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Millan MJ. Multi-target strategies for the improved treatment of depressive states: conceptual foundations and neuronal substrates, drug discovery and therapeutic application. Pharmacol Ther 110: 135-370

Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, 125, Chemin de Ronde, 78290-Croissy/Seine, France.
Pharmacology [?] Therapeutics (Impact Factor: 7.75). 06/2006; 110(2):135-370. DOI: 10.1016/j.pharmthera.2005.11.006
Source: PubMed

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.

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    • "Is it reasonable to expect that we can cure these complex disorders with just a single drug? Multi-target agents may be better suited to improve core and co-morbid symptoms of certain subgroups of patients than selective drugs (Millan, 2006, 2009). For an extended explanation on multi-target approach and some typical examples see Fig. 2. The development of add-on therapy, drugs that augment the effects of cognitive-behavioural therapy may proof another fruitful approach. "
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    ABSTRACT: Psychopharmacology has had some bad publicity lately. Frankly, there have been some major problems along the way in developing new effective drugs for psychiatric disorders. After a prolonged period of high investments but low success rates, big pharmaceutical companies seem to retract their activities in the psychopharmacology field. Yet, the burden of mental disorders is likely to keep on growing in the next decades. In this position paper, we focus on drug development for depression and anxiety disorders, to narrow the scope of the assay. We describe the current situation of the psychopharmacology field, and analyse some of the methods and paradigms that have brought us here, but which should perhaps change to bring us even further. In addition, some of the factors contributing to the current stagnation in psychopharmacology are discussed. Finally, we suggest a number of changes that could lead to a more rational strategy for central nervous system drug development and which may circumvent some of the pitfalls leading to "me too" approaches. Central to the suggested changes, is the notion that mental disorders do not lead to several symptoms, but a network of causally related symptoms convolutes into a mental disorder. We call upon academia to put these changes in the early phases of drug development into effect. Copyright © 2015. Published by Elsevier B.V.
    European journal of pharmacology 03/2015; 759. DOI:10.1016/j.ejphar.2015.03.020 · 2.68 Impact Factor
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    • "Identification of crucial hubs and discrete circuits affected in specific diseases leads to the possibility of their normalisation. This may be effected by (preferably multitarget) medication, psychotherapy and/or electrical stimulation, strategies that act across distributed cerebral networks (Du et al., 2012; Millan, 2006; Ritchey et al., 2011). Graph analyses are also useful in analysing the influence of such treatments upon disrupted cerebral circuits (Bolding et al., 2012). "
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    ABSTRACT: Pharmacotherapy is effective in helping many patients suffering from psychiatric and neurological disorders, and both psychotherapeutic and stimulation-based techniques likewise have important roles to play in their treatment. However, therapeutic progress has recently been slow. Future success for improving the control and prevention of brain disorders will depend upon deeper insights into their causes and pathophysiological substrates. It will also necessitate new and more rigorous methods for identifying, validating, developing and clinically deploying new treatments. A field of Research and Development (R and D) that remains critical to this endeavour is Neuropsychopharmacology which transformed the lives of patients by introducing pharmacological treatments for psychiatric disorder some 60 years ago. For about half of this time, the European College of Neuropsychopharmacology (ECNP) has fostered efforts to enhance our understanding of the brain, and to improve the management of psychiatric disorders. Further, together with partners in academia and industry, and in discussions with regulators and patients, the ECNP is implicated in new initiatives to achieve this goal. This is then an opportune moment to survey the field, to analyse what we have learned from the achievements and failures of the past, and to identify major challenges for the future. It is also important to highlight strategies that are being put in place in the quest for more effective treatment of brain disorders: from experimental research and drug discovery to clinical development and collaborative ventures for reinforcing "R and D". The present article sets the scene, then introduces and interlinks the eight articles that comprise this Special Volume of European Neuropsychopharmacology. A broad-based suite of themes is covered embracing: the past, present and future of "R and D" for psychiatric disorders; complementary contributions of genetics and epigenetics; efforts to improve the treatment of depression, neurodevelopmental and neurodegenerative disorders; and advances in the analysis and neuroimaging of cellular and cerebral circuits. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.
    European Neuropsychopharmacology 02/2015; 25(5). DOI:10.1016/j.euroneuro.2015.01.015 · 5.40 Impact Factor
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    • "That ADS mounts a bio-behavioural stress response suggests that long-term detrimental effects may ensue that will compromise outcome, especially by introducing an additional risk factor into an already vulnerable individual, with the associated risk for relapse and recurrence (Harvey et al., 2003). Although depression is a multi-transmitter illness, current consensus has placed especially the 5-HT 1A and 5-HT 2C receptors at the centre of antidepressant response (Blier, 2003; Millan, 2006), with the 5-HT 2C receptor playing a central role in biobehavioural stress responses (Martin et al., 2014). Hence, their role in ADS may be equally as important. "
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    ABSTRACT: Objective Antidepressants are at best 50–55% effective. Non-compliance and the antidepressant discontinuation syndrome (ADS) are causally related yet poorly appreciated. While ADS is associated with most antidepressants, agomelatine seems to be devoid of such risk. We review the neurobiology and clinical consequences of antidepressant non-compliance and the ADS. Agomelatine is presented as a counterpoint to learn more on how ADS risk is determined by pharmacokinetics and pharmacology.DesignThe relevant literature is reviewed through a MEDLINE search via PubMed, focusing on agomelatine and clinical and preclinical research on ADS.ResultsAltered serotonergic dysfunction appears central to ADS so that how an antidepressant targets serotonin will determine its relative risk for inducing ADS and thereby affect later treatment outcome. Low ADS risk with agomelatine versus other antidepressants can be ascribed to its unique pharmacokinetic characteristics as well as its distinctive actions on serotonin, including melatonergic, monoaminergic and glutamatergic-nitrergic systems.Conclusions This review raises awareness of the long-term negative aspects of non-compliance and inappropriate antidepressant discontinuation, and suggests possible approaches to “design-out” a risk for ADS. It reveals intuitive and rational ideas for antidepressant drug design, and provides new thoughts on antidepressant pharmacology, ADS risk and how these affect long-term outcome. Copyright © 2014 John Wiley & Sons, Ltd.
    Human Psychopharmacology Clinical and Experimental 11/2014; 29(6). DOI:10.1002/hup.2429 · 1.85 Impact Factor
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