EDITORIAL published: 15 June 2021 doi: 10.3389/fphar.2021.704421 Editorial: Pharmacology of BPSD (Behavioral and Psychological Symptoms of Dementia) Lydia Giménez-Llort 1,2 and Björn Johansson 3,4,5* 1 Department of Psychiatry and Forensic Medicine, School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain, 2 Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain, 3Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden, 4Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden, 5Theme Inflammation and Aging, Karolinska University Hospital, Stockholm, Sweden Keywords: behavioral symptoms, dementia, drug discovery, interdisciplinary research, neuropsychiatric symptoms, pharmacology Editorial on the Research Topic Pharmacology of BPSD (Behavioral and Psychological Symptoms of Dementia) This Research Topic started out on a sombre note. Despite being common in older adults and affecting even some young people, awareness is limited about neuropsychiatric symptoms (NPS) in dementia, the so-called BPSD, even among health professionals, and only a few drugs registered for them. Around 2018, several pharmaceutical companies stopped or downsized neuroscience research divisions oriented toward Alzheimer’s disease (AD), some of which had drug candidates of potential interest for BPSD. Antipsychotics had fallen out of favor in many locations, as there were reports of elevated mortality that restricted their use. Nonpharmacological treatments usually mandated by law or guidelines were often given limited resources; there was limited agreement about the optimal nonpharmacological treatment and scarce research on them. To address this situation, this Research Edited and reviewed by: Topic has involved multiple disciplines ranging from clinics to basic research. The idea is to move Nicholas M. Barnes, away from an abstract view of BPSD toward a detailed understanding and optimized therapeutic University of Birmingham, interventions. This Research Topic presents 31 papers (one is this Editorial and one is a correction); United Kingdom 139 authors contributed to these. *Correspondence: Björn Johansson bjorn.johansson@ki.se ANTIPSYCHOTICS, OLD AND NEW Specialty section: The contributions by Calsolaro et al. and Magierski et al. start out by listing the symptoms counted as This article was submitted to BPSD and notice that they may occur at any stage of dementia, the typical time profile depending on Neuropharmacology, the type of dementia. The authors go on to present the more conventional drug treatments for BPSD a section of the journal such as dopamine receptor antagonists and move on to newer drugs. The contribution by Magierski Frontiers in Pharmacology et al. also includes a section on nonpharmacological treatments. The review by Yunusa and El Helou Received: 02 May 2021 deals with the single antipsychotic, risperidone, approved for BPSD (one component of it, Accepted: 13 May 2021 aggression) in many countries. It brings up statistically significant effectiveness of this Published: 15 June 2021 antipsychotic against BPSD in some situations and lists side-effects and regulatory differences Citation: among countries. Ohno et al. point out that antipsychotic drugs can have extrapyramidal side effects, Giménez-Llort L and Johansson B including Parkinsonian symptoms, also when used in elderly with dementia. These authors discuss (2021) Editorial: Pharmacology of drug choice and combination strategies, as cholinesterase inhibitors and antidepressants that are 5- BPSD (Behavioral and Psychological Symptoms of Dementia). HT reuptake inhibitors may potentiate EPS whereas NMDA receptor antagonist memantine and Front. Pharmacol. 12:704421. adrenergic and 5-HT receptor antagonist mirtazapine reduce EPS. These authors go into some detail doi: 10.3389/fphar.2021.704421 on modulation of EPS by 5-HT receptor subtypes. The contribution by Yunusa et al. highlights Frontiers in Pharmacology | www.frontiersin.org 1 June 2021 | Volume 12 | Article 704421 Giménez-Llort and Johansson Editorial: Pharmacology of BPSD encouraging preliminary results on a newer antipsychotic, identify the cause of poor clinical response of cognition and pimavanserin, for the treatment of dementia-related psychosis behavioral and psychological symptoms in patients. This could (already FDA-approved in U.S. for Parkinson-related psychosis), be especially relevant to BPSD, as there is some evidence that the first antipsychotic with little antagonism of adrenergic, relatively higher doses of AChE-I might be needed for BPSD dopaminergic, histaminergic and muscarinic receptors, but than for cognitive impairments. IT is the main theme of two significant interactions with 5-HT receptors. contributions, Piau et al. and Husebo et al. The contribution by Piau et al. focuses on digital biomarkers and points to an unmet need to monitor nature, frequency, severity, impact, NEW LOOKS AT TRADITIONAL MEDICINES progression, and response to treatment of BPSDs after the initial assessment. to reevaluate therapeutic strategies more Looking back in time but also into the future, the papers by quickly and, in some cases, to treat earlier, when symptoms are Park et al. and Fu et al. deal with herbal medicines that have still amenable to therapeutic solutions or even prevention. traditionally been, and still are, given to old people for i.a. These authors suggest digital biomarkers are monitoring more cognitive and depressive symptoms. Both explore how these than diagnostic tools. In addition to the implications for (and potentially other traditional drugs) can be researched using clinical care, several ways to use digital biomarkers for modern methods and formulations improved. Interestingly, both more effective pharmaceutical research are suggested. drugs described have statistically significant effects in some of the Husebo et al. find that technology can often pick up assays used. The systematic review by Fu et al. of a medicine behaviors of BPSD such as sleep disturbances, agitation and traditionally used in the old people found an improvement in wandering, and may be well accepted. These authors also preclinical scores for cognitive functioning and mood. Possible propose a framework for sustainable ethical innovation in mechanisms for Kaixinsan (KXS) were found to be antioxidant, healthcare technology. Advancements in methodology of a anti-inflammatory and antiapoptotic activity, neuroprotection and different kind, i.e., design of clinical trials, are proposed in synapse protection. suggesting that KXS might be considered for Hulshof et al. This study indicates that resources have been depressive symptoms in dementia acting through multiple wasted in clinical trials of antipsychotics for neuropsychiatric mechanisms. The study of PSM-04, derived from a natural symptoms of dementia, because sample sizes were either too medicine, by Park et al. addresses mechanisms of another drug small or unnecessarily large. The article suggests ways to that is traditionally used in elderly with cognitive or depressive improve clinical trials in the BPSD area both during study problems, addressing its mechanisms. In preclinical models, design and when findings are later reported. Interesting PSM-04 had significant neuroprotective effects against methodology developments in the use of animal models are neurotoxicity induced by L-glutamate or oligomeric Aβ and dealt with in the contributions by Torres-Lista et al. and Pifferi decreased oxidative stress induced by H2O2. The drug also et al. A string of publications from the first-mentioned lab reduced cognitive impairment and decreased amyloid deposition shows that BPSD can be modeled in mice. In their mouse in a mouse model. This paper points to the interesting possibility model, the benefits of risperidone were limited, both at that the mood improvement by PSM-04 (and related drugs) may cognitive and BPSD-like level, and there was early and be mediated (in part) by reduction in amyloid deposits. Both Park long-lasting mortality risk. Since mortality from an et al. and Fu et al. mention neuroprotection and reduction in antipsychotic is reproduced in this mouse model, it might oxidative stress, suggesting mechanisms that may be common to be possible to address antipsychotic toxicity using this animal both KXS and PSM-04 and to both cognitive and depressive model. A fresh approach to BPSD may be the one of Pifferi et symptoms. al. Here, it is suggested that the gray mouse lemur, a primate, is a more translatable animal model of dementia and BPSD. Interestingly, effectiveness of approved cognitive enhancers such ADVANCES IN METHODOLOGY AND IT as acetylcholinesterase inhibitors or N-methyl-D-aspartate antagonists is demonstrated in sleep–deprived animals. The contribution of Lin and Lane deals specifically with Knowledge of similarities between age-related symptoms in the glutamate-related mechanisms. It starts from memantine, lemur with BPSD in humans might help understand and the NMDA receptor antagonist used in AD, and notices treat BPSD. evidence that both under- and overactivity can be detrimental, and suggest that “precision medicine,” specifically tailoring treatment to each patient using FOCUS ON DEPRESSIVE AND OTHER NMDA-related biomarkers, can be helpful. Somewhat less SPECIFIC SYMPTOMS high-tech, but possibly important technology development is the blood concentration measurements of AChE Several contributions deal with the depressive symptoms that inhibitors (AChE-I) by Ortner et al. AChE-I are used for commonly co-exist with or precede cognitive impairments in the treatment of cognitive symptoms of dementia but also dementia disorders, and with the related but distinct problem BPSD. Ortner et al. find that serum concentrations below the of apathy in dementia. The contribution by Cassano et al. recommended range in about two thirds of the patients and begins by noticing that the question if depression is a suggest that therapeutic drug monitoring might help to prodromal symptom preceding cognitive deficits or an Frontiers in Pharmacology | www.frontiersin.org 2 June 2021 | Volume 12 | Article 704421 Giménez-Llort and Johansson Editorial: Pharmacology of BPSD independent risk factor for AD is still unclear, although a Thus, there is still limited consensus connecting dementia with connection between depressive disorders and AD is widely anticholinergic activity; however, toward the end of their paper, recognized. Moreover, there is growing evidence reporting that these authors give suggestions to design more definitive studies in conventional antidepressants are not effective in depression the future. Some aids for drug review in dementia discommend associated with AD and, therefore, there is an urgent need to tricyclic antidepressants due to their anticholinergic effects (Religa understand the neurobiological mechanism underlying the et al., 2021, in press). Nevertheless, Hessmann et al., in their resistance to the antidepressants. The paper by Linnemann and contribution, found that patients being diagnosed with dementia Lang explores possible mechanistic relationships between late-life frequently are prescribed tricyclic antidepressants. In many depression and dementia, both of which are common in old age locations, the tricyclics would be deprescribed during regular and often occur together. The fact that depression often comes with medication reviews. However, considering the contribution of Liu cognitive impairment and dementia often presents with depressive et al. suggesting limited increase in dementia risk by a modest symptoms is a challenge. However, more than six several exposure to anticholinergic drugs, and since tricyclics are pathophysiological substrates are proposed to explain the link sometimes prescribed after nonresponse to other between late-life depression and dementia. The Systematic Review antidepressants, could this prescription be warranted in some of Wiels et al. suggests that depressive symptoms and dementia have instances? Disorders of the urinary system are common in common risk factors, that depressive symptoms being a prodromal geriatric patients with dementia. Many such patients have symptom of dementia and/or depression being a risk factor for reduced kidney function, although the only sign of it may be dementia. To the editors, it seems that all these causal relationships abnormal markers such as creatinine. The contribution of Simões e may be operating at the same time. Since clinical diagnostic criteria Silva et al. explores the connection between chronic kidney disease were usually used, not biomarkers, different pathophysiologies and neuropsychiatric disorders, among which depression is might be operative in different patients. The contributions on common. There is some evidence for increased cerebrovascular apathy by Bogdan et al. and Theleritis et al. point out the lack of disease from uremic toxins, but the authors find evidence for drive in many patients with dementia. They notice that apathy in bidirectional cross-talk between brain and kidney through dementia may have separate pathways from depression and points mechanisms including inflammatory cytokines and the renin- to several possible targets for drug treatment in apathy, although angiotensin system. There is evidence for involvement of the approved agents for apathy are still missing. The authors suggest kynurenine pathway, an alternative pathway of tyrosine early treatment is important, as apathy may have a negative impact metabolism, in neuropsychiatric symptoms as well as AD on the disease progression. They suggest that optimizing treatment progression and neurodegeneration. In some tissues with AD- duration and samples sizes may improve future clinical trials. type changes, overactivity of the kynurenine pathway has been Besides Bogdan et al., Gottesman and Stern deal with the demonstrated, which is likely to increase levels of certain question of BPSD and rate of cognitive decline. They make neurotoxic metabolites. Against this background, Fertan et al. the interesting point that BPSD is positively correlated with the tested a whether a novel inhibitor of this pathway could improve rate of decline in AD and suggest that the presentation and cognitive and behavioral changes in a mouse model of AD. DWG- course of AD is highly heterogenous with BPSD contributing to 1036 showed improvements in in memory and behavior in several heterogeneity. The HIDA axis is almost the antithesis of but not all assays used. Could the kynurenine pathway be one that depressive symptoms: connects BPSD and memory loss? The contribution of Tarasov et al. Hyperactivity–Impulsivity–Irritiability–Disinhibition–Aggression– is relevant because of a recent surge in publications implicating a role Agitation. Keszycki et al. argue that some symptoms in the HIDA of astrocytes in AD and other neurodegeneration (Verkhratsky et al., axis do not respond adequately to nonpharmacological treatments, 2019). They review evidence for alterations of astrocytes also necessitating adjunct pharmacological intervention. in schizophrenia in which their role may be neuroinflamation and an indirect influence on dopamine neurons via NMDA receptors. A state of hyperactive dopamine projections in the MECHANISMS OF BPSD AND POSSIBLE mesolimbic system and reduced dopamine projections in the CONNECTIONS WITH OTHER DISORDERS mesocortical system in schizophrenia is mentioned. Could it be that dopamine-related mechanisms of Tarasov et al. be a cause Ng et al. sort the diverse symptoms of BPSD into subsyndromes of hypometabolism in frontal cortical areas in AD with psychosis and notice that they may arrive early in AD, even before the onset reviewed in the contribution by Ng et al.? Autism and BPSD are of cognitive impairment. They point to metabolic dysfunction in seldom considered together, but the contribution by Eissa et al. specific brain areas and networks in the different BPSD. They find compares these two conditions side by side. They identify some that neuropsychiatric symptoms are associated with poorer commonalities in symptoms and mechanistic roles of outcomes in cognition and function and discuss opportunities inflammation, histamine, amyloid precursor protein (APP) and of intervention. The study by Liu et al. addresses whether changes in white matter. The experimental study of Scuteri et al. anticholinergic activity of drugs is associated with risk of points to the possibility that BPSD can be a manifestation of pain, a dementia and BPSD. Drugs with anticholinergic activity are common co-morbidity that these patients can have difficulty to strongly suspected to increase risk of dementia. However, this express. It was found that formalin-induced behavioral pattern in study found limited evidence for such relationships; nevertheless, older mice was different and suggests a possible animal model of with high anticholinergic burden the relationship became apparent. pain in the elderly. Frontiers in Pharmacology | www.frontiersin.org 3 June 2021 | Volume 12 | Article 704421 Giménez-Llort and Johansson Editorial: Pharmacology of BPSD FINAL NOTES (Cummings et al., 2020), and several drugs and mechanisms mentioned in this Research Topic can reasonably be placed in Finalizing this Research Topic, we are now optimistic. A few more than one group. Several of the contributions touch upon trends can be discerned: Antipsychotics, even those that are possibly overlapping neural/mechanistic pathways with strong blockers of dopamine receptors, have not been written comorbidities (pain, urinary system disorders). Bladder off from treatment of BPSD. Side effects of antipsychotics may at dysfunction, for which drugs with anticholinergic activity are often times be effectively dealt with, as described here. New prescribed, may be an integrated part of neurodegenerative disorders antipsychotics with different receptor binding profile may have or a consequence of treatment prescribed (Winge, 2015). Perhaps a better benefit to risk ratio. Improvements in methodology such altered behavior patterns during micturition might be considered a as IT, biomarkers, drug concentration measurements and study specific Behavioral and Psychological Symptom of Dementia? The design will optimize the use of existing drugs and speed discovery evidence that BPSD are associated with quickened cognitive decline of new drugs. Traditional medicines are still of interest, and new is of clear interest to pharmacologists, primarily because some drugs technologies may make them more effective and useful. used in BPSD might quicken cognitive decline (see Gottesman and The new disease classification ICD-11, being introduced Stern). However, an interesting possibility is that optimized internationally, associates dementias with a specific nervous system treatment of BPSD could reduce cognitive decline, as there is disease process and, if needed, BPSD or a specific symptom of BPSD very recent evidence that that the abovementioned antipsychotic (World Health Organization, 2018). The present Research Topic pimavanserin might be disease-modifying in AD (Yuede et al., outlines many mechanistic pathways, containing potential drug 2021) as well as effective against neuropsychiatric symptoms. Park targets, for BPSD but also cognitive impairments and CNS disease et al. presents evidence for an anti-amyloid effect of a natural processes. Candidate drugs against AD are often divided in three medicine used i.a. for depressive symptoms in the elderly, which groups (Cummings et al., 2020), the larger “disease-modifying” group, might be an indication that amyloid contributes to such symptoms. and the groups whose purpose is cognitive enhancement or Figure 1 tries to place mechanisms mentioned in this Research controlling neuropsychiatric symptoms. However, it has been Topic in the context of the multiple clinical manifestations of the noticed that some agents may belong to more than one group dementias. FIGURE 1 | The multiple facets of the dementias, as gleaned from the contributions to this Research Topic. Relationships among cognitive impairments, behavioral problems and co-morbidities such as pain and disorders of the urinary system. This figure is work in progress, as this version is not a complete summary of all mechanisms mentioned in the contributions or all suggestions received from the authors. Frontiers in Pharmacology | www.frontiersin.org 4 June 2021 | Volume 12 | Article 704421 Giménez-Llort and Johansson Editorial: Pharmacology of BPSD We feel that the multidisciplinary approach taken in this ACKNOWLEDGMENTS Research Topic has been successful and will quicken progress in the BPSD treatment. For natural reasons, many therapies described Colleagues’ advice is valued. Authors’ research funded by here are of an experimental nature, so always check with law and European Commission ArrestAD H2020 Fet-OPEN-1-2016- local rules and guidelines before making clinical decisions. 2017-737390, Region Stockholm ALF 20170190, Åhlén- stiftelsen. Research reported in this publication was supported by the National Institute on Alcohol Abuse and Alcoholism of the AUTHOR CONTRIBUTIONS National Institutes of Health under Award Number R01AA028549. 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Editors (Springer Nature The use, distribution or reproduction in other forums is permitted, provided the Singapore Pte Ltd). doi:10.1007/978-981-13-9913-8 original author(s) and the copyright owner(s) are credited and that the original Winge, K. (2015). Lower Urinary Tract Dysfunction in Patients with Parkinsonism publication in this journal is cited, in accordance with accepted academic practice. and Other Neurodegenerative Disorders. Handbook Clin. Neurol. 130 (3rd No use, distribution or reproduction is permitted which does not comply with series) 2015 Elsevier B.V. doi:10.1016/B978-0-444-63247-0.00019-5 these terms. Frontiers in Pharmacology | www.frontiersin.org 5 June 2021 | Volume 12 | Article 704421