Medications for the treatment of behavioral problems associated with dementia

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It is my hope that the following discussion on medications will make the care of the patient with dementia more understandable and improve their functional ability. The major types of dementia are those secondary to Alzheimer's disease, vascular dementia, mixed dementia (vascular and Alzheimer's combined), frontotemporal dementia and dementia with Lewy bodies. There are other recognized types of dementia due to HIV and substance abuse. The comments on behavior therapies can apply to these disorders.

THE USE OF MEDICATIONS IN THE TREATMENT OF DEMENTIA AND THE ASSOCIATED BEHAVIORAL PROBLEMS
GARY W. STEINKE, M.D.

Revised 08/07/05


A few general principles/ideas about medications are important.

Everyone's response may be different so that what works for one individual may not be effective for another individual.

Many medications take 3-4 days (minor tranquilizers) to 4-6 weeks (the antidepressants) before the medication has a chance to be fully effective, so stopping the medication prematurely may be unwise.

The effective dose of a medication may vary from person to person.

Work closely with your health care provider as you adjust and change medications including those you buy over-the-counter.

Monitor for any negative side effects that prevent one from continuing to use a drug.

Don't mix prescription drugs with those you purchase over-the-counter (OTC) or with alcohol. Example: Cold preparations for the flu do not mix well with antipsychotics. Discuss all OTC medicines with your health care providers.

Limit the use of caffeine if you are having problems with anxiousness or agitation. Caffeine can be a potent stimulant in advancing age and comes in the form of coffee, tea and chocolate.

Agitation has been defined in the literature as any verbal, vocal or motor behavior that is disruptive, unsafe, distressing to the patient and interferes with care and is not because of need. Agitation or any acute change in one's behavior or mental ability may be secondary to Dementia Syndrome, i.e. Alzheimer's disease, but it is critical to first evaluate for other causes such as urinary tract and upper respiratory infections, recent strokes, head trauma, pain, arthritis, constipation, new medications that can cause drug interaction, excessive usage of prescribed medications or toxic effects of prescribed drugs. Consider other medical illnesses that may aggravate mental ability such as congestive heart failure, hypoxia, diabetes, hypothyroid, alcohol abuse, sensory deprivation with loss of vision or hearing, or other medications that may have been acutely withdrawn. Many OTC medications and some prescription medications may cause confusion and exacerbate the symptoms of the dementia syndrome.

As a general rule, start all behavioral medications at a lower dose. The therapeutic effect will vary from individual to individual but may be achieved at less than the recommended starting dose. These smaller doses, if effective, may lessen the side effects.

There is no such thing as a truly safe tranquilizer or sedative. All drugs have negative side effects. Be sure the behavior that you feel needs treatment with a medication can't best be treated with behavioral manipulation, daycare participation or with care management technique. Don't use the neuroleptic medications for anxiousness or for insomnia because of the potential serious side effects.

Monitor drugs that have been instituted with an attempt at reduction after several months of utilization especially if the treatment goals have been met. The disease may have changed and the patient may not require the same doses but can achieve the same success with smaller doses.

Current literature suggests that aggressive control of hypertension, diabetes and high cholesterol and lipids may lessen the risks of developing vascular dementia and/or mixed dementia (vascular dementia and Alzheimer's disease together).

Mental (use your brain exercise) exercise are important to brain functioning.

THE CURRENT CHEMICAL TREATMENTS AVAILABLE FOR THE DEMENTIA TYPES MENTIONED ABOVE INCLUDE THE FOLLOWING:

Cholinesterase inhibitors.
Anti-inflammatory drugs.
Ginkgo Biloba.
Antioxidants (Vitamin E).
Lipid lowering agents (statins).
Aspirin.
Memantine (Namenda)

There are several cholinesterase inhibitors that are currently on the market for treating the dementia syndrome. Those drugs are Aricept (Donepezil), Galantamine (Razadyne), Rivastigmine (Exelon). Memantine (Namenda) is a new class. Aricept, Galantamine and Rivastigmine have been approved by the FDA for the treatment of early to middle stage Alzheimer's type dementia. The FDA has approved Namenda for the treatment of advanced Alzheimer's type dementia. These medications may have an affect of improving memory, behavior or one's functional ability (ADLs) and mood. For example, they may improve memory, ability to do activities of daily living and they have also been found to affect mood, i.e. lessening apathy, agitation, delusions, and hallucinations. It is important to discuss with your health care provider the potential side effects of nausea, diarrhea and/or constipation. It is important to consider using Aricept in the morning as it may cause nighttime somnolence. It may be difficult for your health care practitioner to measure improvement with mental status testing but the care provider often will have first hand experience as to whether these medications are making any difference. It is important to realize that not all patients have a positive response to these drugs. It is also important when utilizing these drugs to increase the dose to the maximum dose suggested by the manufacturer. One cannot be certain as to the benefits gained from these drugs unless one uses the highest dose possible. It is important to discuss with your health care practitioner if you are using these drugs in a manner that the FDA has not approved.

The current role of anti-inflammatory drugs, example, Advil, is not determined but some studies suggest a protective effect but other studies suggest no benefit. Anti-inflammatory drugs may cause G.I. bleeding.

There is some research data suggesting the benefit of the above cholinesterase inhibitor in the treatment of mild cognitive impairment (MCI).

Estrogens have not been shown to change the progression of Alzheimer's disease once the diagnosis is established. The current literature suggests an increase in cardiovascular events with the use of estrogens. There is no evidence estrogens prevent onset of dementia.

Vitamin E is an antioxidant that may protect the brain against free radical damage. The dose in the original studies was 1,000 to 2,000 international units per day. The current literature suggests no Vitamin E or less than 400 units be used if one has a cardiovascular history suggesting coronary disease as higher doses of Vitamin E may increase the risk of myocardial infarction.

Selegiline is a selective MAO-B inhibitor that increases the level of brain catecholamines. It may have an antioxidant effect.

Ginkgo Biloba may have antioxidant properties. The dose of Ginkgo Biloba extract used in the studies was 40 mg. three times a day, showing some benefit in improving memory and cognition, resulting in improved functional ability. The data on Ginkgo Biloba has been mixed in studies and needs to be carefully monitored as it has interactions with common drugs.

Aspirin and statin drugs may prevent vascular dementia.

BEHAVIORAL TREATMENT ISSUES FOR PATIENTS WITH THE DEMENTIA SYNDROME

Although cognitive disturbances such as memory impairment, language impairment are probably the most recognized symptoms of dementia, the behavioral psychological symptoms of dementia (BPSD) are also common and cause considerable morbidity and disability in people with Alzheimer's disease. The (BPSD) symptoms may include delusions, hallucinations, agitation, physical aggression, hostility, restlessness, wandering, pacing, verbal outbursts and/or apathy.

I. SEVERE AGITATION

Severe agitation may occur, with or without problematic delusions, paranoia, hallucinations, combativeness and psychomotor agitation.

Non pharmacologic interventions should be tried first or in conjunction with medical therapy.

Use the following drugs only if absolutely necessary because of the undesirable side effects. The inherent risk of getting an irreversible tardive dyskinesia is approximately 50% in elderly after three years of continuous usage of the typical neuroleptics. It is important that the physician utilize the drugs for appropriate situations because of the negative side effect profile. The FDA has recently mandated a warning about all atypical neuroleptic drugs. Use of these drugs for the psychosis of dementia patients may increase the risk for mortality. The FDA is requiring the manufacturers of these atypical neuroleptic drugs notify health providers that they are not approved for the treatment of behavior symptoms in the elderly with dementia. Unfortunately, we often have no choice but to utilize the medications for appropriate behavior with close monitoring by your health care provider.

A. The first category drugs are the typical neuroleptics (antipsychotics). (Best for acute serious agitation as defined above with limited long term usage.)

Haldol - starting dose is usually .125 mg., with a maximum of approximately 1-2 mg. This drug is best used for acute situations needing immediate control. The major side effects are extrapyramidal symptoms.
Mellaril & Thorazine - this drug is effective for critical agitation but has significant side effects including hypotension, anticholinergic symptoms, and drowsiness. Usually start with 10 mg., maximum is 50 to 100 mg. per day. These drugs are rarely used for the psychosis in the dementia syndrome.
Stelazine, Moban, Trilafon and Loxitane. The side effects are in between Mellaril and Haldol. These drugs are rarely used in treating the psychosis of Alzheimer's disease as first line therapy.
Avoid using Cogentin and Artane with the above medications.

B. The next category drugs is the atypical neuroleptics. They are indicated for chronic maintenance and can be utilized initially to treat acute agitation. The atypical neuroleptic drugs have limited extrapyramidal and anti-cholinergic side effects and are less sedating than the typical antipsychotic drugs. The atypical neuroleptics can cause weight gain. Examples of atypical neuroleptics are:

Risperdal (Risperidone) - the initial dose is .125 mg., average dose is .5 to 1.0 mg/day, maximum approximately 2.0 mg. total, given in one daily or divided dosage. One must remember that the extrapyramidal symptoms may occur at 2 mgs or over. Extrapyramidal reactions and sedation are more likely at higher dosages.
Zyprexia (Olanzapine) - initial dose is 1 to 2.5 mg., maximum is 5 to 15 mg., usually given 2 times per day. This medication may be sedating and has weak anticholinergic properties.
Seroquel (Quetiapine) - initial dose is 12.5 mg., maximum dose is 75 to 125 mg., usually given in b.i.d. dosage. The medication has some of the same effective profile as the two listed above but also is sedating. It is usually the drug of choice for older individuals with gait or balance problems.
Abilify (Aripiprazole) - initial starting dose is 2.5 mg. This drug has the least anticholinergic side effects of all of the atypical antipsychotics mentioned. It is currently on Medi-Cal, but like all of the atypical antipsychotics is approved by the FDA for use in acute psychosis (schizophrenia and mania).
Clozaril (Clozapine) - not used routinely because of hematologic toxicity.
Geodon (Ziprasidone) - It is FDA approved for acute psychosis (schizophrenia and mania) with similar side effects as other antipsychotics.
When multiple drugs are utilized, the physician must monitor for drug interactions. It is also important when using the atypical neuroleptics that the physician monitor for the potential development of diabetes and elevated cholesterol with the use of these medications. The risk is the highest in the first six months of usage but can occur at anytime. The monitoring recommendations are available in the literature. The drug with the highest risk for diabetes mellitus is Zyprexia and Clozaril. Less risk of diabetes mellitus with Geodon and Abilify.

C. Other non antipsychotics or anticonvulsant medications that may help modulate behavior and can be mixed with the typical and the atypical neuroleptics are:

Trazodone (Desyrel) - usually start at 12.5 mg., maximum 200 mg.
Buspar.
Tegretol. The physician must monitor the CBC and liver function studies. This medication has significant drug-drug interactions.
Valproate (Depakote) - start with 125 mg. 1-2 times per day and titrate to a blood level approximately 40-90 mg. Physician must monitor liver functions and the coagulation studies (protime, PTT and platelets). This medication may cause extrapyramidal symptoms in predisposed patients. To get behavior modification, the blood level guidelines don't always apply.
Neurontin - this medication has been shown in some individuals to have some modulating effect on aggressive behavior.
The above five drugs can be mixed with the neuroleptics or with minor tranquilizers to achieve the stated goals.

II DELIRIUM - The treatment protocols use the conventional high potency (typical) antipsychotics and the atypical antipsychotics. Delirium is defined as a change in the patient's mental status that is usually characterized as impairment in attention and other intellectual functions. The acute confusional state can fluctuate over minutes and hours and come on abruptly. Delirium is often caused by drug toxicity, dehydration, metabolic problems, infections and other organ failures. It is important to look at the possibility of drugs causing this syndrome.

III SUNDOWNING - Sundowning consists of agitation, confusion, disorientation, that often starts in the late afternoon and become more severe at night. It is suggested that acute treatments might include Trazodone, the atypical neuroleptics or Haldol.

The side effects of the typical and atypical antipsychotic drugs are discussed below:

Peripheral anticholinergic blockade (dry mouth, constipation, atonic bladder, aggravate glaucoma and worsen prostatic hypertrophy).
Central anticholinergic blockade (confusion, disorientation, agitation, assaultiveness and visual hallucinations or delirium).
Orthostatic hypotension.
Dopaminergic blockade (extrapyramidal symptoms).
akathisia (intense feeling of fidgetiness or restlessness)
parkinsonism (tremor, rigidity)
akinesia (decreased energy)
acute dystonic reaction (persistent muscle spasm)
tardive dyskinesia (jerky or slow, involuntary, continuous movement of tongue, jaw, trunk or extremity)

IV. ANXIOUSNESS & INSOMNIA

Recommended drugs are:

Halcion - .125 to .25 at bedtime.
Ambien - 5-10 mg. per day.
Restoril - 7.5 mg. at bedtime.
Serax - 10-15 mg., 1-4 times per day.
Ativan - .5 mg., 1-4 times per day.
Xanax - .5 mg., 1-4 times per day.
Sonata - 5 to 10 mg. per day.
Lunesta - 1-3 mg. per night.
There is no difference between a tranquilizer and a sleeping pill. Some drugs are marketed as tranquilizers and some as sleeping pills.

The p.r.n. usage of the above mentioned medications usually do not worsen cognition but this is a possibility. It is suggested that approximately 10% of the time an individual may get paradoxical excitation rather than sedation from these medications. Many articles suggest the uses of Buspar but this author finds it of limited benefit. Trazodone, if used as a first line drug, may cause excessive sedation and orthostatic hypotension. The recommended starting dose of Trazodone should be 12.5 mg. at bedtime for sleep with monitoring for side effects. Trazodone can be used also for agitation in the daytime.

The SSRIs - (Selective Serotonin Reuptake Inhibitors). Examples of these drugs are Prozac, Paxil, Zoloft, Effexor, Celexia, Lexapro and Luvox. These medications were initially indicated for depression but can also help lower anxiety and help reduce insomnia in the Alzheimer's patient. (See discussion under Depression.) I feel the SSRIs are great drugs to reduce anxiousness and help treat insomnia. One should consult ones health care provider as to the proper dose but it is recommended that the lowest possible dose be initially utilized and slowly increased. These drugs can impair cognition. What works for one individual may cause intolerable side effects in another. The new generation SSRIs (Celexia and Lexapro) have the least potential for side effects but all of these drugs can cause anxiety and worsen insomnia.

SSRIs are first line treatment for chronic anxiety.

Under no circumstances should anyone stop the SSRI medications without their health provider's consent or permission. The patient may undergo, even with a slow taper, a discontinuation syndrome with an exacerbation of the previous symptomatology, i.e. depression or anxiety and new symptoms that mimic upper respiratory infection, vertigo or cause sharp pains in the extremities.

If the patient is awakening to go to the bathroom and this is causing insomnia, consider diminishing fluid intake in the afternoon. It is important to ask the doctor if any of the medications used as antispasmodics to lessen urinary frequency may be of benefit. Many of these medications, i.e. Ditropan, have anticholinergic properties that may aggravate the dementia syndrome.

Medications that have anticholinergic properties can lessen the effects of the cholinesterase inhibitor drugs mentioned above. Drugs that have anticholinergic properties are medications such as Ditropan, many flu and cold preparations, Theophylline, Tagamet, Codeine, Prednisone and many pain medications. These drugs are high likelihood of causing an acute confusional state, but may be required to treat other conditions.

Avoid the use of Benadryl or other over-the-counter medications such as Tylenol PM which have antihistamine effect or is strongly anticholinergic.

Avoid Elavil, Dalmane, Valium, Librium and any other long acting benzodiazepams if possible because of their long duration of action.

V. DEPRESSION

Early in the dementia process, depression and depressive symptoms may require treatment. The drugs of first choice are called Selective Serotonin Reuptake Inhibitors (SSRIs). These drugs are Zoloft, Paxil, Prozac, Luvox, Celexia, Effexor and Lexapro. The depressive symptoms in patients with dementia are usually the same as in other patients but may be missed because they resemble symptoms of medical illnesses. For example, weight loss, sleep disturbances and fatigue. The depression may mask as impaired concentration. These depressive symptoms may be difficult to separate from the dementia symptoms. The clinician needs to evaluate for symptoms of poor sleep and appetite and other non verbal signs of being depressed such as looking at facial expressions of suffering or sadness and possibly verbal expressions of feelings of hopelessness, helplessness and guilt. If the depression is determined to be significant, the following is a list of medications that might be considered. Consult with your health care provider.

Zoloft. Start at 6.25-12.5 mg. This drug may be activating (increase anxiety) or cause sedation.
Paxil - is less activating and more anticholinergic and is best at treating insomnia and depression.
Prozac - can be activating and has a very long half-life. I do not recommend the use of this medication for the geriatric population.
Luvox - use caution when using this medication with the Xanax or Halcion. The drug should be reduced in half.
Celexia - is less anticholinergic and potentially a very good choice. Can cause sedation.
Effexor - is the most potent SSRI plus it inhibits norepinephrine reuptake.
Lexapro - is one of the least anticholinergic and a good choice to start treatment.
As a class, the usual side effects of SSRI may be shaking, sweating, nervousness, insomnia/somnolence, dizziness and various gastrointestinal (nausea) and sexual disturbance such as impotence or decreased sexual desire.

The next class of antidepressants is called the tricyclic antidepressants which are a norepinephrine receptor inhibitor. Example - Doxepin (Sinequan); Desipramine (Norpramin); Nortriptyline (Pamelor). In general, this class has more sedating effects with the elderly and must be started at lower doses.

Sinequan - appears to be useful for depression with agitation and insomnia but may cause orthostatic hypotension and has strong anticholinergic effects.
Desipramine - is more activating and may increase the heart rate.
Pamelor - is more sedating like Desipramine.
Other non-cyclic antidepressants include:

Serzone - good for depression and anxiety. Reduce to ½ the dose when used with Xanax and Halcion.
Wellbutron - is activating. Caution use on agitated patient and those with seizures. Usually give a second dose before 3 PM as to not get insomnia.
Remeron - very potent. Promotes sleep, increases appetite and may cause weight gain.
Remember a full response in all of these medications may require 4-8 weeks. After nine months of utilization when treating depression, consider a very slow taper or reduction.

Gary W. Steinke, M.D.
Chief of Geriatric Section
Division of Medicine
Santa Clara Valley Health & Hospital System
September 2005

REFERENCES

The Treatment of Dementia and Behavioral Disturbances, A Special Report, Postgraduate Medicine, January 2005.

(Posted on the Alzheimer's Assc. website, Northern Ca.)