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Background: Individuals reporting self-injury are at greater risk of several adverse outcomes, including suicide. There is reason to be concerned how these individuals cope when stressful life events increase. This study aimed to investigate the trajectories of anxiety and depressive symptoms and the predictive value of self-injury history in individuals with psychiatric symptoms during the unique and stressful conditions of the COVID-19 pandemic., Methods: In a longitudinal population cohort study (N = 1810) ranging from 2020 to 2022, anxiety (measured by Generalized Anxiety Disorder, GAD-7) and depressive symptoms (measured by Patient Health Questionnaire, PHQ-9) were self-reported monthly during 12 months. Latent growth curve models with and without self-reported self-injury history as predictors were conducted., Results: Overall, anxiety and depressive symptoms decreased from baseline, but remained at moderate severity at follow-up. Individuals reporting suicidal or nonsuicidal self-injury reported significantly higher symptom severity at baseline. In addition, individuals reporting suicidal self-injury demonstrated a slower rate of decline in the symptom load over the course of 12 months., Conclusions: Over the course of 12 months, anxiety and depressive symptoms decreased in individuals with psychiatric symptoms, but still indicate a psychiatric burden. Individuals with a history of self-injury could be more vulnerable in face of stressful conditions such as those experienced during the COVID-19 pandemic., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ojala et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Both suicide and self-harm are disproportionately common in autistic people. Sex differences in risk of self-harm and suicide are observed in the general population, but findings are mixed for autistic people. Self-cutting may be a particularly risky self-harm behaviour for suicide in autistic people. We aimed to explore sex differences and differences in method of self-harm in the association between self-harm and suicide in autistic and non-autistic adolescents and young adults., Methods: We used a total population register of 2.8 million Swedish residents. Participants were followed from age 12 until December 2021 for medical treatment because of self-harm, and death from suicide. We used Cox proportional hazard regression models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of death from suicide following self-harm, and Relative Excessive Risk due to Interaction (RERI) to explore the interaction between self-harm and autism in females and males., Results: We identified 85,143 autistic individuals (31,288 female; 53,855 male) and 2,628,382 non-autistic individuals (1,286,481 female; 1,341,901 male) aged 12-37 years. Incidence of suicide following self-harm was higher in autistic males (incidence per 100,000 risk-years = 169.0 [95% CI 135.1, 211.3]) than females (125.4 [99.4, 158.3]). The relative risk was higher for autistic females (HR 26.1 [95% CI 20.2, 33.7]) than autistic males (12.5 [9.9, 15.8]). An additive effect of both autism and self-harm was observed in both females (RERI = 9.8) and males (2.0). Autistic individuals who self-harmed through cutting were at greatest risk of death from suicide (HR 25.1 [17.9, 35.2]), compared to other methods., Conclusion: Autistic males and females are at increased risk of death from suicide following severe self-harm, particularly self-cutting., (© 2024 The Author(s). Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

In a subset of females, postmenopausal status has been linked to accelerated aging and neurological decline. A complex interplay between reproductive-related factors, mental disorders, and genetics may influence brain function and accelerate the rate of aging in the postmenopausal phase. Using multiple regressions corrected for age, in this preregistered study we investigated the associations between menopause-related factors (i.e., menopausal status, menopause type, age at menopause, and reproductive span) and proxies of cellular aging (leukocyte telomere length, LTL) and brain aging (white and gray matter brain age gap, BAG) in 13,780 females from the UK Biobank (age range 39-82). We then determined how these proxies of aging were associated with each other, and evaluated the effects of menopause-related factors, history of depression (= lifetime broad depression), and APOE ε4 genotype on BAG and LTL, examining both additive and interactive relationships. We found that postmenopausal status and older age at natural menopause were linked to longer LTL and lower BAG. Surgical menopause and longer natural reproductive span were also associated with longer LTL. BAG and LTL were not significantly associated with each other. The greatest variance in each proxy of biological aging was most consistently explained by models with the addition of both lifetime broad depression and APOE ε4 genotype. Overall, this study demonstrates a complex interplay between menopause-related factors, lifetime broad depression, APOE ε4 genotype, and proxies of biological aging. However, results are potentially influenced by a disproportionate number of healthier participants among postmenopausal females. Future longitudinal studies incorporating heterogeneous samples are an essential step towards advancing female health., Competing Interests: Conflict of interest The authors have no conflict of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: This qualitative study explored the perceptions of adult clients participating in a new psychological treatment for attention-deficit/hyperactivity disorder inattentive presentation (ADHD-I, also called "attention deficit disorder", ADD). The study aimed to explore (i) what aspects of treatment the participants found to be helpful, and (ii) if there were areas that ought to be developed to make the protocol more useful to clients with ADHD-I., Methods: Participants were recruited from treatment groups following the protocol of cognitive-behavioral therapy for ADHD-I (CADDI), at three psychiatric outpatient units in Stockholm, Sweden. Individual semi-structured interviews, lasting on average 44,6 minutes, were conducted with 14 adults after the completion of CADDI. Interviews explored participants' perceptions of CADDI, its usefulness, and asked for suggestions for improvement. Interviews were conducted by independent interviewers and were transcribed verbatim. The text was analyzed using reflexive thematic analysis., Results: The analysis generated three themes: "Factors of importance for change", with the subthemes; the group, therapeutic components, structure of treatment, and motivation,"Gains in treatment", with the subthemes; insight and understanding, increased attention, and planning and acting, and "Challenges with ADHD-I and remaining needs", with the subthemes; ADHD as a lifelong condition, maintaining gains in treatment, and wish for further support., Conclusions: Participants emphasized the importance of the group setting as a facilitator of therapeutic effects of increased understanding and self-acceptance. Further, they considered the practice of mindfulness to enhance attention and awareness of thoughts, feelings, and activities and considered the structure of treatment as supporting the work in therapy. These findings support the value of the group setting and confirm the usefulness of CADDI. However, participants were concerned about how to maintain gains of treatment after its termination and suggested follow-up sessions to improve the CADDI protocol., Trial Registration: Preregistered at Clinical Trials: NCT05037903., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Strålin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by diarrhea or constipation and other symptoms such as pain, bloating, and flatulence. The disease often has a negative effect on quality of life and is also associated with symptoms of anxiety and depression. Pharmacological treatments are not always effective, and complementary and alternative treatments are common., Methods: We conducted a study on a group intervention based on the Ashtanga school of yoga. Fourteen participants (three men, 11 women; average age 51.4, SD = 16) were recruited from primary care, and 10 completed treatment. At pre-measurement, 4 participants had severe, 9 moderate, and 1 mild IBS, according to the IBS-SSS scale., Key Results: The intervention was regarded as credible (CEQ M = 39.2 SD = 8.8), and no serious adverse events were reported. The intervention showed significant effects on all measurements at post, as follows: IBS-SSS PRE (M = 272.0 SD = 75.5); IBS-SSS POST (M = 177.0 SD = 103.5); GSRS-IBS PRE (M = 48.4 SD = 15.9); GSRS-IBS POST (M = 37.4 SD = 12.4); VSI PRE (M = 38.8 SD = 10.0) VSI POST (M = 25.9 SD = 10.1); PHQ12 PRE (M = 10.0 SD = 4.3); PHQ12 POST (M = 6.9 SD = 4.3); HADS anxiety PRE (M = 8.9 SD = 5.0) HADS anxiety POST (M = 5.7 SD = 3.3) HADS depression PRE (M = 5.6 SD = 3.2) HADS depression POST (M = 3.8 SD = 2.9) IBS-QOL PRE (M = 64.5 SD = 12.5) IBS-QOL POST (M = 72.3 SD = 10.0). The effects were maintained at follow-up, except for general anxiety and depression. Preliminary effects at 3-month follow-up were in the moderate to large range for main outcomes., Conclusion & Inferences: A 10-week group Ashtanga intervention was a feasible intervention for participants with IBS. Preliminary effects were promising and should be explored further in a randomized trial., (© 2024 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Background: There is debate about the generalisability of results from randomised clinical trials (RCTs) to real-world settings. Studying outcomes of treatments for schizophrenia can shed light on this issue and inform treatment guidelines. We therefore compared the efficacy and effectiveness of antipsychotics for relapse prevention in schizophrenia and estimated overall treatment effects using all available RCT and real-world evidence., Methods: We conducted network meta-analyses using individual participant data from Swedish and Finnish national registries and aggregate data from RCTs. The target population was adults (age >18 and <65 years) with schizophrenia and schizoaffective disorder with stabilised symptoms. We analysed each registry separately to obtain hazard ratios (HRs) and 95% CIs for relapse within 6 months post-antipsychotic initiation as our main outcome. Interventions studied were antipsychotics, no antipsychotic use, and placebo. We compared HRs versus a reference drug (oral haloperidol) between registries, and between registry individuals who would be eligible and ineligible for RCTs, using the ratio of HRs. We synthesised evidence using network meta-analysis and compared results from our network meta-analysis of real-world data with our network meta-analysis of RCT data, including oral versus long-acting injectable (LAI) formulations. Finally, we conducted a joint real-world and RCT network meta-analysis., Findings: We included 90 469 individuals from the Swedish and Finnish registries (mean age 45·9 [SD 14·6] years; 43 025 [47·5%] women and 47 467 [52·5%] men, ethnicity data unavailable) and 10 091 individuals from 30 RCTs (mean age 39·6 years [SD 11·7]; 3724 [36·9%] women and 6367 [63·1%] men, 6022 White [59·7%]). We found good agreement in effectiveness of antipsychotics between Swedish and Finnish registries (HR ratio 0·97, 95% CI 0·88-1·08). Drug effectiveness versus no antipsychotic was larger in RCT-eligible than RCT-ineligible individuals (HR ratio 1·40 [1·24-1·59]). Efficacy versus placebo in RCTs was larger than effectiveness versus no antipsychotic in real-world (HR ratio 2·58 [2·02-3·30]). We found no evidence of differences between effectiveness and efficacy for between-drug comparisons (HR ratio vs oral haloperidol 1·17 [0·83-1·65], where HR ratio >1 means superior effectiveness in real-world to RCTs), except for LAI versus oral comparisons (HR ratio 0·73 [0·53-0·99], indicating superior effectiveness in real-world data relative to RCTs). The real-world network meta-analysis showed clozapine was most effective, followed by olanzapine LAI. The RCT network meta-analysis exhibited heterogeneity and inconsistency. The joint real-world and RCT network meta-analysis identified olanzapine as the most efficacious antipsychotic amongst those present in both RCTs and the real world registries., Interpretation: LAI antipsychotics perform slightly better in the real world than according to RCTs. Otherwise, RCT evidence was in line with real-world evidence for most between-drug comparisons, but RCTs might overestimate effectiveness of antipsychotics observed in routine care settings. Our results further the understanding of the generalisability of RCT findings to clinical practice and can inform preferential prescribing guidelines., Funding: None., Competing Interests: Declaration of interests OE has received honoraria and consulting fees from Biogen to his institution, all unrelated to the current work. JPE has received Continuing Medical Education (CME) speaker fees and other non-financial honoraria from Otsuka, Lundbeck, Casen Recordati, Rovi, Angelini Pharma, Neuraxpharm, and Janssen, outside the submitted work; and has participated in research projects coordinated by IQVIA. EV has received grants and served as consultant, advisor, or CME speaker for AB-Biotics, Abbvie, Aimentia, Angelini, Boehringer Ingelheim, Celon, Dainippon Sumitomo Pharma, Ferrer, Gedeon Richter, GH Research, Glaxo Smith-Kline, Idorsia, Janssen, Lundbeck, Organon, Otsuka, Sage, Sanofi-Aventis, Sunovion, Takeda, and Viatris, outside the submitted work. JT, EMR, HT, and ATa have participated in research projects funded by grants from Janssen-Cilag and Eli Lilly to their employing institution. HT reports personal fees from Gedeon Richter, Janssen-Cilag, Lundbeck, and Otsuka. JT has participated in research projects funded by grants from Janssen to his employing institution. JT has served as a consultant for HLS Therapeutics, Janssen, Orion, and WebMed Global and has received honoraria from Janssen and Otsuka. PFP has received research funds or personal fees from Lundbeck, Angelini, Menarini, Sunovion, Boehringer Ingelheim, and Proxymm Science, outside the current study. AC has received research, educational, and consultancy fees from the Italian Network for Paediatric Trials, CARIPLO Foundation, Lundbeck, and Angelini Pharma, outside the submitted work. He is the Clinical Lead and Principal Investigator of a trial of seltorexant in adolescent depression, sponsored by Janssen. SL has received honoraria as an advisor or for lectures or educational material from Alkermes, Angelini, Apsen, Eisai, Gedeon Richter, Janssen, Karuna, Kynexis, Lundbeck, Medichem, Medscape, Merck Sharpp and Dome, Mitshubishi, Neurotorium, NovoNordisk, Otsuka, Recordati, Roche, Rovi, Sanofi Aventis, and TEVA. NC has received grants and acted as a CME consultant, advisor, or speaker for Angelini, Esteve, Exeltis, Janssen, Lundbeck, Novartis, Pfizer, and Servier, outside the submitted work. All other authors declare no competing interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Sleep problems are common in adolescence and often related to psychopathology and impaired functioning. However, most studies have used summative scores, and little is known about how adolescents with disrupted sleep perceive their specific symptoms and dysfunctions. This study explored differences in levels of psychiatric symptoms and functional ability between Swedish adolescents with and without self-reported disturbed sleep in a school-based sample., Methods: Swedish adolescents ( n = 618, mean age 15.7+/-1.9yrs) answered the PROMIS pediatric measures for fatigue, anxiety, depression, pain interference, anger, physical activity and peer and family relationships. Logistic regression analyses were performed to assess differences between respondents with and without disturbed sleep., Results: Disturbed sleep was associated with higher levels of symptoms of fatigue, anxiety, depression, anger and pain interference, as well as lower functional abilities in terms of physical activity and peer- and family relationships. Adolescents reporting disturbed sleep generally displayed a pattern of impaired executive functioning, internal emotional distress and school- and sleep related worry and dysfunction, as compared to physical disability, aggressive behavior, stress and generalized worry., Conclusions: The present study adds to the understanding of how disturbed sleep and specific psychiatric symptoms and functional ability are interrelated, which may also have clinical implications.

Background: Psychopathic traits have been associated with impaired emotion recognition in criminal, clinical and community samples. A recent study however, suggested that cognitive impairment reduced the relationship between psychopathy and emotion recognition. We therefore investigated if reasoning ability and psychomotor speed were impacting emotion recognition in individuals with psychotic spectrum disorders (PSD) with and without a history of aggression, as well as in healthy individuals, more than self-rated psychopathy ratings on the Triarchic Psychopathy Measure (TriPM)., Methods: Eighty individuals with PSD (schizophrenia, schizoaffective disorder, delusional disorder, other psychoses, psychotic bipolar disorder) and documented history of aggression (PSD+Agg) were compared with 54 individuals with PSD without prior aggression (PSD-Agg) and with 86 healthy individuals on the Emotion Recognition Assessment in Multiple Modalities (ERAM test). Individuals were psychiatrically stable and in remission from possible substance use disorders. Scaled scores on matrix reasoning, averages of dominant hand psychomotor speed and self-rated TriPM scores were obtained., Results: Associations existed between low reasoning ability, low psychomotor speed, patient status and prior aggression with total accuracy on the ERAM test. PSD groups performed worse than the healthy group. Whole group correlations between total and subscale scores of TriPM to ERAM were found, but no associations with TriPM scores within each group or in general linear models when accounting for reasoning ability, psychomotor speed, understanding of emotion words and prior aggression., Conclusion: Self-rated psychopathy was not independently linked to emotion recognition in PSD groups when considering prior aggression, patient status, reasoning ability, psychomotor speed and emotion word understanding., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Högman, Gavalova, Laukka, Kristiansson, Källman, Fischer and Johansson.)

Introduction: Relative to men, women are at a higher risk of developing age-related neurocognitive disorders including Alzheimer's disease. While women's health has historically been understudied, emerging evidence suggests that reproductive life events such as pregnancy and hormone use may influence women's cognition later in life., Methods: We investigated the associations between reproductive history, exogenous hormone use, apolipoprotein ( APOE ) ε4 genotype and cognition in 221,124 middle- to older-aged (mean age 56.2 ± 8.0 years) women from the UK Biobank. Performance on six cognitive tasks was assessed, covering four cognitive domains: episodic visual memory, numeric working memory, processing speed, and executive function., Results: A longer reproductive span, older age at menopause, older age at first and last birth, and use of hormonal contraceptives were positively associated with cognitive performance later in life. Number of live births, hysterectomy without oophorectomy and use of hormone therapy showed mixed findings, with task-specific positive and negative associations. Effect sizes were generally small (Cohen's d < 0.1). While APOE ε4 genotype was associated with reduced processing speed and executive functioning, in a dose-dependent manner, it did not influence the observed associations between female-specific factors and cognition., Discussion: Our findings support previous evidence of associations between a broad range of female-specific factors and cognition. The positive association between a history of hormonal contraceptive use and cognition later in life showed the largest effect sizes (max. d  = 0.1). More research targeting the long-term effects of female-specific factors on cognition and age-related neurocognitive disorders including Alzheimer's disease is crucial for a better understanding of women's brain health and to support women's health care., Competing Interests: For work unrelated to the contents of this manuscript, IA received speaker’s honorarium from Lundbeck. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lindseth, de Lange, van der Meer, Agartz, Westlye, Tamnes and Barth.)

Neurodevelopmental disorders arise due to various risk factors that can perturb different stages of brain development, and a combinatorial impact of these risk factors programs the phenotype in adulthood. While modeling the complete phenotype of a neurodevelopmental disorder is challenging, individual developmental perturbations can be successfully modeled in vivo in animals and in vitro in human cellular models. Nevertheless, our limited knowledge of human brain development restricts modeling strategies and has raised questions of how well a model corresponds to human in vivo brain development. Recent progress in high-resolution analysis of human tissue with single-cell and spatial omics techniques has enhanced our understanding of the complex events that govern the development of the human brain in health and disease. This new knowledge can be utilized to improve modeling of neurodevelopmental disorders and pave the way to more accurately portraying the relevant developmental perturbations in disease models., (© 2022. The Author(s).)

Importance: There are no medications approved by authorities for the treatment of amphetamine or methamphetamine dependence, and studies investigating the effectiveness of pharmacological treatments in hard outcomes, such as hospitalization and death, are lacking., Objective: To investigate the association between pharmacotherapies and hospitalization and mortality outcomes in persons with amphetamine or methamphetamine use disorder., Design, Setting, and Participants: This nationwide register-based cohort study was conducted from July 2006 to December 2018 with a median (IQR) follow-up time of 3.9 (1.0-6.1) years. Data were analyzed from December 1, 2021, to May 24, 2022. All residents aged 16 to 64 years living in Sweden with a registered first-time diagnosis of amphetamine or methamphetamine use disorder and without previous diagnoses of schizophrenia or bipolar disorder were identified from nationwide registers of inpatient care, specialized outpatient care, sickness absence, and disability pension., Exposures: Medications for substance use disorders (SUDs) or for attention-deficit/hyperactive disorder, mood stabilizers, antidepressants, benzodiazepines and related drugs, and antipsychotics. Medication use vs nonuse was modeled with the PRE2DUP (from prescription drug purchases to drug use periods) method., Main Outcomes and Measures: Primary outcomes were hospitalization due to SUD and any hospitalization or death, which were analyzed using within-individual models by comparing use and nonuse periods of 17 specific medications or medication classes in the same individual to minimize selection bias. The secondary outcome was all-cause mortality, studied using between-individual analysis as traditional Cox models., Results: There were 13 965 individuals in the cohort (9671 [69.3%] male; mean [SD] age, 34.4 [13.0] years). During follow-up, 7543 individuals (54.0%) were taking antidepressants, 6101 (43.7%) benzodiazepines, 5067 (36.3%) antipsychotics, 3941 (28.2%) ADHD medications (1511 [10.8%] were taking lisdexamphetamine), 2856 (20.5%) SUD medications, and 1706 (12.2%) mood stabilizers. A total of 10 341 patients (74.0%) were hospitalized due to SUDs, 11 492 patients (82.3%) were hospitalized due to any cause or died, and 1321 patients (9.5%) died of any cause. Lisdexamphetamine was the only medication in this study that was significantly associated with a decrease in risk of 3 outcomes (adjusted hazard ratio [aHR], 0.82; 95% CI, 0.72-0.94 for SUD hospitalization; aHR, 0.86; 95% CI, 0.78-0.95 for any hospitalization or death; aHR, 0.43; 95% CI, 0.24-0.77 for all-cause mortality). Methylphenidate use also was associated with lower all-cause mortality (aHR, 0.56; 95% CI, 0.43-0.74). Use of benzodiazepines was associated with a significantly higher risk of SUD hospitalization (aHR, 1.17; 95% CI, 1.12-1.22), any hospitalization or death (aHR, 1.20; 95% CI, 1.17-1.24), and all-cause mortality (aHR, 1.39; 95% CI, 1.20-1.60). Use of antidepressants or antipsychotics was associated with a slight increase in risk of SUD hospitalization (aHR, 1.07; 95% CI, 1.03-1.11 and aHR, 1.05; 95% CI, 1.01-1.09) as well as any hospitalization or death (aHR, 1.10; 95% CI, 1.06-1.14 and aHR, 1.06; 95% CI, 1.03-1.10, respectively)., Conclusions and Relevance: In this study, use of lisdexamphetamine was associated with improved outcomes in persons with amphetamine or methamphetamine use disorders, encouraging the conduct of randomized clinical trials. Prescription benzodiazepine use was associated with poor outcomes.

Background: Those who suffer from eating disorders often experience serious impairment in quality of life and the majority never receive treatment. Treatment availability may be increased by implementing methods that demand less resources and are more easy accessible such as internet-based treatments, but knowledge about their effects is still insufficient. The study evaluated effects of two types of internet-based cognitive behavioral therapy and a structured day patient program, the latter being a standard treatment at an eating disorder clinic at the time for the study., Methods: 150 participants with bulimic eating disorders randomized to two types of internet based treatments (one pure online treatment and one based on a self-help guide in book-format) or an intensive 16-week day patient program. The number of participants that started treatment was 120 of which 98 in internet treatment and 22 in the day program. Outcome assessments were carried out at baseline, post treatment, and at one-year follow-up., Results: All treatments were associated with significantly improved eating disorder pathology, self-image, and clinical impairment. Although the day program generally showed larger effects, only one significant difference found was in diagnostic remission post treatment; 51 % of the participant was in remission in internet treatment and 88 % in the day program. At one-year follow-up, participants in the internet treatments had continued to improve, whereas in the day patient program the effect sustained. Internet treatment had a 36 % drop out rate, there were no dropouts found in the day program., Conclusions: All treatments were comparable in effect at follow-up, suggesting that internet treatment is a conceivable alternative to standard treatment. Internet treatment in a book-based format was also equally effective as a pure online format. Internet delivered cognitive behavioral treatment forms can make important contributions to achieve increased access to treatment for patients with bulimic eating disorders. Future research and clinical implications for internet delivered treatments in eating disorder services are discussed., Clinical Trial Registration: ISRCTN registry https://www.isrctn.com/ISRCTN44999017. The study was registered retrospectively., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

Sleep disorder is common in children and adolescents, particularly in those with attention deficit hyperactivity disorder (ADHD) or autism spectrum disorder (ASD). While non-pharmacological treatment is first line, occasionally an add-on of an oral drug is needed. The endogenous hormone melatonin is increasingly used for sleep disorders in children and adolescents. In this registry-based cohort study we follow dispensation of melatonin in young individuals, 0-25 years of age, in Stockholm, Sweden during 2016-2019. In all 9980 individuals, were dispensed melatonin in 2016 and followed for 3 years. Child psychiatrist was the most common prescribing specialty, 55% of all prescriptions. Only 20% had a recorded diagnosis of sleep disorder. The majority, 65% had a neuro psychiatric diagnose. Half of the individuals had at least 4 prescribed drugs dispensed during the follow-up. Almost half of our cohort were dispensed melatonin during the entire study period and doses and volumes of drug dispensed increased by 50 and 100%, respectively. Continuous medication was most common among children 6-12 years, where 7 out of 10 individuals were still adherent after three years. As long-term safety data is lacking, we find this concerning, and this illustrates the need of long-term follow-up of melatonin use in children and young individuals., (© 2022 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.)

Aim: To investigate the real-world effectiveness of pharmacological treatments (buprenorphine, methadone) of opioid use disorder (OUD)., Design: A nation-wide, register-based cohort study., Setting: Sweden., Participants: All residents aged 16-64 years living in Sweden using OUD medication from July 2005 to December 2016 (n = 5757, 71.8% men) were identified from registers of prescriptions, inpatient and specialized outpatient care, causes of death, sickness absence and disability pensions., Measurements: Main outcome: hospitalization due to OUD., Secondary Outcomes: hospitalization due to any cause; death due to all, natural and external causes. Mortality was analyzed with between-individual multivariate-adjusted Cox hazards regression model. Recurrent outcomes, such as hospitalizations, were analyzed with within-individual analyses to eliminate selection bias. OUD medication use versus non-use was modelled with PRE2DUP (from prescription drug purchases to drug use periods) method., Findings: Buprenorphine [hazard ratio (HR) = 0.73, 95% confidence interval (CI) = 0.54-0.97] and methadone (HR = 0.74, 95% CI = 0.59-0.93) use were associated with significantly lower risk of OUD hospitalization, but not any-cause hospitalizations, compared with the time-periods when the same individual did not use OUD medication. The use of buprenorphine and methadone were both associated with significantly lower risk of all-cause mortality (HR = 0.45, 95% CI = 0.34-0.59; HR = 0.51, 95% CI = 0.41-0.63, respectively), compared with non-use of both medications. Similar results were found for risk of mortality due to external causes (HR = 0.39; 95% CI = 0.27-0.54; HR = 0.40; 95% CI = 0.29-0.53, respectively), but not for mortality due to natural causes. The risk of OUD hospitalization and all-cause mortality was decreased in all duration categories of studied medications (< 30, 31-180, 181-365 and >365 days), except for methadone use less than 30 days., Conclusions: The use of buprenorphine and methadone are both associated with a significantly lower risk of hospitalization due to opioid use disorder and death due to all and external causes, when compared with non-use., (© 2022 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Little is known about the long-term prognosis of children with pediatric acute-onset neuropsychiatric syndrome (PANS). Out of the 46 eligible patients from the Karolinska PANS cohort, 34 consented to participate in a follow-up (median 3.3 years). Participants underwent a thorough clinical evaluation and were classified according to their clinical course. Resulting groups were compared on clinical characteristics and laboratory test results. We observed significant reductions in clinician-rated PANS symptom severity and improved general function. Two patients were classified as remitted, 20 as relapsing-remitting, and 12 as having a chronic-static/progressive course. The latter group had an earlier onset, greater impairment and received more pharmacological and psychological treatments. Although remission was rare, the majority of children with PANS were significantly improved over the follow-up period but a non-negligible minority of patients displayed a chronic-static/progressive course and required additional treatments. The proposed definitions of flare and clinical course may be useful in future clinical trials., (© 2021. The Author(s).)

Background: Bipolar disorder (BD) is a chronic psychiatric disorder characterized by recurrent mood episodes interspersed with euthymic periods. A growing number of studies have indicated that zinc plays an important role in coordinating immune responses, as well as being involved in synaptic transmission. In the current study, we set out to measure serum levels of zinc in a meticulously phenotyped cohort of 121 euthymic BD subjects and 30 matched controls., Methods: Serum levels of zinc were measured by photometry. To assess the interplay between zinc levels and immune activation in BD, we measured serum levels of high-sensitive C-reactive protein (hsCRP) levels by immunoturbidimetric assay, and serum levels of monocyte chemoattractant protein-1 (MCP-1), chitinase 3-like protein 1 (YKL-40), and soluble cluster of differentiation 14 (sCD14) by electrochemiluminescence enzyme-linked immunosorbent assays. The baseline clinical diagnostic instrument for BD was the Affective Disorder Evaluation, and executive functioning was assessed by using the Delis-Kaplan Executive Function System., Results: Controlling for potential confounding factors, BD patients displayed increased serum levels of zinc unrelated to hsCRP, MCP-1, YKL-40, and sCD14 levels. Serum levels of zinc did not associate with executive functioning or measurements of disease severity., Discussion: This study suggests that the zinc homeostasis is disturbed in BD and that this dyshomeostasis is not related to ongoing mood symptoms or immune activation. Of note, serum levels were increased and hence do not support continuous zinc supplementation in BD., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

This cross-sectional study compared attachment characteristics among women victimized by intimate partner violence (IPV) in no, one, and multiple relationships ( N = 154). Results indicated that compared with the nonvictimized, victimized women had increased likelihood of higher attachment avoidance. Compared with women victimized in one relationship, women victimized in multiple relationships had higher likelihood of higher attachment anxiety scores. Adjusting for childhood adversities, childhood sexual abuse was an independent risk factor for IPV. Childhood emotional abuse mediated the association between attachment anxiety and IPV victimization in multiple relationships in particular. Attachment theory appeared useful for better understanding women's vulnerability for multiple violent relationships.

Previous studies have shown an association between IQ and adaptive global functioning, i.e. how well a person is functioning in different domains of life. However, it is unclear to what extent such an association applies in children with neurodevelopmental disorders (NDDs). The study group consisted of 550 population-screened children assessed with the K-SADS, WISC-IV, and the C-GAS. Approximately half of the sample had been diagnosed with one or several NDDs (ADHD, autism, language disorder and tic disorder). A factorial ANOVA with IQ level and the presence of NDD was conducted, with C-GAS score as the dependent variable. Results revealed a significant interaction effect between IQ-group and NDD-status. In the non-NDD group (49% girls), higher IQ scores were clearly linked with better global adaptive functioning. Among children with NDDs (35% girls), however, higher IQ scores were not clearly associated with better functioning. Thus, the association between IQ and adaptive functioning were found to differ depending on the presence of NDD. These results have implications for the interpretation of IQ test results in neurodevelopmental assessments and point towards the importance of providing support based on an assessment of needs and functioning rather than scores from IQ tests., (Copyright © 2021. Published by Elsevier B.V.)

Background and Aim: Pharmacotherapy for alcohol use disorder (AUD) is recommendable, but under-used, possibly due to deficient knowledge of medications. This study aimed to investigate the real-world effectiveness of approved pharmacological treatments (disulfiram, acamprosate, naltrexone and nalmefene) of AUD., Design: A nation-wide, register-based cohort study., Setting: Sweden., Participants: All residents aged 16-64 years living in Sweden with registered first-time treatment contact due to AUD from July 2006 to December 2016 (n = 125 556, 62.5% men) were identified from nation-wide registers., Measurements: The main outcome was hospitalization due to AUD. The secondary outcomes were hospitalization due to any cause, alcohol-related somatic causes, as well as work disability (sickness absence or disability pension), and death. Mortality was analysed with between-individual analysis using a traditional multivariate-adjusted Cox hazards regression model. Recurrent outcomes, such as hospitalization-based events and work disability, were analysed with within-individual analyses to eliminate selection bias., Findings: Naltrexone combined with acamprosate [hazard ratio (HR) = 0.74; 95% confidence interval (CI) = 0.61-0.89], combined with disulfiram (HR = 0.76, 95% CI = 0.60-0.96) and as monotherapy (HR = 0.89, 95% CI = 0.81-0.97) was associated with a significantly lower risk of AUD-hospitalization compared with no use of AUD medication. Similar results were found for risk of hospitalization due to any cause. Benzodiazepine use and acamprosate monotherapy were associated with an increased risk of AUD-hospitalization (HR = 1.18, 95% CI = 1.14-1.22 and HR = 1.10, 95% CI = 1.04-1.17, respectively). No statistically significant effects were found for work disability or mortality., Conclusions: Naltrexone as monotherapy and when combined with disulfiram and acamprosate appears to be associated with lower risk of hospitalization due to any and alcohol-related causes, compared with no use of alcohol use disorder (AUD) medication. Acamprosate monotherapy and benzodiazepine use appear to be associated with increased risk of AUD-associated hospitalization., (© 2021 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction..)

No robust biomarkers have yet been identified for autism spectrum disorder (ASD) or autistic traits. Familial factors likely influence biomarkers such as protein concentrations. Comparing twins with ASD or high autistic traits to the less affected co-twin allows estimating the impact of familial confounding. We measured 203 proteins in cerebrospinal fluid (n = 86) and serum (n = 127) in twins (mean age 14.2 years, 44.9% females) enriched for ASD and other neurodevelopmental conditions. Autistic traits were assessed by using the parent-report version of the Social Responsiveness Scale-2. In cerebrospinal fluid, autistic traits correlated negatively with three proteins and positively with one. In serum, autistic traits correlated positively with 15 and negatively with one. Also in serum, six were positively-and one negatively-associated with ASD. A pathway analysis of these proteins revealed immune system enrichment. In within twin pair analyses, autistic traits were associated with serum B-cell activating factor (BAFF) only, whereas Cystatin B (CSTB) remained significantly associated with ASD. These associations did not remain significant when only considering monozygotic twins. For the remainder, the within-pair analysis indicated familial confounding, including shared environment and genes, influencing both autism and protein levels. Our findings indicate proteins involved in immunity as putative biomarkers of autistic traits and ASD with partial genetic confounding. Although some results are in line with previous studies in general, further studies are needed for replication., (© 2021 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Background: Research into predictors of outcome in eating disorders (ED) has shown conflicting results, with few studies of long-term predictors and the possible importance of psychological variables that may act as risk- and maintenance factors., Aim: To identify baseline predictors of ED remission nine years after initial clinical assessment using self-report measures of ED psychopathology, psychiatric symptoms, and self-image in a sample of adult ED patients (N = 104) treated at specialist units in Stockholm, Sweden. Sixty patients participated in the follow-up, of whom 41 patients (68%) had achieved remission., Results: Results suggested that the only significant predictor of diagnostic remission after nine years was initial levels of self-blame., Conclusion: In order to ensure long-term recovery in ED it may be important for clinicians to widen their therapeutic repertoire and utilise techniques that reduce self-blame and increase self-compassion. It is difficult to predict how an eating disorder will develop, and research has found varying factors that affect the outcome of the condition. Recovery rates vary from nearly nil to over 90%. This variation could be explained by different research factors, but are more likely due to varying definitions of 'recovery', with less stringent definitions yielding high recovery rates and more stringent definitions yielding lower rates. The present study investigated whether the severity of eating disorder symptoms and other psychiatric symptoms could predict recovery nine years from first admission to specialised eating disorder care. Sixty patients at three eating disorder treatment units participated, and their scores on self-report measures of symptoms were used as predictor variables. Forty-one participants had no eating disorder diagnosis at nine-year follow-up. Most participants with binge-eating disorder had recovered, while the poorest outcome was found for anorexia nervosa with slightly over half of patients recovered after nine years. The only predictor for the nine-year outcome was a higher initial rating of self-blame, measured with the Structural Analysis of the Social Behavior. It was concluded that it may be important for clinicians to detect and address self-blame early in the treatment of eating disorders in order to enhance the possibility of recovery. Treatment should focus on reducing self-blame and increasing self-acceptance.

Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia in the adult population. AF is associated with a poor quality of life (QoL) and, in many patients, current medical treatments are inadequate in alleviating AF symptoms (eg, palpitations). Patients often present with symptom preoccupation in terms of symptom fear, avoidance, and control behaviors. Internet-delivered cognitive behavior therapy is effective for treating other somatic disorders but has never been evaluated in patients with AF., Objective: The aim of this study is to evaluate the efficacy and feasibility of AF-specific internet-delivered cognitive behavior therapy., Methods: We conducted an uncontrolled pilot study in which 19 patients with symptomatic paroxysmal AF underwent internet-delivered cognitive behavior therapy. Participants completed self-assessments at pretreatment, posttreatment, and at a 6-month follow-up along with handheld electrocardiogram measurements with symptom registration. The treatment lasted 10 weeks and included exposure to physical sensations, reduction in avoidance behavior, and behavioral activation., Results: We observed large within-group improvements in the primary outcome, AF-specific QoL (Cohen d=0.80; P<.001), and in symptom preoccupation (Cohen d=1.24; P<.001) at posttreatment; the results were maintained at the 6-month follow-up. Treatment satisfaction and adherence rates were also high. We observed an increased AF burden, measured by electrocardiogram, at the 6-month follow-up, but a significant decrease was observed in the overestimation of AF symptoms at posttreatment and 6-month follow-up. Exploratory mediation analysis showed that a reduction in symptom preoccupation mediated the effects of internet-delivered cognitive behavior therapy on AF-specific QoL., Conclusions: This study presents preliminary evidence for the potential efficacy and feasibility of a novel approach in treating patients with symptomatic AF with internet-delivered cognitive behavior therapy., Trial Registration: ClinicalTrials.gov NCT02694276; https://clinicaltrials.gov/ct2/show/NCT02694276., (©Josefin Särnholm, Helga Skúladóttir, Christian Rück, Sofia Klavebäck, Eva Ólafsdóttir, Susanne S Pedersen, Frieder Braunschweig, Brjánn Ljótsson. Originally published in JMIR Cardio (http://cardio.jmir.org), 02.03.2021.)

Objective: This study aims to explore how the characteristics of an innovation, the 15-method, a stepped care model for treatment of alcohol use disorders in primary care was perceived., Methods/design/setting/subject: General practitioners and heads of primary care units ( n  = 10) that delivered the 15-method in a randomized controlled trial participated in individual interviews at two occasions in Stockholm, Sweden. Data were analyzed with theoretical thematic analysis, using Diffusion of Innovation Theory., Results: The participants described that offering the 15-method met a need among their patients. Participants were positive towards the training and the manual for the method. They mentioned a previous lack of routines to work with alcohol use disorders. The 15-method was described as easy to use. It would however be more feasible to implement in a team of different professions, rather than among general practitioners only. Priorities made by regional health care managers were described as important for the implementation, as well as financial incentives. A barrier to implementation was that alcohol screening was perceived as difficult. While the 15-method was perceived as effective in reducing the patients' alcohol use and cost effective, participants expressed uncertainty about the long-term effects., Conclusions: The 15-method provides structure for treatment of alcohol use disorders and is described by general practitioners and heads as a promising approach. Being able to offer treatment for alcohol dependence may increase the uptake of alcohol interventions in primary care.KEY POINTSLittle attention has been given to develop treatment models for alcohol use disorders that are adapted to primary care settings.This study describes how an innovation, the 15-method, a stepped care model for treatment of alcohol use disorders in primary care was perceived.The 15-method provides structure for treatment of alcohol use disorders in primary care and is described by general practitioners and heads as a promising approach.Being able to offer treatment for alcohol dependence may increase the uptake of alcohol interventions in primary care.

Background: Anorexia nervosa and bulimia nervosa are two severe eating disorders associated with high premature mortality, suicidal risk and serious medical complications. Transition between anorexia nervosa and bulimia nervosa over the illness course and familial co-aggregation of the two eating disorders imply aetiological overlap. However, genetic and environmental liabilities to the overlap are poorly understood. Quantitative genetic research using clinical diagnosis is needed., Methods: We acquired a clinical diagnosis of anorexia nervosa (prevalence = 0.90%) and bulimia nervosa (prevalence = 0.48%) in a large population-based sample (N = 782 938) of randomly selected full-sisters and maternal half-sisters born in Sweden between 1970 and 2005. Structural equation modelling was applied to quantify heritability of clinically diagnosed anorexia nervosa and bulimia nervosa and the contributions of genetic and environmental effects on their overlap., Results: The heritability of clinically diagnosed anorexia nervosa and bulimia nervosa was estimated at 43% [95% confidence interval (CI) (36-50%)] and 41% (31-52%), respectively, in the study population, with the remaining variance explained by variance in unique environmental effects. We found statistically significant genetic [0.66, 95% CI (0.49-0.82)] and unique environmental correlations [0.55 (0.43-0.66)] between the two clinically diagnosed eating disorders; and their overlap was about equally explained by genetic and unique environmental effects [co-heritability 47% (35-58%)]., Conclusions: Our study supports shared mechanisms for anorexia nervosa and bulimia nervosa and extends the literature from self-reported behavioural measures to clinical diagnosis. The findings encourage future molecular genetic research on both eating disorders and emphasize clinical vigilance for symptom fluctuation between them.

Psychopathy is an extreme form of antisocial behavior, with about 1% prevalence in the general population, and 10-30% among incarcerated criminal offenders. Although the heritability of severe antisocial behavior is up to 50%, the genetic background is unclear. The underlying molecular mechanisms have remained unknown but several previous studies suggest that abnormal glucose metabolism and opioidergic neurotransmission contribute to violent offending and psychopathy. Here we show using iPSC-derived cortical neurons and astrocytes from six incarcerated extremely antisocial and violent offenders, three nonpsychopathic individuals with substance abuse, and six healthy controls that there are robust alterations in the expression of several genes and immune response-related molecular pathways which were specific for psychopathy. In neurons, psychopathy was associated with marked upregulation of RPL10P9 and ZNF132, and downregulation of CDH5 and OPRD1. In astrocytes, RPL10P9 and MT-RNR2 were upregulated. Expression of aforementioned genes explained 30-92% of the variance of psychopathic symptoms. The gene expression findings were confirmed with qPCR. These genes may be relevant to the lack of empathy and emotional callousness seen in psychopathy, since several studies have linked these genes to autism and social interaction.

Background: Adolescent depression has negative health and economic outcomes in the short- and long-term. Indicated preventive interventions, in particular group based cognitive behavioural therapy (GB-CBT), are effective in preventing depression in adolescents with subsyndromal depression. However, little is known about the cost-effectiveness of these interventions., Methods: A Markov cohort model was used to conduct cost-effectiveness analyses comparing a GB-CBT indicated preventive intervention for depression, to a no-intervention option in a Swedish setting. Taking a time horizon of 5- and 10 years, incremental differences in societal costs and health benefits expressed as differences in the proportion of cases of depression prevented, and as quality adjusted life years (QALYs) gained were estimated. Through univariate and probabilistic sensitivity analyses, the robustness of the results was explored. Costs, presented in 2018 USD, and effects were discounted at a yearly rate of 3%., Results: The base-case analysis showed that GB-CBT indicated preventive intervention incurred lower costs, prevented a larger proportion of cases of depression and generated higher QALYs compared to the no-intervention option for both time horizons. Offering the intervention was even a cost saving strategy and demonstrated a probability of being cost-effective of over 95%. In the sensitivity analyses, these results were robust to the modelling assumptions., Limitations: The study considered a homogeneous cohort and assumed a constant annual decay rate of the relative treatment effect., Conclusions: GB-CBT indicated preventive interventions for depression in adolescence can generate good value for money compared to leaving adolescents with subsyndromal depression untreated., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Early life adversity (ELA) may lead to an increased risk for mental health problems including suicidal behavior. ELA alters biological stress systems that affect behavior and control within the individual that in turn will affect interpersonal behavior. Strained relations and interpersonal conflicts leading to rejection and isolation have been shown to be factors for suicidal behavior. Difficulties in interpersonal relationships are a common reason for seeking help in psychiatric care. In the present study, we examined relationship between different types of interpersonal problems and adverse childhood experiences in patients with a recent suicide attempt., Method: The study included 181 recent suicide attempters. We assessed early life adversity and specific interpersonal problems by using the Karolinska Interpersonal Violence Scale and the Inventory of Interpersonal problems respectively., Results: Suicide attempters with high levels of early life adversity expressed a more socially avoidant, non-assertive, and exploitable personal style even after adjustment for comorbidities with personality disorder and substance use disorder., Conclusions: Patients with a recent suicide attempt with high levels of early life adversity tend to isolate themselves, of being introvert, and having difficulties to open up and confide in others. They report low self-confidence and self-esteem and problems with feeling and expressing anger. These behaviors complicate interaction with others and make establishment of solid relationships more difficult. In regards to detection of suicidal communication and treatment of suicidal patients, this may lead to misinterpretations and difficulties to fully benefit from treatment given or for professionals to provide the appropriate treatment. Clinicians should closely investigate the presence of early life adversity in suicidal patients and pay attention to their personal style and their difficulties in interpersonal exchange., (Copyright © 2020 Rajalin, Hirvikoski, Renberg, Åsberg and Jokinen.)

Clinical supervision is a cornerstone in psychotherapists' training but there are few empirical evaluations on the effects of supervision on therapists' competencies. The aim of this study was therefore to evaluate the effects of standardized supervision on rater-assessed competency in Cognitive Behavior Therapy (CBT). Six therapists with basic training in CBT were provided with protocol-based clinical supervision in CBT in a single-case experimental multiple baseline design. The supervision focused on specific CBT competencies and used experiential learning methods such as role-play. Each therapist recorded weekly treatment sessions during phases without and with supervision. The therapists' CBT competence was assessed by third-party raters using the Revised Cognitive Therapy Scale (CTS-R). Statistical analyses showed that the therapists' CTS-R scores increased significantly during the phase with supervision with a mean item increase of M = 0.71 (range = 0.50-1.0) on the supervision focus areas. This is one of the first empirical studies that can confirm that supervision affect CBT competencies. The results also suggest that supervision can be manualized and that supervisees have a positive perception of more active training methods. Further studies are needed to replicate the results and to find ways to improve the impact of supervision.

Background: Causes of the comorbidity of substance misuse with anxiety-related and depressive disorders (anxiety/depression) remain poorly known. We estimated associations of substance misuse and anxiety/depression in the general population and tested them while accounting for genetic and shared environmental factors., Methods: We studied individuals born in Sweden 1968-1997 (n = 2 996 398) with follow-up in nationwide register data for 1997-2013. To account for familial effects, stratified analyses were conducted within siblings and twin pairs. Substance misuse was defined as ICD-10 alcohol or drug use disorder or an alcohol/drug-related criminal conviction. Three dimensions of ICD-10 anxiety and depressive disorders and a substance misuse dimension were identified through exploratory factor analysis., Results: Substance misuse was associated with a 4.5-fold (95% CI 4.50-4.58) elevated risk of lifetime generalized anxiety/depression, 4.7-fold (95% CI 4.63-4.82) elevated risk of panic disorder and agora/social phobia, and 2.9-fold elevated risk of phobias/OCD (95% CI 2.82-3.02) as compared to those without substance misuse. The associations were attenuated in within-family analyses but we found elevated risks in monozygotic twin pairs discordant for substance misuse as well as significant non-shared environmental correlations. The association between anxiety/depression and substance misuse was mainly driven by generalized anxiety/depression, whereas other anxiety/depression dimensions had minor or no independent associations with substance misuse., Conclusions: Substance misuse and anxiety/depression are associated at the population level, and these associations are partially explained by familial liabilities. Our findings indicate a common genetic etiology but are also compatible with a potential partially causal relationship between substance misuse and anxiety/depression.

Objective: The purpose of this study was to investigate if brief treatment for alcohol dependence in primary care with the 15-method was as effective as specialist addiction care. In addition, we sought to investigate trajectories for change of alcohol consumption., Method: This study was a randomized controlled noninferiority trial, between-groups parallel design, with a noninferiority limit of 50 g of alcohol per week. A total of 288 adults fulfilling ICD-10 criteria for alcohol dependence were randomized to treatment in primary care or specialist outpatient care at a university addiction clinic. The primary outcome was change in weekly alcohol consumption at the 12-month follow-up. Secondary outcomes were heavy drinking days, severity of dependence, consequences of drinking, psychological health, quality of life, satisfaction with treatment, and biomarkers. Trajectories were investigated using change in World Health Organization drinking risk levels., Results: The intention-to-treat analysis (n = 231) showed that the estimated weekly alcohol consumption in primary care was 18.2 g (95% CI [14.9, 51.3]) higher compared with specialist care (p = .28). Noninferiority was not demonstrated as the confidence interval exceeded the noninferiority limit. The secondary outcomes showed no differences between primary care and specialist care except that patients randomized to specialist care were more satisfied with treatment. The analyses of trajectories showed the main part of change in consumption occurred from baseline to the 6-month follow-up and was maintained to the 12-month follow-up., Conclusions: Although noninferiority could not be demonstrated, based on similar trajectories and sustained reduction of alcohol use, this study indicates brief treatment of alcohol dependence in primary care with the 15-method is a feasible and promising approach.

Infections during brain development appear to contribute to cognitive impairment and aggressive behavior, as well as to a number of developmental mental disorders closely associated with violent criminal behavior. Yet, no study has thus far ever investigated whether infections during brain development increases the risk of violent criminality later in life. In this population-based cohort study, about 2.2 million individuals born in Sweden between the years 1973 and 1995 were included in an effort to estimate the association between infections during childhood (registered ICD-10 diagnoses of infections incurred before the age of 14 years) and violent criminal behavior (registered convictions for a violent crime between the ages of 15 and 38 years, prior to December 31, 2011). After inclusion of several sociodemographic parameters, risks of violent criminal behavior conferred by childhood infections - expressed as hazard ratios (HRs) and 95% confidence intervals (CIs) - were calculated by means of Cox regression. Mediation analyses were performed to explore the effect of psychiatric disorders on the association between infections during childhood and violent criminality. Results revealed a modest, yet significant, association between an infection during childhood and violent criminality later in life (adjusted HR 1.14, 95% CI 1.12-1.16). Infections during the first year of life and infections in the central nervous system were associated with the highest risks of subsequent violent criminality (adjusted HR 1.20, 95% CI 1.18-1.23, and adjusted HR 1.17, 95% CI 1.08-1.26, respectively). The association was partly mediated by the presence of a psychiatric disorder. In summary, independent of a wide range of covariates, our results suggest that infections during brain development could be part of the genesis of violent criminal behavior., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Sweden has a unique opportunity to identify and follow up women presenting with, or at risk for, perinatal mental health problems and disorders because universal screening programmes are provided by its primary healthcare system. Although they are implemented across almost the entire population, screening programmes are not necessarily leading to effective interventions because the multidisciplinary perinatal mental healthcare teams that provide for the assessment and treatment of moderate to severe disorders are very few in number and must be increased. In particular, efforts to reach immigrant parents must be intensified to achieve equal quality of care for all., Competing Interests: Conflicts of interest: None., (© The Authors 2019.)

Background: Autism spectrum disorder (ASD) evolves from an interplay between genetic and environmental factors during prenatal development. Since identifying maternal biomarkers associated with ASD risk in offspring during early pregnancy might result in new strategies for intervention, we investigated maternal metabolic biomarkers in relation to occurrence of ASD in offspring using both univariate logistic regression and multivariate network analysis., Methods: Serum samples from 100 women with an offspring diagnosed with ASD and 100 matched control women with typically developing offspring were collected at week 14 of pregnancy. Concentrations of 62 metabolic biomarkers were determined, including amino acids, vitamins (A, B, D, E, and K), and biomarkers related to folate (vitamin B 9 ) metabolism, lifestyle factors, as well as C-reactive protein (CRP), the kynurenine-tryptophan ratio (KTR), and neopterin as markers of inflammation and immune activation., Results: We found weak evidence for a positive association between higher maternal serum concentrations of folate and increased occurrence of ASD (OR per 1 SD increase: 1.70, 95% CI 1.22-2.37, FDR adjusted P = 0.07). Multivariate network analysis confirmed expected internal biochemical relations between the biomarkers. Neither inflammation markers nor vitamin D 3 levels, all hypothesized to be involved in ASD etiology, displayed associations with ASD occurrence in the offspring., Conclusions: Our findings suggest that high maternal serum folate status during early pregnancy may be associated with the occurrence of ASD in offspring. No inference about physiological mechanisms behind this observation can be made at the present time because blood folate levels may have complex relations with nutritional intake, the cellular folate status and status of other B-vitamins. Therefore, further investigations, which may clarify the potential role and mechanisms of maternal blood folate status in ASD risk and the interplay with other potential risk factors, in larger materials are warranted.

Background: Depression in adolescence is associated with increased healthcare consumption in adulthood, but prior research has not recognized the heterogeneity of depressive disorders. This paper investigated the additional healthcare usage and related costs in mid-adulthood for individuals with adolescent depression, and examined the mediating role of subsequent depression in early adulthood., Methods: This study was based on the Uppsala Longitudinal Adolescent Depression Study, initiated in Sweden in the early 1990s. Depressive disorders were assessed in adolescence (age 16-17) and early adulthood (age 19-30). Healthcare usage and related costs in mid-adulthood (age 31-40) were estimated using nationwide population-based registries. Participants with specific subtypes of adolescent depression (n = 306) were compared with matched non-depressed peers (n = 213)., Results: Women with persistent depressive disorder (PDD) in adolescence utilized significantly more healthcare resources in mid-adulthood. The association was not limited to psychiatric care, and remained after adjustment for individual and parental characteristics. The total additional annual cost for a single age group of females with a history of PDD at a population level was estimated at 3.10 million USD. Depression recurrence in early adulthood mediated the added costs for psychiatric care, but not for somatic care., Limitations: Primary health care data were not available, presumably resulting in an underestimation of the true healthcare consumption. Estimates for males had limited precision due to a relatively small male proportion., Conclusions: On a population level, the additional healthcare costs incurred in mid-adulthood in females with a history of adolescent PDD are considerable. Early treatment and prevention should be prioritized., (Copyright © 2019. Published by Elsevier B.V.)

Objectives: Pediatric acute-onset neuropsychiatric syndrome (PANS) is a descriptive clinical entity defined by the abrupt onset of psychiatric and somatic symptoms leading to significant loss of function. Data on well-characterized PANS patients are limited, biomarkers have yet to be identified, and a solid evidence base to guide treatment is lacking. In this study, we present our experience of a systematic evaluation of the first 45 patients included in a Swedish cohort. Methods: During the period 2014-2018, our clinic received 100 referrals regarding suspected PANS. All patients underwent a standardized psychiatric/medical evaluation by a child/adolescent psychiatrist and a clinical psychologist or a nurse. Those with severe symptoms were also assessed by a pediatric neurologist and a pediatric rheumatologist. Laboratory tests were obtained at different time points in an attempt to capture an active disease state. Results: Of the 100 referrals, 45 met strict PANS criteria and consented to participate in a long-term follow-up study. The median age at intake was 7.2 years (range 3.0-13.1) and 56% were male. Ninety-three percent fulfilled both criteria for acute/atypical onset of PANS symptoms and having had an infection in relation to onset. Sixteen percent had an onset of an autoimmune or inflammatory disorder in temporal relation to the onset of PANS-related symptoms. The most common onset symptoms were obsessive-compulsive disorder (89%), anxiety (78%), and emotional lability (71%). Twenty-four percent had a preexisting autoimmune disease (AD) and 18% a preexisting psychiatric/neuropsychiatric diagnosis. Sixty-four percent of biological relatives had at least one psychiatric disorder and 76% at least one AD or inflammatory disorder. Complement activation (37%), leukopenia (20%), positive antinuclear antibodies (17%), and elevated thyroid antibodies (11%) were the most common laboratory findings. Conclusions: In our PANS cohort, there was a strong indication of an association with AD. Further work is needed to establish whether any of the potential biomarkers identified will be clinically useful. Long-term follow-up of these patients using the Swedish national registers will enable a deeper understanding of the course of this patient group.

Aims: High alcohol consumption and use of illicit drugs among young people is of great concern and there is a need to identify arenas where this group can be reached by preventive measures. The aim of the present study was to study prevalence of risky alcohol consumption, illicit drug use, and risky sexual behaviour (RSB) among young people visiting youth health clinics in Stockholm county. Another aim was to explore the association between risky alcohol consumption, illicit drug use and RSB., Methods: During autumn 2016, an anonymous questionnaire comprising questions about alcohol, illicit drugs and risky sexual behaviour was given to visitors at 11 youth health clinics in Stockholm county., Results: A total of 328 youths ( M = 18.8 years, 89% girls) answered the questionnaire. Results show that 61.7% had risky alcohol consumption and 41.8% had tried illicit drugs. Risky sexual behaviour was more prevalent among respondents with risky alcohol consumption, and it was more common among non-students than students., Conclusions: Findings indicate that a large proportion of visitors at youth health clinics in Stockholm county has a risky alcohol consumption and experiences of other drugs, and also that risky alcohol consumption is associated with three of five RSB outcomes. Non-students seemed to be a particularly exposed risk group with regard to both risky alcohol consumption and RSB. Overall, the results indicate that youth health clinics are an important arena for alcohol prevention., Competing Interests: Declaration of conflicting interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2019.)

Objectives: Some patients with eating disorders (EDs) seem to experience their illness as an entity, a symbolic other to whom they relate, and which may influence both symptom levels and self-image. Extending previous research, this study investigated whether the patient-ED relationship has attachment qualities., Design: Structural Analysis of Social Behaviour was used to operationalize the patient-ED relationship, and the Attachment Style Questionnaire was used to measure attachment., Method: We examined ED patients' (N = 148) relationship with their ED, attachment behaviour, symptoms, and self-image. Attachment dimensions of Confidence, Anxious/ambivalence, and Avoidance were found to be significantly correlated with aspects of the patient-ED relationship. Introjection (i.e., whether ED actions were incorporated into patients' self-image) was investigated by examining the match between self-image profiles and the actions of patients' EDs. A double mediation model was tested in which ED control/emancipation and patients' Self-blame mediated the effect of attachment security on ED symptoms., Results: Attachment insecurity was associated with greater ED control and patient submission. In 28.5% of patients, there was a high degree of correlation between self-image and ED action profile. Data supported the mediation model., Conclusions: Attachment processes appear to be associated with the manner in which ED patients relate to their disorder, at least in some cases. Attempts to maintain psychological proximity to the ED as an introjected attachment figure may help to explain treatment resistance and ambivalence about change. This perspective may be useful in treatment., Practitioner Points: Attachment behaviours are associated with the patient-ED relationship, in which attachment insecurity is correlated with greater eating disorder control and patient submission. Some patients seem to incorporate the actions of the ED in their self-image, suggesting the presence of introjection. The patient-ED relationship may help explain patients' anxiety and ambivalence about change, seen from an attachment perspective. In treatment, it may be important to explore alternative safe havens and secure bases to the ED, such as interpersonal relationships and activities., (© 2018 The British Psychological Society.)

Autism spectrum disorder (ASD) is a neurodevelopmental condition of heterogeneous etiology. While it is widely recognized that genetic and environmental factors and their interactions contribute to autism phenotypes, their precise causal mechanisms remain poorly understood. This article reviews our current understanding of environmental risk factors of ASD and their presumed adverse physiological mechanisms. It comprehensively maps the significance of parental age, teratogenic compounds, perinatal risks, medication, smoking and alcohol use, nutrition, vaccination, toxic exposures, as well as the role of extreme psychosocial factors. Further, we consider the role of potential protective factors such as folate and fatty acid intake. Evidence indicates an increased offspring vulnerability to ASD through advanced maternal and paternal age, valproate intake, toxic chemical exposure, maternal diabetes, enhanced steroidogenic activity, immune activation, and possibly altered zinc-copper cycles and treatment with selective serotonin reuptake inhibitors. Epidemiological studies demonstrate no evidence for vaccination posing an autism risk. It is concluded that future research needs to consider categorical autism, broader autism phenotypes, as well as autistic traits, and examine more homogenous autism variants by subgroup stratification. Our understanding of autism etiology could be advanced by research aimed at disentangling the causal and non-causal environmental effects, both founding and moderating, and gene-environment interplay using twin studies, longitudinal and experimental designs. The specificity of many environmental risks for ASD remains unknown and control of multiple confounders has been limited. Further understanding of the critical windows of neurodevelopmental vulnerability and investigating the fit of multiple hit and cumulative risk models are likely promising approaches in enhancing the understanding of role of environmental factors in the etiology of ASD.

Purpose: To present the Uppsala Longitudinal Adolescent Depression Study, initiated in Uppsala, Sweden, in the early 1990s. The initial aim of this epidemiological investigation was to study the prevalence, characteristics and correlates of adolescent depression, and has subsequently expanded to include a broad range of social, economic and health-related long-term outcomes and cost-of-illness analyses., Participants: The source population was first-year students (aged 16-17) in upper-secondary schools in Uppsala during 1991-1992, of which 2300 (93%) were screened for depression. Adolescents with positive screening and sex/age-matched peers were invited to a comprehensive assessment. A total of 631 adolescents (78% females) completed this assessment, and 409 subsequently completed a 15-year follow-up assessment. At both occasions, extensive information was collected on mental disorders, personality and psychosocial situation. Detailed social, economic and health-related data from 1993 onwards have recently been obtained from the Swedish national registries for 576 of the original participants and an age-matched reference population (N≥200 000)., Findings to Date: The adolescent lifetime prevalence of a major depressive episode was estimated to be 11.4%. Recurrence in young adulthood was reported by the majority, with a particularly poor prognosis for those with a persistent depressive disorder or multiple somatic symptoms. Adolescent depression was also associated with an increased risk of other adversities in adulthood, including additional mental health conditions, low educational attainment and problems related to intimate relationships., Future Plans: Longitudinal studies of adolescent depression are rare and must be responsibly managed and utilised. We therefore intend to follow the cohort continuously by means of registries. Currently, the participants are approaching mid-adulthood. At this stage, we are focusing on the overall long-term burden of adolescent depression. For this purpose, the research group has incorporated expertise in health economics. We would also welcome extended collaboration with researchers managing similar datasets., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The risk of suicide is elevated after discharge from a psychiatric hospital. This study aimed to investigate how recent suicidal behavior affects the risk of suicide in patients with different psychiatric diagnoses immediately after discharge., Methods: Registers with national coverage were linked to create a study cohort including all individuals discharged from psychiatric hospitals in Sweden from 1973 through 2009. Hazard ratios for discharge diagnoses were calculated. The risk of suicide within 30 days after discharge in each diagnostic category when suicidal behavior had been registered within 30 days before admission was estimated., Results: A total of 3,695 suicides occurred after 2,883,088 discharges. If recent suicidal behavior was registered, the risk of completed suicide increased prominently in all diagnostic categories, but particularly for schizophrenia (hazard ratio [HR] = 8.9; 95% CI, 6.4-12.4) and other nonorganic psychosis (HR = 6.8; 95% CI, 5.1-9.0). Patients suffering from depression had the highest overall risk of suicide postdischarge (HR = 3.0; 95% CI, 2.7-3.3). This finding applied especially to male patients with depression (HR = 4.5; 95% CI, 4.0-5.0) or with reaction to crisis (HR = 3.6; 95% CI 3.0-4.4)., Conclusions: A distinct elevation of the risk of suicide was seen in all diagnostic groups if a recent self-harm event had occurred, particularly among patients with psychotic disorders. Overall, the immediate risk of suicide after discharge was high regardless of recent suicidal behavior. The findings in this study have relevance for clinical decisions about immediate after-care and treatment in connection with discharge from psychiatric inpatient care., (© Copyright 2019 Physicians Postgraduate Press, Inc.)

Developmental language disorder (DLD) is a common neurodevelopmental disorder with largely unknown etiology. Rare copy number variants (CNVs) have been implicated in the genetic architecture of other neurodevelopmental disorders (NDDs), which have led to clinical genetic testing recommendations for these disorders; however, the evidence is still lacking for DLD. We analyzed rare and de novo CNVs in 58 probands with severe DLD, their 159 family members and 76 Swedish typically developing children using high-resolution microarray. DLD probands had larger rare CNVs as measured by total length (P = .05), and average length (P = .04). In addition, the rate of rare CNVs overlapping coding genes was increased (P = .03 and P = .01) and in average more genes were affected (P = .006 and P = .03) in the probands and their siblings, respectively. De novo CNVs were found in 4.8% DLD probands (2/42) and 2.4% (1/42) siblings. Clinically significant CNVs or chromosomal anomalies were found in 6.9% (4/58) of the probands of which 2 carried 16p11.2 deletions. We provide further evidence that rare CNVs contribute to the etiology of DLD in loci that overlap with other NDDs. Based on our results and earlier literature, families with DLD should be offered molecular genetic testing as a routine in their clinical follow-up., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: To investigate if treatment for alcohol dependence in primary care is as effective as specialist addiction care., Method: Randomized controlled non-inferiority trial, between groups parallel design, not blinded. The non-inferiority limit was set to 50 grams of alcohol per week. About 288 adults fulfilling ICD-10 criteria for alcohol dependence were randomized to treatment in primary care (men n = 82, women n = 62) or specialist care (men n = 77, women n = 67). General practitioners at 12 primary care centers received 1-day training in a treatment manual for alcohol dependence. Primary outcome was change in weekly alcohol consumption at 6-months follow-up compared with baseline, as measured with timeline follow back. Secondary outcomes were heavy drinking days, severity of dependence, consequences of drinking, psychological health, quality of life, satisfaction with treatment and biomarkers., Results: Intention-to-treat analysis (n = 228) was statistically inconclusive, and could not confirm non-inferiority for the primary outcome, since the high end of the confidence interval exceeded 50 grams (estimated mean weekly alcohol consumption was 30 grams higher in primary care compared with specialist care; 95% confidence interval -10.20; 69.72). However, treatment in specialist care was not significantly superior to primary care (P = 0.146). Subanalysis suggests that specialist care was superior to primary care only for patients with high severity of dependence., Conclusions: Treatment for alcohol dependence in primary care is a promising approach, especially for individuals with low to moderate dependence. This may be a way to broaden the base of treatment for alcohol dependence, reducing the current treatment gap.

Background: Childhood obesity is an urgent public health concern, and there's a need for long-term, high-quality, primary prevention trials targeting parents of young children. The aim of the current study was to evaluate the long-term effect of a parental support program based on motivational interviewing (MI)., Methods: A cluster randomized controlled trial was carried out in eight Swedish counties. Participating families (N = 1355) were enrolled when the child was 9 months old, and participated in nine sessions during ∼39 months. The aim was to pomote healthy food and physical activity (PA) habits using MI and principles from cognitive behavioral therapy. Nurses in Swedish child health services delivered the intervention, and the control group received usual healthcare. The current study was a 1-year follow-up of effects on children's weight-related measures. Regression analyses were conducted using generalized estimating equations, including analyses to investigate potential parental moderators of the effect., Results: There were no statistically significant intervention effects at follow-up [BMI difference = -0.13, p = 0.29, overweight relative risk (RR) = 0.96, p = 0.78, obesity RR = 0.57, p = 0.20]. Maternal waist circumference and unhealthy eating and paternal PA moderated the effect, but effects were small and failed to reach statistical significance after correction for multiple comparisons., Conclusions: A parent-focused primary prevention intervention based on MI delivered within child health services did not result in effects at 1-year follow-up. The results were in line with those obtained at post-assessment and indicated no late onset of effect. Further studies exploring individual and contextual factors influencing the outcome are called for.

Background: Alcohol intoxication among spectators at sporting events and related problems, such as violence, are of great concern in many countries around the world. However, knowledge is scarce about whether or not alcohol is served to obviously intoxicated spectators at licensed premises inside and outside the sporting arenas, and if obviously intoxicated spectators are allowed entrance to these events. The objective of this study was therefore to examine the occurrences of overserving at licensed premises inside and outside arenas, and of allowed entry of obviously intoxicated spectators into arenas., Methods: An observational study assessing the rate of denied alcohol service and denied entry to arenas of trained professional actors portraying a standardized scene of obvious alcohol intoxication (i.e., pseudo-patrons) was conducted. The scene was developed by an expert panel, and each attempt was monitored by an observer. The settings were 2 arenas hosting matches in the Swedish Premier Football League in the largest city in Sweden and 1 arena in the second largest city, including entrances and licensed premises inside and outside the arenas., Results: The rates of denied alcohol service were 66.9% at licensed premises outside the arenas (n = 151) and 24.9% at premises inside the arenas (n = 237). The rate of denied entry to the arenas (n = 102) was 10.8%., Conclusions: Overserving and allowed entry of obviously alcohol-intoxicated spectators are problematic at sporting events in Sweden and may contribute to high overall intoxication levels among spectators. The differences in server intervention rates indicate that serving staff at licensed premises inside the arenas and entrance staff are not likely to have been trained in responsible beverage service. This result underscores the need for server training among staff at the arenas., (Copyright © 2017 by the Research Society on Alcoholism.)

Background: Recent research suggests that having a newborn child is associated with substantially reduced risk for maternal suicide. We studied postpartum suicides in a national cohort of mothers and the role of mental disorder, self-harm and delivery related factors., Methods: We used a nested case-control design with data from Swedish registries. The cohort consisted of all women given birth in Sweden 1974-2009. Mothers who died by suicide during follow-up were considered cases (n = 1,786) and risk of suicide was estimated with proximity to delivery as the explanatory variable. In a second step, association between suicide during the first year following delivery (n = 145) and mental disorder, self-harm and delivery related variables risk factors were analyzed., Results: The first postpartum year was associated with a lower risk of suicide, compared to later (RR 0.80, 95%CI 0.66-0.96), which was unaltered after adjustment for socio-economic status and history of self-harm (aRR 0.82, 95%CI 0.68-0.99). Compared to living mothers, suicide victims of the postpartum year more often had affective disorders (aRR 133.94, 95%CI 45.93-390.61), psychotic disorders (aRR 83.69, 95%CI 36.99-189.31) and history of self-harm (aRR 47.56, 95%CI 18.24-124.02). The aRR of stillbirth was 2.66 (95%CI 0.63-11.30)., Conclusions: We found only a weak negative association between childbirth during the preceding year and suicide, when using mothers as controls. A severe mental disorder after delivery and a history of self-harm was strongly associated with increased risk of suicide in the postpartum year and may inform the clinical assessment postpartum.