Frontiers in Drug Discovery

Major depression is a serious problem of today’s society affecting approximately 14.8 million American adults, or about 6.7 percent of the U.S. population age 18 and older in a given year. In the last decades neuroscientists have focused their efforts to understand depression and find adequate antidepressant treatments. Despite antidepressant drug treatment patients continue to experience low remission rates and some patients are treatment-resistant. Furthermore, current antidepressant drugs display a slow onset of action and clinical benefits are evident only after several weeks of treatment. Most of the marketed antidepressant drugs target the brain monoaminergic systems, i.e., serotonin (5-HT), noradrenaline (NA) and dopamine (DA) sharing common mechanisms of action. Thus, new therapeutic approaches are needed. The purpose of the following manuscript is to take a journey starting from the discovery of the first antidepressant drug to the recent exciting advances in antidepressant therapeutic approaches. In particular, we summarize the discovery of monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), selective serotonin re-uptake inhibitors (SSRIs), dual acting/multi-target antidepressants and ketamine. We also discuss novel therapeutic targets such as glutamate, gamma-aminobutyric acid (GABA), neuropeptides, immune system- and brain-gut axis-related targets among others. Finally, we examine the efficacy and safety of non-pharmacological therapeutic approaches for treatment-resistant patients such as electroconvulsive therapy, transcranial magnetic stimulation, magnetic seizure therapy, transcranial direct current stimulation, deep brain stimulation and vagus nerve stimulation.

Considering the high prevalence of depressive disorders, its social burden and the limitations of currently available antidepressant treatments, animal models of depression aiming at better understanding the neurobiology of this psychiatric disorder and the development of target therapies are essential tools. Although these models fail to mimic all the aspects of this complex psychiatric disorder they have significantly contributed to the development of the field in psychiatry. In this chapter, we summarize the main models of depression that are currently used to assess depression-like phenotypes in rodents. Existing models of depression include stress-based, pharmacological and genetic models, which are evaluated in this chapter in relation to their construct, face and predictive validity as well as their contribution to our understanding of neurobiological mechanisms involved in depression and antidepressant responses.

The need for novel antidepressants is growing with the rate of depression diagnoses. Until recently, systems level analyses of brain physiology have been largely unavailable or outcomes have been overgeneralized to large subsets of neurons in depression. Optogenetics, promoting the use of genetic tools to control light-activated proteins in cells, provides neuroscientists with the ability to specifically control distinct circuits and cell subtypes in order to determine their roles in depression symptomology. This technique affords control at the systems, cellular, and molecular levels. Defining the sub-circuits, mediating depression symptomology through optogenetic studies, can provide information on the brain circuits and cell subtypes to potentially target with electrical and pharmacological therapeutics and treat depression symptoms.

Comparisons between normal individuals and patients are fundamental to improving our pathophysiological models of psychiatric disorders and promoting the development of new treatments. These comparisons are possible by focusing on the basic constituents of human behavior at different levels of organization. This chapter discusses the advantages of exploring psychophysiological, neurophysiological, and psychophysical strategies for the identification of endophenotypes shared by patients with different diagnosis and normal individuals. An integrative but experimentally viable approach to cognitive functions like attention, emotions, decision making, balance control, and social cognition is discussed. The use of new methodologies based on virtual reality for functional studies are also presented. The objective is to demonstrate that the search for new drugs, the improvement of diagnostic systems, and the identification of new endophenotypes are simultaneous and inseparable processes. The efficiency of this search depends on a close integration of pharmacological, cognitive, and neurophysiological strategies in clinical and experimental investigations.

Monoamine oxidase enzyme has been developed as a valid target for the treatment of depression. The development of selective and reversible type of monoamine oxidase-A inhibitors still remains a challenge to medicinal chemists pursuing the research towards the search of innovative chemotypes for the management of depressive states. The present chapter focuses on the history of MAO-A inhibitors, structure and biochemistry of MAO-A. It also covers challenges involved in the drug development of MAO-A inhibitors.

Drug repurposing aims to find new therapeutic indications for existing drugs in the market. Because the process of discovering a new pharmacological compound with desired clinical effectiveness is challenging, drug repurposing is being increasingly utilized in many areas. To address the unmet needs and limitations of treating depressive disorders with available treatments, many pharmacological agents are being investigated for antidepressant efficacy. For example, there have been some promising results with repurposing agents targeting acetylcholinergic and glutamatergic neurotransmission, as well as modulating immune system. Furthermore, anti-glucocorticoid agents also suggested to have possible antidepressant activity. In this chapter, we summarize the results from studies on the repurposing for treating depression of various agents, and search for perspectives on treatment strategies for depression beyond approved antidepressants.

Over the last two decades, several studies have shown the role that the glutamatergic system plays in the pathophysiology of major depressive disorders (MDD). This theory is supported mainly by the fact that glutamatergic modulators have revealed antidepressant effects in animal models as well as in clinical trials. Many of these compounds have been created to be tested as antidepressants. However, there are many other compounds used in the treatment of non-depressive illnesses that have subsequently been discovered to possess antidepressant properties, one such example being ketamine. Ketamine is an antagonist of the N-methyl-D-aspartate receptor, and it has shown to improve the symptoms of patients with MDD, including refractory depression. Laboratory studies have mainly investigated the mechanism of action responsible for the rapid and prolonged antidepressant effects presented by NMDA modulators. This chapter will focus on studies which have demonstrated the antidepressant effects of ketamine, as well as other glutamatergic modulators. Data from experimental studies and clinical trials have also been included, and these will demonstrate the biomarkers and mechanisms of action involved behind the effects of fast acting antidepressants.

Cognitive dysfunction in MDD represents one of the most frequent residual symptoms persistently following the achievement of symptomatic remission. Moreover, emerging evidence indicates that significant cognitive deficits occur early in the course of the disorder and may persist during affective remission. Cognitive impairment lowers the likelihood of achieving the functional recovery. Conventional antidepressant treatments exert a beneficial yet unsatisfactory effect on cognitive dysfunction in MDD. As a consequence, the recognition of treatments capable of specific cognitive improvements is an unmet need. Vortioxetine, a multimodal antidepressant, has cognitive enhancing properties that seem to occur independently of affective improvement. Several routes of research are evaluating the potential of several pharmacological and non-pharmacological interventions in improving cognitive performance. Agents under investigation include lisdexamfetamine, glutamatergic modulators, erythropoietin, anti-inflammatory agents as well as nutraceuticals, such as omega-3-polyunsaturated fatty acids, S-adenosyl-methionine and melatonin. Moreover, neuromodulatory, psychological and biobehavioural approaches provided preliminary encouraging results. However, further investigations are warranted to confirm these findings and to evaluate the potential pseudo-specificity of these approaches.

In this chapter we review the interactions of oxidative and nitrosative stress (O&NS), immune-inflammation, tryptophan catabolites (TRYCATs) and suboptimal mitochondrial functioning in driving changes in the melatonergic pathways in major depressive disorder (MDD). We propose that such interactive biological processes provide a framework for the development of a number of novel pharmaceutical and nutriceutical treatment targets, with relevance to a classification of MDD that is based on biological underpinnings rather than on subjective phenomenology.

Major depressive disorder (MDD) is a common illness representing a social problem worldwide, that is predicted to become the second cause of disability in 2020 by the World Health Organization (WHO), with a heavy economic burden for the western societies. The discovery of the first-generation antidepressants, i.e., monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), followed by selective serotonin reuptake inhibitors (SSRIs), dual-acting serotonin/norepinephrine reuptake inhibitors (SNRIs) and a few others, improved significantly the treatment and the prognosis of MDD, besides promoting the investigation of its possible biological mechanisms. However, the long latency of therapeutic effect, the presence of relevant side effects and the treatment’s resistance are still major problems in MDD management. For those reasons, the pharmacological treatment of MDD is still far from being satisfactory, without any significant paradigm shifts in the psychopharmacology of MDD occurring in the last decades. More recently, other mechanisms, besides monoamines’ modulation, have been explored in the attempt to discover novel and effective antidepressants. To date, a number of novel compounds acting on neuropeptide receptors have been developed and tested in both animals and humans with different results. In this chapter, we will provide a short overview of the main neuropeptides, from their biochemical and molecular characteristics to preclinical and clinical evidence in MDD.

This chapter is aimed to critically review the current literature focusing on alternative treatment strategies using novel antidepressant compounds in major depression. Major depression and stress-related disorders are associated with relevant brain changes such as loss of dendritic spines and synapses, dendritic atrophy as well as a reduction of glial cells (both in number and size) of specific brain areas such as the hippocampus and prefrontal cortex. There are several intracellular pathways (such as cyclic adenosine monophosphate pathway, Wnt/ß-Catenin pathway, and mTOR pathway) that are supposed to be involved in causing major depression. Immune/inflammatory altered pathways have been also hypothesized as one of the most relevant mechanisms implicated in the pathophysiology of major depression. Antidepressant treatment is associated with a substantial induction of neuroplasticity mechanisms reversing the pathological effects of depression and stress-related disorders. The non-competitive NMDA receptor antagonist ketamine may be defined as one of the most intriguing therapeutic options for the treatment of patients with major depressive disorder and treatment-resistant depression. Ketamine is associated with a rapid and sustained glutamate burst stimulating the BDNF-mTORC1 cascade leading to acute synaptogenic action in specific brain areas. Scopolamine, a non-selective M receptor antagonist, the effect of which is dependent on glutamate, may be identified as another rapid-acting antidepressant compound associated with induced mTORC1 and synapse formation. In addition, microRNAs (miRNAs), which regulate gene expression by targeting the three prime untranslated region of genes, have been shown to play a significant role in neurogenesis. Exploring miRNAs effects may help to develop new molecular strategies aimed to modulate the expression of certain genes with an interesting potential in the antidepressant field.

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.

Depression is a world-wide health problem that currently affects approximately 16% of the population in the United States alone. As one of the most common psychiatric disorders, it can be quite debilitating, and is certainly a major financial burden. With current medications suffering from major shortcomings that include slow onset of action, poor efficacy, and unwanted side effects, the search for new and improved antidepressants is ever increasing. Many patients may seek complementary and alternative medicine (CAM) remedies to evade the financial burden, adverse effects, or because of cultural or religious beliefs. Thus these remedies offer a valuable resource for the discovery of new and improved antidepressant medications. This chapter provides an overview of the current knowledge state regarding a variety of natural products commonly used in depression. Herbal medicines discussed have been used in clinical trials for the treatment of mild to moderate depression states include the popular St. John’s wort, saffron, Rhodiola, lavender, Echium, and the Chinese formula banxia houpu. A comprehensive review of both clinical and preclinical aspects of each of the reviewed products is provided.