Experts Discuss Challenges of Treating Neuropsychiatric Symptoms of Dementia

Many patients with dementia experience noncognitive impairments. These symptoms—collectively known as neuropsychiatric symptoms of dementia—can range from depression and anxiety to aggression and psychosis. Such symptoms are often impairing for patients, upsetting for caregivers and loved ones, and difficult to manage.

“As the population ages, we will see a near tripling of Alzheimer’s between now and 2050 without a cure, and that will bring a flood of behavioral complications,” warned Brent P. Forester, M.D., M.Sc., chief of the Division of Geriatric Psychiatry at McLean Hospital, president of the American Association for Geriatric Psychiatry, and vice chair of the APA Council on Psychiatry. “We need biomarkers to diagnose people before their symptoms progress, treatments that halt the disease in its tracks or slow its course and modify the course of illness, and better therapies for the behavioral symptoms. We need to understand the biology of the illness better.”

Unfortunately, the current state of psychotropics for neuropsychiatric symptoms of dementia is lacking due to the absence of any compounds approved by the Food and Drug Administration (FDA) for this use, as well as the limited efficacy and high toxicity of current medications prescribed off-label—namely, antipsychotics and antidepressants. Although second-generation antipsychotics (aripiprazole, olanzapine, quetiapine, and risperidone) have been the most extensively studied medications for neuropsychiatric symptoms of dementia, only about 20% of patients experience improvements on these medications.

The benefits of these medications are often offset by adverse effects like metabolic syndrome, cardiovascular events, gait disturbance, cognitive problems, extrapyramidal side effects, cerebrovascular adverse events, and higher mortality, Forester explained.

“All of the data show … that antipsychotics reduce agitation, aggression, and paranoia modestly better than placebo [in patients with dementia],” Forester said. “The problem is tolerability issues.”

Selective serotonin reuptake inhibitors (SSRIs), such as citalopram, are the other frequently studied class of medications for treating these symptoms. But, as with antipsychotics, the weak efficacy of SSRIs is compounded by an increased risk of cognitive dysfunction, falls, and cardiovascular events. Anticonvulsants, benzodiazepines, and cholinesterase inhibitors similarly have failed to show significant benefit without also introducing tolerability and safety issues.

As a result, APA’s “Practice Guideline for the Treatment of Patients With Alzheimer’s Disease and Other Dementias” recommends that psychiatrists consider antipsychotics and citalopram for neuropsychiatric symptoms only after considering all factors that may contribute to such symptoms.

“Various practice guidelines boil down to the following: If you have someone with dementia, try to find out which specific form of dementia it is, because that matters in terms of treatment and prognosis,” said Pierre N. Tariot, M.D., who co-authored the guideline and whose team at the Banner Alzheimer’s Institute established the Alzheimer’s Prevention Initiative. “If they have Alzheimer’s disease, look at approved Alzheimer’s drugs because those might not only help with cognition and functioning but may mitigate existing symptoms or delay their emergence.”

Although medication should not necessarily be ruled out, if a patient with dementia develops significant neuropsychiatric symptoms, he advises psychiatrists to consider other contributors to the symptoms that may better respond to nonpharmacologic approaches. “Make sure they’re not sick, they’re not delirious, and there’s not a medical problem driving the behavior, or an environmental issue, or an interpersonal issue in how they’re cared for. Try to play Sherlock Holmes to mitigate the symptoms without resorting to psychotropics.”

Turning Disappointment Into Optimism

The limited effectiveness of antidepressants and antipsychotics in clinical trials, combined with the risks associated with these medications, has led researchers to look for new ways they might be able to treat neuropsychiatric symptoms in routine clinical practice. Forester and his colleagues are leading multisite studies (supported by the National Institute on Aging), including one examining electroconvulsive therapy for severe agitation and aggression in Alzheimer’s and another examining dronabinol, a synthetic cannabinoid, for agitation. Tariot and Forester have also been involved in studies exploring anticonvulsants or lithium for agitation.

Additional trials under way in the United States include those looking at stimulants for apathy, lemborexant (an orexin/hypocretin receptor antagonist) for insomnia, prazosin (an alpha-1 adrenergic receptor blocker) for aggression and agitation, pimavanserin (a nondopaminergic, selective serotonin receptor inverse agonist atypical antipsychotic) for dementia-related psychosis, nabilone (a synthetic cannabinoid) for agitation and aggression in Alzheimer’s, and glutamatergic agents for psychosis and mood symptoms.

As the U.S. population continues to age and researchers continue to search for effective medication for neuropsychiatric symptoms, it’s imperative that clinicians understand how to appropriately assess for the condition, select from nonpharmacologic approaches, or otherwise use medications judiciously, Tariot said.

“People who take care of these patients know how challenging it is and know that you need to try to do everything possible to avoid using additional medications,” said Tariot. “Probably 50% or more of what we are trying to help with on a day-in, day-out basis are these very problematic symptoms. And sometimes medications help, but not always. Just navigating that on a case-by-case basis is difficult and demanding but incredibly necessary.” ■