Keywords

1 Introduction. Toward an Integrated Research Paradigm for Psychiatry

During the twentieth century, the field of psychiatry and mental health disciplines experienced what Kenneth Kendler (2005) rightly called the battle of paradigms . At the start of the last century, psychiatry was just establishing itself as a medical branch and as a discipline, especially in the German-speaking world. Among others, Kraepelin, Bleuler, and even Freud were discussing which etiopathogenic principles should organize the nascent psychiatry. As George Makari convincingly shown in his book Revolution in Mind: The Creation of Psychoanalysis (2008), psychoanalysis was, among other things, the proposal that Freud and his group made to the academic world in response to the question of what mental disease is, what causes it, what its mechanisms of production are, and how it should be treated. The story that followed is well-known. During the twentieth century, the rejection by academia of unconscious mental processes and of the notion that it is also possible to become ill due to biographical reasons led to the development of psychoanalysis as an independent hermeneutic discipline, which sought to become epistemologically autonomous. However, the illusion of autarky has resulted in a psychoanalysis that is isolated from natural science and the rest of the disciplines of the mind. This situation may have been inevitable, given that even though Freud never abandoned the idea that the mind and brain are two sides of the same coin and that at some point we would eventually discover drugs that could modify pathological behavior, the knowledge about the brain that academia had in the early twentieth century was not on a level with the central discovery of psychoanalysis: a dynamic mind with unconscious motivations. The neurology of the time had yet to finish describing the macroscopic anatomy of the brain; neurons and synapses were just being discovered. In this context, the main intellectual framework of psychiatry could not go beyond the anatomo-functional paradigm advanced by the German neuropsychiatrist Wilhelm Griesinger (1817–1868) some decades before: mental illnesses are brain diseases. By the way, taking advantage of current knowledge, we do not object to the assertion that mental disorders are brain disorders, with the difference that the definition of brain has changed radically. Evolutionary neuroscience (Burns, 2006; Dunbar, 2009; Dunbar & Shultz, 2007) has hypothesized that the most relevant brain for mental disorders is the so-called social brain , which only develops within the context of personal relationships; thus, we speak about mind/brain as two sides of the same coin. Thus, authors like David Taylor have proposed that “psychoanalysis is best understood as a highly specialized branch of human biology” (Taylor, 2009, p. 263).

The problem with twentieth-century psychiatry then seems to have been that each orientation defended its own paradigm as the only valid explanation and disregarded all others as mistaken or irrelevant. There was a mainstream psychiatry, the biomedical, and others more or less marginal psychiatries, like a psychoanalytical or psychodynamic psychiatry, a phenomenological psychiatry, a behavioral and social psychiatry, etc., without epistemological and methodological interconnections making constructive dialog between them possible.

Just as in the twentieth century various psychiatries were founded that responded to unique etiopathogenic theories and that did not converse with each other, we believe that the twenty-first century offers the possibility for the various etiopathogenic theories and models to interact with each other, in order to move toward an integrated paradigm in mental health. Just as hysteria was the psychopathological model around which Freud built psychoanalysis, the interdisciplinary study of depression offers the possibility that the different etiopathogenic orientations interact with each other. In depression, we have theories and models with a sufficiently developed empirical basis that range from genetics to culture, including biochemical, brain, psychological, and sociocultural models. Such integration of models can only favor patients as it would promote a personalized treatment appropriate to the different groups of depressed patients. Thus, in the scientific study of depression, we have enormous challenges. Not only building a paradigm that allows theories and models of disparate levels of organization to converse with each other but also relating these to the architecture, functions, and connectivity of the brain.

2 Depression Is a Highly Prevalent and Heterogeneous Condition

Depression constitutes a recurrent, frequently chronic, condition requiring long-term clinical management (Hardeveld et al., 2013). Its prevalence among the general population varies from less than 10% and up to 25%, is higher in women than men (Bromet et al., 2011), and, by 2030, is estimated to top the ranking of burden of disease, as measured in disability-adjusted life years (W.H.O, 2008). Both genetic and environmental factors have been implicated in developmental pathways to depression (Saveanu & Nemeroff, 2012; Sullivan, Neale, & Kendler, 2000). In relation to diagnosis, it has been seen that depression is not only misdiagnosed but also frequently overdiagnosed and also underdiagnosed, depending on the population studied and the professionals in charge of diagnosis (Cepoiu et al., 2008). Furthermore, despite the unquestionable progress in the understanding the biological bases and etiopathogeny of depressive disorder (Krishnan & Nestler, 2010), current available treatments have not proven to be effective enough. Regarding pharmacological interventions, naturalistic studies such as Star*D have shown low remission rates, under 30%, at least at initial stages (Insel, 2006). Even though long-term preventive results seem to be more effective both for relapse and recurrences, psychotherapy has rendered similar short-term results compared to medication for mild to moderate cases (Moras, 2006).

According to the World Federation of Societies of Biological Psychiatry, the future of the psychopathology lies in the so-called integrative psychopathology, which depends on the close collaboration with other branches of science concerned with the study of psychiatric phenomena, thus linking theoretical and conceptual knowledge with the findings of empirical research. The main tasks pursued by this approach are the following: to record and describe experimental and behavioral abnormalities within the intersubjective context, to explain their origin from an objective scientific perspective, and to make an effort to understand these abnormalities based on the subjective experience of the patient (Musalek et al., 2010). Berrios (2011) also states that every discipline requires periodical calibration, understood as the adaptation of descriptive language to remain accurate as regards the field of study. Consequently, given the current development of scientific knowledge, and in order to avoid reductionism, understanding depressive disorders requires a multidisciplinary approach that examines depression within the context of the complex mind/brain system (Kendler, 2008).

3 Historical and Clinical Considerations About Depression

Affective states present the first obvious feature: in almost all the cases, they represent, independently of its intensity, experiences in some way already known by the sufferer. In contrast, it is out of our habitual experience to feel – as in phenomena associated with psychosis – that a mysterious evil force controls our thoughts or that anonymous internal voices are commenting on our actions. However, who has not felt anguish at some point in life or suffered pain and deep sadness as a result of some disappointment in love or the loss of a loved person? In other words, what we name as the affective states, no matter how deep or long-lasting they might be, are intuitively grasped. The “affects” have the same quality even when they are not connected with discrete circumstances. If we were to pursue this thought further, the question arises: what do we mean when we talk about affective experiences and use words like mood, emotions, or feelings? Although, as we have said, affective states constitute experiences that we all have had at some point, it is not easy to describe them clearly.

Although there are records of mood disturbances since Egyptian civilization, in Old Testament passages and Plato’s Timaeus, these disturbances began to be considered as possible “medical” diseases from the first descriptions of the school of Hippocrates 25 centuries ago. It was thought that the principles of life were “humor” that in health were perfectly balanced. The excess, the fault, the migration to body regions different of their natural locus, produced illnesses. Melancholy, etymologically, means “black bile,” thus indicating the alteration of one of the fundamental humors: the atrabilis. Areteo de Cappadocia (150 ad) is considered to be the first to observe in the same person alternation of mood exaltation and melancholy. He described such fluctuations as a disease of males, adolescents, and young people. Later, Galen (130–200 ad), a Greek physician, described melancholy as a chronic and recurrent disease. For him, mania (exaltation of mood that strictly means “fury”) could correspond to primary brain disease or be secondary to other diseases. His observations remained influential through much of the Middle Ages. In a recent paper, Kendler (2020) outlines the process by which European Psychiatry between 1780 and 1880 changed the conception of melancholy as primarily a disorder of the intellect, with or without sadness, to one where it is conceived as a mood disorder, in turn causing cognitive disorders such as delusions. In Kendler’s narrative, the first decisive movement away from the cognitive paradigm was made by the Belgian psychiatrist Joseph Guislain (1852) who, writing just after the mid-nineteenth century, defined elementary melancholia as a disorder of mood and then focused on the neglected but illustrative category of non-delusional melancholia. Such patients demonstrated no abnormalities of intellect or judgment. This form of melancholia was, he suggested, a disorder primarily of mood. At the end of the nineteenth century, many authors (Griesinger, Sankey, Maudsley, Krafft-Ebing, and Kraepelin) accepted the primacy of mood in the cause of melancholy and proposed that delusions arise understandably from a deeply altered affective state of mind. Delusion is not the cause of misery, but it engenders it in the mind’s attempt to seek an explanation.

Emil Kraepelin (1856–1926) systematized much contemporary psychiatric knowledge in his psychiatry textbook (Lehrbuch der Psychiatrie). There, he used the expression manic-depressive illness (MDI), which he characterized as periodic and circular mood disturbances, simple mania, melancholy, some cases of amentia, and certain personal constitutions considered as pathological dispositions of humor, which he called fundamental states (Kraepelin, 2012). For Kraepelin, all these pictures represented diverse manifestations of a single pathological process (with types or subgroups more or less differentiated from each other). The contribution of the German psychopathologist can be summarized in three fundamental observations: (1) no reactivity, that is, a lack of association with some external triggers (hence, its “endogenous” character); (2) a similar prognosis that never led to psychic deterioration (as was the case with the dementia praecox, group later called schizophrenia by Eugen Bleuler); and (3) a marked family aggregation, i.e., a hereditary pattern.

Contrary to what might be thought, the classification proposed by Kraepelin considered a series of clinical pictures which, under the current diagnostic criteria, are far from what is strictly known as bipolar disease. In fact, Kraepelin’s ultimate aim was to achieve a correlation between etiopathogenesis, pathological anatomy, clinical description, evolution, and prognosis, ahead of what many years later would be the five criteria – also called phases – proposed by Robins and Guze (1970) as requirements for establishing the validity of a diagnosis in psychiatry: (1) clinical description, (2) laboratory studies, (3) differentiation with other disorders, (4) follow-up studies, and (5) family studies.

In 1980, the term bipolar disorder (BD) was incorporated into the American Psychiatric Association’s (DSM-III) classification system for mental illness. Since then, research has expanded considerably, to encompass what is now known as the affective spectrum and bipolar spectrum (Akiskal, 1996; Akiskal et al., 1977; Akiskal & Pinto, 1999; Angst, 2007; Angst et al., 2018; Cassano et al., 2002) (see Chap. 2). Thus, it has been suggested that there should not be a categorical distinction between bipolar and unipolar disorders; on the contrary, it is thought that some fluctuations (to a different degree) would be present in both entities. This perspective facilitates an understanding of disorders such as recurrent brief depression, the “soft” bipolar spectrum, and cyclothymia. In the case of unipolar depression, Ghaemi et al. (2012) has proposed a dimensional classification of the depressive spectrum disorders. In addition to questioning the scientific validity of the construct, Ghaemi suggests that “major depressive disorder” represents a broad spectrum of depressive conditions (from the most chronic and mild pole to the most episodic and severe pole). Regarding melancholy – a term used to refer to the old “endogenous depression” – there is currently enough evidence to consider it an autonomous clinical category with both psychopathological (environmental reactivity, marked anhedonia, high recurrence, psychomotor alteration, cognitive alterations, and specific vegetative alterations, such as insomnia, low appetite, decreased sexual desire, and a daytime variation with morning worsening and evening improvement) and biological specificities (hypercortisolemia, altered sleep pattern, with decreased REM latency, increased REM time, and decreased deep sleep). In addition, melancholic patients respond better to biological treatments (drugs or electroconvulsive therapy) than to placebo or psychotherapy (Parker et al., 2010; Taylor & Fink, 2008).

As we noted, mood disorders form a heterogeneous clinical group that tend to involve a marked family aggregation, an episodic nature (with variable periods of interepisodic normality), and more or less serious alterations of behavior and psychic processes. Its essential phenomenon is recurrent mood disturbance. According to Jaspers (1996), in abnormal affective states, it is necessary to distinguish two situations: (1) abnormally increased affective states, which can be understood in terms of origins in life circumstances, and (2) altered affective states, whose origin are not caused by external events or conscious causes (“feelings without object”), that is, it is endogenously determined. Therefore, disregarding for the moment the symptoms and attending only to their structure, mood disorders are best defined not by their polarity but by the recurrence of episodes. These episodes are presented to the clinician either by the alteration (increase or decrease) of known psychic phenomena (usually experienced) or by the appearance of such phenomena without a clearly identifiable motivation. However, as we saw, mood disorders can be characterized by their relationship to the polarities represented by mania and depression. In fact, Kraepelin is responsible for the designation of “manic-depressive psychosis” to the whole of what is now called mood disorders and not just the group of bipolar disorders.

3.1 Affective Temperaments

The relationship between temperament as a manifestation of personality and mood alterations comes from Greek antiquity (Berrios & Porter, 1995). Throughout history, the relationship between personality and depression has been conceptualized in at least four ways (Hirschfeld, 2013): (1) personality is a predisposing or vulnerability factor for the development of depression; (2) personality changes are a consequence of mood swings resulting from depression; (3) personality is a subclinical manifestation of depression (affective temperaments); and (4) personality characteristics influence the way depression clinically manifests itself (pathoplastic model).

At the beginning of the last century, Kraepelin (2012) distinguished between affective episodes that disrupted normal functioning (and that generally came as a result of external influences), from those manifestations – the so-called fundamental states – that chronically persisted, independently of such episodes. These alterations consisted of certain characteristics, which he called “constitutions.” He classified these into depressive (“constitutional depression”), manic (“constitutional excitement”), irritable, and cyclothymic (successive alternation of depression and excitement). According to Kraepelin, the “depressive constitution” is characterized by a gloomy and insecure attitude, often accompanied by doubts and worries, with a tendency to sterile cavillations, especially of the hypochondriac type. Often the person feels overwhelmed and desperate, saying that “he has always felt this way.” Everything seems serious to them, full of fears, feelings of guilt, and self-reproach. Each task is transformed into an unattainable enterprise; they devote themselves to their duties with abnegation but are unable to enjoy them. Many of these characteristics are present from youth in a more or less constant way, but it can also be the case that they are imperceptibly transformed into affective episodes, which – Kraepelin says – reveals the intimate kinship that unites the manic-depressive illness with the depressive constitution, the latter corresponding to a preliminary state of the illness. Something similar was described by Kretschmer – with the picnic type in 1925 – and Sheldon – with the endomorphic constitution in 1940 – linking affective psychosis with the cycloid temperament and a particular form of physical constitution characterized by an increase in volume in the visceral cavities, tendency to fat deposits in the lower part of the trunk, rather fine thorax, and thin limbs, with small hands and feet. However, at present no clear evidence has been found regarding the association between bipolarity and body mass index (Ikeda et al., 2018).

Several decades later, in his text of 1946, Kurt Schneider referred to psychopathic personalities as “those personalities who suffer because of their abnormality or because of whose abnormality society suffers” and included in this group depressive psychopaths (Schneider, 1997). The fundamental state of mind of these subjects does not have such a direct relationship with temperament as is the case of hyperthymic psychopaths; however, they also suffer from a constantly oppressed state of mind and a pessimistic and skeptical view of life. They are insecure, anxious, lacking in self-confidence, flooded by multiple doubts and ponderings, and incapable of enjoying themselves, as if they were immersed in deep, grave, and heavy grief.

Later, Hubertus Tellenbach (1976) developed the concept of typus melancholicus to refer to a set of character traits that determine premorbid personality in melancholic depression. For Tellenbach, the essential constituent trait of the depressive is the fixation on a quest for order. This is characterized by its meticulousness, scrupulosity, hypernomy (excessively rigid adaptation to social norms and established practices, leading to a stereotyped application of rules regardless of context), heteronomy (exaggerated influence of usual external practices, where each action of the subject is guided by impersonal motivations referred to socially established criteria), and intolerance to ambiguity, in addition to a permanent interest in the fulfillment of work tasks and an excessive concern for performance, especially compared to others. However, these temperamental dispositions only constitute the premorbid personality of depression. In current thinking, there is a tendency to revisit the concept of affective temperaments (depressive, hyperthymic, cyclothymic, irritable, and anxious), considering them as subclinical manifestations of some disorder within the affective spectrum (Akiskal & Akiskal, 2005). These temperaments have been shown to be universal, with distinctive characteristics and without gender differences (Vazquez et al., 2012).

Throughout life, people face two fundamental psychological challenges: (1) to maintain close, reciprocal, and meaningful interpersonal relationships and (2) to maintain a differentiated, coherent, realistic, and integrated sense of self. Based on these polarities of relationality and self-definition, Blatt (2008) has developed a theoretical model for understanding psychological development, personality organization, sources of psychopathology, and mechanisms of change in psychotherapy. This model is based on a conception of nonlinear, dialectical, and complex psychobiological development in which the progress of certain domains allows the parallel advance of others, such as occurs with the development of the sense of self and interpersonal relations. Its main assumption is that the quality of the depressive experience depends on the personality whose development occurs in a dialectical and synergic interaction between the tendency toward self-definition (identity) and interpersonal relatedness (Blatt & Luyten, 2009). These dimensions have been called, respectively, introjective (autonomy/perfectionism) and anaclitic (dependence/sociotropy). Both dimensions are associated with different personality structures, different relational and attachment styles, a vulnerability to specific environmental events (failure versus loss), a certain clinical presentation, and a characteristic response to pharmacological or psychotherapeutic treatments (Blatt, 2015).

As we have seen, the historical analysis shows that it has not been easy to distinguish and classify depressive states. Current classification manuals such as the DSM-5 have multiple weaknesses when it comes to capturing the full complexity of symptoms typical of depressive experiences (K. S. Kendler, 2016).

4 Depression as a Common Disorder: Depression and General Health

For over 100 years, psychiatry has tried to bring order to the heterogeneity of mental diseases. The synthesis we have made of the history of the psychopathology of depression in the spectrum of affective disorders may give the impression that most depressive conditions are severe or psychotic conditions. However, as pointed out by Glen Gabbard (2000), depression covers the entire spectrum of pathology and health and can be present in mild forms at certain times of stress even in basically healthy people. Individuals with minor depression, i.e., those who fail to meet the DSM criteria for major depression or dysthymia, are responsible for more days of disability than people with major depression. In addition, physicians in the healthcare system see more patients with depressive symptoms than with clearly defined depressive disorders.

We already know that depression is the world’s leading cause of disability and contributes significantly to the overall global burden of disease (WHO, 2008). But that’s not all, because nearly a third of all people with long-term physical conditions have a comorbid mental health problem such as depression or anxiety disorders. These mental health conditions increase the cost of healthcare by at least 45% for a wide range of conditions including cardiovascular disease, diabetes, and chronic obstructive pulmonary disease at each level of severity. Moreover, half of all patients referred for first consultant appointments in primary care level have medically unexplained symptoms, such as back pain, chest pain, and headache (Nimnuan et al., 2001).

There is another important issue: the social gradient of mental illness. Rates of depression, anxiety, and psychosis combined are much higher in the lower quintiles of incomes. Reducing health inequalities clearly requires a much more vigorous approach to mental illness, especially common disorders such as depression and anxiety (Layard, 2012). Several studies have shown the causal impact of environmental and psychosocial factors on the etiology of depression, especially its moderate and subclinical forms (see Chaps. 3, 4 and 12).

5 DSM in the Spotlight

The “battle of paradigms” between different currents and orientations in psychiatry has its origin in the different etiopathogenic theories that support them. Medicine took a giant step when it began to connect symptoms with underlying physiological mechanisms , i.e., semiology with pathophysiology. What would become of medicine if we did not yet know the different mechanisms of production of different types of fever? The pathophysiological knowledge facilitates the application of treatments based on the mechanism of production of symptoms and conditions. This is also the premise behind the psychodynamic theory of pathogenesis: if the symptoms and disorders are produced by unconscious conflictive motivations, making those motivational conflicts conscious will allow patients to resolve the conflicts in the light of conscious reason and considering the dictates of reality. Thus, in Mourning and Melancholia, Freud (2000) advanced the idea that behind depressive symptomatology there is an unconscious mourning process with special characteristics. If normal grief is a conscious reaction to the loss of a loved one or object, in melancholy the subject does not know what he or she has lost and all reproaches for the lost object turn against him or herself. Every psychotherapist, beyond the psychodynamic orientation, knows the therapeutic power of this theory of grief to understand and explain depression to patients. However, clinicians, no matter the range of causal theories they use, also know that not all in depression can be understood by the analogy with grief. Meanwhile, pharmacological research has given us an arsenal of drugs that act at the level of neurotransmitters to treat depressive patients. The model of pathogenesis underpinning drug treatment is diametrically opposed to that proposed by Freud. However, at the time of consultation, most psychiatrists use combined treatments based on both theories of the pathogenesis of depression.

Until DSM II (1968), American psychiatry applied a nosological system based on etiology. From DSM III (1980) onward, American psychiatry broke with this tradition and tried to develop an “atheoretical” and “descriptive” nosology. With this turn, it was hoped to bring order to the existing diagnostic chaos in world psychiatry – with this change, psychiatry moved away from the rest of medicine, which continues to develop diagnoses based on etiopathogenesis. Among many problems and criticisms of the DSM system, a major one is that research in psychiatry has targeted mental disorders defined according to the criteria of DSM (and/or ICD). The central criticism points to the fact that DSM is a diagnostic system based upon clinical presentation of sign and symptom, with reasonable reliability but with a dubious validity. For example, the DSM-IV diagnosis of major depression (the diagnosis of major depression in DSM 5 is basically the same), a highly prevalent disorder, does not meet any of the commonly accepted standards of validity (Maj, 2012). So, research in psychiatry faces the major challenge of the enormous clinical pleomorphism (Mann, 2010). Conversely, it is highly likely that heterogeneous syndromes grouped into one disorder include different pathophysiological mechanisms.

Although there seems to be no other way of making a reliable diagnosis than by defining certain criteria, the real danger is that in practice the criteria are easily confused with reality. Diagnoses become ontological entities, existing beyond their definition. The DSM-5 outlines the criteria presented in Table 1.1 to make a diagnosis of depression.

Table 1.1 Depression in DSM 5
Full size table

6 The Heterogeneity of Depression

Along with the psychiatric development of the concept of melancholy and depression, during the second half of the twentieth century, the term depression became a significant part of colloquial language. Even if we don’t know exactly how to respond when someone says “I’m depressed,” everyone seems to understand immediately what they mean. Moreover, sociologists have shown that depression has become an “idiom of distress,” an expression of malaise in culture and life in society (Ehrenberg, 2010; see Chap. 4 in this book).

From a clinical point of view, depression presents itself in an extremely varied way, where the clinician can assume different causes and origins, even in cases of similar clinical presentations. Depression can refer to many different conditions: It can be a psychiatric diagnosis according to DSM/ICD criteria (MDD; bipolar disorder; dysthymia; cyclothymia); it can be the mourning response to a tragedy, such as the death of a family member. It can also be an expression of a pessimistic way of looking at life (depressive personality); it can be a transitory emotional state (adjustment disorder) or a state underlying complaint such as fatigue, weakness, lack of energy, insomnia, back pain, or headache. Finally, depression may be the response to, or expression of, an underlying medical illness.

However, from the point of view of research requirements, the heterogeneity and imprecision in the diagnosis of depression has important consequences (Mann, 2010). Research results associating biological, psychological, and environmental variables with depression have been repeatedly evaluated as disappointing. One of the most accepted hypotheses is that these results are due to the fact that the diagnosis of depression groups patients with similar clinical presentations, but with different pathogenetic mechanisms. At least three sources of heterogeneity in depression have been described (see Chap. 15).

  1. 1.

    Theoretical heterogeneity: Diagnostic heterogeneity across depression is a structural result of the polythetic diagnostic system of DSM – a given clinical diagnosis can be arrived at by using different combinations of symptoms. As a result, there are 227 different symptom combinations that follow diagnostic rules for depression (Olbert et al., 2014; Zimmerman et al., 2015); resulting combinations can be quite different and even contradictory at the phenotypic level.

  2. 2.

    Empirical heterogeneity, which requires collecting patient-level data, typically using symptoms described in diagnostic systems. Using this method, Fried and Nesse (2015) found 1030 unique symptom patterns emerging from a sample of 3703 outpatients diagnosed with depression from the STAR*D trial. An overwhelming majority of these profiles (84%) were present in only a handful of individuals, and half of the profiles were exclusively exhibited by one individual.

  3. 3.

    Instrumental heterogeneity. Whatever method is used to analyze patient-level data, symptoms need to be collected using specific instrumentation. These instruments can be interview schedules, used by clinicians, or self-report questionnaires. The underlying assumption is that all these instruments map on the same set of symptoms that constitute a prototype for depression. However, many of the widely used screeners for depression are rather idiosyncratic, that is, there is scarce content overlap between items. According to Fried (2017), all in all, the most common measures used for research in depression map on 52 distinct symptoms, and some of them are compound symptoms that can be disaggregated in such a way that even more symptoms are available. Many of these symptoms are idiosyncratic, that is, they are present in only one or two measures. According to his results, only 12% of all symptoms were present in the seven most used depression schedules or questionnaires.

7 The Research Domain Criteria (RDoC) Enters the Scene

Considering this situation, the National Institute of Mental Health has launched the Research Domain Criteria Initiative (RDoC) with the aim to “develop, for research purposes, new ways of classifying mental disorders based on dimensions of observable behavior and neurobiological measures” (Cuthbert & Insel, 2013, p. 4). The RDoC Project proposes that future psychiatric (and psychotherapeutic) research should focus on systems underlying basic psychological capacities (such as reward neurocircuitry and the neural systems implicated in self-representation, theory of mind, attachment/separation fear, and positive and negative valence systems), rather than on discrete DSM disorders. “Rather than starting with symptom-based definitions of disorders and working toward their pathophysiology, RDoC inverts this process. Basic science – in genetics, other areas of neuroscience and behavioral science – serves as the starting point, and disorders are considered in terms of disruptions of the normal-range operation of these systems, with an emphasis on the mechanisms that serve to result in dysfunctions of varying degrees” (Cuthbert & Insel, 2013, p. 4). Therefore, RDoC is a transdiagnostic approach.

In a much-quoted commentary, Thomas Insel, when director of the NIMH, and his team, published the Manifesto of the RDoC scientific initiative: “RDoC classification rests on three assumptions. First, the RDoC framework conceptualizes mental illnesses as brain disorders. In contrast to neurological disorders with identifiable lesions, mental disorders can be addressed as disorders of brain circuits. Second, RDoC classification assumes that the dysfunction in neural circuits can be identified with the tools of clinical neuroscience, including electrophysiology, functional neuroimaging, and new methods for quantifying connections in vivo. Third, the RDoC framework assumes that data from genetics and clinical neuroscience will yield biosignatures that will augment clinical symptoms and signs for clinical management.” (T. Insel et al., 2010, p. 749; italics added).

The difficulty we have in accepting this formulation is the biological reductionism it seems to establish. Such strong assumptions about the importance of biology not only presume that complex phenomena are ultimately derived from a single primary principle but also a mind-body dualism, the doctrine that separates the mental from the somatic (Engel, 1977). Biological reductionism minimizes the importance of subjective structures, the sphere of intrapsychic representational systems as moderators between the environment and the brain. “Intrapsychic representational processes are not just consequences of environmental and genetic effects – they may be critical moderators. […] For Fonagy, the primary evolutionary function of attachment may be the contribution it makes to the creation in the individual of a mental mechanism that could serve to moderate psychosocial experiences relevant to gene expression” (Fonagy, 2003 p. 108; italics in original). Human genomics, an emerging field of research, is demonstrating that external social conditions, especially our subjective perceptions of those conditions, can influence our most basic internal biological processes – namely, the expression of our genes (Slavich & Cole, 2013).

However, despite its initial impression of reductionism, a more careful look shows that RDoC takes a more sophisticated approach. In fact, RDoC does “not suppose that neural dysfunctions are the only causes of mental disorders, but rather recognize developments in mental health sciences showing that causes or risks of mental disorders may operate at many levels, including the genetic and the neural, the individual, the family environment, and the social context. Crucially, this view of multifactorial or multilevel view of causation (or risk) acknowledges and is intended to accommodate the fact that interventions at these various levels may affect onset and course, playing parts in primary prevention and management and treatment after” (Bolton, 2013, p. 24). In this sense, RDoC is a transdiagnostic and multilevel approach that recognizes “bottom-up” causation, as well as “top-down” causation. If we consider the intrapsychic representational processes as intermediate phenotypes (see Chap. 9 and 15), RDoC opens, in our view, a window of opportunity for collaboration between neuroscience and different “psychiatries” including a research-minded psychoanalysis; the twenty-first century may represent a new opportunity for an integrated psychiatric paradigm that embraces natural science and hermeneutics.

8 Depression as Part of a Complex System

One of the oldest questions in psychiatry – and one that is still very alive – concerns how the brain and mind interact and, thus, the possibility of integrating the different approaches that attempt to explain mental disorders. Kendler (2005) considers psychiatric disorders to be etiologically complex phenomena where brain → mind causality is as real as mind → brain causality; therefore, in opposition to a biological explanatory reductionism, and without abandoning conceptual and empirical rigor, he presents a model he calls integrative pluralism.

Depending on their organizational level, complex biological systems such as the human mind/brain are characterized by self-regulation, a function based on internal and external environmental aspects (where the behavior of the parties involved results from the system as a whole), and by their recursive nature, that is, by the fact that both the genetic component and the regulatory systems, determining their expression, are both influenced and affected by the environment surrounding the subject (Mitchell, 2008).

Mood disorders, as a manifestation of an alteration of a complex system like central nervous system, probably constitute the most frequent psychiatric illnesses to be reviewed and classified. From a neurobiological perspective, depression belongs in a heterogeneous group of disorders produced by abnormalities rooted somewhere in the circuitry of emotion (prefrontal cortex, anterior cingulate cortex, hippocampus, and amygdala), where the specific subtype of symptoms depends on the localization and nature of the abnormality (Davidson et al., 2002). According to Mayberg (2007), a major depressive episode can be defined as a pattern of dysfunctional interactions between specific brain regions, such as the cingulate, paralimbic, subcortical, and frontal regions, which are fundamental to maintain emotional homeostasis under conditions of endogenous or exogenous stress.

In this way, complexity is a combination of clinical (e.g., diagnostic), biological, socioeconomic, cultural, environmental, and behavioral factors that are statistically associated with clinical prognosis (Safford et al., 2007; Schaink et al., 2012). Individual patients may have protective or risk factors across these domains, and their overall complexity level results from the sum of risks. Clinical, socioeconomic, and cultural risk factors complicate healthcare outcomes by disrupting the balance between patient workload (i.e., number and difficulty of daily life demands including self-care) and patient capacity (i.e., resources and limitations affecting ability to meet demands).

The concept of cumulative complexity attempts to explain how risk factors accumulate and interact to influence healthcare outcomes (Shippee et al., 2012). In two seminal papers, Kendler, with Gardner and Prescott (2002) and with Prescott, Myers, and Neale 2003), based on studies of twins of both sexes, found a long list of predictors (risk factors) of MDD in adulthood (using DSM-III-R criteria) that grouped into five developmental tiers (see Table 1.2):

Table 1.2 MDD risk factors
Full size table

Depression is a complex behavior of a complex system that depends on multiple causes and multiple levels of organization. Nevertheless, what remains to be known are the relationships between the properties and behaviors at the different levels.

This is however a problem for the study of all psychiatric disorders. Recent studies on the structure of psychopathology have identified a general psychopathology (or “p”) factor underlying common psychopathologies. Models with such a higher-order “p” factor provide a better fit to the data than models with three high-order factors (internalizing, externalizing, and thought disorder). Since Caspi et al.’ (2014) seminal study in this area, several studies have replicated this higher-order factor (Del Giudice, 2016; Laceulle et al., 2015; Lahey et al., 2018; Murray et al., 2016) and have found that this “p” factor increases the chance of most types of common mental health problems and negatively influences the course of these problems, much as (complex) trauma (Nanni et al., 2012; Scott et al., 2012; Teicher & Samson, 2013). The “p” factor appears to be a transdiagnostic vulnerability factor that is also associated with “more life impairment, greater familiarity, worse developmental histories, and more compromised early-life brain function” (Caspi et al., 2014, p. 131). But what is this “p” factor and what are the mechanism underpinning it association with all these factors, and more specifically, how does it relate to depression?

There is increasing evidence for “p” being underpinned by a common genetic risk. A major UK study recently found genetic support for the “p” factor by comparing correlations from four different methods used to estimate genetic correlations: family study, genome-wide complex trait analysis, linkage disequilibrium score regression, and on a matrix of polygenic score correlations constructed for each individual in a UK-representative sample of 7026 unrelated individuals. All the major psychiatric disorder loaded positively on the first unrotated principal component, which accounted for 57, 43, 35, and 22% of the variance, respectively, for the four methods. Schizophrenia, bipolar disorder, and depression were consistently among the highest-loading disorders on this genetic p factor (Selzam et al., 2018).

For our purposes in here, the question then is how can we think about the nature of the trajectory for an individual who moves from being at risk through a genetic vulnerability to developing depressive disorder. Here, Cicchetti and Rogosch’s developmental psychopathology concepts of equifinality and multifinality are, as ever, relevant (Cicchetti & Rogosch, 1996). It appears that executive function and emotion dysregulation are the consistently implicated contenders for the functional difficulties that are commonly associated with most disorders (Beauchaine & Cicchetti, 2019; Macdonald et al., 2016; Martel et al., 2017). We would suggest that phenomenology of depression suggests that MDD is associated with an often serious disruption of the feeling of self and self-experience. Mentalization – the capacity to think about one’s own or other’s thoughts – becomes disrupted, often, misleadingly, replaced by concrete thinking (psychic equivalence), enactment (teleological thinking), and abstract thought unanchored in reality (pretend mode or hypermentalizing), all of which generate ruminations and increasingly unhelpful ways of thinking that become entrenched (as Aaron Beck has carefully documented). We have recently speculated that distorted mentalizing associated with psychopathology may be the “evolutionary flipside” of human social complexity, in particular the capacity for social imagination. Imagination after all is key to social understanding – we have to imagine what may be going on in the mind of a conspecific in order to engage with them in a collaborative task. Individuals whose difficulties with executive function and emotional regulation distort this key social cognitive function generate problematic outcomes from this social imaginative process and will be more likely to develop severe, persistent, and/or comorbid psychological disorder (and they come to be identified as having a high “p factor” because they experience a wide range of symptoms of mental disorder) (Fonagy et al. 2019a). We have further suggested that individuals experiencing such mentalizing difficulties will struggle to gain the regulatory benefits provided by other people’s minds – the necessary social calibration we all depend upon to maintain a balance between being socially imaginative (being open to thinking about minds and their contents) and keeping these cognitions adaptively in check. These regulatory relationships between an individual and surrounding minds are also dependent upon the presence of a sufficiently mentalizing social environment: as a result, we have placed increased emphasis on the role of community, social structures, and mentalizing systems in thinking about mental disorder and prospects for effective treatment (Fonagy & Campbell, 2019; Fonagy et al. 2019b). The role of social support in the causation and maintenance of depression has been a central part of our understanding of the disorder for the past 50 years at least (Brown & Harris, 1978).

To further complicate matters, Markova and Berrios (2012) claim that one of the reasons why many aspects within the definition of mood disorders remain elusive is that psychiatry, one of whose bases is descriptive psychopathology, constitutes a hybrid discipline combining natural science epistemology (biology) with human social sciences (semantics). For this reason, the symptoms of mental disorders can be understood as biological-semantic complexes of variable stability and, therefore, difficult to classify, requiring a new approach to systematize and interpret the knowledge gained about the said disorders.

9 Challenges in the Study of Depression

9.1 The Transdiagnostic Interactive Dynamic Model

Despite its high prevalence, the diagnosis of depression remains problematic. Over the last 30 years, the taxonomy of affective symptoms has not undergone major changes, but regardless (or perhaps because) of the amount of scientific evidence available, there is still some confusion in this area (Cole et al., 2008). We see in practice that the clinical presentation of depression not only varies among patients but also across different episodes in the life of the same patient. This clinical “pleomorphism” of depression (Mann, 2010) poses a challenge to the study of its etiopathogeny.

Currently, the medical causal model, focused on simple biological essences, has proven to be insufficient in capturing the nature of the mental disorder heuristically; it is dependent on multiple explanatory perspectives that, in addition, requires the consideration of the interaction of these elements at different levels (Kendler, 2012). Depression is a complex, clinically heterogeneous disease which can develop as a consequence of a number of factors and whose psychopathologic manifestations are related to personality and depend on the interaction of genetic and environmental factors. Hence, future psychiatric nosology should incorporate an approach integrating clinical observation and causal hypotheses (Luyten & Blatt, 2007).

As a way to solve the problems posed by the diagnostic approach to depression, Luyten et al. (2005) have developed and labelled the “transdiagnostic interactive dynamic model.” Useful across multiple clinical symptoms (transdiagnostic), this model considers the vulnerability/stress paradigm as a source of psychopathy (dynamic) and is interactive; that is, the model considers that the mental illness appears within the context of a permanent interrelation between the genes, early adverse events, vital current stressors, and the various dimensions of the personality (stable cognitive-affective schemes). Besides, it is a model based on the causes (etiologically based) and founded on theory (theoretically founded). Using this model, the authors suggest performing an assessment of depression considering the following: (1) detailed analysis of symptoms and their severity; (2) understanding depression within a dimensional context from the perspective of the vital cycle, i.e., as a deviation from natural development; (3) dynamic (vulnerability/stress) and interactive factors (genes, environment, development, and personality); and (4) a differential indication for treatment.

9.2 From “Vulnerability” to “Differential Sensibility”

The diathesis-stress model has been considered the etiopathogenic paradigm of most mental disorders. According to this model (Monroe & Simons, 1991; Patten, 2013), psychopathology originates in the interaction of premorbid constitutional vulnerability (diathesis) and environmental aggressions (stress). Nevertheless, in the past few years, it has been suggested that, rather than diathesis (understood as an organic predisposition), individuals have a differential susceptibility to environmental influences (Belsky & Pluess, 2009); this means that they are not only more vulnerable to the negative effects of an adverse environment but are also extremely sensitive to the beneficial effects of a positive and nourishing environment or even to the absence of adversity. According to evolutionary models of “biological sensitivity to context” (Boyce & Ellis, 2005; Ellis, Essex, & Boyce, 2005) and of “differentiated susceptibility” (Belsky et al., 2007), the differential effect of any given polymorphism can be seen as supporting the notion of plasticity more than of vulnerability to environmental stress (Brune, 2012). This model proposes that the same allelic variation that involves a predisposition to a psychiatric disorder when linked to adverse vital events could lead to an even better than average response in the same domain when faced with favorable environmental conditions. Therefore, although individuals who are more “sensitive” to environmental stimuli are likely to be the most affected by stressors , they are also likely to be better prepared to respond to positive stimuli (Belsky et al., 2007). Furthermore, considering that genetic polymorphism differentially renders individuals “susceptible to plasticity” in the face of environmental stimuli depending on how adverse or favorable their early experiences have been (Brune, 2012), it would be possible to state that, from an evolutionary perspective, allelic variation poses a selective advantage if external contingencies have been beneficial (Wurzman & Giordano, 2012).

9.3 The Stress-Reward-Mentalizing Model of Depression

According to the stress-reward-mentalizing model of depression proposed by Luyten and Fonagy (Luyten & Fonagy, 2018), depression – particularly when it emerges in childhood and adolescence – results from a series of three-pronged interactions among impairments in three basic biobehavioral systems. It is suggested that three systems evolved in response to the continuing need to adapt to the ever-changing circumstances and the growing complexity of human interpersonal relationships in particular. They are (a) a system that deals with distress following threat (the stress/threat system); (b) a system that produces rewarding features associated with positive environmental features, including the formation of interpersonal relationships involved in infant–mother, mother–infant, pair-bonding, and other attachment relationships, and experiences of agency and autonomy (the reward system); and (c) a mentalizing or social cognition system, which subserves the capacity to understand oneself and others in terms of intentional mental states such as feelings, desires, wishes, attitudes, and values, and delivers the necessary computational power human beings need to navigate their complex interpersonal world and to acquire a sense of agency and autonomy.

While these systems are adaptive, both internal and contextual threats may disrupt their highly interrelated functioning, and the nature of such disruptions may reflect what we have come to see as different forms of depression. These interacting impairments can in turn obstruct the achievement of developmental tasks that rely on capacities associated with these domains, increasing the risk for depression and associated conditions, particularly during developmental transitions (e.g., from childhood to adolescence and from adolescence to early adulthood). In adolescence and early adulthood, in particular, the establishment of new and more complex relationships and an emerging sense of agency and autonomy rely heavily on the stress regulation, reward, and mentalizing systems, which may explain the increased prevalence of depression during these developmental transitions.

The model argues that excessive and/or age-inappropriate stress, most probably in combination with increased stress sensitivity, typically sets in motion a developmental cascade effect. Both biological and environmental factors and their interactions are likely to be involved in the negative development cascade, which may originate in any of these three domains. The negative cascade may lead to a reward deficiency syndrome at a time of increased stress and decreased mentalizing capacities, leading to a state commonly referred to as subclinical or clinical depression, which further interferes with negotiating normative developmental tasks and challenges.

10 Conclusion

In this chapter, we have defined depression as a highly heterogeneous clinical phenomenon that can have different causes and pathogenetic mechanisms, ranging from genes to culture. Thus, depression is a complex condition that belongs to the mind/brain complex system, with different levels of pathogenetic explanation; however, little is known about the interaction between the different levels of organization. One of the properties of complex systems is the recursion between different levels of organization. This makes it necessary to study the system as a whole, since it is not possible to disaggregate its components, due to the multiple loops between levels that constitute it.

In the case of psychopathological phenomena such as depression, when we refer to etiopathogenic models, we are talking not only about the causes and the mechanisms that allow us to explain the origin of the symptoms using the methods of natural-scientific knowledge but also about the reasons, that is, about understanding the psychological motives behind the symptoms. It seems to us that this distinction is fundamental since inevitably the notion that the clinician has about the origin of the mentally ill will condition the way of understanding psychic suffering and, consequently, of implementing the therapeutic indications. In this sense, beyond the “battle of paradigms,” it is necessary to consider that the knowledge of the different etiopathogenic models should be at the service of understanding how and why a certain patient became depressed in order to establish a treatment plan that is as personalized as possible. To achieve this, it is necessary to understand the biological basis of the inheritance of mood disorders and their close relationship with the influences of the psychosocial environment as well as the various paths that emotional development can take, considering the effects of early trauma and adverse life events as well as personality influences.

There is probably no disease that has been subjected to as many classifications as depression. One of the difficulties in its diagnosis is the definition of the clinical picture. Thus, for example, one study showed that if the medical criteria used to define depressive illness are reviewed, it is possible to obtain 227 types of possible combinations of symptoms (van Loo et al., 2012). Therefore, the first problem is to determine the validity of the clinical diagnosis. At this point, we can find at least two aspects that diagnostic manuals such as the dsm-5 do not know about: the relevance of clinical phenomenology as a basis for psychopathological diagnosis and the fact that mental symptoms can change over time. In this sense, it is possible that the “clinical pleomorphism” or “phenotypic heterogeneity” that depression presents is due to our inability to incorporate into the diagnostic process a series of variables that can influence the way depression presents itself, such as personality characteristics and culture.

Depressive feelings can be experienced by all people and are part of the normal affective manifestations of grief and loss. However, how depression is understood, interpreted, discussed, communicated, and treated varies from culture to culture. For example, in some Southeast Asian languages, there is no equivalent to the word “depressed,” while in regions such as Nigeria, only one word is used for depression, anxiety, and anger (Thakker & Ward, 1998). It is known that in Western societies, depression is more commonly viewed as an “illness” with both hereditary and biological components, while a “situational” view that encompasses symptoms in the context of psychosocial stress and interpersonal difficulties is often associated with traditional societies and minority communities. Thus, those who interpret problems as “emotional reactions” to environmental adversities – as opposed to a “pathological” interpretation – are less likely to seek professional help in the field of mental health (Karasz, 2005). Others, on the other hand, will feel more comfortable when a directive and hierarchical relationship is established, much closer to the classic medical model. In Chinese society, for example, the experience of depression is more “physical” than “psychological”; patients rarely report feelings of sadness or discouragement; instead, they present discomfort such as pain, sleepiness, fatigue, and boredom, evidencing a clear somatoform pattern (Kleinman, 2004). This would be explained because in these societies the expression of feelings, especially of negative affections, is considered something unacceptable.

Another difficulty has to do with the very concept of “depressive episode.” There is increasing evidence that the course and natural history of depression is far more complex than a mere “episode.” Research in the field of attachment theory and developmental psychopathology, especially in relation to traumatic events during childhood, supports the notion that depression can be considered not only as an alteration of psychobiological development (Luyten, 2012) that manifests itself throughout the life cycle but also that it can be inherited by the offspring, which has been seen in both animal (Dietz & Nestler, 2012) and human (Fossion et al., 2015; Starr et al., 2014) models. Likewise, the role of social interactions and interpersonal relationships in the origin and maintenance of depressive symptoms has given rise to a series of studies that relate certain aspects of personality with involvement in potentially stressful situations in what has been called “stress generation theory .” According to this model, certain personality traits and some interpersonal styles are capable of exposing the individual to a situation of increased risk of psychosocial stress and are one of the reasons that would explain the recurrence of mood disorders (Liu, 2013). Consequently, depression must be understood as (1) a developmental disorder, (2) occurring in a cultural and interpersonal context (both in origin and recurrence), and (3) which can be transmitted transgenerationally. This approach allows us to consider not only the effect that the environment can have on depressive symptomatology but also the impact that the depressed subject (and his personality characteristics) has on his social environment.

The way in which we approach the various objects of study and, therefore, the conditions in which it is possible to know are determined by the world and the culture in which we live. This condition of knowledge in the most developed societies has been called “postmodern” and finds its expression in a basic disbelief with respect to the meta-narratives (Lyotard, 2008). From the publication of The Structure of Scientific Revolutions by Thomas Kuhn (2007) arises the notion of “paradigm” understood as the achievements that a particular scientific community recognizes for some time as the foundation of its subsequent practice. Such achievements are characterized by the absence of precedents and by being open enough to leave a significant number of problems unsolved for the group. Paradigms are, therefore, frames of reference adopted by a scientific community at a given time and from which the phenomena studied are understood. The development of scientific knowledge occurs in cycles made up of phases of “normal science” (where a certain basic paradigm is accepted) and times of crisis that make new paradigms emerge and then return to a period of “normality.” The problem, Kuhn argues, is that the paradigms that come into conflict are often irreconcilable, and it is impossible to find a common language that will bring them together, so to resolve them, one must often resort to irrational methods that are based on “subjective” or even “aesthetic” motivations. As a way of confronting the hegemony of the “simplification paradigm,” Morin (2011) proposes the need for a new model that he calls “complex thought.” Complexity is the fabric of events, actions, interactions, retroactions, determinations, and fates that constitute our phenomenal world. However, our understanding has historically made an effort to order, systematize, and clarify, rejecting the uncertain and ambiguous, thus depriving the observed phenomena of an essential aspect: their own complexity.

It is likely that, paradoxically, the development of empirical research and theoretical advances around the depressive phenomenon have led us to a kind of dead end represented by the concept of “depressive episode.” It is also likely that today we are witnessing not only a change in the way we understand depression but also in how it presents itself clinically. Our hypothesis is that we are facing a new paradigm in the way of understanding the depressive phenomenon that requires the incorporation of the notion of complexity in its study, through a multidimensional approach that considers the interaction of the different levels of analysis from genes to behavior, including personality and culture.

Kendler (2014) proposes three research goals for the twenty-first century psychiatry: “The first one is to continue the current work and populate the major levels and sublevels of our field with validated risk factors. Critical to this effort are a reliance on an interventionist model in which quality of causal inference is the only relevant criterion and a willingness to use our imaginative understanding to explore risk factors first understood in mental space. This is the best way to deal with our pluralistic values, our debates about the importance of mental, social, and biological causes… The second goal follows on the heels of the first and moves from a descriptive mode to a mechanistic one” (p. 937). This is a scientific effort that has already begun, but there are still few papers that investigate risk factors simultaneously on more than one level of organization. “The third goal is to take these mechanisms understood in a third-person objective perspective and attempt to move them into a first-person perspective – that is, to move from explanation to understanding.” Patients do not consult for a third-person explanation of their subjective suffering: abandonment, loneliness, low self-esteem, or feeling threatened by a hostile world. They seek first of all to be understood by their therapist empathetically. “Here we are seeking first-person understanding for our patients and enlarged powers of empathy for us. The story begins with individual causal risk factors, connected together through mechanistic cross-level processes that can then be re-expressed in comprehensible mental language. This is closing the circle. We begin our investigations with patients displaying symptoms. We categorize and study them. We clarify the nature of their underlying disorders. Our efforts are not complete until we have returned to where we started and can explain to our patients how their symptoms arose” (p. 937; see Chap. 17).