Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

The past decade of efforts to find improved treatment for major depression has been dominated by genome-driven programs of rational drug discovery directed toward highly selective ligands for nonmonoaminergic agents. Selective drugs may prove beneficial for specific symptoms, for certain patient subpopulations, or both. However, network analyses of the brain and its dysfunction suggest that agents with multiple and complementary modes of action are more likely to show broad-based efficacy against core and comorbid symptoms of depression. Strategies for improved multitarget exploitation of monoaminergic mechanisms include triple inhibitors of dopamine, serotonin (5-HT) and noradrenaline reuptake, and drugs interfering with feedback actions of monoamines at inhibitory 5-HT1A, 5-HT1B and possibly 5-HT5A and 5-HT7 receptors. Specific subsets of postsynaptic 5-HT receptors mediating antidepressant actions are under study (e.g., 5-HT4 and 5-HT6). Association of a clinically characterized antidepressant mechanism with a nonmonoaminergic component of activity is an attractive strategy. For example, agomelatine (a melatonin agonist/5-HT2C antagonist) has clinically proven activity in major depression. Dual neurokinin1 antagonists/5-HT reuptake inhibitors (SRIs) and melanocortin4 antagonists/SRIs should display advantages over their selective counterparts, and histamine H3 antagonists/SRIs, GABAB antagonists/SRIs, glutamatergic/SRIs, and cholinergic agents/SRIs may counter the compromised cognitive function of depression. Finally, drugs that suppress 5-HT reuptake and blunt hypothalamo-pituitary-adrenocorticotrophic axis overdrive, or that act at intracellular proteins such as GSK-3β, may abrogate the negative effects of chronic stress on mood and neuronal integrity. This review discusses the discovery and development of dual- and triple-acting antidepressants, focusing on novel concepts and new drugs disclosed over the last 2 to 3 years.