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

Abstract

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.

A Data-Driven Examination of Apathy and Depressive Symptoms in Dementia With Independent Replication

“…Mechanistically, a recent genome wide association study observed a positive association between genetic risk for depressive symptoms and Alzheimer's disease with psychosis, while in younger-aged samples genetic correlations between irritability and depressive symptoms have been observed [31,32]. These observations, alongside the current findings, reflect current opinion that comorbid behavioural symptoms may impact response to treatments [33].…”

A data‐driven examination of apathy and depressive symptoms in dementia with independent replication

“…Mechanistically, a recent genome‐wide association study observed a positive association between genetic risk for depressive symptoms and Alzheimer's disease with psychosis, while in younger‐aged samples genetic correlations between irritability and depressive symptoms have been observed 32,33 . These observations, alongside the current findings, reflect current opinion that comorbid behavioral symptoms may impact response to treatments 34 …”

“…32,33 These observations, alongside the current findings, reflect current opinion that comorbid behavioral symptoms may impact response to treatments. 34 Another interesting observation is that there was a higher probability for agitation in the apathy class relative to the no symptoms class in the L-study. Although only present in one cohort, in which mean age was higher and median dementia severity was slightly greater, this was the only instance in which the apathy class was associated with a higher probability of another NPS.…”

“… 32 , 33 These observations, alongside the current findings, reflect current opinion that comorbid behavioral symptoms may impact response to treatments. 34 …”

Determining Whether Sex and Zygosity Modulates the Association between APOE4 and Psychosis in a Neuropathologically-Confirmed Alzheimer’s Disease Cohort

“…It is important to note that the sample size of the at-risk group was small (n = 18), and this may not be a true representation of this group’s behavior profile. Identifying neuropsychiatric symptoms associated with the presence of psychosis in the at-risk group may help identify potential neuropsychiatric phenotypes that may have implications for treatment [ 20 ].…”