Evidence-Based Reviews

Neuropsychiatric symptoms of dementia: Monotherapy, or combination therapy?

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A cholinesterase inhibitor plus memantine may be more effective than either medication alone.



More than 5 million older Americans are living with Alzheimer’s disease and related dementias—and this number is estimated to rise to almost 14 million by 2050.1 Dementia is associated with high costs for the patient, family, and society. In 2017, nearly 16.1 million caregivers assisted older adults with dementia, devoting more than 18.2 billion hours per year in care.1 In the United States, the cost of caring for individuals with dementia is expected to reach $277 billion in 2018. Additionally, Medicare and Medicaid are expected to pay 67% of the estimated 2018 cost, and 22% is expected to come out of the pockets of patients and their caregivers.1

Although dementia is often viewed as a memory loss disease, neuropsychiatric symptoms (NPS) are common. NPS includes distressing behaviors, such as aggression and wandering, that increase caregiver burden, escalate the cost of care, and contribute to premature institutionalization. This article examines the evidence for the use of a combination of a cholinesterase inhibitor and memantine vs use of either medication alone for treating NPS of Alzheimer’s disease and other types of dementia.

First, rule out reversible causes of NPS

There are no disease-modifying treatments for dementia1; therefore, clinicians focus on decreasing patients’ suffering and improving their quality of life. Nearly all patients with dementia will develop at least one NPS. These commonly include auditory and visual hallucinations, delusions, depression, anxiety, psychosis, psychomotor agitation, aggression, apathy, repetitive questioning, wandering, socially or sexually inappropriate behaviors, and sleep disturbances.2 The underlying cause of these behaviors may be neurobiological,3 an acute medical condition, unmet needs or a pre-existing personality disorder, or other psychiatric illness.2 Because of this complexity, there is no specific treatment for NPS of dementia. Treatment should begin with an assessment to rule out potentially reversible causes of NPS, such as a urinary tract infection, environmental triggers, unmet needs, or untreated psychiatric illness. For mild to moderate NPS, short-term behavioral interventions, followed by pharmacologic interventions, are used. For moderate to severe NPS, pharmacologic interventions and behavioral interventions are often used simultaneously.

Pharmacologic options for treating NPS

The classes of medications frequently used to treat NPS include antidepressants, antipsychotics, mood stabilizers, and memory-enhancing, dementia-specific agents (cholinesterase inhibitors and the N-methyl-D-aspartate [NMDA] agonist memantine). Use of these medications to treat medical, psychiatric, or neurological illnesses in patients who do not have dementia is not covered in this article.

Serotonergic antidepressants are the recommended first-line antidepressant class for NPS in older adults who have dementia because they are generally well-tolerated. Of the serotonergic agents (sertraline, fluoxetine, citalopram, and trazodone), only citalopram has some limited evidence of benefit for patients with NPS.4

Antipsychotic medications are typically reserved for treating specific non-cognitive NPS, such as psychosis and/or severe agitated behavior that causes significant distress. Atypical antipsychotics, such as risperidone, aripiprazole, and olanzapine, currently have the best evidence for efficacy in this population. The effects are modest and use of these medications may be associated with an increased risk of stroke.4,5

The mood stabilizers valproate and carbamazepine have been studied for treating NPS, but available evidence suggests that neither medication provides significant benefit for patients with NPS. Furthermore, there is evidence of significant harm with valproate.4 There are no known studies evaluating the use of lithium for NPS.

Continue to: Evidence for dementia-specific medications


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