George Grossberg, MD, on Helping Families Face Alzheimer Agitation in a Loved One

Agitation is one of the most common and challenging symptoms associated with Alzheimer disease (AD), affecting at least half—and possibly up to 70%—of adults with the condition, depending on the care setting and stage of illness, according to George Grossberg, MD, the Samuel W. Fordyce Professor and Director of Geriatric Psychiatry at Saint Louis University School of Medicine.

In a recent interview with Patient Care®, Grossberg explained that pharmacologic treatment options for agitation have historically been limited to the off-label use of typical and atypical antipsychotics or minor tranquilizers like benzodiazepines, all of which are associated with significant adverse effects. These include sedation, extrapyramidal symptoms, increased risk of cerebrovascular events, hospitalization, and mortality.

Currently, the only medication with FDA approval for the treatment of agitation in Alzheimer disease is brexpiprazole (Rexulti, Otsuka). However, Grossberg noted that another candidate, AXS-05—a dextromethorphan-bupropion combination being developed by Axsome Therapeutics—is in pivotal phase 3 trials and may be nearing final approval. He emphasized that one advantage of AXS-05 is that it is not an antipsychotic, so it avoids the boxed warning associated with that drug class and does not produce the same level of sedation. In the video segment above, Grossberg outlines AXS-05’s mechanism of action and how it may distinguish itself from current treatment options. He also highlights other agents in development, describing a “very rich pipeline” of investigational therapies with more favorable safety profiles that could make them more appealing to patients, caregivers, and clinicians alike.

The following transcript has been edited for clarity and style.

Patient Care: Would you talk about some of the investigational medications for Alzheimer's agitation in the research pipeline?

George Grossberg, MD. Dexmedetomidine might be familiar to our audience because it’s been available for a number of years, but only as an intravenous (IV) formulation. It has been widely used in intensive care units parenterally to quickly calm patients. However, as you can imagine, an IV drug is far from ideal for an ambulatory Alzheimer’s patient who is experiencing psychomotor agitation. It’s a challenge to get a patient in that state to sit still for an IV line—let alone the time it takes to administer the infusion.

About 5 or 6 years ago, the company that manufactures dexmedetomidine developed an oral form. It’s essentially a wafer that can be placed under the tongue or anywhere in the buccal cavity. Unlike other treatments being used for agitation, this formulation works quickly, often within 60 minutes or less—90 minutes at most. So it is an excellent option for situations requiring acute management, such as in emergency departments or hospital settings where a patient is displaying overtly aggressive behavior. That said, it has not been approved yet in that form.

Beyond dexmedetomidine, there are several cannabinoids being explored in the pipeline. We are going to be doing a large multicenter trial with investigators from the UK who have developed a proprietary form of CBD, the non-hallucinogenic component of cannabis, to alleviate agitation in Alzheimer’s dementia patients. And there’s also nabilone, a synthetic cannabinoid, being evaluated and prazosin is showing promise, too. Unfortunately, some other attempts have been less successful. For example, a deuterated form of dextromethorphan-quinidine recently reported negative trial results.

Patient Care: Would you talk in some detail about the Axsome Pharmaceuticals drug for Alzheimer agitation that has good potential for FDA approval?

Grossberg: We now have the first approved drug for this condition (Rexulti, Otsuka), but several others are in the works. One of those is AXS-05, a drug that combines dextromethorphan and bupropion. Dextromethorphan is the primary therapeutic component, while bupropion plays a supporting role. Specifically, bupropion is used in very low doses—not for its antidepressant effects but to extend the half-life of dextromethorphan. Without bupropion, dextromethorphan, which is commonly found in over-the-counter cough medicines, would need to be taken every four hours to maintain stable blood levels. Obviously, no prescription drug would succeed with such frequent dosing. By slowing the metabolism of dextromethorphan, bupropion reduces the need for such frequent administration.

Dextromethorphan itself works on the excitatory neurotransmitter glutamate. By blocking glutamate, which may play a role in agitation, the drug could help manage symptoms. Various neurotransmitters have been implicated in agitation, including norepinephrine (or adrenaline), reduced levels of serotonin (a calming neurotransmitter), and dopamine, which can contribute to hallucinations, delusions, and psychotic symptoms. Different drugs in development target these neurotransmitters and specific brain regions involved in agitated behavior.

A key point about AXS-05, similar to brexpiprazole, the one drug that is FDA approved with this indication, is that it’s not an acute medication. This isn’t something you can use in an emergency room to immediately calm someone who’s out of control. It takes time to show effects—about 2 weeks before we start seeing separation from placebo in clinical trials. But one of the key advantages of AXS-05 is that it’s not an antipsychotic, so it doesn’t come with the boxed warning about increased mortality associated with that drug class. AXS-05 also appears to have a reasonable side effect profile. It doesn’t overly sedate patients or turn them into “zombies.” Instead, it provides therapeutic benefits for agitated behavior without excessive sedation.

We’re looking forward to publication of pivotal trial data for AXS-05. Another ongoing study is expected to provide further evidence. If that trial is positive, AXS-05 could become an FDA-approved treatment for agitation in Alzheimer’s dementia.

Patient Care: Primary care clinicians are often the first to identify Alzheimer disease or the first clinician a family member will confide in. Would you share some clinical pearls on caring for an adult with Alzheimer and possibly with agitation in this frontline setting?

Grossberg: The first piece of advice I would give is to make it a point to ask. When caring for Alzheimer’s patients and their families, ask about behavior at every visit. Talk to the care partner—often a spouse or an adult child—and ask: “How’s Mom? How’s Dad? How’s their behavior? Have you noticed any personality changes or concerning behaviors?”

Families may not volunteer this information unless prompted. Sometimes there’s embarrassment or stigma around discussing these changes. So I suggest really focusing on any behavior change they might have noticed, and not using the word "agitation," because they aren't likely to use that term. They might say things like, “I’m really worried about my mom. She used to be so calm and patient, but now she has such a short fuse. She screams or gets angry over the smallest things. This isn’t her, and it’s been happening for weeks. It's really making it hard for me to continue to care for her.” If we don’t ask, they may not bring it up, and that can delay addressing these issues.

Yes, we’re trying to educate families and caregivers to speak up about behavior changes during appointments, but there’s still a long way to go. It’s our responsibility as health care professionals to lead that conversation.

Another key point is to avoid focusing solely on cognition when assessing an Alzheimer’s patient. Always think about behavior as well. If there are agitated behaviors, don’t immediately assume they’re caused by Alzheimer’s disease. That’s why we developed a decision tree with the Gerontological Society of America for primary care providers.

This decision tree emphasizes considering other potential triggers first:

• Pain: Is it a source of distress?
• Infections: Could there be something like a urinary tract infection?
• Medications: Are there drugs that might be causing adverse effects?
• Delirium or depression: Could these conditions be contributing to the behavior?

Each of these possibilities requires different treatments. If you’ve ruled out these causes and the behavior seems to stem from Alzheimer’s itself, then always consider nonpharmacological interventions first. Look at environmental or behavioral strategies that could help manage the agitation.

If those approaches don't work or you don't have the luxury of time or the resources to implement them, pharmacotherapy may be necessary. We now have one FDA-approved medication for agitation in Alzheimer’s, as well as a promising pipeline of treatments under development. We do have medications that can be and are used off-label, though evidence for their efficacy is often limited. These can help bridge the gap while we await better therapies.

George T Grossberg, MD, is the Samuel W. Fordyce professor and director of Geriatric Psychiatry in the Department of Psychiatry at Saint Louis University School of Medicine. He is a past president of the American Association for Geriatric Psychiatry and of the International Psychogeriatric Association. Grossberg's research focus includes behavioral symptoms in Alzheimer disease and novel therapies for neurocognitive disorders.