“Pharmacological and non-pharmacological approaches to reduce symptoms of disinhibited behaviors in dementia: A systematic review” by Burley etal., Reference Burley, Burns and Brodaty2022) offers a critical summary of research examining various approaches to the reduction of disinhibition associated with dementia. Previously thought to occur only in the moderate to severe stages of disease progression, more recent work demonstrates that disinhibition also occurs early in disease onset (Alagiakrishnan etal., Reference Alagiakrishnan, Lim, Brahim, Wong, Wood and Senthilselvan2005), yet clear characterization and focused interventions have remained elusive. In this work by Burley and colleagues, a systematic review is undertaken to identify intervention research conducted in the past two decades which might elucidate strategies for decreasing disinhibited behaviors. Both pharmacological (e.g. analgesic, antipsychotics, and antidepressant medications) and non-pharmacological interventions (e.g. physical activity, programs addressing education and training, and provision of care) were included. A relatively small number of pharmacological approaches were identified relative to non-pharmacological. Although both showed reduction to disinhibited behaviors, findings suggested that the non-pharmacological approaches had greater impact. This review raises awareness of, and illuminates potential solutions to, a very significant problem in dementia. However, it simultaneously emphasizes the many limitations of this literature.

Neuropsychiatric symptoms (e.g. depression, hallucinations, agitation, and disinhibition) in dementia are both prevalent and problematic. Presenting in some form in up to 97% of individuals with dementia (Steinberg etal., Reference Steinberg2008), these behavioral symptoms are linked to negative outcomes for persons with dementia, such as greater frequency of acute hospitalization (Voisin etal., Reference Voisin, Sourdet, Cantet, Andrieu and Vellas2009), greater morbidity, and swifter cognitive decline (Okura etal., Reference Okura, Plassman, Steffens, Llewellyn, Potter and Langa2011). For caregivers, such symptoms have been linked to caregiver distress (Donaldson etal., Reference Donaldson, Tarrier and Burns1998), lower quality of life, greater depression and anxiety (Chiò etal., Reference Chiò2010), occupational strains (Biegel etal., Reference Biegel, Sales and Schulz1991), greater desire to place the care recipient in institutionalized care (Okura etal., Reference Okura, Plassman, Steffens, Llewellyn, Potter and Langa2011), and greater caregiver burden (Davis and Tremont, Reference Davis and Tremont2007). Behavioral disinhibition may be a particularly stressful neuropsychiatric symptom for family caregivers to deal with (de Vugt etal., Reference de Vugt, Riedijk, Aalten, Tibben, van Swieten and Verhey2006). Because manifestations of behavioral disinhibition can sometimes involve behaviors that are socially stigmatizing or embarrassing (e.g. inappropriate sexual behavior), these symptoms may go underreported or untreated until behaviors become particularly severe. Taken together, focused approaches for disinhibition are important.

Despite this, a key takeaway of the review from Burley and colleagues is that not a single study examining these interventions intentionally targeted disinhibition as a primary outcome. Assessment of outcomes related to disinhibition was relegated to a secondary role, indicating that the treatments examined were not developed with reduction of disinhibition as a principal aim.

The paucity of intervention research addressing disinhibition may in part stem from the unclear characterization of disinhibition within the literature. As noted by Burley and colleagues as well as prior work (Chapman etal., Reference Chapman, Tremont, Malloy and Spitznagel2019), efforts to consistently define and measure disinhibition are lacking. Methods such as retrospective chart review, behavioral observation, and informant-report have all been utilized for the measurement of behavioral disinhibition in prior works, each carrying its own methodological challenges. Burley and colleagues found that the Neuropsychiatric Inventory (NPI), a well-known informant-report measure, was the most widely used outcome measure to capture disinhibition, but the NPI has been shown to under-identify certain manifestations of behavioral disinhibition (Chapman etal., Reference Chapman, Tremont, Malloy and Spitznagel2019). None of the studies reviewed examined subdomains of disinhibition (i.e. vocal, physical, and sexual), making it difficult to determine which specific aspects of disinhibition might benefit from the treatments utilized. As certain presentations of behavioral disinhibition may be linked with very specific brain regions or neurochemical processes (as has been documented in the Parkinson’s disease literature with hypersexuality emerging in the context of initiation of dopamine agonist therapy) more nuanced examination of outcomes is needed. Furthermore, differences in study design (e.g. larger randomized clinical trials [RCTs] and case studies) and outcome measures preclude Burley and colleagues’ ability to directly compare results across studies. These shortcomings of the literature limit interpretation of Burley and colleagues’ findings.

Beyond definitions and measurement of disinhibition, difficulty pinpointing the etiology of disinhibition in dementia further complicates interpretation of findings. For example, non-pharmacological approaches showed a superior effect size in decreasing disinhibition relative to pharmacological interventions. While this could be viewed as evidence that pharmacological approaches in general may be inferior, it could also be interpreted as a call for greater knowledge of the foundations of disinhibition. The interplay of disinhibition and specific disease pathology (e.g. behavioral variant frontotemporal dementia, Alzheimer’s disease, and vascular disease), preexisting characterological traits, premorbid disposition, and neuroanatomical correlates is not yet fully understood (Low etal., Reference Low, Brodaty and Draper2002). Recent work identified the central role of the prefrontal cortex in inhibitory control (Magrath Guimet etal., Reference Magrath Guimet, Miller, Allegri and Rankin2021), but other brain regions have been implicated as well. Identification of optimal targets for pharmacologic interventions will require clearer data regarding underlying mechanisms of disinhibition.

Importantly, Burley and colleagues point out that several of the interventions included in their review utilized multicomponent approaches, with some even combining pharmacological and non-pharmacological approaches. While such combination approaches complicated efforts to tease apart relative effects for the purpose of review, prior work suggests that multicomponent interventions may be more effective than single-component interventions (Van't Leven etal., Reference Van’t Leven, Prick, Groenewoud, Roelofs, de Lange and Pot2013). The efficacy of multicomponent versus single-component approaches may be particularly clear when dealing with heterogenous behavioral presentations such as disinhibition; multicomponent interventions allow for greater flexibility in suiting the needs of individual patients and families and tailoring approaches to specific disease characteristics or severity staging. More work is needed to determine optimal intervention characteristics such as method of delivery, frequency, duration, and dosage.

Another issue requiring further clarification is the possible association between race or ethnicity and the clinical presentation of neuropsychiatric symptoms. For example, some research suggests that individuals who are black may exhibit greater presence of hallucinations, delusions, and agitation, and lower rates of depression when compared to individuals with dementia who are white (Cohen and Carlin, Reference Cohen and Carlin1993). To date, few studies have rigorously considered racial or ethnic discrepancies in the presentation of disinhibition. Research is needed to determine the extent to which sociocultural and biologic influences impact disinhibition, and the influence of potential heterogeneity in presentation when considering treatment (Ballard etal., Reference Ballard, Day, Sharp, Wing and Sorensen2008). More work is also needed to ensure greater access to care and research opportunities among racial and ethnic minorities. Dementia disproportionately impacts minority groups, yet these groups experience delayed diagnosis, lack of access to medical care, reduced research opportunities, and low trust with medical providers (Sluder, Reference Sluder2020). Greater focus must be placed on building trust and outreaching to marginalized groups to ensure improved access to care and inclusion in research. Going forward, interventions with these potential demographically mediated differences in neuropsychiatric symptoms presentation and treatment response are needed.

Burley and colleagues’ review highlights areas in need of additional work. Most of the identified interventions took place in residential care settings, suggesting that existing interventions have largely been designed for implementation in more severe disease states. As disinhibition can also be present in earlier disease stages more work is needed to determine if intervention efficacy partly depends on disease characteristics such as severity. Examination of which interventions are most appropriate for earlier disease states must be conducted. Further, only one intervention included in the review incorporated an informal (i.e. family) caregiver component (i.e. de Oliveira etal., Reference de Oliveira2019). Given that the bulk of caregiving responsibilities typically fall to family caregivers, interventions that incorporate educational materials or behavioral strategies and techniques tailored to family caregivers would likely be of utility.

With an eye toward the future, intervention strategies to target behavioral disinhibition should consider cultural shifts in the context of the ongoing COVID-19 pandemic. Deaths related to Alzheimer’s disease have increased by 16% since the start of the pandemic, and dementia caregivers report greater role strain, possibly related to barriers to accessing appropriate care and increased social isolation (Savla etal., Reference Savla, Roberto, Blieszner, McCann, Hoyt and Knight2020). Intervention strategies and treatment approaches that can be adapted to technology-based formats to reduce personnel costs and increase accessibility may be beneficial. Despite data from the Pew Research Center (Anderson and Perrin, Reference Anderson and Perrin2017) suggesting that a high percentage of older adults have access to smartphone technology, none of the interventions reviewed by Burley and colleagues incorporated the use of technology. While several technology-based non-pharmacological interventions geared toward helping caregivers manage neuropsychiatric symptoms in dementia exist (e.g. Gitlin etal., Reference Gitlin2021), these programs have not been implemented on a larger scale, and they do not appear to specifically target behavioral disinhibition. As access to technology increases for people living with dementia and their family caregivers, the potential role of supportive technology-based intervention strategies deserves more attention. But science must translate to reality. To be useful, research interventions must minimize barriers to implementation, demonstrating effects that can be replicated in practice (Moore and Crawley, Reference Moore and Crawley2020) while meeting needs for cost effectiveness (Burley etal., Reference Burley, Livingston, Knapp, Wimo, Normal and Brodaty2020).

Ultimately, this work by Burley and colleagues lays the groundwork for next steps to pursue in effort to reduce symptoms of disinhibition in persons with dementia. Perhaps equally important, it underscores areas of insufficient work to date. Future research in the domain of behavioral disinhibition will benefit from greater foundational work to consistently characterize disinhibition, understand its mechanisms, intervene with treatments explicitly developed for disinhibition as a primary outcome, with an eye toward caregiver wellbeing, inclusivity, potential group differences, technology-based solutions, and realistic implementation.