Alicia Bigica is the Associate Editorial Director for 

. Prior to joining MJH Life Sciences in 2019, she helped launch leading resources for medical news in the neurology and dermatology specialties. Follow her on Twitter 

Alicia Bigica

Dementia-related psychosis has a prevalence of 10% to 75% across various dementia types.

 Hallucinations and delusions associated with dementia-related psychosis are closely linked with increased caregiver burden and increased risk of nursing home placement.

Awareness of hallucinations and delusions associated with dementia-related psychosis, including how to recognize and report them to the health care team, is an important role for health care professionals (HCPs) and caregivers, as collaboration among providers and caregivers is key to earlier identification, diagnosis, and potential management.

To increase disease awareness and dialogue among HCPs, patients, and caregivers, 

 presented a special broadcast, “More Than Cognition: Understanding the Impact and Consequences of Hallucinations and Delusions Associated With Dementia-related Psychosis,” featuring perspectives from neurologist Alireza Atri, MD, PhD; geriatric psychiatrist Davangere P. Devanand, MBBS, MD; and caregiver Linda Gregory.

Ms. Gregory’s mother was diagnosed with Alzheimer’s dementia and subsequent related psychosis. Ms. Gregory shared her family’s experience of her mother progressing from showing classic symptoms of dementia, including memory loss and confusion, to exhibiting concerning behavior related to hallucinations and delusions. These instances evolved from what originally seemed to Ms. Gregory and her family as harmless memory lapses to fear and paranoia. Concern about her mother’s safety ultimately led Ms. Gregory and her family to pursue full-time care for her mother in a memory care unit.

Ms. Gregory noted that she and her family felt a great deal of confusion and guilt due to their lack of understanding of what exactly dementia-related hallucinations and delusions were, and that a clearer explanation of these symptoms from an HCP would be helpful as caregivers navigate the different symptoms with their family member. Ms. Gregory’s account of the challenges that she and her family faced, including increasingly aggressive behavior from her mother, provided a sobering real-world look at the deep-seated impact that dementia-related psychosis can have on the family unit.

Ms. Gregory’s experience also demonstrates a key point in the care process: Caregivers are often not provided with the full scope of information and expectations to best prepare for handling a loved one’s progressive disease. As Dr. Atri noted, HCPs need to do a better job at communicating information and directing caregivers to appropriate resources so that they feel fully supported and informed.

Dr. Devanand shared that a study in older people with Alzheimer's disease dementia showed that a 10% increase in neuropsychiatric symptoms was associated with a 30% increase in odds of nursing home placement.

 Having this information may help caregivers be more proactive in planning future care for their loved ones and adjusting overall expectations for themselves in terms of their own ability to adequately care for the patient and manage the patient’s symptoms.

Overall, management of dementia-related psychosis remains a large unmet need, as no antipsychotic medications are currently approved for the treatment of the disorder, and all antipsychotics carry a Boxed Warning indicating that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

 Available antipsychotics also have adverse effects and little documented efficacy to support their use in this vulnerable population.

All told, more open communication between HCPs and caregivers—including conversations about the range of symptoms, signs of progression, and access to educational and supportive resources—is key to helping ease the burden of this disease.

To view a recording of the full presentation, 

This nonaccredited presentation is sponsored by Acadia Pharmaceuticals Inc.

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. Silver Spring, MD: US Food and Drug Administration; April 11, 2005.
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Effectiveness of atypical antipsychotic drugs in patient with Alzheimer’s disease.

Articles

Health care professionals and a caregiver discuss the overall burden of hallucinations and delusions associated with dementia-related psychosis, explore unmet needs in diagnosis and management of these symptoms, and discuss the need for increased dialogue between clinicians and caregivers. 

Understanding the Burden of Dementia-related Psychosis

As the world awaits what could be the first disease-modifying treatment for Alzheimer disease, research continues to point us in the direction of various therapeutic targets that could hold promise for prevention. No target is perhaps more promising than those embedded throughout the body—the very channels that circulate blood and oxygen to not only the brain but all other critical organs. Despite the fact that over 50% of cases of AD are attributable to a mixed pathology of vascular and Alzheimer-related factors, much of our therapeutic muscle has been thrown behind drugs that tend to target only a single AD pathology.

Although the idea of preventing such a devastating disease seems far off when we still have little grasp on our ability to actively treat it, a growing body of evidence suggests that a handful of simple “best practices”—maintaining a healthy weight, managing hypertension, staying physically active—might have a significant effect on AD risk reduction by ensuring a more healthy vascular system.

To learn more about the interaction of vascular risk factors and the shortcomings of our current clinical approach, 

® sat down with Costantino Iadecola, MD, director and chair of the Feil Family Brain and Mind Research Institute, and Anne Parrish Titzell Professor of Neurology at Weill Cornell Medicine in New York, New York.

What is our current understanding of how amyloid-β impacts vascular function in the brain? How does this affect those who are genetically predisposed versus sporadic cases?

In people who have a predisposition to Alzheimer disease, there is evidence that as amyloid is being over produced in the brain, it is being removed by 2 vascular mechanisms, either because 

the amyloid kind of goes around the blood vessels and gets out of the brain through that route, or because it goes straight to the blood vessels and gets into the blood and is then being cleared. In familial Alzheimer cases, the problem is amyloid-β overproduction; there’s too much amyloid being made for the brain to clear. It’s [as if] the drain in the sink is working properly, but the water is turned on too high. In that case, amyloid also has an effect on blood vessels as it does on the neurons, by stunning the blood vessels and making them unable to deliver the oxygen and glucose and remove this waste. It’s going to promote accumulation because, even though the vessels per se are healthy, the amyloid is making them unhealthy and unable to do what they normally do. The evidence for this is indirect, but if you measure blood flow in patients with a familial risk of Alzheimer disease way before they become cognitively impaired, you already see a reduction in blood flow. So that suggests that there is something going on with the blood vessels before the brain gets really, really sick.

People with sporadic Alzheimer disease tend to be older, [and] have diabetes, high blood pressure, and other comorbidities that come with age. In this sporadic group, the problem is not that the faucet is turned on too high, but instead the drain is clogged; the vessels and older mechanisms are unable to remove the amyloid-β that is being made. In that case, it is even more important to keep the vessels healthy because that’s really what the problem is; it is an inability to kind of drain the amyloid-β and clear it from the brain.

All these things that come with aging—hypertension, diabetes, obesity, etc—are all harming the blood vessels and making them unhealthy. That unhealthy vessel is going to be less able to supply and nourish the brain with oxygen and glucose, and to clear all the waste that is being made, including amyloid. Although these 

are 2 different conditions, in both cases, maintaining the health of the blood vessels is key. If you’re a young person who is at risk of familial Alzheimer disease, stopping smoking and taking care of your diet is going to help you, and if you’re a 55-year-old man who is hypertensive and diabetic, you really should take care of your comorbidities because you will be better off. In both scenarios, you can make the case for helping the blood vessels to work better.

I think the geriatrician is really a critical element in this brain health clinic, where the health of the brain is going to be seen in the context of the health of the other organs of the body.

Based on this knowledge and our current therapeutic targets, is clearing amyloid-β from the brain enough, or should we be tackling treatment from multiple angles?

Theoretically, it would be easier to approach treatment of the familial forms of AD because we have drugs that block the ability of enzymes to cleave amyloid-β from amyloid precursor protein— we have gamma secretase inhibitors and beta secretase inhibitors. Unfortunately, it has not been as easy as it sounds, because these enzymes do other things that we are just learning now, so if you just shut down the enzymes, you can make things worse. Now we have modulators that do not shut the enzyme down completely, but just reduce certain aspects of the enzymatic activity. Those, I think, will have the maximum advantage, particularly in the familial cases, where overproduction is the main issue. The sporadic cases are much more complex and I don’t think that a single approach is going to work because if you look at the brain of someone who died of sporadic Alzheimer disease, they often have 5 or 6 pathologies at the same time, [such as] amyloid-β, tau, TDP-43, vascular dysfunction, [and] vascular alterations. You would want, somehow, to deal with a bunch of them at the same time. Now, the vessels are easy, because by adhering to a healthy lifestyle, you can better control the vascular risk factors. Because of recent emphasis on control of these risk factors, the mortality for cardiac attacks and strokes is going down 60% to 80%. We know how to do that, but we’re not doing it in the Alzheimer populations, because the idea so far has been, "Well, it’s a disease 

of the brain." But now we know more and we should really broaden our horizons and include the health of the vessels in any treatment plan.

In terms of prevention, what could we be doing better 

from both a patient education standpoint and increasing awareness among neurology and primary care providers?

I think your question raises a very important public health issue. At the research, tertiary referral level, where these huge dementia programs exist and the people who lead these programs are at the top of their field, if this vascular prevention approach is not done in [that environment], then how can we hope to [have this knowledge] trickle down...to the general practitioner, who is going to be the first person to see someone with Alzheimer disease? Bottom line, we have a lot of work to do. We are not empowering the general practitioner with all these things that we know, yet it’s very simple. The American Heart Association has a program called Life’s Simple 7 that is a guide to help keep your vessels healthy; stop smoking, treat your diabetes, treat your blood pressure, exercise, all of those things. There would be no harm in doing those things in the context of a dementia clinic or memory disorder clinic.

In an ideal world, we would have brain health clinics in which you’re going to have a cardiologist, a geriatrician, a neurologist, dietary specialists, etc, that work together on each case. I like to stress the role of the geriatrician because treating older people is not like treating a young person who has become old. Everything changes: Drugs have different interactions [and] dosages, the approaches are completely different, but that approach hasn’t really [arrived] there yet. I think the geriatrician is really a critical element in this brain health clinic, where the health of the brain is going to be seen in the context of the health of the other organs of the body. It could be that the person is going to need to pay more attention to the heart, for example, because maybe the reason why they are having memory problems is because the heart is not pumping enough blood. We have to better identify ourselves with this concept of multidisciplinarity and move away from parcellation of care. You should not hesitate to talk to your colleagues in other disciplines, and you should be aware that the brain is not really an isolated organ—it’s all part of the same thing.

Constantino Iadecola, MD, discusses the interaction of vascular risk factors and the shortcomings of our current clinical approach to Alzheimer disease. 

Alzheimer Disease Crossroads: Why a One-Way Approach to Treatment, Prevention May Be Futile

Harmony Biosciences has announced that the FDA has expanded the indication for pitolisant (Wakix) for the treatment of cataplexy in adults with 

. Notably, pitolisant is the only FDA-approved treatment for both excessive daytime sleepiness and cataplexy in narcolepsy that is not a scheduled controlled substance.

Pitolisant is a novel, selective histamine 3 receptor antagonist/inverse agonist that increases the synthesis and release of wake-promoting histamine via a once-daily, oral administration.

"All people living with narcolepsy have excessive daytime sleepiness and up to two-thirds of them also experience cataplexy, which is one of the most debilitating symptoms of this chronic, rare neurological disorder," said Harmony's chief medical officer, Jeffrey Dayno, MD, in a statement.1 "Today's FDA approval of the cataplexy indication for Wakix, coupled with it being the first and only non-scheduled treatment option approved for adult patients with narcolepsy to treat both excessive daytime sleepiness or cataplexy, provides an opportunity for Wakix to offer broad clinical utility to healthcare professionals managing adult patients living with narcolepsy."

The expanded approval was based on results from the HARMONY CTP (NCT018000450) and HARMONY 1 (NCT01067222) randomized, controlled clinical trials, the results of which were reanalyzed after the FDA issued Harmony a complete response letter in August 2019 regarding data supporting the efficacy of pitolisant for the reduction of cataplexy.

Results from the CTP study demonstrated a 75% reduction in weekly cataplexy rate in patients taking pitolisant compared with 38% in patients in the placebo group (rate ratio 0.512; 95% CI, 0.43-0.60, 

 Post-hoc analyses from the HARMONY 1 trial showed that pitolisant was superior to placebo but not non-inferior to modafinil for improvement in cataplexy rate from baseline.

Additional long-term data showed a 76% reduction cataplexy from baseline to 1 year.

 Adverse events were consistent with what was observed throughout the clinical trial program, with the most common being headache, insomnia, weight increase, anxiety, depression, nausea, vomiting, and irritability.

 for the treatment of excessive daytime sleepiness in adults with narcolepsy in August 2019.

1. Harmony Biosciences receives FDA approval for expanded use of Wakix (pitolisant) for the treatment of cataplexy in adult patients with narcolepsy. News release. Harmony Biosciences. October 14, 2020. Accessed October 14, 2020. https://www.prnewswire.com/news-releases/harmony-biosciences-receives-fda-approval-for-expanded-use-of-wakix-pitolisant-for-the-treatment-of-cataplexy-in-adult-patients-with-narcolepsy-301152078.html

2. Szakacs Z, Dauvilliers Y, Mikhaylov V, et al. Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: a randomised, double-blind, placebo-controlled trial. 

 2017(3):200-207. doi: 10.1016/S1474-4422(16)30333-7

3. Dauvilliers Y, Bassetti C, Lammers GJ, et al. Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. 

 2013(11):1068-1075. doi: 10.1016/S1474-4422(13)70225-4

4. Harmony Biosciences presents 5-year data on pitolisant at International Narcolepsy Symposium. News releases. September 11, 2018. Accessed October 14, 2020. https://www.harmonybiosciences.com/newsroom/harmony-biosciences-presents-5-year-data-on-pitolisant-at-international/

5. WAKIX represents the first and only non-scheduled treatment approved for patients with narcolepsy in the U.S. News release. Harmony Biosciences. August 15, 2019. Accessed October 14, 2020. https://www.finance.yahoo.com/news/harmony-biosciences-announces-fda-approval-120000845.html

The drug, marketed as Wakix, was previously approved for the treatment of excessive daytime sleepiness in adults with narcolepsy. 

FDA Approves Pitolisant for Cataplexy in Narcolepsy

The US FDA has officially cleared the Cefaly Dual neuromodulation device as an over-the-counter product for both the acute and preventive treatment of 

 in adults. Previously only available by prescription, the trigeminal nerve stimulator will be available for purchase by the general public beginning October 13, 2020.

, which includes the Cefaly device, 1 electrode (good for up to 20 uses), power adapter and charging cable, and storage case typically retails for $499. Three-packs of additional electrodes are available for $25 or via a cost-saving subscription service.

“It's our mission to provide consumers with increased access to an effective and safe dual modality migraine treatment that is scientifically proven to reduce the number of monthly migraine days by almost half," said Jennifer Trainor-McDermott, CEO of CEFALY Technology, in a statement.

The device was first granted marketing approval in the US in March 2014 for the prevention of migraine in adults based on clinical data from 2 studies. The first, published in 

 demonstrated a significant reduction in mean migraine days in those who were randomly assigned to 20 minutes of daily treatment with the Cefaly device versus sham treatment over 3 months, with more than 38% of patients in the active treatment group achieving 50% responder rate compared with 12.1% in the sham group. In addition, monthly migraine attacks, monthly headache days, and monthly acute anti-migraine drug intake were all significantly reduced in the treatment group compared with the sham group. Notably, no adverse events were recorded in either group.

Advances in the Management of Acute Treatment of Migraine

In 2017, the FDA approved an expanded indication for the device to be used for acute relief of migraine with or without aura in adults.

 That approval was based on results of the ACME trial (NCT02590939), which included 106 patients experiencing an acute migraine attack who were randomly assigned to active or sham treatment for 1 hour.

 The active treatment group reported nearly a 60% reduction in pain intensity at 1-hour treatment compared with a 30% reduction in the sham group (

 <.0001). Notably, those with migraine without aura recorded a greater reduction in pain intensity versus the sham group compared to those with migraine with aura, who experienced a numerical but not statistically significant reduction in pain intensity versus the sham group. No serious adverse events were reported.

Neuromodulation for migraine has become increasingly popular as patients seek out non-pharmaceutical options to address their acute and chronic migraines. The available approved devices, which currently include Cefaly, the gammaCore vagus nerve stimulator, sTMS mini, which is a transcranial magnetic stimulator, and the Nerivio remote electrical neuromodulator, provide effective alternative treatment options for patients who may have contraindications to more typical oral or injectable migraine therapies.

1. Now over-the-counter: FDA clears Cefaly dual migraine treatment for use without a prescription. News release. Cefaly Technology. October 13, 2020. Accessed October 13, 2020. https://www.prnewswire.com/news-releases/now-over-the-counter-fda-clears-cefaly-dual-migraine-treatment-for-use-without-a-prescription-301150599.html

2. Schoenen J, Vandersmissen B, Jeangette S, et al. Migraine prevention with a supraorbital transcutaneous stimulator: a randomized controlled trial. 

. 2013;80(8):697-704. doi:10.1212/WNL.0b013e3182825055

3. FDA releases Cefaly for acute treatment of migraine attacks. News release. Cefaly Technology. September 21, 2017. Accessed October 13, 2020. 

https://www.prnewswire.com/news-releases/fda-releases-cefaly-for-acute-treatment-of-migraine-attacks-300523385.html

4. Chou DE, Shnayderman yugrakh M, Winegarner D, Rowe V, Kuruvilla D, Schoenen J. Acute migraine therapy with external trigeminal neurostimulation (ACME): A randomized controlled trial. 

. 2019;39(1):3-14. doi:10.1177/0333102418811573

The device is the first FDA-approved trigeminal nerve stimulator for migraine treatment available without a prescription. 

Alicia Bigica

Articles

Understanding the Burden of Dementia-related Psychosis

Alzheimer Disease Crossroads: Why a One-Way Approach to Treatment, Prevention May Be Futile

FDA Approves Pitolisant for Cataplexy in Narcolepsy

Cefaly Wearable Migraine Treatment Now Available Without Prescription