Specific Birth Defects Following Antiseizure Medications Used By Pregnant Women With Epilepsy.

Background and Objectives: Previous research has been limited in the comprehensive study of associations between the use of individual antiseizure medications (ASMs) in pregnancy and specific groups of birth defects, and systematic reviews and meta-analyses on the topic are limited by pooled samples and study designs. This study investigated birth defects related to ASM use in pregnancy in children born to women with epilepsy in Sweden over 20 years. Methods: We used data from Swedish national registers to follow a cohort of 17,996 children born to women diagnosed with epilepsy any time before conception in Sweden from 1996 to 2016, following them through 2017. We examined maternal-reported use of the 4 most commonly reported ASMs: lamotrigine (n = 2,148, 11.9%), carbamazepine (n = 1,940, 10.8%), valproic acid (n = 1,043, 5.80%), and levetiracetam (n = 587, 3.26%). We identified birth defects using diagnoses recorded at the time of discharge from the hospital and inpatient and outpatient diagnoses recorded in the first year of life. Models were estimated in a stepped fashion: unadjusted, adjusted for covariates, among a subcohort born to women diagnosed 10 years before conception (n = 14,586), and restricted to monotherapy. Results: Valproic acid use in pregnancy had the strongest and most widespread associations with birth defects in children, with carbamazepine also having links to several birth defects, including respiratory system and genital organ defects. Lamotrigine use in pregnancy was associated with cleft lip/palate and chromosomal abnormalities. Levetiracetam was most often used with other ASMs and preliminarily associated with many birth defects. Discussion: Our findings support avoidance of valproic acid use in pregnancy whenever possible. Lamotrigine and carbamazepine may be safer alternatives. However, these medications were also associated with certain birth defects, including some not reported previously. We are among the first to examine the possible effects of levetiracetam use in pregnancy, though more research is needed to investigate this further.

Preliminary Validation of a General Factor Model of Chronic Overlapping Pain Conditions.

Chronic overlapping pain conditions (COPCs) by definition, frequently co-occur, perhaps reflecting their shared etiologies. Their overlapping nature presents a methodological challenge, possibly masking associations between COPCs and health outcomes attributable to either general or specific processes. To address this challenge, we used population-based cohort data to evaluate the predictive validity of a bifactor model of 9 self-reported COPCs by assessing its association with incident pain-related clinical diagnoses; pain-relevant pharmacotherapy; and other health outcomes. We obtained data from a 2005 to 2006 study of Swedish adult twins linked with health data from nationwide registers through 2016 (N = 25,418). We then fit a bifactor model comprising a general COPC factor and 2 independent specific factors measuring pain-related somatic symptoms and neck and shoulder pain. Accounting for age, biological sex, and cancer, the general factor was associated with increased risk of all pain-related outcomes (eg, COPC diagnosis adjusted odds ratio [aOR], 1.71; 95% confidence interval [1.62, 1.81]), most mental health-related outcomes (eg, depression aOR, 1.72 [1.60, 1.85]), and overdose and mortality (eg, all-cause mortality aOR, 1.25 [1.09, 1.43]). The somatic symptoms specific factor was associated with pain-relevant pharmacotherapy (eg, prescribed opioids aOR, 1.25 [1.15, 1.36]), most mental health-related outcomes (eg, depression aOR, 1.95 [1.70, 2.23]), and overdose (eg, nonfatal overdose aOR, 1.66 [1.31, 2.10]). The neck and shoulder pain-specific factor was weakly and inconsistently associated with the outcomes. Findings provide initial support for the validity and utility of a general-factor model of COPCs as a tool to strengthen understanding of co-occurrence, etiology, and consequences of chronic pain. PERSPECTIVE: This article presents associations between a novel measurement model of COPCs and various health outcomes. Findings provide support for measuring pain across multiple domains rather than only measuring pain specific to one physical location in both research and clinical contexts.

Racial-Ethnic Differences in ADHD Diagnosis and Treatment During Adolescence and Early Adulthood.

OBJECTIVE: This study examined racial-ethnic differences in attention-deficit hyperactivity disorder (ADHD) diagnosis and treatment during adolescence and early adulthood. METHODS: A national health care claims database was used to identify a cohort of 4,216,757 commercially insured youths with at least 1 year of coverage during 2014-2019. Racial-ethnic differences in the prevalence of visits with a recorded ADHD diagnosis (identified through ICD-9-CM and ICD-10-CM codes) and of ADHD treatment (identified through medical claims for psychosocial treatments and pharmacy claims for ADHD medications) were examined. Period prevalence rates were determined within five age categories, stratified by race-ethnicity. Poisson regression with a natural log link was used within each age category to estimate prevalence ratios (PRs) comparing prevalence in each racially and ethnically minoritized group with prevalence in the White group. RESULTS: The overall prevalence of ADHD diagnosis was 9.1% at ages 12-14 and 5.3% at ages 24-25. In each age category, Asian, Black, and Hispanic youths had lower prevalence of ADHD diagnosis than did White youths (PR=0.29-0.77). Among youths with an ADHD diagnosis, relative racial-ethnic differences in treatment were small (PR=0.92-1.03). CONCLUSIONS: Throughout adolescence and early adulthood, racially and ethnically minoritized youths were less likely than White youths to have health care visits with recorded ADHD diagnoses and, among those with diagnoses, were also slightly less likely to receive treatment. More research is needed to understand the processes underlying these differences and their potential health consequences among racially and ethnically minoritized youths.

Alcohol consumption's effects on working memory: Examining familial confounding.

OBJECTIVE: The purpose of our study was to provide a more rigorous test of the causal hypothesis that chronic alcohol use impairs working memory performance. METHOD: We measured linear associations between a latent factor representing alcohol consumption and accuracy across four working memory tasks before and after accounting for familial confounding using a cotwin control design. Specifically, this study examined accuracy through a latent working memory score, the National Institutes of Health (NIH) Toolbox List Sorting, NIH Toolbox Picture Sequence, Penn Word Memory, and 2-back tasks. The study included data from 158 dizygotic and 278 monozygotic twins (Mage = 29 ± 3 years). RESULTS: In our initial sample-wide analysis, we did not detect any statistically significant associations between alcohol use and working memory accuracy. However, our cotwin control analyses showed that twins with greater levels of alcohol use exhibited worse scores on the latent working memory composite measure (B = -.25, CI [-.43, -.08], p < .01), Picture Sequence (B = -.31, CI [-.55, -.08], p < .01), and List Sorting (B = -.28, CI [-.51, -.06 ], p = .01) tasks than did their cotwins. CONCLUSIONS: These results are consistent with a potentially causal relationship between alcohol use and working memory performance that can be detected only after accounting for confounding familial factors. This highlights the importance of understanding the mechanisms that may underlie negative associations between alcohol use and cognitive performance, as well as the potential factors that influence both alcohol behaviors and cognition. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Attention-Deficit/Hyperactivity Disorder Medications and Long-Term Risk of Cardiovascular Diseases.

Importance: Use of attention-deficit/hyperactivity disorder (ADHD) medications has increased substantially over the past decades. However, the potential risk of cardiovascular disease (CVD) associated with long-term ADHD medication use remains unclear. Objective: To assess the association between long-term use of ADHD medication and the risk of CVD. Design, Setting, and Participants: This case-control study included individuals in Sweden aged 6 to 64 years who received an incident diagnosis of ADHD or ADHD medication dispensation between January 1, 2007, and December 31, 2020. Data on ADHD and CVD diagnoses and ADHD medication dispensation were obtained from the Swedish National Inpatient Register and the Swedish Prescribed Drug Register, respectively. Cases included individuals with ADHD and an incident CVD diagnosis (ischemic heart diseases, cerebrovascular diseases, hypertension, heart failure, arrhythmias, thromboembolic disease, arterial disease, and other forms of heart disease). Incidence density sampling was used to match cases with up to 5 controls without CVD based on age, sex, and calendar time. Cases and controls had the same duration of follow-up. Exposure: Cumulative duration of ADHD medication use up to 14 years. Main Outcomes and Measures: The primary outcome was incident CVD. The association between CVD and cumulative duration of ADHD medication use was measured using adjusted odds ratios (AORs) with 95% CIs. Results: Of 278 027 individuals with ADHD aged 6 to 64 years, 10 388 with CVD were identified (median [IQR] age, 34.6 [20.0-45.7] years; 6154 males [59.2%]) and matched with 51 672 control participants without CVD (median [IQR] age, 34.6 [19.8-45.6] years; 30 601 males [59.2%]). Median (IQR) follow-up time in both groups was 4.1 (1.9-6.8) years. Longer cumulative duration of ADHD medication use was associated with an increased risk of CVD compared with nonuse (0 to ≤1 year: AOR, 0.99 [95% CI, 0.93-1.06]; 1 to ≤2 years: AOR, 1.09 [95% CI, 1.01-1.18]; 2 to ≤3 years: AOR, 1.15 [95% CI, 1.05-1.25]; 3 to ≤5 years: AOR, 1.27 [95% CI, 1.17-1.39]; and >5 years: AOR, 1.23 [95% CI, 1.12-1.36]). Longer cumulative ADHD medication use was associated with an increased risk of hypertension (eg, 3 to ≤5 years: AOR, 1.72 [95% CI, 1.51-1.97] and >5 years: AOR, 1.80 [95% CI, 1.55-2.08]) and arterial disease (eg, 3 to ≤5 years: AOR, 1.65 [95% CI, 1.11-2.45] and >5 years: AOR, 1.49 [95% CI, 0.96-2.32]). Across the 14-year follow-up, each 1-year increase of ADHD medication use was associated with a 4% increased risk of CVD (AOR, 1.04 [95% CI, 1.03-1.05]), with a larger increase in risk in the first 3 years of cumulative use (AOR, 1.08 [95% CI, 1.04-1.11]) and stable risk over the remaining follow-up. Similar patterns were observed in children and youth (aged <25 years) and adults (aged ≥25 years). Conclusions and Relevance: This case-control study found that long-term exposure to ADHD medications was associated with an increased risk of CVDs, especially hypertension and arterial disease. These findings highlight the importance of carefully weighing potential benefits and risks when making treatment decisions about long-term ADHD medication use. Clinicians should regularly and consistently monitor cardiovascular signs and symptoms throughout the course of treatment.

Neuro-ophthalmologic and blood biomarker responses in ADHD following subconcussive head impacts: a case-control trial.

Introduction: This clinical trial aimed to determine the influence of attention-deficit/hyperactivity disorder (ADHD) on neuro-ophthalmologic function and brain-derived blood biomarkers following acute subconcussive head impacts. Methods: The present trial consisted of age- and sex-matched samples with a ratio of 1:1 between two groups with a total sample size of 60 adults (age ± SD; 20.0 ± 1.8 years). Soccer players diagnosed with and medicated daily for ADHD were assigned into an ADHD group (n = 30). Soccer players without ADHD were assigned into a non-ADHD group (n = 30). Participants performed 10 soccer headers with a soccer ball projected at a velocity of 25mph. King-Devick test (KDT), near point of convergence (NPC), and serum levels of NF-L, tau, GFAP, and UCH-L1 were assessed at baseline (pre-heading) and at 2 h and 24 h post-heading. Results: There were no statistically significant group-by-time interactions in outcome measures. However, at baseline, the ADHD group exhibited lower neuro-ophthalmologic functions compared to the non-ADHD group (NPC: p = 0.019; KDT: p = 0.018), and persisted at 2 h-post (NPC: p = 0.007; KDT: p = 0.014) and 24 h-post heading (NPC: p = 0.001). NPC significantly worsened over time in both groups compared to baseline [ADHD: 2 h-post, 1.23 cm, 95%CI:(0.77, 1.69), p < 0.001; 24 h-post, 1.68 cm, 95%CI:(1.22, 2.13), p = 0.001; Non-ADHD: 2 h-post, 0.96 cm, 95%CI:(0.50, 1.42), p < 0.001; 24 h-post, 1.09 cm, 95%CI:(0.63, 1.55), p < 0.001]. Conversely, improvements in KDT time compared to baseline occurred at 2 h-post in the non-ADHD group [-1.32 s, 95%CI:(-2.55, -0.09), p = 0.04] and at 24 h-post in both groups [ADHD: -4.66 s, 95%CI:(-5.89, -3.43), p < 0.001; Non-ADHD: -3.46 s, 95%CI:(-4.69, -2.23), p < 0.001)]. There were no group-by-time interactions for GFAP as both groups exhibited increased levels at 2 h-post [ADHD: 7.75 pg./mL, 95%CI:(1.41, 14.10), p = 0.019; Non-ADHD: 7.91 pg./mL, 95%CI:(1.71, 14.14), p = 0.015)] that returned to baseline at 24 h-post. NF-L levels increased at 2 h-post heading in the ADHD group [0.45 pg./mL, 95%CI:(0.05, 0.86), p = 0.032], but no significant NF-L changes were observed in the non-ADHD group over time. Discussion: Ten soccer headers elevated GFAP levels and NPC impairment in both groups. However, persisting group difference in NPC, blunted KDT performance, and increased NF-L levels in the ADHD group suggest that ADHD may reduce neuro-ophthalmologic function and heighten axonal response to soccer headers. Clinical trial registration: ClinicalTrials.gov, identifier ID: (NCT04880304).

We need to talk: The urgent conversation on chronic pain, mental health, prescribing patterns and the opioid crisis.

The opioid crisis' pathways from first exposure onwards to eventual illnesses and fatalities are multiple, intertwined and difficult to dissect. Here, we offer a multidisciplinary appraisal of the relationships among mental health, chronic pain, prescribing patterns worldwide and the opioid crisis. Because the opioid crisis' toll is especially harsh on young people, emphasis is given on data regarding the younger strata of the population. Because analgesic opioid prescription constitute a recognised entry point towards misuse, opioid use disorder, and ultimately overdose, prescribing patterns across different countries are examined as a modifiable hazard factor along these pathways of risk. Psychiatrists are called to play a more compelling role in this urgent conversation, as they are uniquely placed to provide synthesis and lead action among the different fields of knowledge and care that lie at the crossroads of the opioid crisis. Psychiatrists are also ideally positioned to gauge and disseminate the foundations for diagnosis and clinical management of mental conditions associated with chronic pain, including the identification of hazardous and protective factors. It is our hope to spark more interdisciplinary exchanges and encourage psychiatrists worldwide to become leaders in an urgent conversation with interlocutors from the clinical and basic sciences, policy makers and stakeholders including clients and their families.

A nationwide study of initiation of antidepressant pharmacotherapy and the risk of seizures.

OBJECTIVE: The present study aimed to examine whether antidepressant initiation increases the risk of hospitalizations and unplanned outpatient visits for seizures. Research has provided conflicting evidence as to whether antidepressant initiation causes seizures. Because epilepsy and depression are comorbid, this remains an important question, particularly in the care of those already at-risk for seizures. METHODS: We used Swedish-register data, including 658,766 antidepressant initiators and 1:1 age-, region-, and sex-matched non-initiators, ages 12-65. We used filled prescriptions to identify any antidepressant and serotonergic antidepressant and inpatient hospitalizations and unplanned outpatient (to avoid coding routine epilepsy maintenance as a seizure) visits to identify seizures, respectively. We first compared seizure visit incidence between antidepressant-initiators and matched non-users in the year following initiation from 2006 to 2013. To examine seizure risk over months pre- and post-initiation, within-individual analyses compared risk during the month one year prior to initiation with all subsequent months. We examined associations for any antidepressant and serotonergic antidepressants, as well as for any initiator and initiators with a history of seizures. RESULTS: Our matched-cohort results showed higher incidence of seizure visits among antidepressant users compared with non-users (e.g., adjusted incidence rate ratio [IRR]=3.14, 95% confidence interval [CI]=2.83-3.49). In within-individual analyses, the months after initiation were associated with higher incidence of seizure visits when compared with the month one year prior to initiation (e.g., one month after initiation IRR=1.96, 95%CI=1.64-2.34), but in individuals with a seizure history we observed weaker or no associations in the months after initiation (e.g., two months after initiation IRR=1.12, 95%CI=0.87-1.45). Notably, irrespective of potential seizure history, the months preceding initiation were associated with the greatest risk (e.g., one month before initiation IRR=2.86, 95% CI=2.42-3.38). CONCLUSIONS: Our findings suggest that there may be an elevated risk of seizures during antidepressant treatment, though the period of highest risk was before the initiation of antidepressants. Risk for seizure visits was lower among individuals with a history of prior seizures, which may be reassuring for the clinical care of these patients or indicate lack of treatment seeking following seizures. This study highlights the need to consider seizure risk across time; the failure to account for these dynamics may help account for discrepant findings in previous studies.

Toward more rigorous and informative nutritional epidemiology: The rational space between dismissal and defense of the status quo.

To date, nutritional epidemiology has relied heavily on relatively weak methods including simple observational designs and substandard measurements. Despite low internal validity and other sources of bias, claims of causality are made commonly in this literature. Nutritional epidemiology investigations can be improved through greater scientific rigor and adherence to scientific reporting commensurate with research methods used. Some commentators advocate jettisoning nutritional epidemiology entirely, perhaps believing improvements are impossible. Still others support only normative refinements. But neither abolition nor minor tweaks are appropriate. Nutritional epidemiology, in its present state, offers utility, yet also needs marked, reformational renovation. Changing the status quo will require ongoing, unflinching scrutiny of research questions, practices, and reporting-and a willingness to admit that "good enough" is no longer good enough. As such, a workshop entitled "Toward more rigorous and informative nutritional epidemiology: the rational space between dismissal and defense of the status quo" was held from July 15 to August 14, 2020. This virtual symposium focused on: (1) Stronger Designs, (2) Stronger Measurement, (3) Stronger Analyses, and (4) Stronger Execution and Reporting. Participants from several leading academic institutions explored existing, evolving, and new better practices, tools, and techniques to collaboratively advance specific recommendations for strengthening nutritional epidemiology.

Suicide Risk Before Mental Health Treatment Initiation: Implications for Screening and Access to Care.

With rising suicide rates in the United States over the past two decades, a critical need has emerged to improve interventions to prevent suicide. Previous research has indicated that the period before initiation of mental health treatment may be a particularly vulnerable time for individuals with suicidal behavior. Presence of suicide risk before treatment initiation highlights the need to improve suicide screening and access to care. The authors propose various care and policy considerations to increase, support, and maintain suicide prevention efforts.

Association between prescribed opioid dose and risk of motor vehicle crashes.

ABSTRACT: Opioid-involved motor vehicle traffic fatalities have increased over the past 2 decades. However, the extent to which prescribed opioids increase the risk of motor vehicle crashes remains uncertain. This study used real-world healthcare claims data to examine the association between prescription opioid dose and motor vehicle crash risk. Using nationwide US commercial insurance claims data for 2010 to 2018, we identified 772,404 adults who received incident, noncancer opioid therapy. We examined associations between daily prescription opioid dose, calculated in morphine milligram equivalents (MME) from filled prescription claims, and risk of motor vehicle crashes, assessed as diagnoses of motor vehicle injuries in claims for emergency visits, inpatient hospitalizations, and ambulance transportation. We estimated associations using a within-individual design, which ruled out all time-stable confounding. We complemented the design with time-varying statistical adjustment for other pharmacotherapies and a negative control pain pharmacotherapy analysis (with incident cyclic antidepressant prescriptions). During 2,150,009 person-years of follow-up, there were 12,123 motor vehicle crashes (5.64 crashes per 1000 person-years). In within-individual comparisons, crash risk was greater during opioid prescription periods involving doses ≤60 MME/day (odds ratio [OR], 3.86; 95% confidence interval [CI], 3.54, 4.21), >60 to 120 MME/day (OR, 5.46; 95% CI, 4.44, 6.73), and >120 MME/day (OR, 3.45; 95% CI, 2.31, 5.15) than during off-treatment periods. The negative control analysis supported the specificity of the results to opioids rather than to other processes associated with pharmacologic pain management. These findings suggest that the receipt of prescription opioids, even at doses ≤60 MME/day, is associated with an increased risk of motor vehicle crashes.

Within-person associations of escalated electronic nicotine delivery systems use with cigarette, alcohol, marijuana and drug use behaviors among US young adults.

AIMS: Most extant evidence has addressed between-person differences, short-term or cross-sectional associations of electronic nicotine delivery systems (ENDS) use with other substance use, the majority focusing on current rather than escalated use. The present study aimed to examine within-person changes in escalated ENDS use and their associations with individual and combined substance use over a 6-year period. DESIGN, SETTING AND PARTICIPANTS: This study used a longitudinal cohort design with US young adults. A generalized linear mixed-model approach was employed to fit a series of weighted logistic regression models. Data were drawn from waves 1-5 of the Population Assessment of Tobacco and Health (PATH) study in the United States. Of the 9110 young adults at baseline, aged 18-24 years, a total of 5042 individuals had matched data across all five waves of assessments. MEASUREMENTS: Escalated ENDS use was computed by subtracting the number of days of ENDS use within the past 30 days at wave w - 1 from that at wave w and coded as 1 = escalated, if the value was greater than zero (otherwise, coded as 0 = not escalated). FINDINGS: Escalated ENDS use gradually decreased over time, with the lowest prevalence at wave 4 (4.0%) but sharply increasing at wave 5 (8.4%). Escalated ENDS use was associated with increased odds of using each substance (binge drinking, marijuana use, marijuana vaping, prescription and illicit drugs) and different combinations of polysubstance use between cigarette smoking, binge drinking and marijuana use (Ps < 0.05). In addition, sweet/fruit flavor use (versus menthol/mint) was associated with increased likelihood of reporting co-use of cigarettes and marijuana. CONCLUSIONS: In the United States, the prevalence of young adults using electronic nicotine delivery systems appears to have increased steadily between 2013 and 2019, although the rate of increase may have started to accelerate in recent years. Escalated electronic nicotine delivery systems use and time-lagged established electronic nicotine delivery systems use appear to be prospectively associated with individual and combined substance use, particularly between cigarettes, alcohol and marijuana. Among established electronic nicotine delivery systems users, sweet/fruit flavor appears to be associated with increased risk of co-using cigarettes and marijuana.

Evidence of familial confounding of the association between cannabis use and cerebellar-cortical functional connectivity using a twin study.

Cerebellar-cortical resting-state functional connectivity (rsFC) has been reported to be altered in cannabis users. However, this association may be due to genetic and environmental confounding rather than a causal relationship between cannabis use and changes in rsFC. In this co-twin control study, linear mixed models were used to assess relationships between the number of lifetime cannabis uses (NLCU) and age of cannabis onset (ACO) with cerebellar-cortical rsFC. The rsFC with seven functional networks was evaluated in 147 monozygotic and 82 dizygotic twin pairs. Importantly, the use of genetically informed models in this twin sample facilitated examining whether shared genetic or environmental effects underlie crude associations between cannabis measures and connectivity. Individual-level phenotypic analyses (i.e., accounting for twin-pair non-independence) showed that individuals in the full sample with earlier ACO and higher NLCU had lower cerebellar rsFC within the VA, DA, and FP networks. Yet, there were no significant differences in cerebellar-cortical rsFC between monozygotic twins who were discordant for cannabis measures. These findings suggest shared genetic or environmental confounds contribute to associations between cannabis use and altered cerebellar-cortical rsFC, rather than unique causal impacts of cannabis use on cerebellar-cortical rsFC.

Use of central nervous system drugs in combination with selective serotonin reuptake inhibitor treatment: A Bayesian screening study for risk of suicidal behavior.

Background: Using other central nervous system (CNS) medications in combination with selective serotonin reuptake inhibitor (SSRI) treatment is common. Despite this, there is limited evidence on the impact on suicidal behavior of combining specific medications. We aim to provide evidence on signals for suicidal behavior risk when initiating CNS drugs during and outside of SSRI treatment. Materials and methods: Using a linkage of Swedish national registers, we identified a national cohort of SSRI users aged 6-59 years residing in Sweden 2006-2013. We used a two-stage Bayesian Poisson model to estimate the incidence rate ratio (IRR) of suicidal behavior in periods up to 90 days before and after a CNS drug initiation during SSRI treatment, while accounting for multiple testing. For comparison, and to assess whether there were interactions between SSRIs and other CNS drugs, we also estimated the IRR of initiating the CNS drug without SSRI treatment. Results: We identified 53 common CNS drugs initiated during SSRI treatment, dispensed to 262,721 individuals. We found 20 CNS drugs with statistically significant IRRs. Of these, two showed a greater risk of suicidal behavior after versus before initiating the CNS drug (alprazolam, IRR = 1.39; flunitrazepam, IRR = 1.83). We found several novel signals of drugs that were statistically significantly associated with a reduction in the suicidal behavior risk. We did not find evidence of harmful interactions between SSRIs and the selected CNS drugs. Conclusion: Several of the detected signals for reduced risk correspond to drugs where there is previous evidence of benefit for antidepressant augmentation (e.g., olanzapine, quetiapine, lithium, buspirone, and mirtazapine). Novel signals of reduced suicidal behavior risk, including for lamotrigine, valproic acid, risperidone, and melatonin, warrant further investigation.

Examining protective factors for substance use problems and self-harm behavior during adolescence: A longitudinal co-twin control study.

Sports participation, physical activity, and friendship quality are theorized to have protective effects on the developmental emergence of substance use and self-harm behavior in adolescence, but existing research has been mixed. This ambiguity could reflect, in part, the potential for confounding of observed associations by genetic and environmental factors, which previous research has been unable to rigorously rule out. We used data from the prospective, population-based Child and Adolescent Twin Study in Sweden (n = 18,234 born 1994-2001) and applied a co-twin control design to account for potential genetic and environmental confounding of sports participation, physical activity, and friendship quality (assessed at age 15) as presumed protective factors for adolescent substance use and self-harm behavior (assessed at age 18). While confidence intervals widened to include the null in numerous co-twin control analyses adjusting for childhood psychopathology, parent-reported sports participation and twin-reported positive friendship quality were associated with increased odds of alcohol problems and nicotine use. However, parent-reported sports participation, twin-reported physical activity, and twin-reported friendship quality were associated with decreased odds of self-harm behavior. The findings provide a more nuanced understanding of the risks and benefits of putative protective factors for risky behaviors that emerge during adolescence.

Maternal Serotonergic Antidepressant Use in Pregnancy and Risk of Seizures in Children.

OBJECTIVE: To evaluate whether children born to women who use serotonergic antidepressants during pregnancy have higher risk of neonatal seizures and epilepsy. METHODS: We used Swedish register-based data to examine associations between maternal-reported use of selective-serotonin reuptake inhibitor (SSRI) and selective serotonin-norepinephrine reuptake inhibitors (SNRI) in pregnancy and diagnosis of neonatal seizures and/or epilepsy in over 1.2 million children. To account for systematic differences between exposed and unexposed children we adjusted for a wide range of measured confounders. After first evaluating the role of maternal indication for SSRI/SNRI use (i.e., depression and anxiety) and parental epilepsy, we adjusted for remaining parental background factors (e.g., age, co-morbidities, education, and family socioeconomic indices) and pregnancy-specific characteristics (e.g., maternal use of other psychotropic medications and tobacco smoking in early pregnancy). RESULTS: Compared with all other children, children of women that reported use of SSRI/SNRI in pregnancy had an elevated risk of neonatal seizures and epilepsy (risk ratio [RR]=1.41, 95% confidence interval [CI]=1.03-1.94; hazard ratio [HR]=1.21, 95% CI=1.03-1.43 respectively). The estimates of association were attenuated by adjustment for maternal indications for SSRI/SNRI use (RR=1.30, 95% CI=0.94-1.79; HR = 1.13, 95% CI = 0.95-1.33), but not by additional adjustment for parental history of epilepsy. Full adjustment for all measured parental and pregnancy-specific factors resulted in substantial attenuation of the remaining associations (RR = 1.10, 95% CI = 0.79-1.53; HR = 0.96, 95% CI = 0.81-1.14). CONCLUSIONS: The present study found no support for the concern that maternal SSRI/SNRI use in pregnancy increases children's risk for neonatal seizures or epilepsy. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that exposure to SSRI/SNRI's in the first trimester of pregnancy is not associated with an increased incidence of neo-natal seizures/epilepsy.

Initiation of Opioid Prescription and Risk of Suicidal Behavior Among Youth and Young Adults.

BACKGROUND AND OBJECTIVES: Opioids are involved in an increasing proportion of suicide deaths. This study examined the association between opioid analgesic prescription initiation and suicidal behavior among young people. METHODS: We analyzed Swedish population-register data on 1 895 984 individuals ages 9 to 29 years without prior recorded opioid prescriptions. We identified prescriptions dispensed from January 2007 onward and diagnosed self-injurious behavior and death by suicide through December 2013. We first compared initiators with demographically matched noninitiators. To account for confounding, we applied an active comparator design, which examined suicidal behavior among opioid initiators relative to prescription nonsteroidal antiinflammatory drug (NSAID) initiators while inverse-probability-of-treatment weighting with individual and familial covariates. RESULTS: Among the cohort, 201 433 individuals initiated opioid prescription. Relative to demographically matched noninitiators, initiators (N = 180 808) had more than doubled risk of incident suicidal behavior (hazard ratio = 2.64; 95% confidence interval [CI], 2.47-2.81). However, in the active comparator design, opioid initiators (N = 86 635) had only 19% relatively greater risk of suicidal behavior compared with NSAID initiators (N = 255 096; hazard ratio = 1.19; 95% CI,: 1.11-1.28), corresponding to a weighted 5-year cumulative incidence of 2.2% (95% CI, 2.1-2.4) for opioid and 1.9% (95% CI, 1.9-2.0) for NSAID initiators. Most sensitivity analyses produced comparable results. CONCLUSIONS: Opioid initiation may make only a small contribution to the elevated risk of suicidal behavior among young people receiving pharmacologic pain management. In weighing benefits and harms of opioid initiation, our results suggest that increased risk of suicidal behavior may not be a major concern.