Anette Riisgaard Ribe

Effect of Depression and Diabetes Mellitus on the Risk for Dementia: A National Population-Based Cohort Study

IMPORTANCE Although depression and type 2 diabetes mellitus (DM) may independently increase the risk for dementia, no studies have examined whether the risk for dementia among people with comorbid depression and DM is higher than the sum of each exposure individually. OBJECTIVE To examine the risk for all-cause dementia among persons with depression, DM, or both compared with persons with neither exposure. DESIGN, SETTING, AND PARTICIPANTS We performed a national population-based cohort study of 2 454 532 adults, including 477 133 (19.4%) with depression, 223 174 (9.1%) with DM, and 95 691 (3.9%) with both. We included all living Danish citizens 50 years or older who were free of dementia from January 1, 2007, through December 31, 2013 (followed up through December 31, 2013). Dementia was ascertained by physician diagnosis from the Danish National Patient Register or the Danish Psychiatric Central Register and/or by prescription of a cholinesterase inhibitor or memantine hydrochloride from the Danish National Prescription Registry. Depression was ascertained by psychiatrist diagnosis from the Danish Psychiatric Central Research Register or by prescription of an antidepressant from the Danish National Prescription Registry. Diabetes mellitus was identified using the National Diabetes Register. MAIN OUTCOMES AND MEASURES We estimated the risk for all-cause dementia associated with DM, depression, or both using Cox proportional hazards regression models that adjusted for potential confounding factors (eg, demographics) and potential intermediates (eg, medical comorbidities). RESULTS During 13 834 645 person-years of follow-up, 59 663 participants (2.4%) developed dementia; of these, 6466 (10.8%) had DM, 15 729 (26.4%) had depression, and 4022 (6.7%) had both. The adjusted hazard ratio for developing all-cause dementia was 1.83 (95% CI, 1.80-1.87) for persons with depression, 1.20 (95% CI, 1.17-1.23) for persons with DM, and 2.17 (95% CI, 2.10-2.24) for those with both compared with persons who had neither exposure. The excess risk for all-cause dementia observed for individuals with comorbid depression and DM surpassed the summed risk associated with each exposure individually, especially for persons younger than 65 years (hazard ratio, 4.84 [95% CI, 4.21-5.55]). The corresponding attributable proportion due to the interaction of comorbid depression and DM was 0.25 (95% CI, 0.13-0.36; P < .001) for those younger than 65 years and 0.06 (95% CI, 0.02-0.10; P = .001) for those 65 years or older. CONCLUSIONS AND RELEVANCE Depression and DM were independently associated with a greater risk for dementia, and the combined association of both exposures with the risk for all-cause dementia was stronger than the additive association.

Pain thresholds during and after treatment of severe depression with electroconvulsive therapy

Pain and depression are often associated suggesting that both conditions share a common neurobiological mechanism, which modulate emotional function and processing of noxious information. Pain thresholds are hypothesized to be altered in depressed patients and normalized with the amelioration of depression. The purpose of this study was therefore to determine pain thresholds in patients during and after treatment with electroconvulsive therapy (ECT) of severe depression and in healthy controls. Seventeen depressed patients (Hamilton depression score > 18) and an age and gender matched control group of same size participated in the study. Pain detection and tolerance thresholds to pressure and pain tolerance thresholds to the Cold Pressor Test by exposure to ice‐water was measured twice in depressed patients during and after ECT and twice in controls with a similar time interval. While ECT significantly improved Hamilton depression score (from mean 23.9 (SD:5) to mean 12.5 (SD:5.7)) there was no significant change in pain thresholds during and after ECT in the patient group. However, depressed patients had significantly lower pain tolerance in the Cold Pressor Test on both examinations and on pressure pain tolerance on the second examination day than their corresponding control subjects. The differential effect of ECT on depression score and pain processing indicate that mood and noxious processing are not medicated directly by the same systems but that a complex relationship between pain and depression exists.

Long-term Risk of Dementia in Persons With Schizophrenia: A Danish Population-Based Cohort Study.

IMPORTANCE Although schizophrenia is associated with several age-related disorders and considerable cognitive impairment, it remains unclear whether the risk of dementia is higher among persons with schizophrenia compared with those without schizophrenia. OBJECTIVE To determine the risk of dementia among persons with schizophrenia compared with those without schizophrenia in a large nationwide cohort study with up to 18 years of follow-up, taking age and established risk factors for dementia into account. DESIGN, SETTING, AND PARTICIPANTS This population-based cohort study of more than 2.8 million persons aged 50 years or older used individual data from 6 nationwide registers in Denmark. A total of 20 683 individuals had schizophrenia. Follow-up started on January 1, 1995, and ended on January 1, 2013. Analysis was conducted from January 1, 2015, to April 30, 2015. MAIN OUTCOMES AND MEASURES Incidence rate ratios (IRRs) and cumulative incidence proportions (CIPs) of dementia for persons with schizophrenia compared with persons without schizophrenia. RESULTS During 18 years of follow-up, 136 012 individuals, including 944 individuals with a history of schizophrenia, developed dementia. Schizophrenia was associated with a more than 2-fold higher risk of all-cause dementia (IRR, 2.13; 95% CI, 2.00-2.27) after adjusting for age, sex, and calendar period. The estimates (reported as IRR; 95% CI) did not change substantially when adjusting for medical comorbidities, such as cardiovascular diseases and diabetes mellitus (2.01; 1.89-2.15) but decreased slightly when adjusting for substance abuse (1.71; 1.60-1.82). The association between schizophrenia and dementia risk was stable when evaluated in subgroups characterized by demographics and comorbidities, although the IRR was higher among individuals younger than 65 years (3.77; 3.29-4.33), men (2.38; 2.13-2.66), individuals living with a partner (3.16; 2.71-3.69), those without cerebrovascular disease (2.23; 2.08-2.39), and those without substance abuse (1.96; 1.82-2.11). The CIPs (95% CIs) of developing dementia by the age of 65 years were 1.8% (1.5%-2.2%) for persons with schizophrenia and 0.6% (0.6%-0.7%) for persons without schizophrenia. The respective CIPs for persons with and without schizophrenia were 7.4% (6.8%-8.1%) and 5.8% (5.8%-5.9%) by the age of 80 years. CONCLUSIONS AND RELEVANCE Individuals with schizophrenia, especially those younger than 65 years, had a markedly increased relative risk of dementia that could not be explained by established dementia risk factors.

Long-term mortality of persons with severe mental illness and diabetes: a population-based cohort study in Denmark

BACKGROUND Persons with severe mental illness (SMI) have excess mortality, which may partly be explained by their high prevalence of diabetes. METHOD We compared the overall and cause-specific mortality in persons with SMI and diabetes with that of the general Danish population between 1997 and 2009 by linking data from Danish national registries. RESULTS The cohort counted 4 734 703 persons, and during follow-up 651 080 persons died of whom 1083 persons had SMI and diabetes. Compared with the background population, the overall mortality rate ratios (MRRs) for persons with SMI and diabetes were 4.14 [95% confidence interval (CI) 3.81-4.51] for men and 3.13 (95% CI 2.88-3.40) for women. The cause-specific MRRs for persons with SMI and diabetes were lowest for malignant neoplasms (women: MRR = 1.98, 95% CI 1.64-2.39; men: MRR = 2.08, 95% CI 1.69-2.56) and highest for unnatural causes of death (women: MRR = 12.31, 95% CI 6.80-22.28; men: MRR = 7.89, 95% CI 5.51-11.29). The cumulative risks of death within 7 years of diabetes diagnosis for persons with SMI and diabetes were 15.0% (95% CI 12.4-17.6%) for those younger than 50 years, 30.7% (95% CI 27.8-33.4%) for those aged 50-69 years, and 63.8% (95% CI 58.9-68.2%) for those aged 70 years or older. Among persons suffering from both diseases, 33.4% of natural deaths were attributed to diabetes and 14% of natural deaths were attributed to the interaction between diabetes and SMI. CONCLUSIONS Long-term mortality is high for persons with SMI and diabetes. This calls for effective intervention from a coordinated and collaborating healthcare system.

Serious Mental Illness and Risk for Hospitalizations and Rehospitalizations for Ambulatory Care-sensitive Conditions in Denmark: A Nationwide Population-based Cohort Study.

Background:Hospitalizations for ambulatory care-sensitive conditions (ACSCs) and early rehospitalizations increase health care costs. Objectives:To determine if individuals with serious mental illnesses (SMIs) (eg, schizophrenia or bipolar disorder) are at increased risk for hospitalizations for ACSCs, and rehospitalization for the same or another ACSC, within 30 days. Research Design:Population-based cohort study. Participants:A total of 5.9 million Danish persons aged 18 years and older between January 1, 1999 and December 31, 2013. Measures:The Danish Psychiatric Central Register provided information on SMI diagnoses and the Danish National Patient Register on hospitalizations for ACSCs and 30-day rehospitalizations. Results:SMI was associated with increased risk for having any ACSC-related hospitalization after adjusting for demographics, socioeconomic factors, comorbidities, and prior primary care utilization [incidence rate ratio (IRR): 1.41; 95% confidence interval (95% CI), 1.37–1.45]. Among individual ACSCs, SMI was associated with increased risk for hospitalizations for angina (IRR: 1.14, 95% CI, 1.04–1.25), chronic obstructive pulmonary disease/asthma exacerbation (IRR: 1.87; 95% CI, 1.74–2.00), congestive heart failure exacerbation (IRR: 1.25; 95% CI, 1.16–1.35), and diabetes (IRR: 1.43; 95% CI, 1.31–1.57), appendiceal perforation (IRR: 1.49; 95% CI, 1.30–1.71), pneumonia (IRR: 1.72; 95% CI, 1.66–1.79), and urinary tract infection (IRR: 1.70; 95% CI, 1.62–1.78). SMI was also associated with increased risk for rehospitalization within 30 days for the same (IRR: 1.28; 95% CI, 1.18–1.40) or for another ACSC (IRR: 1.62; 95% CI, 1.49–1.76). Conclusion:Persons with SMI are at increased risk for hospitalizations for ACSCs, and after discharge, are at increased risk for rehospitalizations for ACSCs within 30 days.

Thirty-Day Mortality After Infection Among Persons With Severe Mental Illness: A Population-Based Cohort Study in Denmark

OBJECTIVE Persons with severe mental illness die 15-20 years earlier on average than persons without severe mental illness. Although infection is one of the leading overall causes of death, no studies have evaluated whether persons with severe mental illness have a higher mortality after infection than those without. METHOD The authors studied mortality rate ratios and cumulative mortality proportions after an admission for infection for persons with severe mental illness compared with persons without severe mental illness by linking data from Danish national registries. RESULTS The cohort consisted of all persons hospitalized for infection during the period 1995-2011 in Denmark (N=806,835), of whom 11,343 persons had severe mental illness. Within 30 days after an infection, 1,052 (9.3%) persons with a history of severe mental illness and 58,683 (7.4%) persons without a history of severe mental illness died. Thirty-day mortality after any infection was 52% higher in persons with severe mental illness than in persons without (mortality rate ratio=1.52, 95% CI=1.43-1.61). Mortality was increased for all infections, and the mortality rate ratios ranged from 1.27 (95% CI=1.15-1.39) for persons hospitalized for sepsis to 2.61 (95% CI=1.69-4.02) for persons hospitalized for CNS infections. Depending on age, 1.7 (95% CI=1.2-2.2) to 2.9 (95% CI=2.0-3.7) more deaths were observed within 30 days after an infection per 100 persons with a history of severe mental illness compared with 100 persons without such a history. CONCLUSIONS Persons with severe mental illness have a markedly elevated 30-day mortality after infection. Some of these excess deaths may be prevented by offering individualized and targeted interventions.

Depression and risk of hospitalisations and rehospitalisations for ambulatory care-sensitive conditions in Denmark: a population-based cohort study.

Objective Hospitalisations for ambulatory care-sensitive conditions (ACSCs), a group of chronic and acute illnesses considered not to require inpatient treatment if timely and appropriate ambulatory care is received, and early rehospitalisations are common and costly. We sought to determine whether individuals with depression are at increased risk of hospitalisations for ACSCs, and rehospitalisation for the same or another ACSC, within 30 days. Design National, population-based cohort study. Setting Denmark. Participants 5 049 353 individuals ≥18 years of age between 1 January 2005 and 31 December 2013. Measurements Depression was ascertained via psychiatrist diagnoses in the Danish Psychiatric Central Register or antidepressant prescription redemption from the Danish National Prescription Registry. Hospitalisations for ACSCs and rehospitalisations within 30 days were identified using the Danish National Patient Register. Results Overall, individuals with depression were 2.35 times more likely to be hospitalised for an ACSC (95% CI 2.32 to 2.37) versus those without depression after adjusting for age, sex and calendar period, and 1.45 times more likely after adjusting for socioeconomic factors, comorbidities and primary care utilisation (95% CI 1.43 to 1.46). After adjusting for ACSC-predisposing comorbidity, depression was associated with significantly greater risk of hospitalisations for all chronic (eg, angina, diabetes complications, congestive heart failure exacerbation) and acute ACSCs (eg, pneumonia) compared to those without depression. Compared to those without depression, persons with depression were 1.21 times more likely to be rehospitalised within 30 days for the same ACSC (95% CI 1.18 to 1.24) and 1.19 times more likely to be rehospitalised within 30 days for a different ACSC (95% CI 1.15 to 1.23). Conclusions Individuals with depression are at increased risk of hospitalisations for ACSCs, and once discharged are at elevated risk of rehospitalisations within 30 days for ACSCs.

Long-term risk of dementia among people with traumatic brain injury in Denmark: a population-based observational cohort study

BACKGROUND Traumatic brain injury (TBI) has been associated with increased risk of dementia; however, large-scale studies with long follow-up have been scarce. We investigated the association between TBI, including severity and number of TBIs, and the subsequent long-term risk of dementia. METHODS We did a nationwide population-based observational cohort study in Denmark using information on citizens from national registries. We used the Danish Civil Registration System to establish a population-based cohort consisting of all people born in Denmark who were living in the country on Jan 1, 1995, and who were at least 50 years old at some point during follow-up (between 1999 and 2013). We obtained information on TBIs from the Danish National Patient Register (NPR), and obtained information on dementia by combining data recorded in the NPR, the Danish Psychiatric Central Register, and the Danish National Prescription Registry (DNPR). The long-term risk of dementia after TBI was established using survival analysis. We used three prespecified models for each of the three analyses: different time periods since the TBI, multiple TBIs, and sex. The first model adjusted for sociodemographic factors, the second model added medical and neurological comorbidities, and the third added psychiatric comorbidities. FINDINGS We used data from a cohort of 2 794 852 people for a total of 27 632 020 person-years (mean 9·89 years per patient) at risk of dementia. 132 093 individuals (4·7%) had at least one TBI during 1977-2013, and 126 734 (4·5%) had incident dementia during 1999-2013. The fully adjusted risk of all-cause dementia in people with a history of TBI was higher (hazard ratio [HR] 1·24, 95% CI 1·21-1·27) than in those without a history of TBI, as was the specific risk of Alzheimers disease (1·16, 1·12-1·22). The risk of dementia was highest in the first 6 months after TBI (HR 4·06, 3·79-4·34) and also increased with increasing number of events (1·22, 1·19-1·25 with one TBI to 2·83, 2·14-3·75 with five or more TBIs). Furthermore, TBI was associated with a higher risk of dementia (1·29, 1·26-1·33) in people with TBI than in individuals with a non-TBI fracture not involving the skull or spine. The younger a person was when sustaining a TBI, the higher the HRs for dementia when stratified by time since TBI. INTERPRETATION TBI was associated with an increased risk of dementia both compared with people without a history of TBI and with people with non-TBI trauma. Greater efforts to prevent TBI and identify strategies to ameliorate the risk and impact of subsequent dementia are needed. FUNDING Lundbeck Foundation.

Ten-Year Mortality after a Breast Cancer Diagnosis in Women with Severe Mental Illness: A Danish Population-Based Cohort Study

Background Breast cancer is the leading cause of cancer death in women worldwide. Nevertheless, it is unknown whether higher mortality after breast cancer contributes to the life-expectancy gap of 15 years in women with severe mental illness (SMI). Methods We estimated all-cause mortality rate ratios (MRRs) of women with SMI, women with breast cancer and women with both disorders compared to women with neither disorder using data from nationwide registers in Denmark for 1980–2012. Results The cohort included 2.7 million women, hereof 31,421 women with SMI (12,852 deaths), 104,342 with breast cancer (52,732 deaths), and 1,106 with SMI and breast cancer (656 deaths). Compared to women with neither disorder, the mortality was 118% higher for women with SMI (MRR: 2.18, 95% confidence interval (CI): 2.14–2.22), 144% higher for women with breast cancer (MRR: 2.44, 95% CI: 2.42–2.47) and 327% higher for women with SMI and breast cancer (MRR: 4.27, 95% CI: 3.98–4.57). Among women with both disorders, 15% of deaths could be attributed to interaction. In a sub-cohort of women with breast cancer, the ten-year all-cause-mortality was 59% higher after taking tumor stage into account (MRR: 1.59, 95% CI: 1.47–1.72) for women with versus without SMI. Conclusions The mortality among women with SMI and breast cancer was markedly increased. More information is needed to determine which factors might explain this excess mortality, such as differences between women with and without SMI in access to diagnostics, provision of care for breast cancer or physical comorbidity, health-seeking-behavior, and adherence to treatment.

Perceived Stress, Multimorbidity, and Risk for Hospitalizations for Ambulatory Care–sensitive Conditions: A Population-based Cohort Study

Background: Psychiatric disorders are associated with an increased risk for ambulatory care–sensitive condition (ACSC)-related hospitalizations, but it remains unknown whether this holds for individuals with nonsyndromic stress that is more prevalent in the general population. Objectives: To determine whether perceived stress is associated with ACSC-related hospitalizations and rehospitalizations, and posthospitalization 30-day mortality. Research Design and Measures: Population-based cohort study with 118,410 participants from the Danish National Health Survey 2010, which included data on Cohen’s Perceived Stress Scale, followed from 2010 to 2014, combined with individual-level national register data on hospitalizations and mortality. Multimorbidity was assessed using health register information on diagnoses and drug prescriptions within 39 condition categories. Results: Being in the highest perceived stress quintile was associated with a 2.13-times higher ACSC-related hospitalization risk (95% CI, 1.91, 2.38) versus being in the lowest stress quintile after adjusting for age, sex, follow-up time, and predisposing conditions. The associated risk attenuated to 1.48 (95% CI, 1.32, 1.67) after fully adjusting for multimorbidity and socioeconomic factors. Individuals with above reference stress levels experienced 1703 excess ACSC-related hospitalizations (18% of all). A dose-response relationship was observed between perceived stress and the ACSC-related hospitalization rate regardless of multimorbidity status. Being in the highest stress quintile was associated with a 1.26-times insignificantly increased adjusted risk (95% CI, 0.79, 2.00) for ACSC rehospitalizations and a 1.43-times increased adjusted risk (95% CI, 1.13, 1.81) of mortality within 30 days of admission. Conclusions: Elevated perceived stress levels are associated with increased risk for ACSC-related hospitalization and poor short-term prognosis.