A Case Series of d-Cycloserine Added to Donepezil in the Treatment of Alzheimer's Disease

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.

ACKNOWLEDGMENTS

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.