Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Neurim Pharmaceuticals Ltd.
Approved for: Insomnia
Circadin is an extended-release formulation of melatonin, a hormone that is released by the pineal gland into the CSF at night to regulate circadian rhythms and induce sleepiness. Circadin is being marketed for insomnia in the European Union, Israel, Australia, and countries in Asia and elsewhere. It has been approved in these countries for this indication since 2007, and is in Phase 3 evaluation for sleep disorders in the United States.
Poor sleep has been linked to increased risk of cognitive dysfunction and Alzheimer's (Miyata et al., 2013, Lim et al., 2013, Ju et al., 2014). Melatonin release decreases with age and becomes further dysregulated in AD (Mishima et al., 1999). Alzheimer's disease is frequently accompanied by sleep disturbances, but some sleep medications are counter-indicated because they may increase risk of dementia (Billoti de Gage et al., 2012, Wu et al., 2009).
One trial of Circadin 2 mg, as add-on to standard therapy, has been conducted in Alzheimer's disease patients. Starting in 2009 at five sites in the United States and the United Kingdom, 73 male and female outpatients with mild to moderate AD, with and without diagnosed insomnia, were randomized to a nightly pill of Circadin or placebo for six months, then switched to two weeks of washout with placebo. The primary outcome was cognitive function measured by ADAS-cog; secondary outcomes were global function as measured by IADL and sleep efficiency by way of the Pittsburgh Sleep Quality Index (PSQI). Published results report no treatment benefit on ADAS-cog, but do report a treatment benefit on IADL and on MMSE. PSQI showed no treatment effect in the whole group, but did show a treatment benefit in the co-morbid insomnia subgroup. This small subgroup reportedly showed larger, significant treatment effects on all measures (Wade et al., 2014).
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- 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 Oct;22(5):535-41. Epub 2013 Apr 6 PubMed.
- 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 Dec;70(12):1544-51. PubMed.
- Ju YE, Lucey BP, Holtzman DM. Sleep and Alzheimer disease pathology--a bidirectional relationship. Nat Rev Neurol. 2014 Feb;10(2):115-9. Epub 2013 Dec 24 PubMed.
- 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 Feb 15;45(4):417-21. PubMed.
- Billioti de Gage S, Moride Y, Ducruet T, Kurth T, Verdoux H, Tournier M, Pariente A, Bégaud B. Benzodiazepine use and risk of Alzheimer's disease: case-control study. BMJ. 2014 Sep 9;349:g5205. PubMed.
- 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 Jul;17(7):614-20. PubMed.
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