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  • 1.
    Higier, Rachel G
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; Department of Psychology, Yale University, New Haven CT, USA.
    Jimenez, Amy M
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; Department of Psychology, Yale University, New Haven CT, USA.
    Hultman, Christina M
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; Department of Psychology, Yale University, New Haven CT, USA.
    Borg, Jacqueline
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; Department of Psychology, Yale University, New Haven CT, USA.
    Roman, Cristina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; Department of Psychology, Yale University, New Haven CT, USA.
    Kizling, Isabelle
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; Department of Psychology, Yale University, New Haven CT, USA.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; Department of Psychology, Yale University, New Haven CT, USA.
    Cannon, Tyrone D
    Department of Psychology, University of California, Los Angeles, United States.
    Enhanced neurocognitive functioning and positive temperament in twins discordant for bipolar disorder2014In: American Journal of Psychiatry, ISSN 0002-953X, E-ISSN 1535-7228, Vol. 171, no 11, p. 1191-1198Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Based on evidence linking creativity and bipolar disorder, a model has been proposed whereby factors influencing liability to bipolar disorder confer certain traits with positive effects on reproductive fitness. The authors tested this model by examining key traits known to be associated with evolutionary fitness, namely, temperament and neurocognition, in individuals carrying liability for bipolar disorder. Schizophrenia probands and their co-twins were included as psychiatric controls.

    METHOD: Twin pairs discordant for bipolar disorder and schizophrenia and control pairs were identified through the Swedish Twin Registry. The authors administered a neuropsychological test battery and temperament questionnaires to samples of bipolar probands, bipolar co-twins, schizophrenia probands, schizophrenia co-twins, and controls. Multivariate mixed-model analyses of variance were conducted to compare groups on temperament and neurocognitive scores.

    RESULTS: Bipolar co-twins showed elevated scores on a "positivity" temperament scale compared with controls and bipolar probands, while bipolar probands scored higher on a "negativity" scale compared with their co-twins and controls, who did not differ. Additionally, bipolar co-twins showed superior performance compared with controls on tests of verbal learning and fluency, while bipolar probands showed performance decrements across all neurocognitive domains. In contrast, schizophrenia co-twins showed attenuated impairments in positivity and overall neurocognitive functioning relative to their ill proband counterparts.

    CONCLUSIONS: These findings suggest that supra-normal levels of sociability and verbal functioning may be associated with liability for bipolar disorder. These effects were specific to liability for bipolar disorder and did not apply to schizophrenia. Such benefits may provide a partial explanation for the persistence of bipolar illness in the population.

  • 2.
    Molero, Yasmina
    et al.
    University of Oxford, and the Department of Epidemiology and Biostatistics, Oxford, United Kingdom .
    Zetterqvist, Johan
    University of Oxford, and the Department of Epidemiology and Biostatistics, Oxford, United Kingdom .
    Binswanger, Ingrid A.
    University of Colorado School of Medicine, Division of General Internal Medicine, Denver, United States .
    Hellner, Clara
    University of Oxford, and the Department of Epidemiology and Biostatistics, Oxford, United Kingdom .
    Larsson, Henrik
    Örebro University, School of Medical Sciences. University of Oxford, and the Department of Epidemiology and Biostatistics, Oxford, United Kingdom .
    Fazel, Seena
    University of Oxford, Oxford, United Kingdom .
    Medications for Alcohol and Opioid Use Disorders and Risk of Suicidal Behavior, Accidental Overdoses, and Crime2018In: American Journal of Psychiatry, ISSN 0002-953X, E-ISSN 1535-7228, Vol. 175, no 10, p. 970-978Article in journal (Refereed)
    Abstract [en]

    Objective: The authors examined associations between medications for alcohol and opioid use disorders (acamprosate, naltrexone, methadone, and buprenorphine) and suicidal behavior, accidental overdoses, and crime.

    Method: In this total population cohort study, 21,281 individuals who received treatment with at least one of the four medications between 2005 and 2013 were identified. Data on medication use and outcomes were collected from Swedish population-based registers. A within-individual design (using stratified Cox proportional hazards regression models) was used to compare rates of suicidal behavior, accidental overdoses, and crime for the same individuals during the period when they were receiving the medication compared with the period when they were not.

    Results: No significant associations with any of the primary outcomes were found for acamprosate. For naltrexone, there was a reduction in the hazard ratio for accidental overdoses during periods when individuals received treatment compared with periods when they did not (hazard ratio=0.82, 95% CI=0.70, 0.96). Buprenorphine was associated with reduced arrest rates for all crime categories (i.e., violent, nonviolent, and substance-related) as well as reduction in accidental overdoses (hazard ratio= 0.75, 95% 0=0.60, 0.93). For methadone, there were significant reductions in the rate of suicidal behaviors (hazard ratio=0.60, 95% CI=0.40 -0.88) as well as reductions in all crime categories. However, there was an increased risk for accidental overdoses among individuals taking methadone (hazard ratio=1.25, 95% CI =1.13, 1.38).

    Conclusions: Medications currently used to treat alcohol and opioid use disorders also appear to reduce suicidality and crime during treatment.

  • 3.
    Quinn, Patrick D.
    et al.
    Department of Psychological and Brain Sciences, Indiana University, Bloomington, United States.
    Chang, Zheng
    Hur, Kwan
    Gibbons, Robert D.
    Lahey, Benjamin B.
    Rickert, Martin E.
    Sjölander, Arvid
    Karolinska institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Larsson, Henrik
    Örebro University, School of Medical Sciences.
    D'Onofrio, Brian M.
    ADHD Medication and Substance-Related Problems2017In: American Journal of Psychiatry, ISSN 0002-953X, E-ISSN 1535-7228, Vol. 174, no 9, p. 877-885Article in journal (Refereed)
    Abstract [en]

    Objective: Substance use disorders are major contributors to excess mortality among individuals with attention deficit hyperactivity disorder (ADHD), yet associations between pharmacological ADHD treatment and substance-related problems remain unclear. This study investigated concurrent and tong-term associations between ADHD medication treatment and substance-related events.

    Method: The authors analyzed 2005-2014 commercial health care claims from 2,993,887 (47,2% female) adolescent and adult ADHD patients. Within-individual analyses compared the risk of substance-related events (i.e., emergency department visits related to substance use disorders) during months in which patients received prescribed stimulant medication or atomoxetine relative to the risk during months in which they did not.

    Results: In adjusted within-individual comparisons, relative to periods in which patients did not receive ADHD medication, male patients had 35% lower odds of concurrent substance-related events when receiving medication (odds ratio=0.65, 95% CI=0.64-0.67), and female patients had 31% tower odds of concurrent substance-related events (odds ratio=0.69, 95% CI=0.67-0.71). Moreover, male patients had 19% lower odds of substance-related events 2 years after medication periods (odds ratio=0.81, 95% CI=0.78-0.85), and female patients had 14% tower odds of substance-related events 2 years after medication periods (odds ratio = 0.86, 95% CI= 0.82-0.91). Sensitivity analyses supported most findings but were less consistent for long-term associations among women.

    Conclusions: These results provide evidence that receiving ADHD medication is unlikely to be associated with greater risk of substance-related problems in adolescence or adulthood. Rather, medication was associated with lower concurrent risk of substance-related events and, at least among men, lower long-term risk of future substance-related events.

  • 4. Roberson-Nay, Roxann
    et al.
    Leibenluft, Ellen
    Brotman, Melissa A.
    Myers, John
    Larsson, Henrik
    Lichtenstein, Paul
    Kendler, Kenneth S.
    Longitudinal Stability of Genetic and Environmental Influences on Irritability: From Childhood to Young Adulthood2015In: American Journal of Psychiatry, ISSN 0002-953X, E-ISSN 1535-7228, Vol. 172, no 7, p. 657-664Article in journal (Refereed)
    Abstract [en]

    Objective: Little is known about genetic influences on juvenile irritability and whether such influences are developmentally stable and/or dynamic. This study examined the temporal pattern of genetic and environmental effects on irritability using data from a prospective, four-wave longitudinal twin study.

    Method: Parents and their twin children (N=2,620 children) from the Swedish Twin Study of Child and Adolescent Development reported on the children's irritability, defined using a previously identified scale from the Child Behavior Checklist.

    Results: Genetic effects differed across the sexes, with males exhibiting increasing heritability from early childhood through young adulthood and females exhibiting decreasing heritability. Genetic innovation was also more prominent in males than in females, with new genetic risk factors affecting irritability in early and late adolescence for males. Shared environment was not a primary influence on irritability for males or females. Unique, nonshared environmental factors suggested strong effects early for males followed by an attenuating influence, whereas unique environmental factors were relatively stable for females.

    Conclusions: Genetic effects on irritability are developmentally dynamic from middle childhood through young adulthood, with males and females displaying differing patterns. As males age, genetic influences on irritability increase while nonshared environmental influences weaken. Genetic contributions are quite strong in females early in life but decline in importance with age. In girls, nonshared environmental influences are fairly stable throughout development.

  • 5.
    Song, Jie
    et al.
    Department of Medical and Surgical Sciences, Sahlgrenska Academy, Gothenburg, Sweden .
    Sjölander, Arvid
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Joas, Erik
    Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, Gothenburg, Sweden .
    Bergen, Sarah E.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Runeson, Bo
    Department of Medical and Surgical Sciences, Sahlgrenska Academy, Gothenburg, Sweden .
    Larsson, Henrik
    Örebro University, School of Medical Sciences.
    Landén, Mikael
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Suicidal Behavior During Lithium and Valproate Treatment: A Within-Individual 8-Year Prospective Study of 50,000 Patients With Bipolar Disorder2017In: American Journal of Psychiatry, ISSN 0002-953X, E-ISSN 1535-7228, Vol. 174, no 8, p. 795-802Article in journal (Refereed)
    Abstract [en]

    Objective: Conclusions regarding lithium's antisuicidal effect for bipolar disorder have been limited due to nonrepresentative subjects and potential confounding factors, including varying severity of illness. Findings regarding the effect of valproate, the most common alternative to lithium, are inconsistent for suicidal behavior. This study investigated the associations of these two drugs with the risk of suicide-related events, and possible differences between drugs, by using within-individual designs in a register-based longitudinal cohort.

    Method: Through linkage of multiple Swedish national registers, 51,535 individuals with bipolar disorder were followed from 2005 to 2013 for treatment with lithium and valproate. Stratified Cox regression was used to estimate the hazard ratios of suicide-related events during treated periods compared with untreated periods. For significant associations between medication and suicide-related events, the population attributable fraction was estimated to assess the public health impact for patients with bipolar disorder.

    Results: During follow-up, 10,648 suicide-related events occurred. The incidence rate was significantly decreased by 14% during lithium treatment (hazard ratio 0.86, 95% confidence interval [CI] 0.78-0.95) but not during valproate treatment (hazard ratio 1.02, 95% CI 0.89-1.15). The difference in hazard ratios of suicide-related events between lithium and valproate was statistically significant. Estimates of the population attributable fraction suggested that 12% (95% CI 4% 220%) of suicide-related events could have been avoided if patients had taken lithium during the entire follow-up.

    Conclusions: The results suggest that lithium should be considered for patients with bipolar disorder with suspected suicidal intentions, although risk for suicide is only one of the considerations when providing clinical care.

  • 6. Viktorin, Alexander
    et al.
    Lichtenstein, Paul
    Thase, Michael E
    Larsson, Henrik
    Lundholm, Cecilia
    Magnusson, Patrik K E
    Landén, Mikael
    The risk of switch to mania in patients with bipolar disorder during treatment with an antidepressant alone and in combination with a mood stabilizer2014In: American Journal of Psychiatry, ISSN 0002-953X, E-ISSN 1535-7228, Vol. 171, no 10, p. 1067-1073Article in journal (Refereed)
    Abstract [en]

    Objective: This study examined the risk of antidepressant-induced manic switch in patients with bipolar disorder treated either with antidepressant monotherapy or with an antidepressant in conjunction with a mood stabilizer.

    Method: Using Swedish national registries, the authors identified 3,240 patients with bipolar disorder who started treatment with an antidepressant and had no antidepressant treatment during the previous year. Patients were categorized into those receiving antidepressant monotherapy and those receiving an antidepressant plus a mood stabilizer. A within-individual design was used to control for confounding by disorder severity, genetic makeup, and early environmental factors. Cox regression analyses conditioned on individual were used to compare the rate of mania 0-3 months and 3-9 months after the start of antidepressant treatment with a preceding non-treatment period.

    Results: Nearly 35% of the patients were treated with antidepressant monotherapy. The increased risk of treatment-emergent mania was confined to patients on antidepressant monotherapy (hazard ratio=2.83, 95% CI=1.12, 7.19). Among patients treated with a concurrent mood stabilizer, no acute change in risk of mania was observed during the 3 months after the start of antidepressant treatment (hazard ratio=0.79, 95% CI=0.54, 1.15), and a decreased risk was observed during the period 3-9 months after treatment initiation (hazard ratio=0.63, 95% CI=0.42, 0.93).

    Conclusions: In this national registry study, antidepressant monotherapy was associated with an increased risk of mania. However, no risk of mania was seen in patients receiving an antidepressant while treated with a mood stabilizer. The results highlight the importance of avoiding antidepressant monotherapy in the treatment of bipolar disorder.

  • 7.
    Viktorin, Alexander
    et al.
    Department of Medical Epidemiology and Biostatistics and the Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Rydén, Eleonore
    Thase, Michael E.
    Chang, Zheng
    Lundholm, Cecilia
    D'Onofrio, Brian M.
    Almqvist, Catarina
    Magnusson, Patrik K. E.
    Lichtenstein, Paul
    Larsson, Henrik
    Örebro University, School of Medical Sciences.
    Landén, Mikael
    The Risk of Treatment-Emergent Mania With Methylphenidate in Bipolar Disorder2017In: American Journal of Psychiatry, ISSN 0002-953X, E-ISSN 1535-7228, Vol. 174, no 4, p. 341-348Article in journal (Refereed)
    Abstract [en]

    Objective: The authors sought to determine the risk of treatment-emergent mania associated with methylphenidate, used in monotherapy or with a concomitant mood-stabilizing medication, in patients with bipolar disorder.

    Method: Using linked Swedish national registries, the authors identified 2,307 adults with bipolar disorder who initiated therapy with methylphenidate between 2006 and 2014. The cohort was divided into two groups: those with and those without concomitant mood-stabilizing treatment. To adjust for individual-specific confounders, including disorder severity, genetic makeup, and early environmental factors, Cox regression analyses were used, conditioning on individual to compare the rate of mania (defined as hospitalization for mania or a new dispensation of stabilizing medication) 0-3 months and 3-6 months after medication start following nontreated periods.

    Results: Patients on methylphenidate monotherapy displayed an increased rate of manic episodes within 3 months of medication initiation (hazard ratio=6.7, 95% CI=2.0-22.4), with similar results for the subsequent 3 months. By contrast, for patients taking mood stabilizers, the risk of mania was lower after starting methylphenidate (hazard ratio=0.6, 95% CI=0.4-0.9). Comparable results were observed when only hospitalizations for mania were counted.

    Conclusions: No evidence was found for a positive association between methylphenidate and treatment-emergent mania among patients with bipolar disorder who were concomitantly receiving a mood-stabilizing medication. This is clinically important given that up to 20% of people with bipolar disorder suffer from comorbid ADHD. Given the markedly increased hazard ratio of mania following methylphenidate initiation in bipolar patients not taking mood stabilizers, careful assessment to rule out bipolar disorder is indicated before initiating monotherapy with psychostimulants.

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