0
Get Alert
Please Wait... Processing your request... Please Wait.
You must sign in to sign-up for alerts.

Please confirm that your email address is correct, so you can successfully receive this alert.

1
Letter   |    
A Case Series of d-Cycloserine Added to Donepezil in the Treatment of Alzheimer's Disease
William E. Falk, M.D.; Ella J. Daly, M.B., B.Ch., B.A.O.; Guochuan E. Tsai, M.D., Ph.D.; Jeanette Gunther, M.S.; Patrick Brown, B.A.
The Journal of Neuropsychiatry and Clinical Neurosciences 2002;14:466-467. doi:10.1176/appi.neuropsych.14.4.466
View Author and Article Information

Alzheimer's DiseaseD-CycloserineDonepezil

SIR: Beyond the well-established cholinergic deficits, Alzheimer's disease (AD) affects a number of other neurotransmitter systems, including those using the excitatory amino acids, aspartate and glutamate.1 Activation of the N-methyl-d-aspartate (NMDA) subtype of the glutamate receptor appears to be involved in the processes of learning and memory.2 Loss of presynaptic excitatory amino acids (EAAs) and their postsynaptic receptors suggests that glutamatergic terminal degeneration and deficient EAAs may be related to the symptoms of AD.3

d-Cycloserine, an antibiotic used to treat tuberculosis at high doses, exhibits partial agonist activity at the glycine modulatory site of the NMDA receptor even at low doses and readily crosses the blood—brain barrier. This partial agonist activity has provided a means to enhance NMDA neurotransmission while avoiding the neurotoxic effect of excessive activation.

In two previous studies we looked at the cognitive effects of d-cycloserine at several doses in subjects with AD who were not taking donepezil.4,5d-Cycloserine was associated with significant improvement in scores (comparable to that achieved with cholinesterase inhibitors) on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) when given at a dose of 100 mg/day, but not at the lower doses of 15 mg or 50 mg.

We present now the findings from a small, open-label case series of 5 subjects with AD (2 females and 3 males) treated for 1 month with d-cycloserine 150 mg/day. Each had been taking the cholinesterase inhibitor donepezil (4 subjects at 10 mg/day and 1 subject at 5 mg/day) for at least 8 months (range 8—16 months).

+

Case Series

Baseline and 1-month assessments included the MMSE, ADAS-cog, Instrumental Activities of Daily Living (IADL), Clinical Global Impression of Change (CGIC), and Physical Self-Maintenance Scale (PSMS). Each subject had a caregiver who completed necessary evaluations and supervised medication compliance. At baseline, the mean Mini-Mental State Examination (MMSE) score was 17.2 (range 11—26) and the mean ADAS-cog score was 25.51 (range 9.7—41.7).

After 1 month we examined four outcome measures (MMSE, ADAS-cog, IADL, and PSMS) by means of a related-sample t-test. All 5 subjects showed improvement on the ADAS-cog, while 4 improved on the MMSE. There was no statistically significant effect found with any outcome measures examined at follow-up, although the cognitive measures did show a statistical trend (MMSE, P=0.1; ADAS-cog, P=0.08). No side effects were reported. Our findings support the hypothesis that the addition of d-cycloserine 150 mg/day is associated with possible modest cognitive improvement in AD subjects already taking donepezil.

However, no firm conclusions can be drawn from this case series, which was limited in terms of its small size, short duration, lack of a placebo control group, and unblinded dosage. Further study is needed to determine whether this dose of d-cycloserine adds clinically significant benefit for AD patients already taking cholinesterase inhibitors.

This work was supported in part by the American Federation of Aging Research, a Young Investigator Award from the National Alliance for Research on Schizophrenia and Depression, and a Stanley Foundation Research Award.

Lowe SL, Bowen DM, Francis PT, et al: Antemortem cerebral amino acid concentrations indicate selective degeneration of glutamate-enriched neurons in Alzheimer's disease. Neuroscience  1990; 38:571-577
[CrossRef] | [PubMed]
 
Bischoff D, Tiedke PI: Competitive and non-competitive NMDA receptor antagonists in spatial learning tasks. Eur J Pharmacol  1992; 213:269-273
[CrossRef] | [PubMed]
 
Deutsch SI, Morihisa JM: Glutamatergic abnormalities in Alzheimer's disease and a rationale for clinical trials with l-glutamate. Clin. Neuropharmacology  1998; 11:18-35
 
Tsai GE, Falk WE, Gunther J: A preliminary study of d-cycloserine treatment in Alzheimer's disease. J Neuropsychiatry Clin Neurosci  1998; 10:224-226
[PubMed]
 
Tsai GE, Falk WE, Gunther J, et al: Improved Cognition in Alzheimer's disease with short-term d-cycloserine treatment. Am J Psychiatry  1999; 56:467-469
 
+

References

Lowe SL, Bowen DM, Francis PT, et al: Antemortem cerebral amino acid concentrations indicate selective degeneration of glutamate-enriched neurons in Alzheimer's disease. Neuroscience  1990; 38:571-577
[CrossRef] | [PubMed]
 
Bischoff D, Tiedke PI: Competitive and non-competitive NMDA receptor antagonists in spatial learning tasks. Eur J Pharmacol  1992; 213:269-273
[CrossRef] | [PubMed]
 
Deutsch SI, Morihisa JM: Glutamatergic abnormalities in Alzheimer's disease and a rationale for clinical trials with l-glutamate. Clin. Neuropharmacology  1998; 11:18-35
 
Tsai GE, Falk WE, Gunther J: A preliminary study of d-cycloserine treatment in Alzheimer's disease. J Neuropsychiatry Clin Neurosci  1998; 10:224-226
[PubMed]
 
Tsai GE, Falk WE, Gunther J, et al: Improved Cognition in Alzheimer's disease with short-term d-cycloserine treatment. Am J Psychiatry  1999; 56:467-469
 
+
+

CME Activity

There is currently no quiz available for this resource. Please click here to go to the CME page to find another.
Submit a Comments
Please read the other comments before you post yours. Contributors must reveal any conflict of interest.
Comments are moderated and will appear on the site at the discertion of APA editorial staff.

* = Required Field
(if multiple authors, separate names by comma)
Example: John Doe



Web of Science® Times Cited: 2

Related Content
Books
Manual of Clinical Psychopharmacology, 7th Edition > Chapter 12.  >
Manual of Clinical Psychopharmacology, 7th Edition > Chapter 12.  >
APA Practice Guidelines > Chapter 16.  >
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 41.  >
Topic Collections
Psychiatric News
APA Guidelines
PubMed Articles