Agomelatine – The dawn of a new regime to treat depression with a remarkable safety profile

Depression and its treatment is a hugely complex area. It is a serious, chronic illness that can be extremely debilitating. It’s more than just feeling a bit low, stressed or sad. Rather it’s a pervasive mental health problem that can often make it hard for the sufferer to function every day.

The facts about depression

Depression can manifest itself through a whole range of symptoms. For example a person suffering from depression may start to distance themselves from friends and family, they may be reluctant to join in activities they previously enjoyed, they may lose interest in food, sex, exercise and other pleasurable activities, they may feel increased physical pain and become fatigued, they may experience sleeping problems, start to take unnecessary risks and drink more alcohol.

Whatever the symptoms and whatever the cause someone suffering from depression needs help if they are to successfully recover.

And not only is depression debilitating, it is one of the most common of all mental health problems affecting around 1 in 5 people at some stage of their lives. It can exact a huge toll on both a country’s health and productivity. According to the findings of a review carried out by Mental Health America in 2007, more than 21 million American children and adults are annually affected by depression and it is the leading cause of disability in the United States for individuals ages 15 to 44. Lost productive time among U.S. workers due to depression is estimated to be in excess of a staggering $31 billion per year(1).

Over the years drug companies have invested millions of dollars into the development of antidepressants. Older style antidepressants such as amitriptyline and clomipramine (both belonging to a class of antidepressants known as tricyclic antidepressants) have fallen out of popularity in favour of newer medications such as Prozac® (fluoxetine) and Seroxat® (paroxetine). The latter two are selective serotonin reuptake inhibitors (SSRIs) because these newer drugs tend to be as effective but with fewer side effects. Indeed, when SSRIs were first introduced in the late 1980s they were hailed as wonder drugs and today they are now prescribed as the first line therapy for depressive illness(2). But even though these newer drugs have been able to offer advantages over their older counterparts, antidepressants still aren’t what they should be.

Unfortunately, many antidepressants don’t work as well as we would like them to. It is generally accepted that about 50-70% of patients receiving SSRIs respond satisfactorily although in meta-analyses, the tricyclic antidepressants still tend to emerge as more effective, especially when the illness is severe(2). Indeed, in a recent analysis of studies into the effectiveness of SSRIs published in the US journal “Public Library of Science Medicine”, SSRIs were only really found to be effective for people with severe forms of depression. The analysis concluded that the response of people with milder forms of depression to SSRIs was the same as those receiving a placebo(3)!

What’s more, antidepressants often come with a whole host of side effects some of which can be fairly significant which isn’t much good for someone already battling such a debilitating illness as depression. For example if you take tricyclic antidepressants you may experience constipation, bladder problems, your sexual functioning may become impaired, your heart rate may increase and you may feel drowsy during the day - and these are just some of the more common side effects. Even SSRIs, which are undoubtedly better tolerated than tricyclics, may cause such things as sleep disturbances, sexual problems, lethargy and fatigue and weight gain. In addition, patients run the risk of developing serotonin syndrome - a very dangerous and potentially lethal side effect (4).

Perhaps one of the main criticisms levelled at antidepressants is that they can be very hard to quit. Discontinuation reactions can occur with all types of antidepressants when a patient seeks to stop treatment. For example, with SSRIs the most common discontinuation complaints include dizziness, light-headedness, gastro-intestinal disturbances, anxiety, sleep impairment and headaches(2).

Bearing all the above in mind, it’s easy to see why drug companies have continued to drive forward research into developing better and more effective antidepressants. And we now stand at the dawn of the next generation of antidepressants. Enter Agomelatine - a completely new and innovative way of treating this devastating disease that may change how depression is treated.

What is Agomelatine?

Agomelatine (trade names Valdoxan) is an antidepressant that belongs to a class of drugs known as norepinephrine dopamine disinhibitors (NDDIs). It is unique because not only does Agomelatine target serotonin pathways, it also affects melatonin making it the first melatonergic antidepressant.

What is Melatonin and why is it important?

Melatonin, also known chemically as N-acetyl-5-methoxytryptamine, is a naturally occurring hormone that plays an important role in sleep and the regulation of our body cycles (often referred to as circadian rhythms). Circulating levels of melatonin vary in a daily cycle.

Melatonin is produced by pinealocytes in the pineal gland - a small gland about the size of a pea that is located in the centre of the brain but outside of the blood brain barrier - from the amino acid tryptophan. The synthesis and release of melatonin are stimulated by darkness and suppressed by light with the production of the hormone coming under the direct influence of the suprachiasmatic nuclei (SCN) of the hypothalamus which act as the body’s master clock. The SCN receive information from the retina about the daily pattern of light and darkness. Each evening as it begins to go dark, the increase in melatonin production and secretion is known as Dim-Light Melatonin Onset (DLMO). As levels increase, melatonin chemically causes us to feel drowsy and lowers our body temperature. Peak secretion and blood levels of melatonin occur in the middle of the night, and gradually fall away during the second half of the night. Because of its increased night levels, melatonin is sometimes called “the hormone of darkness”.

Because of its relationship with sleep patterns and circadian rhythms, melatonin is used to treat a number of conditions, particularly sleep related disorders and has already become an accepted therapy for a depressive condition known as seasonal affective disorder.

The importance of sleep

Sleep is vitally important to our health and well being. Sleep is the time when our brains and our bodies recharge themselves in readiness for the next day. Disrupted or poor quality sleep can have an enormous impact on our lives affecting our mood, energy level, concentration and overall functioning(5).

Unfortunately disrupted sleep patterns and circadian dysfunction are common symptoms of depression. Disrupted sleeping patterns can play havoc in even the healthiest of people so it is not hard to see how it can exacerbate a condition like depression. And if you are not consistently getting a quality night's sleep, your depression cannot be fully treated(5).

As there is large prevalence of circadian dysfunction and disrupted sleep patterns associated with depression, the development of Agomelatine, with its melatonergic agonist properties, has evolved into a new, exciting and innovative way of treating depression.

The development of Agomelatine

Agomelatine really is at the cutting edge of treatments for depression. It was developed by the pharmaceutical company Servier and has recently become approved in some European countries under the trade name Valdoxan.

How does Agomelatine work?

Agomelatine appears to act in the following ways within the human body:

First of all, as mentioned above, it belongs to a class of drugs known as NDDIs. As an NDDI, Agomelatine works as a 5HT2C antagonist. 5HT2C receptors are normally activated by the neurotransmitter serotonin. Neurotransmitters are chemicals that act as the brain’s messenger service allowing communication between neurons. When activated 5HT2C receptors cause anxiety, social anxiety, depression, and compulsive behaviours. It is thought that a significant portion of depressed, anxious, and socially anxious individuals may have an over-activity of 5HT2C receptors in their brains. Because of its antagonistic properties towards 5HT2C receptors i.e. it blocks these receptors, Agomelatine causes a rise in both dopamine and norepinephrine levels in many areas of the brain. This makes Agomelatine an effective antidepressant.

Dopamine and norepinephrine are both neurotransmitters. It is already well established that these neurotransmitters are associated with depression with research clearly suggesting that abnormalities in the activity of these neurotransmitters can affect both mood and behaviour. Although the exact nature of why increasing levels of dopamine and norepinephrine helps to alleviate depression is not yet fully understood, what appears to happen is that by increasing their levels, then ‘neurotransmission’ (the sending of nerve impulses) is enhanced which in turn improves and elevates mood.

Agomelatine is also known to be a potent agonist at melatonin receptors and it is this action that makes it unique – indeed Agomelatine is the world’s first melatonergic antidepressant. As a melatonin receptor agonist, Agomelatine binds to cellular melatonin receptors (both MT(1) an MT(2) receptors located primarily in the SCN (see above)), triggering a cellular response that in effect mimics the action of naturally occurring melatonin. Indeed, these receptors are normally activated by natural melatonin.

And because of Agomelatine’s unique pharmacological profile with its action upon melatonin receptors, studies have shown that Agomelatine demonstrates a significant improvement in sleep quality in depressed patients without causing daytime drowsiness(6), by rapidly regulating the sleep-wake cycle. This is undoubtedly a very important feature of Agomelatine. As French researchers noted: “the ability of an antidepressant to relieve sleep complaints with no sedative effects is a key advantage because sleep complaints are a major presenting feature of depression”(7). By positively influencing disturbed circadian rhythms which are all too often found in those suffering from depression, Agomelatine significantly improves all phases of disturbed sleep as well as the overall quality of sleep which is of huge benefit to daytime alertness.

Finally, Agomelatine has also demonstrated anxiolytic properties. An anxiolytic drug (sometimes called an anti-panic or anti-anxiety agent) is a drug used for the treatment of the symptoms of anxiety. Agomelatine anxiolytic properties “bear a striking resemblance to those of selective 5-HT(2C) receptor antagonists”(8). Agomelatine may, therefore, also prove useful in the treatment of anxiety disorders.

Advantages of Agomelatine over conventional treatments

Initial research into the efficacy of Agomelatine has shown that it is at least as effective as already existing antidepressants. In controlled human studies into the treatment of major depression, it compared favourably with two SSRI antidepressants sertraline (Lustral®, Zoloft®) and paroxetine (Seroxat®, Paxil®). Results of these studies demonstrated comparable efficacy rates of 55-62%. Interestingly, although Agomelatine demonstrates antidepressant efficacy in patients experiencing moderately depressive episodes, its treatment efficacy appears to increase with the severity of the disease(8).

But the unique pharmacological profile gives Agomelatine a distinct advantage over pre-existing SSRI antidepressants. Expectations surrounding the use of antidepressants go beyond simply whether it is effective in treating the disease. Tolerability and safety are as important. As previously discussed, even SSRIs carry with them the risk of developing a whole host of side effects some of which are significant and may potentially be very dangerous. Agomelatine, on the other hand, has an excellent safety profile. It is very well tolerated and, in sharp contrast to most SSRIs and other antidepressants, it has not been associated with side effects such as weight gain, sexual problems or sleep disturbances. Indeed, some patients taking Agomelatine have said that it gives them the best sleep that they have ever had. This remarkable safety profile is perhaps one of the most exciting things about Agomelatine.

Another problem with other antidepressants has been the issue of discontinuation. Some antidepressants can become addictive and are notoriously hard to quit. For example, SSRI withdrawal syndrome can mean that some patients suffer such intolerable discontinuation reactions, that they find it extremely hard to stop using the drugs. Symptoms of SSRI withdrawal syndrome can include sweating, nausea, insomnia, electric shock-like sensations, dizziness, tremor, confusion, and vertigo. Agomelatine does not appear to cause any withdrawal syndrome. In a double-blind, placebo-controlled trial set up to investigate the effects of abruptly stopping Agomelatine treatment, no discontinuation symptoms were observed(8). This makes Agomelatine a much attractive proposition when it comes to the treatment of depression.

In conclusion, Agomelatine heralds the dawn of a new age in the treatment of depression. With its unique pharmacological construction, it offers a novel approach to treating an age old illness with the not inconsiderable advantages of efficacy, even in the case of severe depression, combined with an extremely favourable side-effect profile, the hugely significant benefit of sleep regulation and the absence of any withdrawal symptoms.

Dosage
Antidepressant efficacy has been demonstrated in the treatment of major depressive disorder (MDD) at a dose of 25 mg/day taken before bedtime. If necessary, after two weeks the doses can be increased to 25mg twice daily.

Side effects
Although Agomelatine has an extremely favourable side effect profile and appears to be very well tolerated, it may, as with all medicines, cause side effects. The most common adverse effects reported with Agomelatine are headache, nasopharyngitis, and gastrointestinal complaints(6).
The British National Formulary (the UK’s equivilant of Americans Physician’s desk reference) notes the following side effects/ contraindications: mania or hypomania; avoid use of concomitant use of drugs associated with hepatic injury; avoid excessive alcohol consumption; avoid use in renal impairment and despite a lack of significant reporting in the clinical studies- to monitor liver function before treatment and after 6, 12 and 24 weeks of treatment, then if appropriate to discontinue if serum transaminases (liver enzymes) exceed 3 times the upper limit of reference range).

References

1. Mental Health America. Ranking America's Mental Health: An Analysis of Depression Across the States. http://www.mentalhealthamerica.net/go/state-ranking
2. Masterton G. The pros and cons of SSRI antidepressants. May 2003. Published online http://behindthemedicalheadlines.com/articles/the-pros-and-cons-of-ssri-antidepressants
3. Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLoS Med 5(2): e45. doi:10.1371/journal.pmed.0050045
4. Clinical Psychiatry News 26(5):1, 1998
5. Melin G.J. Quality sleep helps treatment. May 2008. Published online http://www.mayoclinic.com/health/depression-and-sleep/MY00054
6. Dolder C R, Nelson M, Snider M. Agomelatine Treatment of Major Depressive Disorder The Annals of Pharmacotherapy. Published online 25 November 2008. www.theannals.com, DOI 10.1345/aph.1L296
7. Rouillon F. Efficacy and tolerance profile of Agomelatine and practical use in depressed patients. Int Clin Psychopharmacol. 2006 Feb;21 Suppl 1:S31-5
8. Kasper S, Hamon M. Beyond the monoaminergic hypothesis: Agomelatine, a new antidepressant with an innovative mechanism of action. World J Biol Psychiatry. 2009 Mar 2:1-11