Review of Pharmacological Treatment in Mood Disorders and Future Directions for Drug Development

Department of Psychiatry and Behavioral Neuroscience, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.83). 09/2011; 37(1):77-101. DOI: 10.1038/npp.2011.198
Source: PubMed

ABSTRACT After a series of serendipitous discoveries of pharmacological treatments for mania and depression several decades ago, relatively little progress has been made for novel hypothesis-driven drug development in mood disorders. Multifactorial etiologies of, and lack of a full understanding of, the core neurobiology of these conditions clearly have contributed to these development challenges. There are, however, relatively novel targets that have raised opportunities for progress in the field, such as glutamate and cholinergic receptor modulators, circadian regulators, and enzyme inhibitors, for alternative treatment. This review will discuss these promising new treatments in mood disorders, the underlying mechanisms of action, and critical issues of their clinical application. For these new treatments to be successful in clinical practice, it is also important to design innovative clinical trials that identify the specific actions of new drugs, and, ideally, to develop biomarkers for monitoring individualized treatment response. It is predicted that future drug development will identify new agents targeting the molecular mechanisms involved in the pathophysiology of mood disorders.

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Available from: Richard C Shelton, Aug 20, 2014
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    • "Newly developed approaches are allowing basic scientists to formulate a circuit-level understanding of dimensions of depression-like behavior (Russo and Nestler, 2013). There is also increased understanding of interactions between the monoaminergic and glutamatergic systems and of mechanisms of neuroplasticity, cellular resilience and synaptic plasticity (Li et al., 2012; Prins et al., 2011; Russo and Nestler, 2013). A growing body of evidence implicates glutamate system dysregulation as a key pathophysiological feature of mood disorders, thereby making the glutamate system a prime target for innovative treatments (Der-Avakian and Markou, 2012; Lapidus et al., 2013; Russo and Nestler, 2013; Stahl, 2013). "
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    ABSTRACT: Many patients with major depressive disorder (MDD) only partially respond, and some have no clinically meaningful response, to current widely used antidepressant drugs. Due to the purported role of dopamine in the pathophysiology of depression, triple-reuptake inhibitors (TRIs) that simultaneously inhibit serotonin (5-HT), norepinephrine (NE) and dopamine reuptake could be a useful addition to the armamentarium of treatments for MDD. A TRI should more effectively activate mesolimbic dopamine-related reward-networks, restore positive mood and reduce potent 5-HT reuptake blockade associated "hypodopaminergic" adverse effects of decreased libido, weight gain and "blunting" of emotions. On the other hand, dopaminergic effects raise concern over abuse liability and TRIs may have many of the cardiovascular effects associated with NET inhibition. Several clinical development programs for potential TRI antidepressants have failed to demonstrate significantly greater efficacy than placebo or standard of care. Successful late-stage clinical development of a TRI is more likely if experimental research studies in the target population of depressed patients have demonstrated target engagement that differentially and dose-dependently improves assessments of reward-network dysfunction relative to existing antidepressants. TRI treatment could be individualized on the basis of predictive markers such as the burden of decreased positive mood symptoms and/or neuroimaging evidence of reward network dysfunction. This review focuses on how the next generation of monoamine-based treatments could be efficiently developed to address unmet medical need in MDD.
    Journal of Psychopharmacology 10/2014; 29(5). DOI:10.1177/0269881114553252 · 2.81 Impact Factor
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    • "ADs are generally classified according to their primary pharmacological targets. The first developed ADs were monoamine oxidase inhibitors (MAOi) and tricyclic (TCA) and tetracyclic agents (Li et al, 2012). Second-generation ADs include the selective serotonin reuptake inhibitors (SSRIs), still the most prescribed ADs worldwide, and norepinephrine and serotonin reuptake inhibitors (NSRIs). "
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    ABSTRACT: Major depression is a highly prevalent, multidimensional disorder. Although several classes of antidepressants (ADs) are currently available, treatment efficacy is limited and relapse rates are high; thus, there is a need to find better therapeutic strategies. Neuroplastic changes in brain regions such as the hippocampal dentate gyrus (DG) accompany depression and its amelioration with ADs. In this study, the unpredictable chronic mild stress (uCMS) rat model of depression was used to determine the molecular mediators of chronic stress and the targets of four ADs with different pharmacological profiles (fluoxetine, imipramine, tianeptine and agomelatine) in the hippocampal DG. All ADs, except agomelatine, reversed the depression-like behavior and neuroplastic changes produced by uCMS. Chronic stress induced significant molecular changes that were generally reversed by fluoxetine, imipramine and tianeptine. Fluoxetine primarily acted on neurons to reduce the expression of pro-inflammatory response genes and increased a set of genes involved in cell metabolism. Similarities were found between the molecular actions and targets of imipramine and tianeptine which activated pathways related to cellular protection. Agomelatine presented a unique profile, with pronounced effects on genes related to Rho-GTPase-related pathways in oligodendrocytes and neurons. These differential molecular signatures of ADs studied contribute to our understanding of the processes implicated in the onset and treatment of depression-like symptoms.Neuropsychopharmacology accepted article preview online, 18 July 2014; doi:10.1038/npp.2014.176.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2014; 40(2). DOI:10.1038/npp.2014.176 · 7.83 Impact Factor
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    • "Valproic acid (VPA) and lithium chloride (LiCl) are two mood-stabilizing drugs used to treat patients with bipolar disorder (Kazantsev and Thompson 2008; Li et al. 2012). It has been reported that the major pharmacological actions of VPA are to inhibit histone deacetylase (HDAC) and glycogen synthase kinase-3 (GSK-3) activities (Phiel et al. 2001; Werstuck et al. 2004), while LiCl is the inhibitor of GSK-3 (Stambolic et al. 1996; Zhang et al. 2003). "
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    ABSTRACT: Valproic acid (VPA) is the primary mood-stabilizing drug to exert neuroprotective effects and to treat bipolar disorder in clinic. Fibroblast growth factor 1 (FGF1) has been shown to regulate cell proliferation, cell division and neurogenesis. Human FGF1 gene 1B promoter (-540 to +31)-driven green fluorescence (F1BGFP) has been shown to recapitulate endogenous FGF1 gene expression and facilitates the isolation of neural stem/progenitor cells (NSPCs) from developing and adult mouse brains. In this study, we provide several lines of evidence to demonstrate the underlying mechanisms of VPA in activating FGF-1B promoter activity: (i) VPA significantly increased the FGF-1B mRNA expression and the percentage of F1BGFP(+) cells; (ii) the increase of F1BGFP expression by VPA involves changes of RFX1-3 transcriptional complexes and the increase of histone H3 acetylation on the 18-bp cis-element of FGF-1B promoter; (iii) treatments of other HDAC inhibitors, sodium butyrate and trichostatin A, significantly increased the expression levels of FGF-1B, RFX2 and RFX3 transcripts; (iv) treatments of GSK-3 inhibitor, lithium, or GSK-3 siRNAs also significantly activated FGF-1B promoter; (v) VPA specifically enhanced neuronal differentiation in F1BGFP(+) embryonic stem cells and NSPCs rather than GFP(-) cells. This study suggested, for the first time, that VPA activates human FGF1 gene promoter through inhibiting HDAC and GSK-3 activities. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 05/2013; DOI:10.1111/jnc.12292 · 4.24 Impact Factor
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