The Search for Antidepressants - An Integrative View of Drug Discovery

Andre F. Carvalho, Gislaine Z. Reus, João Quevedo, Andre F. Carvalho, Gislaine Z. Reus, João Quevedo

• Publisher: Bentham Science Publishers
• Year: 2017
• Print ISBN:
  9781681084749
• eBook ISBN:
  9781681084732
• Topic: Medicine
• Subtopic: Pharmacology

Major depressive disorder (MDD) is a prevalent, chronic, and recurring mental disorder. This disorder is a leading source of disability worldwide, and is associated with excess mortality rates. Currently approved antidepressants primarily enhance, or otherwise modulate monoaminergic neurotransmission, without curing the disease. Evidence indicates that only one third of patients with MDD achieve remission after treatment with a first-line antidepressant agent. Research in the past two decades has provided valuable insights into the pathophysiological understanding of MDD. However, there is an acknowledged 'translational gap' in the field, and few genuinely novel antidepressants have been approved for the treatment of MDD. The Search for Anti Depressants provides readers an in-depth picture of the main pathophysiological mechanisms responsible for the development of MDD in patients. Chapters in the volume focus on possible strategies to spur the discovery of novel antidepressants. This book is an indispensable reference for mental health care providers, students at both under-graduate and graduate levels, and neuroscientists interested in the neurobiology of MDD and recent advances towards the discovery of next generation antidepressants.

Shared Pathophysiology between Depression, Obesity and Metabolic Disturbances: Novel Antidepressant Targets?

Léa Décarie-Spain^*, Dominique Matthys, Stephanie E. Fulton

University of Montreal Hospital Research Center (CRCHUM); Departments of Nutrition and Neuroscience, University of Montreal & Montreal Diabetes Research Centre, Montreal, QC, Canada

Abstract

The prevalence of obesity and related metabolic disorders is largely the result of poor dietary choices and excessive caloric intake. Consumption of palatable, energy-rich foods can lead to obesity and increase the risk of depression. Depression not only impairs the quality of life of obese individuals but also increases the associated risks of obesity and hinders motivation to seek out and adhere to weight loss strategies. In turn, certain forms of depression are closely linked with overeating, promoting an adverse cycle of depressed mood, comfort-food seeking and further weight gain. This chapter provides an overview of the metabolic, immune and neural processes that accompany increased adiposity and obesity and their impact on mood and the development of depression. In this context, potential treatments for the alleviation of depression co-morbid with obesity are discussed.

Keywords: Anhedonia, Animal models, Cortisol, Depressive-like behaviours, Diabetes, Diet-induced obesity, Drug treatment, Inflammation, Insulin, Leptin, Polyunsaturated fatty acids, Reward, Stress.

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^* Corresponding author Léa Décarie-Spain: University of Montreal Hospital Research Center (CRCHUM); Department of Neuroscience, University of Montreal and Montreal Diabetes Research Centre, Montreal, QC, Canada; Tel: [phone] x30209; Fax: [phone]; E-mail: [email protected], [email protected]

I. INTRODUCTION

The consequences associated with obesity and poor nutrition have become a worldwide concern. According to the World Health Organization, more than 3.4 million people die each year from health problems stemming from overweight and

obesity [1]. This number is far from subsiding. The proximity, low cost and ease of accessibility of foods with high caloric density takes center stage of this epidemic. Sweet and fatty energy-rich foods are rewarding and our strong preference for these foods is posited to have evolved to maximize growth and survival [2, 3]. A state of positive energy balance develops when energy intake surpasses energy expenditure, resulting in the storage of excess calories. Indeed, the coupling of over-nutrition with reduced physical activity has led to a doubling in obesity rates since 1980 [1]. This increase is largely due to individuals in developing countries adopting similar lifestyle habits evident in North America: excessive intake of sugars, fats and processed foods and increased sedentarity [4] [5].

Conditions such as cardiovascular disease, cancer, type 2 diabetes and metabolic syndrome are typical ramifications of obesity [6]. Although less recognized, mood disorders account for a significant proportion of obesity comorbidities. Depression is a multifactorial disease that represents a major global health burden [7]. Several lines of evidence highlight a positive correlation between obesity and the development of depressive symptoms. Obesity and the metabolic syndrome are both strong predictors of the onset of depression [8, 9]. Moreover, the significance of weight gain in the link between obesity and depressed mood is suggested by the negative correlation between body mass index (BMI) and emotional state [10, 11]. Of key significance however, the risk of depression in obese individuals appears to depend on metabolic dysfunctions [12, 13]. Obese individuals characterized as metabolically healthy (normal blood pressure, insulin sensitivity, inflammatory and lipid profiles) are much less susceptible to developing depression [12, 13]. Finally, the association between obesity and depression is bidirectional [14]. As adaptations in the neural circuitry controlling emotional state can develop with weight gain and obesity, depressed mood can also lead to overeating to compensate for a reduced affective state [15^-17]. Thus, the complex interface between emotions, food choice and eating behaviour can contribute to a vicious cycle whereby mood impairments can drive poor eating habits and further weight gain [18].

There is a physiological basis underlying the relationship between obesity and depression [19]. At the core of the problem lies alterations in the communication between metabolic tissues and the brain that perturbs signalling in the neural network controlling mood. Reviewed in greater detail in preceding chapters, the circuitry controlling emotions and mood regulation largely resides in corticolimbic and midbrain regions nuclei including the prefrontal cortex (PFC), nucleus accumbens (NAc), dorsal striatum, amygdala, hippocampus and ventral tegmental area (VTA) [20]. Dopamine (DA) release in corticolimbic sites plays a central role in the control of motivated behaviour and mood and is well-implicated in the neuroplastic responses to palatable food intake, weight gain and associated changes in metabolic signals [20, 21]. DA interacts with opioids, serotonin and endocannabinoids in corticolimbic regions and receives input from hypothalamic nuclei that direct energy homeostasis by controlling food intake and energy expenditure [22].

The aim of this chapter is to present an overview of the current status of our knowledge of the biological processes contributing to depressive symptomatology in obesity. The stress axis and alteration in glucocorticoid function in both obesity and depression will be reviewed. Next, a significant part of the discussion is dedicated to growing evidence for the role of the inflammatory processes common to obesity and depression and their impact on neurotransmission and neural plasticity. This will be followed by an overview of the principal peripherally-derived metabolic hormones and nutrients that modulate mood. The chapter will conclude with a review of both available and promising pharmacotherapies for the alleviation of depression co-morbid with obesity.

II. STRESS, OBESITY AND DEPRESSION

By definition, stress is a ...

Table of contents

• Welcome
• Table of Contents
• Title Page
• BENTHAM SCIENCE PUBLISHERS LTD.
• The Search For Novel Antidepressants
• PREFACE
• List of Contributors
• Innovative Solutions to the Development of Novel Antidepressants
• Animal Models of Depression: Current Status and Perspectives
• Potential Role of Optogenetics for The Development of Novel Antidepressants
• The Relevance of Studies in Healthy Human Volunteers for The Development of Novel Antidepressants: Exploring Endophenotypes
• Monoamine Oxidase-A: A Valid Target for the Management of Depression
• Repurposed Drugs: A Shortcut to the Discovery of Novel Antidepressants?
• Ketamine and Glutamatergic Compounds: Exploring Biomarkers and Mechanisms Related to Rapid Antidepressant Action
• Novel Antidepressant Targets for Cognitive Dysfunction in Major Depressive Disorder
• Oxidative and Nitrosative Stress, Immune Inflammation and Trptophan Catabolites in Driving Melatonergic Pathway Alterations in Depression: Treatment Implications
• Novel Non-Monoaminergic Antidepressants: Focus on Neuropeptides
• Novel Antidepressant Drugs: Exploring Neurotrophins and Intracellular Signaling Pathways
• Shared Pathophysiology between Depression, Obesity and Metabolic Disturbances: Novel Antidepressant Targets?
• The Development of Novel Antidepressants: Focus on Plant-based Drugs