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Long-term antipsychotic use, orthostatic hypotension and falls in older adults with Alzheimer’s disease

  • Research Paper
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Key summary points

AbstractSection Aim

We assessed longitudinal relationships between long-term antipsychotic use, orthostatic hypotension and falls/syncope in older adults living with mild-to-moderate dementia due to Alzheimer disease (AD).

AbstractSection Findings

Over 18 months, long-term antipsychotic use in older adults with dementia due to AD was associated with a greater likelihood of experiencing sit-to-stand orthostatic hypotension (ssOH), measured on eight separate study visits. Both ssOH and antipsychotic use were independently associated with incident falls/syncope over 18 months.

AbstractSection Message

Our findings provide supportive evidence that long-term antipsychotic use is associated with both ssOH and falls/syncope in older adults with mild–moderate dementia due to AD—highlighting the need for medication review and screening for symptoms of OH/falls/syncope in older adults with AD prescribed these medications.

Abstract

Purpose

Antipsychotic use in Alzheimer disease (AD) is associated with adverse events and mortality. Whilst postulated to cause/exacerbate orthostatic hypotension (OH), the exact relationship between antipsychotic use and OH has never been explored in AD—a group who are particularly vulnerable to neuro-cardiovascular instability and adverse effects of medication on orthostatic blood pressure (BP) behaviour.

Methods

We analysed longitudinal data from an 18-month trial of Nilvadipine in mild–moderate AD. We assessed the effect of long-term antipsychotic use (for the entire 18-month study duration) on orthostatic BP phenotypes measured on eight occasions, in addition to the relationship between antipsychotic use, BP phenotypes and incident falls.

Results

Of 509 older adults with AD (aged 72.9 ± 8.3 years, 61.9% female), 10.6% (n = 54) were prescribed a long-term antipsychotic. Over 18 months, long-term antipsychotic use was associated with a greater likelihood of experiencing sit-to-stand OH (ssOH) (OR: 1.21; 1.05–1.38, p = 0.009) which persisted on covariate adjustment. Following adjustment for important clinical confounders, both antipsychotic use (IRR: 1.80, 1.11–2.92, p = 0.018) and ssOH (IRR: 1.44, 1.00–2.06, p = 0.048) were associated with a greater risk of falls/syncope over 18 months in older adults with mild–moderate AD.

Conclusion

Even in mild-to-moderate AD, long-term antipsychotic use was associated with ssOH. Both antipsychotic use and ssOH were associated with a greater risk of incident falls/syncope over 18 months. Further attention to optimal prescribing interventions in this cohort is warranted and may involve screening older adults with AD prescribed antipsychotics for both orthostatic symptoms and falls.

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Acknowledgements

NILVAD Study Group: Brian Lawlor, Mercer’s Institute for Research on Ageing, St. James’s Hospital and Department of Medical Gerontology, Trinity College, Dublin, Ireland; Ricardo Segurado, CSTAR and School of Public Health, Physiotherapy and Sport Science, University College Dublin (UCD), Dublin, Ireland; Sean Kennelly, Department of Age Related Healthcare, Tallaght Hospital, Dublin 24 and Department of Medical Gerontology, Trinity College Dublin; Marcel G. M. Olde Rikkert, Department of Geriatric Medicine, Radboudumc Alzheimer Center, Donders Institute of Medical Neurosciences, Radboudumc, Nijmegen, the Netherlands; Robert Howard, Division of Psychiatry, University College London and King’s College London; Florence Pasquier, CHU Lille, Univ. Lille, DISTALZ Laboratory of Excellence, F-59000 Lille, France; Anne Bo¨rjesson-Hanson, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg; Magda Tsolaki, Papanikolaou General Hospital of Thessaloniki, Greece; Ugo Lucca, Laboratory of Geriatric Neuropsychiatry, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy; D. William Molloy, University College Cork Centre for Gerontology and Rehabilitation, Cork, Ireland; Robert Coen, Mercer’s Institute for Research on Ageing, St. James’s Hospital, Dublin, Ireland; Matthias W. Riepe, Department of Geriatrics and Old Age Psychiatry, Psychiatry II, Ulm University at BKH Gu¨nzburg, Germany; Ja´nos Ka´lma´n, Department of Psychiatry, University of Szeged, Hungary; Rose Anne Kenny, Department of Medical Gerontology, Trinity College Dublin (TCD), Dublin, Ireland; Fiona Cregg, Department of Medical Gerontology, Trinity College Dublin (TCD), Dublin, Ireland; Sarah O’Dwyer, Mercer’s Institute for Research on Ageing, St. James’s Hospital, Dublin, Ireland; Cathal Walsh, Health Research Institute and MACSI, Department of Mathematics and Statistics, University of Limerick, Ireland; Jessica Adams, Department of Old Age Psychiatry, King’s College London; Rita Banzi, Laboratory of Geriatric Neuropsychiatry, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy; Laetitia Breuilh, CHU Lille, Univ. Lille, DISTALZ Laboratory of Excellence, F-59000 Lille, France; Leslie Daly, CSTAR and School of Public Health, Physiotherapy and Sport Science, University College Dublin (UCD), Dublin, Ireland; Suzanne Hendrix, Pentara Corporation, 2180 Claybourne Avenue, Salt Lake City, Utah; Paul Aisen, Department of Neurology, University of Southern California; Siobhan Gaynor, Molecular Medicine Ireland [1], Dublin, Ireland; Ali Sheikhi, Health Research Institute and MACSI, Department of Mathematics and Statistics, University of Limerick, Ireland; Diana G. Taekema, Department of Geriatric Medicine, Rijnstate Hospital, Arnhem, the Netherlands; Frans R. Verhey, Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, Maastricht, the Netherlands; Raffaello Nemni, IRCCS Don Gnocchi Foundation-University of Milan, Italy; Flavio Nobili, Dept. of Neuroscience (DINOGMI), University of Genoa, and IRCCS AOU Polyclinic, Hospital San Martino, Genoa, Italy; Massimo Franceschi, Neurology Department, Multimedica, Castellanza, Italy; Giovanni Frisoni, Centro San Giovanni di Dio—IRCCS Fatebenefratelli, Brescia, Italy; Orazio Zanetti, Centro San Giovanni di Dio—IRCCS Fatebenefratelli, Brescia, Italy; Anastasia Konsta, Aristotle University of Thessaloniki [1], First Psychiatric Department, Papageorgiou General Hospital, Greece; Orologas Anastasios, Ahepa University General Hospital of Thessaloniki, Greece; Styliani Nenopoulou, Papanikolaou General Hospital of Thessaloniki, Greece; Fani Tsolaki-Tagaraki, Papanikolaou General Hospital of Thessaloniki, Greece; Magdolna Pakaski, Department of Psychiatry, University of Szeged, Hungary; Olivier Dereeper, Centre Hospitalier de Calais, France; Vincent de la Sayette, Centre Hospitalier Universitaire de Caen, France; Olivier Se´ne´chal, Centre Hospitalier de Lens, France; Isabelle Lavenu, Centre Hospitalier de Be´thune, France; Agnès Devendeville, Centre Hospitalier Universitaire d’Amiens, France; Gauthier Calais, Groupement des Hoˆpitaux de l’Institut Catholique de Lille (GHICL), France; Fiona Crawford, Archer Pharmaceuticals, Sarasota, Florida, and Roskamp Institute, Sarasota, Florida; Michael Mullan, Archer Pharmaceuticals, Sarasota, Florida, and Roskamp Institute, Sarasota, Florida, Pauline Aalten, PhD, Department of Psychiatry and Neuropsychology, School of Mental Health and Neurosciences, Alzheimer Center Limburg, Maastricht University, Maastricht, the Netherlands; Maria A. Berglund, RN, Sahlgrenska University Hospital, Gothenburg, Sweden; Jurgen A. Claassen MD, PhD, Department of Geriatric Medicine, Radboudumc Alzheimer Center, Donders Institute of Medical Neurosciences, Radboudumc, Nijmegen, the Netherlands; Rianne A. De Heus, MSc, Department of Geriatric Medicine, Radboudumc Alzheimer Center, Donders Institute of Medical Neurosciences, Radboudumc, Nijmegen, the Netherlands; Daan L. K. De Jong, MSc, Department of Geriatric Medicine, Radboudumc Alzheimer Center, Donders Institute of Medical Neurosciences, Radboudumc, Nijmegen, the Netherlands; Olivier Godefroy, MD, PhD, Centre Hospitalier Universitaire d’Amiens, France; Siobhan Hutchinson, MD, St. James’s Hospital, Dublin, Ireland; Aikaterini Ioannou, MD, 1st Department of Neurology, Ahepa University General Hospital, Aristotle University of Thessaloniki, Greece; Michael Jonsson, MD, PhD, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden; Annette Kent, PhD, Trinity College Dublin (TCD), Dublin, Ireland; Ju¨rgen Kern MD, PhD, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden; Petros Nemtsas MD, PhD, 1st Department of Neurology, Ahepa University General Hospital, Aristotle University of Thessaloniki, Greece; Minoa-Kalliopi Panidou, BSc, MA, 1st Department of Neurology, Ahepa University General Hospital, Aristotle University of Thessaloniki, Greece; Laila Abdullah, PhD, Roskamp Institute, Sarasota, Florida; Daniel Paris, PhD, Roskamp Institute, Sarasota, Florida; Angelina M. Santoso, MD, MSc, Department of Geriatric Medicine, Radboudumc Alzheimer Center, Donders Institute of Medical Neurosciences, Radboudumc, Nijmegen, the Netherlands; Gerrita J. van Spijker, MSc, Department of Geriatric Medicine, Radboudumc Alzheimer Center, Donders Institute of Medical Neurosciences, Radboudumc, Nijmegen, the Netherlands; Martha Spiliotou MD, PhD, 1st Department of Neurology, Ahepa University General Hospital, Aristotle University of Thessaloniki, Greece; Georgia Thomoglou, BSc, 1st Department of Neurology, Ahepa University General Hospital, Aristotle University of Thessaloniki, Greece; and Anders Wallin, MD, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden.

Funding

Funding from the NILVAD study was from the European Commission Framework 7 Programme Health Theme Collaborative Project (grant 279093; PI: Brian Lawlor). The funding agency had no role in the design, recruitment, conduct and data collection of the clinical trial and no input in the analysis, interpretation of data and presentation of primary/secondary trial results. AHD has been awarded the Irish Clinical Academic Training (ICAT) Programme, supported by the Wellcome Trust and the Health Research Board (Grant Number 203930/B/16/Z), the Health Service Executive, National Doctors Training and Planning and the Health and Social Care, Research and Development Division, Northern Ireland. AHD, LM, HD and SPK are additionally supported by the Meath Foundation, Tallaght University Hospital.

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Authors and Affiliations

  1. Tallaght Institute for Memory and Cognition, Tallaght University Hospital, Dublin, Ireland

    Adam H. Dyer, Claire Murphy, Helena Dolphin, Laura Morrison & Sean P. Kennelly

  2. Department of Medical Gerontology, School of Medicine, Trinity College Dublin, Dublin, Ireland

    Adam H. Dyer, Claire Murphy, Helena Dolphin, Laura Morrison & Sean P. Kennelly

  3. St Vincent’s University Hospital, Dublin, Ireland

    Claire Murphy, Ricardo Segurado, Sean Kennelly, Marcel G. M Rikkert Olde, Robert Howard, Anne Bo¨rjesson-Hanson, Magda Tsolaki, Ugo Lucca, D William Molloy, Robert Coen, Matthias W Riepe, Ja´nos Ka´lma´n, Fiona Cregg, Sarah O’Dwyer, Cathal Walsh, Jessica Adams, Rita Banzi, Laetitia Breuilh, Leslie Daly, Paul Aisen, Siobhan Gaynor, Ali Sheikhi, Diana G Taekema, Frans R Verhey, Raffaello Nemni, Massimo Franceschi, Giovanni Frisoni, Orazio Zanetti, Anastasia Konsta, Orologas Anastasios, Styliani Nenopoulou, Fani Tsolaki-Tagaraki, Magdolna Pakaski, Olivier Dereeper, Olivier Se´ne´chal, Agnès Devendeville, Gauthier Calais, Fiona Crawford, Michael Mullan, Pauline Aalten, Maria A RN Berglund, Jurgen A Claassen, Rianne A Heus, Daan L. K Jong, Olivier Godefroy, Aikaterini Ioannou, Michael Jonsson, Annette Kent, Ju¨rgen Kern, Petros Nemtsas, Minoa-Kalliopi Panidou, Laila Abdullah, Daniel Paris, Angelina M Santoso, Gerrita J Spijker, Martha Spiliotou, Georgia Thomoglou & Anders Wallin

  4. St Mercer’s Institute for Research on Ageing, St James’s Hospital, Dublin, Ireland

    Robert Briggs

  5. Global Brain Health Institute, Trinity College Dublin, Dublin, Ireland

    Brian Lawlor & Sean P. Kennelly

Authors
  1. Adam H. Dyer
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  2. Claire Murphy
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  7. Sean P. Kennelly
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Consortia

NILVAD Study Group

  • Brian Lawlor
  • , Ricardo Segurado
  • , Sean Kennelly
  • , Marcel G. M Rikkert Olde
  • , Robert Howard
  • , Anne Bo¨rjesson-Hanson
  • , Magda Tsolaki
  • , Ugo Lucca
  • , D William Molloy
  • , Robert Coen
  • , Matthias W Riepe
  • , Ja´nos Ka´lma´n
  • , Adam H. Dyer
  • , Fiona Cregg
  • , Sarah O’Dwyer
  • , Cathal Walsh
  • , Jessica Adams
  • , Rita Banzi
  • , Laetitia Breuilh
  • , Leslie Daly
  • , Paul Aisen
  • , Siobhan Gaynor
  • , Ali Sheikhi
  • , Diana G Taekema
  • , Frans R Verhey
  • , Raffaello Nemni
  • , Massimo Franceschi
  • , Giovanni Frisoni
  • , Orazio Zanetti
  • , Anastasia Konsta
  • , Orologas Anastasios
  • , Styliani Nenopoulou
  • , Fani Tsolaki-Tagaraki
  • , Magdolna Pakaski
  • , Olivier Dereeper
  • , Olivier Se´ne´chal
  • , Agnès Devendeville
  • , Gauthier Calais
  • , Fiona Crawford
  • , Michael Mullan
  • , Pauline Aalten
  • , Maria A RN Berglund
  • , Jurgen A Claassen
  • , Rianne A Heus
  • , Daan L. K Jong
  • , Olivier Godefroy
  • , Aikaterini Ioannou
  • , Michael Jonsson
  • , Annette Kent
  • , Ju¨rgen Kern
  • , Petros Nemtsas
  • , Minoa-Kalliopi Panidou
  • , Laila Abdullah
  • , Daniel Paris
  • , Angelina M Santoso
  • , Gerrita J Spijker
  • , Martha Spiliotou
  • , Georgia Thomoglou
  •  & Anders Wallin

Corresponding author

Correspondence to Adam H. Dyer.

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The authors declare that they have no competing interests.

Ethical approval

Ethical approval was granted from appropriate National Competent Authorities, Independent Ethics Committees and Institutional Review Boards for all study 25 sites.

Informed consent

All participants gave full consent to participate in the NILVAD Study, which was conducted in accordance with the Declaration of Helsinki.

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A List of Authors and Their Affiliations Appears at the Acknowledgements.

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Dyer, A.H., Murphy, C., Dolphin, H. et al. Long-term antipsychotic use, orthostatic hypotension and falls in older adults with Alzheimer’s disease. Eur Geriatr Med 15, 527–537 (2024). https://doi.org/10.1007/s41999-023-00910-x

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