Mood Disorders in the Twenty-First Century

doi:10.1017/9781108973922.002

Chapter 1 - Mood Disorders in the Twenty-First Century

Published online by Cambridge University Press: 16 May 2024

Jair C. Soares and

Edited by

Jair C. Soares and

Allan Young: Affiliation:
Institute of Psychiatry, King's College London
Marsal Sanches: Affiliation:
Baylor College of Medicine, Texas
Jair C. Soares: Affiliation:
McGovern Medical School, The University of Texas
Mario Juruena: Affiliation:
King's College London

Book contents

Summary

Mood disorders are among the most prevalent and potentially severe mental disorders. These conditions are associated with important psychological morbidity and functional impact, as well as elevated rates of suicide. While the past several decades have produced valuable contributions to the understanding of the pathophysiology of mood disorders, currently available treatments at times fail to produce full remission and restore patient’s premorbid level of function. Nevertheless, promising new agents and novel therapeutic targets are currently under investigation. The twenty-first century is looking at an individualized approach for the management of mood disorders, with the proper integration of evidence-based, effective biological and psychosocial therapeutic modalities.

Keywords

depression major depressive disorder bipolar disorder pathophysiology

Type: Chapter
Information: Clinical Textbook of Mood Disorders , pp. 1 - 9

DOI: https://doi.org/10.1017/9781108973922.002 [Opens in a new window]

Publisher: Cambridge University Press

Print publication year: 2024

Introduction

Mood disorders are among the most prevalent and potentially severe psychiatric disorders. In the case of major depressive disorder (MDD), despite great geographical variations, data from the World Health Organization point to approximately a 6% 12-month prevalence and a 20% lifetime prevalence [Reference Bromet, Andrade and Hwang1]. With regard to bipolar disorders (BD), epidemiological findings indicate a lifetime prevalence of 0.6% for bipolar type I and 0.4% for bipolar type II, with a 2.4% prevalence when all bipolar spectrum conditions are considered [Reference Merikangas, Jin and He2]. In addition to their significant impact on functional status and quality of life, mood disorders are associated with considerable psychological suffering and elevated rates of suicide [Reference Gaynes3]. Moreover, available evidence shows association between mood disorders and an increased risk for different medical conditions, including cardiovascular disease, diabetes, metabolic disorders, obesity, dyslipidemia, hypertension, and dementia [Reference Wells4,Reference Danese, Moffitt and Harrington5].

Considering all these potential implications of mood disorders for individuals, families, and communities, their early diagnosis and effective management are essential. Researchers have strived to better understand the pathophysiology of these conditions and to identify predictive factors related to response to treatment and outcome [Reference Cleare, Pariante and Young6]. Nevertheless, despite important advances in the management of mood disorders, studies estimate that the currently available antidepressant treatments may be ineffective in 30–50% of patients with MDD [Reference Fava7–Reference Rush, Trivedi and Wisniewski9].

In light of these limitations, as well as the complexity of society in the twenty-first century, which can make the management of mental disorders particularly challenging, a personalized approach for the treatment of mood disorders is highly desirable [Reference Young and Juruena10]. Multidisciplinary collaborations, including the combination of pharmacotherapy with different psychosocial interventions, are strongly recommended.

Diagnostic Aspects

A fundamental limitation of the currently adopted diagnostic systems is related to the inexistence of established biological markers for the different psychiatric conditions. Consequently, the diagnosis of mood disorders is based mostly on the presence of certain criteria, usually comprised by certain core symptoms and specific history data. The Diagnostic and Statistical Manual of Mental Disorders (DSM), currently in its fifth edition (DSM-5), is the best example of such approach.

While these systems usually offer a good degree of diagnostic reliability, they may face problems in contemplating the considerable phenotypical overlap found across different types of mood disorders. Alternative diagnostic formulations, utilizing a dimensional approach in contrast to the standard categorical diagnostic systems, try to take these limitations into consideration. These approaches are based on the idea of a continuum across different mood disorders, being aware of not only clinical but also biological factors shared by different mood disorders.

It is expected that these diagnostic and nosological limitations will be overcome by the identification of validated biomarkers for mood disorders. Based on neurobiological and genetic findings, biomarkers will allow the integration of neuroscience into psychiatric diagnostic practice. By routinely incorporating data on biomarkers, future diagnostic systems should allow the integration of clinical, etiological, and pathophysiological factors, improving our diagnostic accuracy and having the potential to revolutionize the practice of psychiatry.

Depressive Disorders

The impact of depression on individuals’ lives results from a combination of genetic vulnerability and environmental risk factors [Reference Dube, Anda and Felitti11,Reference Kendler, Sheth, Gardner and Prescott12]. While the biological mechanisms behind depressive disorders are not yet completely understood, they seem to involve the hypothalamic–pituitary–adrenal (HPA) axis, genetic and neurodevelopmental factors, monoaminergic deficiencies, and other possible mechanisms [Reference Belmaker and Agam13], such as alteration of the intestinal microbiota [Reference Jiang, Ling and Zhang14,Reference Nikolova, Smith and Hall15].

The influence of stress on the pathophysiology of depression is well known [Reference Navarro-Mateu, Tormo and Salmerón16,Reference Post17]. Many depressive patients experience disturbances in the regulation of the HPA axis, and these dysfunctions are often reflected in changes in cortisol concentrations in blood and saliva [Reference Gold18,Reference Brown, Varghese and McEwen19].

Similarly, abnormalities involving the gut microbiota and the bidirectional communication of the intestine-brain axis [Reference Cryan and Dinan20] have been found to be involved in the pathophysiology of depression. Changes in the composition of the intestinal microbiota, due to factors such as age, diet, stress, use of antibiotics, prebiotics and probiotics, immune status, and intestinal transit [Reference Nikolova, Smith and Hall15,Reference Yatsunenko, Rey and Manary21] may result in intestinal dysbiosis, which shows important correlations with depression and other mental disorders [Reference Nikolova, Smith and Hall15,Reference Yarandi, Peterson, Treisman, Moran and Pasricha22]. Numerous authors recognize this bidirectional gut-brain communication via the autonomic nervous system (ANS), enteric nervous system (ENS), and neuroendocrine and immune systems [Reference Clarke, Grenham and Scully23,Reference Neufeld and Foster24].

Approximately 50% of individuals who receive treatment for a depressive episode will experience a second episode over their lifetime, usually within 5 years, with a lifetime average of four depressive episodes [Reference Kupfer25,Reference Fava, Park and Sonino26]. Moreover, it is estimated that 30 to 50% of depressed patients do not achieve full remission [Reference Rush, Trivedi and Wisniewski9,Reference Quraishi and Frangou27], and patients with depression may have persistent and severe psychosocial and occupational impairments, even after recovery from an acute episode [Reference Ay-Woan, Sarah, Lyinn, Tsyr-Jang and Ping-Chuan28].

Last, as previously mentioned, suicide rates are elevated among individuals with depression. In the National Comorbidity Survey Replication, the risk of suicide attempts in MDD was found to be fivefold higher than in the general population in the United States [Reference Nock, Hwang, Sampson and Kessler29].

Bipolar Disorders

Despite numerous advances observed in the last several decades with regards to the understanding of bipolar disorder (BD), its underlying neurobiological mechanisms remain far from being fully elucidated [Reference Juruena, Jelen, Young and Cleare30]. This results in several limitations involving its diagnosis and treatment, especially with regard to depressive symptoms or episodes.

That is complicated by the fact that approximately 35% of patients with bipolar disorder experience a delay of up to 10 years between symptom onset and the correct diagnosis. Even though BD is typically characterized by alternating periods of depression with symptoms of mania or hypomania, depression is usually the main reason patients with BD seek treatment [Reference Judd and Akiskal31]. Thus, the misdiagnosis of BD as MDD is common, causing delays in the implementation of the most appropriate therapeutic measures [Reference Angst, Azorin and Bowden32].

Currently available treatment options for bipolar disorder are often insufficient to help patients achieve full remission and restore their premorbid functioning. However, in the past few years, we have witnessed a more wide-ranging understanding of the neural circuits and the various mechanisms of synaptic and neural plasticity, the molecular mechanisms of receptors, and the process by which genes code for specific functional proteins [Reference Post33,Reference Barichello, Giridharan and Bhatti34]. It is expected that these advances will help in the identification of novel therapeutic targets.

Moreover, while pharmacological treatment is considered essential for the management of this condition, a growing amount of evidence has emphasized the importance of nonpharmacological interventions, such as psychoeducation and different psychotherapy modalities, in improving patients’ understanding of their illness and their treatment adherence, as well as helping with the identification of prodromal symptoms and early signs of relapse, providing family support, and offering psychosocial rehabilitation [Reference Fountoulakis and Vieta35].

Mood Disorders, Neuroimaging, and Cognition

Cognitive deficits in patients with depression and BD have been the object of great interest, given their importance from a functional and psychopathological perspective [Reference Sanches, Bauer, Galvez, Zunta-Soares and Soares36]. Neuroimaging studies point to the involvement of dysfunctions in neural networks connecting the limbic system and cortical regions in the pathophysiology of mood symptoms and cognitive impairment [Reference Rayner, Jackson and Wilson37,Reference Savitz and Drevets38]. Areas involved in the pathophysiology of cognitive dysfunction in depression include regions of the prefrontal cortex, cingulate cortex, hippocampus, striatum, amygdala, and thalamus [Reference Nestler, Barrot and DiLeone39].

For example, the neocortex and hippocampus collaborate by mediating cognitive aspects of depression, such as guilt, impaired working memory, feelings of worthlessness, and suicidal ideation. On the other hand, interactions between the amygdala and the hippocampus can mediate anhedonia, anxiety, and loss of motivation, in addition to mnemonic changes [Reference Richardson, Strange and Dolan40]. Naturally, these identified regions act in coordination with other parallel circuits, possibly forming a neural network underlying depression [Reference Nestler, Barrot and DiLeone39,Reference Mayberg41–Reference Afifi and Bergman43].

Within this perspective, cognitive impairments in depression may result from high levels of cortisol resulting from stressful situations or dysfunctions in the HPA axis. In response to the prolonged action of stress, the organism passes from a slower conscious control of the top-down type regulated by cognitive processes and memory to an emotional control of the bottom-up type, which is faster and reflexive and related to the amygdala and subcortical structures [Reference Vogel, Fernández, Joëls and Schwabe44].

Depression has been linked to deficits in a wide variety of cognitive domains. During depressive episodes, the most well-known cognitive deficits are a decrease in performance in tasks involving a change of attention focus, memory impairment, and problems related to executive function [Reference Beblo, Sinnamon and Baune45,Reference Taylor, Tavares, Drevets and Sahakian46]. In addition, studies have demonstrated the effects of mood disorders and stress on global cognitive performance [Reference Loman, Wiik, Frenn, Pollak and Gunnar47,Reference Rutter and O’Connor48], executive functioning [Reference Pollak, Nelson and Schlaak49,Reference Colvert, Rutter and Kreppner50], and memory [Reference Young, Gallagher and Watson51–Reference Navalta, Polcari, Webster, Boghossian and Teicher54], in addition to reward processing, processing of social and affective stimuli, and emotional regulation [Reference Pechtel and Pizzagalli55].

Studies investigating cognitive deficits in depressive patients have reported results similar to those with participants who suffered early stress, either in global cognitive performance [Reference Beblo, Sinnamon and Baune45], in executive functions [Reference Kaymak, Demir and Sentürk56–Reference Neu, Bajbouj and Schilling57], and memory [Reference Reppermund, Ising, Lucae and Zihl58]. Thus, the cognitive impairments that result from depression may overlap with deficits related to early stress. Therefore, authors must be aware of depression as a factor to be included in the analysis of the effects of early stress on cognition [Reference Grassi-Oliveira, de Azevedo Gomes and Stein59].

Biomarkers and Pathophysiology

The search for biological markers in psychiatry has proved arduous and somewhat thankless. According to the FDA-NIH Biomarker Working Group, a biological marker is “a defining characteristic that is measured as an indicator of normal biological processes, pathogenic processes or responses to an exposure or intervention” [Reference Cagney, Sul and Huang60]; however, in clinical practice, a good biomarker must have high reproducibility, that is, be present in the vast majority of patients with the same disease, and ideally be dynamically and reliably modified as the clinical picture progresses [Reference Califf61]. Unfortunately, these definitions determine biological markers for psychiatric diseases to be almost unobtainable, given the high rates of comorbidity between different conditions and the fact that dysfunctions in the same neural circuits seem to be involved in the pathophysiology of different mental disorders. Moreover, when discussing biomarkers, it is necessary to consider the importance of genetic polymorphisms and the fact that gene expression can be influenced by different factors and regulatory processes. Therefore, not only gene–gene but also gene–stress interactions are likely to play a cumulative role in the predisposition to mood disorders.

For example, evidence suggests that changes in the hormonal system from stress can induce distortions of thinking and memory and worsen depressive symptoms and bipolar disorder [Reference Watson, Gallagher, Ritchie, Ferrier and Young62]. These abnormalities appear to be related to changes in the ability of circulating glucocorticoids to exert their negative feedback on the secretion of HPA axis hormones by binding to mineralocorticoid (MR) and glucocorticoid (GR) receptors in HPA tissues [Reference Juruena, Agustini, Cleare and Young63]. MR receptors in the brain are involved in regulating stress hormone secretion and complex behaviors such as emotion, memory, and sleep. In humans, the role of MR and GR receptors in the pathophysiology of stress-related psychiatric disorders has not yet been sufficiently characterized. However, studies indicate possibilities for new pharmacotherapies via modulation of the function of these receptors [Reference Geddes and Miklowitz64].

Furthermore, a growing body of evidence suggests that chronic inflammation and oxidative stress are involved in both the pathogenesis and progression of mood disorders, especially bipolar disorders [Reference Andreazza, Kauer-Sant’anna and Frey65], bringing about cellular dysfunction and, eventually, neuronal death. Changes in glutamatergic neurotransmission might represent the downstream effects of these processes, given the prominent role of glutamate in excitotoxicity – overstimulation of neurons via increased intracellular calcium, resulting in cell death [Reference Berk, Plein and Belsham66].

Last, changes in brain maturation follow a trajectory of development throughout life [Reference Pascual-Leone and Taylor67]. Any environmental events generating inappropriate stimulation could alter neurotransmitters, neuroendocrine hormones, and neurotrophic factors crucial for normal brain development and precipitate affective conditions such as depression and bipolar disorder [Reference Andersen68,Reference Sanches, Keshavan, Brambilla and Soares69]. Early stress may impact the development of brain structures [Reference Teicher, Andersen, Polcari, Anderson and Navalta70]. Among the neural systems most frequently implicated in the relationship between early stress and depression, those whose development is completed during childhood and adolescence, such as the amygdala, prefrontal cortex, and hippocampus, are of particular relevance [Reference Lupien, McEwen, Gunnar and Heim71].

In summary, pathophysiological research in mood disorders has moved from the classic monoaminergic theory of depression to more dynamic pathophysiological models emphasizing different levels of disruptions (genetic, neurodevelopmental, physiological, neuroanatomical/neurofunctional, and biochemical). Nonetheless, despite the strong evidence supporting the role of neurobiological abnormalities in the pathophysiology of mood disorders, a unified understanding of how these different abnormalities lead to the development of clinical mood symptoms is still missing.

Treatment

Given the complexity of mood disorders, the variability of characteristics of their clinical forms, and their course among patients, no single treatment or combination of treatments is ideal for all patients. However, appropriate treatment can drastically reduce the functional disability and high mortality associated with the disorder [Reference Fountoulakis and Vieta35].

Diverse therapeutic approaches have been used to treat mood disorders, including medications, neurostimulation treatments, and different psychotherapy modalities [Reference Weich, Nazareth, Morgan and King72]. While the selection of suitable pharmacological treatment is decisive for reaching a therapeutic response [Reference Al-Harbi73,Reference van Westrhenen, Aitchison, Ingelman-Sundberg and Jukić74], the effectiveness of psychopharmacology is also considered modest in parts due to the low adherence rate (30%) to psychopharmacological agents [Reference Weich, Nazareth, Morgan and King72]. Although contemporary pharmacological agents have revolutionized the treatment of mood disorders, long-term outcomes for many patients remain modest [Reference Rush, Trivedi and Wisniewski9,Reference Gitlin, Swendsen, Heller and Hammen75–Reference Thase77]. Therefore, exploring new therapeutic targets for mood disorders is a priority for translational research, with an urgent need for the identification of more effective treatments and the better characterization of treatment guidelines for the management of MDD and BD.

In the case of depression, although the concept of difficult-to-treat depression (DTD) helps to reframe binary definitions of treatment-resistant depression (TRD) and assess response to other treatment modalities [Reference McAllister, Williams, Arango and Blier78], therapeutic options remain limited for individuals who do not respond to conventional biopsychosocial interventions. Traditionally, neurostimulation has been considered an effective strategy for those with DTD. The estimated response rate to electroconvulsive therapy (ECT) in DTD surpasses 50%, making it one of the most effective treatments in psychiatry [Reference Buley, Copland, Hodge and Chaplin79,Reference Haq, Sitzmann, Goldman, Maixner and Mickey80]. Nevertheless, there is a trend toward decreasing the use of this effective treatment. That may be explained by the public stigma around ECT, given its historical misuse and concerns about cognitive complications [Reference Ghaziuddin and Walter81]. Although better accepted, other neurostimulation options, such as transcranial magnetic stimulation (TMS), lack the comparative efficacy and require more prolonged treatment courses [Reference Chen, Zhao, Liu, Fan and Xie82].

Furthermore, over the past 20 years, a large body of evidence has demonstrated the effects of ketamine as a rapid-acting and effective antidepressant, even in those who have failed to respond to previous treatments [Reference McIntyre, Rosenblat and Nemeroff83]. Despite being a novel treatment within psychiatry, ketamine has long been used in medical settings as an anesthetic due to its ability to provide conscious sedation with lower risks of hypotension and respiratory depression compared to other induction agents [Reference Morris, Perris, Klein and Mahoney84]. Sharp declines in suicidal ideation have been reported in association with quick improvements in mood among acutely depressed patients receiving ketamine, corroborating its potential as a valuable acute psychiatric treatment [Reference Wilkinson, Ballard and Bloch85]. As the clinical response from ketamine continues to be clarified, research exploring its underlying neurobiological mechanisms has provided new perspectives on the pathophysiology of depression. Ketamine’s antidepressant functions are largely explained through its actions as a noncompetitive antagonist of N-methyl-d-aspartate (NMDA) receptors. NMDA receptors have multiple neuronal loci, and thus, many mutually inclusive molecular pathways have been implicated [Reference Diazgranados, Ibrahim and Brutsche86–Reference Kadriu, Musazzi and Henter88].

Considering the variable response to available treatments, a more personalized approach to the management of mood disorders is of great interest. Thus, pharmacogenetics represents a promising tool for the individualization of pharmacological treatment [Reference Smith and Nemeroff89]. Therapeutic response, tolerability, and recurrence are some of the outcomes that can be affected by genetic differences between individuals [Reference van Westrhenen, Aitchison, Ingelman-Sundberg and Jukić74,Reference Tornio and Backman90,Reference Veldic, Ahmed and Blacker91]. Genetic variants account for 42% of individual differences in antidepressant response [Reference Han, Wang and Bahk92]. The incorporation of pharmacogenetic tests in clinical practice might increase remission rates and response in TRD patients [Reference Corponi, Fabbri and Serretti93,Reference Greden, Parikh and Rothschild94], in addition to decreasing healthcare costs and polypharmacy [Reference Greden, Parikh and Rothschild94,Reference Winner, Carhart and Altar95]. In the UK, the promising results obtained in several studies are compiled by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and Pharmacogenomics Knowledge Base (PharmGKB), which resulted in the development of pharmacogenetic-informed antidepressant guidelines [Reference Hewett, Oliver and Rubin96–Reference Thorn, Klein and Altman98].

Conclusion

The beginning of the twenty-first century seems to be an era likely to see an essential integration of concepts and knowledge. The full understanding of the pathophysiological pathways involved in the development of mood disorders is of pivotal importance for the development of more precise, biomarker-based diagnostic systems and more effective biological treatments. The concept of neuroprogression in mood disorders supports the need for neuroprotection with biological properties. On the other hand, psychosocial interventions for the treatment of mood disorders are of great importance and a better characterization of their therapeutic role, alone and in combination with biological treatments, is essential. By better understanding, these interactions and their relevance to mood disorders, better treatments and, ultimately, better outcomes for individuals with depression and bipolar affective disorder will be achieved.

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