Behavioral and psychological symptoms of dementia (BPSD) are neuropsychiatric symptoms that occur in the context of Alzheimer’s disease and related dementias (ADRD). The range of symptoms may include anxiety, depression, irritability, sleep disturbance, agitation, aggression, psychosis, and apathy (Lyketsos et al., Reference Lyketsos, Lopez, Jones, Fitzpatrick, Breitner and DeKosky2002). BPSD are associated with poorer outcomes for patients with dementia, including mortality and earlier transition from living at home to higher levels of care. BPSD also have significant implications for caregivers, including increased anxiety, depression, sleep disturbance, and poor medical outcomes (Alzheimer’s Association, 2023). In many ways, BPSD are more debilitating for patients and caregivers than the progressive memory decline that is the hallmark of ADRD.
Because of the burden of BPSD on our patients and their caregivers, effective treatment approaches are imperative. Nonpharmacological interventions are considered first line, and typically focus on addressing underlying medical, social, emotional, and environmental triggers leading to the development of symptoms (Kales et al., Reference Kales, Gitlin and Lyketsos2014). BPSD are not “one size fits all” in either presentation or treatment, requiring close investigation of these and other triggers. Time and effort are required both by the treatment team and caregivers to develop individualized plans that are mindful of the specific variables involved in BPSD triggers and reactions.
When nonpharmacological approaches are either undereffective or ineffective, and also for situations in which there might be emergent safety concerns, pharmacological treatments of BPSD may be considered. There are no FDA-approved medications for the treatment of the neuropsychiatric symptoms of ADRD (Kales et al., Reference Kales, Gitlin and Lyketsos2014). Choice of medications is made based on the patient’s medical and psychiatric history, predominant symptom presentation, medication safety profile, and other individual factors. Among the most concerning safety issues is regarding the use of antipsychotics for patients with ADRD: in 2005, the FDA issued a black-box warning against the use of atypical antipsychotics in older adults with dementia due to increased risk of death. This warning was extended to all antipsychotics in 2008 (Rubino et al., Reference Rubino2020). Due to safety concerns and a lack of convincing data for the use of medications in BPSD, alternative treatment approaches are needed.
In “Treatment of Behavioral and Psychological Symptoms of Dementia Using Transcranial Magnetic Stimulation: a Systematic Review,” Murphy et al. present data from randomized controlled trials (RCTs) investigating the use of transcranial magnetic stimulation (TMS) for the treatment of BPSD. They identified 11 RCTs in which individuals with BSPD were treated with TMS and concluded based on the limited data that repetitive TMS may be beneficial for older adults with BPSD, although more data is needed. The best evidence for the use of TMS was for patients presenting with apathy (Murphy et al., Reference Murphy, Khan, Bachu and Tampi2023).
In recent years, more attention has been given to apathy as a prominent symptom of BPSD, with efforts to better understand its underlying neural circuitry (Steffens et al., Reference Steffens, Fahed, Manning and Wang2022). While classically described as a loss of motivation and goal-directed activity, the diagnostic criteria for apathy are defined more specifically now. In 2021, a consensus panel published diagnostic criteria for apathy among people with neurocognitive disorders and described these patients as exhibiting diminished initiative, interest, and/or emotional expression (Miller et al., Reference Miller2021). These changes impair the individual’s functioning and are not attributable to physical changes, psychiatric illness, or substance use (among other qualifiers).
With better definition of apathy, there has also been more scholarly exploration of apathy in the context of neurocognitive disorders. In International Psychogeriatrics, there have been several recent articles highlighting this topic beyond what is described in Murphy et al. Earlier this year, Connors et al. published their investigation of apathy, depression, and mild cognitive impairment (MCI). They found that apathy increases in MCI and is associated with worse clinical outcomes related to cognition, function, caregiver burden, and other neuropsychiatric symptoms (Connors et al., Reference Connors, Teixeira-Pinto, Ames, Woodward and Brodaty2023). An earlier systematic review in the journal examined the prevalence of depression, anxiety, and apathy across dementias less prevalent than Alzheimer’s disease (AD) and found that these neuropsychiatric symptoms were inconsistently investigated with poor sample sizes, necessitating further research (Collins et al., Reference Collins, Henley and Suarez-Gonzalez2020).
Apathy is the most common behavioral symptom seen in AD with a prevalence estimated just below 50% (Zhao et al., Reference Zhao2016). Rates vary across other etiologies of neurocognitive disorder, with apathy seen among 62−89% of patients with behavioral-variant frontotemporal dementia (FTD) (Mendez et al., Reference Mendez, Lauterbach and Sampson2008) and 35−100% of patients with dementia with Lewy Bodies (DLB) (Liu et al., Reference Liu, Cooper, Weintraub and Dahodwala2019). Historically, apathy was likely under-recognized as a form of BPSD because patients with apathy may not have an identifiable symptom at first glance. This is especially true in higher levels of care such as the nursing home setting, in which patients who are more withdrawn are not considered “problematic” and caregivers may not be familiar with the individual’s baseline level of activity and engagement. A psychiatric analogy might be that apathy is to negative symptoms of schizophrenia what agitation is to positive symptoms. The positive symptoms are often more apparent clinically.
Apathy is difficult to treat. Data to support nonpharmacological interventions are mixed with some evidence of benefit when tailored to the individual patient (Brodaty & Burns, Reference Brodaty and Burns2012). There are no FDA-approved medications for the treatment of apathy in the context of BPSD (Steffens et al., Reference Steffens, Fahed, Manning and Wang2022). If medications are being prescribed, it is important to consider the etiology of the patient’s dementia. Acetylcholinesterase inhibitors have demonstrated some benefits in DLB (Liu et al., Reference Liu, Cooper, Weintraub and Dahodwala2019). Selective serotonin reuptake inhibitors may be slightly beneficial for apathy in FTD (Young et al., Reference Young, Lavakumar, Tampi, Balachandran and Tampi2018). For the treatment of apathy in Alzheimer’s disease, there is some evidence for the use of methylphenidate (Rosenberg et al., Reference Rosenberg2013) with insufficient evidence to support the use of either acetylcholinesterase inhibitors or antidepressants (Ruthirakuhan et al., Reference Ruthirakuhan, Herrmann, Abraham, Chan and Lanctot2008).
With this limited data as context, the systematic review of Murphy et al. addresses the need for alternative approaches to the treatment of apathy (and other symptoms of BPSD) by exploring the data to support TMS. TMS has been demonstrated to be a safe treatment for older adults with AD (Freitas et al., Reference Freitas, Mondragon-Llorca and Pascual-Leone2011) and offers a safer alternative to electroconvulsive therapy, which has been shown to be somewhat effective for the management of agitation and aggression in dementia but has higher risk of delirium and potential cardiovascular complications (van den Berg et al., Reference Van den berg, Kruithof, Kok, Verwijk and Spaans2018).
Although the results of Murphy et al.’s systematic review are encouraging, and the treatment appears safe for older adults with dementia, there are additional considerations that may impact the feasibility of using TMS in this population for the treatment of dementia-related apathy and other BPSD. As alluded to in their conclusion, TMS involves multiple sessions of treatment. This poses a logistical hurdle to patients with dementia who rely on caregivers for coordination of care and transportation support. Additionally, for patients with apathy who already are exhibiting diminished initiative, there may be difficulty engaging them to participate in treatments with that degree of frequency. Although there was some variability in duration across the trials cited by Murphy et al., many required participation for as many as 5 days per week for 2−6 weeks. Even among studies that showed benefit for apathy, some did not demonstrate benefit for apathy until after 4 weeks of treatment (Zhang et al., Reference Zhang, Qin, Xie, Zheng, Huang and Zhang2019) and another showed that benefit for apathy was not sustained 4−8 weeks after treatment (Padala et al., Reference Padala2020). Thus, TMS treatment for apathy may require intensive treatment for several weeks for a benefit that wanes quickly.
As an extension of the limitations of transportation, although TMS is increasingly available, it is not yet practiced in all areas and so it may not be available at a center (private or academic) close enough to the patients to participate. Another potential challenge is that Centers for Medicare and Medicaid Services (CMS) do not identify apathy or BPSD as a clinical indication for treatment with TMS, and a diagnosis of dementia is regarded as a relative contraindication for TMS treatment (cms.gov). More robust data will likely be needed for CMS to consider coverage for this indication.
It is interesting that among the available studies there did not appear to be a significant benefit of TMS for depressive symptoms. Part of the difficulty in evaluating the literature on TMS for BPSD is that BPSD are largely heterogeneous, so having enough subjects to participate in RCTs who have depression as a component of their BPSD presentation may be difficult. In a clinical setting, depression may be considered as a separate diagnosis rather than a neuropsychiatric symptom secondary to dementia. Some studies demonstrated global improvement for BPSD without reporting significant benefit for individual subscales (Murphy et al., Reference Murphy, Khan, Bachu and Tampi2023), so it is possible that improvement for depressive symptoms contributed to the overall Neuropsychiatric Inventory (NPI) improvements.
In summary, effective nonpharmacological treatments for BPSD are needed. Among symptoms of BPSD, apathy is one of the most common and most difficult to treat. TMS shows some potential as an alternative and effective treatment for apathy in dementia, but logistical and financial challenges may make its implementation impractical. Despite these limitations, the research to date serves as a step in the right direction, especially for a neuropsychiatric symptom like apathy that often flies under the radar.
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Behavioral and psychological symptoms of dementia (BPSD) are neuropsychiatric symptoms that occur in the context of Alzheimer’s disease and related dementias (ADRD). The range of symptoms may include anxiety, depression, irritability, sleep disturbance, agitation, aggression, psychosis, and apathy (Lyketsos et al., Reference Lyketsos, Lopez, Jones, Fitzpatrick, Breitner and DeKosky2002). BPSD are associated with poorer outcomes for patients with dementia, including mortality and earlier transition from living at home to higher levels of care. BPSD also have significant implications for caregivers, including increased anxiety, depression, sleep disturbance, and poor medical outcomes (Alzheimer’s Association, 2023). In many ways, BPSD are more debilitating for patients and caregivers than the progressive memory decline that is the hallmark of ADRD.
Because of the burden of BPSD on our patients and their caregivers, effective treatment approaches are imperative. Nonpharmacological interventions are considered first line, and typically focus on addressing underlying medical, social, emotional, and environmental triggers leading to the development of symptoms (Kales et al., Reference Kales, Gitlin and Lyketsos2014). BPSD are not “one size fits all” in either presentation or treatment, requiring close investigation of these and other triggers. Time and effort are required both by the treatment team and caregivers to develop individualized plans that are mindful of the specific variables involved in BPSD triggers and reactions.
When nonpharmacological approaches are either undereffective or ineffective, and also for situations in which there might be emergent safety concerns, pharmacological treatments of BPSD may be considered. There are no FDA-approved medications for the treatment of the neuropsychiatric symptoms of ADRD (Kales et al., Reference Kales, Gitlin and Lyketsos2014). Choice of medications is made based on the patient’s medical and psychiatric history, predominant symptom presentation, medication safety profile, and other individual factors. Among the most concerning safety issues is regarding the use of antipsychotics for patients with ADRD: in 2005, the FDA issued a black-box warning against the use of atypical antipsychotics in older adults with dementia due to increased risk of death. This warning was extended to all antipsychotics in 2008 (Rubino et al., Reference Rubino2020). Due to safety concerns and a lack of convincing data for the use of medications in BPSD, alternative treatment approaches are needed.
In “Treatment of Behavioral and Psychological Symptoms of Dementia Using Transcranial Magnetic Stimulation: a Systematic Review,” Murphy et al. present data from randomized controlled trials (RCTs) investigating the use of transcranial magnetic stimulation (TMS) for the treatment of BPSD. They identified 11 RCTs in which individuals with BSPD were treated with TMS and concluded based on the limited data that repetitive TMS may be beneficial for older adults with BPSD, although more data is needed. The best evidence for the use of TMS was for patients presenting with apathy (Murphy et al., Reference Murphy, Khan, Bachu and Tampi2023).
In recent years, more attention has been given to apathy as a prominent symptom of BPSD, with efforts to better understand its underlying neural circuitry (Steffens et al., Reference Steffens, Fahed, Manning and Wang2022). While classically described as a loss of motivation and goal-directed activity, the diagnostic criteria for apathy are defined more specifically now. In 2021, a consensus panel published diagnostic criteria for apathy among people with neurocognitive disorders and described these patients as exhibiting diminished initiative, interest, and/or emotional expression (Miller et al., Reference Miller2021). These changes impair the individual’s functioning and are not attributable to physical changes, psychiatric illness, or substance use (among other qualifiers).
With better definition of apathy, there has also been more scholarly exploration of apathy in the context of neurocognitive disorders. In International Psychogeriatrics, there have been several recent articles highlighting this topic beyond what is described in Murphy et al. Earlier this year, Connors et al. published their investigation of apathy, depression, and mild cognitive impairment (MCI). They found that apathy increases in MCI and is associated with worse clinical outcomes related to cognition, function, caregiver burden, and other neuropsychiatric symptoms (Connors et al., Reference Connors, Teixeira-Pinto, Ames, Woodward and Brodaty2023). An earlier systematic review in the journal examined the prevalence of depression, anxiety, and apathy across dementias less prevalent than Alzheimer’s disease (AD) and found that these neuropsychiatric symptoms were inconsistently investigated with poor sample sizes, necessitating further research (Collins et al., Reference Collins, Henley and Suarez-Gonzalez2020).
Apathy is the most common behavioral symptom seen in AD with a prevalence estimated just below 50% (Zhao et al., Reference Zhao2016). Rates vary across other etiologies of neurocognitive disorder, with apathy seen among 62−89% of patients with behavioral-variant frontotemporal dementia (FTD) (Mendez et al., Reference Mendez, Lauterbach and Sampson2008) and 35−100% of patients with dementia with Lewy Bodies (DLB) (Liu et al., Reference Liu, Cooper, Weintraub and Dahodwala2019). Historically, apathy was likely under-recognized as a form of BPSD because patients with apathy may not have an identifiable symptom at first glance. This is especially true in higher levels of care such as the nursing home setting, in which patients who are more withdrawn are not considered “problematic” and caregivers may not be familiar with the individual’s baseline level of activity and engagement. A psychiatric analogy might be that apathy is to negative symptoms of schizophrenia what agitation is to positive symptoms. The positive symptoms are often more apparent clinically.
Apathy is difficult to treat. Data to support nonpharmacological interventions are mixed with some evidence of benefit when tailored to the individual patient (Brodaty & Burns, Reference Brodaty and Burns2012). There are no FDA-approved medications for the treatment of apathy in the context of BPSD (Steffens et al., Reference Steffens, Fahed, Manning and Wang2022). If medications are being prescribed, it is important to consider the etiology of the patient’s dementia. Acetylcholinesterase inhibitors have demonstrated some benefits in DLB (Liu et al., Reference Liu, Cooper, Weintraub and Dahodwala2019). Selective serotonin reuptake inhibitors may be slightly beneficial for apathy in FTD (Young et al., Reference Young, Lavakumar, Tampi, Balachandran and Tampi2018). For the treatment of apathy in Alzheimer’s disease, there is some evidence for the use of methylphenidate (Rosenberg et al., Reference Rosenberg2013) with insufficient evidence to support the use of either acetylcholinesterase inhibitors or antidepressants (Ruthirakuhan et al., Reference Ruthirakuhan, Herrmann, Abraham, Chan and Lanctot2008).
With this limited data as context, the systematic review of Murphy et al. addresses the need for alternative approaches to the treatment of apathy (and other symptoms of BPSD) by exploring the data to support TMS. TMS has been demonstrated to be a safe treatment for older adults with AD (Freitas et al., Reference Freitas, Mondragon-Llorca and Pascual-Leone2011) and offers a safer alternative to electroconvulsive therapy, which has been shown to be somewhat effective for the management of agitation and aggression in dementia but has higher risk of delirium and potential cardiovascular complications (van den Berg et al., Reference Van den berg, Kruithof, Kok, Verwijk and Spaans2018).
Although the results of Murphy et al.’s systematic review are encouraging, and the treatment appears safe for older adults with dementia, there are additional considerations that may impact the feasibility of using TMS in this population for the treatment of dementia-related apathy and other BPSD. As alluded to in their conclusion, TMS involves multiple sessions of treatment. This poses a logistical hurdle to patients with dementia who rely on caregivers for coordination of care and transportation support. Additionally, for patients with apathy who already are exhibiting diminished initiative, there may be difficulty engaging them to participate in treatments with that degree of frequency. Although there was some variability in duration across the trials cited by Murphy et al., many required participation for as many as 5 days per week for 2−6 weeks. Even among studies that showed benefit for apathy, some did not demonstrate benefit for apathy until after 4 weeks of treatment (Zhang et al., Reference Zhang, Qin, Xie, Zheng, Huang and Zhang2019) and another showed that benefit for apathy was not sustained 4−8 weeks after treatment (Padala et al., Reference Padala2020). Thus, TMS treatment for apathy may require intensive treatment for several weeks for a benefit that wanes quickly.
As an extension of the limitations of transportation, although TMS is increasingly available, it is not yet practiced in all areas and so it may not be available at a center (private or academic) close enough to the patients to participate. Another potential challenge is that Centers for Medicare and Medicaid Services (CMS) do not identify apathy or BPSD as a clinical indication for treatment with TMS, and a diagnosis of dementia is regarded as a relative contraindication for TMS treatment (cms.gov). More robust data will likely be needed for CMS to consider coverage for this indication.
It is interesting that among the available studies there did not appear to be a significant benefit of TMS for depressive symptoms. Part of the difficulty in evaluating the literature on TMS for BPSD is that BPSD are largely heterogeneous, so having enough subjects to participate in RCTs who have depression as a component of their BPSD presentation may be difficult. In a clinical setting, depression may be considered as a separate diagnosis rather than a neuropsychiatric symptom secondary to dementia. Some studies demonstrated global improvement for BPSD without reporting significant benefit for individual subscales (Murphy et al., Reference Murphy, Khan, Bachu and Tampi2023), so it is possible that improvement for depressive symptoms contributed to the overall Neuropsychiatric Inventory (NPI) improvements.
In summary, effective nonpharmacological treatments for BPSD are needed. Among symptoms of BPSD, apathy is one of the most common and most difficult to treat. TMS shows some potential as an alternative and effective treatment for apathy in dementia, but logistical and financial challenges may make its implementation impractical. Despite these limitations, the research to date serves as a step in the right direction, especially for a neuropsychiatric symptom like apathy that often flies under the radar.
Conflicts of interest
None.
Acknowledgements
Thanks to Dr Neha Jain for assistance with the title of this paper.