Mechanism of action

Disturbances of the sleep-wake cycle and diurnal variation in mood are common symptoms of depression. A role for abnormalities in circadian rhythm in the pathophysiology of depression therefore makes intuitive sense, and has long been explored in treatments such as sleep deprivation and light therapy. ^{Reference Boivin1} However, it is not yet clearly established whether there is a consistent circadian ‘phase-shift’ in patients with major depression or (as seems more likely in this heterogeneous disorder) that some, but not all, patients have variable kinds of circadian disturbances. For example, the pineal hormone melatonin is a reliable marker of circadian rhythm and the activity of the circadian ‘oscillator’ in the suprachiasmatic nucleus (SCN). However, despite many studies it is still not clear whether there are abnormalities in the amplitude and timing of melatonin secretion in patients with depression. ^{Reference Germain and Kupfer2} Nevertheless, it is known that in both animals and humans appropriately timed administration of melatonin has the capacity to shift circadian rhythms, and melatonin is used for this purpose, for example, in delayed sleep-phase syndrome. ^{Reference Pandi-Perumal, Trakht, Spence, Srinivasan, Dagan and Cardinali3}

Agomelatine (N-[2-(7-methoxy-1-napthyl)ethyl]acetamide) is a melatonin analogue, binding with high affinity to MT1 and MT2 G-protein coupled receptors. ^{Reference Millan, Gobert, Lejeune, Dekeyne, Newman-Tancredi and Pasteau4} Melatonin receptors are expressed in numerous regulatory areas of the brain, including the SCN. ^{Reference Pandi-Perumal, Trakht, Srinivasan, Spence, Masetroni and Zisapel5} MT1 activation regulates amplitude of circadian rhythmicity via inhibition of SCN neurons, and MT2 activation is involved in phase-shifts and entrainment of the rhythm. ^{Reference San and Arranz6} Additionally, and distinctly from melatonin, agomelatine is a competitive antagonist at 5-HT_2C and 5-HT_2B receptors, and in animal studies, 5-HT_2C antagonism has the ability to increase noradrenaline and dopamine release in the prefrontal cortex. ^{Reference Millan, Gobert, Lejeune, Dekeyne, Newman-Tancredi and Pasteau4}

The antidepressant effects of agomelatine are claimed to derive from a synergism between its melatonergic and 5-HT_2C actions. Thus results from animal experimental studies of behavioural models of depression show that melatonin or 5-HT_2C antagonists alone are insufficient to produce the full antidepressant activity of agomelatine. ^{Reference Tardito, Molteni, Popoli and Racagni7} Similarly, agomelatine produces an increase in gene expression of brain-derived neurotrophic factor (BDNF) in prefrontal cortex that is not reproduced with melatonin or 5-HT_2C antagonism alone. ^{Reference Molteni, Calabrese, Pisoni, Gabriel, Racagni and Riva8} Brain-derived neurotrophic factor has been implicated in depression and the response to antidepressant therapy. ^{Reference Sen, Duman and Sanacora9}

However, the affinity of agomelatine for 5-HT_2C receptors is significantly lower than its ability to bind melatonin receptors. ^{Reference Millan, Gobert, Lejeune, Dekeyne, Newman-Tancredi and Pasteau4} It is therefore worth noting that there is currently no evidence that at clinically used doses agomelatine blocks brain 5-HT_2C receptors in humans and in fact some evidence to the contrary. ^{Reference Sharpley, Rawlings, Brain, McTavish and Cowen10} In contrast, the melatonergic action of agomelatine has been supported by small healthy volunteer studies in humans which indicate that agomelatine can phase-alter the timing of circadian rhythms. For example, a double-blind placebo study of eight healthy young men showed that agomelatine given at 18.00h produced phase advancement as demonstrated by an earlier drop in core body temperature equivalent to melatonin administration. ^{Reference Krauchi, Cajochen, Mori, Graw and Wirz-Justice11} In a group of older men, 15 days of agomelatine administered at 18.30h phase-advanced the drop in core body temperature by 1.5-2 h, but without significantly affecting any sleep parameters including rapid eye movement (REM) sleep. ^{Reference Leproult, Van Onderbergen, L'hermite-Balériaux, Van Cauter and Copinschi12}

Dose and pharmacokinetics

The starting dose of agomelatine is 25 mg taken at ‘bedtime’, increasing to 50 mg if indicated after 2 weeks. ¹³ Agomelatine is well absorbed after oral administration but subject to extensive first-pass metabolism, which causes significant variation in drug plasma levels between individuals. Peak plasma levels occur within 1-2 h after ingestion and the terminal half-life of the drug is also between 1 and 2 h. Therefore, accumulation of agomelatine does not occur. Agomelatine is metabolised in the liver by CYP1A2 and should therefore not be given with potent CYP1A2 inhibitors such as ciprofloxacin and fluvoxamine. Caution is recommended when using agomelatine with moderate CYP1A2 inhibitors such as propranolol and oestrogens. Conversely, smoking induces CYP1A2 activity and can lower agomelatine levels (www.medicines.org.uk/EMC/medicine/21830/SPC/Valdoxan).

Indications

Agomelatine is licensed by the European Medicines Agency for the treatment of major depressive episodes in adults. There is currently insufficient randomised trial evidence to consider agomelatine in treatment-resistant depression or in bipolar depression, although some open case series are available.

Clinical effects and efficacy

Although narrative reviews of the efficacy of agomelatine emphasise its superior efficacy relative to placebo and certain other antidepressants such as sertraline and fluoxetine, ^{Reference Hickie and Rogers14} formal meta-analyses have found these effects to be less convincing ^{Reference Singh, Singh and Kar15,Reference Barbui and Cipriani16} and of uncertain clinical significance. For example, Singh et al ^{Reference Singh, Singh and Kar15} examined 9 double-blind randomised controlled trials of 3943 patients with major depression in which agomelatine was compared with either other antidepressants or placebo. In pooled analyses, agomelatine was significantly but marginally better than placebo (standardised mean difference in depression rating scales of –0.26). Data from five trials on 1698 patients showed again marginal superiority of agomelatine over the aggregated results of other antidepressants (fluoxetine, paroxetine, sertraline and venlafaxine) but not over any of the other agents examined individually. However, clear separation from placebo is not a problem unique to agomelatine among new antidepressants, perhaps partly because of the methodological difficulties involved in placebo-controlled, regulatory trials. ^{Reference Rihmer, Dome, Baldwin and Gonda17}

In one study, agomelatine appeared effective in the maintenance treatment of depression, although in two other studies a positive effect could not be demonstrated. ^{Reference Hickie and Rogers14}