Therapeutic Areas

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Insomnia in older adults

Quality sleep is essential to survival and quality of life. Insomnia occurring at least 3 nights a week for at least 3 months affects almost 50% of adults aged 65 and older, especially women, and causing significant daytime distress. Insomnia may include one or more symptoms: difficulty initiating sleep, difficulty maintaining sleep, and/or early morning awakening. Two internal biological mechanisms…

Insomnia in older adults

Quality sleep is essential to survival and quality of life. Insomnia occurring at least 3 nights a week for at least 3 months affects almost 50% of adults aged 65 and older, especially women, and causing significant daytime distress. Insomnia may include one or more symptoms: difficulty initiating sleep, difficulty maintaining sleep, and/or early morning awakening.

Two internal biological mechanisms – the brain’s circadian clock and the homeostatic sleep drive – work together to determine the timing and duration of sleep. Melatonin hormone produced by the pineal gland regulates the circadian clock and promotes sleep. But, as we age, neurophysiological and neurochemical changes affect melatonin production, making older adults prone to insomnia. Sleep disruptions in later life may also result from various sleep disorders, obesity, medications, nocturnal urinary frequency and chronic pain, as well as hormonal changes, neurodegeneration, psychiatric conditions, and medical comorbidities.

Why is treatment important?

Untreated insomnia is associated with impaired emotional, social, and physical well-being. People with insomnia are more prone to accidents, work-absenteeism, reduced job performance, decreased quality of life and increased utilization of health care. Furthermore, insomnia is a high-risk factor for health-related quality of life: cardiovascular disease, hypertension, Alzheimer’s disease, depression and diabetes.

References: 1. Ohayon MM. Epidemiology of insomnia: what we know and what we still need to learn. Sleep Medicine Reviews 2002;6(2):97-111. 2. Drake CL, Roehrs T, Roth T. Insomnia Causes, Consequences, and Therapeutics: An Overview. Depression and Anxiety 2003;18:163-76. 3. Monane M. Insomnia in the elderly. J Clin Psychiatry 1992;53(Suppl)::23-8. 4. Dubocovich ML. Melatonin receptor: Role of sleep and circadian rhythm regulation. Sleep Med 2007;8:34-42. 5. Reppert S, Weaver D, Godson C. Melatonin receptors step into the light: cloning and classification of subtypes. TiPS 1996;17:100-02. 6. Nave R, Peled R, Lavie P. Melatonin improves evening napping. European Journal of Pharmacology 1995;275:213-16. 7. Zhdanova IV, Wurtman R. Efficacy of melatonin as a sleep-promoting agent. J Biol Rhythms 1997;12(6):644-50. 8. Wyatt J. K. et al, Sleep-facilitating effect of exogenous melatonin in healthy young men and women is circadian-phase dependent, Sleep. 2006 May;29 (5):609-18. 9. Cajochen C., Krauchi K. and Wirz-Justice A., Role of Melatonin in the Regulation of Human Circadian Rhythms and Sleep, Journal of Neuroendocrinology, 2003, Vnl 15, 432-437. 10. Roth T, Roehrs T. Insomnia: Epidemiology, Characteristics, and Consequences. Clinical Cornerstone Chronic Insomnia 2003;5(3):5-15. 11. Leger D, Guilleminault C, Bader G, Levy E, Paillard M. Medical and socio-professional impact of insomnia. Sleep 2002;25(6):625-9. 12. Mullington, J. M., Haack, M., Toth, M., Serrador, J., & Meier-Ewert, H. (2009). Cardiovascular, Inflammatory and Metabolic Consequences of Sleep Deprivation. Progress in Cardiovascular Diseases, 51(4), 294–302. http://doi.org/10.1016/j.pcad.2008.10.003. 13. Nagai M, Hoshide S, Kario K. Sleep Duration as a Risk Factor for Cardiovascular Disease- a Review of the Recent Literature. Current Cardiology Reviews. 2010;6(1):54-61. doi:10.2174/157340310790231635. 14. Neckelmann, D. et al., Chronic Insomnia as a Risk Factor for Developing Anxiety and Depression, Sleep. 2007; 30 (7): 873-880. 15. Bubu OM, Brannick M, Mortimer J, Umasabor-Bubu O, Sebastião YV, Wen Y, Schwartz S, Borenstein AR, Wu Y, Morgan D, Anderson WM. Sleep, Cognitive impairment, and Alzheimer’s disease: A Systematic Review and Meta-Analysis.Sleep. 2017 Jan 1;40(1).

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Insomnia in children with ASD (autism spectrum disorder)

Insomnia in children is defined as repeated difficulty with sleep initiation, duration, and consolidation that occurs despite age-appropriate time and opportunity for sleep. Among children with ASD it is quite common: up to 80% of the pediatric ASD population have sleep problems that are less likely to remit with age, compared to only 1-6% of the neurotypical pediatric population. ASD-related…

Insomnia in children with ASD (autism spectrum disorder)

Insomnia in children is defined as repeated difficulty with sleep initiation, duration, and consolidation that occurs despite age-appropriate time and opportunity for sleep. Among children with ASD it is quite common: up to 80% of the pediatric ASD population have sleep problems that are less likely to remit with age, compared to only 1-6% of the neurotypical pediatric population. ASD-related insomnia results in impaired daytime functioning for both child and family, including significantly higher behavioral problems: irritability, social withdrawal, stereotypic behavior, externalizing behavior (hyperactivity and aggression) and internalizing behaviors (anxiety and depression).

The increased frequency of sleep disturbances in children and youth with ASD is attributed also to, inter alia, differences in melatonin metabolism and abnormal melatonin secretion, compared to neurotypical children at the same age.

Why is treatment important?

Quality sleep at any age is essential for good health. In early childhood, when neurodevelopment occurs, poor sleep adversely affects behavior, somatic and mental health, immunity, learning capabilities and memory. In children with ASD, sleep problems are associated with more intense symptoms of autism aggressive behavior, regression, stereotypies and anxiety. Disturbed sleep in a child has also a negative impact on the entire family’s health and well-being; inter alia, it is associated with high levels of caregiver stress, maternal depression and family disorganization, and impairs their proper employment or further education.

Identifying and treating ASD children with insomnia may help to offset some of the potentially detrimental effects of prolonged sleep inadequacy in the developing child, and also benefits the family’s emotional health, reduces economic burdens and improves overall quality of life.

References: 1. Tordjman, S., et al., Day and nighttime excretion of 6-sulphatoxymelatonin in adolescents and young adults with autistic disorder. Psychoneuroendocrinology, 2012; 37(12): p. 1990-7. 2. Hoffman CD. et al., Sleep Problems and Mothers’ Stress. Focus on Autism and Other Developmental Disabilities. 2008;23(3):155-165. 3. Schreck, K.A., J.A. Mulick, and A.F. Smith, Sleep problems as possible predictors of intensified symptoms of autism. Research in developmental disabilities, 2004. 25(1): p. 57-66. 4. Schroder, C. M., et al. Pediatric prolonged-release melatonin for insomnia in children and adolescents with autism spectrum disorders. Expert opinion on pharmacotherapy, 2021.p: 1-10., doi:10.1080/14656566.2021.1959549. 5. Devnani, P.A. and A.U. Hegde. Autism and sleep disorders. J Pediatr Neurosci, 2015. 10(4): p. 304-7. 6. May, T., et al., Sleep in high-functioning children with autism: longitudinal developmental change and associations with behavior problems. Behav Sleep Med, 2015. 13(1): p. 2-18. 7. Owens, J.A. and M. Moore. Insomnia in Infants and Young Children. Pediatr Ann, 2017. 46(9): p. e321-e326.

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Alzheimer’s Disease

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is the leading cause of dementia in the elderly population. Today, more than 5 million Americans and more than 40 million people worldwide are living with Alzheimer’s disease and related dementia, and these numbers are growing rapidly. People progressing to AD develop distressing changes in short term memory, daytime functioning, and behavior, which…

Alzheimer’s Disease

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is the leading cause of dementia in the elderly population. Today, more than 5 million Americans and more than 40 million people worldwide are living with Alzheimer’s disease and related dementia, and these numbers are growing rapidly. People progressing to AD develop distressing changes in short term memory, daytime functioning, and behavior, which worsen over time. In early stage AD, impaired episodic memory is most noticeable.

As populations become increasingly elderly, it is predicted that the number of people affected by early stage AD, progressing to dementia, will almost double every 20 years. By 2050, an estimated 115 million people will have the condition.

Why is treatment important?

The primary neuropathologic criteria for AD diagnosis remain the presence of extracellular β-amyloid deposits as neuritic plaque, and intracellular accumulation of hyperphosphorylated tau as neurofibrillary tangles. Yet, numerous phase 3 clinical trials, aimed at the abnormal production and aggregation of Aβ have failed to improve neuropsychological performance and functional abilities, or to slow disease progression.

Sleep disturbances, accompanied by loss of slow-wave sleep, increase synaptic and metabolic activity and impair the brain’s waste clearance during sleep, ultimately leading to increased production of soluble CSF Aβ, increased Aβ aggregation and attenuation of the Aβ diurnal pattern characterizing AD, exacerbating disease progression.

AD progression increasingly impacts a person’s daily life, reducing their independence until they become entirely dependent on others. Effective treatments for the devastating disease are urgently needed as the world’s population continues to age.

References: 1. Gold CA, Budson AE. Memory loss in Alzheimer’s disease: implications for development of therapeutics. Expert Rev Neurother. 2008;8(12):1879-1891. 2. Duthey, B. Alzheimer disease and other dementias. EU, Universiteit Utrecht; Boston University; World Health Organization.2013. 3. Querfurth HW, LaFerla FM. Alzheimer’s disease. N Engl J Med. 2010 Jan 28;362(4):329-44. 4. Lucey BP, Bateman RJ. Amyloid-β diurnal pattern: possible role of sleep in Alzheimer’s disease pathogenesis. Neurobiol Aging. 2014 Sep;35 Suppl 2:S29-34. 5. Long JM, Holtzman DM. Alzheimer Disease: An Update on Pathobiology and Treatment Strategies. Cell. 2019 Oct 3;179(2):312-339.

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Sleep Apnea

Sleep apnea is characterized by repetitive episodes of significant reduction (hypopnea), or cessation (apnea) of breathing during sleep, leading to recurrent micro-arousals from sleep. Core symptoms include snoring or irregular breathing, daytime somnolence, morning headaches, fatigue and non-refreshing sleep. Apneas and hypopneas are classified as obstructive (OSA) or central (CSA). The disease prevalence of OSA is estimated in the range…

Sleep Apnea

Sleep apnea is characterized by repetitive episodes of significant reduction (hypopnea), or cessation (apnea) of breathing during sleep, leading to recurrent micro-arousals from sleep. Core symptoms include snoring or irregular breathing, daytime somnolence, morning headaches, fatigue and non-refreshing sleep. Apneas and hypopneas are classified as obstructive (OSA) or central (CSA). The disease prevalence of OSA is estimated in the range of 3% to 7%. The prevalence of CSA appears to be between 1.1% to 7.5% in adult males, aged 65 years and older. CSA is characterized by repetitive attenuation or cessation of airflow and decline or absence of ventilatory effort during sleep. Common risk factors for CSA include age (65 years and older), male gender, opioid use, and cardiovascular comorbidity.
Causes of OSA include impaired upper airway anatomy (narrow or crowded collapsible upper-airway), as well as some non-anatomical factors such as impaired pharyngeal muscle function, low respiratory arousal threshold and a hypersensitive respiratory control system.

Why is treatment important?

Frequent breathing interruptions associated with sleep apnea can have severe, long-term health consequences including metabolic disorders, cardiovascular disease, cognitive impairments and depression. While first-line therapy typically includes the use of a CPAP (positive air pressure) device, to provide the patient with constant air pressure, very low compliance increases the urgency of developing new pharmacological approaches.

References: 1. Punjabi, N.M., The epidemiology of adult obstructive sleep apnea. Proceedings of the American Thoracic Society 2008. 5(2): p. 136-43. 2. Ramos, Alberto R et al. Obstructive Sleep Apnea Phenotypes and Markers of Vascular Disease: A Review. Front Neurol. 2017;8:659. 3. Edwards, B.A., D.J. Eckert, and A.S. Jordan, Obstructive sleep apnoea pathogenesis from mild to severe: Is it all the same? Respirology, 2016; 22(1): p. 33-42. 4. Foldvary-Schaefer NR, Waters TE. Sleep-Disordered Breathing. Lifelong Learning in Neurology, 2017. 23(4): p. 1093-1116. 5. Donovan LM, Kapur VK. Prevalence and Characteristics of Central Compared to Obstructive Sleep Apnea: Analyses from the Sleep Heart Health Study Cohort. Sleep. 2016;39(7):1353-1359. 6. Libman, E. et al. CPAP Treatment Adherence in Women with Obstructive Sleep Apnea. Sleep Disord. 2017;2017:2760650. 7. Caples, Sean M et al. Surgical modifications of the upper airway for obstructive sleep apnea in adults: a systematic review and meta-analysis. Sleep, 2010; 33(10): p. 1396-1407. 8. Tordjman, S., et al., Day and nighttime excretion of 6-sulphatoxymelatonin in adolescents and young adults with autistic disorder. Psychoneuroendocrinology, 2012; 37(12): p. 1990-7.

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