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

• Published in: Neurotherapeutics Vol. 6; no. 1; pp. 53 - 77
• Main Author: Millan, Mark J.
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 2009; Springer-Verlag; Springer Nature B.V
• Subjects: Adrenergic alpha-2 Receptor Antagonists; Animals; Anti-Anxiety Agents - therapeutic use; Antidepressant; Antidepressants; Antidepressive Agents - therapeutic use; Autoreceptors - antagonists & inhibitors; Biogenic Monoamines - therapeutic use; Biomedical and Life Sciences; Biomedicine; Central Nervous System - drug effects; Central Nervous System - physiopathology; CRF; Depressive Disorder, Major - drug therapy; Depressive Disorder, Major - physiopathology; Drug Design; HPA axis; Humans; Hypothalamo-Hypophyseal System - drug effects; Mental depression; multitarget; network; Neurobiology; Neurokinin-1 Receptor Antagonists; Neurology; Neurosciences; Neurosurgery; Pituitary-Adrenal System - drug effects; Receptors, Glutamate - metabolism; Receptors, Melatonin - metabolism; Review; Review Article; Selective Serotonin Reuptake Inhibitors - chemistry; Selective Serotonin Reuptake Inhibitors - therapeutic use; Serotonin Antagonists - chemistry; Serotonin Antagonists - therapeutic use; stress; Antidepressant; stress; HPA axis; CRF; multitarget; network
• ISSN: 1933-7213; 1878-7479; 1878-7479
• DOI: 10.1016/j.nurt.2008.10.039

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-HT 1A, 5-HT 1B and possibly 5-HT 5A and 5-HT 7 receptors. Specific subsets of postsynaptic 5-HT receptors mediating antidepressant actions are under study (e.g., 5-HT 4 and 5-HT 6). Association of a clinically characterized antidepressant mechanism with a nonmonoaminergic component of activity is an attractive strategy. For example, agomelatine (a melatonin agonist/5-HT 2C antagonist) has clinically proven activity in major depression. Dual neurokinin 1 antagonists/5-HT reuptake inhibitors (SRIs) and melanocortin 4 antagonists/SRIs should display advantages over their selective counterparts, and histamine H 3 antagonists/SRIs, GABA B 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.