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.

Determinants and Outcomes of Suicidal Behavior Among Patients With Major Depressive Disorder.

Importance: Major depressive disorder (MDD) is an important risk factor of suicidal behavior, but the added burden of suicidal behavior and MDD on the patient and societal level, including all-cause mortality, is not well studied. Also, the contribution of various prognostic factors for suicidal behavior has not been quantified in larger samples. Objective: To describe the clinical and societal outcomes, including all-cause mortality, of suicidal behavior in patients with MDD and to explore associated risk factors and clinical management to inform future research and guidelines. Design, Setting, and Participants: This population-based cohort study used health care data from the Stockholm MDD Cohort. Patients aged 18 years or older with episodes of MDD diagnosed between January 1, 2012, and December 31, 2017, in any health care setting were included. The dates of the data analysis were February 1 to November 1, 2022. Exposures: Patients with MDD with and without records of suicidal behavior. Main Outcomes and Measures: The main outcome was all-cause mortality. Secondary outcomes were comorbid conditions, medications, health care resource utilization (HCRU), and work loss. Using Region Stockholm registry variables, a risk score for factors associated with suicidal behavior within 1 year after the start of an MDD episode was calculated. Results: A total of 158 169 unipolar MDD episodes were identified in 145 577 patients; 2240 (1.4%) of these episodes, in 2219 patients, included records of suicidal behavior (mean [SD] patient age, 40.9 [18.6] years; 1415 episodes [63.2%] in women and 825 [36.8%] in men). A total of 11 109 MDD episodes in 9574 matched patients with MDD without records of suicidal behavior were included as controls (mean [SD] patient age, 40.8 [18.5] years; 7046 episodes [63.4%] in women and 4063 [36.6%] in men). The all-cause mortality rate was 2.5 per 100 person-years at risk for the MDD-SB group and 1.0 per 100 person-years at risk for the MDD-non-SB group, based on 466 deaths. Suicidal behavior was associated with higher all-cause mortality (hazard ratio, 2.62 [95% CI, 2.15-3.20]), as well as with HCRU and work loss, compared with the matched controls. Patients with MDD and suicidal behavior were younger and more prone to have psychiatric comorbid conditions, such as personality disorders, substance use, and anxiety, at the start of their episode. The most important factors associated with suicidal behavior within 1 year after the start of an MDD episode were history of suicidal behavior and age, history of substance use and sleep disorders, and care setting in which MDD was diagnosed. Conclusions and Relevance: This cohort study's findings suggest that high mortality, morbidity, HCRU, and work loss associated with MDD may be substantially accentuated in patients with MDD and suicidal behavior. Use of medication aimed at decreasing the risk of all-cause mortality during MDD episodes should be systematically evaluated to improve long-term outcomes.

Effect of Internet-Delivered Emotion Regulation Individual Therapy for Adolescents With Nonsuicidal Self-Injury Disorder: A Randomized Clinical Trial.

Importance: Nonsuicidal self-injury is prevalent in adolescence and associated with adverse clinical outcomes. Effective interventions that are brief, transportable, and scalable are lacking. Objective: To test the hypotheses that an internet-delivered emotion regulation individual therapy for adolescents delivered adjunctive to treatment as usual is superior to treatment as usual only in reducing nonsuicidal self-injury and that improvements in emotion regulation mediate these treatment effects. Design, Setting, and Participants: This 3-site, single-masked, randomized superiority trial enrolled participants from November 20, 2017, to April 9, 2020. Eligible participants were aged between 13 and 17 years and met diagnostic criteria for nonsuicidal self-injury disorder; they were enrolled as a mixed cohort of consecutive patients and volunteers. Parents participated in parallel to their children. The primary end point was at 1 month after treatment. Participants were followed up at 3 months posttreatment. Data collection ended in January 2021. Interventions: Twelve weeks of therapist-guided, internet-delivered emotion regulation individual therapy delivered adjunctive to treatment as usual vs treatment as usual only. Main Outcomes and Measures: Primary outcome was the youth version of the Deliberate Self-harm Inventory, both self-reported by participants prior to treatment, once every week during treatment, and for 4 weeks posttreatment, and clinician-rated by masked assessors prior to treatment and at 1 and 3 months posttreatment. Results: A total of 166 adolescents (mean [SD] age, 15.0 [1.2] years; 154 [92.8%] female) were randomized to internet-delivered emotion regulation therapy plus treatment as usual (84 participants) or treatment as usual only (82 participants). The experimental intervention was superior to the control condition in reducing clinician-rated nonsuicidal self-injury (82% vs 47% reduction; incidence rate ratio, 0.34; 95% CI, 0.20-0.57) from pretreatment to 1-month posttreatment. These results were maintained at 3-month posttreatment. Improvements in emotion dysregulation mediated improvements in self-injury during treatment. Conclusions and Relevance: In this randomized clinical trial, a 12-week, therapist-guided, internet-delivered emotion regulation therapy delivered adjunctive to treatment as usual was efficacious in reducing self-injury, and mediation analysis supported the theorized role of emotion regulation as the mechanism of change in this treatment. This treatment may increase availability of evidence-based psychological treatments for adolescents with nonsuicidal self-injury. Trial Registration: ClinicalTrials.gov Identifier: NCT03353961.

Factors associated with long-term benzodiazepine and Z-drug use across the lifespan and 5-year temporal trajectories among incident users: a Swedish nationwide register-based study.

PURPOSE: Despite being discouraged by guidelines, long-term use of benzodiazepines and related Z-drugs (BZDR) remains frequent in the real-world. An improved understanding of factors associated with the transition from new to long-term BZDR use and of temporal BZDR use trajectories is needed. We aimed to assess the proportion of long-term BZDR use (> 6 months) in incident BZDR-recipients across the lifespan; identify 5-year BZDR use trajectories; and explore individual characteristics (demographic, socioeconomic and clinical) and prescribing-related factors (pharmacological properties of the initial BZDR, prescriber's healthcare level, and concurrent dispensing of other medications) associated with long-term BZDR use and distinct trajectories. METHODS: Our nationwide register-based cohort included all BZDR-recipients in Sweden with first dispensation in 2007-2013. Trajectories of BZDR use days per year were built using group-based trajectory modelling. Cox regression and multinomial logistic regression were fitted to assess the predictors of long-term BZDR use and trajectories' membership. RESULTS: In 930,465 incident BZDR-recipients, long-term use increased with age (20.7%, 41.0%, and 57.4% in 0-17, 18-64, and ≥ 65-year-olds, respectively). Four BZDR use trajectories emerged, labelled 'discontinued', 'decreasing', 'slow decreasing' and 'maintained'. The proportion of the 'discontinued' trajectory members was the largest in all ages, but reduced from 75.0% in the youths to 39.3% in the elderly, whereas the 'maintained' increased with age from 4.6% to 36.7%. Prescribing-related factors, in particular multiple BZDRs at initiation and concurrent dispensing of other medications, were associated with increased risks of long-term (vs short-term) BZDR use and developing other trajectories (vs 'discontinued') in all age groups. CONCLUSIONS: The findings highlight the importance of raising awareness and providing support to prescribers to make evidence-based decisions on initiating and monitoring BZDR treatment across the lifespan.

School-based self-harm prevention programs: A systematic review with implications for international implementation.

Both self-harm and suicidal behaviors have been targeted through school-based prevention programs, many of which have been developed in the United States. The aims of this systematic review were to assess effects of school-based prevention programs on suicide and self-harm and to evaluate whether they are fit to the exporting culture. The review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Our inclusion criteria, structured according to population/problem, intervention, control/comparison, outome, were: children and youth up to 19 years of age, school-based programs at universal, selective or indicated levels compared with teaching as usual or with other programs, and outcomes of suicide or self-harm measured at least 10 weeks after intervention. Studies without a control group or using non-behavioral outcomes were excluded. A comprehensive and systematic literature search was conducted from the 1990s to March 2022. Risk for bias was assessed with checklists adapted from the Cochrane Risk of Bias (ROB) tool. A total of 1,801 abstracts were retrieved. Five studies fulfilled our inclusion criteria, but one had high risk for bias. Confidence in the evidence for effect was assessed with Grading of Recommendations Assessment, Development and Evaluation (GRADE). Studies included in this review were evaluated with respect to applicability in the context of international export. Only two school-based programs demonstrated efficacy in preventing suicidal behaviors. Although implementation of evidence-based interventions is a crucial next step, further replication with simultaneous attention to dissemination and implementation issues are called for. Funding and registration: conducted on assignment by the Swedish government. The protocol is available at the SBU website in Swedish.

Integrated cognitive behavioral treatment for substance use and depressive symptoms: a homeless case series and feasibility study.

BACKGROUND: Homelessness is associated with high prevalence of psychiatric disorders such as substance use disorders, including alcohol use disorder, and depression. METHODS: This case series and feasibility trial evaluated a novel integrated cognitive behavioral treatment (ICBT), which was adapted specifically for homeless individuals and developed to treat substance use and depressive symptoms simultaneously. The ICBT was delivered among four homeless individuals enrolled in the Treatment First program (a social services program where treatment is offered in conjunction with temporary transitional housing), who had access to stable and sober housing milieus. RESULTS: The ICBT was rated high in expectancy of improvement, credibility, and satisfaction, with few treatment-related adverse events, and fairly high treatment retention. At 12 months follow-up, three of four participants were not homeless anymore. Some participants experienced short-term reductions in substance use and/or depressive symptoms. CONCLUSIONS: The study provided preliminary support that the ICBT can be a feasible and potentially effective treatment for homeless individuals with substance use and/or depressive symptoms. However, the delivery format within the Treatment First program was not feasible. The ICBT could be offered within the social services Housing First program instead (where permanent housing is offered before treatment), or to non-homeless individuals. TRIAL REGISTRATION: The study was registered retrospectively at ClinicalTrials.gov (NCT05329181).

Experiences of dialectical behaviour therapy for adolescents: A qualitative analysis.

OBJECTIVES: To explore how former patients in dialectical behaviour therapy for adolescents (DBT-A) experience their treatment, and specifically if there were aspects of the treatment that they retrospectively identify as particularly meaningful, helpful or unhelpful. DESIGN: From a larger sample of 75 former DBT-A patients 19 were selected for a qualitative semi-structured interview study. METHODS: Young adults (N = 19; 18 females, one male), who as adolescents had been enrolled in DBT-A due to self-harming behaviours and features of borderline personality disorder, were interviewed up to 8 years (median 6.0; min 1.3; max 8.2) after end of treatment, at mean age 23 years (SD 2.5). Reflexive thematic analysis was implemented. RESULTS: Six key themes were revealed; (1) The need to be seen, listened to and believed in, (2) the importance of teamwork between patient and therapist, (3) the value of group and structure, (4) therapy as lifesaving and life-changing, (5) the risks of feeling misplaced and (6) the risks of abrupt endings. CONCLUSION: A trusting relationship with the therapist promoted commitment and motivation for treatment. This relationship was facilitated by the therapist showing explicit care and belief in the patient's own competence in changing their destructive behaviours. Meeting peers in group skill training offered a salient form of validation and was reported to be of particular value. The format of meeting peers and the importance of the dialectical therapeutic stance need to be studied further. Not all youth experienced DBT-A as suitable and the need for sufficient treatment dose was emphasized.

The evaluation of a brief ICBT program with therapist support for individuals with gambling problems in the context of a gambling helpline: a randomized pilot trial.

BACKGROUND AND AIMS: Gambling helplines are a natural way of first contact for individuals with gambling problems. However, few studies have evaluated the feasibility and effectiveness of brief interventions in a gambling helpline. To reduce this knowledge gap, this study evaluated the feasibility of an online cognitive behavioral therapy (ICBT) program in the context of a gambling helpline as a first step towards a full-scale RCT. DESIGN: This is a two-group parallel randomized controlled pilot trial where the participants were randomized to either a brief four-module ICBT program (n = 22) or a control group (n = 21). Participants were followed up weekly during the intervention, post intervention, and 6 weeks upon completion of intervention. PARTICIPANTS: A total of 43 self-identified individuals with gambling problems (scoring 3 or more on the Problem Gambling Severity Index) were recruited via the Swedish national gambling helpline, 59% females, mean age 43.7 years. MEASUREMENTS: Feasibility of the procedure and intervention (i.e., recruitment pace, attrition, program engagement, and satisfaction) were the primary outcomes; treatment effect (net gambling losses) was the secondary outcome. RESULTS: Approximately 2 participants per week were randomized, and retention was low, with 47% lost to follow-up at the 6-week follow-up time-point. Most participants engaged in the online modules (86%) and rated their overall satisfaction with the program as high (7.5 out of 10). Both groups decreased their weekly gambling losses at both follow-up time-points, but the between-group comparisons were inconclusive. CONCLUSION: It is not advisable to conduct a full-scale RCT based on the results from this pilot study. Future studies in a gambling helpline should consider interventions that are more suited to be incorporated in a gambling helpline and identify ways to increase participant engagement. TRIAL REGISTRATION: The study was retrospectively registered on ClinicalTrials.gov (ID: NCT04609007 , 29/10/2020).

Association of Treatment-Resistant Depression With Patient Outcomes and Health Care Resource Utilization in a Population-Wide Study.

Importance: The totality of the societal and individual impact of treatment-resistant depression (TRD) is unknown, as is the potential to prognosticate TRD. The generalizability of many observational studies on TRD is limited. Objective: To estimate the burden of TRD in a large population-wide cohort in an area with universal health care by including data from both health care types (psychiatric and nonpsychiatric) and, further, to develop a prognostic model for clinical use. Design, Setting, and Participants: This cohort study, a population-based observational study, assessed data from the Stockholm MDD Cohort for episodes of major depressive disorder (MDD) between 2010 and 2017 that fulfilled predefined criteria for TRD (≥3 consecutive antidepressant treatments). Data analysis was performed from August 2020 to May 2022. Main Outcomes and Measures: Outcomes were psychiatric and nonpsychiatric comorbid conditions, antidepressant treatments, health care resource utilization, lost workdays, all-cause mortality, and intentional self-harm and, in the prognostic model, TRD. Results: A total of 158 169 unipolar MDD episodes (in 145 577 patients) were identified between January 1, 2012, and December 31, 2017 (64.7% women; median [IQR] age, 42 years [30-56]). Of these, 12 793 episodes (11%) fulfilled criteria for TRD. The median (IQR) time from the start of MDD episode to TRD was 552 days (294-932). Selective serotonin reuptake inhibitor was the most common class of antidepressant treatment in all treatment steps, and 5907 patients (46.2%) received psychotherapy at some point before initiation of the third pharmacological antidepressant treatment. Compared with matched non-TRD episodes, TRD episodes had more inpatient bed-days (mean, 3.9 days; 95% CI, 3.6-4.1, vs 1.3 days; 95% CI, 1.2-1.4) and more lost workdays (mean, 132.3 days; 95% CI, 129.5-135.1, vs 58.7 days; 95% CI, 56.8-60.6) 12 months after the index date. Anxiety, stress, sleep disorder, and substance use disorder were all more common comorbid conditions in TRD episodes. Intentional self-harm was more than 4 times more common in TRD episodes. The all-cause mortality rate for patients with MDD with TRD episodes was 10.7/1000 person-years at risk, compared with 8.7/1000 person-years at risk for patients with MDD without TRD episodes (hazard ratio, 1.23; 95% CI, 1.07-1.41). Median time from start of the first antidepressant treatment to start of the second, and from start of the second antidepressant treatment to start of the third, was 165 and 197 days, respectively. The severity of MDD, defined using the self-rating Montgomery-Åsberg Depression Rating Scale (MADRS-S) at time of MDD diagnosis, was found to be the most important prognostic factor for TRD (C index = 0.69). Conclusions and Relevance: In this cohort study, TRD was a common variant of MDD when including patients from both health care types, which is associated with a high disease burden for both patients and society. The median time between initiation of new antidepressant treatments was longer than recommended in current treatment guidelines, suggesting room for more structured and timely depression care.

Parent Management Training Combined with Group-CBT Compared to Parent Management Training Only for Oppositional Defiant Disorder Symptoms: 2-Year Follow-Up of a Randomized Controlled Trial.

Parent management training (PMT) is recommended treatment for children with oppositional defiant disorder (ODD) and child-directed cognitive behavior therapy (CBT) is also recommended for school-aged children. The current study examined 2-year follow-up effects of parent management training (PMT) combined with the CBT based group intervention Coping Power Program (CPP) compared to PMT only. Results showed long-term effectiveness of both PMT and PMT combined with CPP in reduced disruptive behavior problems and harsh parenting strategies, and increased emotion regulation- and social communication skills. The earlier reported increase in emotion regulation- and social communication skills in the PMT with CPP condition during treatment remained stable while the PMT condition showed continued improvement during the follow-up period. To conclude, PMT with CPP did generally not provide significant benefits at the 2-year follow-up compared to PMT, apart from an improvement earlier in time regarding emotion regulation- and social communication skills.Trial registration number ISRCTN10834473, date of registration: 23/12/2015.

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.

Associations of impulsivity, hyperactivity, and inattention with nonsuicidal self-injury and suicidal behavior: longitudinal cohort study following children at risk for neurodevelopmental disorders into mid-adolescence.

BACKGROUND: The knowledge of how the separate Attention-Deficit/Hyperactivity Disorder (ADHD) subdimensions (impulsivity, hyperactivity, and inattention) are associated with nonsuicidal self-injury (NSSI) and suicidal behavior (SB) is limited. The objective of this study was to investigate the associations of childhood ADHD subdimensions with NSSI and SB in children at risk of neurodevelopmental disorders (NDDs; including ADHD). METHODS: The sample (N = 391) included twin pairs where at least one twin screened positive for at least one NDD or common comorbidity at age 9 or 12. Data on ADHD subdimensions was collected through a telephone interview with a caregiver/legal guardian at age 9 or 12, and data on NSSI and SB was collected through an in-person clinical assessment at age 15. The associations between the ADHD subdimensions and NSSI or SB were tested in three different models: (1) univariable, (2) together with the other ADHD subdimensions, and (3) in a confounder-adjusted model including other NDD symptoms in addition to ADHD subdimensions, for NSSI and SB separately. RESULTS: A total of 32 (8.2%) adolescents reported life-time engagement of NSSI, and 18 (4.6%) SB. Childhood impulsivity was associated with SB and childhood inattention with NSSI, in all models. Hyperactivity was not meaningfully associated with any of the outcomes. CONCLUSION: Impulsivity and inattention, but not hyperactivity, may be of particular importance in understanding SB and NSSI. Brief screening for impulsivity and inattention in childhood could facilitate detection of children vulnerable to NSSI and SB and indicate valuable information for preventive and intervention strategies.

What are the effects of implementing patient-controlled admissions in inpatient care? A study protocol of a large-scale implementation and naturalistic evaluation for adult and adolescent patients with severe psychiatric conditions throughout Region Stockholm.

INTRODUCTION: Patient-controlled admissions (PCAs) represent a change in psychiatric inpatient care where patients are allowed to decide for themselves when hospitalisation might be required. Prior research has demonstrated that PCA increase the number of admissions, but decrease days in inpatient care, while both the admissions to and days in involuntary care decrease. However, investigations have been restricted to specific patient groups and have not examined other possible benefits, such as effects on symptoms, quality of life and autonomy. METHODS AND ANALYSIS: This study explores the implementation process and effects of PCA in Region Stockholm, who is currently introducing PCA for all patients with severe psychiatric conditions and extensive healthcare utilisation. In total, the study comprises approximately 45 inpatient wards, including child and adolescent psychiatry. In a naturalistic evaluation, patients assigned PCA will be followed up to 36 months, both with regard to hospitalisation rates and self-reported outcomes. In addition, qualitative studies will explore the experiences of patients, caregivers of adolescents and healthcare providers. ETHICS AND DISSEMINATION: Approval has been granted by the Swedish Ethical Review Authority (Dnr: 2020-06498). The findings from this study will be disseminated via publications in international peer-reviewed journals, at scientific conferences, as part of two doctoral theses, and through the Swedish Partnership for Mental Health. TRIAL REGISTRATION NUMBER: NCT04862897.

The Efficacy of Parent Management Training With or Without Involving the Child in the Treatment Among Children with Clinical Levels of Disruptive Behavior: A Meta-analysis.

A systematic review and meta-analysis was conducted where we evaluated the effects of Parent Management Training (PMT), Parent-Child Interaction Therapy (PCIT) and PMT combined with child cognitive behavioral therapy (CBT) using data from 25 RCTs on children with clinical levels of disruptive behavior (age range 2-13 years). Results showed that PMT (g = 0.64 [95% CI 0.42, 0.86]) and PCIT (g = 1.22 [95% CI 0.75, 1.69]) were more effective than waiting-list (WL) in reducing parent-rated disruptive behavior, and PMT also in improving parental skills (g = 0.83 [95% CI 0.67, 0.98]) and child social skills (g = 0.49 [95% CI 0.30, 0.68]). PCIT versus WL had larger effects in reducing disruptive behavior than PMT versus WL. In the few studies found, the addition of child CBT to PMT did not yield larger effects than PMT or WL. These results support offering PMT to children with clinical levels of disruptive behavior and highlight the additional benefits of PCIT for younger ages.

Childhood symptoms of attention-deficit/hyperactivity disorder and borderline personality disorder.

OBJECTIVE: Childhood attention-deficit /hyperactivity disorder (ADHD) is known to be associated with adult Borderline Personality Disorder (BPD). We investigated if any of the subdimensions of childhood ADHD, that is, impulsivity, inattention, or hyperactivity was more prominent in this association. METHODS: In a nation-wide cohort (N = 13,330), we utilized parent reported symptoms of childhood ADHD and clinically ascertained adult BPD diagnoses. The summed total scores of ADHD symptoms and its three subdimensions were used and standardized for effect size comparison. Associations were analyzed using Cox regression with sex and birth-year adjustments. Secondary outcomes were BPD-associated traits (i.e., self-harm and substance use) analyzed using logistic- and linear regression respectively. RESULTS: ADHD symptom severity was positively associated with BPD with a hazard ratio (HR) of 1.47 (95% confidence interval [CI]: 1.22-1.79) per standard deviation increase in total ADHD symptoms. Impulsivity was the most prominent subdimension with the only statistically significant association when analyzed in a model mutually adjusted for all ADHD subdimensions-HR for inattention: 1.15 (95% CI: 0.85-1.55), hyperactivity: 0.94 (95% CI: 0.69-1.26), impulsivity: 1.46 (95% CI: 1.12-1.91). In secondary analyses, weak positive associations were seen between total ADHD symptom score and self-harm and substance use. In analyses by subdimensions of ADHD, associations were weak and most prominent for inattention in the model with self-harm. CONCLUSION: Childhood ADHD symptoms were associated with subsequent development of BPD diagnosis and appeared to be driven primarily by impulsivity. Our findings are important for understanding the association between childhood symptoms of ADHD and subsequent BPD.

Augmented pain inhibition and higher integration of pain modulatory brain networks in women with self-injury behavior.

Individuals who engage in nonsuicidal self-injury (NSSI) have demonstrated insensitivity to pain compared with individuals without NSSI. Yet, the neural mechanisms behind this difference are unknown. The objective of the present study was to determine which aspects of the pain regulatory system that account for this decreased sensitivity to pain. In a case-control design, 81 women, aged 18-35 (mean [SD] age, 23.4 [3.9]), were included (41 with NSSI and 40 healthy controls). A quantitative sensory testing protocol, including heat pain thresholds, heat pain tolerance, pressure pain thresholds, conditioned pain modulation (assessing central down-regulation of pain), and temporal summation (assessing facilitation of pain signals) was used. Pain-evoked brain responses were assessed by means of fMRI scanning during thermal pain. NSSI participants showed a more effective central down-regulation of pain, compared to controls, assessed with conditioned pain modulation. The neural responses to painful stimulation revealed a stronger relation between nociceptive and pain modulatory brain regions in NSSI compared to controls. In line with previous studies, pressure and heat pain thresholds were higher in participants with NSSI, however, there were no correlations between pain outcomes and NSSI clinical characteristics. The augmented pain inhibition and higher involvement of pain modulatory brain networks in NSSI may represent a pain insensitive endophenotype associated with a greater risk for developing self-injurious behavior.

Prenatal exposure to benzodiazepines and Z-drugs in humans and risk of adverse neurodevelopmental outcomes in offspring: A systematic review.

When used during pregnancy, benzodiazepines (BZDs) and related z-drugs could pass readily through the placenta and the foetal blood-brain barrier, where they can bind to γ-amino butyric acid (GABA) receptors in the developing foetal brain. Yet, data on long-term safety of prenatal BZD and z-drug use and its impact on offspring neurodevelopment are inconclusive. In this systematic review, we qualitatively synthetize the existing evidence on maternal exposure to various BZDs and z-drugs during pregnancy and offspring cognitive, emotional, behavioural, and motor skills developmental outcomes. Nineteen studies were included. We used harvest plots to visualize the directions of reported associations. Despite several associations between distinct types of BZDs and z-drugs and an increased risk of outcomes within different neurodevelopmental domains were observed, a remarkable scarcity of overall research on the topic and considerable discrepancies in methodology, particularly towards controlling for confounding by indication, precluded drawing conclusions with a reasonable degree of certainty. We outline various research strategies to mitigate methodological limitations and provide directions for future empirical studies on the topic.

The effect of autistic traits on response to and side-effects of pharmacological ADHD treatment in children with ADHD: results from a prospective clinical cohort.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a common childhood behavioral condition that globally affects an average of around 5% of children and is associated with several adverse life outcomes. Comorbidity with autism spectrum disorder (ASD) is highly prevalent. Pharmacological treatment for ADHD symptoms has been shown to be effective. However, the prevailing perception is that children with ADHD and concomitant ASD symptoms report poorer efficacy and more side effects. This has been supported by studies on this population, but prospective studies directly comparing children with ADHD and different levels of ASD symptoms are lacking. We aimed to assess if children with ADHD and concomitant ASD symptoms differ regarding effects and side-effects of pharmacological ADHD treatment compared to children with ADHD without ASD traits. This is to our knowledge the second study to directly compare the effect of ADHD medication between ADHD patients with different levels of ASD symptoms. METHODS: In a non-randomized, observational, prospective cohort study, 323 patients aged 6 to 17 years who were diagnosed with ADHD and starting pharmacological treatment were divided into two groups: one with high level of ASD symptoms (ASD group, N=71) and one with low level of ASD symptoms (non-ASD group, N = 252). Treatment outcome was measured as ADHD symptoms, and evaluated using the Swanson, Nolan and Pelham Teacher and Parent ADHD rating scale-version IV (SNAP-IV). Side-effects were evaluated using the Pediatric Side Effects Checklist (P-SEC), at 3 months follow-up. RESULTS: From baseline to 3 months, there was no significant difference in neither treatment effect nor number of clinically significant adverse events experienced between the ASD group and the non-ASD group. CONCLUSIONS: Our results did not implicate that ADHD patients with concomitant ASD symptoms have decreased treatment effect of ADHD medication than patients with ADHD without concomitant ASD symptoms. Neither did the results support that ADHD patients with ASD symptoms experienced significantly more side-effects than ADHD patients without ASD symptoms. Although, we did not analyze different medications separately, this is in line with the only previous study directly comparing methylphenidate treatment in children with or without ASD. TRIAL REGISTRATION: NCT02136147 , May 12, 2014.

Clinical and societal burden of incident major depressive disorder: A population-wide cohort study in Stockholm.

OBJECTIVE: Major depressive disorder (MDD) is a highly prevalent condition and a significant contributor to global disability. The vast majority of MDD is handled by primary care, but most real-life studies on MDD only include data from secondary care. The aim of this study was therefore to estimate the total clinical and societal burden of incident MDD including data from all healthcare levels in a large well-defined western European healthcare region. METHODS: Population-wide observational study included healthcare data from Region Stockholm, Sweden's largest region with approximately 2.4 million inhabitants. All patients in Region Stockholm having their first unipolar MDD episode between January 1, 2012, and December 31, 2018, were included. The sample also included matched study population controls. Outcomes were psychiatric and non-psychiatric comorbid conditions, antidepressant therapy use, healthcare resource utilization, work loss, and all-cause mortality. RESULTS: In the study period, 137,822 patients in Region Stockholm were diagnosed with their first unipolar MDD episode. Compared with matched controls, MDD patients had a higher burden of non-psychiatric and psychiatric comorbid conditions, 3.2 times higher outpatient healthcare resource utilization and 8.6 times more work loss. MDD was also associated with a doubled all-cause mortality compared with matched controls (HR: 2.2 [95% CI: 2.0-2.4]). CONCLUSIONS: The high mortality, morbidity, healthcare resource utilization, and work loss found in this study confirms that MDD is associated with individual suffering and low functioning leading to substantial costs for patients and society. These findings should motivate additional efforts in improving outcomes for MDD patients.