Multi-target strategies for the improved treatment of depressive states: Conceptual foundations and neuronal substrates, drug discovery and therapeutic application.
ABSTRACT 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.
- SourceAvailable from: Domenico De BerardisMelatonin:Therapeutic Value and Neuroprotection, Edited by Venkatramanujan Srinivasan, Gabriella Gobbi, Samuel D. Shillcutt, Sibel Suzen, 01/2015: chapter 16: pages 189-202; CRC Press., ISBN: 9781482220094
Article: An overview of vortioxetine.[Show abstract] [Hide abstract]
ABSTRACT: Six clinicians provide an overview of the serotonergic antidepressant vortioxetine, which was recently approved for the treatment of major depressive disorder in adults. They discuss the pharmacologic profile and receptor-mediated effects of vortioxetine in relation to potential outcomes. Additionally, they summarize the clinical trials, which demonstrate vortioxetine's efficacy, and discuss findings related to safety and tolerability that have high relevance to patient compliance. © Copyright 2014 Physicians Postgraduate Press, Inc.The Journal of Clinical Psychiatry 12/2014; 75(12):1411-8. · 5.14 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Exposure to improvised explosive devices can result in a unique form of traumatic brain injury, blast-induced traumatic brain injury (bTBI). At the mild end of the spectrum (mild bTBI, mbTBI) there are cognitive and mood disturbances. Similar symptoms have been observed in post-traumatic stress disorder caused by exposure to extreme psychological stress without physical injury. The role of the monoaminergic system in mood regulation and stress is well established, but its role in mbTBI is not well understood. To address this gap, we used a rodent model of mbTBI and detected a decrease in immobility behaviour in the forced swim test at one day post-exposure, coupled with an increase in climbing behaviour, but not after 14 d or later, possibly indicating a transient increase in anxiety-like behaviour. Using in situ hybridisation, we found elevated mRNA levels of both tyrosine hydroxylase and tryptophan hydroxylase 2 in the locus coeruleus and the dorsal raphe nucleus, respectively, as early as 2 h post-exposure. HPLC analysis one day post-exposure primarily showed elevated noradrenaline levels in several forebrain regions. Taken together, we report that exposure to mild blast results in transient changes in both anxiety-like behaviour and brain region-specific molecular changes implicating the monoaminergic system in the pathobiology of mbTBI.Journal of Neurotrauma 12/2014; · 3.97 Impact Factor