Dosing levels of antipsychotics and mood stabilizers in bipolar disorder: A Nationwide cohort study on relapse risk and treatment safety.

BACKGROUND: Finding effective treatment regimens for bipolar disorder is challenging, as many patients suffer from significant symptoms despite treatment. This study investigated the risk of relapse (psychiatric hospitalization) and treatment safety (non-psychiatric hospitalization) associated with different doses of antipsychotics and mood stabilizers in persons with bipolar disorder. METHODS: Individuals aged 15-65 with bipolar disorder were identified from Finnish national health registers in 1996-2018. Studied antipsychotics included olanzapine, risperidone, quetiapine, aripiprazole; mood stabilizers lithium, valproic acid, lamotrigine, and carbamazepine. Medication use was divided into three time-varying dose categories: low, standard, and high. The studied outcomes were risk of psychiatric hospitalization (relapse) and the risk of non-psychiatric hospitalization (treatment safety). Stratified Cox regression in within-individual design was used. RESULTS: The cohort included 60,045 individuals (mean age 41.7 years, SD 15.8; 56.4% female). Mean follow-up was 8.3 years (SD 5.8). Of antipsychotics, olanzapine and aripiprazole were associated with a decreased risk of relapse in low and standard doses, and risperidone in low dose. The lowest adjusted hazard ratio (aHR) was observed for standard dose aripiprazole (aHR 0.68, 95% CI 0.57-0.82). Quetiapine was not associated with a decreased risk of relapse at any dose. Mood stabilizers were associated with a decreased risk of relapse in low and standard doses; lowest aHR was observed for standard dose lithium (aHR 0.61, 95% CI 0.56-0.65). Apart from lithium, high doses of antipsychotics and mood stabilizers were associated with an increased risk of non-psychiatric hospitalization. Lithium was associated with a decreased risk of non-psychiatric hospitalization in low (aHR 0.88, 95% CI 0.84-0.93) and standard doses (aHR 0.81, 95% CI 0.74-0.88). CONCLUSIONS: Standard doses of lithium and aripiprazole were associated with the lowest risk of relapse, and standard dose of lithium with the lowest risk of non-psychiatric hospitalization. Quetiapine was not associated with decreased risk of relapse at any dose.

Cardiovascular mortality in bipolar disorder: Population-based cohort study.

BACKGROUND: Limited evidence base on cause-specific excess cardiovascular disease (CVD) mortality in bipolar disorder (BD) is a barrier to developing preventive interventions aimed at reducing the persistent mortality gap in BD. OBJECTIVE: To investigate cause-specific CVD mortality in BD. METHODS: We identified all individuals aged 15+ years during 2004-2018 with a diagnosis of BD using Finnish nationwide routine data. Standardised mortality ratios (SMR) with 95% confidence intervals (CI) were calculated using the mortality rates in the general population as weights. RESULTS: 53,273 individuals with BD (57% women; median age at BD diagnosis, 40 years), were followed up for 428,426 person-years (median, 8.2 years). There were 5988 deaths due to any cause, of which 26% were due to CVD. The leading cause of absolute excess CVD mortality was coronary artery disease (CAD). The leading causes of relative excess mortality were cardiomegaly (SMR, 4.51; 95% CI, 3.58-5.43), venous thromboembolism (3.03; 2.26-3.81), cardiomyopathy (2.46; 1.95-2.97), and hypertensive heart disease (2.12; 1.71-2.54). The leading causes of absolute CVD mortality showed markedly lower relative excess, including CAD (1.47; 1.34-1.61), ischaemic stroke (1.31; 1.06-1.54), and acute myocardial infarction (1.12; 0.98-1.25). Due to the higher relative excess mortality, structural and functional heart disorders contributed as much as atherosclerotic and ischaemic disorders to the absolute excess mortality. CONCLUSIONS: Cardiomyopathy and hypertensive heart disease as the leading causes of relative excess mortality emphasise the contribution of structural and functional heart disorders to the overall excess mortality alongside coronary artery disease. Interventions targeted at these modifiable causes of death should be priorities in the prevention of premature excess CVD mortality in BD.

Real-world effectiveness of pharmacological treatments for bipolar disorder: register-based national cohort study.

BACKGROUND: Pharmacological treatment patterns for bipolar disorder have changed during recent years, but for better or worse? AIMS: To investigate the comparative real-world effectiveness of antipsychotics and mood stabilisers in bipolar disorder. METHOD: Register-based cohort study including all Finnish residents aged 16-65 with a diagnosis of bipolar disorder from in-patient care, specialised out-patient care, sickness absence and disability pensions registers between 1996 and 2018, with a mean follow-up of 9.3 years (s.d. = 6.4). Antipsychotic and mood stabiliser use was modelled using the PRE2DUP method and risk for hospital admission for psychiatric and non-psychiatric reasons when using versus not using medications was estimated using within-individual Cox models. RESULTS: Among 60 045 individuals (56.4% female; mean age 41.7 years, s.d. = 15.8), the five medications associated with lowest risk of psychiatric admissions were olanzapine long-acting injection (LAI) (aHR = 0.54, 95% CI 0.37-0.80), haloperidol LAI (aHR = 0.62, 0.47-0.81), zuclopenthixol LAI (aHR = 0.66, 95% CI 0.52-0.85), lithium (aHR = 0.74, 95% CI 0.71-0.76) and clozapine (aHR = 0.75, 95% CI 0.64-0.87). Only ziprasidone (aHR = 1.26, 95% CI 1.07-1.49) was associated with a statistically higher risk. For non-psychiatric (somatic) admissions, only lithium (aHR = 0.77, 95% CI 0.74-0.81) and carbamazepine (aHR = 0.91, 95% CI 0.85-0.97) were associated with significantly reduced risk, whereas pregabalin, gabapentin and several oral antipsychotics, including quetiapine, were associated with an increased risk. Results for a subcohort of first-episode patients (26 395 individuals, 54.9% female; mean age 38.2 years, s.d. = 13.0) were in line with those of the total cohort. CONCLUSIONS: Lithium and certain LAI antipsychotics were associated with lowest risks of psychiatric admission. Lithium was the only treatment associated with decreased risk of both psychiatric and somatic admissions.

Mortality in psychotic depression: 18-year follow-up study.

BACKGROUND: Evidence on the role of co-occurring psychiatric disorders in mortality associated with psychotic depression is limited. AIMS: To estimate the risk of cause-specific mortality in psychotic depression compared with severe non-psychotic depression while controlling for comorbid psychiatric disorders. METHOD: This cohort study used routine data from nationwide health registers in Finland. Eligible participants had their first diagnosis for psychotic depression or for severe non-psychotic depression between the years 2000 and 2018, had no pre-existing diagnoses for schizophrenia spectrum disorders or bipolar disorder, and were aged 18-65 years at the index diagnosis. Causes of death were defined by ICD-10 codes. The follow-up time was up to 18 years. RESULTS: We included 19 064 individuals with incident psychotic depression and 90 877 individuals with incident non-psychotic depression. Half (1199/2188) of the deaths in those with psychotic depression occurred within 5 years from the index diagnosis and the highest relative risk was during the first year after the diagnosis. Compared with individuals with non-psychotic depression, those with psychotic depression had a higher risk of all-cause mortality (adjusted hazard ratio, aHR = 1.59, 95% CI 1.48-1.70), suicides (aHR = 2.36, 95% CI 2.11-2.64) and fatal accidents (aHR 1.63, 95% CI 1.26-2.10) during the subsequent 5-year period after the index diagnosis. CONCLUSIONS: Psychotic symptoms markedly added to the mortality risk associated with severe depression after controlling for psychiatric comorbidity. Prompt treatment and enhanced monitoring for psychotic symptoms is warranted in all patients with severe depression to prevent deaths because of suicides and other external causes.

Isotretinoin and adverse neuropsychiatric outcomes: retrospective cohort study using routine data.

BACKGROUND: Severe neuropsychiatric outcomes have been reported in individuals exposed to isotretinoin, but the evidence is inconclusive and complicated by several methodological limitations. OBJECTIVES: To establish and quantify the association between isotretinoin use for acne and 1-year incident neuropsychiatric adverse outcomes. METHODS: A propensity score-matched cohort study of electronic medical records between the years 2013 and 2019 with patients followed up for 1 year after their index dispensed prescription was conducted. The database included over 12 million patients aged 12-27 years. We analysed data for individuals with acne in this age range with a dispensed prescription for isotretinoin or a control prescription. Outcomes included diagnoses of any incident sleep or mental health disorder, or nonfatal self-harm within 1 year of the index prescription. RESULTS: We included 30 866 patients prescribed isotretinoin for their acne, 44 748 prescribed oral antibiotics, 108 367 prescribed topical anti-acne agents and 78 666 patients with acne but without an anti-acne prescription. After propensity score matching for baseline confounders, the odds ratio (OR) for any incident neuropsychiatric outcomes in patients with acne exposed to isotretinoin was 0·80 [95% confidence interval (CI) 0·74-0·87] compared with those on oral antibiotics; 0·94 (95% CI 0·87-1·02) compared with those using topical anti-acne medicines; and 1·06 (95% CI 0·97-1·16) compared with those without a prescription for anti-acne medicines. Patients exposed to isotretinoin experienced significantly more incident physical symptoms than patients in any of the three comparison cohorts. CONCLUSIONS: Isotretinoin was not independently associated with excess adverse neuropsychiatric outcomes at the population level. When monitoring potential adverse outcomes during isotretinoin treatment, clinicians should also consider the high mental health burden associated with treatment-resistant acne and the potential contribution of physical side-effects of prescribed medication on mental health.

Risk of major chronic diseases in transport, rescue and security industries: a longitudinal register-based study.

OBJECTIVE: To investigate the risk of hospitalisation for major chronic diseases across representative transport, rescue and security industries. METHODS: We performed a register-based study of 624 571 workers from six industries in Denmark between 2000 and 2005, followed up hospitalisation for chronic diseases up to 17 years, and compared with a 20% random sample of the economically active population. RESULTS: HR from the Cox regression models showed that seafarers had higher risk of lung cancer (men: 1.54, 95% CI 1.31 to 1.81; women: 1.63, 95% CI 1.13 to 2.36), and male seafarers had higher risk of diabetes (1.32, 95% CI 1.21 to 1.43) and oral cancer (1.51, 95% CI 1.21 to 1.88). Men and women in land transport had increased risk of diabetes (men: 1.68, 95% CI 1.63 to 1.73; women 1.55, 95% CI 1.40 to 1.71) and chronic respiratory disease (men: 1.21, 95% CI 1.16 to 1.25; women 1.42, 95% CI 1.32 to 1.53). Among women, a higher risk of gastrointestinal cancer was observed in aviation (1.53, 95% CI 1.23 to 1.89) and police force (1.29, 95% CI 1.01 to 1.65), oral cancer in defence forces (1.83, 95% CI 1.20 to 2.79), and chronic respiratory disease in rescue service (1.47, 95% CI 1.21 to 1.77), while men in defence forces, police force and rescue service had mainly lower risk of these chronic diseases. CONCLUSIONS: We observed considerable health disparities from chronic diseases across transport, rescue and security industries, with workers in seafaring and land transport generally bearing the greatest relative burden.

Associations Among Sleep and Cancer Risk Behaviors: a Scoping Review of Experimental Studies in Healthy Adult Populations.

BACKGROUND: Links among poor sleep and cancer risk behaviors have been largely overlooked in the context of cancer prevention and behavioral medicine. The goal of this scoping review was to determine the extent and nature of experimental studies conducted with healthy adult populations that tested the associations among poor sleep and cancer risk behaviors. METHOD: Electronic databases and major sleep journals were searched to identify experimental studies in healthy adult samples published through January 2018. Studies examined associations among eight pairings of manipulated behaviors and outcomes ("independent variable (IV)-outcome pairs"): the impact of sleep manipulations on physical activity (PA), diet, alcohol consumption, and tobacco use outcomes; and the impact of PA, diet, alcohol consumption, and tobacco use manipulations on sleep outcomes. Studies were characterized in terms of sample characteristics; study design; IV type, dose, and duration; and outcome measurement and duration. RESULTS: Abstracts of 5697 papers and 345 full texts were screened. Eighty-eight studies describing 125 comparisons met inclusion criteria. Only two studies tested the association between tobacco use and sleep; none tested whether sleep influenced alcohol consumption. Sample sizes were typically small, most studies used crossover designs, and studies tended to include younger and more male participants. Within each IV-outcome pair, there was substantial heterogeneity in how behaviors were manipulated, outcome measurement, and type of control group. Few studies assessed mechanisms. CONCLUSION: There is a need for larger experimental studies with more representative samples. Overall, heterogeneity and limitations in study designs make it difficult to synthesize evidence across studies.

Does seafarers' limited access to health care increase risk for community-acquired pneumonia requiring hospital care? A longitudinal register-based analysis.

BACKGROUND: Limited access to medical care can be considered as an occupational risk of seafaring and it may predispose to developing community-acquired pneumonia (CAP) requiring hospital care. We sought to investigate the risk for CAP and other lower respiratory tract infections (LRTI) requiring hospital care among seafarers. We examined the length of hospital stay (LOS) as a proxy for severity of illness. METHODS: The study population in this panel data analysis were all seafarers and a 20% random sample of economically active individuals aged 18-65 years who were residing in Denmark in 1997-2016, constituting more than 11 million person-years of follow-up. Annually-registered socio-demographic and work characteristics were linked to data on cause of hospital admissions. We used fixed-effects and zero-truncated Poisson regression to estimate the rate ratios of hospitalization for CAP and other LRTI, and compared LOS across the two populations. RESULTS: The adjusted incident rate ratio (IRR) for CAP in seafarers compared to the economically active population was 1.42 (95% confidence interval [CI]: 1.15-1.77), whereas the IRR was 0.73 (95% CI: 0.38-1.42) for other LRTI. For LOS, the IRRs for CAP and other LRTI in seafarers were 1.08 (95% CI: 1.04-1.12) and 0.92 (95% CI: 0.83-1.01), respectively. CONCLUSIONS: Our findings indicate that seafaring was associated with an increased risk for CAP requiring hospital care. Limited access to health care may be an important contributing factor.

Hospital Admissions Before an Alcohol-Related Death Among Middle-Aged Employed Men and Women: A Cohort Study Using Routine Data.

BACKGROUND: Due to lack of appropriate longitudinal data, relatively little is known about how and when persons who ultimately die due to alcohol-related causes interact with hospitals during the years before death. Using routinely collected nationwide data, we aimed to establish the timing and causes of all hospitalizations during a 10-year period before an alcohol-related death. METHODS: We traced back the timing and causes of all hospitalizations occurring during a 10-year period before death among men and women (n = 2,981) who were aged 35 and in employment at study entry, and who died from alcohol-related causes at ages 45 to 54 in 1997 to 2007. The study data consisted of 80% of all persons living in Finland who died during the study period. Those who died at ages 45 to 54 without alcohol involvement were used as a reference group. RESULTS: Persons who ultimately died from alcohol-related causes had on average 7 (mean 7.4, SD 9.9) hospital admissions, and they spent on average 56 days (mean 56.2, SD 105.1) in hospital during the study period. By the fifth year before death (from the year -10 to year -5), about three-fifths of these persons had been hospitalized due to any cause at least once, but less than one-third had a hospital admission with an alcohol-related diagnosis. Those who died without alcohol involvement had an average 9 hospital admissions (mean 9.3, SD 11.2), and they spent on average 81 days (mean 81.2, SD 163.9) in hospital during the study period. CONCLUSIONS: The majority of employed middle-aged persons who ultimately died due to alcohol-related causes interacted with hospitals frequently and already several years before death. Additional research is warranted to evaluate whether enhanced patient management at hospitals targeted to this population could potentially reduce alcohol-related harms.

Real-world effectiveness of antidepressants, antipsychotics and their combinations in the maintenance treatment of psychotic depression. Evidence from within-subject analyses of two nationwide cohorts.

Psychotic depression (PD) is a severe mental disorder leading to functional disability and high risk of suicide, but very little is known about the comparative effectiveness of medications used in its maintenance treatment. The objective of this study was to investigate the comparative effectiveness of specific antipsychotics and antidepressants, and their combinations, on the risk of psychiatric hospitalization among persons with PD in routine care. Persons aged 16-65 years with a first-time diagnosis of PD were identified from Finnish (years 2000-2018) and Swedish (years 2006-2021) nationwide registers of inpatient care, specialized outpatient care, sickness absence, and disability pension. The main exposures were specific antipsychotics and antidepressants, and the main outcome measure was psychiatric hospitalization as a marker of severe relapse. The risk of hospitalization associated with periods of use vs. non-use of medications (expressed as adjusted hazard ratio, aHR) was assessed by a within-individual design, using each individual as his/her own control, and analyzed with stratified Cox models. The two national cohorts were first analyzed separately, and then combined using a fixed-effect meta-analysis. The Finnish cohort included 19,330 persons (mean age: 39.8±14.7 years; 57.9% women) and the Swedish cohort 13,684 persons (mean age: 41.3±14.0 years; 53.5% women). Individual antidepressants associated with a decreased risk of relapse vs. non-use of antidepressants were bupropion (aHR=0.73, 95% CI: 0.63-0.85), vortioxetine (aHR=0.78, 95% CI: 0.63-0.96) and venlafaxine (aHR=0.92, 95% CI: 0.86-0.98). Any long-acting injectable antipsychotic (LAI) (aHR=0.60, 95% CI: 0.45-0.80) and clozapine (aHR=0.72, 95% CI: 0.57-0.91) were associated with a decreased risk of relapse vs. non-use of antipsychotics. Among monotherapies, only vortioxetine (aHR=0.67, 95% CI: 0.47-0.95) and bupropion (aHR=0.71, 95% CI: 0.56-0.89) were associated with a significantly decreased risk of relapse vs. non-use of both antidepressants and antipsychotics. In an exploratory analysis of antidepressant-antipsychotic combinations, a decreased relapse risk was found for amitriptyline-olanzapine (aHR=0.45, 95% CI: 0.28-0.71), sertraline-quetiapine (aHR=0.79, 95% CI: 0.67-0.93) and venlafaxine-quetiapine (aHR=0.82, 95% CI: 0.73-0.91) vs. non-use of antidepressants and antipsychotics. Benzodiazepines and related drugs (aHR=1.29, 95% CI: 1.24-1.34) and mirtazapine (aHR=1.17, 95% CI: 1.07-1.29) were associated with an increased risk of relapse. These data indicate that, in the maintenance treatment of PD, bupropion, vortioxetine, venlafaxine, any LAI, clozapine, and only few specific antidepressant-antipsychotic combinations are associated with a decreased risk of relapse. These findings challenge the current recommendation by treatment guidelines to combine an antipsychotic with an antidepressant (without further specification) as standard treatment in PD.

Prevalence of concomitant use of alcohol and sedative-hypnotic drugs in middle and older aged persons: a systematic review.

OBJECTIVE: To systematically review the prevalence of concomitant alcohol and sedative-hypnotic use among middle-aged and older persons. DATA SOURCES: A bibliographic search of English-language literature was performed using MEDLINE, EMBASE, and PsycINFO (January 1990-August 2012). The reference lists of all included articles were screened for additional relevant articles not identified by any of the bibliographic searches. STUDY SELECTION AND DATA EXTRACTION: Population-based studies in which the mean age of participants was 40 years or older were included. For a study to be included in the review, alcohol use had to be reported in terms of the quantity or frequency consumed. Data from included articles were extracted using a standardized data extraction tool. DATA SYNTHESIS: Five population-based studies conducted in North America, 10 in Europe, and 1 in Australia were included in the review. Up to 88% of men and 79% of women who used sedative-hypnotics also consumed alcohol. Up to 28% of those who consumed alcohol were concomitant users of sedative-hypnotics. Alcohol was consumed at higher levels among middle-aged than older persons. Risky drinking (eg, binge drinking, heavy drinking) was more prevalent among middle-aged than older persons. In contrast, sedative-hypnotic use was more prevalent among older persons. CONCLUSIONS: Our review identified a higher prevalence of alcohol consumption among middle-aged than older persons. However, middle-aged persons may experience harm from alcohol/sedative-hypnotic drug interactions due to risky drinking behavior. Despite lower levels of alcohol consumption, older persons may be more susceptible to addictive central nervous system effects than younger persons because of physiologic changes in psychotropic drug and alcohol metabolism. Clinicians should consider patients' alcohol consumption patterns before prescribing sedative-hypnotic drugs.

Socioeconomic disadvantage and indicators of risky alcohol-drinking patterns.

AIM: The purpose was to establish how the association between socioeconomic disadvantage and risky drinking depends on the indicator of risky alcohol-drinking patterns. METHODS: Alcohol-drinking Finnish men (n = 9316) and women (n = 11,888) aged 20-54 years at baseline participated in the Health and Social Support (HeSSup) postal survey in 1998. Socioeconomic disadvantage was measured by low educational level, history of previous unemployment among those currently employed, current unemployment, being on disability pension and history of experiencing financial hardships. Indicators of risky drinking were hazardous weekly intake (≥24 and ≥16 Finnish standard drinks for men and women, respectively), frequency of intoxications/drunkenness, hangovers and alcohol-induced pass-outs. The study participants were also followed up for 7 years for alcohol-specific hospitalizations and deaths. RESULTS: Socioeconomic gradient in risky drinking was observed across all indicators of risky drinking, but the gradient was relatively larger in patterns of risky drinking representing high-intensity drinking occasions such as alcohol-induced hangovers and pass-outs. No marked gender differences were observed. CONCLUSIONS: These results highlight the need to take into account the multidimensionality of risky alcohol-drinking patterns as a contributing factor in the socioeconomic gradient in alcohol use.

The role of modifiable risk factors in incident cancer in transport, rescue, and security industries.

PURPOSE: Examine the risk for site-specific incident cancer across representative transport, rescue, and security industries. METHODS: This Danish nationwide register-based study included all 302,789 workers from transport, rescue and security industries in 2001-2015 and 2,230,877 individuals aged 18-64 years from a total sample of the economically active population for comparison. We used Cox models to estimate the hazard ratios (HRs) of incident cancers. We categorized site-specific cancers by using population-attributable fraction (PAF) estimates from the previous literature. RESULTS: During an average follow-up of 13.4 years, 22,116 incident cancer cases were recorded in these industries. Compared with the reference population, the age-adjusted cancer incidence with a high PAF was higher among men in seafaring (HR 1.28; 95% CI 1.14-1.43), and land transport (HR 1.32; 95% CI: 1.26-1.37), and among women in seafaring (HR 1.26; 95% CI: 1.01-1.57), land transport (HR 1.21; 95% CI: 1.12-1.32), aviation (HR 1.22; 95% CI: 1.05-1.41), and police force (HR 1.21; 95% CI: 1.04-1.40). Overall, tobacco and physical inactivity were the most significant risk factors of cancer. CONCLUSIONS: Regardless of considerable disparities in incident cancer attributable to modifiable risk factors across industries, the total incident cancer rate was elevated in all industries in both sexes.

Psychotic depression and deaths due to suicide.

BACKGROUND: The purpose of this study was to establish the risk of suicide associated with incident psychotic depression (PD) compared to incident non-psychotic severe depression (NPD). METHODS: This cohort study used routine data from nationwide health registers in Finland. Eligible participants were aged 18-59 years at the index diagnosis. Causes of death were defined by the International Classification of Diseases, 10th revision codes. The follow-up time was up to five years. Adjusted Cox regression models were used to analyse risk of death by method of suicide. RESULTS: We included 17,331 individuals with incident PD and 85,989 individuals with incident NPD. Most of the deaths due to suicides occurred within the first two years after the index diagnosis. Compared to NPD, PD was associated with an overall two-fold increased risk of suicide (adjusted hazard ratio, (aHR) 2.19, 95 % confidence interval (CI) 1.95, 2.46), after adjusting for psychiatric comorbidities. In PD, the highest relative risks were for impact-related suicides (aHR 3.03, 95%CI 2.23, 4.13) and for suffocation-related suicides (aHR 2.72, 95%CI 2.23, 3.30), whereas the lowest relative risk was for intentional poisonings (aHR 1.66, 95%CI 1.37, 2.02). LIMITATIONS: Information on all potential confounders is not available in studies using routine data. CONCLUSIONS: Psychotic symptoms doubled the risk of suicides over and above of the risk that was associated with severe depression, after controlling for comorbid psychiatric disorders. The severity of suicidal ideation may be higher in PD than in NPD, which then leads to more lethal methods of self-harm.

Cause-specific excess mortality after first diagnosis of bipolar disorder: population-based cohort study.

BACKGROUND: Bipolar disorder (BD) is associated with increased mortality, but evidence on cause-specific mortality is limited. OBJECTIVE: To investigate cause-specific premature excess mortality in BD. METHODS: Finnish nationwide cohort study of individuals with and without a diagnosis of BD who were aged 15-64 years during 2004-2018. Standardised mortality ratios (SMRs) with 95% CIs were calculated for BD using the mortality rates in the Finnish general population without BD as weights. Causes of death were defined by the International Classification of Diseases, 10th revision codes. FINDINGS: Of the included 47 018 individuals with BD, 3300 (7%) died during follow-up. Individuals with BD had sixfold higher mortality due to external causes (SMR: 6.01, 95% CI: 5.68, 6.34) and twofold higher mortality due to somatic causes (SMR: 2.06, 95% CI: 1.97, 2.15). Of the deaths due to external causes, 83% (1061/1273) were excess deaths, whereas 51% (1043/2027) of the deaths due to somatic causes were excess. About twice the number of potential years of life were lost in excess due to external causes than due to somatic causes. Alcohol-related causes contributed more to excess mortality than deaths due to cardiovascular disease. CONCLUSION: External causes of death contributed more to the mortality gap than somatic causes after controlling for age-specific background general population mortality. CLINICAL IMPLICATION: A balanced consideration between therapeutic response, different treatment options and risk of cause-specific mortality is needed to prevent premature mortality in BD and to reduce the mortality gap.

Associations between antipsychotics and risk of violent crimes and suicidal behaviour in personality disorder.

BACKGROUND: Despite uncertain benefits, people with personality disorder are commonly treated with antipsychotic medication. OBJECTIVE: To investigate the association between antipsychotics and violent crimes and suicidal behaviour in individuals with personality disorder. METHODS: We used nationwide Danish registries to identify all individuals with diagnosed personality disorder aged 18-64 years during 2007 to 2016. Antipsychotics were recorded in dispensed prescriptions, and individuals were followed up for police-recorded suspicions for violent crimes and healthcare presentations of suicidal behaviour. We applied a within-individual design where outcome rates for individuals with personality disorder during medicated periods were compared with rates during non-medicated periods. FINDINGS: The cohort included 166 328 people with diagnosed personality disorder, of whom 79 253 were prescribed antipsychotics, presented at least one outcome and were thus included in the within-individual analyses. Compared with periods when individuals were not on antipsychotic medication, violent crime suspicions were 40% lower (incident rate ratio (IRR) 0.60, 95% CI 0.55 to 0.63) in men and 10% lower (IRR 0.90, 95% CI 0.79 to 1.01) in women, while rates of suicidal behaviour were 32% lower both in men (IRR 0.68, 95% CI 0.66 to 0.71) and in women (IRR 0.68, 95% CI 0.65 to 0.70). In subgroup analyses, the magnitude of the association varied across specific personality disorders for criminal outcomes but less for suicidal behaviour, with largest association in dissocial personality disorder for violent criminality (IRR 0.53, 95% CI 0.47 to 0.59). CONCLUSIONS: Treatment with antipsychotics was associated with reduced risks for violent crime suspicions and suicidal behaviour among individuals with personality disorder. CLINICAL IMPLICATIONS: Potential effects of antipsychotics on suicidal behaviour and violence should be taken into account when considering treatment options for people with personality disorders.

Modifiable risk factors and cancer mortality in transport, rescue, and security industries.

PURPOSE: We investigated the risk of mortality from cancers attributable to modifiable risk factors across representative transport, rescue, and security industries. METHODS: We used nationwide Danish registries to identify all 307,605 workers from these industries from 2001 through 2015 and 2,278,363 other economically active individuals aged 18-64 years at the baseline for comparison. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) for site-specific cancer deaths were calculated using Cox regression. Site-specific cancers were categorized by using population-attributable fraction (PAF) estimates derived from the previous literature. RESULTS: During an average follow-up of 12.8 years, 5977 cancer deaths were registered in these industries. Cancer mortality with a high proportion of avoidable deaths (i.e., high PAF) was elevated in male seafarers (1.37; 1.16-1.62), in men of land transport (1.44; 1.35-1.52), in women of land transport (1.51; 1.29-1.77), and in women of defense forces (1.43; 1.13-1.81). In contrast, cancer mortality with a high PAF was reduced in men of police force (0.63; 0.51-0.78). The total cancer mortality was higher in seafarers (1.24; 1.12-1.37), workers in land transport (1.31; 1.27-1.36), and workers in defense forces (1.14; 1.07-1.22). CONCLUSIONS: We observed considerable cancer mortality disparities associated with modifiable risk factors across transport, rescue, and security industries.

Analysis of Neuropsychiatric Diagnoses After Montelukast Initiation.

Importance: The evidence base for the association between montelukast and adverse neuropsychiatric outcomes is mixed and inconclusive. Several methodological limitations have been identified in the evidence base on the safety of montelukast in observational studies. Objective: To investigate the association between new montelukast exposure and 1-year incident neuropsychiatric diagnoses with improved precision and control for baseline confounders. Design, Setting, and Participants: This propensity score-matched cohort study was conducted using electronic health records from 2015 to 2019 in the TriNetX Analytics Network patient repository of more than 51 million patients from 56 health care organizations, mainly in the US. Included patients were those aged 15 to 64 years at index prescription for montelukast or for control prescription who had a history of asthma or allergic rhinitis. After propensity score matching for various baseline confounders, including comorbidities and dispensed prescription medicines, we included 154 946 patients, of whom 77 473 individuals were exposed to montelukast. Patients were followed up for 12 months. Data were analyzed from June through November 2021. Exposures: New dispensed prescription for leukotriene receptor antagonist montelukast or control medication. Main Outcomes and Measures: Incident neuropsychiatric diagnoses at 12 months identified using International Statistical Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes. Results: There were 72 490 patients with asthma (44 726 [61.7%] women; mean [SD] age at index prescription, 35 [15] years) and 82 456 patients with allergic rhinitis (54 172 [65.7%] women; mean [SD] age at index prescription, 40 [14] years). In patients exposed to montelukast, the odds ratio [OR] for any incident neuropsychiatric outcome was 1.11 (95% CI, 1.04-1.19) in patients with asthma and 1.07 (95% CI, 1.01-1.14) in patients with allergic rhinitis compared with patients who were unexposed. The highest OR was for anxiety disorders (OR, 1.21; 95% CI, 1.05-1.20) among patients with asthma exposed to montelukast and insomnia (OR, 1.15; 95% CI, 1.05-1.27) among patients with allergic rhinitis exposed to montelukast. Conclusions and Relevance: This study found that patients with asthma or allergic rhinitis had increased odds of adverse neuropsychiatric outcomes after montelukast initiation. These findings suggest that clinicians should consider monitoring potential adverse mental health symptoms during montelukast treatment, particularly in individuals with a history of mental health or sleep problems.