Yaari.qxp 30/7/08 12:39 pm Page 33
Combination Therapies for Treating Alzheimer’s Disease
Fluoxetine primary and secondary outcomes, showing efficacy on cognition,
One preliminary study has been performed to assess the effect of a activities of daily living, global outcome, and behavior. Furthermore,
fluoxetine as an adjunct to an AChEI in AD for 12 weeks.
15
One hundred memantine was shown to be safe and well tolerated. More participants
and twenty-two patients with mild to moderate AD (MMSE 10–24) were (n=25 [12.4%]) in the placebo-treated group discontinued treatment
randomized to one of three arms: fluoxetine plus rivastigmine, prematurely because of adverse events than in the memantine group
rivastigmine alone, or placebo. There was a significant improvement in (n=15 [7.4%]). The most common statistically significant adverse events
MMSE and Wechsler Memory Scale 3rd Edition (WMS-III) in both the in the memantine group compared with placebo were confusion
combination group and the rivastigmine alone group, but there was no (p=0.01) and headache (p=0.09). In contrast, there were lower
difference between these two groups. These two groups also incidences of diarrhea and fecal incontinence in the memantine group
significantly improved on the Lawton and Brody ADL scale,
16
with a compared with the placebo group.
statistical significance between the two groups favoring the combination
group. On the Hamilton Depression Scale-17 (HAM-17), both treatment A post hoc analysis of this same study examined the ADCS-ADL19 in
groups had significant benefit compared with placebo, but were not more detail.
26
Patients receiving combination therapy had statistically
clinically significant compared with each other. significantly less decline in ADLs, with item analysis showing that effects
were on grooming, using the toilet, conversing, watching television, and
Memantine and Cholinergic Agents being left alone. The addition of memantine to an AChEI was recently
Glutamatergic neurons are ubiquitous in the central nervous system studied in patients with mild to moderate AD (MMSE 10–22).
27
A total of
(CNS) and are involved in learning, memory, and shaping neuronal 433 patients who were on stable doses of an AChEI (donepezil,
architecture. They are the primary CNS excitatory neurons, and are rivastigmine, or galantamine) were randomized to placebo versus
predominantly ‘projection’ neurons, which provide information about memantine 20mg once daily for 24 weeks. Although memantine was
one brain area to another. In AD, there is thought to be an well tolerated, there were no statistically significant differences in
overstimulation of the glutamatergic N-methyl-D-aspartate (NMDA) primary (ADAS-cog and CIBIC-Plus) or secondary (ADCS-ADL(23), NPI,
receptor. This abnormal glutamate activity leads to an excessive cellular and MMSE) outcome measures.
influx of calcium and sustained low-level activation of NMDA receptors.
This is thought to lead to impaired learned and neuronal death following Conclusions
chronic insult.
17
Memantine, an NMDA receptor antagonist, was shown Most of the combination or add-on studies failed to show significant
to be efficacious in moderate and severe AD as monotherapy.
18,19
benefit or define best practice. Perhaps the most widely cited data
Pre-clinical studies show no inhibition of AChE by memantine, and no come from studies in patients with mild to moderate AD, where the
binding to muscarinic receptors.
20–22
There is no pharmacokinetic or available evidence indicates that memantine can be used alone or in
pharmacodynamic interaction between memantine and donepezil,
23
so combination with a cholinesterase inhibitor, but we do not know
it was quite logical to study memantine together with various whether one approach is truly superior to the other (and we note that
cholinergic therapies. donepezil alone among the cholinesterase inhibitors is also US Food
and Drug Administration [FDA]-approved for the treatment of severe
An open-label study suggested that the combination of memantine and AD). We also do not know whether the order in which these two classes
cholinesterase inhibitors was well tolerated.
24
A subsequent large trial in of agents are administered is important. There are many other
moderate to severe AD examined the efficacy of memantine in patients unanswered questions, including whether the combination of
already receiving stable treatment with donepezil. This double-blind, memantine with other agents might show benefit and whether benefit
placebo-controlled trial randomized 404 AD patients with an MMSE of can be seen in non-AD dementias.
5–14 to memantine versus placebo over a 24-week period.
25
The primary
outcome measures were change from baseline on a cognitive measure, The future of the study of combination therapy will inevitably be far
Severe Impairment Battery (SIB), and a modified 19-item AD Co-operative different from its past. More novel agents, such as those attempting to
Study-Activities of Daily Living Inventory (ADCS-ADL19). Secondary normalize aberrant amyloid processing, will be combined with currently
outcomes included a Clinician’s Interview-Based Impression of Change approved neurotransmitter-based therapies, and within the next five years
Plus Caregiver Input (CIBIC-Plus), the Neuropsychiatric Inventory, and the we will begin to see trials combining novel strategies (e.g. normalizing tau
Behavioral Rating Scale for Geriatric Patients (BGP Care Dependency phosphorylation and regulating amyloid processing)—strategies suggested
Subscale). There was statistical significance favoring memantine in all by the promising pre-clinical work of Ashe, Laferla, and others.
28,29
■
1. Yaari R, et al., Expert Opin Drug Disc, 2008;3(7):745–60. 11. Klatte ET, et al., Alzheimer Dis Assoc Disord, 2003;17(2): 21. Parsons CG, et al., Neuropharmacology, 1999;38(6):735–67.
2. Kaye WH, et al., Biol Psychiatry, 1982;17(2):275–80. 113–16. 22. Wenk GL, Barnes CA, Brain Res, 2000;885(1):1–5.
3. Gauthier S, et al., N Engl J Med, 1990;322(18):1272–6. 12. Morris JC, et al., Neurology, 1989;39(9):1159–65. 23. Periclou AP, et al., Ann Pharmacother, 2004;38(9):1389–94.
4. Chatellier G, et al., BMJ, 1990;300(6723):495–9. 13. Sun Y, et al., Clin Ther, 2007;29(10):2204–14. 24. Hartmann S, Mobius HJ, Int Clin Psychopharmacol,
5. Fitten LJ, et al., Am J Psychiatry, 1990;147(2):239–42. 14. Finkel SI, et al., Int J Geriatr Psychiatry, 2004;19(1):9–18. 2003;18(2):81–5.
6. Bianchetti A, et al., Curr Med Res Opin, 2003;19(4):350–53. 15. Mowla A, et al., J Clin Psychopharmacol, 2007;27(5):484–7. 25. Tariot PN, et al., JAMA, 2004;291(3):317–24.
7. Rigaud AS, et al., Presse Med, 2003;32(35):1649–54. 16. Lawton MP, Brody EM, Gerontologist, 1969;9(3):179–86. 26. Feldman HH, et al., Alzheimer Dis Assoc Disord, 2006;20(4):
8. Sano M, et al., N Engl J Med, 1997;336(17):1216–22. 17. Danysz W, et al., Neurotox Res, 2000;2(2–3):85–97. 263–8.
9. Birks J, Flicker L, Cochrane Database Syst Rev, 2003;(1): 18. Reisberg B, et al., N Engl J Med, 2003;348(14):1333–41. 27. Porsteinsson AP, et al., Curr Alzheimer Res, 2008;5(1):83–9.
CD000442. 19. Winblad B, Poritis N, Int J Geriatr Psychiatry, 1999;14(2):135–46. 28. Ashe KH, Biochem Soc Trans, 2005;33(4):591–4.
10. Miller ER III, et al., Ann Intern Med, 2005;142(1):37–46. 20. Danysz W, et al., Neurosci Biobehav Rev, 1997;21(4):455–68. 29. LaFerla FM, Oddo S, Trends Mol Med, 2005;11(4):170–76.
US NEUROLOGY 33
Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84