Pharmacology of BPSD (Behavioral and Psychological Symptoms of Dementia)

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Background

This Research Topic, to be comprised of both original (in vitro, animal and clinical), review and conceptual articles, researchers and clinicians are welcome to discuss all aspects of drugs in BPSD. Emerging principles for approaching and treating BPSD are encouraged as well as more mundane aspects of optimizing currently available treatments.

While impairment of memory and other cognitive abilities in dementia is recognized by laypersons and subject of many research papers, the fact that dementia is also associated with behavioral and psychological symptoms is unknown to many, even in healthcare. Nearly everyone with dementia has one or more of the Behavioral and Psychological Symptoms of Dementia (BPSD), also termed neuropsychiatric symptoms of dementia, which include aberrant motor disorder, aggression, anxiety, apathy, appetite disorder, delusion, depression, disinhibition, euphoria, hallucination, irritability and sleep disorder. BPSD, often more burdensome than cognitive impairment to the patient and caregivers, can pose risk of self-harm and harm to others.

Psychotic symptoms and agitation in dementia have often been treated off label with antipsychotics (AP). Risperidone is the only licensed drug for the treatment of BPSD (specifically aggressiveness in Alzheimer´s disease). It caused a stir when the Food and Drug Administration (U.S.) and other government agencies in the new millennium warned of increased mortality in dementia patients receiving APs. Ever since, pharmacological treatment of BPSD has been an area of controversy, with efforts to reduce or replace APs with other drugs or nonpharmacological therapy. Drugs from several therapeutic subgroups of the ATC system are used in BPSD: analgesics, anticonvulsants, anti-dementia drugs, antidepressants, AP, hypnotics and sedatives and vitamins. Transmitters/receptors reportedly involved in BPSD and their treatment include 5-HT1A, 5HT2A, 5-HT3, 5-HT6, acetylcholine, adenosine, alpha1-adrenergic, dopamine D2, opioid, orexin and NMDA. Traditional herbal medicines including Crocus sativus, Ginkgo biloba, Hypericum and Yokukansan are in use, and have been also foreseen as a source of drug development. Some of them have shown clinical effectiveness in smaller studies, demonstrable biochemical effects, and their disease modifying actions are under investigation at several clinical centers and research laboratories. While some drugs are considered helpful in BPSD, there are also those that are detrimental. Drugs with anticholinergic activity are considered unsuitable. Analgesics may reduce BPSD in some individuals. While high doses of opioids are unsuitable, low doses were proposed as beneficial. Available studies do not always show a similar effect size for therapeutic effects on cognition vs. BPSD, and effects might even go in opposite directions. This may be true for caffeine, which might protect against cognitive decline while worsening BPSD, possibly related to receptor subtype-selective effects. Vitamins, trace elements and nutraceutical formulations may be of relevance; for example, studies showed correlations between low B12 and BPSD and selenium reversed BPSD in a mouse model. Since drugs in BPSD have shown modest therapeutic effects at best, clinical trials are being supplemented with preclinical research, often using cellular assays to determine the receptor subtype selectivity of substances and natural products with some known effect on BPSD. Recently, animal models have begun to be used in BPSD research; with increasingly sophisticated tests of animal behavior, BPSD-like symptoms have been shown and treated in animals such as APP23 and 3xTgAD mice.

We believe most contributions will fall into one of these categories:1. Antipsychotics and replacement drugs belonging to other classes – experimental and clinical studies - new drug candidates appreciated. 2. Herbal and natural substances – experimental and clinical studies. 3. New ways to think about and research BPSD - including introducing animal, computer and other models, concepts such as cholinergic-mediated attention, understanding the subjective experience of the individual, emergent network properties, nutraceuticals, a proposed role of inflammation and avoiding side effects of antipsychotics by understanding their mechanisms.

Keywords: Behavioral Symptoms, Dementia, Drug discovery, Interdisciplinary Research, Pharmacology

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