Psychosomatics 45:205-209, June 2004
© 2004 The Academy of Psychosomatic Medicine
Amantadine for Executive Dysfunction Syndrome in Patients With Dementia
Shannon J. Drayton, Pharm.D.,
Kendra Davies, Pharm.D., B.C.P.P.,
Martin Steinberg, M.D.,
Iracema Leroi, M.D.,
Adam Rosenblatt, M.D., and
Constantine G. Lyketsos, M.D., M.H.S.
Received March 19, 2003; revision received Aug. 20, 2003; accepted Sept. 16, 2003. From the Department of Pharmacy, Johns Hopkins Hospital; and the Division of Geriatric Psychiatry and Neuropsychiatry, Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore. Address reprint requests to Dr. Lyketsos, Osler 320, Johns Hopkins Hospital, Baltimore, MD 21287; kostas{at}jhmi.edu (e-mail).
|
ABSTRACT
|
This article reports the results of an open uncontrolled chart review study of amantadine treatment for executive dysfunction syndrome in patients with dementia. All patients admitted to the neuropsychiatry or geriatric psychiatry inpatient units of Johns Hopkins Hospital in 2000 and 2001 who were treated empirically with amantadine for executive dysfunction syndrome were included in the review. Of the 30 patients whose cases were reviewed, 17 (57%) were at least "much improved," and most patients were discharged taking amantadine, suggesting that their physicians believed that they may have benefited from it. The medication was well tolerated in this frail group of patients. Most patients were taking one or more concurrent psychotropic medications, which may have contributed to the positive outcomes. Despite its limitations, this study offers preliminary data to support a controlled trial of amantadine in patients with executive dysfunction syndrome.
|
INTRODUCTION
|
Executive dysfunction syndrome, also known as "frontal lobe syndrome," is commonly seen in patients with brain diseases from many causes.1 Executive dysfunction syndrome has been associated with damage to "frontal-subcortical" brain circuits believed to be the anatomical basis of executive control function.2 A variety of neuropsychiatric symptoms indicative of executive dysfunction have been associated with damage to these circuits, including cognitive disturbance, personality change, mood symptoms, and a series of challenging behaviors. Among patients with degenerative dementia, especially advanced dementia, symptoms of executive dysfunction syndrome are common and present a challenging clinical dilemma. While executive dysfunction syndrome occurs with some frequency in patients with Alzheimer's disease,3,4 it is one of the cardinal clinical manifestations of frontotemporal degeneration. Frontotemporal degeneration is a group of disorders with a common histopathology5,6 that involves the degeneration of the frontal and anterior temporal lobes.5,6 This disease has been referred to in the literature by various names, including non-Alzheimer's dementia, semantic dementia, or Pick's disease.5,6 The prevalence of frontotemporal degeneration among all cases of dementia has been estimated to range between 3% and 22%. Frontotemporal degeneration usually presents during the fifth to seventh decades of life and has a strong familial link.5,6 The symptoms of executive dysfunction syndrome usually precede cognitive decline in patients with frontotemporal degeneration.6 Behavioral disinhibition, decreased judgment, and poor insight are common. Executive functioning is usually selectively impaired during the early stages of frontotemporal degeneration. However, in an older person with dementia, it is very difficult to distinguish executive dysfunction syndrome due to Alzheimer's disease from that due to frontotemporal degeneration on clinical grounds, other than by careful history taking.7
The treatment of executive dysfunction syndrome, especially in the context of frontotemporal degeneration, has been very challenging and mostly unsuccessful.1 Reports have suggested that selective serotonin reuptake inhibitors, bromocriptine, carbamazepine, lithium, and other agents may have efficacy in treating executive dysfunction syndrome. However, there is a dearth of controlled trials in this area, and there have been only a few case series reported. In general, treatments have focused on manipulation of the dopamine, serotonin, or cholinergic neurotransmitter systems that are thought to be modulators of the frontal-subcortical loops involved in the pathogenesis of executive dysfunction syndrome.1
We report here the results from an open, uncontrolled chart review study of our experience using the antiviral drug amantadine to treat executive dysfunction syndrome in patients with dementia. Several years ago, clinicians on our team began to use amantadine empirically, outside its labeled use, for the treatment of these symptoms without a formal protocol. This was based on a report that amantadine helped executive dysfunction syndrome in patients with traumatic brain injury8 and by a case series suggesting that dopamine "augmentation" with bromocriptine reduces problem behaviors related to executive dysfunction syndrome.9 The precise mechanism of amantadine's brain action is unknown. It appears to have dopamine-modulating activity in the peripheral and CNS by augmenting the release and inhibiting the cellular reuptake of dopamine.10 Amantadine is also a N-methyl-D-aspartic acid receptor antagonist, which may indirectly enhance dopaminergic transmission and confer neuroprotective effects, similar to its analogue, memantine.11 Moreover, amantadine is known to alter the function of nicotinic acetylcholine receptors in muscle and has a weak antagonist effect on mammalian hippocampal nicotinic acetylcholine receptors. This may signify protective effects in neurodegenerative disorders or in cholinergic toxicity.12
|
METHOD
|
This was a systematic chart review study conducted by two of the authors (S.J.D. and K.D.), who had not been directly involved in the care of the patients included. The institutional review board of Johns Hopkins Hospital exempted the study from review.
All patients admitted to the geriatric psychiatry or neuropsychiatry inpatient units of Johns Hopkins Hospital during 2000 and 2001 who had been treated with amantadine at some point during their hospital stays were evaluated for inclusion. A total of 38 patients were identified who had been treated with amantadine during this time frame. Of these, the records for five patients could not be located, leaving 33 charts that were reviewed. Of these, one patient was excluded because he had been treated with amantadine for the prevention of extrapyramidal side effects caused by a neuroleptic and did not exhibit executive dysfunction syndrome. Two other patients had executive dysfunction syndrome but had only received a few doses of amantadine, which was then discontinued for lack of efficacy. Their response could not be assessed, and they were also excluded. The remaining 30 patients were included in the study because they had been treated for the symptoms of executive dysfunction syndrome with amantadine for at least a week so that a judgment could be made in the chart review about its effects.
A series of demographic and clinical characteristics were recorded as summarized in Table 1. Included were age, gender, race, living situation, marital status, psychiatric diagnosis, concurrent medications, and the symptoms that indicated use of amantadine based on what was stated in the chart. All diagnoses were made after a comprehensive psychiatric evaluation was performed on admission to the hospital. The terms used in the medical charts as indications were recorded and are presented in Table 1. In many cases, several target symptoms for amantadine treatment were recorded in the chart. In addition, the reviewers recorded any side effects caused by amantadine, as documented in the chart.
View this table:
[in this window]
[in a new window]
|
TABLE 1. Demographic and Clinical Characteristics of 30 Patients With Executive Dysfunction Syndrome and Dementia Before Amantadine Treatment
|
The reviewers used the information recorded in clinical notes in the medical charts to form a global opinion about whether or not each patient benefited from amantadine treatment. They recorded this opinion by rating it on a 7-point Clinical Global Impression (CGI) scale, ranging from "very much worse" to "very much better." This opinion was formed based on reading the clinical notes in the chart and by assessing statements in the notes made by the clinical team about whether the patients were benefiting from treatment with amantadine and the change in the symptoms for which amantadine was prescribed after it was started. The two reviewers rated all charts independently of each other. There was 100% agreement in CGI ratings between the two reviewers. As a secondary method of assessing treatment outcome, the reviewers recorded whether or not the patients were taking amantadine at discharge from the hospital, which might be indicative of the fact that the clinicians caring for them believed that they were benefitting (or at least were not being harmed).
The primary method of analysis was descriptive. We summarized data by using a table and a figure. We also conducted a series of internal subgroup comparisons on nominal variables by using exact and chi-square tests, or continuous variables by using analysis of variance.
|
RESULTS
|
Overall Response
The majority (17 of 30, or 57%) were rated as at least "much improved" after amantadine treatment. After taking into account CGI scores of 5, which indicated that the patient had at least "minimal" improvement, the overall response rate was 20 of 30 patients (67%). There were no patients whose CGI scores worsened after amantadine treatment. In addition, 23 of 30 (76%) were discharged while taking amantadine, indicating that the clinicians caring for them believed they had benefited. However, it is noteworthy that of these 23, only 16 were rated a 6 or 7 on the CGI. Apparently, the clinicians believed that the other 7 might have benefited, although this was not evident in the chart review. Of the 17 patients who were rated as "much improved" or better on the CGI, 16 (94%) were taking amantadine at discharge. The reason for which the one patient who had a clear response was not discharged while taking amantadine was unclear.
Predictors of Response
To assess possible predictors of response among clinical variables, we divided the 30 patients into two groups: "responders," defined by a rating of 6 or 7 on the CGI (at least "much improved"), and "nonresponders," defined by a rating of <6 on the CGI ("no change" or "minimally improved"). This conservative approach was designed to focus on the patients who clearly improved after amantadine treatment. Figure 1 displays ratings of response (number and percent of responders) by baseline symptoms for executive dysfunction syndrome (present versus absent). Since many patients had several co-occurring symptoms, we were unable to rate response for each symptom in isolation; rather, we compared rates of response in patients who did or did not have any of the target symptoms in Table 1. While none of the comparisons of response in those with each symptom to those without were statistically significant (p>0.10), as the table shows, response may have been best when stimulus-bound behavior was present (75%) and worse when wandering was present (30%). There was no relationship between response and mean number of symptoms of executive dysfunction syndrome in an analysis of variance (p>0.10)
View larger version (15K):
[in this window]
[in a new window]
|
FIGURE 1. Rates of Response by the Presence of Baseline Symptoms of Executive Dysfunction Syndrome on the Clinical Global Impression Scale for 30 Patients With Dementia Who Were Treated With Amantadinea
aResponse was defined as a score of 6 or 7 on the Clinical Global Impression scale. Patients may have had more than one symptom; therefore, percents do not always total 100.
|
When we examined the relationship between response and diagnosis, 63% (five of eight) of the patients with frontotemporal degeneration were responders. One patient with frontotemporal degeneration showed an equivocal response, and 25% (two of eight) were considered nonresponders. Patients with Alzheimer's disease showed a response rate of 36% (five of 14). The difference in response rate between the patients with frontotemporal degeneration and those with Alzheimer's disease was not statistically significant (exact p=0.22).
Regarding the relationship between amantadine dose and response, 18 of 30 patients reached a stable dose, defined as the same dose for at least 7 days. The peak stable total dose was 50–100 mg/day for five patients, 200 mg/day for 18, 300 mg/day for five, and 400 mg/day for one patient. Thus, most patients received a stable dose of 200 mg/day. There was no clear relationship between dose and rate of response (exact p>0.10); three of four taking 100 mg/day, 11 of 18 taking 200 mg/day, but only two of five taking 300 mg/day were responders. One patient receiving 400 mg/day was a responder.
Most patients were taking one or more concurrent psychotropic medications, all of which had been started before amantadine. The frequency of concurrent medication use by class was as follows: benzodiazepines, 19%; neuroleptics, 53%; antidepressants, 56%; mood stabilizers, 47%; cholinesterase inhibitors, 19%. The mean number of concurrent medications was 1.9 (SD=0.9). Six percent were taking no concurrent psychotropics, 22% were taking one, 44% two, 25% three, and 3% four. However, there was no relationship between the number or type of concurrent medications and response ratings in chi-square tests or analyses of variance, respectively (p>0.10).
There was no significant relationship between response and age, gender, race, or concurrent nondementia psychiatric diagnosis, such as major depression or psychosis (in all cases, p>0.10, with chi-square analysis).
Side Effects
Side effects of amantadine treatment recorded in the charts included hallucinations, insomnia, and constipation—one each in different patients. Overall, only 10% (three of 30) of the patients experienced side effects with amantadine; none was severe enough to require discontinuation. All patients with evident side effects were in the responder group.
|
DISCUSSION
|
The aim of this chart review study was to evaluate the possible benefits of amantadine in the treatment of executive dysfunction syndrome in a large case series of patients with dementia due to various neuropsychiatric conditions. We found that amantadine may be helpful in treating the symptoms of executive dysfunction syndrome in more than half of the patients. Amantadine was well tolerated, which is consistent with other case studies.8,11
In addition to the typical limitations of a chart review, most patients were taking concurrent psychotropic medications, which might have been responsible for the improvement in their symptoms alone or in combination with amantadine. Data on long-term response were not available for the patients included in this review. Length-of-stay data after initiation of amantadine were not collected. There was no control group, and the group size was small. While the systematic chart review was conducted by two of the authors (S.J.D. and K.D.) who had not been directly involved in the care of the patients, both were aware that the patients were treated with amantadine. Alternatively, it is possible that patients in whom CGI scores reflected "no change" may have actually done worse without treatment and that the patients who were considered responders may have actually done better without amantadine.
Despite these limitations, we conclude that amantadine may improve the symptoms of executive dysfunction syndrome in the context of dementia from multiple causes. Amantadine is a safe and inexpensive treatment that should be considered in treating these patients. We believe that on the basis of these data, a larger controlled trial should be conducted since this small retrospective review serves as preliminary evidence for further study.
|
REFERENCES
|
- Lyketsos CG, Rosenblatt A, Rabins P: Forgotten frontal lobe syndrome or "executive dysfunction syndrome." Psychosomatics 2004; 45:247–255[Free Full Text]
- Royall DR, Lauterbach EC, Cummings JL, Reeve A, Rummans TA, Kaufer DI, LaFrance WC, Coffey CE: Executive control function: a review of its promise and challenges for clinical research. J Neuropsych Clin Neurosci 2002; 14:377–405[Abstract/Free Full Text]
- Lyketsos CG, Lopez O, Jones B, Fitzpatrick AL, Breitner J, DeKosky S: Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment. JAMA 2002; 288:1475–1483[Abstract/Free Full Text]
- Lyketsos CG, Steinberg M, Tschantz J, Norton M, Steffens D, Breitner JCS: Mental and behavioral disturbances in dementia: findings from the Cache County Study on Memory in Aging. Am J Psychiatry 2000; 157:708–714[Abstract/Free Full Text]
- Hooten RM, Lyketsos CG: Fronto-temporal dementia: a clinical pathological review of four post-mortem studies. J Neuropsychiatry Clin Neurosciences 1996; 8:10–19[Abstract/Free Full Text]
- McKhann GM, Albert MS, Grossman M, Miller B, Dickson D, Trojanowski JQ: Clinical and pathological diagnosis of frontotemporal dementia. Arch Neurol 2001; 28:1803–1809
- Hooten WM, Lyketsos CG: Differentiating Alzheimer's disease and frontotemporal dementia: receiver operator characteristic curve analysis of four rating scales. Dementia 1998; 9:164–174
- Kraus MF, Maki PM: Effects of amantadine hydrochloride on symptoms of frontal lobe dysfunction in brain injury: case studies and review. J Neuropsychiatry Clin Neurosci 1997; 9:222–230[Abstract/Free Full Text]
- Imamura T, Takanashi M, Hattori N, Fujimori M, Yamashita H, Ishii K, Yamadori A: Bromocriptine treatment for perseveration in demented patients. Alzheimer Dis Assoc Disord 1998; 12:109–113[CrossRef][Medline]
- http://www.micromedex.com
- Metman LV, Morris MJ, Farmer C, Gillespie M, Mosby K, Wuu J, Chase TN: Huntington's disease: a randomized, controlled trial using the NMDA-antagonist amantadine. Neurology 2002; 59:694–699[Abstract/Free Full Text]
- Matsubayashi KL, Albuquerque S, Albuquerque EX: Amantadine inhibits nicotinic acetylcholine receptor function in hippocampal neurons. J Pharm Exper Therap 1997; 281:834–844[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
E. D. Huey, K. T. Putnam, and J. Grafman
A systematic review of neurotransmitter deficits and treatments in frontotemporal dementia
Neurology,
January 10, 2006;
66(1):
17 - 22.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. G. Lyketsos, A. Rosenblatt, and P. Rabins
Forgotten Frontal Lobe Syndrome or "Executive Dysfunction Syndrome"
Psychosomatics,
June 1, 2004;
45(3):
247 - 255.
[Full Text]
[PDF]
|
|
|
Get information about faster international access.
Privacy Policy
Copyright © 2004
Academy of Psychosomatic Medicine.
All rights reserved.
Home
| Search
| Current Issue
| Past Issues
| Subscribe
| All APPI Journals
| Help
| Contact Us
|
TOP
ABSTRACT
INTRODUCTION
