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Uh-oh. The long-term care facility for which you’ve agreed to act as a consultant is calling you. Mr. Clarkson is acting up again and has become so agitated that he’s interfering with the care of other residents. He could lose this place to live. And then where would a 78-year-old with dementia go?
Hi! Jim Phelps here for the Psychopharmacology Institute. This is tricky. You have to balance Mr. Clarkson’s needs and rights vs those of other residents at his place of living, as well as those of the staff, whose burnout risk you also must consider. So, what are your options? A new article by Dr. Claudia Carrarini and colleagues lays out alternatives, and they began with a useful view of differential diagnoses in 5 categories—neurological (e.g., stroke, tumor, infection), metabolic (e.g., electrolyte disturbance, hyper- or hypoglycemia), toxicologic (e.g., medications, alcohol, carbon monoxide), infectious (e.g., systemic infection or sepsis), and finally, psychiatric. The authors include both schizophrenia and bipolar disorder, but one could also consider an agitated depression or even an exaggerated presentation of an anxiety disorder in terms of exacerbating agitation in someone with dementia.
What can be done to prevent this type of agitation? As basic as this may sound, randomized trials support involvement in engaging activities, including music and combined stimuli-like tasks, reading, physical manipulation, and the most effective activity was live socialization. Now, the COVID pandemic has been associated with an increase in behavioral dyscontrol due to decreased opportunities for these activities. What about medication? Without equivocation, Carrarini and colleagues placed haloperidol first, using doses of 0.5 mg to 1 mg, not to exceed 3 mg to 5 mg in 24 hours. The exception, of course, would be in patients with Parkinson’s or potential Lewy body dementia.
For other options beyond haloperidol, these authors present a table of randomized trials of nearly every medication you might consider. If you’re a geriatric specialist, you’ll want to see that list of studies and read the authors’ text remarks regarding each medication trial outcome.
For the rest of us, here are some high points. First, several antidepressants have shown benefit for chronic agitation. Citalopram has multiple studies showing a reduction in agitation vs placebo, and several blinded trials vs antipsychotics also show equivalent improvement with citalopram. Escitalopram, which has less potential for QT prolongation as long as the dose stays low, has a trial vs risperidone showing equal efficacy in chronic agitation. The weight of evidence behind these particular antidepressants puts them ahead of nearly everything else. Mirtazapine, which might be appealing for its sleep effects, has an open trial showing benefit.
Now, the acetylcholinesterase inhibitors, although they can protect memory, have not been shown to have direct benefit regarding agitation. For anticonvulsants, carbamazepine has some evidence for benefit, but its enzyme-induction effects limit its use. Valproate? A 2009 Cochrane review of multiple placebo-controlled trials concluded that valproate is ineffective for agitation. Lamotrigine? Well, it’s not mentioned in this review by Carrarini, but an intriguing case report presented in a poster at a 2018 psychopharmacology conference describes an apparent response to 100 mg of lamotrigine after a lack of response to quetiapine and risperidone in a woman with frontotemporal dementia. Prazosin? Well, orthostasis is an obvious concern, but in a 22-person randomized trial vs placebo, prazosin was superior to placebo without a greater incidence of adverse effects. Provocative, isn’t it?
A provocative study was on low-dose lithium, and this was a 6-person case series in patients with frontotemporal dementia. The authors in the study conclude, “Short-term to intermediate-term follow-up indicated that lithium was effective in treating agitation and other behavioral disturbances.” Again, this was a 6-person case series with no comparison group.
In summary, this review presents a broad differential diagnoses for agitation in dementia and a useful table of clinical trial data for several classes of medications. For more on this, geriatric specialists will appreciate the scope of the paper’s Table 2, with a presentation of all of the different classes of medications.
Abstract
Agitation and Dementia: Prevention and Treatment Strategies in Acute and Chronic Conditions
Claudia Carrarini, Mirella Russo, Fedele Dono, Filomena Barbone, Marianna G Rispoli, Laura Ferri, Martina Di Pietro, Anna Digiovanni, Paola Ajdinaj, Rino Speranza, Alberto Granzotto, Valerio Frazzini, Astrid Thomas, Andrea Pilotto, Alessandro Padovani, Marco Onofrj, Stefano L Sensi, Laura Bonanni
Agitation is a behavioral syndrome characterized by increased, often undirected, motor activity, restlessness, aggressiveness, and emotional distress. According to several observations, agitation prevalence ranges from 30 to 50% in Alzheimer’s disease, 30% in dementia with Lewy bodies, 40% in frontotemporal dementia, and 40% in vascular dementia (VaD). With an overall prevalence of about 30%, agitation is the third most common neuropsychiatric symptoms (NPS) in dementia, after apathy and depression, and it is even more frequent (80%) in residents of nursing homes. The pathophysiological mechanism underlying agitation is represented by a frontal lobe dysfunction, mostly involving the anterior cingulate cortex (ACC) and the orbitofrontal cortex (OFC), respectively, meaningful in selecting the salient stimuli and subsequent decision-making and behavioral reactions. Furthermore, increased sensitivity to noradrenergic signaling has been observed, possibly due to a frontal lobe up-regulation of adrenergic receptors, as a reaction to the depletion of noradrenergic neurons within the locus coeruleus (LC). Indeed, LC neurons mainly project toward the OFC and ACC. These observations may explain the abnormal reactivity to weak stimuli and the global arousal found in many patients who have dementia. Furthermore, agitation can be precipitated by several factors, e.g., the sunset or low lighted environments as in the sundown syndrome, hospitalization, the admission to nursing residencies, or changes in pharmacological regimens. In recent days, the global pandemic has increased agitation incidence among dementia patients and generated higher distress levels in patients and caregivers. Hence, given the increasing presence of this condition and its related burden on society and the health system, the present point of view aims at providing an extensive guide to facilitate the identification, prevention, and management of acute and chronic agitation in dementia patients.
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Reference
Carrarini, C., Russo, M., Dono, F., Barbone, F., Rispoli, M. G., Ferri, L., Di Pietro, M., Digiovanni, A., Ajdinaj, P., Speranza, R., Granzotto, A., Frazzini, V., Thomas, A., Pilotto, A., Padovani, A., Onofrj, M., Sensi, S. L., & Bonanni, L. (2021). Agitation and dementia: Prevention and treatment strategies in acute and chronic conditions. Frontiers in Neurology, 12, 480.
