Alzheimer’s disease (AD) is a global public health concern whose hallmark is progressive cognitive and functional decline [1
]. Neuropsychiatric symptoms (NPS) are common in AD, affecting almost all patients over the course of the illness [2
]. Agitation is an important and particularly serious NPS which involves emotional distress, excessive psychomotor activity, aggressive behaviors, irritability and disinhibition. Over the 5-year follow-up of the Cache County study, 42% of dementia participants developed agitation [8
]. Agitation is a chronic problem for patients at all levels of dementia severity [6
] resulting in impaired quality of life, caregiver burden, dangerous behaviors, institutionalization, restraint use, and psychiatric admission [11
]. Therefore the management of agitation is a major priority in caring for people with AD.
Despite the clinical impact of agitation in dementia, an ideal treatment has not been found and options remain limited. A systematic review of 162 studies of non-pharmacologic approaches to managing NPS in dementia concluded that there is evidence, based primarily on uncontrolled or single-blind trials, for the effectiveness of caregiver education and caregiver- or patient-oriented behavioral management techniques [12
]. Benefits were typically limited to milder forms of agitation. Psychological approaches, even if feasible to implement, do not preclude the use of adjunctive pharmacologic treatment. In terms of pharmacological management, the most studied medication classes have been antipsychotics (APs), both conventional and atypical, which are often the first-line treatment for management of agitation in AD. Several randomized clinical trials (RCTs) have demonstrated the utility of conventional agents [2
] and atypical APs [14
]. However these agents have significant risks associated with their use including weight gain, dyslipidemia, blood glucose dysregulation, orthostasis, extrapyramidal side effects, prolonged QTc-interval on the electrocardiogram, drowsiness, peripheral edema, cerebrovascular events and mortality [15
]. The risk of mortality also increases with treatment duration and decreases with treatment cessation, demonstrated in one trial which found significantly higher 12-month mortality for nursing home patients with AD who continued on APs versus those who discontinued APs [19
] though observations from a few naturalistic nursing home surveys have not shown a higher mortality rate for patients receiving APs [20
]. Overall, evidence of efficacy for all types of antipsychotics for agitation in dementia is at best modest, and given concerns about the safety profile, it is not clear that their risk to benefit ratio warrants their use as a first-line treatment in most cases [14
]. Other medications have been assessed for agitation in AD primarily from post-hoc analyses, including anxiolytics, anticonvulsants, cholinesterase inhibitors and memantine and most have demonstrated equivocal utility for agitation, an adverse risk-benefit ratio and significant drug-drug interactions [23
]. Thus further trials and alternative treatment avenues are needed.
], neuroimaging [31
] and genetic polymorphism studies [29
] have implicated serotonergic nuclei and serotonin loss as potentially playing a role in the agitation seen in AD. Preliminary studies also support the role of selective serotonin reuptake inhibitors (SSRIs) in the treatment of agitation in AD. Investigators of a Nordic multicenter study found that Alzheimer’s patients treated with citalopram showed greater improvements in irritability and restlessness than those taking placebo [36
]. Simlarly, Nyth, et al., found improvements in agitation in those taking citalopram to be greater than placebo in elderly patients with depression [37
], and in an uncontrolled study, Ragneskog, et al., reported a reduction in irritability, anxiety and restlessness in elderly patients taking citalopram [38
]. More recently, Pollock and colleagues demonstrated the utility of citalopram for behavioral disturbances in dementia in a short-term, unmasked study, with improvements in disinhibition, agitation, hostility and suspiciousness [39
]. In a randomized, placebo-controlled follow-up study, citalopram was compared to placebo for management of behavioral disturbances in non-depressed agitated dementia patients [40
]. Citalopram, compared to placebo, significantly reduced total Neurobehavioral Rating Scale (NBRS) scores; significant improvement in agitation specifically was seen only with citalopram. Subsequently, in the Continuing Pharmacotherapy for Agitation in Dementia study (CPAD), Pollock and colleagues compared citalopram and risperidone in a 12-week RCT of 103 agitated dementia inpatients. For the primary outcome measure, citalopram was associated with a 13% decrease in agitation versus 8% for risperidone, and had a lower side effect burden [39
]. Thus, citalopram has shown potential for efficacy in treating agitation in dementia, but the preliminary data require replication specific to an AD population in a larger randomized controlled trial.