One of the greatest uncertainties in nursing home management is the treatment of agitation associated with the dementias. This is a controversial area in which target symptoms are unclear, the mechanism of action for reason for action) of medications is unclear, and prescribing is still based on clinical judgment without established practice guidelines. The issue of behaviors that are "reactive" (clear precipitant) versus "endogenous" (no precipitant) is not a good predictor of medication response.
As with attention-deficit and disruptive behavior disorders in younger populations, strict environmental control may compensate for problems in affective flooding, selfregulation, distractibility, hyperactivity, or impulsivity. However, the extent of structuring that is needed may be unobtainable even in a hospital setting. Medication may bring sufficient improvement to allow individuals to function in a normal environment. Medications often appear necessary for aggressive behaviors (personality change due to the organic condition, aggressive type, 310.1 DSMIV), severe restlessness (e.g., excessive pacing, screaming), or persistent behaviors that prove dangerous to the patient or others.1
Since the nursing home reforms brought about by the Omnibus Budget Reconciliation Act of 1987 (OBRA 87), there has been up to a 45% reduction in the use of neuroleptics in nursing homes. The need for caution is highlighted by a single double-blind, crossover design study of a neuroleptic and placebo in which there were four deaths during the placebo phases of the study (2 from pneumonia and 2 from myocardial infarctions).2 However, the bulk of information suggests that a very large number of patients for whom neuroleptics were used had no behavioral or physical decline after discontinuation. Two recently published reports exemplify the issue. A 12month review of medical charts of a 485-bed nursing home where an attempt was made to stop or reduce antipsychotic drugs in 75% of the 107 residents on neuroleptics showed antipsychotics were discontinued safely in 45% of residents who had a dementia-only diagnosis.3 Similarly, in a study of 12 community nursing homes, 64 of 271 residents receiving neuroleptics at baseline had the drug discontinued with no change in the frequency of behavior problems as measured by Activities of Daily Living, the Brief Psychiatric Rating Scale, the MiniMental State Examination, or the Geriatric Depression Rating Scale.4
Such findings were not unexpected given the published reviews of the, at best, moderate efficacy of neuroleptics in the management of agitation in dementia.5"7 However, it should be remembered that more than one half of individuals in the studies had indications for continued use of neuroleptic medication and had apparent benefit from medication continuation.
This review provides an update of pharmacologie therapies for behavioral disturbance in dementia to allow the clinician to make rational decisions about medication for the "other sources of agitation."
FREQUENCY OF OCCURRENCE OF SYMPTOMS AND CAUSES
Agitation may be defined as any inappropriate verbal, vocal, or motor activity that is not an obvious expression of need or confusion. It is not a diagnostic term, but a group of symptoms that occur in a functional or organic psychiatric disorder, a medical illness, as an adverse effect of medication, or the result of sensory/communication difficulty.8 Agitated behaviors (e.g., pacing, verbal aggression, physical aggression, screaming, restlessness, complaining, attention seeking) are conservatively reported to occur in over one half of victims with Alzheimer's disease.9 An observational study in a nursing home setting confirmed the high frequency of agitation reported in other interview-based studies. Approximately 60% of these residents with probable Alzheimer's disease who showed behavioral disturbance had multiple behavioral problems.10
Conditions Considered Potentially Responsive to Pharmacologie Intervention
Agitation may be associated with a variety of coexisting psychiatric and medical disorders such as delirium, major depression, psychosis, anxiety, panic disorders, pain, or acute illness. In studies of Alzheimer's dementia, 31% to 40%' of patients were noted to report delusions, 7% to 57%' reported paranoia, up to 30% exhibited hallucinations, up to 57% had depression, and aggression was seen in 10% to 65%'. n In addition, "personality changes" may be due to the neuropathologic changes seen in various dementias (310. Ix, Organic Personality Change, DSM-IV). In Alzheimer's disease, the "organic personality changes" have been reported to include decreased energy, indifference, egocentricity, impulsivity, or irritability, which may have neuropathologic and neurochemical correlates.12'13 However, these changes vary widely between individuals and do not seem to be fully explained by specific brain localization.9
INDICATIONS FOR TREATMENT
Decisions for medication use, similar to practice guidelines established for other psychiatric disorders, should be based on diagnosis, target symptoms, and putative biochemical understanding of medication action. Unfortunately, except for treatment of comorbid psychiatric conditions such as major depression or psychosis, these indicators have not been clearcut for agitation in dementia. Generalizabiìity of findings from existing studies on treatment of agitation has often been questioned because of uncertainty of the diagnoses of patients or even specification of specific target behaviors. Most studies also were not randomized trials and showed clear sample bias plus open label design (known medication with no double-blind placebo control). Nevertheless, case reports, small case series, and more rigorous double-blind placebo-controlled studies all demonstrate modest effects with both neuroleptics and nonneuroleptic use.1
In establishing a clearer definition of target symptoms, Cohen Mansfield derived a list of behaviors referred to by nursing home staff as "agitation."14 She codified this into a scale based on frequency of occurrence rather than global severity, to improve objectivity of appraisals by caregivers. Each of the 29 items on the instrument is rated on a 7-point scale (1 = never occurs, 7 = occurs several times an hour) based on a staff member's estimate of average waking behaviors over the past week. The 29 items are clustered around physical aggression (hitting, kicking, pushing, scratching, grabbing, cursing), verbal agitation (screaming, negativism, constant requests for attention, complaining), physically nonaggressive behavior (pacing, disrobing or inappropriate robing, repetitious verbalizations or mannerisms, trying to get to a different place, general restlessness), and hiding/hoarding behavior. Oddly, items such as biting, spitting, or making strange noises were fairly nonspecific and coexisted with many other behaviors. Clinically, discussing specific behaviors and frequencies often makes it easier to probe for temporal associations and to clarify target behaviors currently thought to be responsive to psychotropic medication.
Non-Neuroleptic Medications for Agitation
Agitated behaviors that are considered potentially responsive to pharmacologie interventions are listed in Table I.1,15
In practice, many physicians are often fearful of being accused of noncompliance with the law when treating agitation with pharmacologie agents. Standards established by consensus panels or regulatory bodies such as the Health Care Financing Administration (HCFA) have been subject to frequent modification to reflect information that was not available when the regulations were established. Although it may be difficult to follow the frequent modifications, it is fairly safe to say that if a clinician documents the indication for use, notes specific target behaviors that are being used to judge efficacy, monitors potential side effects, and states what behavioral interventions have been tried, it will satisfy the regulatory guidelines. The regulations do not forbid the use of psychotropic medication, only cavalier use.
Neuroleptics have long been advocated for the noncognitive behavioral problems assodated with Alzheimer's disease and other organic brain syndromes, primarily due to the similarities between mental status changes in the dementias and changes usually described as a formal thought disorder.1 For example, speech may be irrelevant, circumstantial, or logically unconnected; motor activity may be abnormal; mood may be inconsistent; or patients may complain of having nonexistent visitors, may misidentify others, and show poor judgment, insight, and abstracting capacities. In addition, cognitive functions, by definition, are impaired.
Although there have been several qualitative reviews on neuroleptics in the elderly, only a few have focused on neuroleptic use in agitation associated with dementia. Helms, in a review of the literature over two decades, found that only three studies using neuroleptics for agitation in dementia had random assignment of patients and double-blind, parallel-group designs appropriate for statistical testing. Qualitative comparison of these studies showed only a modest positive response.5
In 1986, a more extensive review by Sunderland and Silver was reported. Of 20 doubleblind studies between 1954 and 1986, only 10 had a placebo control group. Of these, 5 showed a positive effect, 3 showed no effect, and 2 showed deterioration.6
In 1990, Schneider, Pollock, and Lyness published a meta-analysis of comparable double-blind, placebo-controlled studies of neuroleptic use in the elderly. They found no significant difference between neuroleptic and placebo in any study when analyzed by chi square tests (two-tailed), although the direction of effect was in favor of the neuroleptic. In combining significance levels and weighting each study by the number of subjects, the authors concluded that about 18% did better than on placebo.7
Additional outcome studies have been reviewed by Raskind showing similar modest improvement (reduction in symptoms, not elimination of symptoms, seen more often than with placebo). In terms of haloperidol, changes seem to occur at lower plasma concentrations than postulated as an effective haloperidol therapeutic window (5 to 12 ng/mL) for schizophrenia.1
To determine relative efficacy of neuroleptics versus other agents, Herz et al16 compared thiothixene, oxazepam, and diphenhydramine in a double-blind, crossover design for "resistive" Alzheimer's patients. They used 1-week medication trials at fixed doses separated by 1-week washout periods to try to determine which medication would have the most efficacy. The design avoided both polypharmacy and high doses of medication. Thiothixene was found to be the most effective at a mean dose of 3 mg/dL, using an infrequently used Behavioral Adjustment Scale.16 Further titration would be possible with resumption of the most effective medication in the series.
Nevertheless, it is now commonly accepted knowledge that the risk of side effects from neuroleptics, including the risk of tardive dyskinesia and memory impairment from anticholinergic effects, is higher in the elderly and may be highest in patients with dementia.17 The use of novel neuroleptic agents with more specific action and less receptor occupancy in the striatum (hence, fewer extrapyramidal symptoms) may cause less side effects, as suggested in the report on clozapine by Oberholzer.18 Eighteen patients with dementia and behavioral problems showed improvement on the Nurse's Observation Scale for Inpatient Evaluation and the Sandoz Clinical Assessment-Geriatric on clozapine. Although there were four discontinuations due to side effects, improvement was seen in all others with reduced extrapyramidal side effects for the seven patients previously on a neuroleptic.
It remains an unanswered question whether characterization of specific target symptoms may improve predictability of medication response, to further reduce possible adverse effects and ineffective medication trials.
Most of the literature of non-neuroleptic management of agitation in dementia consists of case reports or sequential case series with an open-label design. Non-neuroleptic medications, such as anticonvulsants and antidepressants, have been advocated as useful in treating certain symptoms based on these reports, but placebo-controlled, double-blind studies are generally lacking. Often, symptoms appear to have an affective component due to affective lability (with denial of dysphoric mood), preoccupation, irritability, sleep disturbance, abandoned social skills, and appetite change. Moodstabilizing medications have been used frequently. Medication with strong serotonergic affinity has been a theoretically important addition, considering the central role of the serotonergic system in aggression, mood stabilization, obsessive-compulsive behavior, and sleep.19
Research findings up to 1992 are reviewed by Smith and Perry20 and Schneider and Sobin21 and are summarized in Table 2. A MEDLINE search for relevant articles since 1992 added only a few new studies showing the efficacy of non-neuroleptic medication for agitation in dementia, as summarized in Table 3.
In our program, we have used a heuristic management algorithm to help clarify the diagnostic considerations and initial medication decisions (Figure). Potential medical and environmental factors and comorbid major psychiatric illness must be considered before psychotropic medication trials are initiated. Once medication trials are initiated, it is probably best to follow a sequential single therapy approach to try to avoid polypharmacy and the potential negative cognitive effects from drug interactions or highdose psychotropic medications. As recommended in a new Alzheimer's Association Research and Practice publication, doses should be low and the patient's status should be monitored frequently.22 Specific target symptoms along lines of the Cohen-Mansfield Agitation Inventory are sought to gauge efficacy and end-points for treatment.
Non-Neuroleptic Medications in Agitation (Update)
The initial selection of medication for agitation or depression is, at present, based on clinical judgment. Neuroleptics have been used most frequently. Often, a chlorpromazine equivalent dose of about 25 to 100 mg/day (e.g., 0.5 to 2 mg/day of haloperidol) is effective with high-potency neuroleptics being preferred due to lower sedative and anticholinergic profiles. A variety of alternative non-neuroleptics have been advocated in the literature. However, our preference has been to use non-neuroleptic management initially unless there are clear psychotic features. Buspirone is one alternative due to its S1 serotonergic activity and low sedation and side effect profile. The usual starting dose is 5 mg tid, increased rapidly until behavioral improvement is noted or the maximum dose of 60 mg/day is reached. Alternatively, trazodone HCl is often used, especially if there is a need for sedation or presence of dysphoric mood. Doses of 50 mg/day are usually sufficient for behavioral improvement. However, concomitant neuroleptic medications may be required for acute behavioral problems at the beginning of a trial.
After 4 weeks at maximum doses, a medication change is considered if there has been minimal improvement in target symptoms. If there has been no significant improvement throughout the initial medication trial, we usually substitute a neuroleptic if it has not been tried initially. If a neuroleptic has failed or is not tolerated, we generally will seek a different non-neuroleptic medication described above or an SSRI if there is mild dysphoric mood without a need for sedation.
If there is minimal response after 4 weeks at maximum doses, we usually substitute an anticonvulsant such as valproic acid or carbamazepine titrated upward to therapeutic blood levels. Again, acute behavioral problems are treated with the addition of a short-term, low-dose neuroleptic.
Benzodiazepines are rarely used due to our experience of excessive sedation, confusion, and gait disturbance at therapeutic doses for this frail population. If an anxiolytic is indicated, we often use alprazolam due to reported lower amnestic effects compared to other benzodiazepines, but differences between intermediate benzodiazepines do not appear great. Lithium, tricyclics, and estrogene similarly are rarely used unless there has been a history of prior use and response.
Figure. Management algorithm for agitation in dementia.
Augmentation is only used if there has been significant partial response to single medication that would warrant continuation of that medication with the addition of a medication in a different category. Also, according to current HCFA nursing home regulations, drug discontinuation is suggested after 6 months unless there are specific indications for continuation.
Throughout medication trials, attempts are made to help the staff develop behavioral treatment approaches, especially around communication skills and low-stimulus environments in an attempt to reduce potential environmental factors that might escalate pathological behavior.
Despite the lack of clarity in the current literature to guide effective medication selection, it is clear that many behavioral disturbances associated with dementias are related to the underlying neuropsychiatrie disorder and that psychotropic medication is often required to bring relief to the patient. A diagnostic evaluation with particular attention to the assessment of potential medical or psychosocial précipitants and treatments for those causes should precede psychotropic medication use. When psychotropic medications are indicated, a rational selection of medications based on target symptoms, adequate therapeutic trials, and the avoidance of polypharmacy remain the essential features of current thinking. Monitoring for possible adverse effects, including increases in confusion or sedation or problems in mobility, should be done frequently. More reliable guidance to prescribing will be clearer from the literature in the near future as results of current clinical trials of psychotropics for agitation in dementia are published.
1. Raskind MA. Alzheimer's disease: treatment of noncognitive behavioral abnormalities. In: Bloom FE, Kupfer DJ, eds. PsychopharmacoLogy: The Fourth Generation of Progress. New York: Raven Press; 1995:1427-1435.
2. Semla TP, Palla K, Poddig B, Brauner DJ. Effect of the Omnibus Reconciliation Act 1987 on antipsychotic prescribing in nursing home residents. J Am Geriatr Soc. 1994; 42:648-652.
3. Funkel SE, Lyons JS, Anderson RL, et al. A randomized, placebo-controlled trial of thiothixene in agitated demented nursing home patients. International Journal of Geriatric Psychiatry. 1995; 10:129-136.
4. Thapa PB, Meador DG1 Gideon P, Fought RL, Ray WA. Effects of antipsychotic withdrawal in elderly nursing home residents. J Am Geriatr Soc. 1994; 42:280-286.
5. Helms PM. Efficacy of antipsychotics in the treatment of the behavioral complications of dementia: a review of the literature. JAm Geriatr Soc. 1985; 33:206-209.
6. Sunderland T, Silver MA. Neuroleptics in the treatment of dementia. International Journal of Geriatric Psychiatry. 1988; 3:784-790.
7. Schneider LS, Pollock VE, Lyness SA. A metaanalysis of controlled trials of neuroleptic treatment of dementia. J Am Geriatr Soc. 1990; 38:553-563.
8. Cohen-Mansfield J, Billig N. Agitated behaviors in the elderly: a conceptual review. J Am Geriatr Soc. 1986; 34:711-721.
9. Patterson MB, Böiger JP. Assessment of behavioral symptoms in Alzheimer's disease. Alzheimer Dis Assoc Disord. 1994; SCsuppI 3):4-20.
10. Teri L, Larson EL, Reifler BV. Behavioral disturbances in dementia of the Alzheimer's type. JAm Geriatr Soc. 1988; 36:1-6.
11. Mendez FM, Martin RJ, Smyth KA, Whitehouse PJ. Psychiatric symptoms associated with Alzheimer's disease. J Neuropsychiatry. 1990; 2(1):28-33.
12. Group for the Advancement of Psychiatry, Committee on Aging. The Psychiatric Treatment of Alzheimer's Disease. New York: Brunner/Mazel; 1989.
13. Bolger JP, Carpenter BD, Strauss ME. Behavior and affect in Alzheimer's disease. In: Friedland RP, ed. Clinics in Geriatric Medicine: Alzheimer's Disease Update. 1994; 10:315-337.
14. Cohen-Mansfield J, Marx MS, Rosenthal AS. A description of agitation in a nursing home. J Gerontol. 1989; 44(3):M77-84.
15. Maletta GJ. Pharmacologie treatment and management of the aggressive demented patient. Psychiatric Annals. 1990; 20:446-455.
16. Herz LR, Volicer L, Ross V, Rheaume Y. A single-casestudy method for treating resistiveness in patients with Alzheimer's disease. Hosp Community Psychiatry. 1992; 43:720-724.
17. Sakauye KM. Psychotic disorders: guidelines and problems with antipsychotic medications in the elderly. Psychiatric Annals. 1990; 20:456-465.
18. Oberholzer AF, Hendriksen C, Monsch AU, Heierli B, Stahelin HB. Safety and effectiveness of low-dose clozapine in psychogeriatric patients: a preliminary study. Int Psychogeriatr. 1992; 4(2):187-195.
19. Heninger GR. Indolamines: the role of serotonin in clinical disorders. In: Bloom FE, Kupfer DJ, eds. Psychopharmacology: The Fourth Generation of Progress. New York: Raven Press; 1995:471-482.
20. Smith DA, Perry PJ. Non-neuroleptic treatment of disruptive behavior in organic syndromes. Ann Pharm,acother. 1992; 26:1400-1408.
21. Schneider LS, Sobin PB. Non-neuroleptic treatment of behavioral symptoms and agitation in Alzheimer's disease and other dementias. Psychophar mami Bull. 1992; 28(1):71-79.
22. Alzheimer's Association. Treating agitation in Alzheimer's Disease. Research and Practice: Practical Information for Health Care Professionals. Vol 4; 1995.
23. Tariot PN, Erb R, Reibovici A, et al. Carbamazepine treatment of agitation in nursing home patients with dementia: a preliminary study. J Am Geriatr Soc. 1994; 42:1160-1166.
24. Friedman R, Gryfe CI, Tal DT, Freedman M. The noisy elderly patient: prevalence, assessment, and response to the antidepressant doxepin. J Geriatr Psychiatr Neurol 1992; 4:187-191.
25. Sakauye KM, Camp CJ, Ford PA. Effects of buspirone on agitation associated with dementia. American Journal of Geriatric Psychiatry. 1993;1(1):82-84.
26. Kyomen HH, Nobel KW, Wei JY. The use of estrogen to decrease aggressive physical behavior in elderly men with dementia. J Am Geriatr Soc. 1991; 39:1110-1112.
Conditions Considered Potentially Responsive to Pharmacologie Intervention
Non-Neuroleptic Medications for Agitation
Non-Neuroleptic Medications in Agitation (Update)