Psychosis-related disturbances. Psychosis, agitation, and disinhibition in Alzheimer's disease: Definitions and treatment options

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Approximately 50% to 80% of persons diagnosed with Alzheimer's disease (AD) have some type of behavioral or psychiatric condition (eg, agitation, psychosis, and/or disinhibition). Agitation is defined in the context of restlessness, irritability, and resistiveness. Psychosis is recognized as a disturbance in the perception of objective reality. Disinhibition means a chronic loss of social restraint. In the case of AD, disinhibition can present as aggression, hyperactivity, and socially intrusive behavior. Such conditions can be burdensome for physicians and caregivers to manage. Consequences may include caregiver burnout or illness, patient abuse, and even institutionalization for the patient. Management of behavioral disturbances is no longer primarily handled by psychiatrists, but is now entering the realm of family practice and primary care. This article provides evaluation methods and treatment options for the aforementioned behavioral disturbances.

Key words: psychosis • agitation • disinhibition • Alzheimer's disease

Drugs discussed: antidepressants • atypical and typical antipsychotics cholinesterase inhibitors • mood stabilizers • NMDA receptor antagonists selective serotonin reuptake inhibitors

Lesser JM, Hughes SV. Psychosis-related disturbances. Psychosis, agitation, and disinhibition in Alzheimer's disease: Definitions and treatment options. GERIATRICS 2006 (Nov): 14-20.

Approximately 4.5 million adults have been diagnosed with Alzheimer's disease (AD) in the United States;1 50% to 80% of those diagnosed experience some form of behavioral or psychiatric disturbance, including agitation, psychosis, and/or disinhibition.1,2 These syndromes are disruptive to patient support systems (eg, elderly spouse, adult children) and are a challenge for physicians to manage. The consequences of ineffective psychiatric treatment of AD include caregiver burnout or illness, patient abuse, and potentially avoidable institutionalization. From a medical perspective, agitation places added stress, for example, on the cardiovascular system. With increasing numbers of home-dwelling AD patients, management of behavioral disturbance is no longer the exclusive province of psychiatrists, but increasingly that of family practitioners and primary care physicians.3

Defining terms

Psychosis is defined as a disturbance in the perception and/or appreciation of objective reality, characterized by hallucinations and/or delusions.

Hallucinations can involve any sensory modality, but in dementia, are frequently visual.4

Dementia-related delusions tend to be poorly systemized and fluctuating, and often persecutory in nature (ie, a patient accuses others of stealing his/her objects).

Disinhibition means a generally chronic loss of normal social restraints, and, in the case of AD, often presents itself as aggression, hyperactivity, wandering, socially intrusive behavior, inappropriate sexual behavior, or uncharacteristic use of profanity.4,5


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Table 1. Risk factors for psychosis, agitation, and disinhibition as per clinical experiences of the authors

Non-modifiable
1. Severity of dementia (roughly correlated)
2. Presence of multiple concomitant medical problems
3. Prior history of personality disorder (explosive, anti-social, or paranoid)

Modifiable
1. Substance use
2. Multiple medications (eg, anticholinergic or sedatives)
3. Chaotic living situation, as defined above (particularly contributes to agitation)
4. Untrained or impaired caregiver (particularly contributes to agitation)
5. Acute medical problem manifested by fever, such as a infection, a fecal impaction, bladder distention, pain, or uncontrolled diabetes
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Agitation is difficult to define. Terms commonly used include restlessness, irritability, hostility, and resistiveness. The common denominator in these descriptions may be an increase in restlessness, often purposeless activity, and signs of anxiety or depression. Differentiating this type of restlessness from akathisia can be difficult, particularly if the patient is on an antipsychotic, a selective serotonin reuptake inhibitor, or divalproex sodium. As a rule, agitation should be periodic or intermittent and reduced by engaging the patient's interest. Akathisia should be relatively continuous and should persist even when the patient is occupied.

Causes and evaluation

While it is not possible to associate a single cause with a particular symptom, there are factors that increase risk of psychotic behavior, agitation, and disinhibition, as listed in table 1. Risk of behavioral issues is increased in the presence of more severe dementia (ie, MMSE score <12), multiple concomitant medical problems, and multiple medications. Modifiable factors include a chaotic support system (eg, lack of routine mealtimes, changing caregivers, familial discord), caregiver burnout, and poor control of medical problems, such as uncontrolled hypertension and diabetes mellitus.

Psychotic symptoms, especially delusions, may be related more to the patient's stage of AD and can be seen as an intrinsic part of the dementia. Disinhibition reflects impairment of higher cortical function or frontal lobe dementia, especially in the later stages of AD.6


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Table 2 Evaluation of behavioral or psychiatric disturbances per clinical experiences of the authors

Characteristics of syndrome
- Description of behavior
- Chronic or episodic timing (am versus pm) and consistency of timing
- Presence or absence of precipitant (precipitants include arguments, caregiver anger, overcorrection by caregiver, or patient's frustration at the inability to perform a task)
- Type of precipitant
- Frequency

Chronology of syndrome
- When did it start?
- Relationship to any major change in household routine
- Relationship to any change in medical status
- Relationship to any change in medications
- Recent change in appetite, weight, energy, or sleep

Support system
- Competency and stability of caregiver(s)
- Organization/disorganization of household
- Availability of alcohol or other drugs to patient or caregiver

Background
- Current medical problems
- Current medications (including OTC)
- Stage of dementia
- History of past psychiatric illness

Investigations
- Physical examination
- CBC, blood chemistries, urinalysis, electrocardiogram, chest x-ray, CT scan, and as indicated
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The evaluation of behavioral/psychiatric disturbance consists of careful description of target symptomatology, frequency, and precipitants. The physician must then carefully evaluate for any modifiable cause: medication side effect or drug-drug interaction, undiagnosed or exacerbation of a medical illness or pain syndrome, and/or support system instability. Table 2 lists the components of the evaluation.

Dementia with Lewy bodies (DLB) constitutes approximately 15% to 25% of dementia cases with variable presentations graduating into Parkinson's and Alzheimer's with Parkinsonian features.7 Early in the evaluation process, physicians need to consider the possible diagnosis of DLB.8 The clinical features of DLB can be variable. Symptomatology of DLB exists in the domains of cognitive impairment, neuropsychiatric symptoms, motor dysfunction, sleep disorders, and autonomic dysfunction.9

DLB patients present with a range of cognitive and/or behavioral symptoms that include amnesia, executive dysfunction, apathy, and slowed mental processing.9 A common feature is marked fluctuation in the cognitive disturbance with considerable variations in memory, orientation, and lucidity. Typical neuropsychiatric symptoms of DLB included vivid and well-formed visual hallucinations, illusions, and persecutory delusions, including the Capgras syndrome, the delusion that familiar persons are imposters.9 DLB is also notable for intense nightmares accompanied by agitation, resulting in self-injury. In addition, orthostatis, urinary incontinence, and constipation are often seen in DLB patients.

The significance of recognizing DLB relates to the care required to manage symptoms. Cholinesterase inhibitors improve cognitive symptoms and hallucinations in DLB.10 DLB patients are markedly sensitive to typical neuroleptics, and somewhat less so to atypicals.10 Clozapine,11 risperidone,12 olanzapine,13 and quetiapine11 show some benefit in the treatment of psychosis and agitation in DLB.

Agitation: Paradigm for behavior disturbance

The authors suggest that the common complaint of "agitation" can be divided into three subtypes: spontaneous, reactive, and disinhibited.


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Table 3 Management of behavioral symptoms of dementia: Practical suggestions for caregivers

Psychosis and/or paranoia
- Refrain from arguing with a person who suffers from hallucinations and/or delusions. Validate that you understand the person's perceptions
- Adjust lighting to the patient's comfort level to reduce shadows that may provoke fear and paranoia
- Remove mirrors, stuffed animals, and/or dolls as they may stimulate illusions, delusions, and/or hallucinations
- Redirect a person's attention to a simple activity (eg, offer food, a walk) to reduce auditory or visual hallucinations and persecutory thoughts
- Provide words of reassurance that the person is safe and unthreatened
- Point out that all doors and windows are locked securely to prevent intruders from entering
- Avoid lengthy meal preparation in the presence of the patient to minimize olfactory hallucinations

Agitation/aggression
- Plan structured activities, such as taking an accompanied walk along a nature trail, bird watching, painting, crafts, gardening
- Keep a selection of soft music available to promote a soothing, calming environment free of loud noises that can exacerbate agitation or aggressive behavior
- Minimize he patient's interaction with strangers and unfamiliar settings
- Be aware that patient may be in physical pain or discomfort and unable to express his/her needs appropriately; observe and/or probe for physical signs of pain, fatigue
- Display digital clocks and calendar for easy viewing by a person who may feel frustration by his or her own disorientation to time
- Limit physical household chores that may be too difficult to achieve and lead to frustration, agitation and/or aggressive behavior

Disinhibition
- Ignore behavior that is nothing other than annoying to the caregiver as long as the patient is not engaging in risky or unsafe behaviors. Refrain from arguing about annoying behaviors
- Reward positive behavior exercised by the person (particularly in social situations)
- Limit outings in crowded settings
- Be mindful of your stress and frustration level as a caregiver, as your behavior may set an example for the disinhibited patient
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"SPONTANEOUS" AGITATION is episodic, usually appearing in the evening with no obvious precipitant, and is often termed "sundowning." It is frequently accompanied by disorientation, and sometimes, hallucinations. Behavioral nonpharmacologic treatment approaches include: avoiding caffeine, increasing activity level during the day, and avoiding daytime naps. In many cases, sundowning responds to low-dose antipsychotic. Some literature support use of trazodone, a serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant for this agitation.14

A number of small open-label studies have shown improvement in agitation and aggression in mixed demented patients treated with trazodone,15 and a double-blind trazodone-haldol study in 28 demented subjects found both drugs effective for different symptoms.16 Haloperidol reduced restlessness, pacing and escape attempts, whereas trazodone tended to reduce perseveration and oppositionality.16

"REACTIVE" AGITATION is, by definition, preceded by an identifiable precipitant, such as a change in daily routine, refusal of a demand or request, or an argument with a caregiver. (Caregivers are only advised to argue with an AD patient if the patient is in imminent harm.) Reactive agitation manifests itself as irritability, anger, explosiveness, or acute despair. It resembles a temper tantrum and can last minutes to hours depending on the circumstances. Caregiver support and education may resolve the behavior.

"DISINHIBITED" AGITATION, by contrast, is chronic and unrelenting, with no clear periodicity or trigger. The patient is described as garrulous, intrusive, restless, sexually suggestive, physically aggressive or uncharacteristically coarse. Such patients show an indifference to the needs of other people. There may be a resemblance to a manic state. Disinhibited patients are generally less responsive to psychotropic agents, compared with psychotic and agitated patients, although anticonvulsants, such as valproate (50 to 100 mg/d), may improve symptoms.17 Environmental limit setting (eg, daycare programs) provide structure and caregiver respite.

Elucidation of type of behavior, timing, and presence/type of precipitating event are important elements of the evaluation, as defining target symptoms, severity and frequency allow accurate monitoring of treatment response.

Nonpharmacologic management

When symptoms of psychosis, agitation, or aggression have strong environmental roots, changing the support system (if possible) can greatly reduce behavioral problems. Two common triggers are a chaotic living situation and an exhausted or impaired caregiver.

Demented patients require structure and predictability. Structure makes the world a simpler, less threatening place, allowing the patient to conserve mental energy. A chaotic setting yields a frenzied, frightened patient. Consistent, regular mealtimes; familiar faces; clear, simple communications—all have a calming effect.18 The following case illustrates an appropriate response by a caregiver (Mrs. S) to her spouse (Mr. S), who experiences occasional visual hallucinations as a result of advanced dementia.

Mr. S: "Honey, are you sure it will be o.k. for our guests in the living room to stay for dinner?"

Mrs. S: Glancing into their empty living room, "Sure, I've prepared enough food for everyone...no need to worry. Why don't we take a walk in the neighborhood, as it is such a beautiful afternoon."

Here, Mrs. S validates her spouse by leading him to think she believes his hallucinations are real. She quickly suggests a distraction task in an attempt to redirect her spouse's attention. Avoiding arguments, insisting that the demented patient's hallucinations are false, and belittling all serve to escalate the situation and possibly incite agitation or aggression. Table 3 reflects other strategies caregivers can use to diminish behavioral symptoms in the demented patient.

An impaired, burned out, or uninformed caregiver can induce agitation, or even worsen it. Arguing with a demented person is counterproductive, as are belittling, screaming, and cursing. A major problem exists when an inadequate or impaired caregiver is the only available caregiver, and social agencies may need to be contacted at the discretion of the PCP.

Pharmacological management

Table 4 refers to the standard psychotropic agents recommended.

There is no ideal medication for agitation, psychosis or disinhibition in AD. A 2005 evidence-based review19 found little efficacy in typical antipsychotics, but did find modest, statistically significant effects for olanzapine and risperidone, and significantly lower adverse effects for atypicals versus typicals. The same review finds only citalopram effective among antidepressants, for neuropsychiatric symptoms, such as agitation other than depression.


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Table 4 Some recommended psychotropics

Antipsychotics -- typical

- Haloperidol
* Recommended dose: 0.25mg to 5mg/bid
* Advantage: Essentially no anticholinergic nor orthostatic effect
* Disadvantage: 1) Highly antidopaminergic effect with frequent EPS; 2) may cause Neuroleptic Malignant Syndrome prolongation; 2) efficacy in placebo-controlled studies is small at best, as with other conventional antipsychotics[19]


Antipsychotics -- atypical

- Risperidone
* Recommended dose: 0.5 - 2mg/bid
* Advantage: Fewer antidopaminergic effects than classic antipsychotics (lower incidence of extrapyramidal symptoms, tardive dyskinesia)
* Disadvantage: Potential for weight gain, diabetes, and hyperlipidemia

- Clozapine
* Recommended dose: 12.5 - 25 mg/d
* Advantage: Very little potential for EPS, TD
* Disadvantage: Considerable anticholinergic effect; potential for blood dyscrasia requiring frequent monitoring; considerable orthostatic effect; high risk of weight gain, diabetes, and hyperlipidemia

- Quetiapine
* Recommended dose: 50 - 200 mg/d
* Advantage: Within atypical group very little potential for EPS/TD; may be preferred in patients with Parkinsonism
* Disadvantage: Some potential for weight gain and diabetes

- Olanzapine
* Recommended dose: 2.5 - 10 mg/d
* Advantage: Little EPS/TD
* Disadvantage: High risk of weight gain, diabetes, and hyperlipidemia


Cholinesterase inhibitors

- Donepezil
* Recommended dose: 10 mg/d
* Advantage: Generally well tolerated; may supplement effect of an antipsychotic or antimanic drug
* Disadvantage: Potential for significant bradycarda; potential for gastrointestinal disturbance. Caution must be used when administered to a patient who cannot communicate gastrointestinal distress
- Galantamine


SSRIs

-Sertraline
* Recommended dose: 25 - 75 mg/d
* Advantage: May be useful for milder irritability/aggression particularly where a depressive component exists
* Disadvantage: Can cause nausea and gastric irritation; risk of falls; Paxil is highly anticholinergic

- Paroxetine
* Recommended dose: 12.5 - 25 mg/d
- Citalopram
* Recommended dose: 10 - 30 mg/d


Mood stabilizers

- Valproic acid
* Recommended dose: 50 - 100 mg/d
* Advantage: May be effective in reducing disruptive and disinhibited behaviors
* Disadvantage: Can produce thrombocytopenia and liver enzyme elevations

- Carbamezepine
* Recommended dose: 200 - 600 mg/d
* Advantage: May reduce problem behaviors in disinhibited patients, particularly aggression
* Disadvantage: Can produce acute bone marrow suppression and elevated liver enzymes; multiple drug-drug interactions


Antidepressants

- Trazodone
* Recommended dose: 50 - 100 mg/d
* Advantage: Demonstrated efficacy in the reduction of disruptive behavior in dementia
* Disadvantage: Anticholinergic effect can potentially worsen confusion

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EPS=extrapyramidal symptoms; TD=tardive dyskinesia
Based on information from references 19, 22-25
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The empirical data on mood stabilizers is equally controversial; while previous reports suggested valproate may benefit disruptive behavior in AD patients,17 a 2005 trial with 153 nursing home residents found no statistical difference between valproate and placebo.20 Similarly, data for carbamazepine are conflicting.19 There is consistent evidence for a small positive effect on behavioral disturbance with cholinesterase inhibitors with no marked differences between special drugs.19 Studies of memantine in this regard, are inclusive.19

Consequently, any guidelines for pharmacotherapy of psychosis, agitation, or aggression in Alzheimer's patients must be tentative. Certain points can be made. Clearly, a preferred psychotropic should be low in anticholinergic effect, low in orthostatis, create few drug-drug interactions, and have few or no cardiovascular side effects.

Further, atypical antipsychotics have demonstrable, if modest efficacy and should be considered first line drugs.19 Cholinesterase inhibitors, while basically used for cognitive symptoms, also appear to improve psychiatric symptoms.19

As table 4 reflects, the role of hormonal treatments remains unsettled.

Available evidence does not suggest any differences in efficacy among specific SSRIs, neuroleptics, nor atypical antipsychotics. The choice of medication with a class depends on side effect profile. Low potency neuroleptics, such as thioridazine, are not recommended because of their anticholinergic and orthostatic effects. High potency typicals, such as haloperidol, have been routinely used but are limited by the propensity to produce extrapyramidal symptoms and tardive dyskinesia. Among atypicals, weight gain, with associated risk of diabetes mellitus and dyslipidemia, varies from highest with clozapine and olanzapine use, risperidone and quetiapine present moderate risk, and ziprasidone and aripiprazole offer the lowest risk.21

Conclusion

Pharmacotherapy is sometimes the least difficult aspect of management. In fact, the authors' clinical experience suggests that the most important element is maintaining strong communication and rapport with the caregiver, as a physician is likely to have an accurate picture of behavioral problems in a patient if s/he inquires about caregiver/patient interactions and caregiver knowledge.

The other element that must be shared by a physician and caregiver is patience. Medications may take several days to weeks to be efficacious. Improvements must be viewed as incremental rather than all or nothing. Expectations of pharmacotherapy must be realistic. Physicians should strive to disseminate treatment options to patients and caregivers while maintaining empathic understanding of the presenting circumstances. A demented patient with disruptive behavior does not exist in a vacuum, and the goal of any treating physician should be to improve quality of life for both patients and their caregivers.

Dr. Lesser is associate professor of psychiatry and chief of the gero-psychiatry clinic at the University of Texas Medical School in Houston.

Ms. Hughes is senior research associate to Dr. Lesser at the University of Texas Mental Sciences Institute in Houston.

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