For Agitation in Alzheimer Disease, a Novel, Oral NMDA Receptor Antagonist Could be the Next Targeted Treatment

"One of the good things about [AXS-05] is that it's not an antipsychotic, so it's not going to have the boxed warning about mortality...or knock the patient out."

There is one medication approved by the FDA specifically for Alzheimer agitation and a "rich pipeline," of others in development, George Grossberg, MD, told Patient Care® in a recent interview. He stressed that newer agents have much more favorable side effect profiles than current treatment options that will make them more attractive both to to adults with AD as well as their caregivers and health care professionals. In the video segment above Grossberg highlights a drug in pivotal phase 3 clinical trials that has shown significant promise. The dextromethorphan-bupropion combination, aka, AXS-05, is in development by Axsome Therapeutics. A geriatric psychiatrist and the Samuel W. Fordyce professor and director of Geriatric Psychiatry in the Department of Psychiatry at Saint Louis University School of Medicine, is also a researcher dedicated to developing novel therapies for neurocognitive disorders. He describes the AXS-05 mechanism of action that could help separate the medication from both typical and atypical antipsychotics.

Agitation in Alzheimer disease (AD) may affect up to 70% of adults with the dementia, depending on the individual and the setting. Traditionally pharmacologic treatment has been limited to the off label use of the typical antipsychotic medications, which are associated with significant negative side effects that include somnolence, cerebrovascular events, extrapyramidal symptoms, increased rates of hospitalization, and mortality.

The following transcript has been lightly edited for clarity and style

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

George Grossberg, MD: Before we dive into AXS-05 in particular, it's important to acknowledge the broader context. There’s a fairly rich pipeline of treatments being developed in the area of agitation in Alzheimer’s dementia. We now have the first approved drug for this condition, 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. y, 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.

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.