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Adverse Effects of Psychotropic Drugs in Old Age

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Adverse Effects of Psychotropic Drugs in Old Age Adverse Effects of Psychotropic Drugs in Old Age Jon Albin Brännström Adverse Effects of Psychotropic Drugs in Old Age Jon Albin Brännström Department of Community Medicine and Rehabilitation, Geriatric Medicine Umeå & Skellefteå 2020 Responsible publisher under Swedish law: the Dean of the Medical Faculty This work is protected by the Swedish Copyright Legislation (Act 1960:729) Dissertation for PhD ISBN: 978-91-7855-357-0 (print) ISBN: 978-91-7855-358-7 (pdf) ISSN: 0346-6612 New Series No: 2098 Electronic version available at: http://umu.diva-portal.org/ Printed by: Cityprint i Norr AB Umeå, Sweden 2020 Drugs are bad, m’kay -Mr. Mackey Table of Contents Table of Contents ..................................................................... i Abstract ................................................................................. iii Abbreviations ......................................................................... v Original papers ..................................................................... vii Populärvetenskaplig sammanfattning ................................. viii Introduction and Background ................................................ 1 Psychiatric disorders and symptoms in old age ..................................... 2 Major neurocognitive disorder .......................................................... 2 Neuropsychiatric symptoms of major neurocognitive disorder ...... 3 Depression ........................................................................................... 4 Anxiety and Sleep-wake disorders ..................................................... 4 Schizophrenia ...................................................................................... 5 Psychotropic Drugs ................................................................................. 6 Antipsychotics ..................................................................................... 8 Antidepressants ................................................................................. 14 Anxiolytics and hypnotics ................................................................. 21 Adverse Effects of Psychotropic Drugs ................................................. 24 Antipsychotics ................................................................................... 27 Antidepressants ................................................................................. 35 Anxiolytics and hypnotics ................................................................. 40 Aims ..................................................................................... 43 Materials and Methods ......................................................... 44 Data sources .......................................................................................... 45 Umeå 85+/GERDA ............................................................................ 45 FOPANU ............................................................................................ 46 REMANU ........................................................................................... 46 UMDEX .............................................................................................. 46 Registers ............................................................................................ 47 Participants ........................................................................................... 48 Paper I ............................................................................................... 48 Paper II .............................................................................................. 48 Paper III ............................................................................................ 51 Paper IV ............................................................................................. 51 i Materials and Methods (continued) Measurements, exposures and outcomes (Papers I and II) ................ 52 Measurements, exposures and outcomes (Papers III and IV) ............ 55 Statistics ................................................................................................ 57 General .............................................................................................. 57 Mortality ............................................................................................ 57 Hip fracture ....................................................................................... 57 Statistics specific for each paper ...................................................... 58 Ethics ................................................................................... 63 Results .................................................................................. 64 Antidepressants and mortality in the very old (Paper I) ..................... 64 Psychotropic drugs and mortality in major NCD (Paper II) ............... 68 Antidepressants and hip fracture (Paper III) ..................................... 73 Antipsychotics and hip fracture (Paper IV) ......................................... 79 Discussion ............................................................................ 87 Main findings ........................................................................................ 87 Psychotropic drug use and mortality (Papers I and II) ...................... 88 Methodology - strengths and limitations ........................................ 88 Antidepressants and mortality ......................................................... 89 Antipsychotics and mortality ........................................................... 91 Anxiolytics and hypnotics and mortality ......................................... 92 Psychotropic drug use and hip fracture (Papers III and IV) ............... 93 Methodology - strengths and limitations ......................................... 93 Antidepressants and hip fracture ..................................................... 95 Antipsychotics and hip fracture ....................................................... 97 Prevalence of psychotropic drug use .................................................. 100 Implications ........................................................................................ 103 Conclusions ......................................................................... 107 Acknowledgements ............................................................. 108 References .......................................................................... 109 Papers I-IV List of dissertations ii Abstract 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 iii 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
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