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Prog. Neuro-Psychopharmacol. t? Viol. Psychiot. 1986. Vol. 10, pp. 567-590 Printed in Great Britain. All rights reserved. 027~5646/66 $0.00 + .50 Copyright 0 1986 Pergamon Journals Ltd. NALTREXONE AND ALZHEIMER’S DISEASE MICRAEL SERBY, RICHARD RESNICK, BARBARAJORDAN, JOHN ADLER, JDNE CORWINand JOHN P. ROTROSEN Psychiatry Service, N.Y. Veterans Administration Medical Center and Department of Psychiatry, New York University School of Medicine, New York, U.S.A. (Final form, February 1986) Abstract Serby, Michael, Richard Resnick, Barbara Jordan, John Adler, June Corwin and John P. Rotrosen: Naltrexone in Alzheimer’s disease. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1986, x (3-5): 587-590. 1. Naltrexone, an oral opiate antagonist, was administered to nine patients with a diagnosis of Alsheimer’s-type dementia (ATD) in a two-phase design: (a) an open dose-ranging phase and (b) a double-blind placebo-controlled trial for patients who showed improvement during the open phase. 2. After a three day placebo (baseline) period, patients received increasing doses of naltrexone over two weeks up to a maximum daily dose of 100 mg. Assessments were made at baseline and at daily dose of 5 mg, 50 mg and 100 mg. Testing was done 2 to 4 hours after medication was administered. Any patient who showed cognitive/behavioral improvement on a given dose of naltrexone was then treated with this dosage in a double-blind crossover comparison to placebo. Criteria for inclusion in the double-blind phase consisted of improvement on three behavioral scales and at least one cognitive test on a given dose of naltrexone. Each double-blind phase followed a one-week washout and was two weeks long. 3. Two of the nine patients demonstrated apparent cognitive enhancement on 100 mg daily of naltrexone and were then tested in the double-blind crossover period. Only one of these patients improved during active naltrexone administration. 4. We conclude that the opiate antagonist naltrexone in a dosage range of 5-100 mg daily is not efficacious in ATD. Keywords : Alzheimer’s disease, dementia, Naltrexone, opiate antagonist Abbreviations: Alzheimer’s-type dementia (ATD); Electroconvulsive treatment (ECT); false alarms (FA). Introduction In recent years experimental evidence has implicated reduced functional activity of the central cholinergic system in Alzheimer’s type dementia (ATD), leading to various attemps to treat this disorder via cholinergic enhancement (Bartus et al, 1982 and Davis et al 1979). A number of non-cholinergic agents have also been tried in ATD but with limited success (Crook and Gershon, 1981). Opiate antagonists have been considered as possible therapeutic agents because endorphins and enkephalins may impair memory (Rigter et al 1980 and Iequierdo et al 1980). The opiate antagonist naloxone was found to be efficacious in five ATD patients tested in a double-blind crossover design (Reisberg, et al, 1983a). Improvement was evident in several cognitive measures 15 to 45 minutes after IV infusion of naloxone. However, subsequent experience with this agent has not corroborated the initial report (Blass, et al, 1983). Naltrexone is an opiate antagonist which has the advantages or oral administration and a longer duration of action. We now report the results of a trial of naltrexone in patients with ATD. 587

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Page 1: Naltrexone and Alzheimer's disease

Prog. Neuro-Psychopharmacol. t? Viol. Psychiot. 1986. Vol. 10, pp. 567-590 Printed in Great Britain. All rights reserved.

027~5646/66 $0.00 + .50 Copyright 0 1986 Pergamon Journals Ltd.

NALTREXONE AND ALZHEIMER’S DISEASE

MICRAEL SERBY, RICHARD RESNICK, BARBARA JORDAN, JOHN ADLER, JDNE CORWIN and JOHN P. ROTROSEN

Psychiatry Service, N.Y. Veterans Administration Medical Center and Department of Psychiatry, New York University School of Medicine,

New York, U.S.A.

(Final form, February 1986)

Abstract

Serby, Michael, Richard Resnick, Barbara Jordan, John Adler, June Corwin and John P. Rotrosen: Naltrexone in Alzheimer’s disease. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1986, x (3-5): 587-590.

1. Naltrexone, an oral opiate antagonist, was administered to nine patients with a diagnosis of Alsheimer’s-type dementia (ATD) in a two-phase design: (a) an open dose-ranging phase and (b) a double-blind placebo-controlled trial for patients who showed improvement during the open phase.

2. After a three day placebo (baseline) period, patients received increasing doses of naltrexone over two weeks up to a maximum daily dose of 100 mg. Assessments were made at baseline and at daily dose of 5 mg, 50 mg and 100 mg. Testing was done 2 to 4 hours after medication was administered. Any patient who showed cognitive/behavioral improvement on a given dose of naltrexone was then treated with this dosage in a double-blind crossover comparison to placebo. Criteria for inclusion in the double-blind phase consisted of improvement on three behavioral scales and at least one cognitive test on a given dose of naltrexone. Each double-blind phase followed a one-week washout and was two weeks long.

3. Two of the nine patients demonstrated apparent cognitive enhancement on 100 mg daily of naltrexone and were then tested in the double-blind crossover period. Only one of these patients improved during active naltrexone administration.

4. We conclude that the opiate antagonist naltrexone in a dosage range of 5-100 mg daily is not efficacious in ATD.

Keywords : Alzheimer’s disease, dementia, Naltrexone, opiate antagonist

Abbreviations: Alzheimer’s-type dementia (ATD); Electroconvulsive treatment (ECT); false alarms (FA).

Introduction

In recent years experimental evidence has implicated reduced functional activity of the central cholinergic system in Alzheimer’s type dementia (ATD), leading to various attemps to treat this disorder via cholinergic enhancement (Bartus et al, 1982 and Davis et al 1979). A number of non-cholinergic agents have also been tried in ATD but with limited success (Crook and Gershon, 1981). Opiate antagonists have been considered as possible therapeutic agents because endorphins and enkephalins may impair memory (Rigter et al 1980 and Iequierdo et al 1980). The opiate antagonist naloxone was found to be efficacious in five ATD patients tested in a double-blind crossover design (Reisberg, et al, 1983a). Improvement was evident in several cognitive measures 15 to 45 minutes after IV infusion of naloxone. However, subsequent experience with this agent has not corroborated the initial report (Blass, et al, 1983). Naltrexone is an opiate antagonist which has the advantages or oral administration and a longer duration of action. We now report the results of a trial of naltrexone in patients with ATD.

587

Page 2: Naltrexone and Alzheimer's disease

588 M. Serby et al.

Methods

Subjects. Nine subjects were included, all of whom met DSM III criteria for primary degenerative dementia and the NIN&S/ADRDA work group criteria for Alzheimer’s disease (McKhann, et al, 1984). Significant cardiovascular, renal, hepatic or peptic ulcer disease, or a history of alcoholism was cause for exclusion. All patients had moderate to moderately severe cognitive deficits. Patients deemed capable of giving informed consent were asked to do so; otherwise consent was obtained from the nearest relative.

Assessments. The Brief repeated cognitive assessment battery included the Buschke Selective Reminding Task (Buschke and Fuld, 1984), the Washington Square Picture Memory Task (Corwin and Snodgrass, 19851, and the Paragraph Subtest of the NYU Memory Test (Randt et al, 1980). Patients were also rated behaviorally on the NOSIE (Guy, 19761, BCRS (Reisberg et al, 1983b), and SCAG (Shader et al, 1984).

Procedure. After a 3-day placebo period, patients received increasing doses of naltrexone over 1 to 2 weeks to a maximum daily dose of 100 mg (single-blind trial). Assessments were made at baseline and during the 5 mg, 50 mg and 100 mg dosage levels. Testing was done 2 to 4 hours after medication was administered. Any patient who showed cognitive/behavioral improvement on a given dose of naltrexone was then treated with this dosage in a double-blind crossover comparison to placebo. Each double-blind phase followed a 1 week washout and was 2 weeks long. Criteria for inclusion in the double-blind phase consisted of improvement on all three behavioral scales and at least one cognitive test on a given dose of naltrexone.

Results

Cognitive and behavioral ratings made during the open dose-ranging phase were subjected to one-way repeated measures analyses of variance. The only significant difference (at p. < .05) was noted in the third of three picture memory trials. This was due to worse performance on the 5 mg dose (Table 1).

Two patients did well enough on 100 mg of naltrexone to be included in the double-blind procedure. One of these two patients did better during the active phase (on the BCRS, SCAG and paragraph); the second patient scored equally during the two phases.

Table 1

Performance of ATD Patients at Baseline and on Three Different Doses of Naltrexone. Scores are Means f SD of all Patients Tested

BASELINE 5 MG 50 MG 100 MG

NOSIE +SD BCRS - SCAG PICTURES 1 (HITS-FA) PICTURES 2 PICTURES 3* PICTURES D PARAGRAPH BUSCHKE (%I STORAGE RETRIEVAL CONS RETR REC FAIL

68.63+13.72 24.22y4.49 51.o+q.77 6.67z3.08

6.5+2.88 6.8?+4.26 5.67T4.23 4.63z4.14

67.14216.81 24.22+5.63 51.33T8.05 2.83+i;.12 -

4.67+3.08 3.67T3.88 5 * 5+T. 95 4.oT3.11

81.57+16.28 83.29+9.99 50.43515.25 5o.o+i1.06 16.57T12.26 18.47+15.71 19.71211.74 13.57T14.83

66.5~14.14 24.11+4.59 51.44T9.44 3.33zT. 27

5.5+4.04 6.573.56 6.67+3.56 4.2522.66

74.43+16.26 47.o+i9.58 15.4-5;19.74 22.71z24.0

65.88+12.5 23.44+6.23 48.55+10.27 2.5O+F.32

4.83+5.34 6.83T2.93 5.33T4.41 4.aaz5.0

82.86+6.74 50.14~10.37 19.57T12.79 13.5729.4

*SIGNIFICANT AT P = .05. Picture recognition is recorded as hits minus false alarms (FA). CONS. RETR. denotes consistent retrieval; REC. FAIL. is recall failure.

Page 3: Naltrexone and Alzheimer's disease

Naltrexone and Alzheimer’s disease 589

Discussion

Numerous studies have investigated the role of endogenous opiates in memory function. It appears that endorphins and enkphalins may interfere with memory processes (Rigter et al, 1980; Izquierdo, et al 1980) and that such effects may be prevented by naloxone (Garzon, et al, 1981). However, some authors have noted a facilitation of memory by endogenous opiates (Dewied et al, 1978; Kastin et al, 1981) and a naloxone-induced impairment in memory processing (Cohen, et al, 1983). Differences in methodology may account for these discrepant results.

A well-established means of producing amnesia, electroconvulsive treatment (ECT), is associated with an acute transient increase in endorphin levels (Misiaszek et al 1984). Acetylcholine release may be modulated by endogenous opiates and increased by naloxone (Mathews et al 1983). Thus, trials of opiate antagonists seem warranted in cognitive disorders, including ATD.

We were able, however, to demonstrate therapeutic effects in only two of nine ATD subjects in the single-blind dose ranging phase of this study. Only one of these two patients had better cognitive processing during the active portion of the double-blind phase. This “responder” was later treated openly with naloxone infusions with no resultant change in cognitive status.

Conclusion

Our results suggest that naltrexone lacks efficacy in ATD. It is unlikely that naltrexone’s minimal opiate agonist effects blocked its potential effectiveness; naloxone, a pure antagonist, also fails to reverse ATD memory deficits. Although opiate antagonism is an unsuccessful treatment strategy in ATD, the use of naloxone and naltrexone should be considered in other memory disorders, including post-ECT amnesia.

Acknowledgement

This study was supported in part by the Veterans Administration.

References

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Inquiries and reprint requests should be addressed to:

Michael Serby, M.D. Psychiatry Service/ll6A Veterans Administration Medical Center First Avenue at E. 24th Street New York, New York 10010, USA