Add-on prolonged-release melatonin for cognitive function and sleep in mild to moderate Alzheimer's disease: A 6-month, randomized, placebo-controlled, multicenter trial

Clinical Interventions in Aging

Volumn 9, Issue , 2014, Pages 947-961

  Wade, Alan G ^a   Farmer, Mildred ^b   Harari, Gil ^c   Fund, Naama ^c   Laudon, Moshe ^d   Nir, Tali ^d   Frydman Marom, Anat ^d   Zisapel, Nava ^d,e  

^a CPS Research   (United Kingdom)

^b Meridien Research   (United States)

^c Medistat Ltd   (Israel)

^d NEURIM PHARMACEUTICALS LTD   (Israel)

^e TEL AVIV UNIVERSITY   (Israel)

Author keywords

Acetylcholinesterase inhibitors; Insomnia; Memantine

Indexed keywords

CHOLINESTERASE INHIBITOR; CREATININE; GLUCOSE; MELATONIN; MEMANTINE; PLACEBO; DELAYED RELEASE FORMULATION; DOPAMINE RECEPTOR STIMULATING AGENT;

ABDOMINAL DISCOMFORT; ABNORMAL DREAMING; ADULT; AGED; ALZHEIMER DISEASE; ANGINA PECTORIS; ARTICLE; ASSESSMENT SCALE COGNITION; BACKACHE; BURNING FEET SYNDROME; COGNITION; COGNITIVE DEFECT; COMORBIDITY; CONTROLLED STUDY; COUGHING; CREATININE BLOOD LEVEL; DECREASED APPETITE; DELUSION; DIARRHEA; DISEASE SEVERITY; DRUG EFFICACY; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; FATIGUE; FEMALE; GLUCOSE BLOOD LEVEL; HEADACHE; HUMAN; INSOMNIA; INSTRUMENTAL ACTIVITIES OF DAILY LIVING; MAJOR CLINICAL STUDY; MALE; MINI MENTAL STATE EXAMINATION; MULTICENTER STUDY; NAUSEA; PITTSBURGH SLEEP QUALITY INDEX; RANDOMIZED CONTROLLED TRIAL; RATING SCALE; RESTLESSNESS; RHINOPHARYNGITIS; SIDE EFFECT; SLEEP QUALITY; SOMNOLENCE; THYROID TUMOR; TREATMENT DURATION; UPPER RESPIRATORY TRACT INFECTION; URINARY TRACT INFECTION; VOMITING; CLINICAL TRIAL; COMPLICATION; DELAYED RELEASE FORMULATION; DRUG COMBINATION; DRUG EFFECTS; MIDDLE AGED; SEVERITY OF ILLNESS INDEX; SLEEP; SLEEP INITIATION AND MAINTENANCE DISORDERS; TREATMENT OUTCOME; VERY ELDERLY;

AGED; AGED, 80 AND OVER; ALZHEIMER DISEASE; CHOLINESTERASE INHIBITORS; COGNITION; DELAYED-ACTION PREPARATIONS; DOPAMINE AGENTS; DRUG THERAPY, COMBINATION; FEMALE; HUMANS; MALE; MELATONIN; MEMANTINE; MIDDLE AGED; PLACEBOS; SEVERITY OF ILLNESS INDEX; SLEEP; SLEEP INITIATION AND MAINTENANCE DISORDERS; TREATMENT OUTCOME;

EID: 84902963042     PISSN: 11769092     EISSN: 11781998     Source Type: Journal    
DOI: 10.2147/CIA.S65625     Document Type: Article

References (68)

1. Querfurth HW, LaFerla FM. Alzheimer's disease. N Engl J Med. 2010; 362(4):329-344.
2. Pollak CP, Perlick D. Sleep problems and institutionalization of the elderly. J Geriatr Psychiatry Neurol. 1991;4(4):204-210.
3. Maquet P. The role of sleep in learning and memory. Science. 2001; 294(5544):1048-1052.
4. Backhaus J, Junghanns K, Born J, Hohaus K, Faasch F, Hohagen F. Impaired declarative memory consolidation during sleep in patients with primary insomnia: Influence of sleep architecture and nocturnal cortisol release. Biol Psychiatry. 2006;60(12):1324-1330.
5. Miyata S, Noda A, Iwamoto K, Kawano N, Okuda M, Ozaki N. Poor sleep quality impairs cognitive performance in older adults. J Sleep Res. 2013;22(5):535-541.
6. Murre JM, Kristo G, Janssen SM. The effect of self-reported habitual sleep quality and sleep length on autobiographical memory. Memory. 2014;22(6):633-645.
7. Lim AS, Yu L, Kowgier M, Schneider JA, Buchman AS, Bennett DA. Modification of the relationship of the apolipoprotein E ε4 allele to the risk of Alzheimer disease and neurofibrillary tangle density by sleep. JAMA Neurol. 2013;70(12):1544-1551.
8. Ju YE, Lucey BP, Holtzman DM. Sleep and Alzheimer disease pathology - a bidirectional relationship. Nat Rev Neurol. 2014;10(2):115-119.
9. Hansen RA, Gartlehner G, Webb AP, Morgan LC, Moore CG, Jonas DE. Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer's disease: a systematic review and meta-analysis. Clin Interv Aging. 2008;3(2):211-225.
10. Rive B, Gauthier S, Costello S, Marre C, François C. Synthesis and comparison of the meta-analyses evaluating the efficacy of memantine in moderate to severe stages of Alzheimer's disease. CNS Drugs. 2013; 27(7):573-582.
11. Chavant F, Favrelière S, Lafay-Chebassier C, Plazanet C, Pérault-Pochat MC. Memory disorders associated with consumption of drugs: updating through a case/noncase study in the French PharmacoVigilance Database. Br J Clin Pharmacol. 2011;72(6):898-904.
12. Leufkens TR, Lund JS, Vermeeren A. Highway driving performance and cognitive functioning the morning after bedtime and middle-of-the-night use of gaboxadol, zopiclone and zolpidem. J Sleep Res. 2009; 18(4):387-396.
13. Otmani S, Demazières A, Staner C, et al. Effects of prolonged-release melatonin, zolpidem, and their combination on psychomotor functions, memory recall, and driving skills in healthy middle aged and elderly volunteers. Hum Psychopharmacol. 2008;23(8):693-705.
14. Vermeeren A, Coenen AM. Effects of the use of hypnotics on cognition. Prog Brain Res. 2011;190:89-103.
15. Billioti de Gage S, Bégaud B, Bazin F, et al. Benzodiazepine use and risk of dementia: prospective population based study. BMJ. 2012; 345:e6231.
16. Wu CS, Wang SC, Chang IS, Lin KM. The association between dementia and long-term use of benzodiazepine in the elderly: nested case-control study using claims data. Am J Geriatr Psychiatry. 2009;17(7):614-620.
17. Zisapel N. Melatonin and sleep. Open Neuroendocrinol J. 2010; 3:85-95.
18. Tohgi H, Abe T, Takahashi S, Kimura M, Takahashi J, Kikuchi T. Concentrations of serotonin and its related substances in the cerebrospinal fluid in patients with Alzheimer type dementia. Neurosci Lett. 1992;141(1):9-12.
19. Mishima K, Tozawa T, Satoh K, Matsumoto Y, Hishikawa Y, Okawa M. Melatonin secretion rhythm disorders in patients with senile dementia of Alzheimer's type with disturbed sleep-waking. Biol Psychiatry. 1999; 45(4):417-421.
20. Srinivasan V, Kaur C, Pandi-Perumal S, Brown GM, Cardinali DP. Melatonin and its agonist ramelteon in Alzheimer's disease: possible therapeutic value. Int J Alzheimers Dis. 2010;(2011):1-15.
21. Asayama K, Yamadera H, Ito T, Suzuki H, Kudo Y, Endo S. Double blind study of melatonin effects on the sleep-wake rhythm, cognitive and non-cognitive functions in Alzheimer type dementia. J Nippon Med Sch. 2003;70(4):334-341.
22. Brusco LI, Márquez M, Cardinali DP. Monozygotic twins with Alzheimer's disease treated with melatonin: Case report. J Pineal Res. 1998;25(4):260-263.
23. Brusco LI, Márquez M, Cardinali DP. Melatonin treatment stabilizes chronobiologic and cognitive symptoms in Alzheimer's disease. Neuro Endocrinol Lett. 2000;21(1):39-42.
24. Cardinali DP, Vigo DE, Olivar N, Vidal MF, Furio AM, Brusco LI. Therapeutic application of melatonin in mild cognitive impairment. Am J Neurodegener Dis. 2012;1(3):280-291.
25. Rondanelli M, Opizzi A, Faliva M, et al. Effects of a diet integration with an oily emulsion of DHA-phospholipids containing melatonin and tryptophan in elderly patients suffering from mild cognitive impairment. Nutr Neurosci. 2012;15(2):46-54.
26. Lemoine P, Zisapel N. Prolonged-release formulation of melatonin (Circadin) for the treatment of insomnia. Expert Opin Pharmacother. 2012;13(6):895-905.
27. Wade A, Downie S. Prolonged-release melatonin for the treatment of insomnia in patients over 55 years. Expert Opin Investig Drugs. 2008;17(10):1567-1572.
28. Garfinkel D, Laudon M, Nof D, Zisapel N. Improvement of sleep quality in elderly people by controlled-release melatonin. Lancet. 1995; 346(8974):541-544.
29. Otmani S, Metzger D, Guichard N, et al. Effects of prolonged-release melatonin and zolpidem on postural stability in older adults. Hum Psychopharmacol. 2012;27(3):270-276.
30. Altena E, Ramautar JR, Van Der Werf YD, Van Someren EJ. Do sleep complaints contribute to age-related cognitive decline? Prog Brain Res. 2010;185:181-205.
31. Markus RP, Silva CL, Franco DG, Barbosa EM, Ferreira ZS. Is modulation of nicotinic acetylcholine receptors by melatonin relevant for therapy with cholinergic drugs? Pharmacol Ther. 2010;126(3): 251-262.
32. Riemersma-van der Lek RF, Swaab DF, Twisk J, Hol EM, Hoogendijk WJ, Van Someren EJ. Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: a randomized controlled trial. JAMA. 2008;299(22):2642-2655.
33. Mohs RC, Knopman D, Petersen RC, et al. Development of cognitive instruments for use in clinical trials of antidementia drugs: additions to the Alzheimer's Disease Assessment Scale that broaden its scope. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord. 1997;11 Suppl 2:S13-S21.
34. Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist. 1969;9(3): 179-186.
35. Folstein MF, Folstein SE, McHugh PR. "Mini-Mental State". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189-198.
36. Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989;28(2):193-213.
37. Guy W. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: US Department of Health, Education, and Welfare; 1976.
38. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology. 1994;44(12): 2308-2314.
39. Bech P, Olsen LR, Kjoller M, Rasmussen NK. Measuring well-being rather than the absence of distress symptoms: a comparison of the SF-36 Mental Health subscale and the WHO-Five Well-Being Scale. Int J Methods Psychiatr Res. 2003;12(2):85-91.
40. Tractenberg RE, Singer CM, Cummings JL, Thal LJ. The Sleep Disorders Inventory: an instrument for studies of sleep disturbance in persons with Alzheimer's disease. J Sleep Res. 2003;12(4):331-337.
41. Prakash A, Risser RC, Mallinckrodt CH. The impact of analytic method on interpretation of outcomes in longitudinal clinical trials. Int J Clin Pract. 2008;62(8):1147-1158.
42. Howard R, Phillips P, Johnson T, et al. Determining the minimum clinically important differences for outcomes in the DOMINO trial. Int J Geriatr Psychiatry. 2011;26(8):812-817.
43. Schrag A, Schott JM; Alzheimer's Disease Neuroimaging Initiative. What is the clinically relevant change on the ADAS-Cog? J Neurol Neurosurg Psychiatry. 2012;83(2):171-173.
44. Rockwood K, Fay S, Gorman M. The ADAS-cog and clinically meaningful change in the VISTA clinical trial of galantamine for Alzheimer's disease. Int J Geriatr Psychiatry. 2010;25(2):191-201.
45. Andrew MK, Rockwood K. A five-point change in Modified Mini-Mental State Examination was clinically meaningful in community-dwelling elderly people. J Clin Epidemiol. 2008;61(8):827-831.
46. Rogers SL, Farlow MR, Doody RS, Mohrs R, Friedhoff LT; Donepezil Study Group*. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Neurology. 1998;50(1): 136-145.
47. Knopman DS. Clinical trial design issues in mild to moderate Alzheimer disease. Cogn Behav Neurol. 2008;21(4):197-201.
48. Yu JM, Tseng IJ, Yuan RY, Sheu JJ, Liu HC, Hu CJ. Low sleep efficiency in patients with cognitive impairment. Acta Neurol Taiwan. 2009;18(2):91-97.
49. Jan JE, Hamilton D, Seward N, Fast DK, Freeman RD, Laudon M. Clinical trials of controlled-release melatonin in children with sleep-wake cycle disorders. J Pineal Res. 2000;29(1):34-39.
50. Gringras P, Gamble C, Jones AP, et al; MENDS Study Group. Melatonin for sleep problems in children with neurodevelopmental disorders: randomised double masked placebo controlled trial. BMJ. 2012; 345:e6664.
51. De Leersnyder H, Zisapel N, Laudon M. Prolonged-release melatonin for children with neurodevelopmental disorders. Pediatr Neurol. 2011; 45(1):23-26.
52. Gorfine T, Zisapel N. Late evening brain activation patterns and their relation to the internal biological time, melatonin, and homeostatic sleep debt. Hum Brain Mapp. 2009;30(2):541-552.
53. Gorfine T, Zisapel N. Melatonin and the human hippocampus, a time dependent interplay. J Pineal Res. 2007;43(1):80-86.
54. Serfaty M, Kennell-Webb S, Warner J, Blizard R, Raven P. Double blind randomised placebo controlled trial of low dose melatonin for sleep disorders in dementia. Int J Geriatr Psychiatry. 2002;17(12): 1120-1127.
55. Mahlberg R, Walther S. Actigraphy in agitated patients with dementia. Monitoring treatment outcomes. Z Gerontol Geriatr. 2007;40(3): 178-184.
56. Gehrman PR, Connor DJ, Martin JL, Shochat T, Corey-Bloom J, Ancoli-Israel S. Melatonin fails to improve sleep or agitation in double-blind randomized placebo-controlled trial of institutionalized patients with Alzheimer disease. Am J Geriatr Psychiatry. 2009;17(2): 166-169.
57. Dowling GA, Burr RL, Van Someren EJ, et al. Melatonin and bright-light treatment for rest-activity disruption in institutionalized patients with Alzheimer's disease. J Am Geriatr Soc. 2008;56(2):239-246.
58. Singer C, Tractenberg RE, Kaye J, et al; Alzheimer's Disease Cooperative Study. A multicenter, placebo-controlled trial of melatonin for sleep disturbance in Alzheimer's disease. Sleep. 2003;26(7):893-901.
59. Kawada T. Sleep evaluation by actigraphy for patients with Alzheimer disease. JAMA Neurol. 2013;70(8):1074.
60. Ju YE, Holtzman DM. Sleep evaluation by actigraphy for patients with Alzheimer disease - reply. JAMA Neurol. 2013;70(8):1074-1075.
61. Wade AG, Crawford G, Ford I, et al. Prolonged release melatonin in the treatment of primary insomnia: evaluation of the age cut-off for short- and long-term response. Curr Med Res Opin. 2011;27(1):87-98.
62. Ju YE, McLeland JS, Toedebusch CD, et al. Sleep quality and preclinical Alzheimer disease. JAMA Neurol. 2013;70(5):587-593.
63. Wade AG, Ford I, Crawford G, et al. Efficacy of prolonged release melatonin in insomnia patients aged 55-80 years: quality of sleep and next-day alertness outcomes. Curr Med Res Opin. 2007;23(10):2597-2605.
64. Luthringer R, Muzet M, Zisapel N, Staner L. The effect of prolonged-release melatonin on sleep measures and psychomotor performance in elderly patients with insomnia. Int Clin Psychopharmacol. 2009;24(5): 239-249.
65. Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from the adult brain. Science. 2013;342(6156):373-377.
66. Spira AP, Gamaldo AA, An Y, et al. Self-reported sleep and β-amyloid deposition in community-dwelling older adults. JAMA Neurol. 2013; 70(12):1537-1543.
67. Lipartiti M, Franceschini D, Zanoni R, et al. Neuroprotective effects of melatonin. Adv Exp Med Biol. 1996;398:315-321.
68. García-Mesa Y, Giménez-Llort L, López LC, et al. Melatonin plus physical exercise are highly neuroprotective in the 3xTg-AD mouse. Neurobiol Aging. 2012;33(6):1124.e13-e29.