Tuesday, August 20, 2013

Melatonin Receptor-Based Antidepressant Therapy in USA?

Self-medication is not the best way of dealing with a severe form of depression. Various psychoactive natural compounds are typically used in this potentially harmful practice. These compounds range from alcohol to over-the-counter products including the hormone melatonin. Hormonal therapies are best suited for the replacement of pathologically low or missing levels of endogenous hormones; using insulin to treat diabetes is a good example. It's difficult to make a simple and convincing case for the use of melatonin replacement therapy - too many miracle cures have already been associated with melatonin. Possibly the best use of this hormone would be to regulate sleep patterns or to prevent jet lag. But could melatonin be therapeutic for conditions such as severe depression? No clinical data are available to conclusively support the use of melatonin in antidepressant therapy. However, clinical results suggest that melatonin receptors may be involved.

A search for clinical trials with melatonin in the U.S. Government-sponsored database called ClinicalTrials.gov on June 7, 2011 revealed 128 studies. Most of these trials have been designed to explore the effects of melatonin supplementation on sleep. None of them investigated melatonin supplementation in the treatment of depression. One study measured melatonin levels in the blood of patients with major depressive disorder, and a couple of studies investigated the effects of light therapy in depression and measured melatonin levels in treated subjects. This is in a stark contrast to the number of clinical trials with a drug that stimulates melatonin receptors, a target considered to be specific for the cellular actions of melatonin. The compound in case, agomelatine, has been approved in Europe for treatment of depression and is now being investigated in the U.S.

How would melatonin receptors work to alleviate symptoms of severe depression? Imagine for a moment you've just won a huge Mega Millions jackpot and you've bought yourself a mansion. It's a huge castle with lots of doors, each with at least one lock and some with several. These locks are the melatonin receptors. There are two main types of these receptors, MT1 and MT2. You've also got the master key, melatonin, which opens both types of locks. To the in-laws who poured in to visit as soon as they'd heard of your fortune you only give keys to certain locks, the MT1 or the MT2, so you can keep some privacy. For the special room in which you keep your most valued possessions, you have an additional layer of security, a door equipped not only with both MT1 and MT2 locks, but also with an unusual lock, the serotonin receptor called 5-HT2C. To open this door, the 5-HT2C lock must be locked at the same time you are using the master key to unlock the MT1 and MT2 locks. Quite a task!

Apparently, you can do the same to your brain 5-HT2C, MT1, and MT2 receptors by taking agomelatine, a drug that acts simultaneously on the MT1 and MT2 melatonin receptors (as their agonist) and on the 5-HT2C serotonin receptors (as their antagonist). Scientists believed that this simultaneous manipulation of brain melatonin and 5-HT2C serotonin receptors reduces the symptoms of major depression. According to this concept, using melatonin only would not produce the same effect.

In their article The Pattern of Melatonin Receptor Expression in the Brain may Influence Antidepressant Treatment, Dr. Eric Hirsch-Rodriguez and colleagues from the Department of Psychiatry at the University of Illinois at Chicago described how the presence of melatonin receptors such as MT1 and MT2 in different brain areas changes over time and can be affected by illness and drug treatment. For example, prolonged treatment with classical antidepressants changes the content of the MT1 and MT receptors. These investigators suggested that melatonin or drugs based on melatonin would produce antidepressant effects only if an optimal amount and brain distribution of melatonin receptors are available for drug action and that clinical trials with such drugs would need to take into consideration the characterization of patients' melatonin receptors.

Agomelatine, the first melatonin receptor-based antidepressant, is currently being clinically evaluated for approval for use in U.S. On June 7, 2011, ClinicalTrials.gov listed 9 clinical trials (one has been withdrawn) with agomelatine. Seven of these trials are investigating the use of agomelatine in the treatment of major depressive disorder. Their outcome along with the experience from the ongoing use of agomelatine in Europe may decide the future of melatonin receptor-based therapy on health improvement for U.S. patients with major depression.

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