Original Article
Lack of Efficacy of Hydergine in Patients with Alzheimer's Disease
N Engl J Med 1990; 323:445-448August 16, 1990
- Abstract
- Abstract
Background.
There is no effective pharmacologic treatment for Alzheimer's disease, the most common dementing illness in the United States. Hydergine, a combination of ergoloid mesylates, is the only approved medication for Alzheimer's disease, but despite widespread use its efficacy remains to be established. We conducted a clinical trial of Hydergine-LC, a newer preparation of ergoloid mesylates in the form of a liquid in a capsule (LC) that may have greater bioavailability, to determine its value in patients with Alzheimer's disease.
Methods and Results.
Eighty older adults with probable Alzheimer's disease participated in this double-blind, placebo-controlled trial of Hydergine-LC for 24 weeks. The recommended dose of 1 mg orally three times daily was used. Cognition and behavior were evaluated before and after the trial, and the patients were monitored for adverse effects. The medication was safe and well tolerated. The Hydergine-LC group did not perform better after treatment than the placebo group on any test, and its performance was worse (P<0.01 and P<0.02, respectively) on one cognitive measure (Wechsler Adult Intelligence Scale Digit Symbol Substitution Task) and on one behavioral scale (the Geriatric Evaluation by Relatives Rating Instrument).
Conclusions.
Hydergine-LC appears to be ineffective as a treatment for Alzheimer's disease. (N Engl J Med 1990;323:445–8.)
Media in This Article
Table 1
Changes in Cognitive and Behavioral Measures in Patients with Alzheimer's Disease after Treatment with Hydergine-LC or Placebo.*Article Activity
- Article
ALZHEIMER'S disease is the most common dementing illness and may be the fourth leading cause of death in the United States. It severely affects about 1.4 million Americans, and this number is predicted to increase fivefold in the next half century.1 2 3 4 The current direct and indirect annual cost of Alzheimer's disease in the United States is estimated to be $24 billion to $48 billion.4 , 5 The disease has no known cause or effective treatment, although a wide variety of therapeutic approaches have been considered.6 One medication used for Alzheimer's disease is Hydergine (Sandoz brand of ergoloid mesylates), a preparation containing 0.333 mg each of dihydroergocornine mesylate, dihydroergocristine mesylate, and dihydroergocryptine mesylate, the last of which consists of dihydro-α-ergocryptine mesylate and dihydro-β-ergocryptine mesylate in a proportion of 2:1. In 1984, Hydergine was the 11th most widely prescribed drug in the world,7 and it is the only medication approved by the Food and Drug Administration for Alzheimer's disease. Initially thought to act as a cerebral vasodilator, Hydergine is now considered to be a metabolic enhancer, because it may improve some aspects of neuronal metabolism and neurotransmitter activity.8
Although more than 20 double-blind, placebo-controlled trials have shown favorable results with ergoloid mesylates, many clinicians remain skeptical of its efficacy; uncertainties persist about placebo responses, the heterogeneity of study groups, and the clinical importance of the observed beneficial effects.7 Hydergine-LC, a newer preparation of ergoloid mesylates, delivers the drug as a liquid in a capsule (LC), a form that may have greater bioavailability.9 To test the safety and efficacy of this new formulation, we conducted a double-blind, placebo-controlled trial of Hydergine-LC in a group of patients with a clinical diagnosis of Alzheimer's disease.
Methods
Eighty patients, 55 through 79 years of age, were entered in this clinical trial. There were 46 women and 34 men. The patients were recruited through local media announcements and by solicitation of practicing neurologists; 319 patients were screened, and 80 (25 percent) met the study criteria described below. All the patients were able to read, write, speak, and understand English. The study was approved by the Human Subjects Committee of the University of Colorado Health Science Center. Informed consent was obtained after the study had been fully explained; patients could give consent if they were judged competent, and if not, their legal guardians could give consent. All patients met the criteria for primary degenerative dementia of the Diagnostic and Statistical Manual of Mental Disorders (third edition)10 and the criteria for probable Alzheimer's disease of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association.11 All the patients also had been given this diagnosis by their physician at least six months before entry into the trial. If evidence of depression or another possible cause of dementia was also present, the patient was excluded. For help in excluding multiinfarct dementia, the Modified Hachinski Ischemia Scoring Scale12 was used. All patients entered in the trial scored less than 4 on this scale; patients with Alzheimer's disease typically score less than 4, whereas those with vascular dementia score from 4 to 10.
The patients underwent base-line physical examination and clinical-laboratory screening tests, including tests for syphilis; measurements of serum thyroxine, vitamin B12, and folate; a complete blood count; a blood-chemistry profile; and urinalysis. Patients were excluded if the results of any of these tests suggested possible causes of dementia. Patients with stable medical illnesses that were not likely to influence mentation during the study, such as degenerative joint disease, were not excluded, nor were those taking drugs that have no central nervous system effects, such as ibuprofen. In addition, the patients underwent computed tomography or magnetic resonance imaging of the brain and electroencephalography if they had not had one of these imaging tests and electroencephalography within the previous 12 months, in order to exclude the presence of multi-infarct dementia and other demonstrable neurologic disease.
To evaluate whether the symptoms of dementia were due to major depression, the Hamilton Psychiatric Rating Scale for Depression13 was used. Only patients with a score of 18 or less were included in the study. The Sandoz Clinical Assessment-Geriatric Scale,14 designed to evaluate the degree of behavioral impairment associated with dementia, was used to ensure that patients had only mild-to-moderate impairment. Their score on the Mini—Mental State Examination15 had to be at least 10 but no greater than 23. (This examination is a frequently used assessment measure for dementia, and scores of less than 23 generally indicate the presence of dementia in persons of average or better educational background.) An Inventory of Psychic and Somatic Complaints in the Elderly16 was used during the base-line phase as well; it measured patients' reports of problems with attention, orientation, and memory. All these tests were used to determine eligibility, and all but the Mini—Mental State Examination were also used to evaluate the efficacy of treatment.
Eligible patients were required to complete a two-week washout period, during which time drugs with cognitive side effects were discontinued. Each patient subsequently underwent a psychometric evaluation, which consisted of the Wechsler Adult Intelligence Scale (WAIS) Digit Symbol Substitution Task,17 the Russell revision of the Wechsler Memory Scale, which includes logical memory and visual reproduction components,18 and the Geriatric Evaluation by Relatives Rating Instrument (GERRI).19 These tests were all used to evaluate the efficacy of treatment. Through random assignment of study numbers, those who qualified for the study were then assigned to receive either Hydergine-LC or placebo. The patients were assigned numbers sequentially as they entered the study. At no time were the study personnel evaluating the patients aware of which numbers or patients were assigned to either the Hydergine-LC or the placebo group.
The patients were then entered in the active-treatment phase, during which they were seen every six weeks by the study nurse. Medications were dispensed at six-week intervals as identical capsules packaged in bottles labeled only with the investigator's name and telephone number, dosage regimen, and the patient's name and study number. This information was printed on a two-piece label composed of a portion permanently fastened to the bottle and a removable portion to be detached by the study nurse and attached to the patient's case-report form when the drug was dispensed. The inside of the removable portion contained drug-code information and was to be opened only in an emergency.
The WAIS Digit Symbol Substitution Task, Wechsler Memory Scale, Sandoz Clinical Assessment—Geriatric Scale, and Inventory of Psychic and Somatic Complaints in the Elderly were repeated during week 12 and at the conclusion of the study (week 24), and the Hamilton Psychiatric Rating Scale for Depression was repeated during week 24. At each visit, the patient's daily care giver used the GERRI to assess the patient's condition in the home environment. Compliance was measured at each visit by a pill count. Patients who had not taken two thirds of the medication since their last visit were excluded from further study.
The evaluations done 12 and 24 weeks after the initiation of either Hydergine-LC or placebo were used to compare the effectiveness of the two regimens. An end-point analysis of the last available results for each patient also was performed. There were no notable differences among these analytic approaches, so the end-point results are presented. For each of the behavioral rating scales and psychometric tests, the change in the score was used to compare the outcomes in the two groups. A one-way analysis of covariance, with the pretreatment base-line values as the covariant, yielded results virtually identical to those for the more familiar t-test, so the t-test results are presented.
A total of 12 patients, 6 in each group, dropped out of the study before the 24-week evaluation. Of the six patients who left the Hydergine-LC treatment group, two deteriorated mentally and required placement in nursing homes, two had cerebrovascular accidents, one was noncompliant, and one decided not to complete the study. Of the six patients who left the placebo group, two deteriorated mentally and could not cooperate sufficiently to follow test instructions, one deteriorated mentally and required placement in a nursing home, one had a fatal myocardial infarction, one was noncompliant, and one decided not to complete the study.
Results
There were no significant differences in characteristics between the 39 patients receiving Hydergine-LC and the 41 patients receiving placebo. The mean ages (72 vs. 70 years) and the percentages of men (54 vs. 63 percent) were similar in the two groups, and the mean number of years of education (12) and the mean duration of illness (4 years) were the same. The mean score on the Mini—Mental State Examination was 17.3 for the group receiving Hydergine-LC, as compared with 18.3 for the group receiving placebo, and the mean score on the Hamilton Psychiatric Rating Scale for Depression was 4.3, as compared with 4.5. No patient in either group had severe dementia; all were ambulatory and living at home, and nearly all were judged competent to give consent.
The changes in cognitive and behavioral test scores for the treatment and placebo groups from base line to the last assessment after 24 weeks are shown in Table 1Table 1
Changes in Cognitive and Behavioral Measures in Patients with Alzheimer's Disease after Treatment with Hydergine-LC or Placebo.*. Both groups had slightly but not significantly fewer depressive symptoms (as measured by the Hamilton Psychiatric Rating Scale for Depression) at the end of the study, and improvement was similar in both groups. On one cognitive scale (the WAIS Digit Symbol Substitution Task) and one behavioral scale (the GERRI), the mean score of the Hydergine-LC group declined significantly more than the mean score of the placebo group. On all other tests, there were no significant differences between the groups in the magnitude of decline in test scores from the initial to the final assessment.There were no significant changes in vital signs in either group during the study. Adverse side effects in the Hydergine-LC group were limited to one patient, who reported a bad taste in his mouth.
Discussion
The results of this study indicate that the administration of Hydergine-LC for up to 24 weeks, although safe and well tolerated, had no notable beneficial effects on our patients with probable Alzheimer's disease. Since autopsy or biopsy verification of Alzheimer's disease was not available, the diagnosis was considered probable; however, the accuracy of the clinical diagnosis of Alzheimer's disease with the use of our criteria11 approaches 90 percent,1 so the results of this study raise major doubts about the value of ergoloid mesylates for this disease.
With the exception of the Hamilton Psychiatric Rating Scale for Depression, the results of the cognitive and behavioral tests showed that the condition of the patients in both groups deteriorated during the treatment period. Hydergine-LC had no beneficial effect, and the results of two tests — the WAIS Digit Symbol Substitution Task and the GERRI — indicated that the Hydergine-LC group actually had more deterioration than the placebo group. The minimal improvement in scores on the Hamilton Psychiatric Rating Scale for Depression was not significant in either group.
The negative results of our study differ from the more favorable results of a number of previous studies.7 It is possible that we failed to detect a beneficial effect that was, in fact, present; however, we believe that it is more likely that our study improves on previous efforts. First, we studied more patients than most of the earlier trials.20 Second, we treated the patients for 24 weeks, whereas in most previous trials the treatment period was 12 to 13 weeks.7 Finally, we performed a rigorous evaluation to identify patients with probable Alzheimer's disease, whereas other studies often included patients with dementia due to various other disorders that may have biased the results toward demonstrating efficacy for Hydergine.7
The greater decline of the scores on the WAIS Digit Symbol Substitution Task and GERRI in treated patients is surprising. Ergoloid mesylates have no known side effects on the central nervous system, and it is unclear why this greater worsening might occur. After 12 weeks, the results were mixed; the detrimental effect was evident on the WAIS Digit Symbol Substitution Task (change, −9.96; P<0.001) but not on the GERRI (change, −0.09; P not significant). We can only speculate that the drug may cause cognitive dysfunction, perhaps through a direct toxic effect or by accelerating the progression of Alzheimer's disease.
The recommended dosage for Hydergine-LC in the United States is 3 mg daily, in divided doses. It is possible that larger doses of the drug might be efficacious. In Europe and Japan, up to 12 mg of Hydergine per day has been used without worrisome side effects,7 so it may be appropriate to conduct a trial using higher doses of Hydergine-LC. It should be emphasized, however, that the choice of a reasonable dose remains solely empirical. Longer trials of Hydergine-LC or other ergoloid mesylates in combination with other treatments for Alzheimer's disease also might be considered.
Alzheimer's disease is a growing medical, neurologic, and psychiatric problem, and ergoloid mesylates continue to be widely prescribed for this and other illnesses characterized by dementia. On the basis of the results of this study, however, we cannot recommend Hydergine-LC as a treatment for patients with probable Alzheimer's disease. Since Hydergine-LC is reported to be more bioavailable and therefore might be considered at least as efficacious as standard Hydergine at comparable doses, we also cannot recommend Hydergine (1 mg orally three times daily) for patients with probable Alzheimer's disease.
Supported by a grant from Sandoz Research Institute.
We are indebted to Drs. Albert Dessertine and Barry A. Sachais of Sandoz and to Dr. Rodney J. Pelchat for reviewing a draft of this paper.
Source Information
From the Departments of Psychiatry (C.M.F.), Medicine (W.D.M., K.M.C., M.LoV., R.L.B.), and Neurology (C.M.F.), University of Colorado School of Medicine, Denver; and the Department of Psychiatry, Jefferson Medical College, Philadelphia (T.L.T.). Address reprint requests to Dr. Thompson at the Department of Psychiatry, Jefferson Medical College, 1015 Walnut St., Philadelphia, PA 19107.
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- Citing Articles (14)
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Robert H. Howland. (2011) Alternative Drug Therapies for Dementia. Journal of Psychosocial Nursing and Mental Health Services 49:5, 17-20
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M. Belgeri, J. E. Morley. (2004) A Step Back in Time: Is There a Place for Older Drugs in the Treatment of Dementia?. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 59:10, M1025-M1028
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Christopher M. Filley. (2002) Drug Treatment of Alzheimer???s Disease. Primary Care Case Reviews 5:2, 77-85
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Lon Schneider, Jason T Olin, Adrian Novit, Susan Luczak, Jason T Olin. 2000. Hydergine for dementia. .
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Nandor Ludvig. (1997) Microdialysis-coupled place cell detection in the hippocampus: A new strategy for the search for cognition enhancer drugs. Progress in Neuro-Psychopharmacology and Biological Psychiatry 21:2, 249-271
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Christopher M. Filley. (1997) Alzheimer's disease in women. American Journal of Obstetrics and Gynecology 176:1, 1-7
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Jair C. Soares, Samuel Gershon. (1994) Advances in the pharmacotherapy of Alzheimer's disease. European Archives of Psychiatry and Clinical Neuroscience 244:5, 261-271
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Lawrence J. Nardozzi. (1994) Evaluation and care of the dementia patient. New Directions for Mental Health Services 1993:57, 89-98
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Paul T. Francis, Menelas N. Pangalos, David M. Bowen. (1992) Animal and drug modelling for Alzheimer synaptic pathology. Progress in Neurobiology 39:5, 517-545
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Martin Sarter, Jim Hagan, Paul Dudchenko. (1992) Behavioral screening for cognition enhancers: from indiscriminate to valid testing: Part I. Psychopharmacology 107:2-3, 144-159
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(1991) Lack of Efficacy of Hydergine in Alzheimer's Disease. New England Journal of Medicine 324:3, 197-198
Full Text14
Martin Sarter. (1991) Taking stock of cognition enhancers. Trends in Pharmacological Sciences 12, 456-461
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