Emerging drugs for major depressive disorder

Perelman School of Medicine of the University of Pennsylvania, Philadelphia Veterans Affairs Medical Center, 3900 Woodland Avenue, Philadelphia, PA 19104, USA.
Expert Opinion on Emerging Drugs (Impact Factor: 3.06). 02/2012; 17(1):105-26. DOI: 10.1517/14728214.2012.660146
Source: PubMed

ABSTRACT INTRODUCTION: Major depressive disorder (MDD) remains a major public health concern, and one that continues to suffer an incompletely-met need for effective and acceptable treatments. The development of antidepressants, to date, has focused primarily on increasing monoamine neurotransmission with increasing efficacy while minimizing adverse effects. Medications currently recommended as 'first-line' are far more tolerable than the older medications they replaced, but as many as 70% of patients continue to suffer significant depressive symptoms after treatment with one of these agents, and as many as 50% will discontinue a trial due to issues with acceptability. This review will summarize antidepressants that have recently entered the market as well as those still in development to help characterize the current state of antidepressant development. AREAS COVERED: Currently available first-line antidepressants are reviewed with respect to efficacy and tolerability, and their weaknesses are discussed as targets for future development. The background, clinical trial data and potential significance of the three most recently introduced antidepressants (trazodone-ER, desvenlafaxine and vilazodone) and the most recently approved augmentation agents (aripiprazole and quetiapine) are discussed. Following a review of the current market, all medications currently in Phase II or later clinical trials are listed and discussed, based on a thorough review of the US National Institutes of Health index for trials using medications to treat MDD and a search of the Informa Pharmaprojects database for medications currently being developed for a depression indication. Compounds thus identified were then used as search terms in a PubMed search of each medication. Based on pharmacologic properties, medications in development were grouped into those acting on: i) monoamine neurotransmission; ii) cholinergic neurotransmission; iii) glutamatergic neurotransmission; iv) opioid receptors; v) sigma receptors; vi) neurokinin receptors; vii) corticotrophin-releasing factor receptors and viii) other mechanisms. In the discussion of each, a brief review of the pharmacology and physiology of the related system is provided. Potential issues for the future of antidepressant development and an expert opinion are discussed. EXPERT OPINION: The past decade has not yielded a large number of new antidepressants and, with the possible exception of agomelatine, none of the newer medications that have been introduced have decisively addressed the several unmet needs in this area of therapeutics. Among the various novel strategies that are being evaluated, results of several small studies of ketamine suggest that drugs that modulate glutamatergic neurotransmission may hold the greatest promise for exerting rapid and large antidepressant effects in patients who have not responded to SSRIs or SNRIs.

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    • "New opportunities are still under investigation mainly based on exploiting serotonergic mechanisms via the differential roles of specific 5-HT receptor subtypes, like 5-HT 4 and 5-HT 7 (Artigas, 2013; Millan, 2006). These properties would preferentially be exploited in combination with complementary, nonserotonergic mechanisms rather than on their own (Connolly and Thase, 2012; de Bodinat et al., 2010; Millan 2006, 2014a). While not decrying the enduring relevance of monoamines (a likely hub upon which all modes of depression-relief may converge), it is obviously desirable to explore other therapeutic territories. "
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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 · 4.37 Impact Factor
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    • "Depression is the leading cause of disability worldwide and has an average prevalence of approximately 20% (Kessler et al., 1994). Current pharmacotherapy for depression acts primarily on the monoamine neurotransmitter systems, modulating the synaptic availability of neurotransmitters like serotonin and noradrenaline (Connolly and Thase, 2012). However, only about 2 | International Journal of Neuropsychopharmacology, 2015 60–70 percent of depressed patients achieve full remission, indicating a need for development of alternative antidepressant drugs (Fava, 2003; Ressler and Mayberg, 2007). "
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    ABSTRACT: Epigenetic drugs like sodium butyrate (NaB) show antidepressant-like effects in preclinical studies, but the exact molecular mechanisms of the antidepressant effects remain unknown. While research using NaB has mainly focused on its role as a histone deacetylase inhibitor (HDACi), there is also evidence that NaB affects DNA methylation. The purpose of this study was to examine NaB's putative antidepressant-like efficacy in relation to DNA methylation changes in the prefrontal cortex of an established genetic rat model of depression (the Flinders Sensitive Line [FSL]) and its controls (the Flinders Resistant Line). The FSL rats had lower levels of ten-eleven translocation methylcytosine dioxygenase 1 (TET1), which catalyzes the conversion of DNA methylation to hydroxymethylation. As indicated by the behavioral despair test, chronic administration of NaB had antidepressant-like effects in the FSL and was accompanied by increased levels of TET1. The TET1 upregulation was also associated with an increase of hydroxymethylation and a decrease of methylation in brain-derived neurotrophic factor (Bdnf), a gene associated with neurogenesis and synaptic plasticity. These epigenetic changes were associated with a corresponding BDNF overexpression. Our data support the antidepressant efficacy of HDACis and suggest that their epigenetic effects may also include DNA methylation changes that are mediated by demethylation-facilitating enzymes like TET1. © The Author 2015. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 01/2014; 18(2). DOI:10.1093/ijnp/pyu032 · 4.01 Impact Factor
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    • "Although today's treatments are generally safe and effective, 30% of depressed patients treated with antidepressants available already on the market are resistant to these drugs. In addition, it is necessary to administer these drugs for weeks or months to see clinical benefit (Connolly & Thase, 2012). Therefore, there is still a great need for faster acting, safer and more effective treatments for depressive disorders. "
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    ABSTRACT: The endocannabinoid system (ECS), comprising two G protein-coupled receptors (the cannabinoid receptors 1 and 2 [CB1 and CB2] for marijuana's psychoactive principle Δ(9)-tetrahydrocannabinol [Δ(9)-THC]), their endogenous small lipid ligands (namely anandamide [AEA] and 2-arachidonoylglycerol [2-AG], also known as endocannabinoids), and the proteins for endocannabinoid biosynthesis and degradation, has been suggested as a pro-homeostatic and pleiotropic signaling system activated in a time- and tissue-specific way during physiopathological conditions. In the brain activation of this system modulates the release of excitatory and inhibitory neurotransmitters and of cytokines from glial cells. As such, the ECS is strongly involved in neuropsychiatric disorders, particularly in affective disturbances such as anxiety and depression. It has been proposed that synthetic molecules that inhibit endocannabinoid degradation can exploit the selectivity of endocannabinoid action, thus activating cannabinoid receptors only in those tissues where there is perturbed endocannabinoid turnover due to the disorder, and avoiding the potential side effects of direct CB1 and CB2 activation. However, the realization that endocannabinoids, and AEA in particular, also act at other molecular targets, and that these mediators can be deactivated by redundant pathways, has recently led to question the efficacy of such approach, thus opening the way to new multi-target therapeutic strategies, and to the use of non-psychotropic cannabinoids, such as cannabidiol (CBD), which act via several parallel mechanisms, including indirect interactions with the ECS. The state of the art of the possible therapeutic use of endocannabinoid deactivation inhibitors and phytocannabinoids in mood disorders is discussed in this review article.
    Pharmacology [?] Therapeutics 12/2012; 138(1). DOI:10.1016/j.pharmthera.2012.12.002 · 9.72 Impact Factor
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