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Scheduled Low-Dose Risperidone for Agitation in Elderly Patients
In geriatric patients, agitation from delirium or dementia is a frequent reason for or complication of medical hospitalization. Agitation prolongs hospitalization and increases the risk of morbidity and mortality. Antipsychotics have been the mainstay of pharmacologictreatment of agitation in the elderly. The authors report on two patients in their 70s who presented to the hospital with agitation and confusion that evolved into aggression. Following treatment with scheduled low-dose risperidone, their symptoms quickly resolved with minimal side effects. The authors indicate that subclinical and clinical symptoms of agitation and confusion can be successfully and efficaciously treated with low doses of scheduled antipsychotics rather than using as-needed higher doses once the symptoms have escalated into physical agitation and aggression. The authors suggest that this general course of treatment will lower the total daily doses of medication, and, subsequently, minimize the risk for adverse effects and prolonged hospitalizations in geriatric patients.
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Agitation is a common problem in elderly patients who are hospitalized for delirium, dementia, or both. It is a symptom of a condition, rather than a condition itself.1 Elderly patients have an increased risk of agitation in hospital settings because of disrupted sleep-wake cycles, the presence of multiple comorbidities, and the administration of multiple medications.12 One of the most important risk factors for developing delirium is dementia.2 Antipsychotics are the mainstay of pharmacologic treatment of agitation in elderly patients with delirium or dementia, with haloperidol being the most studied first-generation agent3 and risperidone being one of the most studied second-generation agents.4 Several studies have demonstrated the efficacy of both typical and atypical antipsychotics, including risperidone, in the management of agitation and aggression in persons with delirium, dementia, or both.4-6
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Antipsychotics are commonly used on an as-needed basis to control severe agitation in elderly patients. This often requires high doses of medications that may result in oversedation or other side effects. This report serves to introduce the concept of scheduled dosing of low-dose antipsychotics and suggests that this dosing strategy may allow for more efficacious treatment of agitated states. Ideally, this would allow less total daily doses of antipsychotics to be administered, thereby further minimizing the potential of adverse effects. This latter point is especially important given the inclusion of U.S. Food and Drug Administration (FDA) black box warnings on antipsychotic medications outlining the increased risk of mortality from heart-related events and infection in elderly patients with dementia who are receiving these agents to treat behavioral disorders.7
Case 1
A 70-year-old white man was admitted to the internal medicine service from a nursing home because of increased agitation and physical aggression. He was reported to have a baseline of dementia, but the timing and onset of his symptoms were unclear as there were no family members present to elaborate on the nature of his dementia. The nursing home reports indicated that a few days before his admission to the internal medicine department, the patient became even more agitated than usual and reportedly swung at a staff member, which led to his transfer to the emergency department. A computed tomography (CT) scan of the head and routine laboratory assessments, including a complete blood count (CBC), basic metabolic panel (BMP), liver function tests, thyroid-stimulating hormone test, and urinalysis, demonstrated no significant abnormalities that could account for the change in the patient’s behavior.
During his hospitalization, the patient required 4-point soft restraints, because he attempted to pull out his intravenous (IV) lines, was physically combative with the nursing staff, and his aggression could not be redirected. The patient’s primary care team attempted to use haloperidol and lorazepam on an as-needed basis. While haloperidol 5 mg intramuscular (IM) helped to calm the patient, it primarily sedated him. Lorazepam 1 mg IM also initially helped to control his agitation, but the nurses reported that these benefits wore off during the 24 to 48 hours that preceded the initial consultation with psychiatry, which occurred on hospital day 7.
On initial psychiatric evaluation, the patient was wearing the 4-point restraints and was somnolent. A Folstein Mini-Mental State Examination (MMSE) revealed a score of 7/27. The patient was disoriented to time and place, knew only his name, and had difficulty following one-step commands; however, during the 24-hour period preceding the initial psychiatric evaluation, the patient received two doses of lorazepam 1 mg IM and one dose of haloperidol 5 mg IM. Based on our assessment, we made the following recommendations to the patient’s primary care team: (1) perform a baseline electrocardiogram (ECG) to determine his corrected QT interval (QTc), as antipsychotics have a propensity to prolong the QTc interval, especially in elderly patients with preexisting cardiac risk factors or electrolyte abnormalities7; (2) discontinue the as-needed lorazepam, as benzodiazepines could worsen behavioral disinhibition; (3) monitor his creatinine phosphokinase (CPK) levels, as the patient had been in restraints intermittently and undetected rhabdomyolysis could lead to acute renal failure; and (4) begin scheduled risperidone 0.125 mg orally three times daily.
The first day after risperidone was started, the patient received one dose of haloperidol 5 mg IM for physical aggression. On the second day, risperidone was increased to 0.25 mg orally three times daily to minimize the necessity of as-needed haloperidol. After this dose adjustment, the patient did not require any further haloperidol treatments. Over the next few days, restraints were needed less frequently, and eventually the patient was restraint-free. The primary care team’s medical work-up revealed no clear source for the acute mental status change reported by the nursing facility. Although the patient remained disoriented to time and place, his ability to communicate with staff improved. After a 48-hour period of virtually no physical aggression and decreased agitation without the use of restraints, the patient was discharged back to the nursing facility on risperidone 0.25 mg orally three times daily.
Case 2
A 75-year-old black woman was admitted to the internal medicine service from an outside hospital for refractory thrombocytopenia. During her hospitalization, she developed an upperextremity deep vein thrombosis and multiple infections, including a urinary tract infection, methicillin-resistant Staphylococcus aureus discitis, and subsequent bacteremia. It was unclear whether she had baseline dementia, as she lived alone and family members could not recount her recent mental status. Whereas she had previously been pleasant and cooperative, she began to become confused and aggressive 2 weeks into her hospitalization. She started throwing objects in her room at the staff and repeatedly pulled out her peripherally inserted central catheter (PICC) and peripheral IV lines, necessitating the use of restraints. She also began refusing to eat and to take her oral medications, and she did not allow the staff to assess her vital signs.
Laboratory assessment upon admission showed a BMP within normal limits and a CBC remarkable for an elevated white blood cell count at 13.4 x 109/L (normal, 4.5-11.0 x 109/L) and a decreased platelet count at 36 x 109/L (normal, 150-450 x 109/L). A urine sample obtained via catheter was positive for Pseudomonas aeruginosa. CT scans and magnetic resonance imaging of her head showed arrested hydrocephalus that remained unchanged throughout her hospitalization. An ECG showed a QTc of 445 ms (prolonged in women, >470 ms). The primary care team started her on risperidone 0.5 mg orally every night, but this made her too sedated. On hospital day 30, psychiatry was consulted to help manage her agitation.
On initial psychiatric evaluation, the patient was lying in bed in 4-point restraints. Her eye contact and grooming were poor, and she appeared to be lethargic and to have psychomotor retardation. Blunted affect and a paucity of speech were also observed, with the patient only answering “yes” or “no” intermittently. The patient was oriented to the correct state and being in a hospital, but otherwise could not participate in the MMSE. Based on our assessment of the patient, we made the following recommendations to the primary care team: (1) decrease risperidone to 0.125 mg orally at night, as the higher dose of 0.5 mg was too sedating; (2) repeat the ECG to assess her QTc interval; and (3) monitor CPK, as the patient had been in restraints intermittently and undetected rhabdomyolysis could lead to acute renal failure.
The day after the initial psychiatry consultation, the patient did not receive any doses of risperidone because she continued to refuse oral medications. We recommended continuing soft restraints as needed and placing a flexible nasogastric feeding tube to allow nutrition and oral medications to be administered. Scheduled risperidone was increased to 0.25 mg orally twice daily, with another 0.25 mg orally to be administered as needed every 6 hours for agitation. We recommended the increased dose and twice-daily dosing because the patient’s noncompliance would likely prevent her from receiving all doses of a lower, more frequently scheduled regimen. After the first day of receiving risperidone 0.25 mg twice daily through her feeding tube, the patient was calm enough to allow for PICC and peripheral IV placement. On day 3 of risperidone treatment, we increased the dose to 0.25 mg orally three times daily, and she did not require any further as-needed doses. She began taking oral medications, allowing for the removal of the nasogastric tube. She continued to receive risperidone and IV antibiotics throughout the remainder of her hospital stay. After she was without agitation for 48 hours, it was thought to be safe to discharge her from the hospital on risperidone 0.25 mg orally three times daily.
Discussion
Antipsychotics have been shown to help control agitation in elderly patients with delirium, dementia, or both4-6; however, agitation is not the only symptom of delirium or dementia. Confusion, disorientation, and memory impairment are common in both disorders and may precipitate agitation or aggressive behaviors. Decreased acetylcholine activity, which has been observed with both dementia and delirium, contributes to confusion and memory impairment, as acetylcholine transmission is important in memory formation.8 Because there is an inverse relationship between dopamine and acetylcholine, antipsychotics may aid in memory formation by decreasing dopamine levels, which results in a relative increase in acetylcholine levels.8
Rationale for Lower Scheduled Doses
Scheduling antipsychotics may help patients with delirium or dementia and confusion regain some orientation and ameliorate confusion before they become physically agitated. In contrast, waiting to use as-needed antipsychotics prevents subclinical symptoms from being treated before they escalate into the clinical syndrome of agitation, which can require higher doses of medication to control. In addition, a patient who is agitated may need physical restraints, which may lead to injury and worsen agitation, requiring the assistance of considerably more staff members. Treating subclinical delirium before an acute episode of agitation is advantageous and safer for patients and staff. Ideally such treatments would also include nonpharmacologic interventions, such as lighting changes to accurately reflect the time of day, placing a correctly set clock and/or calendar in the room, and providing the appropriate amount of auditory and visual stimulation.9
Our experience suggests that smaller total daily doses of antipsychotics may be used if they are scheduled. With both case patients, a total daily dose of 0.75 mg (administered at 0.25 mg doses three times daily) was sufficient. Scheduled low doses may minimize blood level peaks and troughs, establishing a more even medication steady state. This principle can be observed when considering the use of basal insulin doses to control inpatient hyperglycemia rather than relying solely on sliding scale insulin. Using the sliding scale to react to extreme fluctuations in glucose levels tends to overshoot and lower glucose levels too much, eventually causing a physiologic response that increases glucose to a less desirable level than that observed before insulin treatment was initiated.10 Similarly, treating extremes of behavior such as physical agitation with high doses of antipsychotics may lead to overmedication, increasing the risk of oversedation and other side effects. Daytime oversedation from antipsychotic use may further disrupt the patient’s sleep-wake cycle by leading to rebound insomnia at night and, potentially, a phenomenon known as sundowning, which is a state of confusion at the end of the day and into the night that may contribute to the development or worsening of delirium. Just as basal insulin with correctional doses are preferred to treat hyperglycemia,10 scheduled low-dose antipsychotics may decrease the frequency of peaks and troughs of consciousness and arousal, thereby treating confusion and agitation in dementia or delirium more successfully.
Our Choice of Risperidone
We chose risperidone over other atypical antipsychotics to treat our patients because it has more evidence from doubleblind controlled trials showing it to be safe and efficacious in treating agitation, aggression, and psychosis in patients with dementia.4 Risperidone is often regarded as the first-line agent for treating agitation in dementia,5 partly due to its favorable side effect profile and relative lack of propensity to cause extrapyramidal symptoms at low doses.5,6 Risperidone also has less propensity compared with other atypical antipsychotics to cause anticholinergic side effects, which could worsen delirium or dementia by interfering with anterograde memory formation.7
Limitations of Our Treatment Recommendation
There are several limitations to our findings and subsequent recommendation of using scheduled low-dose antipsychotics to treat agitation in patients with delirium, dementia, or both. It is clinically difficult to differentiate delirium from agitation in dementia. We were not able to obtain much collateral information from our patients’ families or from their medical records to ascertain their baseline mental status before hospital admission, but it is likely that these patients also had underlying dementia. When dementia and delirium occur concomitantly, it can be challenging for clinicians to determine which symptoms are being caused by one condition or the other2; however, because patients with dementia are more prone to delirium, and antipsychotics have been shown to be helpful in controlling agitation in both conditions,3,11 our treatment regimen has merit regardless of which condition(s) is causing the symptoms. A question that remains to be answered is whether higher doses of antipsychotics are required in patients with delirium superimposed on dementia versus only one condition.
Another limitation is that our recommendation is based on the improvements in mental status that we observed following our treatment regimen in two patients, and not on the results of randomized controlled trials. We also did not use any delirium or dementia rating scales to determine clinical improvement in our patients. In addition, the psychiatry department was consulted only after interventions at controlling agitation had been attempted by the primary care team. In case 1, benzodiazepines were used, which could have exacerbated anterograde memory formation. In case 2, a higher dose of an antipsychotic was administered, which could have led to oversedation. It is possible that the removal of these treatment strategies also contributed to the clinical improvement observed in our patients.
The ability of the patient to take oral medications is crucial to our recommended treatment regimen, which may limit its utility. In case 2, a feeding tube needed to be placed to allow medication administration. Administration of oral medications may be difficult in some patients with agitation from delirium, dementia, or both, and alternate strategies should be considered in such cases.
Need for Future Research
More research is needed to investigate the specific therapeutic efficacy of using lower scheduled doses of antipsychotics to treat agitation in patients with dementia, delirium, or both. Additionally, there is a lack of data regarding a protocol to taper or discontinue antipsychotic medications once symptoms are resolved or better controlled. The American Psychiatric Association practice guidelines for the treatment of patients with delirium indicate a variable range of duration for delirium, from less than 1 week to 2 months, with elderly patients more likely to have a prolonged course lasting at least 1 month.9 For this reason, we usually recommend continuing the medication for at least 2 weeks with follow-up in outpatient psychiatry to determine if medication adjustments are needed.
Conclusion
A broad literature search did not reveal any articles or case reports discussing scheduled dosing of antipsychotics at low doses for the treatment of agitation in elderly patients. There was also no literature comparing the effects of scheduled dosing with as-needed dosing in the elderly. Our report introduces the idea that scheduled low doses of antipsychotics may be as efficacious, if not more so, than high as-needed doses in treating agitation in elderly patients. Lower total daily dosing minimizes the potential for adverse reactions. This is especially important in elderly individuals, as these patients may be more sensitive to psychoactive medications, which are noted in FDA black box warnings to increase the risk of morbidity and mortality.7,12
The authors report no relevant financial relationships. Dr. Nguyen is chief of psychiatry consultation liaison services, Department of Psychiatry, University of Florida College of Medicine, Gainesville, FL; Dr. Patel is a geriatric psychiatry fellow, PGY-5, Department of Psychiatry, Yale University, New Haven, CT; and Dr. Shapiro is a general psychiatry resident, PGY-3, Department of Psychiatry, University of Florida College of Medicine, Gainesville, FL.
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