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Dementia refers to a group of conditions characterized by cognitive decline beyond that which would be expected to occur due to normal aging.

The most common form of dementia is Alzheimer’s disease, a progressive and irreversible brain disease caused by complex changes to the brain due to cellular damage. The disease results in declining memory, cognitive function, and the ability to perform daily activities of life.

In addition to cognitive symptoms, neuropsychiatric symptoms of Alzheimer’s disease include agitation, aggression, psychotic symptoms, and depression

Some combination of these symptoms is present in nearly all patients with Alzheimer’s, but they remain underdiagnosed.

Neuropsychiatric symptoms further diminish a patient’s functional status and quality of life, but efficacious treatments for these symptoms are lacking.

Agitation has been reported in approximately three-quarters, and aggression in more than one-quarter, of patients with Alzheimer’s disease.

A systematic review found that psychosis was present in 41% of people with Alzheimer’s disease. Of these, 23% suffered only from delusions, 5% suffered only from hallucinations, and 13% presented with both delusions and hallucinations.

Aggression, agitation, and psychotic symptoms are the leading causes of hospitalization and institutionalization in patients with Alzheimer’s disease. These symptoms may in fact be more distressing to caregivers than other core symptoms of Alzheimer’s, such as declines in memory and executive function.

Whereas in Alzheimer’s disease, aggression, agitation, and psychotic symptoms are likely to manifest as overt behavioral expressions, depression is present in up to 40% of patients with Alzheimer’s and tends to present as apathy, loss of interest, and social withdrawal.

Pharmacologic options for neuropsychiatric symptoms in patients with Alzheimer’s disease are limited.

Drugs that treat the cognitive deficits of Alzheimer’s disease, which include cholinesterase inhibitors and the NMDA receptor antagonist memantine, have not demonstrated significant disease-modifying activity or clinically relevant efficacy in treating neuropsychiatric symptoms.

Second-generation antipsychotics remain the mainstay for the treatment of agitation, aggression, and psychotic symptoms in Alzheimer’s disease.

These agents exert antidopaminergic and serotonergic effects, with potential benefits on mood, emotions, and behavior.

However, agitation, aggression, and psychosis stem from a complex network of structural and functional changes in the brain, including an accumulation of neurofibrillary tangles and amyloid plaque. Neurotransmitters other than dopamine and serotonin have been implicated, notably acetylcholine.

Medical, environmental, and caregiver issues can aggravate neuropsychiatric symptoms.

Genetics can play a role, as some patients with Alzheimer’s disease are predisposed to psychotic symptoms.

Without direct effects on the primary mechanism of disease in Alzheimer’s, antipsychotic medications have shown only modest efficacy in treating agitation, aggression, and psychotic symptoms.

However, drug development efforts are ongoing.

Brexpiprazole, a serotonin 5HTA1 and dopamine D2 partial agonist with antagonist activity at the serotonin 5-HT2A and noradrenaline α1B/α2C receptors, became the first FDA-approved drug for agitation in Alzheimer’s disease in May 2023.

In two 6-week placebo-controlled trials and a 52-week open-label follow-up study, this agent produced significant reductions in the Positive and Negative Symptom Scale Excited Component (PANSS-EC), suggesting therapeutic potential for agitation in Alzheimer’s disease with or without hostility.

Small but significant positive effects of olanzapine and aripiprazole on psychotic symptoms also have been reported.

The potential benefits of antipsychotics must be weighed against the potential for adverse effects that may be heightened in elderly patients with Alzheimer’s disease.

These include somnolence, additional cognitive decline, movement disorders, susceptibility to infections, edema, weight and metabolic effects, and hypotension.

Patients with dementia receiving antipsychotics are at increased risk of falls, stroke, and death in patients with Alzheimer’s disease.

For depression, the Alzheimer’s Association and guidelines in the United States, European Union, and Canada recommend pharmacologic therapy with a selective serotonin reuptake inhibitor (SSRI) or another monoamine-targeted antidepressant.

These agents modulate neurotransmitter function, most notably serotonin, dopamine, and norepinephrine, with potential benefits on mood, emotions, and behavior.

However, as with agitation, aggression, and psychotic symptoms, depression in Alzheimer’s disease has been associated with the underlying neuropathology of the disease.

There are data suggesting that depression in Alzheimer’s disease is related to neuroinflammation and immune system dysregulation, and with neurotransmitters other than the monoamines.

Monoamine-based antidepressants have shown only modest efficacy. In fact, in a meta-analysis of 6 clinical trials, monoamine-based antidepressants were no more effective than placebo in patients with Alzheimer’s disease-associated depression.

SSRIs are generally well tolerated.

However, patients with severe cognitive deficit are more likely to experience standard SSRI-related adverse effects.

Moreover, citalopram, the SSRI with the most data supporting its use in patients with Alzheimer’s disease, may worsen cognitive function. Citalopram can also prolong the QTc interval, particularly at higher doses and in older patients taking multiple medications that might collectively contribute to this effect.

With limited pharmacotherapeutic options for neuropsychiatric symptoms of Alzheimer’s disease, clinicians and their caregivers must rely heavily on nonpharmacologic interventions, which typically involve:

• Monitoring the patient’s personal comfort, including hunger, thirst, and room temperature;
• Avoiding being confrontational or arguing about facts;
• Encouraging the patient’s participation in activities they enjoy;
• Creating a calm environment;
• Allowing adequate rest between stimulating events; and
• Consulting a healthcare provider to identify any causes related to medications or illness.

In addition, there are data showing that stress or depression in caregivers can trigger or exacerbate neuropsychiatric symptoms in Alzheimer’s disease.

Offering supportive and educational interventions to caregivers, while helping them ensure a stable living environment for patients, can help mitigate the impact of Alzheimer’s on all concerned, and may potentially help alleviate the symptoms themselves.

Supported caregivers are supportive caregivers