INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, VOL. 5: 317-321 (1990)

TETRAHYDROAMINOACRIDINE IN ALZHEIMER'S DISEASE

B . DAVIES," D. ANDREWES,~ R. STARGATT,$ D. A M E S , ~ v. TUCKWELL** AND s. DAVIS§$ "Projessor of Psychiatry, ?Lecturer in Neuropsychology, $Neuropsychologist, $Senior Lecturer in Psychiatry,

**ScientiJic Oficer, $3 Neurologist, Department of Psychiatry, University of Melbourne, Clinical Sciences Building, Royal Melbourne Hospital, Victoria 30.50, Australia

SUMMARY Tetrahydroaminoacridine (THA), a centrally acting anticholinesterase, was used in a two-month, double-blind,

placebo-controlled crossover trial to treat 10 patients meeting DSM-111-R criteria for dementia of the Alzheimer type. Eight patients continued to take THA for a further three months. Nausea was a frequent side-effect. Five patients developed abnormal liver function tests; liver biopsies showed evidence of liver cell necrosis in three patients, a granulomatous reaction in one, and one recovered after reduction of THA dosage. During the trial, patients as a group showed a significantly better performance on one of 10 memory tests when taking THA as compared to placebo. One patient showed a marked clinical improvement, six showed some improvement, and three patients showed no improvement with the active treatment. The group of eight patients who completed a further three months of THA treatment showed a significant deterioration on two psychological test scores.

KEY wom-Tetrahydroaminoacridine, Alzheimer's disease, double blind, therapeutic trial.

The theory that cholinergic deficits observed at autopsy may be central to the production of the cognitive impairment seen in sufferers from Alz- heimer's disease (AD) (Perry, 1988) has led to a search for agents which might act on the cholinergic system to produce a clinically relevant improve- ment in the cognition of such patients (Kendell, 1987). Tetrahydroaminoacridine (THA) was intro- duced into medical practice in the early 1950s. It is used with morphia to treat patients with intrac- table cancer pain and also in anaesthesia to prolong the action of suxamethonium (Albert, 1966). It has many actions on the brain (Perry, 1988), but Summers ef al., (1986) used THA with lecithin to treat patients diagnosed as having AD because of its centrally acting anticholinesterase properties. Following an initial open evaluation, 14 patients completed a double-blind, crossover, placebo- controlled trial of six weeks' duration. Significant improvements on clinical and psychological assess- ments were reported. The aim of this study was to attempt replication of these findings.

PATIENTS AND METHODS

Patients meeting DSM-111-R diagnostic criteria for mild or moderate primary degenerative dementia

0885-6230/90/0503 17-05$05.00 0 1990 by John Wiley & Sons, Ltd.

of the Alzheimer type (American Psychiatric Association, 1987) were included in the trial. Diag- nosis was made after full clinical history, negative physical examination and negative investigation for other causes of dementia. Investigations included serum creatinine, electrolytes and liver function tests, full blood examination, erythrocyte sedimen- tation rate, syphilis serology, thyroid function tests, chest X-ray, cerebral CT and magnetic resonance imaging, and electroencephalography. Neuro- psychological testing showed abnormalities charac- teristic of AD (Dodwell, 1987). Patients were allocated to a two-month, placebo-controlled, double-blind crossover treatment programme (phase 1). For one month THA was prescribed together with lecithin (9600 mg/day) and a peri- pheral anticholinergic agent, glycopyrrolate ( 2 4 mglday), and for one month placebo tablets with lecithin and glycopyrrolate. There was no 'wash- out' period between treatments. Active and placebo administration was arranged by random allocation at the pharmacy. Half the patients received THA in the first month and placebo in the second, the remainder received placebo followed by THA. Dosage of THA commenced at 50 mg daily and was increased gradually so that all patients were taking 150-200 mg of THA or placebo after seven

Received 19 July 1989 Accepted 14 November 1989

318 B. DAVIES, D. ANDREWES, R. STARGATT, D. AMES, V. TUCKWELL AND S . DAVIS

to 10 days. Medication was given four times a day by carers. Patients and carers were seen each two weeks in phase 1 by two psychiatrists and were tested each two weeks by neuropsychologists who used the following tests: modified RANDT memory tests (which include tests of information and orientation, digit span, and a five-item word list) (Glosser, 1983), a five-item word-paired associ- ate learning test, and a test involving the manipula- tion of coloured tokens (Boller and Vignolo, 1966). Two subtests from the Kendrick (1985) cognitive tests for the elderly (the Kendrick Object Learning Test (KOLT) and Kendrick Digit Copying Task (KDCT)) were performed only at the end of each month. Tests relating to everyday functioning included the Instrumental Activities of Daily Living (IADL) (Lawton and Brody, 1969); Physical Self Maintenance Scale (PSM) (Lawton and Brody, 1969); CAPE Behaviour Rating Scale (Pattie and Gilleard, 1975); and a modified Everyday Memory Questionnaire (Sunderland and Harris, 1984). An observer-completed depression scale (Hamilton, 1960, 1967) and a self-report (Carroll et al., 1981) depression questionnaire also were completed each two weeks. After phase 1, patients were given active THA for a further three months of open study, together with lecithin at the same dosage (phase 2). During this period, patients were seen each month by the psychiatrists and tested at the end of the three months by a neuropsychologist.

The two-month crossover trial was designed to assess 10 patients in detail. Twenty patients were assessed for inclusion in the study and six were excluded when magnetic resonance imaging (MRI) revealed possible vascular lesions in the brain not shown on CT scanning. Fourteen patients com- menced phase 1, but two had to be withdrawn after four weeks because of abnormal liver function tests (LFT) and one dropped out after two weeks because of nausea. All three had been prescribed THA rather than placebo. Two patients who com- pleted phase 1 were withdrawn in the follow-up phase 2 because of abnormal LFTs. One other patient had significant depressive symptoms and an HDRS score of 15 at study entry. Her depression ratings fell when taking THA, and her memory functions also improved. Her cognitive function did not decline in the 18 months following the end of her participation in the trial. It was decided not to include this patient in the analysis of results because of the likelihood that she had a depressive pseudomentia (Kiloh, 1961). No other subject had a Hamilton score above 7 at study entry. Thus

results were available for 10 patients completing phase 1 and for eight completing the follow-up phase 2. The 10 patients completing phase 1 com- prised six males and four females. Five had mild and five moderate AD by DSM-111-R criteria. By the clinical staging method described by Summers et al., (1981), all were in stages 1-111 of dementia. The age range of the patients was 50-81 (mean 68, SD 9.5). Eight lived with their spouses or children and two were in a nursing home.

SIDE-EFFECTS

Nausea and occasional vomiting occurred in five of 14 patients when the dosage of THA was increased above 150 mg/day. For this reason the psychiatrists were not blind to the month of active treatment in these patients, four of whom com- pleted phase 1. Side-effects were not reported to the neuropsychologists, who thus retained blind- ness.

LFTs were done each two weeks and five patients (taking 150-200 mg THA/day) developed abnor- malities of plasma aspartate transaminase (AST), two in phase 1 and three in phase 2 of treatment. The AST of one patient rose in phase 2 but returned to normal after reduction of the THA dose from 175 to 100 mg per day. Liver biopsies were done on the remaining four patients. One biopsy showed evidence of a granulomatous drug reaction (Ames et al., 1988) and three biopsies showed evidence of liver cell necrosis. These four patients reported no symptoms and on stopping the medication the AST levels returned to normal within four weeks. The liver biopsy findings are reported in detail in a recent paper (Ames et al., 1990).

STATISTICAL ANALYSIS

Non-parametric statistics were used to analyse the neuropsychological test results, comparing the scores obtained on THA and placebo in phase 1. Later, scores at the end of phase 2 were compared with those obtained after one month of THA treat- ment in phase 1. The Mann-Whitney U-test was used to compare group differences and the Wilcoxon matched pairs signed rank test to test within-group change. One-tailed tests of signifi- cance were used in the crossover trial and two- tailed tests in the analysis of the results at the end of phase 2.

THA IN ALZHEIMER’S DISEASE 319

RESULTS

Group results

Neuropsychological test results for 10 patients completing phase 1 and eight patients completing phase 2 are shown in Table 1.

Table 1. Means and standard deviations of test results in placebo phase, active phase and three-month follow-up

Placebo Active Three months N = l O N = l O N = 8

Information/ orientation (max. = 14)

Digit total

Five items (max. = 30)

Token test (niax. = 27)

Paired associates (max. = 40)

KOLT (max. = 70)

Digit copying (sec to copy 100 items)

Digit copying (no. copied in 2 min)

IADL & PSM

CAPE? (rnax. = 18)

Everyday Memory Questionnaire? (max. = 128)

9.80 (4.59)

9.20 (1.77) 14.19 (8.57) 17.86 (5.89) 12.75 (9.46) 13.63

(11.16) 137.87 (96.88)

82.75 (28.42)

8.50 (3.75) 5.70

(5.71) 75.56

(20.85)

9.75 (5.06)

9.80 (2.08) 16.12 (8.37) 19.94 (6.18) 12.63 (9.1 1) 17,12*

(14.23) 152.75

(126.40)

82.37 (28.00)

8.44 (4.59) 5.30

(4.99) 68.50

(2 1.06)

8.63 (5.63)

7.38** (2.83) 10.67 (6.80) 17.67 (6.22) 12.43 (9.90) 12.17

(10.98) 122.00 (77.66)

74.50 (40.86)

5.71 (4-31) 6.50

(7.05) 78.88***

(29.48)

~ ~~

t Low score indicates better function. * p = 0.025 (one-tailed) improvement. * * p = 0.025 (two-tailed deterioration. ***p = 0.018 (two-tailed) deterioration.

In phase 1 patients’ scores on the KOLT were significantly better (p < 0.05) when taking THA than when receiving placebo. In all, seven patients performed better on this test when taking THA, and the results were not influenced by the order of placebo/THA administration. The chance of accepting the difference between the KOLT means as a significant result at the p = 0.05 level when in actual fact it is a chance fluctuation (type I1 error) is 0.01 (Felt and Mahmoud, 1958). The five items

memory test showed a trend towards improvement during the THA condition, the difference when compared with the placebo condition having a p value of 0.081. Further calculation indicated that the result would attain significance at the 0.05 level if the same degree of difference persisted for a further 10 patients. No other test results approached a significant difference between the THA and placebo conditions. There was little vari- ability in test performance at two and four weeks in either condition.

Eight patients completed a further three months of open THA treatment. Two neuropsychological tests showed statistically significant deterioration (p c 0.05) when the results at the end of phase 2 for these patients were compared with their results after one month of THA in phase 1. These were the digits total subtests of the RANDT and the Everyday Memory Questionnaire. The other test results were not significantly different from those found after one month of THA treatment in phase 1. Comparison of the means shown in Table 1 suggested that there had been some deterioration in all tests by the end of phase 2, including the KOLT, the only test to show any benefit with THA treatment in phase 1.

Individual results Analysis of groups can obscure treatment effects

occurring in particular individuals, but examin- ation of the raw data indicated little difference between the active and placebo conditions for most patients in most tests. Clinically, one patient showed improvement in memory with THA in phase 1, as evidenced by the report of her husband and an improved recall of current events. Six patients were reported to be more alert and socially active on THA. Three patients, all of whom received 200 mg of THA daily, showed no clinical change throughout phase 1.

Patients reported no improvement during the placebo condition, but there were a number of favourable reports by patients and carers during the THA condition as follows.

Patient 1 was reported by her husband to be more active in the garden and better able to cope with household activities such as the preparation of meals. Her husband thought her memory was ‘a little better’.

Patient 3 reported that her memory was ‘30% better’, she had more energy and her eyesight had improved.

3 20 B . DAVIES, D. ANDREWES, R. STARGATT, D. AMES, V. TUCKWELL AND S . DAVIS

Patient 4 felt her memory was a little better. Her daughter thought that there was little change but definitely no deterioration.

Patient 5 said his memory was no better but that he was more relaxed. His wife agreed that his memory had not changed but that he was playing cards better and that he appeared to ‘feel better’.

Patient 6 reported that his memory and word- finding difficulty were about the same but he felt more at east and described a general feeling of well- being. His wife was in agreement with this and that he was ‘brighter and more alert’ and seemed to be able to concentrate better.

Patient 11 was described by her husband as ‘much improved’, able to take telephone messages and to have recovered some memory functions.

Patient 12 was thought by his wife to have improved alertness when taking both THA and placebo, but described himself as ‘more perky’ when taking THA.

The remaining patients either failed to complete phase 1 or reported no improvement with either treatment.

study did not employ this method of pretrial selec- tion, but our patients had milder disease than those treated by Summers’ team, and there are theoretical reasons for believing that THA might be of most benefit to early cases with AD (Perry, 1988).

Although THA is thought to enhance cholinergic transmission, potentially leading to improvement in short-term memory (Summers ef al., 1986), memory enhancement was not the most common treatment effect observed in our cohort. Several carers commented on the improved alertness and attention of their relative with AD while he or she was receiving THA. The analeptic properties of THA are well documented (Albert, 1966), and it is known to have effects on the brain quite un- related to cholinergic transmission (Perry, 1988). It seems possible that at least some ofits therapeutic effect may be due to an increase in general alertness which might equally well be produced by other stimulant drugs. Further study of this ‘alerting effect’ is required.

CONCLUSION DISCUSSION

The small numbers involved in this study and the lack of a ‘washout’ period between treatment con- ditions mean that the results of the investigation should be interpreted with caution. However, as there was no marked difference in outcome between the five patients who received THA in the first month and the five who received THA in the second month, it seems unlikely that carryover effects or progression of disease in individual patients have biased the study to any great extent.

Our results suggest that some patients who meet diagnostic criteria for AD will show both clinical and neuropsychological improvement in the early weeks of treatment with THA. However, after a further three months of treatment, evidence of deterioration on neuropsychological testing was found in a group of eight patients. Only one patient showed unequivocal memory improvement throughout four months of THA treatment. The long-term effects of THA are unknown, but four patients had to be withdrawn because of potentially serious hepatic dysfunction.

Summers et al., (1986) studied patients for six weeks in a crossover placebo-controlled trial, but only admitted to the trial patients who had appeared to improve in an open evaluation. Our

This small but detailed study of patients with AD has indicated some clinical and slight neuropsycho- logical improvement in the first month of THA treatment, but a further three months ofTHA treat- ment was not able to offset cognitive deterioration in most patients. One patient improved throughout the period of study but four patients developed significant liver problems. Despite encouraging reports from some carers concerning improved alertness and improved concentration, objective measures did not reveal the degree of improvement reported in an earlier trial. Larger trials are needed to establish the place of THA in the treatment of AD, and to determine which patients are most likely to benefit. The high incidence of hepatic side- effects may limit the clinical usefulness of THA.

ACKNOWLEDGEMENTS

We are grateful to Woods Pharmaceuticals Melbourne for providing the active THA and placebo tablets, to Professor Brian Tress for inter- preting and discussing the MRI scans, to the medi- cal and nursing staff of Ward 1 North at the Royal Melbourne Hospital, to Dr Arthur Harrison and

THA IN ALZHEIMER’S DISEASE 321

the staff of Over ton Nursing Home, t o M r s Yvonne Liddicoat for typing the manuscript , and t o the patients and their carers.

REFERENCES

Albert, A . (1966) The Acridines, 2nd edn. Edward Arnold. London, pp. 403433.

American Psychiatric Association (1 987) Diagnostic and S ta t i s t id Manual of Mental Disorders 3rd edn, revised. American Psychiatric Association, Wash- ington I X .

Ames, D. .I., Bhathal, P. S., Davies, B. M. and Fraser, J. R. E. (1988) Hepatotoxicity of tetrahydroacridine. Lancet i . 887.

Ames, D. J., Bhathal, P. S., Davies, B. M., Fraser, J. R. E., Gibson, P. R., Roberts, S. ( 1 990) Heterogeneity of adverse hepatic reactions to tetrahydroaminoacri- dine. Atist. N Z J . Med. 20, 193-195.

Boller, F. and Vignolo, L. A. (1966) Latent sensory aphasia in hemisphere damaged patients: An experi- mental study with the Token Test. Bruin 99,459496.

Carroll, B. J., Feinberg, M., Smouse, P. E., Rawson, S. G. and Greden, J. F. (1981) The Carroll rating scale for depression-development, reliability and valida- tion. Brit. J . Psychiat. 138, 194200.

Dodwell, D. (1987) Alzheimer’s disease: The clinical picture. In Dernentiu (B. Pitt Ed.). Churchill Living- stone, Edinburgh.

Felt, C. S. and Mahmoud, M. W. (1958) Psychometrika 23,201-210.

Glosser, D. ( 1983) Instructions for Computer-Aided

Administration of RANDT Memory Test. Life Science Associates, New York.

Hamilton, M. (1960) A rating scale for depression. J . Neurol. Ncurosurg. Psych. 23, 56-62.

Hamilton, M. (1967) Development of a rating scale for primary depressive illness. Brit. J. Soc. Clin. Psychol. 6,278-296.

Kendell. M. (1987) Drugs for dementia. In Dementiu (B. Pitt Ed.). Churchill Livingstone, Edinburgh.

Kendrick, D. (1985) Kendrick Cognitive Tests for the Elderly. NFER Nelson UK, Windsor.

Kiloh, L. G . (1961) Pseudo-dementia. Acfa. Psychiatr. Scand. 37,336-351.

Lawton, M. P. and Brody, E. M. (1969) Assessment of older people: Self maintaining and instrumental activi- ties of daily living. Gerontologist 9, 179-1 86.

Pattie, A. H. and Gilleard, C. J. (1975) A brief psycho- geriatric assessment schedule. Validation against psychiatric diagnosis and discharge from hospital. Brit. J. Psychid. 127,489493.

Perry, E. K. (1988) Acetylcholine and Alzheimer’s Disease. Brit. J. Psychiat. 152, 737-740.

Summers, W. K., Majorvski, L. V., Marsh, G. M., Tachiki, K. and Kling, A. (1986) Oral tetrahydro- aminoacridine in long term treatment of senile dementia, Alzheimer type. N . Engl. J . Meci. 315, 1241- 1245.

Summers, W. K., Viesselnian, J . O., Marsh, G. M. and Candelora, K. (1981) Use ofTHA in treatment ofAlz- heimer-like dementia: Pilot study in twelve patients. Bid. Psychiut. 16, 145-153.

Sunderland, A. and Harris, J. E. (1984) Memory failures in everyday life following severe head injury. J. Clin. Neuropsychol. 6, 127-142.