Patrício, Patrícia Carvalho

Pinto, Luísa

Frontiers in Behavioral Neuroscience

Universidade do Minho: RepositoriUM

CroniconO P E N  A C C E S S EC NEUROLOGYEditorialMolecular Mediators of Depression Pathophysiology and  Treatment: Neuroscience-Based Approaches for Personalized CarePatrícia Patrício1,2,3 and Luísa Pinto1,2,3*1Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal2ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal3BnML – Behavioral and Molecular Lab, Braga, Portugal*Corresponding Author: Luísa Pinto, Assistant Investigator, Life and Health Sciences Research Institute, School of Medicine, University of Minho, Campus de Gualtar, Braga, Portugal.Citation: Patrícia Patrício and Luísa Pinto. “Molecular Mediators of Depression Pathophysiology and Treatment: Neuroscience-Based Approaches for Personalized Care”. EC Neurology 7.3 (2017): 85-88.Received: June 21, 2017; Published: July 21, 2017Keywords: Depression; Antidepressants; Molecular Mechanisms; Pathophysiology; DiagnosisDepression is a complex multidimensional disorder affecting around 20% of the world population and is now the leading cause of disability worldwide [1]. Although much improvement has been done on the comprehension of depression’s pathophysiology, this hasn’t been reflected yet in the clinical setting, as depression prevails as one of the world’s major public health concerns [2,3]. This is a complex and heterogeneous clinical entity [4] that may overlap with other neuropsychiatric disorders, such as anxiety disorders [5]. Moreover, the diagnosis of depression is based on relatively subjective evaluations of symptoms, relying exclusively on clinical presentation informa-tion. Also, the reason why some patients respond well to some of the currently available therapeutic options while others don’t, remains pretty much unclear. In this sense, the stratification of patients based on specific pathophysiological characteristics would indubitably have major implications for the diagnosis and treatment of this disorder, towards a more personalized approach. But do we have enough preclinical and clinical data to support the use of pathophysiological biomarkers for the categorization of depressive patients? And if so, can we take advantage of the singularities of each currently available antidepressant therapy? At this point certainly not, but it is reason-able to envision that this is the way the field will evolve. Several studies have supported this view suggesting that, for instance, peripheral markers, such as cortisol levels [6], and inflammatory response molecules levels [7], as well as neural connectivity patterns [8,9] may allow the identification of patients’ subgroups and at risk for treatment non-response to first line treatments.Since the serendipitous discovery of the first antidepressant molecules, in the 1950’s, many other drugs with similar antidepressant properties have emerged [10]. Strikingly, the advent of novel antidepressants development has dropped massively in recent years [11], and the field is still lacking effective drugs for a great proportion of patients. This poses a major problem for an ever growing “depressed society”. Indeed, not only currently available antidepressant treatments are ineffective in a significant proportion of the depressed pa-tients but also relapse rates are high, emphasizing the need for better therapeutic strategies. Newer antidepressants were developed to be more selective for their neurochemical targets, being thus undeniably safer than those developed back in the 1950’s. Nevertheless, there’s a lack of mechanistic novelty in the way that, despite a few exceptions, most antidepressants primarily target monoaminergic neuro-transmission. Paradoxically, we have been watching the dawn of new hypotheses on the pathophysiology of depression and appreciating that antidepressants mechanisms of action go considerably beyond those initially assumed. In fact, the knowledge on the neurobiological mechanisms underlying depression has progressed substantially in the last years, partly due to animal models of depression. Studies from our group and others have shown that these are useful and robust approaches to understand the mechanisms of action of currently available antidepressants [12-15] but also to explore novel therapeutic opportunities [16-18], when used with an understanding of its limitations.86Molecular Mediators of Depression Pathophysiology and Treatment: Neuroscience-Based Approaches for Personalized CareCitation: Patrícia Patrício and Luísa Pinto. “Molecular Mediators of Depression Pathophysiology and Treatment: Neuroscience-Based Approaches for Personalized Care”. EC Neurology 7.3 (2017): 85-88.Treatment resistance and the delayed onset of action of clinically prescribed antidepressants represent additional major challenges in this field [19]. The oversimplification of depression pathophysiology as solely a neurochemical imbalance disorder has biased the research of new antidepressants for decades. Fortunately, it is now recognized that depression is a systems disorder affecting neural plasticity and brain connectivity [9,12,15,20], and that the currently available pharmacological approaches have a rather limited action. Specifically targeting these networks may foster the development of more effective treatment options for refractory patients. Regarding novel putative targets and therapeutic strategies under investigation, one may highlight the modulation of glutamatergic signalling [21], the resynchronization of circadian rhythms [22,23], and the prominent, previously underestimated, role of the gut microbiome [24,25].Taking into account the higher prevalence of depression in women compared to men [26], and the evident bias on research towards male preclinical studies, it is urgent to re-orientate the focus in the field and invert this trend. Likewise, emerging data have disclosed sex differences in the response to stress at several levels including, molecular and cellular responses, activation of brain circuits, neural plasticity mechanisms and therefore, behavioral outcomes [27-30].Recognizing that depression has a biological basis represented a major step for research in this field, as it implied the shift to a neu-roscience-based approach of this formerly underestimated medical condition. Hopefully, by integrating preclinical and clinical data, we will reach a stage where we can specifically pinpoint the underlying imbalances and try to develop personalized care to restructure faulty circuits in the depressed brain.Conflict of InterestThe authors declare no conflict of interest.Bibliography1. World Health Organization. “Depression Fact Sheet” (2017). 2. Lepine JP and M Briley. “The increasing burden of depression”. Neuropsychiatric Disease and Treatment 7.1 (2011): 3-7.3. Collins PY., et al. “Grand challenges in global mental health”. Nature 475.7354 (2011): 27-30.4. Smith KM., et al. “The diagnosis of depression: current and emerging methods”. Comprehensive Psychiatry 54.1 (2013): 1-6.5. Hettema JM. “The nosologic relationship between generalized anxiety disorder and major depression”. Depress Anxiety 25.4 (2008): 300-316.6. Ventura-Junca R., et al. “Relationship of cortisol levels and genetic polymorphisms to antidepressant response to placebo and fluox-etine in patients with major depressive disorder: a prospective study”. BMC Psychiatry 14 (2014): 220.7. Hashimoto K. “Inflammatory biomarkers as differential predictors of antidepressant response”. International Journal of Molecular Sciences 16.4 (2015): 7796-7801.8. MacQueen G and T Frodl. “The hippocampus in major depression: evidence for the convergence of the bench and bedside in psychi-atric research?” Molecular Psychiatry 16.3 (2011): 252-264.9. Drysdale AT., et al. “Resting-state connectivity biomarkers define neurophysiological subtypes of depression”. Nature Medicine 23.1 (2017): 28-38.10. Millan MJ., et al. “Learning from the past and looking to the future: Emerging perspectives for improving the treatment of psychiatric disorders”. European Neuropsychopharmacology 25.5 (2015): 599-656.Citation: Patrícia Patrício and Luísa Pinto. “Molecular Mediators of Depression Pathophysiology and Treatment: Neuroscience-Based Approaches for Personalized Care”. EC Neurology 7.3 (2017): 85-88.Molecular Mediators of Depression Pathophysiology and Treatment: Neuroscience-Based Approaches for Personalized Care 8711. Hyman SE. “Psychiatric drug development: diagnosing a crisis”. Cerebrum (2013): 5.12. Mateus-Pinheiro A., et al. “Cell genesis and dendritic plasticity: a neuroplastic pas de deux in the onset and remission from depres-sion”. Molecular Psychiatry 18.7 (2013): 748-750.13. Mateus-Pinheiro A., et al. “Sustained remission from depressive-like behavior depends on hippocampal neurogenesis”. Translational Psychiatry 3 (2013): e210.14. Patricio P., et al. “Differential and converging molecular mechanisms of antidepressants’ action in the hippocampal dentate gyrus”. Neuropsychopharmacology 40.2 (2015): 338-349.15. Alves ND., et al. “Adult hippocampal neuroplasticity triggers susceptibility to recurrent depression”. Translational Psychiatry 7.3 (2017): e1058.16. Lau T., et al. “Stress-induced structural plasticity of medial amygdala stellate neurons and rapid prevention by a candidate antide-pressant”. Molecular Psychiatry 22.2 (2017): 227-234.17. Harmer CJ., et al. “How do antidepressants work? New perspectives for refining future treatment approaches”. Lancet Psychiatry 4.5 (2017): 409-418.18. Morais M., et al. “The modulation of adult neuroplasticity is involved in the mood-improving actions of atypical antipsychotics in an animal model of depression”. Translational Psychiatry 7.6 (2017): e1146.19. Rush AJ., et al. “Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report”. American Journal of Psychiatry 163.11 (2006): 1905-1917.20. Pittenger C and RS Duman. “Stress, depression, and neuroplasticity: a convergence of mechanisms”. Neuropsychopharmacology 33.1 (2008): 88-109.21. Murrough JW., et al. “Targeting glutamate signalling in depression: progress and prospects”. Nature Reviews Drug Discovery 16.7 (2017): 472-486.22. Bunney BG., et al. “Circadian dysregulation of clock genes: clues to rapid treatments in major depressive disorder”. Molecular Psy-chiatry 20.1 (2015): 48-55.23. Edgar N and CA McClung. “Major depressive disorder: a loss of circadian synchrony?” Bioessays 35.11 (2013): 940-944.24. Dinan TG., et al. “Psychobiotics: a novel class of psychotropic”. Biological Psychiatry 74.10 (2013): 720-726.25. Moloney RD., et al. “The microbiome: stress, health and disease”. Mammalian Genome 25.1-2 (2014): 49-74.26. American Psychiatric Association. “Diagnostic and Statistical Manual of Mental Disorders”. 5th edition, Washington, DC: APA Press (2013).27. McEwen BS., et al. “Recognizing Resilience: Learning from the Effects of Stress on the Brain”. Neurobiology of Stress 1 (2015): 1-11.28. Dalla C., et al. “Females do not express learned helplessness like males do”. Neuropsychopharmacology 33.7 (2008): 1559-1569.Citation: Patrícia Patrício and Luísa Pinto. “Molecular Mediators of Depression Pathophysiology and Treatment: Neuroscience-Based Approaches for Personalized Care”. EC Neurology 7.3 (2017): 85-88.Molecular Mediators of Depression Pathophysiology and Treatment: Neuroscience-Based Approaches for Personalized Care 8829. Hodes GE., et al. “Sex Differences in Nucleus Accumbens Transcriptome Profiles Associated with Susceptibility versus Resilience to Subchronic Variable Stress”. Journal of Neuroscience 35.50 (2015): 16362-16376.30. Bangasser DA and RJ Valentino. “Sex differences in molecular and cellular substrates of stress”. Cellular and Molecular Neurobiology 32.5 (2012): 709-723.Volume 7 Issue 2 July 2017© All rights reserved by Patrícia Patrício and Luísa Pinto.

Molecular Mediators of Depression Pathophysiology and Treatment: Neuroscience-Based Approaches for Personalized Care

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Molecular Mediators of Depression Pathophysiology and Treatment: Neuroscience-Based Approaches for Personalized Care

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