Despite a declining age-specific incidence of dementia in high-income countries, the absolute numbers of patients with cognitive decline continues to rise as the population ages [1]. Treatment with cognition-enhancing/preserving medication, including cholinesterase inhibitors and memantine, is typically pursued in all but the least and most severely afflicted [2]. Noncognitive symptoms of dementia occur in 98% of individuals at some point in their disease and are often the most distressing to caregivers and patients themselves [3]. Neuropsychiatric symptoms (NPS), including apathy, depression, sleep disorders, hallucinations, delusions, psychosis, agitation, and aggression, are exceedingly prevalent [4, 5]. The presence of depression in dementia has been shown to accelerate the rate of cognitive decline, even beyond education level and sex [6]. Dementia symptoms will wax and wane as a natural course, according to both environmental factors and disease progression-related factors [7]. In their most severe manifestations, NPS can lead to worse patient outcomes, accelerated disease progression, institutionalization, morbidity and mortality, and significant caregiver stress and financial strain [4, 5, 8]. Studies have shown that determinants of nursing home placement in patients with dementia include difficult behaviors; patients scoring the highest on psychotic and behavioral symptoms are over two times more likely to be institutionalized [9, 10]. It is possible that caregivers may be willing to delay hospitalization or institutionalization if behaviors can be managed, though this theory has not yet been studied.

The presentations of NPS appear at different times during various types of dementia, and presentation frequencies may vary depending on setting. In early Alzheimer’s disease (AD), depression, disinhibition, apathy, and sleep disorders are prevalent, and disease progression leads to an increase in delusions, hallucinations, and aggression [11,12,13,14,15]. A naturalistic study of patients in a geriatric psychiatry unit in Germany found aggression, including both verbal and physical, was the most frequent symptom, occurring in approximately 57% of patients. However, the authors noted that symptoms such as depression and apathy might not warrant acute treatment or hospitalization, except in severe cases [16]. Apathy, arising from primary amotivation, appears to be the most common and lasting NPS of AD, affecting up to 76% of patients with AD [11, 17]. A recent systematic review by Theleritis et al. [18] focused on describing apathy and management approaches, so we refer readers to this review for more comprehensive discussion. Conversely, in Parkinson’s disease (PD), visual hallucinations appear earlier, and disease progression results in the gradual appearance of Parkinson’s disease dementia (PDD), intertwined commonly with depression, anxiety, and sleep disorders [19]. In vascular dementia, sleep disorders, agitation, depression, and anxiety are not associated with a specific stage of the disease [20]. Similar to PDD, dementia with Lewy bodies (DLB) is most often accompanied by nonthreatening visual hallucinations, sleep disorders, and anxiety [12, 13]. In a population-based study evaluating the frequency of symptoms in people with dementia, apathy was the most frequent symptom, followed by depression and agitation/aggression [21]. The majority of patients had AD, although people with vascular dementia, PDD, and others were also represented.

While it is clear that NPS can cause increased disease burden for both patients and caregivers, less clear guidelines regarding the appropriate management of NPS have been published. The American Association for Geriatric Psychiatry (AAGP), the Alzheimer’s Association, the American Geriatrics (AGS) Society, the National Institute for Health and Care Excellence (NICE), the American Psychiatric Association (APA) and the Detroit Expert Panel on the Assessment and Management of the NPS of Dementia agree and emphasize that nonpharmacologic treatment should be implemented as first-line management of NPS [3, 22,23,24,25,26]. Nonpharmacologic management is similar among guidelines, suggesting the use of techniques including but not limited to the removal or avoidance of triggers, environmental modifications, treatment of precipitating medical conditions, discontinuation of offending pharmacologic agents, aromatherapy, animal-assisted therapy, and exercise, music, art, and reminiscence therapies [3, 22,23,24,25, 27, 28].

However, even when nonpharmacologic approaches are effectively employed, a high percentage of patients with dementia are eventually treated with psychotropic medications, recently demonstrated to be 84% of nursing home and 29% of community-dwelling elders residing in the USA [29]. It is important to use all available evidence to select agents and doses of psychotropic medications to minimize risk and maximize the potential for benefit in these vulnerable patients.

Certain guidelines suggest that pharmacologic management may be considered first line after a thorough risk/benefit assessment in the following situations: significant risk of harm to patient or others due to psychosis or aggression, severely distressed patient or caregivers, and major depression with or without suicidal ideation [3, 22,23,24,25]. A noted difference among guidelines appears in those provided by the APA, in which only the patients are discussed in situations that may warrant pharmacologic treatment, and the feelings/distress of caregivers are omitted [25]. If nonpharmacologic interventions prove ineffective or if any of the aforementioned situations exist, recommendations from various groups, including the AAGP, AGS, and Alzheimer’s Association, as well as the APA and NICE, are that the use of pharmacologic therapy may be warranted [3, 22,23,24,25].

Recommendations regarding the choice of pharmacologic treatment vary greatly regarding the agents used for specific NPS, but a common theme does exist: pharmacologics should be used judiciously in the elderly [3, 22, 24,25,26]. Recommendations about the duration of treatment appear only in reference to the use of psychotropics and suggest that medications should be tapered and withdrawn if no clinically significant response to therapy occurs after a 4-week trial of adequate doses [25]. Furthermore, it is recommended that attempts to taper antipsychotics occur within 4 months of initiation [25]. In general, pharmacologic agents used for the management of NPS should be initiated at the lowest dose and titrated up to the minimum effective dose as tolerated. These agents should not be continued indefinitely, and their use should be continually reassessed [3, 22, 24,25,26]. The purpose of this article was to describe the current literature on medication management of NPS of dementia and highlight approaches to and concerns about the treatment of NPS to assist the practicing clinician. We sought to give perspectives as to why an individualized approach is imperative and to provide suggestions for why psychotropics may be perceived as having minimal and variable efficacy across patients with dementia-related NPS. If a clinician has a low threshold for starting a given psychotropic for any NPS, has expectations for nonspecific or global improvement of NPS, and has an unclear threshold for discontinuing the given psychotropic, the patient can ultimately be at risk for intolerabilities in addition to inefficacy. Thus, this review is a practical, yet detailed discussion with highlights from recently published randomized controlled trials aimed at any clinician who may care for patients with dementia and NPS. Selected common symptoms were identified for further discussion. We avoided elaboration where a specific symptom had recently been the subject of a comprehensive, systematic review, instead referring readers to that publication. Specific information regarding clinical trials designed to assess the use of pharmacologic agents for NPS in patients with dementia is included in Tables 1 and 2, which we revisit throughout this article.

Table 1 Randomized, blinded, controlled trials of agents (available in the USA) for neuropsychiatric symptoms of dementia since 2004 Full size table