Can antidepressant medication relieve agitation in Alzheimer’s disease?

Abstract

Neuropsychiatric symptoms (NPS) are a major concern in the treatment of Alzheimer’s disease. Historically, NPS are difficult to treat effectively due to a high side-effect burden associated with commonly used medications, such as atypical antipsychotics. Non-pharmacological treatment approaches have become the first line option. However, when such treatment fails, pharmacological options are often used. Thus, a push toward finding safer alternative pharmacological treatments has occurred. Antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs) have shown promise in clinical trials for alleviating the burden of NPS. Lower overall agitation and caregiver stress has been reported to correlate to treatment with the SSRI citalopram. However, certain side effects of citalopram, such as QTc interval prolongation and increased cognitive decline, carry clinical concern and should be weighed when prescribing their use.

Keywords::

• agitation
• Alzheimer’s disease
• antidepressants
• citalopram
• neuropsychiatric symptoms
• selective serotonin reuptake inhibitors
• treatment

While cognitive decline is the hallmark feature of Alzheimer’s disease (AD), concurrent development of neuropsychiatric symptoms (NPS) during the course of the illness is usually the rule rather than the exception. Agitation is among the most prevalent NPS [1,2] in AD, occurring in about 20–30% of outpatients with AD and in 40–60% of care home residents. Agitated behavior is more prominent in those with moderate or severe dementia, tends to persist over the course of AD [1] and is grouped with depression and psychosis as one of the most burdensome NPS for both patients and caregivers [2]. Agitation is associated with increased caregiver stress often leading to institutionalization [2], an important clinical marker of disease progression precipitating further cognitive decline and poorer overall outcomes. For decades, antipsychotics have been the pragmatic mainstay of treatment despite their limited efficacy and history of adverse events outweighing potential benefits [3]. Major efforts are underway in the US and worldwide to limit the use of antipsychotics in patients with dementia due to these safety concerns. However, safe and effective treatments remain elusive and options are limited. Development of new treatments has become a major public health priority [4]. Consequently, first-line treatment has shifted to non-pharmacological methods, such as psychosocial interventions, grounded in the presupposition of a ‘heightened vulnerability to the environment as cognitive ability declines’ [5]. The focus of these interventions is on evaluating the underlying cause of the behavior, such as triggering events, and educating the caregiver on strategies to understand and prevent the behavior from occurring [5]. Caregiver education focuses on addressing unmet needs of the patient, such as pain, hunger, thirst, over-/understimulation, boredom, overcrowding and fear of endangerment and abandonment, and through environmental and daily routine changes concentrating on relaxation techniques, distraction, exercise, individualized outlets for pent up energy and avoidance of behavioral triggers [2]. However, practical concerns, such as cost or lack of appropriate skill sets, limit wide use of psychosocial interventions. Further, these interventions alone often fail to improve agitation in all individuals with Alzheimer’s dementia [3,6], leaving clinicians with little choice but to treat unremitting agitation with off-label psychotropic medications (i.e. atypical antipsychotics) despite their FDA ‘black-box’ warning including excess mortality when used in patients with dementia [7].

The NPSs of AD are commonly associated with polymorphisms of the serotoninergic, cholinergic and dopaminergic systems. A hypothesized cause of agitation in AD is that disease-associated neurodegeneration gradually disrupts and then destroys the brain monoamine system, specifically the ascending serotonergic pathways. One group of researchers has demonstrated, using FDG-PET, a correlation between decreased metabolic activity in the right lateral temporal, right lateral frontal and bilateral cingulate cortices and agitation symptoms in AD patients [8,9]. This has led to efforts focused on manipulating the serotonergic system in order to reduce or eliminate agitation. The mechanism of action of selective serotonin reuptake inhibitors (SSRIs), targeting serotonergic neurotransmission, is favorable to atypical antipsychotic treatments that target mainly dopaminergic pathways and tricyclic antidepressants with anticholinergic properties; both carrying heavy side-effect burdens [10]. Good tolerability of SSRIs has been suggested in several studies, involving participants with various dementia types, in which withdrawal rates due to adverse events were comparable between SSRI and placebo groups [6]. SSRIs have been proposed as both an alternative to atypical antipsychotics and as concurrent treatment with non-pharmacological intervention, when such intervention fails to produce clinically significant improvement.

A recent study, the Citalopram in Alzheimer’s Disease (CitAD) clinical trial, explored the efficacy of the SSRI citalopram to treat agitation in individuals with AD and without major depression. The study also evaluated the safety and tolerability of treatment on several measures as well as the effect treatment had on caregiver stress [11]. This 9-week double-blind, parallel-group trial enrolled 186 participants, diagnosed with probable AD (MMSE score between 5 and 28 points) that suffered from clinically significant agitation. Participants were randomized to two groups receiving either citalopram 30 mg daily dose (titrated up from 10 mg over 3 weeks, as indicated and tolerated) or placebo. Both groups also received psychosocial intervention (educational materials, 24-h crisis management access and a 20- to 30-min counseling session at each visit).

The study’s findings were multifaceted. On the positive side, the primary outcome measures, the Neurobehavioral Rating Scale agitation subscale and the modified Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC), showed a statistically significant reduction in agitation favoring citalopram that was also clinically apparent. The Neuropsychiatric Inventory, a secondary outcome measure, also showed a significant reduction in total scores and caregiver distress. Unfortunately, at the 30-mg daily dose, citalopram showed greater cognitive decline than placebo and prolonged the QTc interval on ECG (mean 18.2 ms elongation). The QTc prolongation was consistent with the recent FDA required change to the label for citalopram, warning against its use at doses above 20 mg daily in patients older than age 60. The increased cognitive decline was indicated by a one-point reduction of score (less than the minimum clinically significant change of 1.4 points) on the Mini-Mental State Examination (MMSE).

Significant discussion has ensued since the publication of the CitAD results in regard to the tolerability findings. In the CitAD trial, there was a significant baseline difference in MMSE scores between the citalopram and placebo groups. Over the 9 weeks of treatment, the citalopram group showed a modest and expected worsening on the MMSE from 17.0 to 16.83, but the placebo group showed a more notable and unexpected improvement from 14.4 to 15.33. It is possible that the change in MMSE scores represented a drift toward the mean for both groups. However, this finding should be regarded as a factor of concern when prescribing citalopram until validity is established with further investigation. Recent animal studies in transgenic mice have provided evidence that citalopram may actually decrease beta amyloid burden, the hallmark pathology in AD, and research has recently transitioned to investigating the effect citalopram has on beta amyloid in humans [12]. Furthermore, the clinical relevance of the prolongation of the QTc interval with higher doses of citalopram has been questioned. It did not reach suggested clinical significance (>500 ms) in any one participant as defined by one group of researchers [13]. Nonetheless, a clinical concern still remains in the eyes of this group of authors.

There was no difference in adherence or completion rates between the two groups and the vast majority of participants on citalopram completed the study on a 30-mg daily dose, suggesting an overall low rate of troublesome adverse events requiring dose adjustments. Good general tolerability and the addition of psychosocial intervention are thought to have contributed to the 90% completion rate for both groups. Similarly, previous studies that compared the efficacy and effectiveness of both citalopram and escitalopram against risperidone have demonstrated a lower rate of adverse events in concurrence with higher completion rates in the SSRI groups [14,15].

What is the best treatment option for patients with AD with disruptive agitation? An assessment of individual patient circumstances, including symptom severity, value of improvement, cognitive function and change, cardiac conduction, vulnerability to adverse effects and effectiveness of behavioral interventions can help guide appropriate medication use in patients with marked agitation or aggression. Psychosocial interventions should be tried first in a way that positively impacts the experience of caregivers and patients. Focusing on distracting patients, tailoring activities that offer a different outlet for pent up energy and avoiding behavioral triggers along with supporting and educating the caregiver are most promising. For the patients who do not adequately respond to these interventions, a judicious pharmacological intervention is indicated.

The CitAD study will likely have a major impact on practice in the field. Improvement over the course of the trial, as measured by total Neuropsychiatric Inventory scores, was comparable with that of antipsychotic drugs in other trials [12], and improvement on the mADCS-CGIC was superior in CitAD [11,16]. Adverse events were generally modest and consistent with known SSRI-mediated adverse events (increases in gastrointestinal complaints, respiratory tract infections and falls), except that no weight loss or hyponatremia was seen. Thus, citalopram represents a good therapeutic choice based on both tolerability and efficacy. It is not a magic bullet and it would not work for everyone as agitation is such a heterogeneous symptom. A starting dose of 10 mg daily with an increase to 20 mg daily in 1 week, as clinically indicated based on benefits and side effects, is a reasonable first option even as more data are gathered to establish efficacy at the lower doses. The data support screening for a history of prolonged QT syndrome, recent history of electrolyte imbalance and concurrent medications known to meaningfully prolong QT intervals as those effects may be additive. Neither clinical data nor the FDA warning suggest the need to get ECGs or electrolyte panels before using citalopram up to a maximum dose of 20 mg daily in this age group. Due to the clinical concern associated with the observed cognitive worsening and QT interval prolongation in the citalopram group, the 30 mg daily dose cannot generally be recommended. In the CitAD study, where the target dose was 30 mg daily, electrolyte panels including magnesium as well as a baseline ECG and a repeat ECG once the 30 mg dose was reached was standard practice. In rare instances, where agitation is unresponsive to other interventions, clinicians may suggest using this higher dose. Considering the alternatives, in such situations, some patients and families might elect to use the higher dose if it was likely to be beneficial despite the possible QT prolongation, particularly if the risk could be monitored using ECGs and electrolyte panels.

Financial & competing interests disclosure

AP Porsteinsson reports receipt of a grant to his institution from Avanir, Baxter, BMS, Elan, EnVivo, Genentech/Roche, Janssen Alzheimer Initiative, Eli Lilly, Merck, Pfizer, Toyama, Medivation, the National Institutes of Health (NIH), the National Institute of Mental Health (NIMH), The National Institute on Aging (NIA), and the Department of Defense; paid consultancy for Elan, Janssen Alzheimer Initiative, Lundbeck, Pfizer, and TransTech Pharma; membership on data safety and monitoring boards for Quintiles, Functional Neuromodulation, and the New York State Psychiatric Institute; participation on a speaker’s bureau for Forest; and development of educational presentations for CME Inc. and PRI. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.