New Rx for psychoses in Alzheimer's, Parkinson's.

TODAY, HALF OF ALL NURSING HOME RESIDENTS SUFFER from Alzheimer's disease or a related degenerative neurologic disorder. The average cost of caring for these residents in a nursing home is $42,000 per year, according to the Alzeimer's Association. And while most Alzheimer's sufferers are not in nursing homes--70 percent are cared for by family, friends, or paid caregivers--the cost to society is still huge. The disease costs United States businesses $33 billion annually, $26 billion of that in lost worker productivity. This cost may rise dramatically over the next 25 years, as it is estimated that 14 million Americans will be suffering from Alzheimer's by 2025.

Given these sober statistics, it is not surprising to learn that when Americans are asked what worries them most about growing older, they say they are "very" or "somewhat" more concerned about succumbing to Alzheimer's disease (81 percent) and the potential for a decline in their mental skills (81 percent) as they age, than depression (67 percent). [1] As the baby boomers age and life expectancy increases, these are very real fears. The challenge of caring for a population that suffers from Alzheimer's disease--with its progressive, negative effect on mental and social function--while maintaining a good quality of life for these patients looms large on the social and institutional landscape. The burden will fall heaviest on family and professional caregivers as they deal with one devastating group of symptoms seen in both disorders--psychosis.

Psychotic symptoms like hallucinations or delusions are endured by many of the 4.3 million Americans with Alzheimer's or the 1 million Americans with Parkinson's disease. Elderly psychotic patients are often belligerent and uncooperative as well and create management problems for their caregivers.

Conventional antipsychotic medications for psychosis are often effective, but have many undesirable side effects--particularly extra-pyramidal symptoms (EPS).

These symptoms include involuntary movements, such as mouth and tongue movements, tremors and tics; impairment of voluntary movement (stiffness and slowness); restlessness, and changes in muscle tone and posture. EPS is more severe in older patients. One of a new class of "atypical" antipsychotic drugs--quetiapine fumarate--has been shown to be particularly effective in treating the psychotic symptoms associated with these diseases without inducing or worsening EPS.

Managing psychosis in Alzheimer's disease

Up to 70 percent of Alzheimer's patients manifest psychotic symptoms during the course of their diseas. [2-5] Psychosis in the elderly Alzheimer's patient engenders much uncontrolled hostility, which can result in the need for institutionalization. Standard antipsychotics can reduce this hostility, hut physiologic changes in elderly patients render them particularly vulnerable to the side effects of standard antipsychotic medications, especially EPS.

Atypical antipsychotic agents have shown promise because of their apparent lack of EPS; however, some can present other problems for the elderly patient. For example, clozapine can cause sedation or anticholinergic effects, as well as increased agranulocytosis and delirium in older patients. [6-8] The drug's cardiac effects can also limit its use in older patients. [9] Risperidone, another atypical agent, produces less EPS than haloperidol, but its potential for producing EPS appears to be dose-related. [9] Olanzapine also produces less EPS than haloperidol, but treatment-emergent parkinsonism has been known to occur with olanzapine (12.5 to 17.5 mg/day). [10]

Quetiapine is a new dibenzothiazepine derivative with a novel pharmacologic profile. Like clozapine, quetiapine has greater affinity for 5-HT2a than dopamine D2 receptors. A preliminary pharmacokinetic and safety trial of quetiapine in elderly patients with psychotic disorders showed that the drug was well tolerated in this population, and did not raise significant safety concerns. [11]

An exploratory subanalysis from a one-year, open-label trial of 80 elderly patients diagnosed with Alzhemier's disease who were treated with quetiapine compared with a subset of patients who were at least mildly hostile at baseline (n=46) showed significant improvement in total Brief Psychiatric Rating Scale (BPRS) scores and in three hostility measures (Factor V, BPRS Hostility Item, and Hostility Cluster Score). [12] These results were noted at all time points analyzed for patients with hostility and at most time points for the other patients.

Managing psychosis in Parkinson's disease

Parkinson's disease has a complex relationship to dementia and depression, as well as to the medications used to treat the motor components of the illness. Up to 40 percent of Parkinson's patients experience a related psychosis, and the incidence increases with age. [10] Drug-induced psychosis (DIP) occurs in many patients being treated with dopaminergic drugs like 1-dopa.[11]

The first approach to managing DIP--reducing the anti-Parkinson's medication until the psychosis resolves--often results in an unacceptable decline in motor performance. The addition of an atypical antipsychotic can control the psychosis without altering the anti-Parkinson's medication, thus preserving the patient's motor function.

Friedman and associates found that quetiapine is useful and well tolerated as a possible first-line therapy to treat DIP in Parkinson's disease.[13] Juncos and colleagues showed an as-yet-unexplained short-term improvement in patients' motor performance when they took quetiapine. [14] Juncos recommended that high-potency antipsychotics such as haloperidol be avoided because of their rapid and often profound aggravation of parkinsonian symptoms, which include tremors, stooped posture, rigidity, poor balance, and slowness in body movements (bradykinesia). [15] The risk of tardive dyskinesia--which often presents as involuntary movements of the face, mouth, and neck--and acute EPS in this neurologically impaired population is higher than in a comparable elderly population. Some of the atypical antipsychotics, like quetiapine, can treat the psychotic symptoms without exacerbating the severity of parkinsonism.

In a trial of patients with advanced parkinsonism and drug-induced psychosis, quetiapine was found to be safe and effective in patients with psychosis.[16] This group included patients with idiopathic Parkinson's disease (IPD), progressive supranuclear palsy, Lewy body dementia (LBD), and overlapping syndromes of IPD/Alzheimer's disease and senile dementia of the Alzheimer's type/LBD.

Parkinsonian motor symptoms improved during the first six months. At one year, symptoms approached those observed at baseline. Significantly, there was no detectable EPS in the patients in this study. The median antipsychotic dose was 70 mg/day with a range of 12.5 to 200 mg/day.

Rosenfeld and associates found in an eight-week, open-label study that quetiapine allowed 20 of 24 patients with parkinsonian symptoms to report "marked" subjective improvement of psychotic symptoms without any objective decline in motor function.[17] Also, using BPRS, 10 of these patients demonstrated significant improvement in psychotic symptoms during a four-week follow-up.

When caring for an Alzheimer's or Parkinson's disease patient, caregivers may be confronted with psychotic symptoms. Management of psychotic symptoms can be disconcerting to the family and the caregiver. But new treatments can give caregivers and health care providers effective tools to manage this potentially devastating aspect of these diseases, and thereby improve the patient's quality of life.

Steven Targum is known for his research in psychopharmacology and clinical psychobiology. He is vice president for the CNS Venture group of ICSL, a clinical trials research company with more than 25 sites throughout the United States.

References:

(1.) Public's Concerned About Aging survey conducted by Wirthlin Worldwide, October 1998.

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(4.) Reisberg B, Gershon S. Side effects associated with lithium therapy. Arch Gen Psychiatry. 1979;36:879-87.

(5.) Zayas EM, Grossberg GT. The treatment of psychosis in late life. J Clin Psychiatry. 1998;59(suppl 14):21-9.

(6.) Lieberman JA, Safferman AZ. Clinical profile of clozapine: Adverse reactions and agranulocytosis. Psychiatr Q. 1992;62:51-70.

(7.) Alvir JM, Lieberman JA. Safferman AZ, et al. Clozapine-induced agranulo-cytosis: Incidence and risk factors in the United States. N Engl J Med. 1993; 329:162-7.

(8.) Schuster P, Gabriel E, Kifferle B. Reversal by physostigmine of clozapine induced delirium. Clin Toxicol, 1997; 10:437-41.

(9.) Gregory C, McKenna P. Pharmacological management of schizophrenia in older patients. Drugs Aging. 1994; 5:254-62.

(10.) Beasley CM, Tollefson G, Tran P, et al. Olanzapine versus placebo and haloperidol: Acute phase results of the North American double-blind olanzapine trial. Neuropsychopharmacology. 1996;14:111-23.

(11.) Wong J, Ewing BJ, Jaskiw, G, et al. Multiple-dose pharmacokinetics of Seroquel (quetiapine) in elderly psychotic patients [abstract] Schizophr Res 1997;24:200.

(12.) Schneider L, Yeung P, Sweitzer, D, et al. Effects of Seroquel (quetiapine) on reducing hostility and psychosis in patients with Alzheimer's disease. Poster presented at the American Psychiatric Association Annual Meeting in Washington, DC, May 16-20, 1999.

(13.) Friedman J, Fernandez H, Jacques C, et al. Quetiapine for the treatment of drug-induced psychosis in Parkinson's disease. Poster presented at the American Psychiatric Association Annual Meeting, Washington, DC, May 16-20, 1999.

(14.) Juncos J, Yeung P, Sweitzer D, et al. Seroquel (quetiapine) improves psychotic symptoms associated with Parkinson's disease. Poster presented at the American Psychiatric Association Annual Meeting, Washington, DC, May 16-20, 1999.

(15.) Juncos, JL. Management of psychotic aspects of Parkinson's disease. J Clin Psychiatry. 1999;60(suppl 8): 42-53.

(16.) Juncos J, Evatt ML, Jewart D. Long-term effects of quetiapine fumarate in parkinsonism complicated by psychosis. Neurology. 1998;50:70-1.

(17.) Rosenfeld MJ, Friedman JH, Jacques C. Quetiapine pilot trial in dopaminomemic psychosis (DP) in Parkinson's disease and movement disorders. October 10-14, 1998: New York, NY.