Psychosis as a Treatment Target in Dementia: A Roadmap for Designing Interventions


Luis Agüera-Ortiz, Department of Psychiatry, Instituto de Investigacion Sanitaria (imas12), Hospital Universitario 12 de Octubre, Madrid, Spain.
Ganesh M. Babulal, Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
Marie-Andrée Bruneau, Department of Psychiatry and Addictology, Faculty of Medicine, University of Montreal, Quebec, Canada.
Byron Creese, Medical School, College of Medicine and Health, University of Exeter, UK.
Fabrizia D'Antonio, Department of Human Neuroscience, Sapienza University of Rome, Italy.
Corinne E. Fischer, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.
Jennifer R. Gatchel, Harvard Medical School; Massachusetts General Hospital, Boston MA, USA.
Zahinoor Ismail, Medical School, College of Medicine and Health, University of Exeter, UK.
Sanjeev Kumar, Adult Neurodevelopmental and Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
William J. McGeown, School of Psychological Sciences and Health, University of Strathclyde, Glasgow, UK.
Moyra E. Mortby, School of Psychology, University of New South Wales, Sydney, Australia.
Nicolas A. Nuñez, Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
Fabricio F. de Oliveira, Department of Neurology and Neurosurgery, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo, Brazil.
Arturo X. Pereiro, Facultade de Psicoloxía, Universidade de Santiago de Compostela, Spain.
Ramit Ravona-Springer, Sheba Medical Center, Tel Hashomer, Israel & Sackler School of Medicine, Tel Aviv University, Israel.
Hillary J. Rouse, School of Aging Studies, University of South Florida, Tampa, FL, USA.
Huali Wang, Dementia Care and Research Center, Peking University Institute of Mental Health; National Clinical Research Center for Mental Disorders, Beijing, China.
Krista L. Lanctôt, Hurvitz Brain Sciences Program, Sunnybrook Research Institute and Departments of Psychiatry and Pharmacology, University of Toronto, Toronto, Ontario, Canada.

Document Type

Journal Article

Publication Date



Journal of Alzheimer's disease : JAD




Clinical trials; delusions; dementia; hallucinations; investigational therapies; psychotic disorders


Psychotic phenomena are among the most severe and disruptive symptoms of dementias and appear in 30% to 50% of patients. They are associated with a worse evolution and great suffering to patients and caregivers. Their current treatments obtain limited results and are not free of adverse effects, which are sometimes serious. It is therefore crucial to develop new treatments that can improve this situation. We review available data that could enlighten the future design of clinical trials with psychosis in dementia as main target. Along with an explanation of its prevalence in the common diseases that cause dementia, we present proposals aimed at improving the definition of symptoms and what should be included and excluded in clinical trials. A review of the available information regarding the neurobiological basis of symptoms, in terms of pathology, neuroimaging, and genomics, is provided as a guide towards new therapeutic targets. The correct evaluation of symptoms is transcendental in any therapeutic trial and these aspects are extensively addressed. Finally, a critical overview of existing pharmacological and non-pharmacological treatments is made, revealing the unmet needs, in terms of efficacy and safety. Our work emphasizes the need for better definition and measurement of psychotic symptoms in dementias in order to highlight their differences with symptoms that appear in non-dementing diseases such as schizophrenia. Advances in neurobiology should illuminate the development of new, more effective and safer molecules for which this review can serve as a roadmap in the design of future clinical trials.


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