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Psychotropic drug use and mortality in old people with dementia: investigating sex differences
Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.ORCID iD: 0000-0002-8276-1844
Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.ORCID iD: 0000-0003-2924-508X
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2017 (English)In: BMC Pharmacology & Toxicology, E-ISSN 2050-6511, Vol. 18, article id 36Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2017. Vol. 18, article id 36
Keywords [en]
Alzheimer’s disease, antidepressants, antipsychotics, benzodiazepines, cohort study, dementia, gender, mortality, old age, psychotropic drugs, vascular dementia
National Category
Geriatrics
Research subject
Geriatrics
Identifiers
URN: urn:nbn:se:umu:diva-119011DOI: 10.1186/s40360-017-0142-9ISI: 000402184000001PubMedID: 28545507Scopus ID: 2-s2.0-85019695950OAI: oai:DiVA.org:umu-119011DiVA, id: diva2:917708
Note

Originally published in manuscript form with title "Psychotropic drug use and mortality in old people with dementia: a gender-sensitive analysis"

Available from: 2016-04-07 Created: 2016-04-07 Last updated: 2023-03-24Bibliographically approved
In thesis
1. Depression in older people with and without dementia: non-pharmacological interventions and associations between psychotropic drugs and mortality
Open this publication in new window or tab >>Depression in older people with and without dementia: non-pharmacological interventions and associations between psychotropic drugs and mortality
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Depression hos äldre människor med och utan demenssjukdom : icke-farmakologiska interventioner och associationer mellan psykofarmaka och död
Abstract [en]

The aim of this thesis was to investigate associations between psychotropic drug use and death, associations between functional capacity, dependency in ADL and depression, and to evaluate a non-pharmacological intervention to reduce depressive symptoms, among older people with and without dementia.

There is limited knowledge about the risk of death associated with psychotropic drug use among those aged ≥85 years, those with dementia, or those living in residential care facilities; groups that have a higher intake of psychotropic drugs and who are also more prone to adverse drug reactions. In a representative sample of people ≥85 years (n = 992), baseline antidepressant use was not associated with an increased 5-year mortality risk when adjusting for confounding factors. A significant interaction between gender and antidepressant use was found, with a higher mortality risk in women, than in men.  When analyzing men and women separately, no significant associations were found. In a sample of older people (i.e. ≥65 years) with dementia (n = 1037), there was a significant gender difference in 2-year mortality associated with the baseline use of antidepressant drugs, with a lower mortality risk in men, than in women. In men, the mortality risk was significantly reduced with antidepressant use, while there was no significant association in women. The association between baseline use of benzodiazepines and mortality had a tendency toward an increased risk during the first year of follow-up, although this became non-significant after adjustments. In this time period, the interaction term for sex was significant, with a higher mortality risk among men than women. When the sexes were analyzed separately, no significant associations were found. No significant associations were found between baseline use of antipsychotic drugs and mortality.

Drug treatment for depression seems to have a limited effect in older people and may have no effect in people with dementia. In order to find alternative ways of treating or preventing depression in older age, it is important to increase our knowledge about factors associated with this condition. Functional capacity and dependency in activities of daily living (ADL) are associated with depression in community-dwelling older people. However, it is uncertain whether the same associations are to be found in very old people (i.e. ≥80 years), including those with severe cognitive or physical impairments. In a heterogeneous sample (n = 392) with a high mean age, a large range of cognitive and functional capacity, a wide spectrum of dependency in ADL, and a high prevalence of comorbidities, depressive symptoms were significantly associated with functional balance capacity, but not with overall dependency in ADL. Among individual ADL tasks, dependency in transfer and dressing were associated with depressive symptoms.

Physical exercise has shown effect sizes similar to those of antidepressants in reducing depressive symptoms among older people without dementia, with moderate–high-intensity exercise being more effective than low-intensity exercise. However, these effects are unclear among older people with dementia. Care-facility residents with dementia (n = 186) were cluster-randomized to a high-intensity functional exercise program or a non-exercise control activity conducted for 45 minutes every other weekday for 4 months. No significant difference between the exercise and control activity was found in depressive symptoms at 4 or 7 months. Among participants with high levels of depressive symptoms, reductions were observed in both the exercise and control groups at 4 and 7 months.

In conclusion, ongoing treatment at baseline with any of the three psychotropic drug classes antidepressants, antipsychotics and benzodiazepines did not increase the risk of mortality in older people with dementia.  Neither did antidepressant drugs in very old people. In both samples, gender differences were found in the mortality risk due to antidepressant use. In those with dementia, the mortality risk due to benzodiazepine use also differed by gender. The potential risk from initial treatment and gender differences regarding mortality risk require further investigation in randomized controlled trials or in large cohort studies properly controlled for confounding factors. In older people, living in community and residential care facilities, functional capacity seems to be independently associated with depressive symptoms whereas overall ADL performance may not be associated. Dependency in the individual ADL tasks of transfer and dressing appear to be independently associated with depressive symptoms and may be an important focus for future interdisciplinary multifactorial intervention studies. Among older people with dementia living in residential care facilities, a 4-month high-intensity functional exercise program has no superior effect on depressive symptoms than a control activity. Both exercise and non-exercise group activities may reduce high levels of depressive symptoms. However, this finding must be confirmed in three-armed randomized controlled trials including control groups receiving standard care.

Abstract [sv]

Syftet med avhandlingen var att utreda sambandet mellan risken för död och användningen av psykofarmaka (läkemedel som används vid olika psykiatriska tillstånd) och att utforska samband mellan funktionell kapacitet, hjälpberoende i aktiviteter i det dagliga livet (ADL) och depression hos äldre personer med och utan demenssjukdom. Syftet var även att utvärdera effekten av högintensiv funktionell träning på depressiva symtom hos äldre människor med demenssjukdom som bor på särskilt boende.

Kunskapen är begränsad om risken för död vid psykofarmakaanvändning hos de som är 85 år eller äldre, har demenssjukdom eller bor på särskilt boende. Människor i dessa grupper får oftare utskrivet psykofarmaka och är mer benägna att drabbas av biverkningar än yngre och friskare människor. I ett representativt urval av personer som var 85 år eller äldre (n = 992) hade inte antidepressiv medicinering vid baslinjen (d.v.s. studiestarten) något signifikant samband med risken att dö under en uppföljning på 5 år, kontrollerat för störfaktorer. Sambandet mellan risken för död och användningen av antidepressiva läkemedel skiljde sig mellan kvinnor och män, med en relativt högre risk för död hos kvinnor jämfört med män. I separata analyser av män och kvinnor hittades dock inga signifikanta samband. I ett annat urval, där äldre personer med demenssjukdom (n = 1037) följdes i upp till 2 år, hittades också en skillnad mellan män och kvinnor i risken att dö relaterad till antidepressiv användning vid studiestarten. Risken för död var relativt lägre hos män jämfört med kvinnor. När män analyserades separat hittades ett signifikant samband mellan en lägre risk för död och användning av antidepressiva läkemedel, samtidigt som inget samband kunde ses hos kvinnor. Det fanns en tendens mot en ökad risk för död relaterad till användning av bensodiazepiner under det första årets uppföljning. Detta samband försvann dock, när analyserna justerades för störfaktorer. Under det första årets uppföljning fanns det också en könsskillnad i risken för död vid användning av bensodiazepiner. Denna risk var relativt högre hos män jämfört med kvinnor. När män och kvinnor analyserades separat fanns dock inga samband. Inga signifikanta samband hittades heller mellan användning av antipsykotiska läkemedel vid studiestarten och risken för död.

Läkemedelsbehandling vid depression verkar ha en begränsad effekt hos äldre människor och kan möjligtvis sakna effekt hos personer med demens. För att hitta alternativa sätt att behandla eller förebygga depression hos äldre är det därför viktigt att öka kunskapen om faktorer som har samband med depression. Nedsatt funktionell kapacitet och hjälpberoende i ADL är associerat med depression hos relativt friska äldre människor som bor i ordinärt boende. Det är dock osäkert om dessa samband också finns hos personer som är 80 år eller äldre, inklusive de med gravt nedsatt kognitiv eller fysisk funktion och inklusive de som bor på särskilt boende. I ett heterogent urval (n = 392) med hög medelålder, stor variation av kognitiv och fysisk funktion, mycket varierat hjälpbehov i ADL och hög förekomst av sjukdomar, var depressiva symptom signifikant associerade med nedsatt funktionell balanskapacitet, men inte med övergripande beroende i ADL. Bland enskilda ADL-uppgifter var depressiva symtom relaterade till hjälpberoende i överflyttning och påklädning.

Fysisk träning har haft effekter liknande antidepressiva läkemedel i att minska depressiva symtom hos äldre personer utan demenssjukdom, med bättre effekt av måttlig-högintensiv träning än lågintensiv träning. Hos äldre personer med demenssjukdom är det osäkert om fysisk träning kan minska depressiva symtom. Äldre personer med demenssjukdom (n = 186) som bodde på särskilt boende lottades till att delta i ett högintensivt funktionellt träningsprogram eller till en stillasittande kontrollaktivitet, under 45 minuter varannan vardag i 4 månader. Ingen signifikant skillnad hittades mellan träningen och kontrollaktiviteten i förändring av depressiva symtom vid 4 eller 7 månaders uppföljning. Bland deltagarna med höga nivåer av depressiva symtom sågs signifikanta minskningar i både tränings- och kontrollgruppen vid 4 och 7 månader.

Sammanfattningsvis hittades ingen ökad risk för död hos äldre personer med demens som vid studiestarten behandlades med bensodiazepiner, antidepressiva läkemedel eller antipsykotiska läkemedel. Inte heller hos mycket gamla människor hittades något samband mellan en ökad risk för död och behandling med antidepressiva läkemedel. I båda urvalen hittades könsskillnader i risken för död vid användning av antidepressiva läkemedel. Hos de med demenssjukdom hittades också en könsskillnad i risken för död i samband med användning av bensodiazepiner. Den potentiella risken med initial behandling, samt könsskillnader i risken för död, bör utforskas vidare i randomiserade kontrollerade studier eller i stora kohortstudier med noggranna justeringar för störfaktorer. Hos äldre människor som bor i ordinärt boende eller särskilt boende verkar funktionell kapacitet vara oberoende associerat med depressiva symtom, samtidigt som övergripande ADL-beroende inte verkar vara det. Beroende i de enskilda ADL-uppgifterna överflyttning och påklädning verkar ha oberoende samband med depressiva symtom och kan vara ett viktigt fokus i framtida studier. Bland äldre personer med demenssjukdom som bor på särskilt boende har 4 månaders högintensiv funktionell träning inte bättre effekt på depressiva symtom än en stillasittande aktivitet. Både gruppträning och andra gruppaktiviteter skulle kunna minska höga nivåer av depressiva symtom, men det behöver bekräftas i interventionsstudier som även inkluderar en kontrollgrupp som får sedvanlig vård.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2016. p. 89
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1797
Keywords
Depression, Dementia, Exercise, Randomized controlled trial, Psychotropic drugs, Mortality, Gender, Residential facilities, Frail elderly, Epidemiology, Cohort study
National Category
Geriatrics Physiotherapy
Research subject
Geriatrics; Physiotherapy
Identifiers
urn:nbn:se:umu:diva-119016 (URN)978-91-7601-452-3 (ISBN)
Public defence
2016-05-04, Aulan, Vårdvetarhuset, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2016-04-13 Created: 2016-04-07 Last updated: 2018-06-07Bibliographically approved
2. Adverse effects of psychotropic drugs in old age
Open this publication in new window or tab >>Adverse effects of psychotropic drugs in old age
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

AimsThis 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. 

Place, publisher, year, edition, pages
Umeå: Umeå University, Department of Community Medicine and Rehabilitation, Geriatric Medicine, 2020. p. 127
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2098
Keywords
Geriatric medicine, psychotropic drugs, adverse effects, mortality, hip fracture, cohort study, old age
National Category
Geriatrics
Research subject
Geriatrics
Identifiers
urn:nbn:se:umu:diva-175902 (URN)978-91-7855-357-0 (ISBN)978-91-7855-358-7 (ISBN)
Public defence
2020-11-06, Forumsalen, Campus, Skellefteå, Bockholmsvägen 23, Skellefteå, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2020-10-16 Created: 2020-10-13 Last updated: 2022-01-03Bibliographically approved

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Brännström, JonBoström, GustafRosendahl, ErikNordström, PeterLittbrand, HåkanLövheim, HugoGustafson, Yngve

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