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Medical approaches to treating dementia and Alzheimer disease have been mostly unsuccessful. In this Mental Health Minute, Peter J. Whitehouse, MD, PhD, recommends that clinicians go beyond biomedical approaches. Instead, he advocates a suite of public health approaches, based on the research in his latest book, 

American Dementia: Brain Health in an Unhealthy Society

is professor of Neurology and Psychiatry at Case Western Reserve University, and professor of Medicine at the University of Toronto. Along with Daniel R. George, PhD, MSc, of 

How could you incorporate public health into your practice? 

Share comments with your colleagues by emailing 

. Comments may be shared online pending review and editing for style.

Decades of efforts to find effective medical treatments for dementia and Alzheimers disease have largely failed. Would a public health approach be more effective? 

New Directions for Alzheimer and Dementia Treatment

When it comes to Alzheimer disease (AD) and dementia, treatment gets more attention than prevention. Maybe it is time for that to change, because by combining preventative measures, it is possible to improve up to 40% of the overall risk factors for diseases like AD.

In this Mental Health Minute, James Galvin, MD, MPH, suggests simple but evidence-supported behavioral plans that psychiatrists can recommend to their patients.

is a professor of neurology at the University of Miami Miller School of Medicine and founding director of the Comprehensive Center for Brain Health.

How do you help your patients maintain their brain health? 

What advice can clinicians give patients to lower their overall risk for neurodegenerative diseases? 

How to Reduce the Risk of Late-Life Dementia—Starting in Childhood

The English word apathy originates from the Greek word apathes, which means “without pathos or feeling,”

 but scholars have shared various definitions. For example, Robert S. Martin, MD, defined apathy as a syndrome of primary motivational loss that is not attributable to emotional distress, intellectual impairment, or 

 According to Drs Richard Levy and Bruno Dubois apathy is the quantitative reduction of self-generated voluntary and purposeful behaviors, which are observable and can be quantified.

 In addition, the underlying mechanism(s) responsible for apathy may be seen as dysfunctions occurring at the level of elaboration, execution, and control of goal-directed behaviors. According to an international consensus criterion, apathy is defined as a disorder of motivation in which the symptoms are present for at least 4 weeks.

 In addition, 2 of the following 3 should be present: reduced goal-directed behavior, reduced goal-directed cognitive activity, and reduced emotions. Furthermore, these symptoms cause clinically significant impairments in personal, social, occupational, or other important areas of functioning, with such symptoms not exclusively explained by or due to other causes (ie, physical disabilities [such as blindness or loss of hearing], motor disabilities, diminished level of consciousness, or direct physiological effects of a substance [such as a drug of abuse or a medication]).

 of individuals who have no cognitive deficits.

 It is also seen among individuals with major depressive disorder, schizophrenia, strokes, multiple sclerosis, and traumatic brain injury. Apathy is more prevalent among individuals with neurodegenerative disorders than in those free of such disorders.

Apathy has been noted throughout the spectrum of neurocognitive disorders (

 The prevalence rates for apathy among individuals with mild cognitive impairment ranges from 

 Apathy is also the most frequently reported behavioral symptom among individuals with dementia. The results of one study showed that individuals with frontotemporal dementia (FTD) and vascular dementia (VaD) report more severe apathy than individuals with Alzheimer disease (AD).

Apathy usually appears early in dementia and tends to persist throughout; it is associated with longer illness duration and it worsens with the 

 Risk factors for developing apathy include older age and greater severity of cognitive impairment. Akyol et al found that apathy was correlated with the degree of cognitive impairment among individuals with AD and VaD, but not with FTD; but apathy did not correlate with age or gender in individuals with AD, FTD, and VaD. Additionally, the degree of apathy correlated with the level of functional impairment and dementia severity across all 3 types of dementia.

Individuals with dementia who present with apathy often have more rapid cognitive decline and are more impaired in their activities of daily living.

 In addition, apathy increases the risk for earlier institutionalization among individuals with dementia.

 Distress is also significantly higher among caregivers of individuals with dementia who have apathy, when compared with individuals with dementia without it.

Emerging evidence indicates that apathy in individuals with dementia occurs due to a complex interaction among neuroanatomy, neuropathology, neurochemistry, and genetics.

 Among individuals with AD, apathy is associated with an increased neurofibrillary tangle burden in the parahippocampal, frontal, and parietal regions, in addition to the anterior cingulate gyrus. Emerging evidence indicates that the severity of apathy is also associated with amyloid plaque burden, especially in bilateral frontal cortices and the right anterior cingulate gyrus along with 

One study that evaluated the cerebrospinal fluid (CSF) biomarkers among individuals with AD showed that apathy was significantly correlated with tau and p-tau, but not with amyloid β١–٤٢.

 Another study examined regions of cortical thinning and CSF biomarkers (amyloid-β ١-٤٢, total tau, and phosphorylated tau) among 3 groups—clinically normal elderly individuals, individuals with mild cognitive impairment, and individuals with mild AD dementia with apathy—and found that reduced baseline inferior temporal cortical thickness was predictive of increasing apathy over time.

 The investigators of this study did not find any association between CSF biomarkers and the severity of apathy in cross-sectional or longitudinal analyses.

Another study found that individuals with AD and apathy had a loss of white matter integrity in the genu of the corpus callosum when compared with individuals with AD without apathy.

 In addition, the loss of white matter integrity in the genu, body, and splenium of the corpus callosum was negatively correlated with the severity of apathy among individuals with AD. Neuroradiological studies indicate that the dysfunction of the anterior cingulate cortex is the strongest anatomical correlate of apathy in AD, whereas lesions of the basal ganglia are the most common correlates of apathy in cerebrovascular disorders.

Neuroimaging studies indicate that the apathy among individuals with behavioral variant of FTD is associated with prominent atrophy in: the dorsal anterior cingulate cortex, dorsolateral prefrontal cortex, right caudate (including the ventral striatum), right temporoparietal junction, right posterior inferior and middle temporal gyri, and left frontal operculum-anterior insula region.

A recent meta-analysis that analyzed data from 41 studies indicated that apathy is associated with hypometabolism and a decrease in gray matter volume in the left inferior frontal gyrus.

 The investigators also found altered brain perfusion and decreased gray matter volume in the anterior cingulate cortex among individuals with AD, and decreased gray matter volume in the inferior frontal gyrus and parietal cortex among individuals with FTD. These findings indicate that apathy occurs due to a cortical dysfunction of areas involved with executive cognitive processing (action planning) and emotional regulation (autoactivation and reward processing).

Individuals with AD and apathy have been found to have reduced dopaminergic activity in the putamen, reduced acetylcholine in the lateral frontal cortex, and lower levels of plasma gamma-aminobutyric acid.

 In evaluating the association between apolipoprotein E ɛ4 allele and apathy in probable AD, investigators found that the presence of this allele was indeed significantly associated with apathy in these individuals.

Among individuals with dementia, the assessment of apathy is often complicated. It is particularly difficult to distinguish between reduced motivation to do things due to apathy and the loss of ability or motivation secondary to cognitive dysfunction. Additionally, there may be overlap between symptoms of apathy and depression (

 Often, as well, psychotropic medications (ie, antipsychotics, antidepressants) are used to treat neuropsychiatric symptoms (NPS) of dementia, and the adverse effects of these medications include fatigue, lethargy, listlessness, and decreased initiative to respond to external stimuli. These AEs can mimic symptoms of apathy among individuals with dementia.

The scales that have been developed for the assessment of apathy include the Apathy Evaluation Scale (AES), the Structured Clinical Interview for Apathy, the Apathy Scale, the Apathy Inventory, the Dementia Apathy Interview and Rating (DAIR), and the Lille Apathy Rating Scale (LARS).

 Among these scales, only the DAIR was designed for use among individuals with dementia. The Apathy Scale for Dementia Patients in Nursing Homes was designed to measure apathy among individuals with dementia who live in institutional settings.

 The Neuropsychiatric Inventory (NPI) is considered the gold standard for the assessment of NPS among individuals with dementia. However, the use of a single domain from the NPS prevents a comprehensive assessment of all dimensions of apathy among individuals with dementia. A recent systematic review found that the DAIR, the AES–clinical version (AES-C) in AD, and the LARS in Parkinson disease (PD) had psychometrically favorable qualities and the highest quality among the scales used to assess apathy among individuals with neurodegenerative disorders.

Available evidence indicates that both nonpharmacological and pharmacological treatment modalities can benefit individuals with dementia who present with apathy (

A systematic review by Brodaty et al found that therapeutic activities—including stimulation, creative activities, cooking, Montessori methods, music, exercise, multisensory stimulation, and pet therapy—as well as placement in special care units may improve apathy among individuals with dementia.

 Another recent systematic review by Cai et al, evaluating the effectiveness of nonpharmacological interventions among individuals with dementia and apathy, also found that multisensory stimulation, music therapy, cognitive stimulation, and pet therapy are useful in improving symptoms of apathy.

 Cai et al found limited evidence as well for the efficacy of art, exercise, reminiscence, and occupational therapies; dementia special care units; comprehensive interventions; nursing staff education; and behavioral management techniques (ie, therapeutic conversations, progressive muscle relaxation). They found that the effects of psychomotor therapy and validation therapy were still unclear; evidence also indicates that receptive music therapy is better than interactive music therapy. Pet therapy that includes the introduction of domestic pets and companion robots tends to reduce loneliness and improve well-being. Tailoring the overall lifestyle of individuals with dementia to increase recreational activities, physical exercise, cognitive stimulation, and social activities also reduces apathy.

Various pharmacological agents have been trialed for the treatment of apathy,

 including acetylcholinesterase inhibitors (ChEIs), memantine, stimulants, calcium antagonists, and antipsychotics.

 In their systematic review and meta-analysis, Sepehry et al found a total of 15 randomized controlled trials that assessed the efficacy of pharmacotherapy.

 For cognitive enhancers (donepezil and galantamine), there was no was significant effect of treatment on apathy (Hedges’ g = –0.055; 

 = .687). The average donepezil dosage was 10 mg/day, while galantamine dosage ranged between 16 mg/day and 32 mg/day. All but 1 study used the NPI-apathy subscale as an outcome measure, and these trials included individuals with mild-to-severe AD.

For memantine, the investigators found a small and nonsignificant benefit for apathy (Hedges g = .092; P = .423). The average dose of memantine was 20 mg/day, and the trials included individuals with moderate-to-severe AD and used the NPI-apathy subscale. The effect of psychostimulants on apathy was small and nonsignificant when compared with placebo (Hedges’ g = –.063; 

 = .903). All stimulant trials included individuals with mild-to-moderate AD, used multiple scales including the NPI-apathy and Frontal Systems Behavior Scale (FrSBe) apathy subscale, and included mixed drugs with noncomparable dosages. The investigators did not find enough individual studies to do a meta-analysis for antipsychotics and drug classes with antidepressant properties, but the data from the individual atypical antipsychotic studies did not support their use for apathy in AD. The investigators indicated that the analysis for cognitive enhancers and memantine were appropriately powered, whereas the psychostimulant studies were underpowered due to limited patient enrollment in each arm of the trials.

In another quantitative meta-analysis, Ruthirakuhan et al included data from 21 studies.

 The investigators found that methylphenidate may improve apathy when compared with placebo; this held true when apathy was assessed using the AES (mean difference [MD] = – 4.99) but not when using the NPI-apathy subscale (MD = –.08).

The investigators further found that methylphenidate may also improve cognition (MD = –.08) and instrumental activities of daily living (MD = 2.30), when compared with placebo. There was no difference between methylphenidate and placebo in the risk of developing an adverse event (risk ratio = 1.28). The investigators indicated that there was insufficient evidence from a small study of modafinil to determine its effect on apathy assessed with the FrSBe-apathy subscale (MD = 0.27). They reported that in all other included studies, apathy was a secondary outcome and participants were not selected on the basis of clinically significant apathy at baseline. The investigators considered the evidence on apathy from these studies to be indirect and associated with publication bias. They reported that there was low or very low quality of evidence on ChEIs, ChEI discontinuation, antipsychotics, antipsychotic discontinuation, antidepressants (2 studies), and valproate for the treatment of apathy in dementia.

A recent systematic review by Theleritis et al evaluated data from 90 unique studies and relevant reviews but noted that in many studies, apathy was not considered the primary outcome measure.

 They concluded that after considering the amount of evidence, ChEIs may be the best available pharmacological treatment choice for the treatment of apathy, while data from 3 studies indicated that gingko biloba may also be effective. The investigators found weaker evidence for memantine’s efficacy. Stimulants like methylphenidate alone or in combination with ChEIs were found to be beneficial in treating apathy. Atypical antipsychotics, however, appear to have limited benefit for this purpose, and their long-term use is not recommended due to their adverse effect profile. Data from one study indicated that the combination of citalopram and memantine reduced apathy among individuals with AD when compared with placebo.

Apathy can be described as the quantitative reduction of self-generated voluntary and purposeful behaviors that are observable and quantifiable. Apathy commonly presents in individuals with many different illnesses, including major depressive disorder, schizophrenia, strokes, multiple sclerosis, and traumatic brain injury. However, apathy is more prevalent among individuals with neurodegenerative disorders, including dementias. Among individuals with dementia, apathy is considered to be the most frequently reported behavioral symptom. Apathy worsens morbidity and mortality in AD and is associated with greater caregiver distress.

The exact neurobiological mechanisms associated with apathy in dementia are unclear, but emerging evidence indicates a complex interaction among neuroanatomy, neuropathology, neurochemistry, and genetics. The assessment of apathy is often complicated, and it is difficult to distinguish between reduced initiative to do things due to the loss of cognitive ability vs the loss of motivation due to apathy. In addition, there may be an overlap between symptoms of apathy and depression. Among the many scales that have been developed to assess apathy, the DAIR, the AES-C in AD, and the LARS in PD have the highest quality. Emerging evidence indicates efficacy for both nonpharmacological and pharmacological treatments for improving apathy. Multisensory stimulation, music therapy, cognitive stimulation, and pet therapy are beneficial nonpharmacological treatments; and among pharmacotherapy options, ChEIs may be the best available treatment choice, followed by gingko biloba, memantine, and stimulants like methylphenidate either alone or in combination with ChEIs.

Future directions in the evaluation of apathy in dementia should include the study of animal models as well as genetic studies that improve the knowledge of the neurobiological mechanisms underlying this condition. In addition, well-designed clinical trials of nonpharmacologic and pharmacological interventions that exclusively target apathy in dementia are needed. These trials should assess not only the symptomatic improvement of apathy but also evaluate its effect on the individual’s functioning and on caregiver burden. These studies should use advances in both neuroimaging techniques and biomarkers to provide surrogate metrics for treatment response.

is chairman of the Department of Psychiatry & Behavioral Sciences, Cleveland Clinic Akron General, Akron, Ohio; chief, Section for Geriatric Psychiatry, Cleveland Clinic, Ohio; and professor of medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio; The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

1. Cipriani G, Lucetti C, Danti S, Nuti A. Apathy and dementia. nosology, assessment and management. 

2. Marin RS. Apathy: a neuropsychiatric syndrome. 

3. Levy R, Dubois B. Apathy and the functional anatomy of the prefrontal cortex–basal ganglia circuits. 

4. Robert P, Onyike CU, Leentjens AFG, et al. Proposed diagnostic criteria for apathy in Alzheimer’s disease and other neuropsychiatric disorders. 

5. Harrison F, Aerts L, Brodaty H. Apathy in dementia: systematic review of recent evidence on pharmacological treatments. 

6. Theleritis C, Politis A, Siarkos K, Lyketsos CG. A review of neuroimaging findings of apathy in Alzheimer’s disease. 

7. Lanctôt KL, Agüera-Ortiz L, Brodaty H, et al. Apathy associated with neurocognitive disorders: recent progress and future directions. 

8. Sherman C, Liu CS, Herrmann N, Lanctôt KL. Prevalence, neurobiology, and treatments for apathy in prodromal dementia. 

9. Berman K, Brodaty H, Withall A, Seeher K. Pharmacologic treatment of apathy in dementia. 

10. van Dyck CH, Arnsten AFT, Padala PR, et al. Neurobiologic rationale for treatment of apathy in Alzheimer’s disease with methylphenidate. 

11. Mele B, Van S, Holroyd-Leduc J, et al. Diagnosis, treatment and management of apathy in Parkinson’s disease: a scoping review. 

12. Akyol MA, Küçükgüçlü Ö, Yener G. Investigation of factors affecting apathy in three major types of dementia. 

13. Sepehry AA, Sarai M, Hsiung G-YR. Pharmacological therapy for apathy in Alzheimer’s disease: a systematic review and meta-analysis. 

14. Mori T, Shimada H, Shinotoh H, et al. Apathy correlates with prefrontal amyloid β deposition in Alzheimer’s disease. 

15. Marshall GA, Donovan NJ, Lorius N, et al. Apathy is associated with increased amyloid burden in mild cognitive impairment. 

16. Skogseth R, Mulugeta E, Jones E, et al. Neuropsychiatric correlates of cerebrospinal fluid biomarkers in Alzheimer’s disease. 

17. Donovan NJ, Wadsworth LP, Lorius N, et al; Alzheimer Disease Neuroimaging Initiative. Regional cortical thinning predicts worsening apathy and hallucinations across the Alzheimer disease spectrum. 

18. Hahn C, Lim H-K, Won WY, et al. Apathy and white matter integrity in Alzheimer’s disease: a whole brain analysis with tract-based spatial statistics. 

19. Starkstein SE, Brockman S. The neuroimaging basis of apathy: empirical findings and conceptual challenges. 

20. Massimo L, Powers C, Moore P, et al. Neuroanatomy of apathy and disinhibition in frontotemporal lobar degeneration. 

21. Eslinger PJ, Moore P, Antani S, et al. Apathy in frontotemporal dementia: behavioral and neuroimaging correlates. 

22. Raimo S, Santangelo G, D’Iorio A, et al. Neural correlates of apathy in patients with neurodegenerative disorders: an activation likelihood estimation (ALE) meta-analysis. 

23. Agüera-Ortiz L, Gil-Ruiz N, Cruz-Orduña I, et al. A novel rating scale for the measurement of apathy in institutionalized persons with dementia: the APADEM-NH. 

24. Radakovic R, Harley C, Abrahams S, Starr JM. A systematic review of the validity and reliability of apathy scales in neurodegenerative conditions. 

25. Brodaty H, Burns K. Nonpharmacological management of apathy in dementia: a systematic review. 

26. Cai Y, Li L, Xu C, Wang Z. The effectiveness of non-pharmacological interventions on apathy in patients with dementia: a systematic review of systematic reviews. 

27. Ruthirakuhan MT, Herrmann N, Abraham EH, et al. Pharmacological interventions for apathy in Alzheimer’s disease. 

28. Theleritis CG, Siarkos KT, Politis AM. Unmet needs in pharmacological treatment of apathy in Alzheimer’s disease: a systematic review. 

29. Zhou T, Wang J, Xin C, et al. Effect of memantine combined with citalopram on cognition of BPSD and moderate Alzheimer’s disease: a clinical trial. 

Apathy occurs throughout the spectrum of neurocognitive disorders, but it is easy to mistake for other conditions, like depression. How can clinicians identify apathy, and treat it?

Addressing Apathy in Dementia

“Sleep problems are understudied,” Ellen Lee, MD, told attendees at the 2021 American Psychiatric Association (APA) Annual Meeting. “They’re underdiagnosed and undertreated in people with mental illness.” Thus, Lee encouraged clinicians to screen for sleep problems, because sleep “is a modifiable and important target for intervention.” Lee, along with other colleagues, shared insights and preliminary research results on how sleep may impact mental health and psychiatric disorders.

Sleep problems affect between 30 and 80% of individuals with schizophrenia and are associated with lower quality of life and poorer cognitive and frontal lobe functioning, explained Lee, assistant professor in residence in the Department of Psychiatry at the University of California at 

 In as-yet unpublished research, Lee found that sleep apnea is associated with increased inflammation, while higher subjective reports of sleep quality are associated with lower levels of inflammation. Since inflammation is also associated with 

 treating sleep problems could also improve the symptoms of mental illnesses.

Beyond schizophrenia, sleep issues also appear in mood disorders like depression. Stephen Smagula, PhD, presented research on possible links between morning activation deficits and depression among family members caring for patients with dementia.

Older individuals with depression often report difficulty getting up and active in the 

 Morning activation deficits are sometimes thought to be immutable (some individuals are just not morning people), but in functional magnetic resonance imaging readings, dementia caregivers with depression showed higher resting-state amygdala-PCC connectivity, which is associated with stress, fear, and 

 “Although this is speculative,” Smagula cautioned, “it seems plausible that the non-morning type caregivers are doing behaviorally disengaged, emotion-focused coping. So put another way, some caregivers might wake up, feel overwhelmed, say ‘Expletive! I’m going back to bed.’”

This raises the possibility, according to Smagula, who is assistant professor of psychiatry and epidemiology at the University of Pittsburg, that “instead of treating the depression and hoping the morning activation deficit goes away, we could be targeting the morning activation deficit to treat the depression.” Clinicians could consider treatments such as activity scheduling, which would get the caregivers up and moving, increase their light exposure, decrease fragmented sleep, and limit the time they spend ruminating—all of which could improve their depressive symptoms.

Sleep also affects cognition, especially in older adults. Ruth O’Hara, PhD, presented initial data on the impacts of delta activity at sleep onset (DASO). Study participants with DASO demonstrated better affective function overall and over time, which led O’Hara to conclude that testing DASO or other variables may help clinicians predict patients’ cognitive futures. “We think that characterizing sleep dysregulation in older adults may in fact identify valuable biomarkers,” explained O’Hara, who is the Josephine Q. Berry Professor of Psychiatry and Behavioral Sciences at Stanford University. They could “help us predict cognitive decline and onset of dementia, as well as predicting affective dysfunction.”

1. Cohrs S. Sleep disturbances in patients with schizophrenia: impact and effect of antipsychotics. 

2. Keshavan MS, Montrose DM, Miewald JM, Jindal RD. Sleep correlates of cognition in early course psychotic disorders. 

3. Bromundt V, Köster M, Georgiev-Kill A, et al. Sleep-wake cycles and cognitive functioning in schizophrenia. 

4. Lee EE, Ancoli-Israel S, Eyler LT, et al. Sleep disturbances and inflammatory biomarkers in schizophrenia: focus on sex differences. 

5. Smagula SF, Capps CS, Krafty RT. Evaluating the timing of differences in activity related to depression symptoms across adulthood in the United States. 

6. Smagula SF, Karim HT, Ibrahim TS, et al. Resting-state function connectivity associated with being a "morning-type" dementia caregiver and having lower depression symptom severity. 

Sleep problems are understudied, underdiagnosed, and undertreated. 

Dreaming of New Treatments

 has partially clarified the role of microglia cells in the progression of Alzheimer disease (AD), which in turn may lead to new targets for 

Normally, microglia cells are responsible for clearing out amyloid plaques and other kinds of cellular debris, but in cases of AD progression 

 Investigators at Duke-National University of Singapore (NUS) Medical School and Monash University set out to discover why. “We sought to understand the molecular mechanisms and differences between microglia that were actively engulfing amyloid plaques in Alzheimer’s disease and those that weren’t,” Enrico Petretto, PhD, associate professor at Duke-NUS Medical School, said in a statement to the press.

When comparing microglia that were and were not eliminating amyloid plaque, Petretto and his co-investigators found that they had different gene expression patterns induced by the 

 gene. The researchers found that microglia cells with reduced 

 expression also had a decreased ability to take up and eliminate an abnormal protein like amyloid. Conversely, high expressions of 

 were associated with more active and effective microglia cells.

“Understanding this mechanism is important because now we have several new targets to go after, and in the future, these targets may open a new front against this devastating disease,” added Jose M. Polo, PhD, an ARC Future Fellow at Monash University.

 This research is built on a larger Duke-NUS initiative to create a comprehensive map of gene expression changes that are associated with AD 

 and AD remains incompletely understood, “future work could focus on using gene editing tool CRISPR to test the impact of manipulating Hif1a on symptom severity and disease progression,” Gabriel Chow, MD-PhD candidate at Duke-NUS Medical School, further explained.

1. Grubman A, Choo XY, Chew G, et al. Transcriptional signature in microglia associated with Aβ plaque phagocytosis. 

Scientists discover gene signature for plaque-eating microglia in Alzheimer’s disease

Duke-NUS study reveals how individual cell types in the brain contribute to Alzheimer’s disease

. Duke-NUS Medical School. November 28, 2019. Accessed May 27, 2021. 

Gene expressions in microglia cells may explain why some of them are ineffective and allow dementia to progress. 

A New Target for Intervention in Alzheimer Disease? 

The US Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) to Acadia Pharmaceuticals regarding their supplemental New Drug Application (sNDA) for pimavanserin for the treatment of hallucinations and delusions in patients with dementia-related psychosis (DRP). The FDA indicated the application cannot be approved in its current state.

The CRL cited the lack of substantial evidence of effectiveness needed for approval—specifically, lack of statistical significance in some of the subgroups of dementia and insufficient numbers of patients with less common forms of dementia.

“Acadia stands behind the robustly positive results from the pivotal Phase 3 HARMONY study and the prospectively agreed trial design and criteria for establishing efficacy in DRP. Over the entire course of the review, the Division did not raise any concerns regarding the agreed upon study design, including the issues raised in the CRL,” said Steve Davis, Chief Executive Officer of Acadia. “We will immediately request a Type A meeting to work with the FDA to address the CRL and determine an expeditious path forward for the approval of pimavanserin in DRP.”

Type A meetings are considered “immediately necessary for an otherwise stalled drug development program to proceed,” according to the 

Prior agreements with the FDA Division of Psychiatry regarding the pivotal phase 3 HARMONY study design concluded the intent was to target a broad DRP patient population analyzed as a single group. Prespecified requirements did not include statistical separation by dementia subgroups and minimum numbers of patients with specific subtypes.

The CRL also stated that the phase 2 Alzheimer disease psychosis study -019, a supportive study included in the sNDA filing, was inadequate and not well controlled.

 Reasoning for this belief included that it was a single center study, and there was no type I error control of secondary endpoints in which protocol deviations took place. Despite this, Acadia believes there is no impact on the positive results, nor on the study’s overall efficacy.

1. Acadia Pharmaceuticals. Acadia Pharmaceuticals receives Complete Response Letter from US FDA for supplemental New Drug Application for pimavanserin for the treatment of hallucinations and delusions associated with dementia-related psychosis. News release. April 5, 2021. 

https://www.businesswire.com/news/home/20210405005229/en/Acadia-Pharmaceuticals-Receives-Complete-Response-Letter-from-U.S.-FDA-for-Supplemental-New-Drug-Application-for-Pimavanserin-for-the-Treatment-of-Hallucinations-and-Delusions-Associated-with-Dementia-Related-Psychosis

2. US Food and Drug Administration. Type A Meetings. Accessed April 7, 2021. 

https://www.accessdata.fda.gov/cder/sb-navigate/topic3/topic3/da_01_03_0090.htm

3. Park B. FDA rejects pimavanserin sNDA for dementia-related psychosis. 

https://www.empr.com/home/news/drugs-in-the-pipeline/fda-rejects-pimavanserin-snda-for-dementia-related-psychosis/

CRL cites lack of substantial evidence of efficacy needed for approval. 

Dementia-Related Psychosis Treatment Receives Complete Response Letter

The medical science and research company Clarivate has named aducanumab, a potential Alzheimer disease (AD) treatment, as one of its top 5 “Drugs to Watch 2021.”

 Clarivate, which has published the “Drugs to Watch” list 

, included aducanumab on the list because it has a new mechanism of action and would be the first novel therapeutic for AD in more than 15 years. The company selects drugs in phase 2 or 3 trials that have the potential to bring in $1 billion in sales 

. Aducanumab is in phase 3 trials, and the US Food and Drug Administration (FDA) has promised to render its verdict in June.

, expects it will be a game changer. Lavretsky, professor in-residence in the Department of Psychiatry at the University of California, Los Angeles, told 

, “It will revolutionize Alzheimer disease treatment and care, and will have a profound impact on the lives of millions of family caregivers, who will be relieved from caring for their relatives, or the time of caregiving will be shortened, improving lives of millions of people around the world, and reducing the cost of the disease to the society.”

Aducanumab would be the first approved drug in the last 15 years that could slow down the cognitive decline associated with AD. 

, for cases across the spectrum from mild to severe, are 

The drug might address a root cause of AD. It builds on the amyloid cascade hypothesis, in which “production and accumulation of excessive amyloid-β (Aβ) may be the main cause in the onset and progression of Alzheimer's disease.”

 If so, removing or lowering of Aβ in patients with presymptomatic and early AD could be an effective therapy, and even used as a preventive, subunit vaccine.

, noted, “this drug will be the first antiamyloid therapy and disease modifying therapy for Alzheimer disease.” Tampi is professor and chairman of the Department of Psychiatry & Behavioral Sciences at the Cleveland Clinic. Lavretsky described aducanumab as a “breakthrough treatment with a novel mechanism as recombinant chimeric human IgG1 mAb targeting beta-amyloid.”

Excitement is especially strong for the drug since innovation in therapies for AD has been frustratingly slow. The problem, Tampi explained, is that AD is caused by neurological degeneration, and “it is very difficult to develop different therapies to reverse these neurobiological changes in the brain.”

Finding effective treatments has also been difficult due to “uncertainty about the underlying mechanisms of the disease, the reliance on postmortem diagnosis, and the lack of reliable biomarkers for disease early diagnosis and progression, despite almost 120-year history of research,” Lavretsky added. “Many potential therapies failed to document efficacy and did not achieve the FDA approvals.”

Sure enough, despite its promise, aducanumab has had its own set of struggles. Last November brought disappointment, when the FDA published a negative review of aducanumab, citing insufficient evidence of clinical efficacy.

The news was especially disappointing, given aducanumab’s success in previous trials. In 2015, aducanumab underwent two phase 3 efficacy trials.

 The 221AD301 ENGAGE study enrolled 1350 participants with mild cognitive impairment due to AD. It compared monthly infusions of 1 or 3 doses of aducanumab with placebo over an 18-month period, and their effects on cognitive decline. In 2017 and 2018, data from the trials showed that the treatment was slowing cognitive decline. Consequently, aducanumab became the first such DMT for AD to demonstrate clinical efficacy in a phase 3 trial.

However, in March 2019 Biogen and Eisai announced termination of ongoing aducanumab trials, due to missing primary endpoints.

 Despite the termination, further analysis of the data suggested that a subgroup of participants experienced slower cognitive decline.

Trials resumed on January 27, 2020, when Biogen announced a phase 3b study of 2400 participants who had previously used aducanumab.

 Participants were scheduled to receive monthly injections over the next 2 years. Based on this trial, Biogen requested priority review from the FDA for licensing. The FDA turned down the application in November 2020, citing the weakness of efficacy data.

After aducanumab’s developers, Biogen Inc and Eisai Co Ltd, submitted additional data, the FDA extended its decision date to June 7, 2021.

If approved, aducanumab would meet an enormous need.

“It will offer a new hope to patients and their families and therapeutic optimism to geriatric clinicians and researchers,” said Lavretsky.

https://clarivate.com/drugs-to-watch/drugs-to-watch-listing/aducanumab/

2. Yu YZ, Xu Q. Prophylactic immunotherapy of Alzheimer's disease using recombinant amyloid-β B-cell epitope chimeric protein as subunit vaccine. 

3. Talan J. FDA Panel Votes ‘No’ to Approving Audcanumab for Alzheimer’s, Citing Inconsistent Data. 

. December 3, 2020. Accessed March 9, 2021. 

https://journals.lww.com/neurotodayonline/Fulltext/2020/12030/FDA_Panel_Votes__No__to_Approving_Aducanumab_for.1.aspx

4. Aducanumab. Therapeutics. Alzforum: networking for a cure. Accessed March 9, 2021. 

https://www.alzforum.org/therapeutics/aducanumab

5. Biogen/Eisai Halt Phase 3 Aducanumab Trials. Alzforum: networking for a cure. March 21, 2019. Accessed March 9, 2021. 

https://www.alzforum.org/news/research-news/biogeneisai-halt-phase-3-aducanumab-trials

6. Biogen and Eisai Announce FDA’s 3-Month Extension of Review Period for the Biologics License Application for Aducanumab. News release. GlobeNewswire. January 29, 2021. Accessed March 9, 2021. 

https://www.globenewswire.com/news-release/2021/01/29/2166560/0/en/Biogen-and-Eisai-Announce-FDA-s-3-Month-Extension-of-Review-Period-for-the-Biologics-License-Application-for-Aducanumab.html

Aducanumab is named 1 of the 5 “Drugs to Watch” for 2021.

Is the First Disease-Modifying Therapy for Alzheimer Disease on the Horizon?

Gary Small, MD, talks about dementia-related psychosis and the one of the tools he's utilizing to help: Acadia Pharmaceutical's 

is Chair of Psychiatry and Physician in Chief for Behavioral Health at Hackensack Meridian Health.

About 2.4 million people in the US experience dementia related psychosis, yet only half ever receive a diagnosis. 

Treating Symptoms of Dementia-Related Psychosis

In this conclusion of his miniseries on dementia, John J. Miller, MD, talks about keeping everyone safe when patients get violent, plus other nuances of care. 

is medical director, Brain Health, Exeter, NH; editor in chief,

; staff psychiatrist, Seacoast Mental Health Center, Exeter, NH; consulting psychiatrist, Exeter Hospital, Exeter, NH; consulting psychiatrist, Insight Meditation Society, Barre, MA.

Handling aggression in patients with dementia can be difficult...

Aggression in Patients With Dementia

John J. Miller, MD, talks about approved treatments for early, mild-to-moderate dementia, one of which makes an appearance in "The Odyssey." 

What dementia treatment makes an interesting appearance in classical literature? 