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: 7.05). 09/2011; 37(1):77-101. DOI: 10.1038/npp.2011.198
Source: PubMed


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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    • "It is conceivable that these contrasting results are due to different levels of system xc-inhibition (acute and partial with sulfasalazine, versus chronic and complete in xCT −/− mice), or the species of animals used. At the same time, however, sulfasalazine is known to have poor blood–brain barrier permeability in intact animals (Liu et al., 2012), and peripheral and central off-target effects, such as anti-inflammatory properties (inhibition of nuclear factor kappa B, see (Wahl et al., 1998)) and blockade of NMDA receptors (Ryu et al., 2003), that could influence acute effects on behavior. Future studies will be of particular importance evaluating acute versus chronic modulation of system xc-and its relation to emotional behavior. "
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    ABSTRACT: There is considerable preclinical and clinical evidence indicating that abnormal changes in glutamatergic signaling underlie the development of mood disorders. Astrocytic glutamate dysfunction, in particular, has been recently linked with the pathogenesis and treatment of mood disorders, including anxiety and depression. System xc- is a glial cystine/glutamate antiporter that is responsible for nonvesicular glutamate release in various regions of the brain. Although system xc- is involved in glutamate signal transduction, its possible role in mediating anxiety or depressive-like behaviors is currently unknown. In the present study, we phenotyped adult and aged system xc- deficient mice in a battery of tests for anxiety and depressive-like behavior (open field, light/dark test, elevated plus maze, novelty suppressed feeding, forced swim test, tail suspension test). Concomitantly, we evaluated the sensorimotor function of system xc- deficient mice, using motor and sensorimotor based tests (rotarod, adhesive removal test, nest building test). Finally, due to the presence and potential functional relevance of system xc- in the eye, we investigated the visual acuity of system xc- deficient mice (optomotor test). Our results indicate that loss of system xc- does not affect motor or sensorimotor function, in either adult or aged mice, in any of the paradigms investigated. Similarly, loss of system xc- does not affect basic visual acuity, in either adult or aged mice. On the other hand, in the open field and light/dark tests, and forced swim and tail suspension tests respectively, we could observe significant anxiolytic and antidepressive-like effects in system xc- deficient mice that in certain cases (light/dark, forced swim) were age-dependent. These findings indicate that, under physiological conditions, nonvesicular glutamate release via system xc- mediates aspects of higher brain function related to anxiety and depression, but does not influence sensorimotor function or spatial vision. As such, modulation of system xc- might constitute the basis of innovative interventions in mood disorders.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 01/2015; 59. DOI:10.1016/j.pnpbp.2015.01.010 · 3.69 Impact Factor
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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 · 3.59 Impact Factor
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    • "Additionally, glycogen synthase kinase-3 (GSK-3), a multifunctional kinase important for neuronal survival and cellular response to stress (61), establishes neuronal polarity through signaling into pathways responsible for cytoskeletal organization and microtubule stabilization (62). It has also been implicated in the development of mood disorders including bipolar disorder, depression, and schizophrenia (63, 64). In fact lithium, one of the first psychotropic drugs identified and confirmed through clinical trials to be effective against bipolar disorder, does so in part through inhibition of GSK-3 (65–67). "
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    ABSTRACT: The progress of developing effective interventions against psychiatric disorders has been limited due to a lack of understanding of the underlying cellular and functional mechanisms. Recent research findings focused on exploring novel causes of psychiatric disorders have highlighted the importance of the axonal initial segment (AIS), a highly specialized neuronal structure critical for spike initiation of the action potential. In particular, the role of voltage-gated sodium channels, and their interactions with other protein partners in a tightly regulated macromolecular complex has been emphasized as a key component in the regulation of neuronal excitability. Deficits and excesses of excitability have been linked to the pathogenesis of brain disorders. Identification of the factors and regulatory pathways involved in proper AIS function, or its disruption, can lead to the development of novel interventions that target these mechanistic interactions, increasing treatment efficacy while reducing deleterious off-target effects for psychiatric disorders.
    Frontiers in Psychiatry 08/2014; 5:109. DOI:10.3389/fpsyt.2014.00109
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