Change search
Refine search result
1 - 41 of 41
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1.
    Andersson, Erik
    et al.
    Karolinska Institutet.
    Hedman, Erik
    Karolinska Institutet.
    Enander, Jesper
    Karolinska Institutet.
    Djurfeldt, Diana Radu
    Karolinska Institutet.
    Ljotsson, Brjann
    Karolinska Institutet.
    Cervenka, Simon
    Karolinska Institutet.
    Isung, Josef
    Karolinska Institutet.
    Svanborg, Cecilia
    Karolinska Institutet.
    Mataix-Cols, David
    Karolinska Institutet.
    Kaldo, Viktor
    Karolinska Institutet.
    Andersson, Gerhard
    Karolinska Institutet;Linköping University.
    Lindefors, Nils
    Karolinska Institutet.
    Rück, Christian
    Karolinska Institutet.
    d-Cycloserine vs Placebo as Adjunct to Cognitive Behavioral Therapy for Obsessive-Compulsive Disorder and Interaction With Antidepressants A Randomized Clinical Trial2015In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 72, no 7, p. 659-667Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE It is unclear whether D-cycloserine (DCS), a partial N-methyl-D-aspartate agonist that enhances fear extinction, can augment the effects of exposure-based cognitive behavioral therapy (CBT) for obsessive-compulsive disorder (OCD). OBJECTIVES To examine whether DCS augments the effects of CBT for OCD and to explore (post hoc) whether concomitant antidepressant medication moderates the effects of DCS. DESIGN, SETTING, AND PARTICIPANTS A 12-week, double-blind randomized clinical trial with 3-month follow-up conducted at an academic medical center between September 4, 2012, and September 26, 2013. Participants included 128 adult outpatients with a primary diagnosis of OCD and a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score of 16 or higher. Concurrent antidepressant medication was permitted if the dose had been stable for at least 2 months prior to enrollment and remained unchanged during the trial. The main analysis was by intention-to-treat population. INTERVENTIONS All participants received a previously validated Internet-based CBT protocol over 12 weeks and were randomized to receive either 50 mg of DCS or placebo, administered 1 hour before each of 5 exposure and response prevention tasks. MAIN OUTCOMES AND MEASURES Clinician-administered Y-BOCS score at week 12 and at 3-month follow-up. Remission was defined as a score of 12 or lower on the Y-BOCS. RESULTS In the primary intention-to-treat analyses, DCS did not augment the effects of CBT compared with placebo (mean [SD] clinician-rated Y-BOCS score, DCS: 13.86 [6.50] at week 12 and 12.35 [7.75] at 3-month follow-up; placebo: 11.77 [5.95] at week 12 and 12.37 [6.68] at 3-month follow-up) but showed a significant interaction with antidepressants (clinician-rated Y-BOCS, B = -1.08; Z = -2.79; P = .005). Post hoc analyses revealed that antidepressants significantly impaired treatment response in the DCS group but not the placebo group, at both posttreatment and follow-up (clinician-rated Y-BOCS: t(62) = -3.00; P = .004; and t(61) = -3.49; P < .001, respectively). In the DCS group, a significantly greater proportion of antidepressant-free patients achieved remission status at follow-up (60% [95% CI, 45%-74%]) than antidepressant-medicated patients (24% [95% CI, 9%-48%]) (P = .008). Antidepressants had no effect in the placebo group (50% [95% CI, 36%-64%] remission rate in both groups). CONCLUSIONS AND RELEVANCE The findings suggest that antidepressants may interact with DCS to block its facilitating effect on fear extinction. Use of DCS may be a promising CBT augmentation strategy but only in antidepressant-free patients with OCD.

  • 2.
    Andersson, Erik
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Hedman, Erik
    Karolinska Institutet, Stockholm, Sweden.
    Enander, Jesper
    Karolinska Institutet, Stockholm, Sweden.
    Radu Djurfeldt, Diana
    Karolinska Institutet, Stockholm, Sweden.
    Ljótsson, Brjánn
    Karolinska Institutet, Stockholm, Sweden.
    Cervenka, Simon
    Karolinska Institutet, Stockholm, Sweden.
    Isung, Josef
    Karolinska Institutet, Stockholm, Sweden.
    Svanborg, Cecilia
    Karolinska Institutet, Stockholm, Sweden.
    Mataix-Cols, David
    Karolinska Institutet, Stockholm, Sweden.
    Kaldo, Viktor
    Karolinska Institutet, Stockholm, Sweden.
    Andersson, Gerhard
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences. Karolinska Inst, Div Psychiat, Dept Clin Neurosci, Stockholm, Sweden.
    Lindefors, Nils
    Karolinska Institutet, Stockholm, Sweden.
    Rück, Christian
    Karolinska Institutet, Stockholm, Sweden.
    D-Cycloserine vs Placebo as Adjunct to Cognitive Behavioral Therapy for Obsessive-Compulsive Disorder and Interaction With Antidepressants: A Randomized Clinical Trial.2015In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 72, no 7, p. 659-667Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE: It is unclear whether d-cycloserine (DCS), a partial N-methyl-d-aspartate agonist that enhances fear extinction, can augment the effects of exposure-based cognitive behavioral therapy (CBT) for obsessive-compulsive disorder (OCD).

    OBJECTIVES: To examine whether DCS augments the effects of CBT for OCD and to explore (post hoc) whether concomitant antidepressant medication moderates the effects of DCS.

    DESIGN, SETTING, AND PARTICIPANTS: A 12-week, double-blind randomized clinical trial with 3-month follow-up conducted at an academic medical center between September 4, 2012, and September 26, 2013. Participants included 128 adult outpatients with a primary diagnosis of OCD and a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score of 16 or higher. Concurrent antidepressant medication was permitted if the dose had been stable for at least 2 months prior to enrollment and remained unchanged during the trial. The main analysis was by intention-to-treat population.

    INTERVENTIONS: All participants received a previously validated Internet-based CBT protocol over 12 weeks and were randomized to receive either 50 mg of DCS or placebo, administered 1 hour before each of 5 exposure and response prevention tasks.

    MAIN OUTCOMES AND MEASURES: Clinician-administered Y-BOCS score at week 12 and at 3-month follow-up. Remission was defined as a score of 12 or lower on the Y-BOCS.

    RESULTS: In the primary intention-to-treat analyses, DCS did not augment the effects of CBT compared with placebo (mean [SD] clinician-rated Y-BOCS score, DCS: 13.86 [6.50] at week 12 and 12.35 [7.75] at 3-month follow-up; placebo: 11.77 [5.95] at week 12 and 12.37 [6.68] at 3-month follow-up) but showed a significant interaction with antidepressants (clinician-rated Y-BOCS, B = -1.08; Z = -2.79; P = .005). Post hoc analyses revealed that antidepressants significantly impaired treatment response in the DCS group but not the placebo group, at both posttreatment and follow-up (clinician-rated Y-BOCS: t62 = -3.00; P = .004; and t61 = -3.49; P < .001, respectively). In the DCS group, a significantly greater proportion of antidepressant-free patients achieved remission status at follow-up (60% [95% CI, 45%-74%]) than antidepressant-medicated patients (24% [95% CI, 9%-48%]) (P = .008). Antidepressants had no effect in the placebo group (50% [95% CI, 36%-64%] remission rate in both groups).

    CONCLUSIONS AND RELEVANCE: The findings suggest that antidepressants may interact with DCS to block its facilitating effect on fear extinction. Use of DCS may be a promising CBT augmentation strategy but only in antidepressant-free patients with OCD.

    TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01649895.

  • 3. Björkenstam, Emma
    et al.
    Hjern, Anders
    Stockholm University, Faculty of Social Sciences, Centre for Health Equity Studies (CHESS). Karolinska Institutet, Sweden.
    Björkenstam, Charlotte
    Kosidou, Kyriaki
    Association of Cumulative Childhood Adversity and Adolescent Violent Offending With Suicide in Early Adulthood2018In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 75, no 2, p. 185-193Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Childhood adversity (CA) is associated with an increased risk of suicide in young adulthood that might be explained by maladaptive trajectories during adolescence. Although adolescent violent offending is linked with suicide, little is known about its role in the association between CA and suicide. OBJECTIVE To examine whether adolescent violent offending mediates the association between CA and suicide in early adulthood. DESIGN, SETTING, AND PARTICIPANTS This population-based, longitudinal cohort study with a follow-up time spanning 5 to 9 years included 476 103 individuals born in Sweden between 1984 and 1988. The study population was prospectively followed up from 20 years of age until December 31, 2013, with respect to suicide. Data analysis was performed from January 1, 1984, to December 31, 2013. EXPOSURES Register-based CAs included parental death, parental substance abuse and psychiatric disorder, parental criminal offending, parental separation, public assistance recipiency, child welfare intervention, and residential instability. Adolescent violent offending was defined as being convicted of a violent crime between the ages of 15 and 19 years. MAIN OUTCOMES AND MEASURES Estimates of risk of suicide after 20 years of age (from 2004 if born in 1984 and from 2008 if born in 1988) until the end of 2013 were calculated as incidence rate ratios (IRRs) with 95% CIs using Poisson regression analysis. Adjustments were made for demographics and psychiatric disorder. In addition, binary mediation analysis with logistic regression was used. RESULTS A total of 476 103 individuals (231 699 [48.7%] female) were included in the study. Those with a conviction for violent offending had been exposed to all CAs to a greater extent than those with no violent offending. Cumulative CA was associated with risk of suicide in nonconvicted (adjusted IRR, 2.4; 95% CI, 1.5-3.9) and convicted youths, who had a higher risk of suicide (adjusted IRR, 8.5; 95% CI, 4.6-15.7). Adolescent violent offending partly mediated the association between CA and suicide. CONCLUSIONS AND RELEVANCE Individuals with a history of CA who also engage in violent offending in adolescence have a high risk of suicide. Interventions to prevent externalizing behavior during childhood and increased support to youths with delinquent behavior may have the potential to prevent suicide related to CA.

  • 4.
    Björkenstam, Emma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital. Karolinska Inst, Dept Publ Hlth Sci, Div Social Med, Box 45436, SE-104 31 Stockholm, Sweden.
    Hjern, Anders
    Stockholm Univ, Ctr Hlth Equity Studies, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden.;Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden..
    Björkenstam, Charlotte
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Kosidou, Kyriaki
    Karolinska Inst, Dept Publ Hlth Sci, Div Publ Hlth Epidemiol, Stockholm, Sweden.;Ctr Epidemiol & Community Med, Stockholm Cty Council, Stockholm, Sweden..
    Association of Cumulative Childhood Adversity and Adolescent Violent Offending With Suicide in Early Adulthood2018In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 75, no 2, p. 185-193Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE: Childhood adversity (CA) is associated with an increased risk of suicide in young adulthood that might be explained by maladaptive trajectories during adolescence. Although adolescent violent offending is linked with suicide, little is known about its role in the association between CA and suicide.

    OBJECTIVE: To examine whether adolescent violent offending mediates the association between CA and suicide in early adulthood.

    DESIGN, SETTING, AND PARTICIPANTS: This population-based, longitudinal cohort study with a follow-up time spanning 5 to 9 years included 476 103 individuals born in Sweden between 1984 and 1988. The study population was prospectively followed up from 20 years of age until December 31, 2013, with respect to suicide. Data analysis was performed from January 1, 1984, to December 31, 2013.

    EXPOSURES: Register-based CAs included parental death, parental substance abuse and psychiatric disorder, parental criminal offending, parental separation, public assistance recipiency, child welfare intervention, and residential instability. Adolescent violent offending was defined as being convicted of a violent crime between the ages of 15 and 19 years.

    MAIN OUTCOMES AND MEASURES: Estimates of risk of suicide after 20 years of age (from 2004 if born in 1984 and from 2008 if born in 1988) until the end of 2013 were calculated as incidence rate ratios (IRRs) with 95% CIs using Poisson regression analysis. Adjustments were made for demographics and psychiatric disorder. In addition, binary mediation analysis with logistic regression was used.

    RESULTS: A total of 476 103 individuals (231 699 [48.7%] female) were included in the study. Those with a conviction for violent offending had been exposed to all CAs to a greater extent than those with no violent offending. Cumulative CA was associated with risk of suicide in nonconvicted (adjusted IRR, 2.4; 95% CI, 1.5-3.9) and convicted youths, who had a higher risk of suicide (adjusted IRR, 8.5; 95% CI, 4.6-15.7). Adolescent violent offending partly mediated the association between CA and suicide.

    CONCLUSIONS AND RELEVANCE: Individuals with a history of CA who also engage in violent offending in adolescence have a high risk of suicide. Interventions to prevent externalizing behavior during childhood and increased support to youths with delinquent behavior may have the potential to prevent suicide related to CA.

  • 5.
    Björnsdotter Åberg, Malin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. University of Gothenburg, Sweden.
    Wang, Nancy
    Yale School Med, CT USA.
    Pelphrey, Kevin
    George Washington University, DC USA; Childrens National Medical Centre, DC 20010 USA.
    Kaiser, Martha D.
    Yale School Med, CT USA.
    Evaluation of Quantified Social Perception Circuit Activity as a Neurobiological Marker of Autism Spectrum Disorder2016In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 73, no 6, p. 614-621Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Autism spectrum disorder (ASD) is marked by social disability and is associated with dysfunction in brain circuits supporting social cue perception. The degree to which neural functioning reflects individual-level behavioral phenotype is unclear, slowing the search for functional neuroimaging biomarkers of ASD. OBJECTIVE To examine whether quantified neural function in social perception circuits may serve as an individual-level marker of ASD in children and adolescents. DESIGN, SETTING, AND PARTICIPANTS The cohort study was conducted at the Yale Child Study Center and involved children and adolescents diagnosed as having ASD and typically developing participants. Participants included a discovery cohort and a larger replication cohort. Individual-level social perception circuit functioning was assessed as functional magnetic resonance imaging brain responses to point-light displays of coherent vs scrambled human motion. MAIN OUTCOMES AND MEASURES Outcome measures included performance of quantified brain responses in affected male and female participants in terms of area under the receiver operating characteristic curve (AUC), sensitivity and specificity, and correlations between brain responses and social behavior. RESULTS Of the 39 participants in the discovery cohort aged 4 to 17 years, 22 had ASD and 30 were boys. Of the 75 participants in the replication cohort aged 7 to 20 years, 37 had ASD and 52 were boys. A relative reduction in social perception circuit responses was identified in discovery cohort boys with ASD at an AUC of 0.75 (95% CI, 0.52-0.89; P = .01); however, typically developing girls and girls with ASD could not be distinguished (P = .54). The results were confirmed in the replication cohort, where brain responses were identified in boys with ASD at an AUC of 0.79 (95% CI, 0.64-0.91; P amp;lt; .001) and failed to distinguish affected and unaffected girls (P = .82). Across both cohorts, boys were identified at an AUC of 0.77 (95% CI, 0.64-0.86) with corresponding sensitivity and specificity of 76% each. Additionally, brain responses were associated with social behavior in boys but not in girls. CONCLUSIONS AND RELEVANCE Quantified social perception circuit activity is a promising individual-level candidate neural marker of the male ASD behavioral phenotype. Our findings highlight the need to better understand effects of sex on social perception processing in relation to ASD phenotype manifestations.

  • 6.
    Brander, Gustaf
    et al.
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Rydell, Mina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Fernández de la Cruz, Lorena
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Serlachius, Eva
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden .
    Rück, Christian
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden .
    D'Onofrio, Brian M.
    Department of Psychological and Brain Sciences, Indiana University, Bloomington IN, USA.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Mataix-Cols, David
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Association of Perinatal Risk Factors With Obsessive-Compulsive Disorder: A Population-Based Birth Cohort, Sibling Control Study2016In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 73, no 11, p. 1135-1144Article in journal (Refereed)
    Abstract [en]

    Importance: Perinatal complications may increase the risk of obsessive-compulsive disorder (OCD). Previous reports were based on small, retrospective, specialist clinic-based studies that were unable to rigorously control for unmeasured environmental and genetic confounding.

    Objective: To prospectively investigate a wide range of potential perinatal risk factors for OCD, controlling for unmeasured factors shared between siblings in the analyses.

    Design, Setting, and Participants: This population-based birth cohort study included all 2 421 284 children from singleton births in Sweden from January 1, 1973, to December 31, 1996, who were followed up through December 31, 2013. From the 1 403 651 families in the cohort, differentially exposed siblings from the 743 885 families with siblings were evaluated; of these, 11 592 families included clusters of full siblings that were discordant for OCD. Analysis of the data was conducted from January, 26, 2015, to September, 5, 2016.

    Exposures: Perinatal data were collected from the Swedish Medical Birth Register and included maternal smoking during pregnancy, labor presentation, obstetric delivery, gestational age (for preterm birth), birth weight, birth weight in relation to gestational age, 5-minute Apgar score, and head circumference.

    Main Outcomes and Measures: Previously validated OCD codes (International Statistical Classification of Diseases and Health Related Problems, Tenth Revision, code F42) in the Swedish National Patient Register.

    Results: Of 2 421 284 individuals included in the cohort, 17 305 persons were diagnosed with OCD. Of these, 7111 were men (41.1%). The mean (SD) age of individuals at first diagnosis of OCD was 23.4 (6.5) years. An increased risk for OCD remained after controlling for shared familial confounders and measured covariates (including sex, year of birth, maternal and paternal age at birth, and parity), for smoking 10 or more cigarettes per day during pregnancy (hazard ratio [HR], 1.27; 95% CI, 1.02-1.58), breech presentation (HR, 1.35; 95% CI, 1.06-1.71), delivery by cesarean section (HR, 1.17; 95% CI, 1.01-1.34), preterm birth (HR, 1.24; 95% CI, 1.07-1.43), birth weight 1501 to 2500 g (HR, 1.30; 95% CI, 1.05-1.62) and 2501 to 3500 g (HR, 1.08; 95% CI, 1.01-1.16), being large for gestational age (HR, 1.23; 95% CI, 1.05-1.45), and Apgar distress scores at 5 minutes (HR, 1.50; 95% CI, 1.07-2.09). Gestational age and birth weight followed inverse dose-response associations, whereby an increasingly higher risk for OCD was noted in children with a shorter gestational age and lower birth weight. We also observed a dose-response association between the number of perinatal events and increased OCD risk, with HRs ranging from 1.11 (95% CI, 1.07-1.15) for 1 event to 1.51 (95% CI, 1.18-1.94) for 5 or more events.

    Conclusions and Relevance: A range of perinatal risk factors is associated with a higher risk for OCD independent of shared familial confounders, suggesting that perinatal risk factors may be in the causal pathway to OCD.

  • 7.
    Brännström, Jon
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Lövheim, Hugo
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Gustafson, Yngve
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Association Between Antidepressant Drug Use and Hip Fracture in Older People Before and After Treatment Initiation2019In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 76, no 2, p. 172-179Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE: Treatment with antidepressants has been associated with hip fracture. This association could restrict the treatment options, especially in older patients. OBJECTIVE: To investigate the association between antidepressant drug treatment and hip fracture starting 1 year before the initiation of treatment. DESIGN, SETTING, AND PARTICIPANTS: In this nationwide cohort study, 204 072 individuals in the Prescribed Drugs Register of Sweden's National Board of Health and Welfare aged 65 years or older who had a prescription of antidepressants filled between July 1, 2006, and December 31, 2011, were matched by birth year and sex to 1 control participant who was not prescribed antidepressants (for a total of 408 144 people in the register). Outcome data were collected from 1 year before to 1 year after the index date (date of prescription being filled). Data analysis was performed from July 1, 2005, to December 31, 2012. EXPOSURES: First filled prescription of an antidepressant drug. MAIN OUTCOMES AND MEASURES: Incident hip fractures occurring in the year before and year after initiation of antidepressant therapy were registered. Associations were investigated using multivariable conditional logistic regression models and flexible parametric models. RESULTS: Of the 408 144 people in the register who were included in the study, 257 486 (63.1%) were women, with a mean (SD) age of 80.1 (7.2) years. Antidepressant users sustained more than twice as many hip fractures than did nonusers in the year before and year after the initiation of therapy (2.8% vs 1.1% and 3.5% vs 1.3%, respectively, per actual incidence figures). In adjusted analyses, the odds ratios were highest for the associations between antidepressant use and hip fracture 16 to 30 days before the prescription was filled (odds ratio, 5.76; 95% CI, 4.73-7.01). In all separate analyses of age groups, of men and women, and of individual antidepressants, the highest odds ratios were seen 16 to 30 days before initiation of treatment, and no clear dose-response relationship was seen. CONCLUSIONS AND RELEVANCE: The present study found an association between antidepressant drug use and hip fracture before and after the initiation of therapy. This finding raises questions about the association that should be further investigated in treatment studies.

  • 8.
    Chang, Zheng
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Asherson, Philip J.
    Institute of Psychiatry, King's College London, London, United Kingdom .
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Center of Neurodevelopmental Disorders, Karolinska Institutet, Stockholm, Sweden .
    Developmental twin study of attention problems: high heritabilities throughout development.2013In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 70, no 3, p. 311-318Article in journal (Refereed)
    Abstract [en]

    Context: The genetic and environmental link between attention-deficit/hyperactivity disorder in childhood and the adult manifestation of the disorder is poorly understood because of a lack of longitudinal studies with cross-informant data.

    Objective: To explore the relative contribution of genetic and environmental influences on symptoms of attention problems from childhood to early adulthood.

    Design: Analysis was conducted using longitudinal structural equation modeling with multiple informants.

    Setting The Swedish Twin Study of Child and Adolescent Development.

    Participants: One thousand four hundred eighty twin pairs were prospectively followed up from childhood to young adulthood.

    Main outcome measures: Symptoms were obtained using parent and self-ratings of the Attention Problems Scale at ages 8 to 9, 13 to 14, 16 to 17, and 19 to 20 years.

    Results: The best-fitting model revealed high heritability of attention problems as indexed by parent and self-ratings from childhood to early adulthood (h² = 0.77-0.82). Genetic effects operating at age 8 to 9 years continued, explaining 41%, 34%, and 24% of the total variance at ages 13 to 14, 16 to 17, and 19 to 20 years. Moreover, new sets of genetic risk factors emerged at ages 13 to 14, 16 to 17, and 19 to 20 years.

    Conclusions: The shared view of self- and informant-rated attention problems is highly heritable in childhood, adolescence, and early adulthood, suggesting that the previous reports of low heritability for attention-deficit/hyperactivity disorder in adults are best explained by rater effects. Both genetic stability and genetic innovation were present throughout this developmental stage, suggesting that attention problems are a developmentally complex phenotype characterized by both continuity and change across the life span.

  • 9.
    Chang, Zheng
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    D'Onofrio, Brian M.
    Department of Psychological and Brain Sciences, Indiana University, Bloomington, United States .
    Sjölander, Arvid
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Serious transport accidents in adults with attention-deficit/hyperactivity disorder and the effect of medication: a population-based study2014In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 71, no 3, p. 319-325Article in journal (Refereed)
    Abstract [en]

    Importance: Studies have shown that attention-deficit/hyperactivity disorder (ADHD) is associated with transport accidents, but the magnitude of the association remains unclear. Most important, it is also unclear whether ADHD medication reduces this risk.

    Objectives: To estimate the association between ADHD and the risk of serious transport accidents and to explore the extent to which ADHD medication influences this risk among patients with ADHD.

    Design, setting and participants: In total, 17,408 patients with a diagnosis of ADHD were observed from January 1, 2006, through December 31, 2009, for serious transport accidents documented in Swedish national registers. The association between ADHD and accidents was estimated with Cox proportional hazards regression. To study the effect of ADHD medication, we used stratified Cox regression to compare the risk of accidents during the medication period with the risk during the nonmedication period within the same patients.

    Main outcomes and measures: Serious transport accident, identified as an emergency hospital visit or death due to transport accident.

    Results: Compared with individuals without ADHD, male patients with ADHD (adjusted hazard ratio, 1.47; 95% CI, 1.32-1.63) and female patients with ADHD (1.45; 1.24-1.71) had an increased risk of serious transport accidents. In male patients with ADHD, medication was associated with a 58% risk reduction (hazard ratio, 0.42; 95% CI, 0.23-0.75), but there was no statistically significant association in female patients. Estimates of the population-attributable fractions suggested that 41% to 49% of the accidents in male patients with ADHD could have been avoided if they had been receiving treatment during the entire follow-up.

    Conclusions and relevance: Attention-deficit/hyperactivity disorder is associated with an increased risk of serious transport accidents, and this risk seems to be possibly reduced by ADHD medication, at least among male patients. This should lead to increased awareness among clinicians and patients of the association between serious transport accidents and ADHD medication.

  • 10.
    Chang, Zheng
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Center for Health Statistics, University of Chicago, Chicago IL, United States.
    Quinn, Patrick D.
    Center for Health Statistics, University of Chicago, Chicago IL, United States; Department of Psychological and Brain Sciences, Indiana University, Bloomington, United States.
    Hur, Kwan
    Center for Health Statistics, University of Chicago, Chicago IL, United States.
    Gibbons, Robert D.
    Center for Health Statistics, University of Chicago, Chicago IL, United States.
    Sjolander, Arvid
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    D'Onofrio, Brian M.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychological and Brain Sciences, Indiana University, Bloomington, United States.
    Association Between Medication Use for Attention-Deficit/Hyperactivity Disorder and Risk of Motor Vehicle Crashes2017In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 74, no 6, p. 597-603Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE: Motor vehicle crashes (MVCs) are a major public health problem. Research has demonstrated that individuals with attention-deficit/hyperactivity disorder (ADHD) are more likely to experience MVCs, but the effect of ADHD medication treatment on the risk of MVCs remains unclear.

    OBJECTIVE: To explore associations between ADHD medication use and risk of MVCs in a large cohort of patients with ADHD.

    DESIGN, SETTING, AND PARTICIPANTS: For this study, a US national cohort of patients with ADHD (n = 2 319 450) was identified from commercial health insurance claims between January 1, 2005, and December 31, 2014, and followed up for emergency department visits for MVCs. The study used within-individual analyses to compare the risk of MVCs during months in which patients received ADHD medication with the risk of MVCs during months in which they did not receive ADHD medication.

    EXPOSURES: Dispensed prescription of ADHD medications.

    MAIN OUTCOMES AND MEASURES: Emergency department visits for MVCs.

    RESULTS: Among 2 319 450 patients identified with ADHD, the mean (SD) age was 32.5 (12.8) years, and 51.7% were female. In the within-individual analyses, male patients with ADHD had a 38%(odds ratio, 0.62; 95% CI, 0.56-0.67) lower risk of MVCs in months when receiving ADHD medication compared with months when not receiving medication, and female patients had a 42%(odds ratio, 0.58; 95% CI, 0.53-0.62) lower risk of MVCs in months when receiving ADHD medication. Similar reductions were found across all age groups, across multiple sensitivity analyses, and when considering the long-term association between ADHD medication use and MVCs. Estimates of the population-attributable fraction suggested that up to 22.1% of the MVCs in patients with ADHD could have been avoided if they had received medication during the entire follow-up.

    CONCLUSIONS AND RELEVANCE: Among patients with ADHD, rates of MVCs were lower during periods when they received ADHD medication. Considering the high prevalence of ADHD and its association with MVCs, these findings warrant attention to this prevalent and preventable cause of mortality and morbidity.

  • 11. Donker, Tara
    et al.
    Cornelisz, Ilja
    van Klaveren, Chris
    van Straten, Annemieke
    Carlbring, Per
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Clinical psychology. University of Southern Denmark, Denmark.
    Cuijpers, Pim
    van Gelder, Jean-Louis
    Effectiveness of Self-guided App-Based Virtual Reality Cognitive Behavior Therapy for Acrophobia: A Randomized Clinical Trial2019In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 76, no 7, p. 682-690Article in journal (Refereed)
    Abstract [en]

    Importance Globally, access to evidence-based psychological treatment is limited. Innovative self-help methods using smartphone applications and low-cost virtual reality have the potential to significantly improve the accessibility and scalability of psychological treatments.

    Objective To examine the effectiveness of ZeroPhobia, a fully self-guided app-based virtual reality cognitive behavior therapy (VR CBT) using low-cost (cardboard) virtual reality goggles compared with a wait-list control group and to determine its user friendliness.

    Design, Setting, and Participants In a single-blind randomized clinical trial, participants were enrolled between March 24 and September 28, 2017, and randomly assigned (1:1) by an independent researcher to either VR CBT app or a wait-list control group. A total of 193 individuals aged 18 to 65 years from the Dutch general population with acrophobia symptoms and access to an Android smartphone participated. The 6 animated modules of the VR-CBT app and gamified virtual reality environments were delivered over a 3-week period in participants’ natural environment. Assessments were completed at baseline, immediately after treatment, and at 3-month follow-up. Analysis began April 6, 2018, and was intention to treat.

    Intervention Self-guided app-based VR CBT.

    Main Outcomes and Measures The primary outcome measure was the Acrophobia Questionnaire. The hypothesis was formulated prior to data collection.

    Results In total, 193 participants (129 women [66.84%]; mean [SD] age, 41.33 [13.64] years) were randomly assigned to intervention (n = 96) or a wait-list control group (n = 97). An intent-to-treat analysis showed a significant reduction of acrophobia symptoms at posttest at 3 months for the VR-CBT app compared with the controls (b = –26.73 [95% CI, −32.12 to −21.34]; P < .001; d = 1.14 [95% CI, 0.84 to 1.44]). The number needed to treat was 1.7. Sensitivity and robustness analysis confirmed these findings. Pretreatment attrition was 22 of 96 (23%) because of smartphone incompatibility. Of the 74 participants who started using the VR-CBT app, 57 (77%) completed the intervention fully.

    Conclusions and Relevance A low-cost fully self-guided app-based virtual reality cognitive behavioral therapy with rudimentary virtual reality goggles can produce large acrophobia symptom reductions. To our knowledge, this study is the first to show that virtual reality acrophobia treatment can be done at home without the intervention of a therapist.

    Trial Registration Trialregister.nl identifier: NTR6442

  • 12.
    D'Onofrio, Brian M.
    et al.
    Department of Psychological and Brain Sciences, Indiana University, Bloomington, United States.
    Class, Quetzal A.
    Department of Psychological and Brain Sciences, Indiana University, Bloomington, United States.
    Rickert, Martin E.
    Department of Psychological and Brain Sciences, Indiana University, Bloomington, United States.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Långström, Niklas
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Preterm birth and mortality and morbidity: a population-based quasi-experimental study2013In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 70, no 11, p. 1231-1240Article in journal (Refereed)
    Abstract [en]

    Importance: Preterm birth is associated with increased mortality and morbidity. However, previous studies have been unable to rigorously examine whether confounding factors cause these associations rather than the harmful effects of being born preterm.

    Objective: To estimate the extent to which the associations between early gestational age and offspring mortality and morbidity are the result of confounding factors by using a quasi-experimental design, the sibling-comparison approach, and by controlling for statistical covariates that varied within families.

    Design, setting and participants: A population-based cohort study, combining Swedish registries to identify all individuals born in Sweden from 1973 to 2008 (3,300,708 offspring of 1,736,735 mothers) and link them with multiple outcomes.

    Main outcomes and measures: Offspring mortality (during infancy and throughout young adulthood) and psychiatric (psychotic or bipolar disorder, autism, attention-deficit/hyperactivity disorder, suicide attempts, substance use, and criminality), academic (failing grades and educational attainment), and social (partnering, parenthood, low income, and social welfare benefits) outcomes through 2009.

    Results: In the population, there was a dose-response relationship between early gestation and the outcome measures. For example, extreme preterm birth (23-27 weeks of gestation) was associated with infant mortality (odds ratio, 288.1; 95% CI, 271.7-305.5), autism (hazard ratio [HR], 3.2; 95% CI, 2.6-4.0), low educational attainment (HR, 1.7; 1.5-2.0), and social welfare benefits (HR, 1.3; 1.2-1.5) compared with offspring born at term. The associations between early gestation and mortality and psychiatric morbidity generally were robust when comparing differentially exposed siblings and controlling for statistical covariates, whereas the associations with academic and some social problems were greatly or completely attenuated in the fixed-effects models.

    Conclusions and relevance: The mechanisms responsible for the associations between preterm birth and mortality and morbidity are outcome-specific. Associations between preterm birth and mortality and psychiatric morbidity are largely independent of shared familial confounds and measured covariates, consistent with a causal inference. However, some associations, particularly predicting suicide attempt, educational attainment, and social welfare benefits, are the result of confounding factors. The findings emphasize the importance of both reducing preterm birth and providing wraparound services to all siblings in families with an offspring born preterm.

  • 13.
    D'Onofrio, Brian M.
    et al.
    Department of Psychological and Brain Sciences, Indiana University, Bloomington, United States.
    Rickert, Martin E.
    Department of Psychological and Brain Sciences, Indiana University, Bloomington, United States.
    Frans, Emma
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Lung and Allergy Unit, Astrid Lindgren Children's Hospital, Stockholm, Sweden .
    Sjölander, Arvid
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Paternal age at childbearing and offspring psychiatric and academic morbidity2014In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 71, no 4, p. 432-438Article in journal (Refereed)
    Abstract [en]

    Importance: Advancing paternal age is associated with increased genetic mutations during spermatogenesis, which research suggests may cause psychiatric morbidity in the offspring. The effects of advancing paternal age at childbearing on offspring morbidity remain unclear, however, because of inconsistent epidemiologic findings and the inability of previous studies to rigorously rule out confounding factors.

    Objective: To examine the associations between advancing paternal age at childbearing and numerous indexes of offspring morbidity.

    Design, setting and participants: We performed a population-based cohort study of all individuals born in Sweden in 1973-2001 (N = 2,615,081), with subsets of the data used to predict childhood or adolescent morbidity. We estimated the risk of psychiatric and academic morbidity associated with advancing paternal age using several quasi-experimental designs, including the comparison of differentially exposed siblings, cousins, and first-born cousins.

    Exposure: Paternal age at childbearing.

    Main outcomes and measures: Psychiatric (autism, attention-deficit/hyperactivity disorder, psychosis, bipolar disorder, suicide attempt, and substance use problem) and academic (failing grades and low educational attainment) morbidity.

    Results: In the study population, advancing paternal age was associated with increased risk of some psychiatric disorders (eg, autism, psychosis, and bipolar disorders) but decreased risk of the other indexes of morbidity. In contrast, the sibling-comparison analyses indicated that advancing paternal age had a dose-response relationship with every index of morbidity, with the magnitude of the associations being as large or larger than the estimates in the entire population. Compared with offspring born to fathers 20 to 24 years old, offspring of fathers 45 years and older were at heightened risk of autism (hazard ratio [HR] = 3.45; 95% CI, 1.62-7.33), attention-deficit/hyperactivity disorder (HR = 13.13; 95% CI, 6.85-25.16), psychosis (HR = 2.07; 95% CI, 1.35-3.20), bipolar disorder (HR = 24.70; 95% CI, 12.12-50.31), suicide attempts (HR = 2.72; 95% CI, 2.08-3.56), substance use problems (HR = 2.44; 95% CI, 1.98-2.99), failing a grade (odds ratio [OR] = 1.59; 95% CI, 1.37-1.85), and low educational attainment (OR = 1.70; 95% CI, 1.50-1.93) in within-sibling comparisons. Additional analyses using several quasi-experimental designs obtained commensurate results, further strengthening the internal and external validity of the findings.

    Conclusions and relevance: Advancing paternal age is associated with increased risk of psychiatric and academic morbidity, with the magnitude of the risks being as large or larger than previous estimates. These findings are consistent with the hypothesis that new genetic mutations that occur during spermatogenesis are causally related to offspring morbidity.

  • 14.
    Frick, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Use of 5-Hydroxytryptophan Labeled With Carbon 11 in Social Anxiety Disorder Reply2016In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 73, no 2, p. 177-178Article in journal (Refereed)
  • 15. Frick, Andreas
    et al.
    Åhs, Fredrik
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Engman, Jonas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Jonasson, My
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Alaie, Iman
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Björkstrand, Johannes
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Frans, Örjan
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Faria, Vanda
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Linnman, Clas
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wahlstedt, Kurt
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Serotonin Synthesis and Reuptake in Social Anxiety Disorder: A Positron Emission Tomography Study.2015In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 72, no 8, p. 794-802Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE: Serotonin is involved in negative affect, but whether anxiety syndromes, such as social anxiety disorder (SAD), are characterized by an overactive or underactive serotonin system has not been established. Serotonin 1A autoreceptors, which inhibit serotonin synthesis and release, are downregulated in SAD, and serotonin transporter availability might be increased; however, presynaptic serotonin activity has not been evaluated extensively.

    OBJECTIVE: To examine the serotonin synthesis rate and serotonin transporter availability in patients with SAD and healthy control individuals using positron emission tomography (PET) with the radioligands 5-hydroxytryptophan labeled with carbon 11 ([11C]5-HTP) and 11C-labeled 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile [11C]DASB.

    DESIGN, SETTING, AND PARTICIPANTS: We performed a cross-sectional study at an academic clinical research center. Eighteen patients with SAD (9 men and 9 women; mean [SD] age, 32.6 [8.2] years) and 18 sex- and age-matched healthy controls (9 men and 9 women; mean [SD] age, 34.7 [9.2] years) underwent [11C]5-HTP PET imaging. We acquired [11C]DASB PET images for 26 additional patients with SAD (14 men and 12 women; mean [SD] age, 35.2 [10.7] years) and the same 18 sex- and age-matched healthy controls. Participants were recruited through newspaper advertisements. Data were acquired from March 12, 2002, through March 5, 2012, and analyzed from March 28, 2013, through August 29, 2014.

    MAIN OUTCOMES AND MEASURES: The influx rate of [11C]5-HTP as a measure of serotonin synthesis rate capacity and [11C]DASB binding potential as an index of serotonin transporter availability were acquired during rest. We used the Liebowitz Social Anxiety Scale to measure severity of social anxiety symptoms.

    RESULTS: The PET data were not available for analysis in 1 control for each scan. Increased [11C]5-HTP influx rate was observed in the amygdala, raphe nuclei region, caudate nucleus, putamen, hippocampus, and anterior cingulate cortex of patients with SAD compared with healthy controls (P < .05 corrected), supporting an enhanced serotonin synthesis rate. Increased serotonin transporter availability in the patients with SAD relative to healthy controls was reflected by elevated [11C]DASB binding potential in the raphe nuclei region, caudate nucleus, putamen, thalamus, and insula cortex (P < .05 corrected).

    CONCLUSIONS AND RELEVANCE: Neurotransmission in SAD is characterized by an overactive presynaptic serotonin system, with increased serotonin synthesis and transporter availability. Our findings could provide important new insights into the etiology of anxiety disorders.

  • 16.
    Fusar-Poli, Paolo
    et al.
    Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Psychosis Studies, Early Psychosis Intervent & Clin Detect EPIC Lab, London, England;South London & Maudsley Natl Hlth Serv Fdn Trust, OASIS Serv, London, England;Univ Pavia, Dept Brain & Behav Sci, Pavia, Italy.
    Hijazi, Ziad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Stahl, Daniel
    Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Biostat & Hlth Informat, London, England.
    Steyerberg, Ewout W.
    Leiden Univ, Med Ctr, Dept Biomed Data Sci Med Stat & Med Decis Making, Leiden, Netherlands.
    The Science of Prognosis in Psychiatry: A Review2018In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 75, no 12, p. 1289-1297Article, review/survey (Refereed)
    Abstract [en]

    IMPORTANCE Prognosis is a venerable component of medical knowledge introduced by Hippocrates (460-377 BC). This educational review presents a contemporary evidence-based approach for how to incorporate clinical risk prediction models in modern psychiatry. The article is organized around key methodological themes most relevant for the science of prognosis in psychiatry. Within each theme, the article highlights key challenges and makes pragmatic recommendations to improve scientific understanding of prognosis in psychiatry.

    OBSERVATIONS The initial step to building clinical risk prediction models that can affect psychiatric care involves designing the model: preparation of the protocol and definition of the outcomes and of the statistical methods (theme 1). Further initial steps involve carefully selecting the predictors, preparing the data, and developing the model in these data. A subsequent step is the validation of the model to accurately test its generalizability (theme 2). The next consideration is that the accuracy of the clinical prediction model is affected by the incidence of the psychiatric condition under investigation (theme 3). Eventually, clinical prediction models need to be implemented in real-world clinical routine, and this is usually the most challenging step (theme 4). Advanced methods such as machine learning approaches can overcome some problems that undermine the previous steps (theme 5). The relevance of each of these themes to current clinical risk prediction modeling in psychiatry is discussed and recommendations are given.

    CONCLUSIONS AND RELEVANCE Together, these perspectives intend to contribute to an integrative, evidence-based science of prognosis in psychiatry. By focusing on the outcome of the individuals, rather than on the disease, clinical risk prediction modeling can become the cornerstone for a scientific and personalized psychiatry.

  • 17.
    Georgakis, Marios K.
    et al.
    Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, 75 Mikras Asias St, Athens 11527, Greece..
    Skalkidou, Alkistis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Petridou, Eleni Th.
    Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, 75 Mikras Asias St, Athens 11527, Greece..
    Estrogen-Based Therapies and Depression in Women Who Naturally Enter Menopause Before Population Average Reply2016In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 73, no 8, p. 874-875Article in journal (Refereed)
  • 18. Georgakis, Marios K
    et al.
    Thomopoulos, Thomas P
    Diamantaras, Andreas-Antonios
    Kalogirou, Eleni I
    Skalkidou, Alkistis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Daskalopoulou, Stella S
    Petridou, Eleni Th
    Association of Age at Menopause and Duration of Reproductive Period With Depression After Menopause: A Systematic Review and Meta-analysis2016In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 73, no 2, p. 139-149Article, review/survey (Refereed)
    Abstract [en]

    Importance: Estrogens have neuroprotective and antidepressive effects; however, associations between indices of reduced endogenous estrogens and risk for postmenopausal depression have not been systematically explored.

    Objective: To investigate the association of age at menopause and the duration of the reproductive period with the risk for depression among postmenopausal women with naturally occurring menopause.

    Data Sources: A search strategy for use of MEDLINE was developed (through January 1, 2015) using the key terms menopause, climacteric, reproductive period, depression, and mood disorders. References of included studies and reviews were also screened; authors were contacted to maximize synthesized evidence.

    Study Selection: A total of 12 323 articles, without language restriction, were screened by pairs of reviewers to identify observational studies related to the study hypothesis; 14 studies were eligible for meta-analysis.

    Data Extraction and Synthesis: Pairs of reviewers independently extracted information on study design and type of analysis by participants' characteristics and methods of depression ascertainment. Study quality was assessed using the Newcastle-Ottawa Scale, and fixed- or random-effects models were implemented.

    Main Outcomes and Measures: Pooled-effect estimates for depression, defined by psychiatric evaluation or validated instruments, by age at menopause and duration of the reproductive period.

    Results: The 14 studies included in the meta-analysis represented 67 714 women. An inverse association (reported as odds ratio [OR]; 95% CI of 2-year increments) with depression in postmenopausal women was shown for increasing age at menopause (0.98; 0.96-0.99 [67 434 unique participants; 13 studies]) and duration of the reproductive period (0.98; 0.96-0.99 [54 715 unique participants; 5 studies]). Menopause at age 40 or more years compared with premature menopause was associated with a 50% decreased risk for depression (3033 unique participants; 4 studies). Pooling of studies examining severe depression showed a 5% decrease in risk of severe depression with increasing (2-year increment) age at menopause (52 736 unique participants; 3 studies); sensitivity analysis of studies controlling for past depression revealed similar results for age at menopause (0.98; 0.96-1.00 [48 894 unique participants; 3 studies). No heterogeneity or publication bias was evident in the main analyses.

    Conclusions and Relevance: Longer exposure to endogenous estrogens, expressed as older age at menopause and longer reproductive period, is associated with a lower risk of depression in later life. Identifying women at higher risk for depression due to early menopause who could benefit from psychiatric intervention or estrogen-based therapies could be useful in the clinical setting.

  • 19.
    Hooshmand, Babak
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Klinikum Augsburg, Germany.
    Mangialasche, Francesca
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Kalpouzos, Gregoria
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Solomon, Alina
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Kåreholt, Ingemar
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Jönköping University, Sweden.
    Smith, A. David
    Refsum, Helga
    Wang, Rui
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Muehlmann, Marc
    Ertl-Wagner, Birgit
    Jonsson Laukka, Erika
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Bäckman, Lars
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Kivipelto, Miia
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Association of Vitamin B-12, Folate, and Sulfur Amino Acids With Brain Magnetic Resonance Imaging Measures in Older Adults A Longitudinal Population-Based Study2016In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 73, no 6, p. 606-613Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Vitamin B-12, folate, and sulfur amino acids may be modifiable risk factors for structural brain changes that precede clinical dementia. OBJECTIVE To investigate the association of circulating levels of vitamin B-12, red blood cell folate, and sulfur amino acids with the rate of total brain volume loss and the change in white matter hyperintensity volume as measured by fluid-attenuated inversion recovery in older adults. DESIGN, SETTING, AND PARTICIPANTS The magnetic resonance imaging subsample of the Swedish National Study on Aging and Care in Kungsholmen, a population-based longitudinal study in Stockholm, Sweden, was conducted in 501 participants aged 60 years or older who were free of dementia at baseline. A total of 299 participants underwent repeated structural brain magnetic resonance imaging scans from September 17, 2001, to December 17, 2009. MAIN OUTCOMES AND MEASURES The rate of brain tissue volume loss and the progression of total white matter hyperintensity volume. RESULTS In the multi-adjusted linear mixed models, among 501 participants (300 women [59.9%]; mean [SD] age, 70.9 [9.1] years), higher baseline vitamin B-12 and holotranscobalamin levels were associated with a decreased rate of total brain volume loss during the study period: for each increase of 1 SD, beta (SE) was 0.048 (0.013) for vitamin B-12 (P < .001) and 0.040 (0.013) for holotranscobalamin (P = .002). Increased total homocysteine levels were associated with faster rates of total brain volume loss in the whole sample (beta [SE] per 1-SD increase, -0.035 [0.015]; P = .02) and with the progression of white matter hyperintensity among participants with systolic blood pressure greater than 140mmHg (beta [SE] per 1-SD increase, 0.000019 [0.00001]; P = .047). No longitudinal associations were found for red blood cell folate and other sulfur amino acids. CONCLUSIONS AND RELEVANCE This study suggests that both vitamin B-12 and total homocysteine concentrations may be related to accelerated aging of the brain. Randomized clinical trials are needed to determine the importance of vitamin B-12 supplementation on slowing brain aging in older adults.

  • 20.
    Hooshmand, Babak
    et al.
    Center for Alzheimer Research–Aging Research Center, Karolinska Institutet, Stockholm University, Stockholm, Sweden.
    Mangialasche, Francesca
    Center for Alzheimer Research–Aging Research Center, Karolinska Institutet, Stockholm University, Stockholm, Sweden, and Department of Neurology, Klinikum Augsburg, Augsburg, Germany.
    Kalpouzos, Grégoria
    Center for Alzheimer Research–Aging Research Center, Karolinska Institutet, Stockholm University, Stockholm, Sweden.
    Solomon, Alina
    Center for Alzheimer Research–Aging Research Center, Karolinska Institutet, Stockholm University, Stockholm, Sweden.
    Kåreholt, Ingemar
    Jönköping University, School of Health and Welfare, HHJ, Institute of Gerontology. Jönköping University, School of Health and Welfare, HHJ. ARN-J (Aging Research Network - Jönköping). Center for Alzheimer Research–Aging Research Center, Karolinska Institutet, Stockholm University, Stockholm, Sweden.
    Smith, David
    Department of Pharmacology, University of Oxford, Oxford, UK.
    Refsum, Helga
    Department of Pharmacology, University of Oxford, Oxford, UK, and Institute of Nutrition, University of Oslo, Oslo, Norway.
    Wang, Rui
    Center for Alzheimer Research–Aging Research Center, Karolinska Institutet, Stockholm University, Stockholm, Sweden.
    Mühlmann, Marc
    Institute for Clinical Radiology, Ludwig-Maximillian University Hospital, Munich, Germany.
    Ertl-Wagner, Birgit
    Institute for Clinical Radiology, Ludwig-Maximillian University Hospital, Munich, Germany.
    Jonsson, Erika
    Center for Alzheimer Research–Aging Research Center, Karolinska Institutet, Stockholm University, Stockholm, Sweden.
    Bäckman, Lars
    Center for Alzheimer Research–Aging Research Center, Karolinska Institutet, Stockholm University, Stockholm, Sweden.
    Fratiglioni, Laura
    Center for Alzheimer Research–Aging Research Center, Karolinska Institutet, Stockholm University, Stockholm, Sweden.
    Kivipelto, Miia
    Center for Alzheimer Research–Aging Research Center, Karolinska Institutet, Stockholm University, Stockholm, Sweden.
    Association of vitamin B12, folate, and sulfur amino acids with brain magnetic resonance imaging measures in older adults: A longitudinal population-based study2016In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 73, no 6, p. 606-613Article in journal (Refereed)
    Abstract [en]

    Importance 

    Vitamin B12, folate, and sulfur amino acids may be modifiable risk factors for structural brain changes that precede clinical dementia.

    Objective 

    To investigate the association of circulating levels of vitamin B12, red blood cell folate, and sulfur amino acids with the rate of total brain volume loss and the change in white matter hyperintensity volume as measured by fluid-attenuated inversion recovery in older adults.

    Design, Setting, and Participants 

    The magnetic resonance imaging subsample of the Swedish National Study on Aging and Care in Kungsholmen, a population-based longitudinal study in Stockholm, Sweden, was conducted in 501 participants aged 60 years or older who were free of dementia at baseline. A total of 299 participants underwent repeated structural brain magnetic resonance imaging scans from September 17, 2001, to December 17, 2009.

    Main Outcomes and Measures 

    The rate of brain tissue volume loss and the progression of total white matter hyperintensity volume.

    Results 

    In the multi-adjusted linear mixed models, among 501 participants (300 women [59.9%]; mean [SD] age, 70.9 [9.1] years), higher baseline vitamin B12 and holotranscobalamin levels were associated with a decreased rate of total brain volume loss during the study period: for each increase of 1 SD, β (SE) was 0.048 (0.013) for vitamin B12 (P < .001) and 0.040 (0.013) for holotranscobalamin (P  = .002). Increased total homocysteine levels were associated with faster rates of total brain volume loss in the whole sample (β [SE] per 1-SD increase, –0.035 [0.015]; P = .02) and with the progression of white matter hyperintensity among participants with systolic blood pressure greater than 140 mm Hg (β [SE] per 1-SD increase, 0.000019 [0.00001]; P = .047). No longitudinal associations were found for red blood cell folate and other sulfur amino acids.

    Conclusions and Relevance 

    This study suggests that both vitamin B12 and total homocysteine concentrations may be related to accelerated aging of the brain. Randomized clinical trials are needed to determine the importance of vitamin B12 supplementation on slowing brain aging in older adults.

  • 21.
    Karyotaki, Eirini
    et al.
    Vrije University of Amsterdam, Netherlands.
    Riper, Heleen
    Vrije University of Amsterdam, Netherlands.
    Twisk, Jos
    University of Amsterdam, Netherlands.
    Hoogendoorn, Adriaan
    Geestelijke Gezondheidszorg inGeest inGeest, Netherlands; University of Medical Centre, Netherlands; Vrije University of Amsterdam, Netherlands.
    Kleiboer, Annet
    Vrije University of Amsterdam, Netherlands.
    Mira, Adriana
    Jaume University, Spain.
    Mackinnon, Andrew
    University of Amsterdam, Netherlands; Prince Wales Hospital, Australia.
    Meyer, Bjorn
    University of Amsterdam, Netherlands; Gaia AG, Germany; IBER Physiopathol Obes and Nutr, Spain.
    Botella, Cristina
    Jaume University, Spain.
    Littlewood, Elizabeth
    University of York, England.
    Andersson, Gerhard
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences. Karolinska Institute Disabil Research, Sweden.
    Christensen, Helen
    University of Amsterdam, Netherlands; Prince Wales Hospital, Australia.
    Klein, Jan P.
    Luebeck University, Germany.
    Schroeder, Johanna
    University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
    Breton-Lopez, Juana
    Jaume University, Spain.
    Scheider, Justine
    University of Medical Centre Hamburg Eppendorf, Germany; University of Nottingham, England.
    Griffiths, Kathy
    Australian National University, Australia.
    Farrer, Louise
    Australian National University, Australia.
    Huibers, Marcus J. H.
    Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
    Phillips, Rachel
    Kings Coll London, England.
    Gilbody, Simon
    University of York, England.
    Moritz, Steffen
    University of Medical Centre Hamburg Eppendorf, Germany.
    Berger, Thomas
    University of Bern, Switzerland.
    Pop, Victor
    Tilburg University of and Diagnost Centre Eindhoven, Netherlands.
    Spek, Viola
    Tilburg University of and Diagnost Centre Eindhoven, Netherlands.
    Cuijpers, Pim
    Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
    Efficacy of Self-guided Internet-Based Cognitive Behavioral Therapy in the Treatment of Depressive Symptoms A Meta-analysis of Individual Participant Data2017In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 74, no 4, p. 351-359Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Self-guided internet-based cognitive behavioral therapy (iCBT) has the potential to increase access and availability of evidence-based therapy and reduce the cost of depression treatment. OBJECTIVES To estimate the effect of self-guided iCBT in treating adults with depressive symptoms compared with controls and evaluate the moderating effects of treatment outcome and response. DATA SOURCES A total of 13 384 abstracts were retrieved through a systematic literature search in PubMed, Embase, PsycINFO, and Cochrane Library from database inception to January 1, 2016. STUDY SELECTION Randomized clinical trials in which self-guided iCBT was compared with a control (usual care, waiting list, or attention control) in individuals with symptoms of depression. DATA EXTRACTION AND SYNTHESIS Primary authors provided individual participant data from 3876 participants from 13 of 16 eligible studies. Missing data were handled using multiple imputations. Mixed-effects models with participants nested within studies were used to examine treatment outcomes and moderators. MAIN OUTCOMES AND MEASURES Outcomes included the Beck Depression Inventory, Center for Epidemiological Studies-Depression Scale, and 9-item Patient Health Questionnaire scores. Scales were standardized across the pool of the included studies. RESULTS Of the 3876 study participants, the mean (SD) age was 42.0 (11.7) years, 2531 (66.0%) of 3832 were female, 1368 (53.1%) of 2574 completed secondary education, and 2262 (71.9%) of 3146 were employed. Self-guided iCBT was significantly more effective than controls on depressive symptoms severity (beta = -0.21; Hedges g = 0.27) and treatment response (beta = 0.53; odds ratio, 1.95; 95% CI, 1.52-2.50; number needed to treat, 8). Adherence to treatment was associated with lower depressive symptoms (beta = -0.19; P = .001) and greater response to treatment (beta = 0.90; P amp;lt; .001). None of the examined participant and study-level variables moderated treatment outcomes. CONCLUSIONS AND RELEVANCE Self-guided iCBT is effective in treating depressive symptoms. The use of meta-analyses of individual participant data provides substantial evidence for clinical and policy decision making because self-guided iCBT can be considered as an evidence-based first-step approach in treating symptoms of depression. Several limitations of the iCBT should be addressed before it can be disseminated into routine care.

  • 22.
    Latvala, Antti
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden2Department of Public Health, University of Helsinki, Helsinki, Finland.
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden: Astrid Lindgren Children's Hospital, Lung and Allergy Unit, Karolinska University Hospital, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    A Longitudinal Study of Resting Heart Rate and Violent Criminality in More Than 700 000 Men2015In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 72, no 10, p. 971-978Article in journal (Refereed)
    Abstract [en]

    Importance: Low resting heart rate is a well-replicated physiological correlate of aggressive and antisocial behavior in children and adolescents, but whether low resting heart rate increases the risk of violence and other antisocial and risk-taking behaviors in adulthood has not been studied in representative samples.

    Objective: To study the predictive association of resting heart rate with violent and nonviolent criminality and with fatal and nonfatal injuries owing to assaults and unintentional injuries in the population.

    Design, setting and participants: We conducted a study of data from several Swedish national registers on 710 264 Swedish men in the general population born from 1958 to 1991, with a follow-up of up to 35.7 years. Outcome data were available and analyzed from January 1, 1973, through December 31, 2009. Resting heart rate was measured together with blood pressure at mandatory military conscription testing at a mean (SD) age of 18.2 (0.5) years.

    Main outcomes and measures: Violent and nonviolent criminal convictions and medical treatments or deaths owing to assaults and unintentional injuries.

    Results: In models adjusted for physical, cardiovascular, psychiatric, cognitive, and socioeconomic covariates, compared with 139 511 men in the highest quintile of the distribution of resting heart rate (≥83 beats/min), 132 595 men with the lowest quintile (heart rate, ≤60 beats/min) had a 39% (95% CI, 35%-44%) higher hazard of being convicted of violent crimes and a 25% (95% CI, 23%-28%) higher hazard of being convicted of nonviolent crimes. The corresponding hazard was 39% higher for assault injuries (95% CI, 33%-46%) and for unintentional injuries (95% CI, 38%-41%). Further adjustment for cardiorespiratory fitness in a subset of 572 610 men with data from an exercise test did not reduce the associations. Similar associations were found between low systolic blood pressure and violent and nonviolent criminality and for assault injuries when systolic blood pressure was studied instead of resting heart rate in more than 1 million men.

    Conclusions and relevance: Among men, low resting heart rate in late adolescence was associated with an increased risk for violent criminality, nonviolent criminality, exposure to assault, and unintentional injury in adulthood. Most of these results were replicated with low systolic blood pressure. Resting heart rate and other autonomic measures merit further study in the development and prevention of violence and antisocial behavior.

  • 23.
    Latvala, Antti
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Public Health, University of Helsinki, Helsinki, Finland.
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Rück, Christian
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    D'Onofrio, Brian M.
    Department of Psychological and Brain Sciences, Indiana University, Bloomington IN, USA.
    Jernberg, Tomas
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Lung and Allergy Unit, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Mataix-Cols, David
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Association of Resting Heart Rate and Blood Pressure in Late Adolescence With Subsequent Mental Disorders: A Longitudinal Population Study of More Than 1 Million Men in Sweden2016In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 73, no 12, p. 1268-1275Article in journal (Refereed)
    Abstract [en]

    Importance: Differences in cardiovascular autonomic activity between individuals with psychiatric disorders and healthy controls have been observed, but whether cardiovascular autonomic abnormalities are associated with subsequent psychiatric disorders is unknown.

    Objective: To investigate whether differences in cardiac autonomic function as indexed by resting heart rate and blood pressure are associated with psychiatric disorders during the lifetime of men in Sweden.

    Design, Setting, and Participants: We conducted a longitudinal register-based study of Swedish men whose resting heart rate (n = 1 039 443) and blood pressure (n = 1 555 979) were measured at military conscription at a mean (SD) age of 18.3 (0.6) years during the period from 1969 to 2010, with register-based follow-up data available until the end of 2013. Analyses were performed from November 18, 2015, to June 9, 2016.

    Main Outcomes and Measures: Dates of inpatient/outpatient diagnoses of anxiety disorders, obsessive-compulsive disorder, posttraumatic stress disorder, depressive disorders, bipolar disorder, schizophrenia, and substance use disorders and convictions for violent crimes, between 1973 and 2013, were obtained from nationwide registers. Adjustments were made for height, weight, body mass index, cardiorespiratory fitness, cognitive ability, and socioeconomic covariates.

    Results: After adjustment for covariates, Cox regression models with up to 45 years of follow-up data showed that men (mean [SD] age of 18.3 [0.6] years at conscription) with resting heart rates above 82 beats per minute had a 69% (95% CI, 46%-94%) increased risk for obsessive-compulsive disorder, a 21% (95% CI, 11%-33%) increased risk for schizophrenia, and an 18% (95% CI, 13%-22%) increased risk for anxiety disorders compared with men with resting heart rates below 62 beats per minute. Similar associations were observed with systolic/diastolic blood pressure. In contrast, lower resting heart rate and lower systolic blood pressure were associated with substance use disorders and violent criminality.

    Conclusions and Relevance: Our results suggest that for men, differences in heart rate and blood pressure in late adolescence are associated with lifetime major psychiatric disorders, with higher levels associated with obsessive-compulsive disorder, schizophrenia, and anxiety disorders and lower levels associated with substance use disorders and violent behavior. Differences in autonomic nervous system functioning may predate or represent an early marker of psychiatric disorders.

  • 24.
    Ljung, Therese
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Chen, Qi
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Common etiological factors of attention-deficit/hyperactivity disorder and suicidal behavior: a population-based study in Sweden2014In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 71, no 8, p. 958-964Article in journal (Refereed)
    Abstract [en]

    Importance: The prevention of suicidal behavior is one of the most important tasks for mental health clinicians. Although a few studies have indicated an increased risk of suicidal behavior among individuals with attention-deficit/hyperactivity disorder, the development of more effective ways of identifying and modifying the risk is hampered by our limited understanding of the underlying mechanisms for this association.

    Objective To explore whether attention-deficit/hyperactivity disorder and suicidal behavior share genetic and environmental risk factors.

    Design, setting and participants: Matched cohort design across different levels of family relatedness recorded from January 1, 1987, to December 31, 2009. We identified 51 707 patients with attention-deficit/hyperactivity disorder (through patient and prescribed drug registers) in Sweden and their relatives by linking longitudinal population-based registers. Control participants were matched 1:5 on sex and birth year.

    Main outcomes and measures: Any record of suicide attempt or completed suicide defined by discharge diagnoses of the International Classification of Diseases.

    Results: Individuals with attention-deficit/hyperactivity disorder (probands) had increased risks of attempted and completed suicide, even after adjusting for comorbid psychiatric disorders (odds ratio [OR] = 3.62 [95% CI, 3.29-3.98] and 5.91 [95% CI, 2.45-14.27], respectively). The highest familial risk was observed among first-degree relatives (attempted suicide: OR = 2.42 [95% CI, 2.36-2.49] among parents of probands with ADHD and OR = 2.28 [95% CI, 2.17-2.40] among full siblings of probands with ADHD; completed suicide: OR = 2.24 [95% CI, 2.06-2.43] and OR = 2.23 [1.83-2.73], respectively), whereas the risk was considerably lower among more genetically distant relatives (attempted suicide: OR = 1.59 [95% CI, 1.47-1.73] among maternal half siblings, OR = 1.57 [95% CI, 1.45-1.70] among paternal half siblings, and OR = 1.39 [95% CI, 1.35-1.43] among cousins; completed suicide: OR = 1.51 [95% CI, 1.08-2.10], OR = 2.02 [95% CI, 1.47-2.79], and OR = 1.51 [95% CI, 1.36-1.67], respectively). These familial aggregation patterns remained similar across sex, after excluding relatives with attention-deficit/hyperactivity disorder and probands with suicidal behavior, and after excluding probands and relatives with severe comorbid disorders.

    Conclusions and relevance: Attention-deficit/hyperactivity disorder is associated with an increased risk of both attempted and completed suicide. The pattern of familial risks across different levels of relatedness suggests that shared genetic factors are important for this association. This is an important first step toward identifying the underlying mechanisms for the risk of suicidal behavior in patients with attention-deficit/hyperactivity disorder and suggests that individuals with attention-deficit/hyperactivity disorder and their family members are important targets for suicide prevention and treatment.

  • 25.
    Lu, Yi
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Statistical Genetics, Genetics, and Computational Biology Department, QIMR Berghofer Medical Research Institute, Brisbane QLD, Australia.
    Sjölander, Arvid
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Cederlöf, Martin
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    D'Onofrio, Brian M.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychological and Brain Sciences, Indiana University, Bloomington, USA.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Pediatric Allergy and Pulmonology Unit, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Association Between Medication Use and Performance on Higher Education Entrance Tests in Individuals With Attention-Deficit/Hyperactivity Disorder2017In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 74, no 8, p. 815-822Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE: Individuals with attention-deficit/hyperactivity disorder (ADHD) are at greater risk for academic problems. Pharmacologic treatment is effective in reducing the core symptoms of ADHD, but it is unclear whether it helps to improve academic outcomes.

    OBJECTIVE: To investigate the association between the use of ADHD medication and performance on higher education entrance tests in individuals with ADHD.

    DESIGN, SETTING, AND PARTICIPANTS: This cohort study observed 61 640 individuals with a diagnosis of ADHD from January 1, 2006, to December 31, 2013. Records of their pharmacologic treatment were extracted from Swedish national registers along with data from the Swedish Scholastic Aptitude Test. Using a within-patient design, test scores when patients were taking medication for ADHD were compared with scores when they were not taking such medication. Data analysis was performed from November 24, 2015, to November 4, 2016.

    EXPOSURES: Periods with and without ADHD medication use. MAIN OUTCOMES AND MEASURES Scores from the higher education entrance examination (score range, 1-200 points).

    RESULTS: Among 930 individuals (493 males and 437 females; mean [SD] age, 22.2 [3.2] years) who had taken multiple entrance tests (n = 2524) and used ADHD medications intermittently, the test scores were a mean of 4.80 points higher (95% CI, 2.26-7.34; P<.001) during periods they were taking medication vs nonmedicated periods, after adjusting for age and practice effects. Similar associations between ADHD medication use and test scores were detected in sensitivity analyses.

    CONCLUSIONS AND RELEVANCE: Individuals with ADHD had higher scores on the higher education entrance tests during periods they were taking ADHD medication vs nonmedicated periods. These findings suggest that ADHD medications may help ameliorate educationally relevant outcomes in individuals with ADHD.

  • 26.
    Ludvigsson, Jonas F.
    et al.
    Örebro University Hospital. Clin Epidemiol Unit, Dept Med, Karolinska University Hospital, Stockholm, Sweden; Dept Med Epidemiol & Biostat, Karolinska Instute; Dept Pediat, Örebro University Hospital, Örebro, Sweden; Coll Med, Dept Med, Div Gastroenterol & Hepatol, Mayo Clin, Rochester MN, USA.
    Reichenberg, Abraham
    Inst Psychiat, Dept Psychosis Studies, Kings Coll London, London, England; Dept Psychiat, Mt Sinai Sch Med, New York NY, USA.
    Hultman, Christina M.
    Dept Med Epidemiol & Biostat, Karolinska Inst, Stockholm, Sweden.
    Murray, Joseph A.
    Coll Med, Dept Med, Div Gastroenterol & Hepatol, Mayo Clin, Rochester MN, USA.
    A Nationwide Study of the Association Between Celiac Disease and the Risk of Autistic Spectrum Disorders2013In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 70, no 11, p. 1224-1230Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Most case reports suggest an association between autistic spectrum disorders (ASDs) and celiac disease (CD) or positive CD serologic test results, but larger studies are contradictory. OBJECTIVE To examine the association between ASDs and CD according to small intestinal histopathologic findings. DESIGN AND SETTING Nationwide case-control study in Sweden. MAIN OUTCOMES AND MEASURES Through 28 Swedish biopsy registers, we collected data about 26 995 individuals with CD(equal to villous atrophy, Marsh stage 3), 12 304 individuals with inflammation (Marsh stages 1-2), and 3719 individuals with normal mucosa (Marsh stage 0) but positive CD serologic test results (IgA/IgG gliadin, endomysium, or tissue transglutaminase) and compared them with 213 208 age-and sex-matched controls. Conditional logistic regression estimated odds ratios (ORs) for having a prior diagnosis of an ASD according to the Swedish National Patient Register. In another analysis, we used the Cox proportional hazards regression model to estimate hazard ratios (HRs) for future ASDs in individuals undergoing small intestinal biopsy. RESULTS A prior ASD was not associated with CD (OR, 0.93; 95% CI, 0.51-1.68) or inflammation (OR 1.03; 95% CI, 0.40-2.64) but was associated with a markedly increased risk of having a normal mucosa but a positive CD serologic test result (OR, 4.57; 95% CI, 1.58-13.22). Restricting our data to individuals without a diagnosis of an ASD at the time of biopsy, CD (HR, 1.39; 95% CI, 1.13-1.71) and inflammation (HR, 2.01; 95% CI, 1.29-3.13) were both associated with moderate excess risks of later ASDs, whereas the HR for later ASDs in individuals with normal mucosa but positive CD serologic test results was 3.09 (95% CI, 1.99-4.80). CONCLUSIONS AND RELEVANCE Although this study found no association between CD or inflammation and earlier ASDs, there was a markedly increased risk of ASDs in individuals with normal mucosa but a positive CD serologic test result.

  • 27.
    Mataix-Cols, David
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Isomura, Kayoko
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Pérez-Vigil, Ana
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Chang, Zheng
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Rück, Christian
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Larsson, K. Johan
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Leckman, James F.
    Child Study Center, Yale University, New Haven CT, USA; Department of Psychiatry, Yale University, New Haven CT, USA; Department of Pediatrics and Psychology, Yale University, New Haven CT, USA.
    Serlachius, Eva
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Familial Risks of Tourette Syndrome and Chronic Tic Disorders: A Population-Based Cohort Study2015In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 72, no 8, p. 787-793Article in journal (Refereed)
    Abstract [en]

    Importance: Tic disorders, including Tourette syndrome (TS) and chronic tic disorders (CTDs), are assumed to be strongly familial and heritable. Although gene-searching efforts are well under way, precise estimates of familial risk and heritability are lacking. Previous controlled family studies were small and typically conducted within specialist clinics, resulting in potential ascertainment biases. They were also underpowered to disentangle genetic from environmental factors that contribute to the observed familiality. Twin studies have been either very small or based on parent-reported tics in population-based (nonclinical) twin samples.

    Objective: To provide unbiased estimates of familial risk and heritability of tic disorders at the population level.

    Design, setting, and participants: In this population cohort, multigenerational family study, we used a validated algorithm to identify 4826 individuals diagnosed as having TS or CTDs (76.2% male) in the Swedish National Patient Register from January 1, 1969, through December 31, 2009.

    Main outcomes and measures: We studied risks for TS or CTDs in all biological relatives of probands compared with relatives of unaffected individuals (matched on a 1:10 ratio) from the general population. Structural equation modeling was used to estimate the heritability of tic disorders.

    Results: The risk for tic disorders among relatives of probands with tic disorders increased proportionally to the degree of genetic relatedness. The risks for first-degree relatives (odds ratio [OR], 18.69; 95% CI, 14.53-24.05) were significantly higher than for second-degree relatives (OR, 4.58; 95% CI, 3.22-6.52) and third-degree relatives (OR, 3.07; 95% CI, 2.08-4.51). First-degree relatives at similar genetic distances (eg, parents, siblings, and offspring) had similar risks for tic disorders despite different degrees of shared environment. The risks for full siblings (50% genetic similarity; OR, 17.68; 95% CI, 12.90-24.23) were significantly higher than those for maternal half siblings (25% genetic similarity; OR, 4.41; 95% CI, 2.24-8.67) despite similar environmental exposures. The heritability of tic disorders was estimated to be 0.77 (95% CI, 0.70-0.85). There were no differences in familial risk or heritability between male and female patients.

    Conclusions and relevance: Tic disorders, including TS and CTDs, cluster in families primarily because of genetic factors and appear to be among the most heritable neuropsychiatric conditions.

  • 28. Musliner, Katherine L.
    et al.
    Mortensen, Preben B.
    McGrath, John J.
    Suppli, Nis P.
    Hougaard, David M.
    Bybjerg-Grauholm, Jonas
    Bækvad-Hansen, Marie
    Andreassen, Ole
    Pedersen, Carsten B.
    Pedersen, Marianne G.
    Mors, Ole
    Nordentoft, Merete
    Børglum, Anders D.
    Werge, Thomas
    Agerbo, Esben
    Nordin Adolfsson, Annelie (Contributor)
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Association of Polygenic Liabilities for Major Depression, Bipolar Disorder, and Schizophrenia With Risk for Depression in the Danish Population2019In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 76, no 5, p. 516-525Article in journal (Refereed)
    Abstract [en]

    Importance: Although the usefulness of polygenic risk scores as a measure of genetic liability for major depression (MD) has been established, their association with depression in the general population remains relatively unexplored.

    Objective: To evaluate whether polygenic risk scores for MD, bipolar disorder (BD), and schizophrenia (SZ) are associated with depression in the general population and explore whether these polygenic liabilities are associated with heterogeneity in terms of age at onset and severity at the initial depression diagnosis.

    Design, Setting, and Participants: Participants were drawn from the Danish iPSYCH2012 case-cohort study, a representative sample drawn from the population of Denmark born between May 1, 1981, and December 31, 2005. The hazard of depression was estimated using Cox regressions modified to accommodate the case-cohort design. Case-only analyses were conducted using linear and multinomial regressions. The data analysis was conducted from February 2017 to June 2018.

    Exposures: Polygenic risk scores for MD, BD, and SZ trained using the most recent genome-wide association study results from the Psychiatric Genomics Consortium.

    Main Outcomes and Measures: The main outcome was first depressive episode (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] code F32) treated in hospital-based psychiatric care. Severity at the initial diagnosis was measured using the ICD-10 code severity specifications (mild, moderate, severe without psychosis, and severe with psychosis) and treatment setting (inpatient, outpatient, and emergency).

    Results: Of 34 573 participants aged 10 to 31 years at censoring, 68% of those with depression were female compared with 48.9% of participants without depression. Each SD increase in polygenic liability for MD, BD, and SZ was associated with 30% (hazard ratio [HR], 1.30; 95% CI, 1.27-1.33), 5% (HR, 1.05; 95% CI, 1.02-1.07), and 12% (HR, 1.12; 95% CI, 1.09-1.15) increases in the hazard of depression, respectively. Among cases, a higher polygenic liability for BD was associated with earlier depression onset (β = -.07; SE = .02; P = .002).

    Conclusions and Relevance: Polygenic liability for MD is associated with first depression in the general population, which supports the idea that these scores tap into an underlying liability for developing the disorder. The fact that polygenic risk for BD and polygenic risk for SZ also were associated with depression is consistent with prior evidence that these disorders share some common genetic overlap. Variations in polygenic liability may contribute slightly to heterogeneity in clinical presentation, but these associations appear minimal.

  • 29.
    Nordsletten, Ashley E.
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden .
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Crowley, James J.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, USA.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden .
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Mataix-Cols, David
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden .
    Patterns of Nonrandom Mating Within and Across 11 Major Psychiatric Disorders2016In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 73, no 4, p. 354-361Article in journal (Refereed)
    Abstract [en]

    Importance: Psychiatric disorders are heritable, polygenic traits, which often share risk alleles and for which nonrandom mating has been suggested. However, despite the potential etiological implications, the scale of nonrandom mating within and across major psychiatric conditions remains unclear.

    Objective: To quantify the nature and extent of nonrandom mating within and across a broad range of psychiatric conditions at the population level.

    Design, setting and participants: Population-based cohort using Swedish population registers. Participants were all Swedish residents with a psychiatric diagnosis of interest (attention-deficit/hyperactivity disorder, autism spectrum disorder, schizophrenia, bipolar disorder, major depression, generalized anxiety disorder, agoraphobia, social phobia, obsessive-compulsive disorder, anorexia, or substance abuse), along with their mates. Individuals with select nonpsychiatric disorders (Crohn's disease, type 1 and type 2 diabetes mellitus, multiple sclerosis, or rheumatoid arthritis) were included for comparison. General population samples were also derived and matched 1:5 with each case proband. Inpatient and outpatient diagnostic data were derived from the Swedish National Patient Register (1973-2009), with analyses conducted between June 2014 and May 2015.

    MAIN OUTCOMES AND MEASURES: Correlation in the diagnostic status of mates both within and across disorders. Conditional logistic regression was used to quantify the odds of each diagnosis in the mates of cases relative to matched population controls.

    RESULTS: Across cohorts, data corresponded to 707 263 unique case individuals, with women constituting 45.7% of the full population. Positive correlations in diagnostic status were evident between mates. Within-disorder correlations were marginally higher (range, 0.11-0.48) than cross-disorder correlations (range, 0.01-0.42). Relative to matched populations, the odds of psychiatric case probands having an affected mate were significantly elevated. Differences in the magnitude of observed relationships were apparent by disorder (odds ratio range, 0.8-11.4). The number of comorbidities in a case proband was associated with the proportion of affected mates. These relationships were not apparent or weaker in magnitude among nonpsychiatric conditions (correlation range, -0.03 to 0.17).

    CONCLUSIONS AND RELEVANCE: Nonrandom mating is evident in psychiatric populations both within specific disorders and across the spectrum of psychiatric conditions. This phenomenon may hold important implications for how we understand the familial transmission of these disorders and for psychiatric genetic research.

  • 30.
    Pettersson, Erik
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    D'Onofrio, Brian
    Department of Psychology, University of Indiana, Bloomington.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Association of Fetal Growth With General and Specific Mental Health Conditions2019In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 76, no 5, p. 536-543Article in journal (Refereed)
    Abstract [en]

    Importance: It is unclear if the associations between fetal growth and later mental health conditions remain after controlling for familial factors and psychiatric comorbidity.

    Objective: To examine the associations between fetal growth and general and specific mental health conditions, controlling for familial factors.

    Design, Setting, and Participants: This register-based study conducted in Sweden analyzed 546 894 pairs of full siblings born between January 1, 1973, and December 31, 1998. Sibling pairs were followed up through December 31, 2013. First, population-based and within-sibling pair associations (which controlled for time-invariant familial confounders) between fetal growth and the outcomes were estimated. Second, exploratory factor analysis was applied to the outcomes to derive 1 general factor and 4 specific and independent factors. Third, the general and specific factors were regressed on fetal growth. Statistical analysis was performed from March 27, 2017, to October 27, 2018.

    Main Outcome and Measures: The outcomes were 11 psychiatric diagnoses (depression, anxiety, obsessive-compulsive disorder, posttraumatic stress disorder, bipolar disorder, alcohol abuse, drug use, attention-deficit/hyperactivity disorder, autism, schizophrenia, and schizoaffective disorder) and court convictions of violent crimes. Birth weight (in kilograms) statistically adjusted for gestational age was the exposure.

    Results: The mean (SD) age of the 1 093 788 participants was 27.2 (6.8) years (range, 15.1-40.9 years) and 51.5% were male. Nine outcomes were significantly associated with birth weight in the population at large: depression (odds ratio [OR], 0.96; 95% CI, 0.95-0.98), anxiety (OR, 0.94; 95% CI, 0.92-0.95), posttraumatic stress disorder (OR, 0.91; 95% CI, 0.89-0.93), bipolar disorder (OR, 0.94; 95% CI, 0.89-1.00), alcohol abuse (OR, 0.89; 95% CI, 0.87-0.91), drug use (OR, 0.83; 95% CI, 0.80-0.85), violent crimes (OR, 0.85; 95% CI, 0.83-0.86), attention-deficit/hyperactivity disorder (OR, 0.88; 95% CI, 0.86-0.90), and autism (OR, 0.95; 95% CI, 0.92-0.97). Only depression (OR, 0.95; 95% CI 0.92-0.98), obsessive-compulsive disorder (OR, 0.93; 95% CI, 0.87-0.99), attention-deficit/hyperactivity disorder (OR, 0.86; 95% CI, 0.82-0.89), and autism (OR, 0.72; 95% CI, 0.69-0.76) remained significantly associated within sibling pairs. An exploratory factor analysis indicated that 1 general and 4 specific factors (capturing anxiety, externalizing, neurodevelopmental, and psychotic conditions) fit the outcomes well. Across almost all sensitivity analyses, an increase in birth weight by 1 kg significantly reduced the general (β, -0.047; 95% CI, -0.071 to -0.023) and the specific neurodevelopmental factors (β, -0.159; 95% CI, -0.190 to -0.128) within sibling pairs.

    Conclusions and Relevance: Controlling for familial confounders, reduced fetal growth was associated with a small but significant increase in the general factor of psychopathology and a moderate increase in a specific neurodevelopmental factor.

  • 31.
    Pérez-Vigil, Ana
    et al.
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Child and Adolescent Psychiatry and Psychology, Institute of Neuroscience, Hospital Clínic de Barcelona, Barcelona, Spain.
    Fernández de la Cruz, Lorena
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden .
    Brander, Gustaf
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden .
    Isomura, Kayoko
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden .
    Jangmo, Andreas
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Feldman, Inna
    Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
    Hesselmark, Eva
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden .
    Serlachius, Eva
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden .
    Lázaro, Luisa
    Department of Child and Adolescent Psychiatry and Psychology, Institute of Neuroscience, Hospital Clínic de Barcelona, Barcelona, Spain; Department of Medicine, University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental, Barcelona, Spain.
    Rück, Christian
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden .
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    D'Onofrio, Brian M.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychological and Brain Sciences, Indiana University, Bloomington, USA.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Mataix-Cols, David
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden .
    Association of Obsessive-Compulsive Disorder With Objective Indicators of Educational Attainment: A Nationwide Register-Based Sibling Control Study2018In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 75, no 1, p. 47-55Article in journal (Refereed)
    Abstract [en]

    Importance: To our knowledge, the association of obsessive-compulsive disorder (OCD) and academic performance has not been objectively quantified.

    Objective: To investigate the association of OCD with objectively measured educational outcomes in a nationwide cohort, adjusting for covariates and unmeasured factors shared between siblings.

    Design, Setting, And Participants: This population-based birth cohort study included 2 115 554 individuals who were born in Sweden between January 1, 1976, and December 31, 1998, and followed up through December 31, 2013. Using the Swedish National Patient Register and previously validated International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes, we identified persons with OCD; within the cohort, we identified 726 198 families with 2 or more full siblings, and identified 11 482 families with full siblings discordant for OCD. Data analyses were conducted from October 1, 2016, to September 25, 2017.

    Main Outcomes and Measures: The study evaluates the following educational milestones: eligibility to access upper secondary school after compulsory education, finishing upper secondary school, starting a university degree, finishing a university degree, and finishing postgraduate education.

    Results: Of the 2 115 554 individuals in the cohort, 15 120 were diagnosed with OCD (59% females). Compared with unexposed individuals, those with OCD were significantly less likely to pass all core and additional courses at the end of compulsory school (adjusted odds ratio [aOR] range, 0.35-0.60) and to access a vocational or academic program in upper secondary education (aOR, 0.47; 95% CI, 0.45-0.50 and aOR, 0.61; 95% CI, 0.58-0.63, for vocational and academic programs, respectively). People with OCD were also less likely to finish upper secondary education (aOR, 0.43; 95% CI, 0.41-0.44), start a university degree (aOR, 0.72; 95% CI, 0.69-0.75), finish a university degree (aOR, 0.59; 95% CI, 0.56-0.62), and finish postgraduate education (aOR, 0.52; 95% CI, 0.36-0.77). The results were similar in the sibling comparison models. Individuals diagnosed with OCD before age 18 years showed worse educational attainment across all educational levels compared with those diagnosed at or after age 18 years. Exclusion of patients with comorbid neuropsychiatric disorders, psychotic, anxiety, mood, substance use, and other psychiatric disorders resulted in attenuated estimates, but patients with OCD were still impaired across all educational outcomes.

    Conclusions and Relevance: Obsessive-compulsive disorder, particularly when it has an early onset, is associated with a pervasive and profound decrease in educational attainment, spanning from compulsory school to postgraduate education.

  • 32. Pérez-Vigil, Ana
    et al.
    Fernández de la Cruz, Lorena
    Brander, Gustaf
    Isomura, Kayoko
    Jangmo, Andreas
    Feldman, Inna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Social medicine/CHAP.
    Hesselmark, Eva
    Serlachius, Eva
    Lázaro, Luisa
    Rück, Christian
    Kuja-Halkola, Ralf
    D'Onofrio, Brian M
    Larsson, Henrik
    Mataix-Cols, David
    Association of Obsessive-Compulsive Disorder With Objective Indicators of Educational Attainment: A Nationwide Register-Based Sibling Control Study2018In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 75, no 1, p. 47-55Article in journal (Refereed)
    Abstract [en]

    Importance: To our knowledge, the association of obsessive-compulsive disorder (OCD) and academic performance has not been objectively quantified.

    Objective: To investigate the association of OCD with objectively measured educational outcomes in a nationwide cohort, adjusting for covariates and unmeasured factors shared between siblings.

    Design, Setting, And Participants: This population-based birth cohort study included 2 115 554 individuals who were born in Sweden between January 1, 1976, and December 31, 1998, and followed up through December 31, 2013. Using the Swedish National Patient Register and previously validated International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes, we identified persons with OCD; within the cohort, we identified 726 198 families with 2 or more full siblings, and identified 11 482 families with full siblings discordant for OCD. Data analyses were conducted from October 1, 2016, to September 25, 2017.

    Main Outcomes and Measures: The study evaluates the following educational milestones: eligibility to access upper secondary school after compulsory education, finishing upper secondary school, starting a university degree, finishing a university degree, and finishing postgraduate education.

    Results: Of the 2 115 554 individuals in the cohort, 15 120 were diagnosed with OCD (59% females). Compared with unexposed individuals, those with OCD were significantly less likely to pass all core and additional courses at the end of compulsory school (adjusted odds ratio [aOR] range, 0.35-0.60) and to access a vocational or academic program in upper secondary education (aOR, 0.47; 95% CI, 0.45-0.50 and aOR, 0.61; 95% CI, 0.58-0.63, for vocational and academic programs, respectively). People with OCD were also less likely to finish upper secondary education (aOR, 0.43; 95% CI, 0.41-0.44), start a university degree (aOR, 0.72; 95% CI, 0.69-0.75), finish a university degree (aOR, 0.59; 95% CI, 0.56-0.62), and finish postgraduate education (aOR, 0.52; 95% CI, 0.36-0.77). The results were similar in the sibling comparison models. Individuals diagnosed with OCD before age 18 years showed worse educational attainment across all educational levels compared with those diagnosed at or after age 18 years. Exclusion of patients with comorbid neuropsychiatric disorders, psychotic, anxiety, mood, substance use, and other psychiatric disorders resulted in attenuated estimates, but patients with OCD were still impaired across all educational outcomes.

    Conclusions and Relevance: Obsessive-compulsive disorder, particularly when it has an early onset, is associated with a pervasive and profound decrease in educational attainment, spanning from compulsory school to postgraduate education.

  • 33.
    Quinn, Patrick D.
    et al.
    Department of Psychological and Brain Sciences, Indiana University, Bloomington IN, United States.
    Rickert, Martin E.
    Department of Psychological and Brain Sciences, Indiana University, Bloomington IN, United States.
    Weibull, Caroline E.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Johansson, Anna L. V.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Iliadou, Anastasia N.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    D'Onofrio, Brian M.
    Department of Psychological and Brain Sciences, Indiana University, Bloomington IN, United States.
    Association Between Maternal Smoking During Pregnancy and Severe Mental Illness in Offspring2017In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 74, no 6, p. 589-596Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE: Several recent population-based studies have linked exposure to maternal smoking during pregnancy to increased risk of severe mental illness in offspring (eg, bipolar disorder, schizophrenia). It is not yet clear, however, whether this association results from causal teratogenic effects or from confounding influences shared by smoking and severe mental illness.

    OBJECTIVE: To examine the association between smoking during pregnancy and severe mental illness in offspring, adjusting for measured covariates and unmeasured confounding using family-based designs.

    DESIGN, SETTING, AND PARTICIPANTS: This study analyzed population register data through December 31, 2013, for a cohort of 1 680 219 individuals born in Sweden from January 1, 1983, to December 31, 2001. Associations between smoking during pregnancy and severe mental illness in offspring were estimated with adjustment for measured covariates. Cousins and siblings who were discordant on smoking during pregnancy and severe mental illness were then compared, which helped to account for unmeasured genetic and environmental confounding by design.

    EXPOSURES: Maternal self-reported smoking during pregnancy, obtained from antenatal visits.

    MAIN OUTCOMES AND MEASURES: Severe mental illness, with clinical diagnosis obtained from inpatient and outpatient visits and defined using International Classification of Diseases codes for bipolar disorder and schizophrenia spectrum disorders.

    RESULTS: Of the 1 680 219 offspring included in the analysis, 816 775 (48.61%) were female. At the population level, offspring exposed to moderate and high levels of smoking during pregnancy had greater severe mental illness rates than did unexposed offspring (moderate smoking during pregnancy: hazard ratio [HR], 1.25; 95% CI, 1.19-1.30; high smoking during pregnancy: HR, 1.51; 95% CI, 1.44-1.59). These associations decreased in strength with increasing statistical and methodologic controls for familial confounding. In sibling comparisons with within-family covariates, associations were substantially weaker and nonsignificant (moderate smoking during pregnancy: HR, 1.09; 95% CI, 0.94-1.26; high smoking during pregnancy: HR, 1.14; 95% CI, 0.96-1.35). The pattern of associations was consistent across subsets of severe mental illness disorders and was supported by further sensitivity analyses.

    CONCLUSIONS AND RELEVANCE: This population-and family-based study failed to find support for a causal effect of smoking during pregnancy on risk of severe mental illness in offspring. Rather, these results suggest that much of the observed population-level association can be explained by measured and unmeasured factors shared by siblings.

  • 34. Sahlin, Hanna
    et al.
    Kuja-Halkola, Ralf
    Bjureberg, Johan
    Lichtenstein, Paul
    Molero, Yasmina
    Rydell, Mina
    Hedman, Erik
    Runeson, Bo
    Jokinen, Jussi
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Karolinska Inst, Dept Clin Neurosci, Ctr Psychiat Res, Stockholm, Sweden.
    Ljotsson, Brjann
    Hellner, Clara
    Association Between Deliberate Self-harm and Violent Criminality2017In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 74, no 6, p. 615-621Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Individuals who self-harm may have an increased risk of aggression toward others, but this association has been insufficiently investigated. More conclusive evidence may affect assessment, treatment interventions, and clinical guidelines. OBJECTIVE To investigate the association between nonfatal self-harm and violent crime. DESIGN, SETTING, AND PARTICIPANTS This population-based longitudinal cohort study, conducted from January 1, 1997, through December 31, 2013, studied all Swedish citizens born between 1982 and 1998 who were 15 years and older (N = 1 850 252). Individuals who emigrated from Sweden before the age of 15 years (n = 104 051) or immigrated to Sweden after the age of 13 years (ie, <2 years before the beginning of the follow-up; n = 22 009) were excluded. Data analysis was performed from April 21, 2016, to June 4, 2016. EXPOSURES Receipt of self-harm-associated clinical care. MAIN OUTCOMES AND MEASURES Conviction of a violent crime according to the Swedish penal code. RESULTS The study cohort consisted of 1 850 525 individuals (950 382 males and 900 143 females), and the mean (SD) follow-up time was 8.1 (4.7) years (range, 0-17.0 years; minimum age, 15 years; maximum age, 32 years). During a mean follow-up period of 8.1 years, 55 185 individuals (3.0%) received clinical care for self-harm. The crude hazard ratio was 4.9 (95% CI, 4.8-5.0) for violent crime conviction in exposed individuals compared with the unexposed group. Women who self-harm were at particularly high risk for expressing violent behaviors. After adjustment for relevant psychiatric comorbidities and socioeconomic status, an almost doubled hazard of violent offense remained (hazard ratio, 1.8; 95% CI, 1.8-1.9). CONCLUSIONS AND RELEVANCE Self-harm is associated with an increased risk of conviction for a violent offense in both sexes. The risk of violence, as well as the risk of suicide and self-harm, should be assessed among offending and self-harming individuals.

  • 35.
    Santavirta, Torsten
    et al.
    Stockholm University, Faculty of Social Sciences, The Swedish Institute for Social Research (SOFI). Uppsala University, Sweden.
    Santavirta, Nina
    Gilman, Stephen E.
    Association of the World War II Finnish Evacuation of Children With Psychiatric Hospitalization in the Next Generation2018In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 75, no 1, p. 21-27Article in journal (Refereed)
    Abstract [en]

    Importance: Although there is evidence that adverse childhood experiences are associated with worse mental health in adulthood, scarce evidence is available regarding an emerging concern that the next generation might also be affected.

    Objective: To compare the risk of psychiatric hospitalization in cousins whose parents were vs were not exposed to the Finnish evacuation policy that involved a mean 2-year stay with a Swedish foster family.

    Design, Setting, and Participants: This multigenerational, population-based cohort study of Finnish individuals and their siblings born between January 1, 1933, and December 31, 1944, analyzed the association of evacuee status as a child during World War II in the first generation with the risk of psychiatric hospitalization among offspring in the second generation. Evacuee status during World War II was determined using the Finnish National Archive’s registry of participants in the Finnish evacuation. Data on evacuee status were linked to the psychiatric diagnoses in the Finnish Hospital Discharge Register from January 1, 1971, through December 31, 2012, for offspring (n = 93 391) born between January 1, 1950, and December 31, 2010. Sex-specific Cox proportional hazards regression models were used to estimate hazard ratios for risk of psychiatric hospitalization during the follow-up period. Because offspring of evacuees and their nonevacuated siblings are cousins, the Cox proportional hazards regression models included fixed effects to adjust for confounding factors in families. Data analysis was performed from June 15, 2016, to August 26, 2017.

    Exposures: Parental participation in the evacuation during World War II (coded 1 for parents who were evacuated and placed in foster care and 0 for those not evacuated).

    Main Outcomes and Measures: Offspring’s initial admission to the hospital for a psychiatric disorder, obtained from the Finnish Hospital Discharge Register from January 1, 1971, through December 31, 2012.

    Results: Of the 93 391 study persons, 45 955 (49.2%) were women and 47 436 (50.8) were men; mean (SD) age in 2012 among survivors was 45.4 (6.58) years. Female offspring of mothers evacuated to Sweden during childhood had an elevated risk of psychiatric hospitalization (hazard ratio for any type of psychiatric disorder: 2.04 [95% CI, 1.04-4.01]; hazard ratio for mood disorder: 4.68 [95% CI, 1.92-11.42]). There was no excess risk of being hospitalized for a psychiatric disorder among women whose fathers were exposed to the Finnish evacuation policy during World War II or among men whose mothers or fathers were exposed.

    Conclusions and Relevance: In a prior follow-up study of the Finnish evacuees, girls evacuated to Swedish foster families during World War II were more likely to be hospitalized for a psychiatric disorder—in particular, a mood disorder—in adulthood than their nonevacuated sisters. The present study found that the offspring of these individuals were also at risk for mental health problems that required hospitalization and suggests that early-life adversities, including war-related exposures, may be associated with mental health disorders that persist across generations.

  • 36.
    Santavirta, Torsten
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Institute for Housing and Urban Research. Stockholm Univ, Swedish Inst Social Res., Sweden.
    Santavirta, Nina
    Department of Education, Faculty of Educational Sciences, University of Helsinki, Helsinki, Finland.
    Gilman, Stephen E.
    Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.; Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Hlth Behav Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD USA..
    Association of the World War II Finnish Evacuation of Children With Psychiatric Hospitalization in the Next Generation2018In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 75, no 1, p. 21-27Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Although there is evidence that adverse childhood experiences are associated with worse mental health in adulthood, scarce evidence is available regarding an emerging concern that the next generation might also be affected.

    OBJECTIVE To compare the risk of psychiatric hospitalization in cousins whose parents were vs were not exposed to the Finnish evacuation policy that involved a mean 2-year stay with a Swedish foster family.

    DESIGN, SETTING, AND PARTICIPANTS This multigenerational, population-based cohort study of Finnish individuals and their siblings born between January 1, 1933, and December 31, 1944, analyzed the association of evacuee status as a child during World War II in the first generation with the risk of psychiatric hospitalization among offspring in the second generation. Evacuee status during World War II was determined using the Finnish National Archive’s registry of participants in the Finnish evacuation. Data on evacuee status were linked to the psychiatric diagnoses in the Finnish Hospital Discharge Register from January 1, 1971, through December 31, 2012, for offspring (n = 93 391) born between January 1, 1950, and December 31, 2010. Sex-specific Cox proportional hazards regression models were used to estimate hazard ratios for risk of psychiatric hospitalization during the follow-up period. Because offspring of evacuees and their nonevacuated siblings are cousins, the Cox proportional hazards regression models included fixed effects to adjust for confounding factors in families. Data analysis was performed from June 15, 2016, to August 26, 2017.

    EXPOSURES Parental participation in the evacuation during World War II (coded 1 for parents who were evacuated and placed in foster care and 0 for those not evacuated).

    MAIN OUTCOMES AND MEASURES Offspring’s initial admission to the hospital for a psychiatric disorder, obtained from the Finnish Hospital Discharge Register from January 1, 1971, through December 31, 2012.

    RESULTS Of the 93 391 study persons, 45 955 (49.2%) were women and 47 436 (50.8) were men; mean (SD) age in 2012 among survivors was 45.4 (6.58) years. Female offspring of mothers evacuated to Sweden during childhood had an elevated risk of psychiatric hospitalization (hazard ratio for any type of psychiatric disorder: 2.04 [95% CI, 1.04-4.01]; hazard ratio for mood disorder: 4.68 [95% CI, 1.92-11.42]). There was no excess risk of being hospitalized for a psychiatric disorder among women whose fathers were exposed to the Finnish evacuation policy during World War II or among men whose mothers or fathers were exposed.

    CONCLUSIONS AND RELEVANCE In a prior follow-up study of the Finnish evacuees, girls evacuated to Swedish foster families during World War II were more likely to be hospitalized for a psychiatric disorder—in particular, a mood disorder—in adulthood than their nonevacuated sisters. The present study found that the offspring of these individuals were also at risk for mental health problems that required hospitalization and suggests that early-life adversities, including war-related exposures, may be associated with mental health disorders that persist across generations.

  • 37.
    Sariaslan, Amir
    et al.
    Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, United Kingdom.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences.
    Fazel, Seena
    Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, United Kingdom.
    Triggers for Violent Criminality in Patients With Psychotic Disorders2016In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 73, no 8, p. 796-803Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE: Absolute and relative risks of violence are increased in patients with psychotic disorders, but the contribution of triggers for violent acts to these risks is uncertain.

    OBJECTIVE: To examine whether a range of triggers for violent acts are associated with risks of violence in patients diagnosed with psychotic disorders and in individuals without a psychiatric diagnosis.

    DESIGN, SETTING, AND PARTICIPANTS: Using a sample of all individuals born in Sweden between 1958 and 1988 (N = 3 123 724), we identified patients in the National Patient Register who were diagnosed with schizophrenia spectrum disorders (n = 34 903) and bipolar disorder (n = 29 692), as well as unaffected controls (n = 2 763 012). We then identified, within each subsample, persons who had experienced any of the following triggers for violent acts between January 1, 2001, and December 15, 2013: exposure to violence, parental bereavement, self-harm, traumatic brain injury, unintentional injuries, and substance intoxication. By using within-individual models, we conducted conditional logistic regression to compare the risk of the individual engaging in violent acts in the week following the exposure to a trigger with the risk during earlier periods of equivalent length. All time-invariant confounders (eg, genetic and early environmental influences) were controlled for by this research design and we further adjusted for time-varying sociodemographic factors.

    MAIN OUTCOMES AND MEASURES: Adjusted odds ratios (aORs) of violent crime occurring in the week following the exposure to a trigger event compared with earlier periods.

    RESULTS: Among the sample of 2 827 607 individuals (1 492 186 male and 1 335 421 female), all of the examined trigger events were associated with increased risk of violent crime in the week following exposure. The largest 1-week absolute risk of violent crime was observed following exposure to violence (70-177 violent crimes per 10 000 persons). For most triggers, the relative risks did not vary significantly by diagnosis, including unintentional injuries (aOR range, 3.5-4.8), self-harm (aOR range, 3.9-4.2), and substance intoxication (aOR range, 3.0-4.0). Differences by diagnosis included parental bereavement, which was significantly higher in patients with schizophrenia spectrum disorders (aOR, 5.0; 95% CI, 3.0-8.1) compared with controls (aOR, 1.7; 95% CI, 1.3-2.2).

    CONCLUSIONS AND RELEVANCE: In addition to identifying risk factors for violence, clarifying the timing of the triggers may provide opportunities to improve risk assessment and management in individuals with psychotic disorders.

  • 38. Smeland, Olav B.
    et al.
    Frei, Oleksandr
    Kauppi, Karolina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Department of Radiology, University of California San Diego, La Jolla; Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla.
    Hill, W. David
    Li, Wen
    Wang, Yunpeng
    Krull, Florian
    Bettella, Francesco
    Eriksen, Jon A.
    Witoelar, Aree
    Davies, Gail
    Fan, Chun C.
    Thompson, Wesley K.
    Lam, Max
    Lencz, Todd
    Chen, Chi-Hua
    Ueland, Torill
    Jönsson, Erik G.
    Djurovic, Srdjan
    Deary, Ian J.
    Dale, Anders M.
    Andreassen, Ole A.
    Identification of Genetic Loci Jointly Influencing Schizophrenia Risk and the Cognitive Traits of Verbal-Numerical Reasoning, Reaction Time, and General Cognitive Function2017In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 74, no 10, p. 1065-1075Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Schizophrenia is associated with widespread cognitive impairments. Although cognitive deficits are one of the factors most strongly associated with functional outcome in schizophrenia, current treatment strategies largely fail to ameliorate these impairments. To develop more efficient treatment strategies in patients with schizophrenia, a better understanding of the pathogenesis of these cognitive deficits is needed. Accumulating evidence indicates that genetic risk of schizophrenia may contribute to cognitive dysfunction. OBJECTIVE To identify genomic regions jointly influencing schizophrenia and the cognitive domains of reaction time and verbal-numerical reasoning, aswell as general cognitive function, a phenotype that captures the shared variation in performance across cognitive domains. DESIGN, SETTING, AND PARTICIPANTS Combining data from genome-wide association studies from multiple phenotypes using conditional false discovery rate analysis provides increased power to discover genetic variants and could elucidate shared molecular genetic mechanisms. Data from the following genome-wide association studies, published from July 24, 2014, to January 17, 2017, were combined: schizophrenia in the Psychiatric Genomics Consortium cohort (n = 79 757 [ cases, 34 486; controls, 45 271]); verbal-numerical reasoning (n = 36 035) and reaction time (n = 111 483) in the UK Biobank cohort; and general cognitive function in CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) (n = 53 949) and COGENT (Cognitive Genomics Consortium) (n = 27 888). MAIN OUTCOMES AND MEASURES Genetic loci identified by conditional false discovery rate analysis. Brain messenger RNA expression and brain expression quantitative trait locus functionality were determined. RESULTS Among the participants in the genome-wide association studies, 21 loci jointly influencing schizophrenia and cognitive traits were identified: 2 loci shared between schizophrenia and verbal-numerical reasoning, 6 loci shared between schizophrenia and reaction time, and 14 loci shared between schizophrenia and general cognitive function. One locus was shared between schizophrenia and 2 cognitive traits and represented the strongest shared signal detected (nearest gene TCF20; chromosome 22q13.2), and was shared between schizophrenia (z score, 5.01; P = 5.53 x 10(-7)), general cognitive function (z score, - 4.43; P = 9.42 x 10(-6)), and verbal-numerical reasoning (z score, - 5.43; P = 5.64 x 10(-8)). For 18 loci, schizophrenia risk alleles were associated with poorer cognitive performance. The implicated genes are expressed in the developmental and adult human brain. Replicable expression quantitative trait locus functionality was identified for 4 loci in the adult human brain. CONCLUSIONS AND RELEVANCE The discovered loci improve the understanding of the common genetic basis underlying schizophrenia and cognitive function, suggesting novel molecular genetic mechanisms.

  • 39.
    Sun, Shihua
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Faraone, Stephen V.
    Department of Psychiatry, State University of New York (SUNY) Upstate Medical University, Syracuse, USA; Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, USA.
    D'Onofrio, Brian M.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychological and Brain Sciences, Indiana University, Bloomington,USA.
    Dalsgaard, Søren
    National Centre for Register-Based Research, Department of Economics and Business Economics, Aarhus University, Aarhus, Denmark; iPSYCH-The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark; Department for Child and Adolescent Psychiatry, Hospital of Telemark, Kragerø, Norway.
    Chang, Zheng
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences.
    Association of Psychiatric Comorbidity With the Risk of Premature Death Among Children and Adults With Attention-Deficit/Hyperactivity Disorder2019In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622XArticle in journal (Refereed)
    Abstract [en]

    Importance: A previous register-based study reported elevated all-cause mortality in attention-deficit/hyperactivity disorder (ADHD), but cause-specific risks and the potential associations of psychiatric comorbidities remain unknown.

    Objectives: To investigate the all-cause and cause-specific mortality risks in ADHD and to explore the potential role of psychiatric comorbidities.

    Design, Setting, and Participants: This prospective cohort study used Swedish national registers to identify 2 675 615 individuals born in Sweden from January 1, 1983, through December 31, 2009, as the study population, among whom 86 670 individuals (3.2%) received a diagnosis of ADHD during follow-up. Follow-up was completed December 31, 2013, and data were analyzed from October 2018 through March 2019.

    Exposures: Attention-deficit/hyperactivity disorder identified by first clinical diagnosis or first prescription of ADHD medications as recorded in Swedish registers. Clinical diagnosis of psychiatric comorbidity was available in the National Patient Register.

    Main Outcomes and Measures: All-cause and cause-specific mortalities and hazard ratios (HRs) using Cox proportional hazards regression models.

    Results: In the overall cohort of 2 675 615 individuals, 1 374 790 (51.4%) were male (57 919 with an ADHD diagnosis) and 1 300 825 (48.6%) were female (28 751 with an ADHD diagnosis). Mean (SD) age at study entry was 6.4 (5.6) years. During follow-up, 424 individuals with ADHD and 6231 without ADHD died, resulting in mortality rates of 11.57 and 2.16 per 10 000 person-years, respectively. The association was stronger in adulthood (HR, 4.64; 95% CI, 4.11-5.25) compared with childhood (HR, 1.41; 95% CI, 0.97-2.04) and increased substantially with the number of psychiatric comorbidities with ADHD (HR for individuals with only ADHD, 1.41 [95% CI, 1.01-1.97]; HR for those with ≥4 comorbidities, 25.22 [95% CI, 19.60-32.46]). In adulthood, when adjusting for early-onset psychiatric comorbidity, the association between ADHD and risk of death due to natural causes was attenuated substantially and was no longer statistically significant (HR, 1.32; 95% CI, 0.94-1.85). When adjusting for later-onset psychiatric disorders, the association was attenuated to statistical nonsignificance for death due to suicide (HR, 1.13; 95% CI, 0.88-1.45) but remained statistically significant for death caused by unintentional injury (HR, 2.14; 95% CI, 1.71-2.68) or other external causes (HR, 1.75; 95% CI, 1.23-2.48).

    Conclusions and Relevance: Psychiatric comorbidity appears to play an important role in all-cause and cause-specific mortality risks in ADHD. In adulthood, early-onset psychiatric comorbidity contributed primarily to the association with death due to natural causes, whereas later-onset psychiatric comorbidity mainly influenced death due to unnatural causes, including suicide and unintentional injury. These findings suggest that health care professionals should closely monitor specific psychiatric comorbidities in individuals with ADHD to identify high-risk groups for prevention efforts.

  • 40.
    Taylor, Mark J.
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Martin, Joanna
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom.
    Lu, Yi
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Brikell, Isabell
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lundström, Sebastian
    Institute of Neuroscience and Physiology, Gillberg Neuropsychiatry Centre, Centre for Ethics Law and Mental Health, University of Gothenburg, Gothenburg, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Association of Genetic Risk Factors for Psychiatric Disorders and Traits of These Disorders in a Swedish Population Twin Sample2019In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 76, no 3, p. 280-289Article in journal (Refereed)
    Abstract [en]

    Importance: Psychiatric traits associated with categorically defined psychiatric disorders are heritable and present to varying degrees in the general population. It is commonly assumed that diagnoses represent the extreme end of continuously distributed traits in the population, but this assumption has yet to be robustly tested for many psychiatric phenotypes.

    Objective: To assess whether genetic risk factors associated with psychiatric disorders are also associated with continuous variation in milder population traits.

    Design, Setting, and Participants: This study combined a novel twin analytic approach with polygenic risk score (PRS) analyses in a large population-based twin sample. Phenotypic and genetic data were available from the Child and Adolescent Twin Study in Sweden. Inpatient data were available for January 1, 1987, to December 31, 2014, and outpatient data for January 1, 2001, to December 31, 2013. The last day of follow-up was December 31, 2014. Data analysis was performed from January 1, 2017, to September 30, 2017.

    Main Outcomes and Measures: Questionnaires that assessed traits of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), learning difficulties, tic disorders (TDs), obsessive-compulsive disorder (OCD), anxiety, major depressive disorder (MDD), mania, and psychotic experiences were administered to a large Swedish twin sample. Individuals with clinical psychiatric diagnoses were identified using the Swedish National Patient Register. Joint categorical/continuous twin modeling was used to estimate genetic correlations between psychiatric diagnoses and continuous traits. The PRSs for psychiatric disorders were calculated based on independent discovery genetic data. The association between PRSs for each disorder and associated continuous traits was tested.

    Results: Phenotype data were available for 13 923 twin pairs (35.1% opposite sex and 31.7% same-sex females) at 9 years of age, 5165 pairs (36.9% opposite sex and 34.0% same-sex females) at 15 years of age, and 4273 pairs (36.5% opposite sex and 34.4% same-sex females) at 18 years of age. Genetic data were available for 13 412 individuals (50.2% females). Twin genetic correlations between numerous psychiatric diagnoses and corresponding traits ranged from 0.31 to 0.69. Disorder PRSs were associated with related population traits for ASD (β [SE] = 0.04 [0.01] at 9 years of age), ADHD (β [SE] = 0.27 [0.03] at 9 years of age), TDs (β [SE] = 0.02 [0.004] at 9 years of age), OCD (β [SE] = 0.13 [0.05] at 18 years of age), anxiety (β [SE] = 0.18 [0.08] at 9 years of age; β [SE] = 0.07 [0.02] at 15 years of age; and β [SE] = 0.40 [0.17] at 18 years of age), MDD (β [SE] = 0.10 [0.03] at 9 years of age; β [SE] = 0.11 [0.02] at 15 years of age; and β [SE] = 0.41 [0.10] at 18 years of age), and schizophrenia (β [SE] = 0.02 [0.01] at 18 years of age). Polygenic risk scores for depressive symptoms were associated with MDD diagnoses (odds ratio, 1.16; 95% CI, 1.02-1.32).

    Conclusions and Relevance: These results suggest that genetic factors associated with psychiatric disorders are also associated with milder variation in characteristic traits throughout the general population for many psychiatric phenotypes. This study suggests that many psychiatric disorders are likely to be continuous phenotypes rather than the categorical entities currently defined in diagnostic manuals, which has strong implications for genetic research in particular.

  • 41.
    Yao, Shuyang
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Thornton, Laura M.
    Department of Psychiatry, University of North Carolina, Chapel Hill, United States.
    Runfola, Cristin D.
    Department of Psychiatry, University of North Carolina, Chapel Hill, United States.
    D'Onofrio, Brian M
    Department of Psychological and Brain Science, Indiana University, Bloomington, United States.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Sjölander, Arvid
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Bulik, Cynthia M
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychiatry, University of North Carolina, Chapel Hill, United States; Department of Nutrition, University of North Carolina, Chapel Hill, United States .
    Familial Liability for Eating Disorders and Suicide Attempts: Evidence From a Population Registry in Sweden2016In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 73, no 3, p. 284-291Article in journal (Refereed)
    Abstract [en]

    Importance: Suicide attempts are common in individuals with eating disorders. More precise understanding of the mechanisms underlying their concomitant occurrence is needed.

    Objective: To examine the association between eating disorders and suicide attempts and whether familial risk factors contribute to the association.

    Design, setting and participants: A Swedish birth cohort including individuals born in Sweden between January 1, 1979, and December 31, 2001, was followed up from age 6 years to December 31, 2009 (N = 2,268,786). Information was acquired from Swedish national registers. All individuals were linked to their biological full siblings, maternal half siblings, paternal half siblings, full cousins, and half cousins. Data analysis was conducted from October 5, 2014, to April 28, 2015.

    Main outcomes and measures: Eating disorders were captured by 3 variables (any eating disorder, anorexia nervosa, and bulimia nervosa) identified by any lifetime diagnoses recorded in the registers. Suicide attempts were defined as any suicide attempts, including death by suicide, recorded in the registers. We examined the association between eating disorders and death by suicide separately, but the study was underpowered to explore familial liability for this association.

    Results: Of 2,268,786 individuals, 15,457 females (1.40% of all females) and 991 males (0.09% of all males) had any eating disorder, 7680 females (0.70%) and 453 males (0.04%) had anorexia nervosa, and 3349 females (0.30%), and 61 males (0.01%) had bulimia nervosa. Individuals with any eating disorder had an increased risk (reported as odds ratio [95% CI]) of suicide attempts (5.28 [5.04-5.54]) and death by suicide (5.39 [4.00-7.25]). The risks were attenuated but remained significant after adjusting for comorbid major depressive disorder, anxiety disorder, and substance use disorder (suicide attempts: 1.82 [1.72-1.93]; death by suicide: 2.04 [1.49-2.80]). Similar results were found for anorexia nervosa (suicide attempts: crude, 4.42 [4.12-4.74] vs adjusted, 1.70 [1.56-1.85]; death by suicide: crude, 6.46 [4.38-9.54] vs adjusted, 2.67 [1.78-4.01]) and bulimia nervosa (suicide attempts: crude, 6.26 [5.73-6.85] vs adjusted, 1.88 [1.68-2.10]; death by suicide: crude, 4.45 [2.44-8.11] vs adjusted, 1.48 [0.81-2.72]). Individuals (index) who had a full sibling with any eating disorder had an increased risk of suicide attempts (1.41 [1.29-1.53]). The risk was attenuated for any eating disorder in more-distant relatives (maternal half siblings, 1.10 [0.90-1.34]; paternal half siblings, 1.21 [0.98-1.49]; full cousins, 1.11 [1.06-1.18]; half cousins, 0.90 [0.78-1.03]). This familial pattern remained stable after adjusting for the index individuals' eating disorders. Similar patterns were found for anorexia nervosa and bulimia nervosa.

    Conclusions and relevance: These results suggest an increased risk of suicide attempts in individuals with lifetime eating disorders and their relatives. The pattern of familial coaggregation suggests familial liability for the association between eating disorders and suicide. Psychiatric comorbidities partially explain this association, suggesting particularly high-risk presentations.

1 - 41 of 41
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf