Comparative effectiveness of selective serotonin reuptake inhibitors (SSRIs) for depression in 43,061 older adults with chronic somatic diseases: A Danish target trial emulation study.

OBJECTIVE: To investigate the comparative effectiveness of commonly used selective serotonin reuptake inhibitors (SSRIs) for comorbid depression in older adults with chronic somatic diseases by applying a target-trial-emulation framework. METHODS: Danish target-trial-emulation study including 43,061 individuals aged ≥65 years (54.1% females, mean age 77.8 years) with a first redeemed prescription for depression with sertraline (n = 6673), escitalopram (n = 7104) or citalopram (n = 29,284) in 2006-2017. Individuals had cancer, cardiovascular diseases (CVD), chronic-obstructive-pulmonary-disease (COPD)/asthma, diabetes, neurodegenerative disorders, or osteoporosis. Outcomes were treatment switching, combination/augmentation, psychiatric hospital contact for depression, and any psychiatric in-patient care. Follow-up was one year and adjusted Cox regression analyses calculated hazard rate ratios (HRR) within each somatic disease. RESULTS: Across all six disease groups and four outcomes, we found that citalopram use, compared with sertraline, was associated with lower risks in several analyses, with statistically significant results in cancer, CVD, COPD/asthma, and diabetes (e.g., HRRs for psychiatric hospital contacts for depression/any psychiatric in-patient care ranging between 0.47 and 0.61). For escitalopram, compared with sertraline, some analyses indicated poorer outcomes with significantly higher risks for combination/augmentation treatment (HRRs ranging between 1.15 and 1.40). CONCLUSIONS: Although observational studies are prone to confounding, these findings indicate clinically relevant differences between the SSRIs, with better outcomes in citalopram users and poorer outcomes in escitalopram users than sertraline, urging the need for clinical studies in this vulnerable patient population.

Real-World Evidence on Clinical Outcomes of Commonly Used Antidepressants in Older Adults Initiating Antidepressants for Depression: A Nationwide Cohort Study in Denmark.

OBJECTIVE: The authors investigated the clinical outcomes of commonly used antidepressants among older adults who initiated first-time antidepressants for depression by analyzing the 1-year risk of selected clinically relevant outcomes. METHODS: This cohort study used nationwide Danish registry data and included all older adults who redeemed a first-time (since 1995) antidepressant prescription with an indication of depression between 2006 and 2017. Only the 10 most frequently redeemed antidepressants were included in the analyses. Outcomes included discontinuation, switching, augmentation, psychiatric hospital contacts, suicide attempt or self-harm, fall-related injuries, cardiovascular events, and all-cause mortality. Incidence rate ratios (IRRs) and 95% confidence intervals were estimated using Poisson regression models, controlling for potential confounders. RESULTS: The study sample included 93,883 older adults (mean age, 78.0 years, SD=7.5 years; 56% female). The most frequently prescribed antidepressants were selective serotonin reuptake inhibitors (citalopram, 47.04%; escitalopram, 11.81%; fluoxetine, 0.55%; paroxetine, 0.52%; sertraline, 11.17%), serotonin-norepinephrine reuptake inhibitors (duloxetine, 0.71%; venlafaxine, 1.54%), a tricyclic antidepressant (amitriptyline, 1.86%), and two atypical antidepressants (mianserin, 1.93%; mirtazapine, 22.87%). Compared with users of sertraline (the reference drug in this analysis, as Danish guidelines recommend it as the first-choice treatment for depression), users of most of the other nine antidepressants had a significantly higher risk of discontinuation (e.g., mirtazapine: IRR=1.55, 95% CI=1.50-1.61; venlafaxine: IRR=1.22, 95% CI=1.12-1.32), switching (amitriptyline: IRR=1.45, 95% CI=1.15-1.81; venlafaxine: IRR=1.47, 95% CI=1.20-1.80), augmentation, cardiovascular events, and mortality. Overall, mirtazapine and venlafaxine users had the most adverse outcomes compared with sertraline users. These results remained consistent in analyses stratified by sex and age (≤75 years vs. >75 years). CONCLUSIONS: This real-world evidence suggests that clinical outcomes may vary among initiators of commonly used antidepressants in older adults, which may inform benefit-risk evaluation at treatment initiation, and highlights the importance of careful selection of antidepressant treatment.

Do sociodemographic and clinical factors affect the selection of initial antidepressant treatment for depression in older adults? Results from a nationwide descriptive study in Denmark.

BACKGROUND: The choice of antidepressants for initial pharmacological treatment of depression in older adults and associated patients' characteristics are understudied. We aimed to describe the first selected antidepressant (first-choice) for depression in older adults (≥65 years) and whether patients' sociodemographic and clinical characteristics influence selecting an alternative first-choice (any other antidepressant than the nationally recommended first-choice sertraline) in Denmark. METHODS: Register-based cross-sectional study including all older adults who redeemed their first antidepressant prescription for depression at community pharmacies in Denmark in 2015-2019. We analyzed the effect of patients' characteristics on the first-choice antidepressant selection using multinomial logistic regression. RESULTS: Among 34,337 older adults with a first antidepressant-prescription, over two-thirds filled alternative first-choice antidepressants than sertraline (28.9 %): escitalopram or citalopram (30.3 %) or mirtazapine (34.4 %). Socially disadvantaged older adults (e.g., with short educational attainment, being single, or of non-western ethnicity) and clinically vulnerable older adults (e.g., having somatic diagnoses and hospital contacts) were more likely to use alternative first-choice antidepressants. LIMITATIONS: Information on prescribers and in-hospital medications was not included in this study. CONCLUSIONS: Further investigation of the first antidepressant selection and its impact on depression treatment outcomes in older adults is necessary. Moreover, for older patients, national guidelines on depression treatment should be more specific. ARTICLE SUMMARY: Antidepressant selection for initial pharmacological treatment of depression in older adults can be difficult due to comorbidity, polypharmacy, and age-related changes in pharmacokinetics and pharmacodynamics. Real-world evidence/knowledge on first-choice antidepressant selection and associated user characteristics are rare. This Danish register-based cross-sectional study found over two-thirds of older adults filled alternative antidepressants (primarily escitalopram/citalopram or mirtazapine) than nationally recommended first-choice sertraline for depression treatment and identified wide-ranging sociodemographic and clinical factors influencing the first antidepressant selection.

Trends, Patterns and Associated User Characteristics of Antidepressant Prescriptions in Older Adults: A Nationwide Descriptive Cohort Study in Denmark.

BACKGROUND AND OBJECTIVE: Antidepressant use in older adults (≥ 65 years) is understudied in large population-based samples, particularly in recent years and regarding user characteristics. We aimed to describe the trends, patterns, and associated user characteristics of all antidepressant prescriptions redeemed by older adults at community pharmacies in Denmark during 2015-2019. METHODS: This register-based study used a cross-sectional design to characterize antidepressant prescription trends and patterns, and a cohort design to describe user characteristics associated with antidepressant prescription initiation. We used descriptive statistics to characterize trends and patterns, and Poisson regression for analyzing user characteristics. RESULTS: During the years 2015-2019, 17.9% of 1.2 million older adults redeemed 4.84 million antidepressant prescriptions, where 48.5% were selective serotonin reuptake inhibitors, followed by noradrenergic and specific serotonergic antidepressants (26.2%), serotonin-norepinephrine reuptake inhibitors (12.7%), tricyclic antidepressants (11.2%), and others (1.4%). Amitriptyline and nortriptyline, considered potentially inappropriate medications, were among the 10 most frequently redeemed antidepressants. Only 60.5% of prescriptions had a treatment indication of depression. Prescription-proportion trends by drug classes and individual antidepressants remained consistent. A higher incidence rate ratio (IRR) and 95% confidence interval (CI) of initiating antidepressants was associated with female sex (IRR 1.20, 95% CI 1.07-1.34), older age (e.g., 81-85 years vs. 65-70 years: IRR 1.74, 95% CI 1.44-2.11), living in rural areas (North Denmark vs. Capital Region: IRR 1.31, 95% CI 1.09-1.58), and having somatic and psychiatric diagnoses (e.g., per one psychiatric diagnosis: IRR 1.10, 95% CI 1.05-1.15), while a lower ratio was associated with being non-Western (vs. Danish: IRR 0.50, 95% CI 0.28-0.89) and having hospital contacts for psychiatric treatment (per each contact: IRR 0.96, 95% CI 0.93-1.00). CONCLUSION: SSRIs were the most commonly redeemed antidepressants, with consistent trends in Danish older adults. Besides clinical conditions, sociodemographics, e.g., sex, age, ethnicity, and place of residence, may influence antidepressant use.

Concurrent use of polypharmacy and potentially inappropriate medications with antidepressants in older adults: A nationwide descriptive study in Denmark during 2015-2019.

OBJECTIVE: Concurrent polypharmacy and potentially-inappropriate-medication (PIMs) use with antidepressants in older adults is understudied. We investigated the prevalence and associated user characteristics of concurrent polypharmacy (≥5 drugs) and PIMs with antidepressants in all older adults (≥65 years) in Denmark based on prescriptions filled at community pharmacies during 2015-2019. METHOD: We applied a cross-sectional and cohort study design using socio-demographic and clinical data from Danish registers. RESULTS: A total of 261,479 older adults (mean age 76 years, females 63%) redeemed at least one prescription of antidepressants during 2015-2019. The prevalence of polypharmacy was 73%, and PIMs was 56%, with over 80% using at least one other nervous system drug or cardiovascular system drug concomitantly with antidepressants. Characteristics associated with higher concurrent use of polypharmacy and PIM with antidepressants were older age, marital status as widow/widower/separated/single, place of residence predominantly in the rural regions, non-western origin, and having somatic diagnoses. Some characteristics showed opposite directions of the associations with the two outcomes, including previous antidepressant use and psychiatric diagnoses being associated with higher use of polypharmacy but lower use of PIM. CONCLUSION: High polypharmacy and PIM use with antidepressants underline the importance of regularly reviewing pharmacological treatments in older adults with depression.

Antidepressant treatment initiation and public sick-leave compensation in the following year: a register-based prospective cohort study in Denmark.

OBJECTIVES: Mental disorders have caused increasing sickness absence and related benefit claims in the OECD countries. This study investigates the association between antidepressant treatment initiation and public sick leave compensation (PLSC) in the following year in Denmark. METHODS: The study was designed as a register-based prospective cohort study. We included 39,401 adults (aged 18-65 years) with at least 12 consecutive months of full-time labour market attachment who had initiated first-time antidepressant monotherapy for depression or anxiety between 1 January 2015 and 31 December 2018. PLSC was estimated for the year following the incident prescription of various antidepressants for depression or anxiety disorders. RESULTS: The most frequently prescribed antidepressant medication was SSRIs (66.8%), with sertraline being the leading choice. Compared with sertraline, mirtazapine and mianserin were associated with the highest risks of PSLC in the year following initiation, with IRRs of 2.74 (95% CI: 2.63 to 2.86) and 5.79 (95% CI: 5.18 to 6.47), respectively. Compared with sertraline, citalopram (IRR 1.22, 95%CI 1.17-1.28), venlafaxine (IRR 1.34, 95%CI 1.23-1.45) and duloxetine (IRR 1.48, 95%CI 1.35-1.62) were all associated with increased PSLC. In contrast, paroxetine (IRR 0.85, 95% CI 0.74-0.98), fluoxetine (IRR 0.51, 95%CI 0.42-0.62) and vortioxetine (IRR 0.78, 95% CI 0.63-0.97) were all associated with a significantly lower risk of PSLC compared with sertraline. CONCLUSIONS: Antidepressant treatment initiation was associated with PLSC. The highest risk of PLSC was seen for antidepressants with sedative side effects. Some types of antidepressants were associated with a lower risk of PLSC in the year following treatment initiation.

Treatment indications and potential off-label use of antidepressants among older adults: A population-based descriptive study in Denmark.

OBJECTIVES: Off-label prescriptions of antidepressants may be of special concern in older-adults. We aimed to study the potential off-label use of antidepressants among adults ≥65 years by describing the patterns, trends, and factors associated with missing and unspecified treatment indications. METHODS: We used registry data to describe indications of all antidepressant prescriptions (N = 13.8 million) redeemed by older-adults in 2006-2019. We investigated factors associated with off-label use by considering prescriptions with missing and unspecified indications of the first antidepressant prescription using a multinomial logistic regression with the 'depression' indication as a reference category and reported odds ratios (ORs) with 95% confidence intervals (CI). RESULTS: Overall, 18.1% of all antidepressant prescriptions had missing indications, and 9.9% had unspecified indications. The proportion of potential off-label use based on missing and unspecified prescriptions remained mostly consistent during 2006-2019. We identified similar associations in user characteristics whether considering missing or unspecified first prescription. ORs with 95% CI were raised in non-western ethnicity (vs. Danish, 1.12 (0.99-1.26) for missing indication and 1.28 (1.11-1.48) for unspecified indication) and female sex (vs. male, 1.05 (1.02-1.07) and 1.05 (1.02-1.07) respectively). ORs were reduced for shorter educational attainment (vs. long, 0.90 (0.87-0.94) and 0.92 (0.88-0.96)), older age (≥81 vs. 67-70 years, 0.66 (0.65-0.71) and 0.73 (0.70-0.76)) and hospital psychiatric diagnosis (per diagnosis 0.76 (0.73-0.78) and 0.88 (0.86-0.91)). CONCLUSIONS: Nearly one-third of all antidepressant prescriptions redeemed by older-adults in Denmark had either missing or unspecified treatment indications. Whether these prescriptions were actual off-label use needs to be validated. Clinicians should pay special attention to patients' characteristics linking missing and unspecified indications and maintain adequate documentation while prescribing medication.

Clinical Impact of Functional CYP2C19 and CYP2D6 Gene Variants on Treatment with Antidepressants in Young People with Depression: A Danish Cohort Study.

Background: The clinical impact of the functional CYP2C19 and CYP2D6 gene variants on antidepressant treatment in people with depression is not well studied. Here, we evaluate the utility of pharmacogenetic (PGx) testing in psychiatry by investigating the association between the phenotype status of the cytochrome P450 (CYP) 2C19/2D6 enzymes and the one-year risks of clinical outcomes in patients with depression with incident new-use of (es)citalopram, sertraline, or fluoxetine. Methods: This study is a population-based cohort study of 17,297 individuals who were born between 1981 and 2005 with a depression diagnosis between 1996 and 2012. Using array-based single-nucleotide-polymorphism genotype data, the individuals were categorized according to their metabolizing status of CYP2C19/CYP2D6 as normal (NM, reference group), ultra-rapid- (UM), rapid- (RM), intermediate- (IM), or poor-metabolizer (PM). The outcomes were treatment switching or discontinuation, psychiatric emergency department contacts, and suicide attempt/self-harm. By using Poisson regression analyses, we have estimated the incidence rate ratios (IRR) with 95% confidence intervals (95% CI) that were adjusted for covariates and potential confounders, by age groups (<18 (children and adolescents), 19−25 (young adults), and 26+ years (adults)), comparing the outcomes in individuals with NM status (reference) versus the mutant metabolizer status. For statistically significant outcomes, we have calculated the number needed to treat (NNT) and the number needed to genotype (NNG) in order to prevent one outcome. Results: The children and adolescents who were using (es)citalopram with CYP2C19 PM status had increased risks of switching (IRR = 1.64 [95% CI: 1.10−2.43]) and suicide attempt/self-harm (IRR = 2.67 [95% CI; 1.57−4.52]). The young adults with CYP2C19 PM status who were using sertraline had an increased risk of switching (IRR = 2.06 [95% CI; 1.03−4.11]). The young adults with CYP2D6 PM status who were using fluoxetine had an increased risk of emergency department contacts (IRR = 3.28 [95% CI; 1.11−9.63]). No significant associations were detected in the adults. The NNG for preventing one suicide attempt/suicide in the children who were using (es)citalopram was 463, and the NNT was 11. Conclusion: The CYP2C19 and CYP2D6 PM phenotype statuses were associated with outcomes in children, adolescents, and young adults with depression with incident new-use of (es)citalopram, sertraline, or fluoxetine, therefore indicating the utility of PGx testing, particularly in younger people, for PGx-guided antidepressant treatment.

Treatment History Characteristics Associated With Use of Isocarboxazid: A Nationwide Register-Based Study.

PURPOSE/BACKGROUND: The monoamine oxidase inhibitor isocarboxazid (Marplan) is occasionally used in the treatment of depression, but there is only little knowledge on the nature of the use of isocarboxazid in clinical practice. We aimed to identify treatment history characteristics associated with this use. METHODS/PROCEDURES: Via the nationwide Danish registers, we identified all adult incident users of isocarboxazid in the period from 2001 to 2018, as well as up to 5 matched controls using another antidepressant (matched on date of redeemed prescription, age, sex, and region of residence). The 5-year treatment history of the isocarboxazid users and the controls was assessed via the Danish registers. The association between treatment history characteristics and isocarboxazid use was examined by multivariate conditional logistic regression. FINDINGS/RESULTS: We identified 1455 isocarboxazid users and 7045 controls using another antidepressant. The following characteristics were associated with statistically significant increased likelihood of receiving isocarboxazid treatment: Prior treatment with a selective serotonin reuptake inhibitor (odds ratio [OR], 1.80 with 95% confidence interval [CI], 1.46-2.23), a serotonin-norepinephrine reuptake inhibitor (OR, 4.90; 95% CI, 4.08-5.89), a noradrenergic and specific serotonergic antidepressant (OR, 1.56; 95% CI, 1.30-1.88), a tricyclic antidepressant (OR, 5.05; 95% CI, 4.19-6.08), other antidepressants (OR, 4.74; 95% CI, 3.74-6.01), lithium (OR, 6.70; 95% CI, 5.08-8.83), an antipsychotic (OR, 1.43; 95% CI, 1.19-1.73), and each diagnosis of depression received in relation to psychiatric hospital treatment (OR, 1.31; 95% CI, 1.23-1.39). Forty percent of those initiating isocarboxazid had received treatment with drugs from 5 or more different psychopharmacological classes in the 5 preceding years. IMPLICATIONS/CONCLUSIONS: These findings suggest that isocarboxazid is typically used for treatment-resistant depression, consistent with guideline recommendations.

Effect of antipsychotics on mortality risk in patients with dementia with and without comorbidities.

BACKGROUND: We investigated the mortality risk associated with the initiation of antipsychotic treatment among patients with dementia and whether comorbidities related to the cardiovascular system and diabetes interact with antipsychotic treatment to increase the mortality risk beyond the risk of death independently associated with antipsychotics and comorbidity alone. METHODS: We designed a matched cohort study using nationwide registry data. All Danish residents aged 65-95 years diagnosed with dementia between 2009 and 2014 were included. Dementia was assessed as a first-time registered dementia diagnosis in the Danish National Patient Register or the Danish Psychiatric Central Research Register and/or a first-time prescription for antidementia medication. Patients exposed to antipsychotics were matched with up to three unexposed patients. Cox proportional hazards models were used to compare rates of death within 180 days after the initiation of antipsychotic treatment. The models were adjusted for potential confounders. Analyses were stratified for diabetes, heart disease, and cerebrovascular disease, and we calculated the relative excess risk due to interaction (RERI). RESULTS: The study cohort included 8244 exposed patients and 24,730 unexposed patients. A total of 5938 patients died during the first 180 days of follow-up. Patients exposed to antipsychotics had a significantly higher adjusted risk of death (hazard ratio: 1.35, 95% confidence interval: 1.27-1.43) than unexposed patients. Crude mortality rates were higher among patients with heart disease and diabetes when antipsychotic treatment was initiated compared with patients without comorbidities. Relative risk estimates did not differ between patients with and without heart disease, cerebrovascular disease, and diabetes, and RERI suggested no positive additive interaction. Risk analysis suggested higher mortality in patients without cerebrovascular disease who initiated antipsychotics. CONCLUSION: This nationwide study adds to the evidence that antipsychotic treatment is associated with increased mortality and suggests that attention should be paid to all initiators of antipsychotics irrespective of cardiovascular disease and diabetes.

Life-time Actionable Pharmacogenetic Drug Use: A Population-based Cohort Study in 86 040 Young People With and Without Mental Disorders in Denmark.

OBJECTIVE: To describe life-time use of current actionable pharmacogenetic (PGx) somatic and psychotropic drugs according to international PGx consortia in people with and without hospital-diagnosed mental disorders in the Danish population. METHODS: Population- and register-based observational drug utilization study in 56 065 individuals with mental disorders, i. e. attention-deficit/hyperactivity disorder, autism, bipolar disorder, depression and schizophrenia, and a random, representative sample of 29 975 individuals of the Danish population, born between 1981 and 2005. Individuals were followed from 1995 or birth until 2016 (for a maximum of 22 years). We report prevalence and incidence rates of PGx drug use by age, sex and mental disorders based on redeemed prescriptions between 1995 and 2016. RESULTS: Of the 69 PGx drugs, prescriptions of 39 drugs had been redeemed by the study population by 35 years of age. The use of at least 1 PGx drug varied between 23.1% in males without mental disorders and 97.2% in females with schizophrenia. Males with ADHD or autism were the youngest first-time PGx drug users at a mean of 11.6 years. The mean number of different PGx drugs used was 1.2 in males without mental disorders and 5.6 in individuals with schizophrenia. The prevalence of different PGx drugs linked to more than one gene was 25.3% in males without mental disorders to 94.1% in females with schizophrenia. CONCLUSION: PGx drugs are commonly used by younger people, more often by individuals with mental disorders and by females. Panel-based PGx testing could contribute to treatment decisions at a very young age.

Socioeconomic Position and Late-Onset Dementia: A Nationwide Register-Based Study.

OBJECTIVES: Previous research on the association between socioeconomic position (SEP) and dementia has not sufficiently accounted for the complex relationship between education and occupation. We investigated the independent and joint effects of educational attainment and occupation-based SEP on dementia. METHODS: We used register-based information about educational attainment, occupation-based SEP, and dementia from 1,210,720 individuals. Information about cognitive ability at conscription was available for a subsample of men. RESULTS: When mutually adjusted, lower educational attainment and occupation-based SEP were associated with higher dementia risk in a dose-response manner. Higher occupation-based SEP partly mitigated the higher dementia risk associated with lower educational attainment. After adjusting for cognitive ability in a subgroup of men, only unskilled work was associated with higher dementia risk. DISCUSSION: Occupation-based SEP is independently associated with dementia and may mitigate the higher dementia risk associated with short education. Future research should elucidate the mechanisms underlying social inequality in dementia.

Stress diagnoses in midlife and risk of dementia: a register-based follow-up study.

OBJECTIVES: Previous studies indicated that stress diagnoses increase the risk of dementia. However, previous results may be biased by confounding, reverse causation and misclassification. Therefore, the main aim of this study was to investigate the association between clinically diagnosed stress in midlife and later dementia risk, while addressing limitations of previous studies. METHODS: The study population was selected from all individuals in Denmark born 1935-1956. Individuals diagnosed with stress in midlife (aged 37-58 years) were matched (1:5) with individuals without stress diagnoses based on sex and birthdate (N = 103,484). Data were retrieved from national registers. Cox regression models were adjusted for socio-demographic factors and different morbidities. RESULTS: We found a 2.20 (95% CI: 1.93-2.50) times higher rate of dementia among individuals with any stress diagnosis registered in midlife compared with no stress diagnosis. Hazard rate ratios of dementia were 1.73 (95% CI: 1.13-2.65) among individuals with acute stress reactions, 2.37 (95% CI: 2.05-2.74) among individuals with adjustment disorders, and 2.20 (95% CI: 1.73-2.80) among individuals with unspecified stress reactions. Individuals with PTSD and other stress reactions had non-significantly elevated rates of dementia. Adjustment for confounding only slightly attenuated the association, and reverse causation did not appear to bias the results substantially. CONCLUSION: Our results support the hypothesis that severe stress in midlife is an important risk factor for dementia. This finding emphasizes the importance of identifying and treating severe stress in midlife to reduce potential detrimental consequences for brain health in later life.

Survival Rate Following Involuntary Electroconvulsive Therapy: A Population-Based Study.

OBJECTIVE: Involuntary electroconvulsive therapy (ECT) can be a lifesaving intervention for patients suffering from potentially lethal conditions who are unable to give informed consent. However, its use is not widespread, probably partly because of the scarce data on hard outcomes following involuntary ECT. In Denmark, involuntary ECT is only used when patients are at imminent/potential risk of dying if not receiving ECT. Here, we aimed to estimate the 1-year survival rate after the administration of involuntary ECT as a proxy for the effectiveness of this treatment. METHODS: We conducted a register-based cohort study involving (i) all patients receiving involuntary ECT in Denmark between 2008 and 2019, (ii) age- and sex-matched patients receiving voluntary ECT, and (iii) age- and sex-matched individuals from the general population. One-year survival rates were compared via mortality rate ratios. RESULTS: We identified 618 patients receiving involuntary ECT, 547 patients receiving voluntary ECT, and 3080 population-based controls. The survival rate in the year after involuntary ECT was 90%. For patients receiving involuntary ECT, the 1-year mortality rate ratios were 3.1 (95% confidence interval, 1.9-5.2) and 5.8 (95% confidence interval, 4.0-8.2) compared with those receiving voluntarily ECT and to the population-based controls, respectively. Risk factors for early death among patients receiving involuntary ECT were male sex, being 70 years or older and having organic mental disorder as the treatment indication. CONCLUSIONS: Treatment with involuntary ECT is associated with a high survival rate, suggesting that the intervention is effective. However, patients receiving involuntary ECT constitute a high-risk population that should be monitored closely after this treatment.

Does Midlife Forgetfulness Influence Positive and Negative Aspects of Social Relations at Work?: Results From the Danish Working Environment Cohort Study.

OBJECTIVES: We investigated whether midlife forgetfulness was prospectively associated with changes in social relations at work (SRW) among occupationally active individuals in Denmark. METHODS: We analyzed data of 2339 men and women participating in the first (1990) and second (1995) survey of the Danish Work Environment Cohort Study, responding to questions on working environment, SRW, and forgetfulness. We used multiple linear regression analysis while adjusting for potential confounders. RESULTS: At baseline (1990), 517 (22.1%) study participants were categorized as forgetful. Forgetfulness was prospectively associated with a decline in one of the investigated items reflecting a negative aspect of SRW (experiencing teasing, regression coefficient = 0.07, 95% CI: 0.03 to 0.11), while no association was observed with positive aspects of SRW. CONCLUSIONS: Our findings did not support the hypothesis that memory problems such as midlife forgetfulness negatively affect SRW.

Medical diseases prior to first-time depression diagnosis and subsequent risk of admissions for depression: A nationwide study of 117,585 patients.

BACKGROUND: Medical diseases and depression frequently co-occur, but it remains uncertain whether specific medical diseases or the disease load, affect the clinical course of depression. METHODS: We identified all adults (≥18 years) at their first hospital-based diagnosis of unipolar depression in Denmark between 1996 and 2015. All medical hospital contacts since 1977 and all drug prescriptions during the previous year were identified. We followed patients for up to five years regarding hospital admissions with depression and performed adjusted Cox regression analyses calculating hazard rate ratios (HRR) including 95%-confidence intervals (CI) to test the association between medical diseases and depression admission following the index depressive episode. RESULTS: Among 117,585 patients with depression (444,696 person-years follow-up), any prior medical hospital contact (N = 114,206; 97.1%) was associated with increased risks of admission for depression among individuals aged 18-30 (HRR=1.50; 95%CI=1.15-1.95), 31-65 (HRR=1.69; 95%CI=1.28-2.21), and >65 years (HRR=1.38; 95%CI=1.10-1.75), fitting a dose-response relationship (p<0.005) with increasing number of prior medical diseases among those aged <65. All specific medical diseases were associated with increased risks of admission for depression, particularly among individuals aged<65 (HRR ranging from 1.57 to 2.38). Drug prescriptions and medical hospital contacts in the year before the depression diagnosis were associated with reduced risks of admission. CONCLUSION: The medical load seems to be associated with an increased risk for depression admission, particularly among individuals aged <65. The lower risk for people in medical care during the previous year may indicate better compliance and care/treatment.

Primary Care Prescription Drug Use and Related Actionable Drug-Gene Interactions in the Danish Population.

Pharmacogenetics (PGx) aims to improve drug therapy using the individual patients' genetic make-up. Little is known about the potential impact of PGx on the population level, possibly hindering implementation of PGx in clinical care. Therefore, we investigated how many patients use actionable PGx drugs, have actionable genotypes or phenotypes and which patients could benefit the most of PGx testing. We included PGx recommendations from two international PGx consortia (Clinical Pharmacogenetics Implementation Consortium (CPIC) and Dutch Pharmacogenetics Working Group (DPWG)). Using data from publically accessible sales information drawn from the Danish Register of Medicinal Product Statistics (MEDSTAT), we identified the number of users of actionable prescription PGx drugs among the total Danish population in 2017. We estimated actionable genotypes or phenotypes based on reported frequencies from literature. We identified 49 drug-gene interactions related to 41 unique prescription drugs. The estimated median frequency of actionable genotypes or phenotypes among prescription drug users was 25% (interquartile range 7-26%). Six of 41 drugs were used more than twice as much in women. Actionable PGx drugs were most frequently used by 45-79 year old patients (62%), followed by 25-44 year old patients (18%). Almost half of the actionable PGx drugs (19/41) were psychotropics (i.e., antidepressants, antipsychotics, or psychostimulants). PGx testing can have a substantial impact on the population, as one in four prescription drug users has an actionable genotype or phenotype and could thus benefit from PGx testing. We advocate for prospective panel-based PGx testing at the time of the first PGx drug prescription ("as needed"), with PGx results ready prior to start of the first, and all future, therapies.

Perceived stress and dementia: Results from the Copenhagen city heart study.

Objectives: We investigated if perceived stress in midlife increased the risk of dementia. Furthermore, we explored differences between subgroups related to sex, age and employment status when reporting stress.Methods: In this longitudinal study, we used information on perceived stress from 10,814 participants (mean age 56.7 years). Participants were followed through Danish national registers for development of dementia. Participants were considered at risk of dementia from the date they turned 60 years. Perceived stress was assessed as a combination of self-reported intensity and frequency of stress, and categorized into low (score 0-1), medium (score 2-4), and high stress (score 5-6). We used Poisson regression to estimate incidence rate ratios (IRR) and their 95% confidence intervals (CI) and adjusted for sociodemographic factors and psychiatric morbidity at baseline (main model) as well as cardio/cerebrovascular diseases and health behaviors at baseline (additional model).Results: The mean follow-up time was 13.8 years, and 1,519 participants were registered with dementia. Dementia risk was higher in participants reporting medium stress (IRR = 1.11, 95% CI: 0.99-1.24) and high stress (IRR = 1.36, 95% CI: 1.13-1.65). Adjustment for cardio/cerebrovascular diseases and health behaviors did not alter the results. We did not find strong support for differences between subgroups, although the association between stress and dementia was stronger for those who were employed at the time of reporting high stress.Conclusion: Our results provide empirical support for an effect of perceived stress on the risk of dementia in old age.

Midlife Forgetfulness and Risk of Dementia in Old Age: Results from the Danish Working Environment Cohort Study.

BACKGROUND: Despite the current evidence of a high prevalence of forgetfulness in middle-aged individuals, and the evidence of a link between midlife memory complaints and biological changes in the brain, no previous study has yet investigated midlife forgetfulness in relation to risk of dementia in old age. AIMS: We investigated whether midlife forgetfulness was an indicator of an increased risk of dementia in old age. METHODS: We used data from 3,136 employed men and women who participated in the Danish Work Environment Cohort Study in 1990. These data were linked to Danish national registers. Participants were asked whether their closest relative had ever told them that they were forgetful. Incidence rate ratios (IRR) were estimated using Poisson regression analysis. RESULTS: At baseline, 749 (24%) study participants were categorized as forgetful, and 86 (2.7%) participants were diagnosed with dementia during a total of 31,724 person-years at risk. After adjusting for sociodemographic factors, comorbidities, and work-related factors, midlife forgetfulness was associated with a higher risk of dementia (IRR = 1.82; 95% CI: 1.12-2.97). CONCLUSIONS: This study is the first to investigate midlife forgetfulness and dementia, and the results suggest that midlife forgetfulness is an early indicator of an increased risk of dementia in old age.

Night shift work, long working hours and dementia: a longitudinal study of the Danish Work Environment Cohort Study.

OBJECTIVE: Shift work and long working hours are potential risk factors for dementia, but previous studies on shift work, long working hours and dementia are sparse and their findings are conflicting. Therefore, we investigated the effect of night shift work and long working hours on dementia. DESIGN: A longitudinal study. SETTING: Denmark. PARTICIPANTS: 3435 occupationally active men and women from the general working population. METHODS: Work schedule covered day work (reference) and shift schedules without/with night work. Working hours covered <27, 28-36, 37 (reference), 38-44, and ≥45 hours/week. As the primary outcome, we used register-based information about dementia, and estimated incidence rate ratios (IRR) and 95% CI. Estimates were adjusted for gender, age, psychosocial work factors and cardiovascular risk factors. RESULTS: We identified 85 dementia cases during a mean of 9.8 years of follow-up. We found a positive, but statistically insignificant association between night shift work and dementia (IRR=2.01; 95% CI: 0.87-4.65). Post hoc analyses indicated that this was only due to a higher risk in permanent night workers (IRR=3.25; 95% CI: 1.35-7.83). The dementia risk was also significantly higher among participants working 38-44 hours/week (IRR=2.08; 95% CI: 1.11-3.90) compared with those working 37 hours/week. We found no indications of a higher risk of dementia in participants working <37 hours/week or ≥45 hours/week. CONCLUSION: We did not find arguments that night shift work or long working hours increased dementia risk in general. However, we found a higher risk of dementia in specific subgroups, that is, permanent night workers and employees with moderately longer weekly working hours than the standard.