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Introduction: Herpesviruses, including Herpes simplex virus type 1 (HSV1) and varicella zoster‐virus (VZV), have been implicated in Alzheimer's disease (AD) development. Likewise, antiviral treatment has been suggested to protect against dementia development in herpes‐infected individuals.

Methods: The study enrolled 265,172 subjects aged ≥ 50 years, with diagnoses of VZV or HSV, or prescribed antiviral drugs between 31 December 2005 and 31 December 2017. Controls were matched in a 1:1 ratio by sex and birth year.

Results: Antiviral treatment was associated with decreased risk of dementia (adjusted hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.86 to 0.92), while herpes infection without antiviral drugs increased the risk of dementia (adjusted HR 1.50, 95% CI 1.29 to 1.74).

Discussion: Antiviral treatment was associated with a reduced long‐term risk of dementia among individuals with overt signs of herpes infection. This is consistent with earlier findings indicating that herpesviruses are involved in the pathogenesis of AD.

Background: With increasing age, the body and mind transform. Many of our organs gradually lose capacity, making them more sensitive to the effects of several drugs. In parallel, many of us accumulate an increasing burden of disease and other conditions warranting the use of medications. Hence, the use of most classes of drugs increases with age, especially so in elderly women.At the same time, medical science is lagging behind due to the fact that the oldest people in society often are excluded from pharmacological studies, where young males are the most coveted subjects.In the absence of strong evidence, much of the knowledge about the clinical and adverse effects of several drugs in the elderly is derived from observational studies, prone to bias and confounding. The use of psychotropic drugs in elderly people is particularly controversial, and even more so in people suffering from major neurocognitive disorders (NCD). Psychotropics have been associated with several adverse effects as well as limited clinical effect. Still, they are frequently prescribed to elderly patients.

Aims: This thesis aims to explore the associations between several types of psychotropic drugs and two of the most severe adversities attributed to their use, increased mortality and the risk of hip fracture. It aims to explore mortality in data from well-controlled studies. It also aims to employ novel statistical methods to investigate the associations between drug exposure and hip fracture, in an attempt to gain information on possible causality from observational data.

Methods: This thesis uses quantitative, comparative and epidemiological methods, prospective as well as retrospective. Two of the four papers are based on data collections conducted by the Department of Community Medicine and Rehabilitation, Umeå University, and include 992 and 1,037 individuals, respectively. The other two papers are based on Swedish nationwide registers and include 408,144 and 255,274 subjects, respectively. In all four papers multivariable regression models were used to investigate the associations between the exposures and outcomes, adjusted for possible confounding variables.

Results: In a population-based sample of very old people, and in old people with major NCD, ongoing use of psychotropic drugs was not independently associated with increased mortality. Analyses did show, however, a significant impact of sex on the mortality risk, with tendencies for antidepressant drug use to be protective in men, but not in women, and for benzodiazepines to increase the mortality risk in men, but not in women. 

In two cohorts of old people, based on several nationwide registers, investigating the associations between psychotropic drug use and hip fracture revealed that users of antidepressants, as well as users of antipsychotics, had significantly increased risks of hip fracture, independent of a wide range of covariates. However, when studying how the risk changed over time, the strongest associations were found before the initiation of treatment with the respective drug, and no dose-response relationships were found.

Discussion: The finding that psychotropic drug use was not independently associated with an elevated mortality risk was not in line with previous research, most of which have been based on data from large registers, and shown an increased risk of mortality. One reason for this difference is that the cohorts studied in this thesis were thoroughly investigated and characterised, making it possible to perform extensive adjusting for confounding variables. Hence, we expect a lesser amount of residual confounding, than in most other studies. Another explanation is that we studied ongoing drug use at baseline, rather than associations following initiation of treatment.  This might have introduced a selection bias in our studies, where the individuals most sensitive to adverse effects would have discontinued treatment or passed away. The finding of a significant impact of sex on the risk of mortality adds to the unexplored field of sex differences in drug responses in old age, and warrants further investigation.

In our register studies of psychotropic drug use and the risk of hip fracture, novel methods were applied. We have tried to overcome the hurdles of several types of confounding through the investigation of associations before and after the initiation of antidepressants, and antipsychotics, respectively. Our finding that the associations between psychotropic drug use and hip fracture were not only present, but indeed strongest, before the initiation of treatment indicates a strong presence of residual confounding and confounding by indication, and points toward the absence of a causal relationship between psychotropic drug use and hip fracture.

Conclusion: The evidence supporting causal relationships between psychotropic drug use and serious adverse events in old age is insufficient. Our results point towards bias and confounding having strong influences on the observed associations between psychotropic drug use and mortality, and hip fracture, respectively. 

Objective: To study the association between antipsychotic drug treatment and hip fracture, before and after the initiation of treatment.

Design: Nationwide cohort study.

Setting and Participants: In this study based on several Swedish registers, all individuals age ≥65 years who filled prescriptions for antipsychotic drugs in 2007–2017 were matched 1:1 by sex and age with controls, resulting in a cohort of 255,274 individuals.

Measures: Associations between antipsychotic drug treatment and hip fracture were investigated using multivariable conditional logistic regression models and flexible parametric survival models for nonproportional hazards, starting 1 year before the first prescription was filled and extending to 1 year thereafter.

Results: The studied cohort had a mean age of 81.5 (standard deviation, 8.1) years; 152,890 (59.9%) individuals were women. Antipsychotic drug use was associated with an increased risk of hip fracture in all studied time frames, before and after the initiation of treatment. The risk was highest 16–30 days before the initiation of treatment (odds ratio 9.09; 95% confidence interval 7.00–11.81). The pattern was consistent in subgroup analyses of users of conventional and atypical antipsychotics, men and women, as well as in younger old and older old participants. The association with hip fracture was not influenced by antipsychotic drug dose.

Conclusions and Implications: The association between antipsychotic drug use and the risk of hip fracture was observed before the initiation of antipsychotic treatment. This finding suggests that factors other than exposure to antipsychotic drugs are responsible for the increased risk of hip fracture in the treatment group.

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

Background: Psychotropic drugs are common among old people with dementia, and have been associated with increased mortality. Previous studies have not investigated sex differences in this risk. This study was conducted to analyse associations between the use of antipsychotics, antidepressants, and benzodiazepines and 2-year mortality in old people with dementia, and to investigate sex differences therein.

Methods: In total, 1037 participants (74% women; mean age, 89 years) with dementia were included from four cohort studies and followed for 2 years. Data were collected through home visits and medical records. Cox proportional hazard regression models were used to analyse associations between ongoing baseline drug use and mortality. Multiple possible confounders were evaluated and adjusted for.

Results: In fully adjusted models including data from the whole population, no association between baseline psychotropic drug use and increased 2-year mortality was seen. Significant sex differences were found in mortality associated with antidepressant use, which was protective in men, but not in women (hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.40–0.92 and HR 1.09, 95% CI 0.87–1.38, respectively). The interaction term for sex was significant in analyses of benzodiazepine use, with a higher mortality risk among men than among women.

Conclusions: Among old people with dementia, ongoing psychotropic drug use at baseline was not associated with increased mortality in analyses adjusted for multiple confounders. Sex differences in mortality risk associated with antidepressant and benzodiazepine use were seen, highlighting the need for further investigation of the impact of sex.

BACKGROUND: Antidepressant treatment may increase the risk of death. The association between antidepressants and mortality has been evaluated in community-dwelling older people, but not in representative samples of very old people, among whom dementia, multimorbidity, and disability are common.

METHODS: Umeå 85+/GERDA study participants (n = 992) aged 85, 90, and ≥95 years were followed for up to five years. Cox proportional hazard regression models were used to analyze mortality risk associated with baseline antidepressant treatment, adjusted for potential confounders.

RESULTS: Mean age was 89 years; 27% of participants had dementia, 20% had stroke histories, 29% had heart failure, and 16% used antidepressants. In age- and sex-adjusted analyses, antidepressant use was associated with a 76% increased mortality risk (hazard ratio [HR] = 1.76; 95% confidence interval [CI], 1.41-2.19). Adding adjustment for Geriatric Depression Scale score, HR was 1.62 (95% CI, 1.29-2.03). The association was not significant when adjusting for additional confounding factors (HR = 1.08; 95% CI, 0.85-1.38). Interaction analyses in the fully adjusted model revealed a significant interaction between sex and antidepressant use (HR: 1.76; 95% CI, 1.05-2.94). Among male and female antidepressant users, the HRs for death were 0.76 (95% CI, 0.47-1.24) and 1.28 (95% CI, 0.97-1.70), respectively.

CONCLUSION: Among very old people, baseline antidepressant treatment does not seem to be independently associated with increased mortality risk. However, the risk may be different in men and women. This difference and the potential risk of initial treatment require further investigation in future cohort studies of very old people.

BACKGROUND: There are many reports of disparities in health and medical care both between women and men and between various age groups. In most cases, men receive better treatment than women and young and middle-aged people are privileged compared with the old and the very old. Cardiovascular morbidity and diabetes mellitus are common, increase with age and are often treated extensively with drugs, many of which are known to have significant adverse effects.

OBJECTIVE: The aim of the study was to analyse gender differences in the pharmacological treatment of cardiovascular disease and diabetes among very old people.

METHODS: The study took the form of an epidemiological, cross-sectional survey. A structured interview was administered during one or more home visits, and data were further retrieved from medical charts and interviews with relatives, healthcare staff and other carers. Home-dwelling people as well as people living in institutional care in six municipalities in the county of Västerbotten, Sweden, in 2005-7 were included in the study. Half of all people aged 85 years, all of those aged 90 years and all of those aged ≥95 years living in the selected municipalities were selected for inclusion in the study. In total, 467 people were included in the present analysis. The main study outcome measures were medical diagnoses and drug use.

RESULTS: In total, women were prescribed a larger number of drugs than men (mean 7.2 vs 5.4, p < 0.001). Multiple logistic regression models adjusted for age and other background variables as well as relevant medical diagnoses (hypertension, heart failure) showed strong associations between female sex and prescriptions of thiazide diuretics (odds ratio [OR] 4.4; 95% CI 1.8, 10.8; p = 0.001), potassium-sparing diuretics (OR 3.5; 95% CI 1.4, 8.7; p = 0.006) and diuretics as a whole (OR 1.8; 95% CI 1.1, 2.9; p = 0.021). A similar model, adjusted for angina pectoris, showed that female sex was associated with prescription of short-acting nitroglycerin (OR 3.7; 95% CI 1.6, 8.9; p = 0.003). However, more men had been offered coronary artery surgery (p = 0.001). Of the participants diagnosed with diabetes, 55% of the women and 85% of the men used oral antihyperglycaemic drugs (p = 0.020), whereas no gender difference was seen in prescriptions of insulin.

CONCLUSIONS: Significant gender disparities in the prescription of several drugs, such as diuretics, nitroglycerin and oral antihyperglycaemic drugs, were observed in this study of very old people. In most cases, women were prescribed more drugs than men. Men more often had undergone coronary artery surgery. These disparities could only in part be explained by differences in diagnoses and symptoms.