European Neuropsychopharmacology (v.16, #S5)

The essential linkage of sleep disturbance and clinical depression has long been recognized. Almost all patients with major depression report some form of sleep difficulty including insomnia, oversleeping, and poor-quality sleep. Some have argued that these changes in the sleep-wake cycle are actually aspects of a more fundamental alteration in circadian rhythms. Antidepressants that reduce restless sleep and awakenings and improve daytime alertness are desirable. It also appears that compounds that “rearrange” the intensity of rapid eye movement and slow-wave sleep may provide the best clinical effects on sleep besides antidepressant clinical efficacy. Agomelatine, a new antidepressant with melatonergic activity and 5-HT2c antagonist properties, has shown its efficacy in major depression. Beyond this antidepressant efficacy, agomelatine demonstrates sleep electroencephalographic changes consistent with desirable sleep architecture improvements, as well as improved subjective sleep quality within the first week of administration accompanied by an improvement in daytime alertness.
Keywords: Delta sleep; REM sleep; Sleep continuity disturbance;

Agomelatine is a new antidepressant with an innovative pharmacological profile. It is a potent melatonergic agonist (MT1 and MT2) and also has 5-HT2c antagonist properties. Agometatine's efficacy in treating major depressive disorder (MDD) was first described in a placebo-controlled, dose-ranging study with paroxetine as a validator. In a recent placebo-controlled study, 212 MDD patients were randomly assigned double-blind to receive placebo or agomelatine 25 and 50 mg/day. There was a significant advantage for agomelatine after 6 weeks according to scores on the Hamilton Depression Rating Scale (HAM-D) (P = 0.026) and the Clinical Global Impression Severity (P = 0.017), with an improved response rate (P = 0.03). Robust evidence of agomelatine's efficacy in severe depression comes from analysis of a patient subgroup with baseline HAM-D scores >25. Analysis of pooled data from three different trials confirmed this observation and suggested that the agomelatine-placebo difference tends to increase with the severity of depression. Results suggest favorable tolerabitity of agomelatine compared with a serotonin and noradrenaline reuptake inhibitor, and agomelatine is associated with less sexual side effects that are troublesome with some antidepressants. As predicted from its pharmacological profile, agomelatine improves sleep quality without associated daytime drowsiness. Agomelatine was also shown not to induce a discontinuation syndrome. Agomelatine may fill the gap in the current therapeutic armamentarium by combining efficacy with a favorable tolerability profile and additional clinical benefits.
Keywords: Major depressive disorder; Agomelatine; Melatonergic agonist; Paroxetine; Venlafaxine; Severe depression; Sexual dysfunction; Daytime alertness; Discontinuation syndrome;

Most antidepressant drugs act not only on molecular targets directly responsible for their expected therapeutic action (monoamine transporters, monoamine oxidase A, presynaptic inhibitory auto and hetero-receptors), but also on secondary targets at the origin of side effects. In particular, tricyclic antidepressants, which inhibit serotonin and/or noradrenaline reuptake, are most often endowed with antagonist properties at histamine H1, muscarinic and α1-adrenergic receptors, thereby causing sedation, body weight gain, constipation, memory disorders, orthostatic hypotension, etc. The selective monoamine reuptake inhibitors are better tolerated because they are generally devoid of such secondary effects. However, through the indirect promotion of serotonin action at specific receptors, they unavoidably produce some gastrointestinal, sleep and sexual disorders. Agomelatine markedly differs from other classes of antidepressant drugs: its primary molecular targets in vivo are the melatonin MT1 and MT2 receptors, where it acts as a potent agonist, and the 5-HT2c receptors, where it exerts clear-cut antagonist properties. The unique pharmacological profile of agomelatine explains its antidepressant efficacy and good tolerability.
Keywords: Antidepressants; Agomelatine; Monoamine; transporters; Monoamine receptors; Side effects;

A review of antidepressant treatments today by Sidney H. Kennedy (S619-S623).
Major depressive disorder (MDD) is defined in a manner that overlooks the heterogeneous nature and high rate of comorbidity. The similitude between depressive symptomatology and the side-effect profile of available antidepressants further complicates the treatment of MDD. Weight gain, sexual dysfunction, cognitive impairment and disruption of sleep patterns are the most commonly reported side effects leading to discontinuation.
Keywords: Major depressive disorder; Antidepressants; Side effect burden; Sexual dysfunction; Sleep disruption; Weight gain;

Editorial by Stuart A. Montgomery (v).