Antidepressant Use and Risk of Manic Episodes in Children and Adolescents With Unipolar Depression.

Importance: Antidepressants are increasingly prescribed to pediatric patients with unipolar depression, but little is known about the risk of treatment-emergent mania. Previous research suggests pediatric patients may be particularly vulnerable to this adverse outcome. Objective: To estimate whether pediatric patients treated with antidepressants have an increased incidence of mania/hypomania compared with patients not treated with antidepressants and to identify patient characteristics associated with the risk of mania/hypomania. Design, Setting, and Participants: In a cohort study applying the target trial emulation framework, nationwide inpatient and outpatient care in Sweden from July 1, 2006, to December 31, 2019, was evaluated. Follow-up was conducted for 12 and 52 weeks after treatment initiation, with administrative follow-up ending December 31, 2020. Data were analyzed between May 1, 2022, and June 28, 2023. Individuals aged 4 to 17 years with a diagnosis of depression, but without a prior diagnosis of mania/hypomania, bipolar disorder, or psychosis or treatment with mood stabilizer (lithium, valproate, or carbamazepine), prescriptions were included. Exposures: The treatment group included patients who initiated any antidepressant medication within 90 days of diagnosis. The control group included patients who did not initiate antidepressants within 90 days. Main Outcomes and Measures: Diagnosis of mania/hypomania or initiation of mood stabilizer therapy. Incidences were estimated with Kaplan-Meier estimator, and inverse probability of treatment weighting was used to adjust for group differences at baseline. Results: The cohort included 43 677 patients (28 885 [66%] girls); 24 573 in the treatment group and 19 104 in the control group. The median age was 15 (IQR, 14-16) years. The outcome occurred in 96 individuals by 12 weeks and in 291 by 52 weeks. The cumulative incidence of mania was 0.26% (95% CI, 0.19%-0.33%) in the treatment group and 0.20% (95% CI, 0.13%-0.27%) in the control group at 12 weeks, with a risk difference of 0.06% (95% CI, -0.04% to 0.16%). At 52 weeks, the cumulative incidence was 0.79% (95% CI, 0.68%-0.91%) in the treatment group and 0.52% (95% CI, 0.40%-0.63%) in the control group (risk difference, 0.28%; 95% CI, 0.12%-0.44%). Hospitalizations, parental bipolar disorder, and use of antipsychotics and antiepileptics were the most important predictors of mania/hypomania by 12 weeks. Conclusion: This cohort study found no evidence of treatment-emergent mania/hypomania by 12 weeks in children and adolescents. This corresponds to the time frame for antidepressants to exert their psychotropic effect. A small risk difference was found only with longer follow-up. Certain patient characteristics were associated with mania/hypomania, which warrants clinical attention.

Comparative Safety of Antidepressants in Adults with CKD.

BACKGROUND: Depression is prevalent in patients with CKD and is related to poor prognosis. Despite the widespread use of antidepressants in the CKD population, their safety remains unclear. METHODS: We identified adults with CKD stages G3-5 (eGFR <60 ml/min per 1.73 m2 not treated with dialysis) and incident depression diagnosis during 2007-2019 from the Stockholm Creatinine Measurements project. Using the target trial emulation framework, we compared the following treatment strategies: (1) initiating versus not initiating antidepressants, (2) initiating mirtazapine versus selective serotonin reuptake inhibitors (SSRIs), and (3) initiating SSRIs with a lower dose versus a standard dose. RESULTS: Of 7798 eligible individuals, 5743 (74%) initiated antidepressant treatment. Compared with noninitiation, initiation of antidepressants was associated with higher hazards of short-term outcomes, including hip fracture (hazard ratio [HR], 1.23; 95% confidence interval [CI], 0.88 to 1.74) and upper gastrointestinal bleeding (HR, 1.38; 95% CI, 0.82 to 2.31), although not statistically significant. Initiation of antidepressants was not associated with long-term outcomes, including all-cause mortality, major adverse cardiovascular event, CKD progression, and suicidal behavior. Compared with SSRIs, initiation of mirtazapine was associated with a lower hazard of upper gastrointestinal bleeding (HR, 0.52; 95% CI, 0.29 to 0.96), but a higher hazard of mortality (HR, 1.11; 95% CI, 1.00 to 1.22). Compared with the standard dose, initiation of SSRIs with a lower dose was associated with nonstatistically significantly lower hazards of upper gastrointestinal bleeding (HR, 0.68; 95% CI, 0.35 to 1.34) and CKD progression (HR, 0.80; 95% CI, 0.63 to 1.02), but a higher hazard of cardiac arrest (HR, 2.34; 95% CI, 1.02 to 5.40). CONCLUSIONS: Antidepressant treatment was associated with short-term adverse outcomes but not long-term outcomes in people with CKD and depression.

Psychotropic Medication Use in Children and Adolescents With Type 1 Diabetes.

Importance: Children and adolescents with type 1 diabetes (T1D) face elevated risks of psychiatric disorders. Despite their nonnegligible adverse effects, psychotropic medications are a common cost-effective approach to alleviating psychiatric symptoms, but evidence regarding their dispensation to children and adolescents with T1D remains lacking. Objective: To examine the trends and patterns of psychotropic medication dispensation among children and adolescents with T1D in Sweden between 2006 and 2019. Design, Setting, and Participants: This cohort study used data from multiple Swedish registers. The main study cohort included children and adolescents residing in Sweden from 2006 to 2019 and was followed up until the earliest of December 31, 2019, 18th birthday, emigration, or death. Data analyses were conducted from November 1, 2022, to April 30, 2023. Exposures: Type 1 diabetes. Main Outcomes and Measures: The primary outcomes were trends and patterns of psychotropic medication dispensation (including antipsychotics, antidepressants, anxiolytics, hypnotics, mood stabilizers, and medications for attention-deficit/hyperactivity disorder [ADHD]), psychotropic medication initiation, and history of neurodevelopmental and psychiatric diagnosis. Cumulative incidence curves and Cox proportional hazard models were used to estimate the aggregated incidence and hazard ratios of medication initiation after diabetes onset. Results: Of 3 723 745 children and adolescents (1 896 199 boys [50.9%]), 13 200 (0.4%; 7242 boys [54.9%]) had T1D (median [IQR] age at diagnosis, 11.1 [7.6-14.7] years). Between 2006 and 2019, psychotropic medication dispensation increased from 0.85% (95% CI, 0.65%-1.10%) to 3.84% (3.11%-4.69%) among children and from 2.72% (95% CI, 2.15%-3.39%) to 13.54% (95% CI, 12.88%-14.23%) among adolescents with T1D, consistently higher than their peers without T1D. The most commonly dispensed medications included hypnotics, ADHD medications, anxiolytics, and selective serotonin reuptake inhibitors, and all exhibited increasing trends. For those with T1D, psychiatric care was the primary prescription source, and up to 50.1% of treatments lasted more than 12 months. In addition, children and adolescents with T1D showed higher cumulative incidence and hazard ratios of medication initiation after diabetes onset than their same-age and same-sex counterparts. Conclusions and Relevance: This cohort study found an increasing trend in psychotropic medication dispensation among children and adolescents with T1D from 2006 to 2019, persistently higher than those without T1D. These findings call for further in-depth investigations into the benefits and risks of psychotropic medications within this population and highlight the importance of integrating pediatric diabetes care and mental health care for early detection of psychological needs and careful monitoring of medication use.

Predicting risk of suicidal behaviour after initiation of selective serotonin reuptake inhibitors in children, adolescents and young adults: protocol for development and validation of clinical prediction models.

INTRODUCTION: There is concern regarding suicidal behaviour risk during selective serotonin reuptake inhibitor (SSRI) treatment among the young. A clinically useful model for predicting suicidal behaviour risk should have high predictive performance in terms of discrimination and calibration; transparency and ease of implementation are desirable. METHODS AND ANALYSIS: Using Swedish national registers, we will identify individuals initiating an SSRI aged 8-24 years 2007-2020. We will develop: (A) a model based on a broad set of predictors, and (B) a model based on a restricted set of predictors. For the broad predictor model, we will consider an ensemble of four base models: XGBoost (XG), neural net (NN), elastic net logistic regression (EN) and support vector machine (SVM). The predictors with the greatest contribution to predictive performance in the base models will be determined. For the restricted predictor model, clinical input will be used to select predictors based on the top predictors in the broad model, and inputted in each of the XG, NN, EN and SVM models. If any show superiority in predictive performance as defined by the area under the receiver-operator curve, this model will be selected as the final model; otherwise, the EN model will be selected. The training and testing samples will consist of data from 2007 to 2017 and from 2018 to 2020, respectively. We will additionally assess the final model performance in individuals receiving a depression diagnosis within 90 days before SSRI initiation.The aims are to (A) develop a model predicting suicidal behaviour risk after SSRI initiation among children and youths, using machine learning methods, and (B) develop a model with a restricted set of predictors, favouring transparency and scalability. ETHICS AND DISSEMINATION: The research is approved by the Swedish Ethical Review Authority (2020-06540). We will disseminate findings by publishing in peer-reviewed open-access journals, and presenting at international conferences.

Effect of selective serotonin reuptake inhibitor treatment following diagnosis of depression on suicidal behaviour risk: a target trial emulation.

There is concern regarding the impact of selective serotonin reuptake inhibitors (SSRIs) on suicidal behaviour. Using the target trial framework, we investigated the effect on suicidal behaviour of SSRI treatment following a depression diagnosis. We identified 162,267 individuals receiving a depression diagnosis aged 6-59 years during 2006-2018 in Stockholm County, Sweden, after at least 1 year without antidepressant dispensation. Individuals who initiated an SSRI within 28 days of the diagnosis were assigned as SSRI initiators, others as non-initiators. Intention-to-treat and per-protocol effects were estimated; for the latter, individuals were censored when they ceased adhering to their assigned treatment strategy. We applied inverse probability weighting (IPW) to account for baseline confounding in the intention-to-treat analysis, and additionally for treatment non-adherence and time-varying confounding in the per-protocol analysis. The suicidal behaviour risk difference (RD), and risk ratio (RR) between SSRI initiators and non-initiators were estimated at 12 weeks. In the overall cohort, we found an increased risk of suicidal behaviour among SSRI initiators (intention-to-treat RR = 1.50, 95% CI = 1.25, 1.80; per-protocol RR = 1.69, 95% CI = 1.20, 2.36). In age strata, we only found evidence of an increased risk among individuals under age 25, with the greatest risk among 6-17-year-olds (intention-to-treat RR = 2.90, 95% CI = 1.72, 4.91; per-protocol RR = 3.34, 95% CI = 1.59, 7.00). Our finding of an increased suicidal behaviour risk among individuals under age 25 reflects evidence from RCTs. We found no evidence of an effect in the high-risk group of individuals with past suicidal behaviour. Further studies with information on a wider array of confounders are called for.

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.

Melatonin use and the risk of self-harm and unintentional injuries in youths with and without psychiatric disorders.

BACKGROUND: Sleep disorders in youth have been associated with increased risks of injury, including suicidal behavior. This study investigated whether melatonin, which is the most common medication for sleep disturbances in youth in Sweden, is associated with a decreased risk of injury. METHODS: This population-based cohort study included 25,575 youths who initiated melatonin treatment between ages 6 and 18. Poisson regression was used to estimate rate of injuries in the year prior to and following melatonin treatment initiation. A within-individual design was used to estimate relative risks by comparing injury risk in the last unmedicated month with injury risks in the 12 months after medication initiation. Analyses were stratified by sex, injury type, psychiatric comorbidities and age at melatonin-treatment initiation. RESULTS: While body injuries, falls and transport accident rates were comparable in the year before and after melatonin-treatment initiation, the risk of self-harm was highest in the months immediately prior to medication, and decreased thereafter. This was particularly prominent among adolescents with depression and/or anxiety, with females displaying greater absolute risks than males. Compared to the last unmedicated month, the 12 months post medication initiation had decreased relative risks for self-harm, with an IRR [95% CI] in the month following melatonin-treatment initiation of 0.46 [0.27-0.76] among adolescent females with psychiatric disorders, after excluding antidepressant users. CONCLUSIONS: Decreased risk of intentional self-harm was observed following melatonin-treatment initiation among females with depression and anxiety, suggesting that sleep interventions could be considered in an effort to reduce risk of self-harm in this population.

Use of hormonal contraceptives and antidepressants and risks of suicidal behavior and accidents among women with premenstrual disorders: a nationwide cohort study.

BACKGROUND: Women with premenstrual disorders (PMDs) are at increased risks of suicidal behavior and accidents. However, the effect of PMD first-line treatment on such risks have not been assessed. METHODS: To study the association between use of hormonal contraceptives or antidepressants and subsequent risks of suicidal behavior and accidents among women with PMDs. We conducted a nationwide register-based cohort study with between- and within-individual analyses in Sweden. All women with a clinical diagnosis/indication of PMDs recorded in the Patient Register and the Prescribed Drug Register during 1987-2011 were included (n = 23 029, age 15-52 years). Information on hormonal contraceptives and antidepressants prescribed for these women was obtained from the Prescribed Drug Register. Events of suicidal behavior (complete suicide and suicide attempt) and accidents were separately identified through the Patient and the Causes of Death Registers. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) of suicidal behavior and accidents after use of hormonal contraceptives or antidepressants were estimated in between-individual and within-individual analyses (i.e., comparing the risk between use and no use in the same individual) using Poisson regression. RESULTS: Women with PMDs were followed for a median of 6.2 years. Compared to no use of hormonal contraceptives, use of hormonal contraceptives was associated with a lower risk of suicidal behavior in both between-individual (IRR 0.76, 0.43-1.34) and within-individual analyses (IRR 0.65, 0.51-0.83). These risk reductions were primarily restricted to combined products (IRR 0.18, 0.07-0.47 and 0.19, 0.08-0.42 in between- and within-individual analyses) and observed among women with/without psychiatric comorbidities (p for interaction 0.830 and 0.043 in between- and within-individual analyses). Yet, the use of hormonal contraceptives was not consistently associated with risk of accidents between between-individual (IRR 1.13, 1.01-1.27) and within-individual analyses (IRR 1.01, 0.92-1.11). Use of antidepressants was associated with a higher risk of suicidal behavior and accidents in both between- and within-individual analyses. CONCLUSIONS: Our findings suggest that use of hormonal contraceptives, particularly combined products, is associated with reduced rates of suicidal behaviors, but not accidents, among women with PMDs. The estimates for antidepressants may be biased by indication.

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.

Kidney function and prescribed dose in middle-aged and older patients starting selective serotonin reuptake inhibitors.

PURPOSE: To avoid adverse drug reactions, dose reductions are recommended when prescribing selective serotonin reuptake inhibitors (SSRIs) to patients with impaired kidney function. The extent of this practice in routine clinical care is however unknown. We aimed to evaluate the starting and maintenance SSRI doses prescribed to patients stratified by levels of kidney function in real-world practice. METHODS: Using data from the Stockholm CREAtinine Measurements (SCREAM) project, we identified 101 409 new users of antidepressants (including 52 286 SSRI users) in the region of Stockholm during 2006-2019, who were ≥50 years of age and had a recent creatinine test taken in order to estimate glomerular filtration rate (eGFR). SSRI dose reduction was defined as a prescribed SSRI dose of ≤0.5 defined daily doses, according to current recommendations. We examined the associations between eGFR and reductions in initial dose and maintenance dose of SSRIs using logistic regression models. RESULTS: Overall, reductions in initial and maintenance dose were observed among 54.1% and 34.1% of new SSRI users. Nevertheless, about 40% of individuals with an eGFR <30 ml/min/1.73 m2 were prescribed an SSRI without dose reduction. After adjusting for age and other covariates, lower eGFR was associated with moderately higher odds of dose reduction, for both initial and maintenance dose. Compared to individuals with an eGFR of 90-104 ml/min/1.73 m2 , the adjusted odds ratios for those with an eGFR <30 ml/min/1.73 m2 were 1.18 (95% CI: 1.03, 1.36) for initial dose reduction, and 1.49 (1.29, 1.72) for maintenance dose reduction. Stratified analyses showed stronger associations between lower eGFR and SSRI dose reduction among individuals aged 50-64 years and in those receiving prescriptions from psychiatric care. CONCLUSIONS: Lower kidney function was moderately associated with a reduced SSRI dose, independently of age. Prescribing SSRIs to middle-aged and older patients should not only consider patients' age but also their kidney function.

Selective serotonin reuptake inhibitors and suicidal behaviour: a population-based cohort study.

There is concern that selective serotonin reuptake inhibitor (SSRI) treatment may increase the risk of suicide attempts or deaths, particularly among children and adolescents. However, debate remains regarding the nature of the relationship. Using nationwide Swedish registers, we identified all individuals aged 6-59 years with an incident SSRI dispensation (N = 538,577) from 2006 to 2013. To account for selection into treatment, we used a within-individual design to compare the risk of suicide attempts or deaths (suicidal behaviour) in time periods before and after SSRI-treatment initiation. Within-individual incidence rate ratios (IRRs) of suicidal behaviour were estimated. The 30 days before SSRI-treatment initiation was associated with the highest risk of suicidal behaviour compared with the 30 days 1 year before SSRI initiation (IRR = 7.35, 95% CI 6.60-8.18). Compared with the 30 days before SSRI initiation, treatment periods after initiation had a reduced risk-the IRR in the 30 days after initiation was 0.62 (95% CI 0.58-0.65). The risk then declined over treatment time. These patterns were similar across age strata, and when stratifying on history of suicide attempts. Initiation with escitalopram was associated with the greatest risk reduction, though CIs for the IRRs of the different SSRI types were overlapping. The results do not suggest that SSRI-treatment increases the risk for suicidal behaviour in either youths or adults; rather, it may reduce the risk. Further research with different study designs and in different populations is warranted.

Association of selective serotonin re-uptake inhibitor (SSRI) treatment with acute substance misuse outcomes.

BACKGROUND AND AIMS: Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed medications for patients with anxiety/depression. These patients often have problems with substance use, but it remains unclear whether the risk of substance misuse is influenced by SSRI treatment. We aimed to determine whether SSRI treatment is associated with a decreased risk of acute substance misuse-related outcomes. DESIGN: Cohort study following individuals through Swedish nation-wide registers between July 2005 and December 2013 and comparing the risk of substance misuse outcomes during periods on- versus off-treatment within the same individual. SETTING: Swedish general population. PARTICIPANTS: Individuals with a newly dispensed prescription of SSRIs between July 2006 and December 2013 and an ICD-10 diagnosis of anxiety/depressive disorder before the first treatment initiation. The cohort included 146 114 individuals (60.7% women). MEASUREMENTS: Substance misuse outcomes included ICD-10 diagnoses of acute intoxications (F10.0-F19.0), accidental poisonings by alcohol or drugs (X41-X42, X45-X46) and substance-related criminal offenses. FINDINGS: The absolute rate of substance misuse increased sharply before the onset of SSRI treatment and decreased after treatment initiation. Stratified Cox regression models showed an elevated risk [hazard ratio (HR) = 1.70, 95% confidence interval (CI) = 1.62-1.78] of substance misuse outcomes during a 1-month period preceding treatment initiation, compared with the reference period of more than 1 month before treatment start. The on-treatment estimates (1-30 days, HR = 1.29, 95% CI = 1.23-1.37; 31-120 days, HR = 1.30, 95% CI = 1.24-1.35; and > 120 days, HR = 1.24, 95% CI = 1.18-1.30 after treatment initiation] were consistently lower than the 1-month pre-treatment estimate, but still elevated compared with the reference period. CONCLUSIONS: For people with anxiety/depression, the risk of substance misuse appears to be particularly elevated immediately before initiating selective serotonin reuptake inhibitor (SSRI) treatment, which may reflect the emergence or worsening of substance use problems concurrently with anxiety/depression. SSRI treatment appears to be associated with a lower risk of substance misuse compared with the 1-month period preceding treatment initiation, but causality remains uncertain.

Prediction of treatment dosage and duration from free-text prescriptions: an application to ADHD medications in the Swedish prescribed drug register.

BACKGROUND: Accurate estimation of daily dosage and duration of medication use is essential to pharmacoepidemiological studies using electronic healthcare databases. However, such information is not directly available in many prescription databases, including the Swedish Prescribed Drug Register. OBJECTIVE: To develop and validate an algorithm for predicting prescribed daily dosage and treatment duration from free-text prescriptions, and apply the algorithm to ADHD medication prescriptions. METHODS: We developed an algorithm to predict daily dosage from free-text prescriptions using 8000 ADHD medication prescriptions as the training sample, and estimated treatment periods while taking into account several features including titration, stockpiling and non-perfect adherence. The algorithm was implemented to all ADHD medication prescriptions from the Swedish Prescribed Drug Register in 2013. A validation sample of 1000 ADHD medication prescriptions, independent of the training sample, was used to assess the accuracy for predicted daily dosage. FINDINGS: In the validation sample, the overall accuracy for predicting daily dosage was 96.8%. Specifically, the natural language processing model (NLP1 and NLP2) have an accuracy of 99.2% and 96.3%, respectively. In an application to ADHD medication prescriptions in 2013, young adult ADHD medication users had the highest probability of discontinuing treatments as compared with other age groups. The daily dose of methylphenidate use increased with age substantially. CONCLUSIONS: The algorithm provides a flexible approach to estimate prescribed daily dosage and treatment duration from free-text prescriptions using register data. The algorithm showed a good performance for predicting daily dosage in external validation. CLINICAL IMPLICATIONS: The structured output of the algorithm could serve as basis for future pharmacoepidemiological studies evaluating utilization, effectiveness, and safety of medication use, which would facilitate evidence-based treatment decision-making.

Study designs and statistical approaches to suicide and prevention research in real-world data.

OBJECTIVE: To provide researchers, clinicians and policy makers with a primer to study designs, statistical approaches and graphical reporting methods for suicide research in real world data (RWD). METHODS: Study designs, statistical method and graphical reporting standards are detailed with examples from the recently published literature. RESULTS: Data sources and codes for identifying suicidal behavior are described. Study designs are described in detail for post-market surveillance, retrospective cohort studies, case control and nested case-control studies, and self-controlled (within-individual) studies including applications of marginal structural models. Graphical reporting of designs is described using an original research study. CONCLUSIONS: Compared to RCTs, RWE studies offer larger sample sizes, greater generalizability, and real-world validity. However, these non-experimental data risk uncontrolled confounding and potential introduction of bias unless data, design and statistical approaches are rigorously aligned.

Comedication and Polypharmacy With ADHD Medications in Adults: A Swedish Nationwide Study.

Objective: Evidence regarding comedication among individuals with ADHD is lacking, especially in adults. This study investigated comedication and polypharmacy with ADHD medications in adults. Method: We identified adults dispensed with ADHD medications during 2013 in Sweden and matched them to controls. Logistic regression was used to calculate odds ratios (ORs) of receiving other medications. Results: Individuals receiving ADHD medications had higher risk of receiving any major classes of somatic medications (ORs ranged from 4.1, 95% confidence interval [CI] = [4.0, 4.3], to 7.4, 95% CI = [6.5, 8.5] across age groups). They were more likely to receive respiratory system, alimentary tract and metabolic system, and cardiovascular system medications. In addition, they had higher risk of receiving any other psychotropic medications. The proportion of polypharmacy with five or more medication classes increased from 10.1% to 60.4% from 18 to 64 years. Conclusion: Comedication was more common in adults receiving ADHD medications. Potential benefits and harms of comedication and polypharmacy require further research. (J. of Att. Dis. XXXX; XX[X] XX-XX).

Associations between selective serotonin reuptake inhibitors and violent crime in adolescents, young, and older adults - a Swedish register-based study.

This study identified individuals ever dispensed a selective serotonin reuptake inhibitor (SSRI) aged 15-60 years during 2006-2013, using Swedish national registers. The outcome was violent crime conviction. The main statistical analyses assessed risks of violent crime during periods on compared to off SSRI treatment within individuals. Further analyses investigated risk over time in relation to treatment initiation and discontinuation. The study identified 785,337 individuals (64.2% female), experiencing 32,203 violent crimes in 5,707,293 person-years. Between-individual analyses found statistically significantly elevated Hazard Ratios (HRs) overall (HR = 1.10), and in 15-24 and 25-34 year-olds (HR = 1.19 and 1.16), but non-significant HRs in 35-44 and 45-60-year-olds (HR = 1.02 and 1.04). In within-individual analyses, where 2.6% of SSRI users were informative, hazards were elevated overall (HR = 1.26, 95% CI = 1.19, 1.34), and across age groups (HR of 1.35 [95% CI = 1.19, 1.54] in 25-34-year-olds to 1.15 [95% CI = 0.99, 1.33] in 35-44-year-olds). In the overall cohort, the within-individual HRs were significantly elevated throughout treatment (HRs of 1.24 to 1.35) and for up to 12 weeks post-discontinuation (HRs of 1.37 and 1.20). While questions on causality remain, these results indicate that there may be an increased risk of violent crime during SSRI treatment in a small group of individuals. It may persist throughout medicated periods, across age groups, and after treatment discontinuation. Further confirmation is needed from studies with different designs, and clinical focus should be on high-risk individuals, as a majority of SSRI-users (around 97% in our cohort) will not commit violent crimes.

Maternal pre-pregnancy overweight/obesity and the risk of attention-deficit/hyperactivity disorder in offspring: a systematic review, meta-analysis and quasi-experimental family-based study.

BACKGROUND: Previous studies are inconclusive concerning the association between maternal pre-pregnancy overweight/obesity and risk of attention-deficit/hyperactivity disorder (ADHD) in offspring. We therefore conducted a systematic review and meta-analysis to clarify this association. To address the variation in confounding adjustment between studies, especially inadequate adjustment of unmeasured familial confounding in most studies, we further performed cousin and sibling comparisons in a nationwide population-based cohort in Sweden. METHODS: We searched PubMed, Embase and PsycINFO during 1975-2018. We used random-effects models to calculate pooled risk ratios (RRs) with 95% confidence interval. In the population-based study, Cox proportional hazard models were used to calculate the unadjusted hazard ratios (HRs) and HRs adjusted for all confounders identified in previous studies. Stratified Cox models were applied to data on full cousins and full siblings to further control for unmeasured familial confounding. RESULTS: Eight cohorts with a total of 784 804 mother-child pairs were included in the meta-analysis. Maternal overweight [RRoverweight = 1.31 (1.25-1.38), I2 = 6.80%] and obesity [RRobesity = 1.92 (1.84-2.00), I2 = 0.00%] were both associated with an increased risk of ADHD in offspring. In the population-based cohort of 971 501 individuals born between 1992 and 2004, unadjusted Cox models revealed similar associations [HRoverweight = 1.30 (1.28-1.34), HRobesity = 1.92 (1.87-1.98)]. These associations gradually attenuated towards the null when adjusted for measured confounders [HRoverweight = 1.21 (1.19-1.25), HRobesity = 1.60 (1.55-1.65)], unmeasured factors shared by cousins [HRoverweight = 1.10 (0.98-1.23), HRobesity = 1.44 (1.22-1.70)] and unmeasured factors shared by siblings [HRoverweight = 1.01 (0.92-1.11), HRobesity = 1.10 (0.94-1.27)]. CONCLUSION: Pre-pregnancy overweight/obesity is associated with an increased risk of ADHD in offspring. The observed association is largely due to unmeasured familial confounding.

Current Genetic Service Delivery Models for the Provision of Genetic Testing in Europe: A Systematic Review of the Literature.

Background: The provision of genetic services, along with research in the fields of genomics and genetics, has evolved in recent years to meet the increasing demand of consumers interested in prediction of genetic diseases and various inherited traits. The aim of this study is to evaluate genetic services in order to identify and classify delivery models for the provision of genetic testing in European and in extra-European countries. Methods: A systematic review of the literature was conducted using five electronic resources. Inclusion criteria were that studies be published in English or Italian during the period 2000-2015 and carried out in European or extra-European countries (Canada, USA, Australia, or New Zealand). Results: 148 genetic programs were identified in 117 articles and were delivered mostly in the UK (59, 40%), USA (35, 24%) or Australia (16, 11%). The programs were available nationally (66; 45%), regionally (49; 33%) or in urban areas (21, 14%). Ninety-six (64%) of the programs were integrated into healthcare systems, 48 (32.21%) were pilot programs and five (3%) were direct-to-consumer genetic services. The genetic tests offered were mainly for BRCA1/2 (59, 40%), Lynch syndrome (23, 16%), and newborn screening (18, 12%). Healthcare professionals with different backgrounds are increasingly engaged in the provision of genetic services. Based on which healthcare professionals have prominent roles in the respective patient care pathways, genetic programs were classified into five models: (i) the geneticists model; (ii) the primary care model; (iii) the medical specialist model; (iv) the population screening programs model; and (v) the direct-to-consumer model. Conclusions: New models of genetic service delivery are currently under development worldwide to address the increasing demand for accessible and affordable services. These models require the integration of genetics into all medical specialties, collaboration among different healthcare professionals, and the redistribution of professional roles. An appropriate model for genetic service provision in a specific setting should ideally be defined according to the type of healthcare system, the genetic test provided within a genetic program, and the cost-effectiveness of the intervention. Only applications with proven efficacy and cost-effectiveness should be implemented in healthcare systems and made available to all citizens.

Antidepressant prescription patterns and CNS polypharmacy with antidepressants among children, adolescents, and young adults: a population-based study in Sweden.

This study examines trends in antidepressant drug dispensations among young people aged 0-24 years in Sweden during the period 2006-2013, as well as prescription patterns and central nervous system (CNS) polypharmacy with antidepressants. Using linkage of Swedish national registers, we identified all Swedish residents aged 0-24 years that collected at least one antidepressant prescription (here defined as antidepressant users) between 1 January 2006 and 31 December 2013 (n = 174,237), and categorized them as children (0-11 years), adolescents (12-17 years), and young adults (18-24 years). Prevalence of antidepressant dispensation rose from 1.4 to 2.1% between 2006 and 2013, with the greatest relative increase in adolescents [by 97.8% in males (from 0.6 to 1.3%) and by 86.3% in females (from 1.1 to 2.1%)]. Most individuals across age categories were prescribed selective serotonin reuptake inhibitors, received their prescriptions from psychiatric specialist care, and had treatment periods of over 12 months. Prevalence of CNS polypharmacy (dispensation of other CNS drug classes in addition to antidepressants) increased across age categories, with an overall increase in prevalence from 52.4% in 2006 to 62.1% in 2013. Children experienced the largest increase in polypharmacy of three or more psychotropic drug classes (4.4-10.1%). Anxiolytics, hypnotics, and sedatives comprised the most common additional CNS drug class among persons who were prescribed antidepressants. These findings show that the dispensation of antidepressants among the young is prevalent and growing in Sweden. The substantial degree of CNS polypharmacy in young patients receiving antidepressants requires careful monitoring and further research into potential benefits and harms.