Multi-target strategies for the improved treatment of depressive states: Conceptual foundations and neuronal substrates, drug discovery and therapeutic application.
Major depression is a debilitating and recurrent disorder with a substantial lifetime risk and a high social cost. Depressed patients generally display co-morbid symptoms, and depression frequently accompanies other serious disorders. Currently available drugs display limited efficacy and a pronounced delay to onset of action, and all provoke distressing side effects. Cloning of the human genome has fuelled expectations that symptomatic treatment may soon become more rapid and effective, and that depressive states may ultimately be "prevented" or "cured". In pursuing these objectives, in particular for genome-derived, non-monoaminergic targets, "specificity" of drug actions is often emphasized. That is, priority is afforded to agents that interact exclusively with a single site hypothesized as critically involved in the pathogenesis and/or control of depression. Certain highly selective drugs may prove effective, and they remain indispensable in the experimental (and clinical) evaluation of the significance of novel mechanisms. However, by analogy to other multifactorial disorders, "multi-target" agents may be better adapted to the improved treatment of depressive states. Support for this contention is garnered from a broad palette of observations, ranging from mechanisms of action of adjunctive drug combinations and electroconvulsive therapy to "network theory" analysis of the etiology and management of depressive states. The review also outlines opportunities to be exploited, and challenges to be addressed, in the discovery and characterization of drugs recognizing multiple targets. Finally, a diversity of multi-target strategies is proposed for the more efficacious and rapid control of core and co-morbid symptoms of depression, together with improved tolerance relative to currently available agents.
Millan
Mark J
MJ
Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, 125, Chemin de Ronde, 78290-Croissy/Seine, France. mark.millan@fr.netgrs.com
D018759:Adrenergic Uptake Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D000818:Animals; D000928:Antidepressive Agents / Q000009:adverse effects / Q000145:classification / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D016642:Bupropion / Q000494:pharmacology / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D003511:Cyclohexanols / Q000009:adverse effects / Q000627:therapeutic use; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D016503:Drug Delivery Systems; D015195:Drug Design; D004359:Drug Therapy, Combination; D006801:Humans; D009025:Morpholines / Q000009:adverse effects / Q000627:therapeutic use; D009415:Nerve Net / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D000077593:Reboxetine; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D000069470:Venlafaxine Hydrochloride
D018759:Adrenergic Uptake Inhibitors; D000928:Antidepressive Agents; D016642:Bupropion; D003511:Cyclohexanols; D004298:Dopamine; D018765:Dopamine Uptake Inhibitors; D009025:Morpholines; D009638:Norepinephrine; D000077593:Reboxetine; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D000069470:Venlafaxine Hydrochloride