A 2010 review written by F. Lopez-Munoz and co-workers published in "Revista de Neurologia" nicely described the history and profile of melatonin. That's a hormone released from the pineal gland primarily at night. This neuromodulator plays a unique role in human physiology and behavior because it can penetrate every cell in the body. Yet its main target are hypothalamic structures deep in the brain. The pineal gland and the suprachiasmatic nucleus form a circuit which regulates bodily rhythms. Foremost among these rhythms is the sleep-wake schedule. Three new medications, specifically designed to affect the melatonin pathway, are safe and effective sleep aids.
Ramelteon
Ramelteon is the first melatonin agonist marketed as a sleep aid. Approved in 2005, it's sold under the trade name of Rozerem by Takeda Pharmaceuticals. This facilitator selectively binds to melatonin receptors in the suprachiasmatic nucleus. Thus it has direct access to the body-rhythm circuit described above. Ramelteon typically decreases sleep onset latency and increases total sleep time in people with insomnia. For example, a 2009 study by S. Wang-Weigand and associates published in "Current Medical Research in Opinion" showed a 13 minute reduction in the latency to persistent sleep in chronic insomniacs. The drug was well tolerated in this study. That's not surprising given that melatonin agonists are not associated with the overdose and dependence issues commonly found with other sleep aids such as barbiturates and benzodiazepines.
In fact, ramelteon is currently the only noncontrolled substance marketed for insomnia. Yet a 2005 review by A. D. Krystal presented in the "Journal of Family Practice" mentioned concerns about the agonist increasing cancer, birth defects, and hyperprolactinaemia. Yet these effects were only apparent at unusually large doses. Using the recommended amounts, a 2009 experiment by G. S. Richardson and colleagues published in the "Journal of Clinical Psychiatry" revealed no adverse effects after 1 year of intake by older adults with chronic insomnia.
Tasimelteon
Ramelteon is the only pineal-gland facilitator approved by the Food and Drug Administration. Yet a similar drug called "tasimelteon" is currently under investigation. Invented in 2003, this medication is also known as "BMS-214778" and "VEC-162" and it is being marketed by Bristol-Myers Squibb. A 2009 study by S. M. W. Rajaratnam published in "Lancet" tested the effects of tasimelteon in an artificial model of insomnia. Subjects experienced a rapid advance of sleep-wake schedule and then were forced to sleep after being given drug or placebo.
Results indicated that tasimelteon improved sleep latency, sleep efficiency, and sleep maintenance relative to placebo. In addition, the drug appeared to work through biological-clock mechanisms as endogenous time was shifted by tasimelteon. Untoward effects did not differ between the two conditions suggesting that the melatonin agonist was safe and effective.
Agomelatine
The third melatonin agonist currently being tested for potential soporific effects is called "agomelatine". Developed in 2005, this drug is marketed by Servier Laboratories under the trade names of "Valdoxan", "Melitor", and "Thymanax". The European Union approved the sale and use of agomelatine in 2009. This agonist was developed as an antidepressant given the likely role of the melatonin pathway in affective illness. For example, a 2010 paper by A. J. Lewy and associates offered in "Sleep Medicine Clinics" described the role biological clocks play in winter depression.
Agomelatine in known to improve mood and enhance sleep. M. A. Quera-Salva and colleagues (2010) tested the effects of agomelatine on wake and rest in patients with depression. The results of this study were published in "Human Psychopharmacology" and indicated that agomelatine improved nighttime sleep and increased daytime functioning. Some concerns have been voiced about the safety of agomelatine. Yet, a 2010 experiment by R. H. McAllister-Williams and co-workers presented in "Human Psychopharmacology" suggested that the drug is safe, although liver function tests are required.
References
- "Revista de Neurologia"; Historical background of the pineal gland...; F. Lopez-Munoz et al.; January 2010
- "Current Medical Research and Opinion"; Effects of ramelteon...; S. Wang-Weigand et al.; May 2009
- "Journal of Family Practice"; Hypnotic agent targets delayed sleep onset; A. D. Krystal; November 2005
- "Journal of Clinical Psychiatry"; Safety and subjective sleep effects of...; G. S. Richardson et al.; April 2009
- "Lancet"; Melatonin agonist tasimelteon (VEC-162) for...; S. M. W. Rajaratnam et al.; February 7, 2009
