Have you heard the news? Not only is there a novel anti-depressant with a "unique" mechanism of action on the horizon, it is also more effective than Prozac and with none of the side-effects! (1) What is this new wonder drug? Is it truly the ideal anti-depressant? (2) The new drug is agomelatine (Valdoxan, 3). The questions that should be asked are, does it really live up to the hype? Or is the hype just a marketing ploy?
First, the boring stuff.
Agomelatine is a potent agonist of melatonin receptors MT1 and MT2 (same as Rozerem). Moreover, it is an antagonist (i.e., blocker) of the serotonin 5HT-2c receptor. Agomelatine is metabolised by the liver and excreted mainly in urine. The drug's half-life (i.e., time it takes to eliminate half of the compound) is 2.3 hours.
The drug is theorized to work in two ways. First, its actions at the MT1 and MT2 receptors are supposed to help "reset" circadian rhythms and improve sleep architecture. That seems simple enough, as melatonin is freely bought at any drug store; however, whether people with depression have a true circadian rhythm disorder (e.g., delayed sleep phase syndrome) or if their insomnia (or hypersomnia) is connected to another biological mechanism (hyper-or-hypo-cortisolism) is a matter of debate (My bias is with the latter theory).
The second mechanism is antagonism of the 5HT-2c receptor. This particular serotonin receptor is a post-synaptic receptor that is mainly found in the choroid plexus (4), cerebral cortex (5), globus pallidus (6), substantia nigra (7), and spinal cord (8). Drugs that affect the 5HT-2c receptor represent a subclass of anti-depressant known as norepinephrine/dopamine disinhibitors (NDDI).
According to psychopharmacology god Stephen Stahl, "Serotonin action at 5HT-2c receptors inhibits both NE and DA release...Drugs that block 5HT-2c receptors have the opposite action and thus disinhibit both NE and DA release." Keep in mind that is has only been demonstrated in rats. It is much harder to prove in humans. Stahl also notes that, "...this action is generally activating and may be why many patients, even from the first dose, detect an energizing and fatigue-reducing effect."
Did anyone pick-up on the drug's paradoxical mechanism of action? It is both a sedative-hypnotic and activating-energizing. I'm not sure how that works out when the drug is supposed to be taken at night (Any patient testimonials?). Also, as Neuroskeptic pointed out to me, "it is also very rapidly metabolised so if you take it at night there's probably none left by the next day..." With a half-life of 2.3 hours, most (but not all of the drug) will have been excreted by the time you wake-up in the morning and almost completely gone by next dosing time.
All anti-depressants have pretty lengthy half-lives (minus paroxetine), and a steady-state blood level is required for the drug to have a consistent effect. Usually it is the rapid shift in blood levels that contribute to side-effect severity (hence paroxetine's problems). With such a short half-life, can this drug truly be more effective? Is our current paradigm of how previous anti-depressants work just plain wrong?
Sleep and Depression
Now, more boring stuff.
Will this drug's action at the MT1 and MT2 receptors contribute to its overall efficacy? I have not been able to find any published studies utilizing polysomnography to measure its effects. Why is it important to test this drug with a polysomnograph? Here are some of the sleep findings in pateints with depression:
Depression is associated with a relative increase in central cholinergic activity compared with monoaminergic activity (i.e., serotonin); cholinergic systems reduce short-wave sleep (SWS) and increase REM sleep.
Initial insomnia is inversely proportional to age: the young do not fall asleep easily and complain of initial insomnia; older adults have trouble with sleep maintenance and complain of early morning awakening.
REM sleep abnormalities may persist after successful treatment of depression; short REM latency and SWS deficits can be familial and are found in relatives of depressed patients who do not have depression. Also, depressed individuals have increased sleep fragmentation; their sleep is unstable.
You might think it wise to discover if the drug actually benefits depressed people by resolving at least some of these problems. We'll see if any of the research addresses these issues.
Another MT1 and MT2 agonist drug on the market, Rozerem (ramelteon) is not very effective. According to the medical letter: "Ramelteon (Rozerem), a melatonin receptor agonist, is not a controlled substance and apparently has no potential for abuse, but its hypnotic effect is not impressive. In clinical trials, it produced small, statistically significant improvements in sleep latency, but had little effect on sleep maintenance." The two drugs have similar melotonin properties and half-lives (2.3 hours versus 2.6 hours) Also, it should be noted that depression associated insomnia is distinct from primary insomnia (i.e., psychophysiological insomnia). Typically, people who have insomnia that is a manifestation of a primary psychiatric illness tend not to respond well to the hypnotic class of drugs. As mentioned-above, the drug is somehow both sedating and activating. It's hard to tell how that will affect sleep quality as well.
In the real world, it is unlikely this property (i.e., MT1 & MT2 agonism) will have a clinically meaningful effect.