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: 9.72). 06/2006; 110(2):135-370. DOI: 10.1016/j.pharmthera.2005.11.006
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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- "selective serotonin reuptake inhibitors, SSRIs, tricyclic antidepressants, TCAs) or its metabolism (monoamine oxidase inhibitors, MAOIs), or postsynaptically by acting in monoamine receptors (e.g. mianserine)  . Based on these findings, it was first hypothesized that depression would result from deficits in the monoaminergic system, mainly serotonin and noradrenaline signaling, which would be restored by chronic antidepressant treatment (reviewed in . "
ABSTRACT: Since the first report that the mechanism of action of antidepressants involves the facilitation of monoaminergic neurotransmission in the brain in the 1960s, the leading hypothesis about the neurobiology of depression has been the so called "monoaminergic hypothesis". However, a growing body of evidence from the last two decades also supports important involvement of non-monoaminergic mechanisms in the neurobiology of depression and antidepressant action. The discovery of nitric oxide (NO) and endocannabinoid signaling in the brain during the 1990s challenged the well-established criteria of classical neurotransmission. These transmitters are synthesized and released on demand by the post-synaptic neurons, and may act as a retrograde messenger on the presynaptic terminal, modulating neurotransmitter release. These unconventional signaling mechanisms and the important role as neural messengers have classified NO and endocannabinoids as atypical neurotransmitters. They are able to modulate neural signaling mediated by the main conventional neurotransmitters systems in the brain, including the monoaminergic, glutamatergic and GABAergic signaling systems. This review aims at discussing the fundamental aspects of NO- and endocannabinoid-mediated signaling in the brain, and how they can be related to the neurobiology of depression. Both preclinical and clinical evidence supporting the involvement of these atypical neurotransmitters in the neurobiology of depression, and in the antidepressant effects are presented here. The evidence is discussed on basis of their ability to modulate different neurotransmitter systems in the brain, including monoaminergic and glutamatergic ones. A better comprehension of NO and endocannabinoid signaling mechanisms in the neurobiology depression could provide new avenues for the development of novel non-monoamine based antidepressants.
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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. "
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.
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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). "
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.