Editorial [Hot Topic: New Antidepressant Drugs: Beyond Monoaminergic Mechanisms (Executive Editors: Cecilio Alamo and Francisco Lopez-Munoz)]

Depression constitutes one of the most prevalent psychiatric disorders in our society. According to the World Health Organization (WHO), some 121 million people are currently suffering from depression, with an annual prevalence of 5.8% for men and 9.5% for women [1]. However, these figures may vary according to the population studied and the criteria or diagnostic instruments used. A recent study carried out in 6 European countries found that prevalence over the life course was 12.8% in the case of major depression and 14% for any depressive disorder (9.5% in men and 18.2% in women) [2]. Depression is the leading cause of disability as measured by Years Lived with Disability (YLDs), and was the fourth greatest contributor to the global burden of disease in 2000. By the year 2020, depression is projected to reach second place in the ranking of Disability Adjusted Life Years (DALYs) calculated for all ages and both sexes. Today, depression is already the second cause of DALYs in the age category 15-44 years for the two sexes combined [3]. With respect to the treatment of depression, the introduction by serendipity of iproniazid, the first monoamine oxidase inhibitor (MAOI), and imipramine, pioneer of tricyclic antidepressants, in the 1950s (“the psychopharmacological revolution decade”) substantially modified the conceptualization of the therapeutic approach, contributing to a reduction in the suffering of patients who previously went untreated, or were treated with archaic and dangerous biological therapies, often in conditions of institutionalization [4]. Moreover, these agents have constituted an indispensable research tool for neurobiology and psychopharmacology, permitting, among other things, the postulation of the first aetiopathogenic hypothesis of depressive disorders: “the monoamine hypothesis of depression”. As we have shown in our review (Francisco Lopez-Munoz and Cecilio Alamo, University of Alcala, Spain) [5], in the last 50 years the monoamine hypothesis has been the pharmacological target for the treatment of depression. The introduction of the so-called atypical, heterocyclic or “second generation” antidepressants (maprotiline, nomifensine, trazodone, mianserine, among others) in the 1970s, and the development and clinical introduction of the third generation of antidepressants, represented by selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, sertraline, citalopram and paroxetine, in the late 1980s, once again revolutionized therapy for depression. Furthermore, they opened the way for new families of antidepressants: norepinephrine reuptake inhibitors (NARI), reboxetine, or dual-acting serotonin norepinephrine reuptake inhibitors (SNRI), venlafaxine and more recently duloxetine. Nevertheless, all of them, including the presynaptic receptor antagonist mirtazapine, continue to employ the same action mechanism as the classic drugs, that is, the modulation of monoaminergic neurotransmission at a synaptic level [6]. Given that all the antidepressants initiate their effect with a monoaminergic increase at the synaptic cleft, this may condition their action onset, generally more than 3-4 weeks, as well influencing their lack of effectiveness in approximately 30% of patients with major depressive disorder (MDD). In this regard, recent advances involving the new agents has been based not so much on important distinctions from the point of view of therapeutic effectiveness (in some it is not even as high as for the classic drugs), as on a different profiles of adverse side effects and the greater confidence they inspire on the part of general practitioners [3]. Nevertheless, in spite of these advantages, problems in the treatment of depressive patients have not been solved completely, and there is still considerable need for safer, faster-acting and more effective agents that go beyond the “solely monoaminergic” perspective [7].