes of routine mental health services are rarely recorded or reported; however, an exception is the English Improving Access to Psychological Therapies (IAPT) service, which delivers psychological therapies recommended by the National Institute for Health and Care Excellence for depression and anxiety disorders to more than 537 000 patients in the UK each year. A session-by-session outcome monitoring system ensures that IAPT obtains symptom scores before and after treatment for 98% of patients. Service outcomes can then be reported, along with contextual information, on public websites. METHODS: We used publicly available data to identify predictors of variability in clinical performance. Using ß regression models, we analysed the outcome data released by National Health Service Digital and Public Health England for the 2014-15 financial year (April 1, 2014, to March 31, 2015) and developed a predictive model of reliable improvement and reliable recovery. We then tested whether these predictors were also associated with changes in service outcome between 2014-15 and 2015-16. FINDINGS: Five service organisation features predicted clinical outcomes in 2014-15. Percentage of cases with a problem descriptor, number of treatment sessions, and percentage of referrals treated were positively associated with outcome. The time waited to start treatment and percentage of appointments missed were negatively associated with outcome. Additive odd ratios suggest that moving from the lowest to highest level on an organisational factor could improve service outcomes by 11-42%, dependent on the factor. Consistent with a causal model, most organisational factors also predicted between-year changes in outcome, together accounting for 33% of variance in reliable improvement and 22% for reliable recovery. Social deprivation was negatively associated with some outcomes, but the effect was partly mitigated by the organisational factors. INTERPRETATION: Traditionally, efforts to improve mental health outcomes have largely focused on the development of new and more effective treatments. Our analyses show that the way psychological therapy services are implemented could be similarly important. Mental health services elsewhere in the UK and in other countries might benefit from adopting IAPT's approach to recording and publicly reporting clinical outcomes. FUNDING: Wellcome Trust.

Paternal Age Alters Social Development in Offspring.

OBJECTIVE: Advanced paternal age (APA) at conception has been linked with autism and schizophrenia in offspring, neurodevelopmental disorders that affect social functioning. The current study explored the effects of paternal age on social development in the general population. METHOD: We used multilevel growth modeling to investigate APA effects on socioemotional development from early childhood until adolescence, as measured by the Strengths and Difficulties Questionnaire (SDQ) in the Twins Early Development Study (TEDS) sample. We also investigated genetic and environmental underpinnings of the paternal age effects on development, using the Additive genetics, Common environment, unique Environment (ACE) and gene-environment (GxE) models. RESULTS: In the general population, both very young and advanced paternal ages were associated with altered trajectory of social development (intercept: p = .01; slope: p = .03). No other behavioral domain was affected by either young or advanced age at fatherhood, suggesting specificity of paternal age effects. Increased importance of genetic factors in social development was recorded in the offspring of older but not very young fathers, suggesting distinct underpinnings of the paternal age effects at these two extremes. CONCLUSION: Our findings highlight that the APA-related deficits that lead to autism and schizophrenia are likely continuously distributed in the population.

Genetic polymorphisms and their association with brain and behavioural measures in heterogeneous stock mice.

Although the search for quantitative trait loci for behaviour remains a considerable challenge, the complicated genetic architecture of quantitative traits is beginning to be understood. The current project utilised heterogeneous stock (HS) male mice (n = 580) to investigate the genetic basis for brain weights, activity, anxiety and cognitive phenotypes. We identified 126 single nucleotide polymorphisms (SNPs) in genes involved in regulation of neurotransmitter systems, nerve growth/death and gene expression, and subsequently investigated their associations with changes in behaviour and/or brain weights in our sample. We found significant associations between four SNP-phenotype pairs, after controlling for multiple testing. Specificity protein 2 (Sp2, rs3708840), tryptophan hydroxylase 1 (Tph1, rs262731280) and serotonin receptor 3A (Htr3a, rs50670893) were associated with activity/anxiety behaviours, and microtubule-associated protein 2 (Map2, rs13475902) was associated with cognitive performance. All these genes except for Tph1 were expressed in the brain above the array median, and remained significantly associated with relevant behaviours after controlling for the family structure. Additionally, we found evidence for a correlation between Htr3a expression and activity. We discuss our findings in the light of the advantages and limitations of currently available mouse genetic tools, suggesting further directions for association studies in rodents.