Neurobiology of Depression: Road to Novel Therapeutics

Chapter 1

The Classification of Depression: Embracing Phenotypic Heterogeneity in the Era of the RDoC

Elizabeth D. Ballard; Ioline D. Henter; Carlos A. Zarate, Jr.    Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, United States

Abstract

The development of new, effective treatments for depression has been hampered by an incomplete understanding of its neurobiology. Research efforts such as the NIMH Research Domain Criteria (RDoC) have advocated for the delineation of specific unidimensional constructs that can be studied translationally across genes, cells, circuits, and behavioral measures using a dimensional—rather than a categorical—approach. This chapter details a number of methods that can be used to parse the heterogeneity of depression. The chapter first describes methods that use clinical symptomatology to define subgroups of depressed individuals, then delineates the methods that use biological markers to define biotypes of depression. The chapter also discusses an experimental therapeutics approach using rapid-acting interventions in which clinical trials are used to define potential bio-signatures of antidepressant response as well as biotypes of patients most likely to respond to treatment.

Keywords

Depression; Treatment-resistant depression; Suicide; Ketamine; Neurobiology; Factor analysis

Acknowledgments

The authors thank the 7SE research unit and staff for their support.

Worldwide, more than 10% of individuals suffer from mood disorders every year. Indeed, depression is the leading cause of disability worldwide, ranking ahead of ischemic heart disease, cerebrovascular disease, cancers, and infectious diseases [1]. Moreover, depression is associated with increased risk of death at any age, independent of suicide, smoking, or other risk factors [2]. Individuals with major depression sometimes describe an emotional pain much worse than any physical pain that they have ever experienced.

Although a variety of treatments—including more than a dozen conventional antidepressants, transcranial magnetic stimulation (TMS), and psychotherapies—exist for depression, a substantial majority of individuals with depression do not respond to these [3]. For instance, it is estimated that approximately one third of patients will not respond to four courses of currently available antidepressants, and evidence suggests that, even after two trials of close to six months of treatment, only 50% of patients achieve remission [4]. Furthermore, considerable lag exists in the onset of full improvement, even for those who do respond to currently available treatments, which often take 10–14 weeks to exert their full antidepressant effects [4]; one notable exception is electroconvulsive therapy (ECT), to which most patients respond within one week [5]. A significant number of all patients with depression exhibit resistance to all available standard treatments, and these are often characterized as having treatment-resistant depression (TRD). The lack of rapid-acting, safe, and effective therapeutics for TRD is a major public health concern. Inadequately treated depression, and TRD in particular, are associated with unemployment, poor quality of life, increased medical and psychiatric comorbidity, higher healthcare use, risk of suicide, disability, and premature death [1,3]. Moreover, the rate of suicide, which is often associated with mood disorders, has increased over the past decade, especially for middle-aged adults [6]; if current trends persist, even the best-case scenario predicts that 54,000 Americans will kill themselves by 2025 [7].

In general, incomplete knowledge of the neurobiological mechanisms underlying depression and suicide has impeded progress in improving clinical outcomes. Challenges that have prevented researchers from identifying more effective treatments include the heterogeneity of depressive symptoms, the high rates of physical and mental comorbidity that accompany a diagnosis of depression, and the lack of evidence for valid biobehavioral subtypes or biomarkers of response [8–12]. Broadly speaking, mood disorders manifest as heterogeneous problems of mood, behavior, energy, sleep, circadian rhythms, and activity levels. The Diagnostic and Statistical Manual (DSM) is one method of classifying psychiatric illnesses. To meet DSM-5 criteria for a major depressive episode, an individual must meet five of nine core symptoms. In fact, under DSM-5 criteria, an estimated 227 combinations of symptoms will lead to the diagnosis of a depressive episode. Moreover, a number of other disorders are often comorbid with major depressive disorder (MDD), which makes any attempt to decipher the precise etiology and pathophysiology of depression even more complicated. For example, PTSD is often comorbid with MDD; one recent report suggested that, under the DSM-5, there were more than 600,000 ways to diagnose PTSD, an eightfold expansion from DSM-IV [13]. As a result, a wide range of individuals who meet criteria for depression may, nevertheless, overlap on only a limited number of symptoms [14,15]. This heterogeneity is manifested not only in psychiatric and behavioral signs and symptoms, but also in the accompanying systemic manifestations seen in individuals with depression. Individuals with depression may present with increased rates of a variety of comorbid medical conditions, including migraines and thyroid disease, or they may have alterations of their HPA axis, cortisol levels, innate immune system, cardiovascular system, GI system, bone metabolism, and brain and circuit homeostasis. As with psychiatric symptoms, patients with depression may manifest varied disturbances in the systems affected, further challenging our ability to obtain biologically enriched subgroups in order to develop better and improved treatments.

Furthermore, while the DSM is a useful tool for diagnosing individuals and communicating with clinicians, family members, and patients, it does not determine which treatments should be prescribed for a particular individual, a term loosely defined as personalized medicine [16]. As noted above, there are considerable limits with regard to the efficacy of currently available antidepressants. In addition to low remission rates and lag of onset of antidepressant and antisuicidal effects, other limitations include the questionable efficacy of these medications for bipolar depression and their limited ability to improve comorbid systemic manifestations associated with depression. Resources for suicidal individuals are even more sparse; presently, only one medication—clozapine—has been FDA-approved for suicidal behavior, and it is indicated for individuals with schizophrenia diagnoses [17]. Furthermore, data suggest that suicide risk peaks in the first nine days after initial antidepressant administration, making the therapeutic use of antidepressants challenging for those at risk for suicide [18]. While there is a longstanding history of using ECT, lithium, and psychotherapies such as Dialectical or Cognitive Behavioral Therapy (DBT or CBT) to reduce suicide risk, improvement only occurs over the course of months (with the exception of ECT); thus, these therapies are not indicated for acute suicidal ideation [19–21].

In this context, next-generation treatments for depression will need to exert rapid-onset antidepressant and antisuicidal ideation effects within hours, as well as address the altered biological indices that accompany depression. In addition to relieving the pain and suffering associated with depression and suicide risk, such novel therapeutics would also have enormous public health effects in terms of their ability to reduce suicide risk as well as the amount of time that individuals with depression are impaired in terms of their work, home, and school functioning. However, developing the next generation of therapeutics whose onset of antidepressant action occurs within a few hours will require us to identify the precise cellular and molecular targets implicated in depression or that of highly robust, rapid-acting antidepressant and antisuicidal ideation agents, such as the glutamatergic modulator ketamine.

Toward this end, attempting to decipher the etiology and pathophysiology of depression is quite challenging. Despite considerable efforts, current research has not translated into improved therapeutics for psychiatric illnesses. As noted above, one of the major contributing factors to this problem is that existing criteria for diagnosing psychiatric illnesses—most notably the DSM—are largely symptom-based and do not overlap with pathophysiology. In 2010, the NIMH proposed the Research Domain Criteria (RDoC), which combine a new classification framework for research into mental disorders with a strategy intended to enhance our ability to learn more about the etiology and pathophysiology of depression [22]. Broadly, the RDoC proposes to deconstruct our current heterogeneous collection of symptoms (e.g., depression) into simpler constructs that are more amenable to study and that would be present across a range of disorders, possibly even to some degree in healthy individuals [23]. One example would be disturbances in reward processes. These deficits are found not only in depression, but also in panic disorder, schizophrenia, and even healthy individuals. Disturbances in reward processing can be modeled preclinically and have been connected to specific neural circuits that can be evaluated in both healthy volunteer and psychiatric patients [24]. A spectrum of reward processes—ranging from optimal function to significant dysfunction—would be amenable to further investigation and give us greater insight into psychopathology across a range of disorders. This knowledge, in turn, would allow us to use a dimensional approach to study the specific construct across units of biology ranging from genes to cells to circuits and even to behavioral and social manifestations, taking into account developmental and environmental influences [25]. With time, research would then fill our gaps in knowledge at these different units of analysis, with the ultimate goal of more precisely identifying the specific neurobiology underlying these deficits. For example, a treatment could be developed that affects altered reward circuits—perhaps manifested as clinical symptoms such as lack of pleasure or anhedonia—that would improve pleasure and would also correlate with improvement in functional changes within the specific reward circuit and normalize its function. While no treatment is currently FDA-approved for this indication, this type of intervention could benefit a wide range of patients. Furthermore, future treatments could be developed that modulate the specific brain regions or circuits implicated in anhedonia rather than targeting a given symptom. However, because future treatments will also need to stabilize the alterations that would likely occur at multiple levels in order to achieve long-lasting remission or recovery, implementation of RDoC still remains in its preliminary stages and has not yet influenced clinical practice [26].

In addition to the heterogeneity of depressive symptoms, another key reason for the limited translation of neurobiological findings into novel therapeutics is the heterogeneity of research methods. Results may vary depending on which research methods are used and these, in turn, can vary by research site. For example, one site may only use behavioral ratings to assess depressive symptoms, but another site may use a specific 3T fMRI sequence and yet another site may use a slightly different sequence with a stronger magnetic field. The resulting heterogeneity of the research findings not only makes it difficult to compare results, but also compounds the problem of parsing out biologically enriched subgroups. It should be noted, however, that laudable efforts are underway in depression-related research to standardize methods across research sites, and these are likely to be extremely helpful in future research [27,28].

In this context, increased efforts to deconstruct, parse, and diagnose depression and depression-related constructs have been underway in recent years. At the symptom level, researchers often use a combination of depression rating scales to assess symptoms in order to account for the heterogeneity of depressive symptoms; these can include depressed mood, anhedonia, negative cognitive biases, and altered activity levels, among others. In a recent exploratory factor analysis (EFA), we identified unidimensional constructs obtained across rating scales for depression, including the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Depression Rating Scale (HAM-D), the Beck Depression Inventory (BDI), and the Snaith-Hamilton Pleasure Scale (SHAPS) [29]. The best solution to the data resulted in eight factors: Depressed Mood, Tension, Negative Cognition, Impaired Sleep, Suicidal Thoughts, Reduced Appetite, Anhedonia, and Amotivation. Various patterns were observed across response to the glutamatergic modulator ketamine, both in terms of treatment effect (ketamine versus placebo) and degree of placebo response, suggesting that the use of these unidimensional constructs may reveal patterns not observed with traditional scoring of individual instruments (Fig. 1). In particular, empirical identification of unidimensional constructs creates more refined scores that may elucidate the connection between specific symptoms and underlying pathophysiology. Another recent paper used a latent transition analysis to study depression subtypes in men enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study and reported differences in treatment response [30]. Using defined unidimensional constructs would allow researchers to study the neurobiology of these specific constructs or factors rather than the heterogeneous collection of symptoms grouped together under the umbrella of a specific disorder like depression. The hope is that using clinically defined subgroups would allow researchers to amass more biologically enriched subgroups as well as tease out those symptoms most likely to be implicated in the etiology of specific subgroups.

Fig. 1 Results of mixed models in Bipolar Depression analysis ( n  = 41). Item-mean scores reflect the average proportion of points endorsed to points available across items on the subscale. For all constructs except Tension and Reduced Appetite , the difference between ketamine and placebo was statistically significant ( p  < 0.05) at all post-baseline assessments. The effect of drug on Tension was significant at 40, 80, and 120 min post-ketamine infusion, and again at Day 2 only. The effect of drug on Reduced Appetite reversed midway through the study, with significant between-group differences at timepoints 40, 80, and 120 min as well as at Day 1 and Day 2. BDI: Beck Depression Inventory; HAM-D: Hamilton Rating Scale for Depression; MADRS: Montgomery-Asberg Depression Rating Scale; SHAPS: Snaith-Hamilton Pleasure Scale. (Reproduced from [29]).

Another potential approach would be to parse out enriched subgroups based on biology rather than clinical symptoms. Fig. 2 shows a possible strategy for deconstructing and parsing out current mental disorders [31]. Briefly, one would broadly define depression regardless of subtype—for instance, MDD, mild depression, bipolar depression, etc.—and, using integrated data, parse subgroups out based on a certain variable, for example, brain activity, physiology, or genetic risk (polygenic risk score) [31]. Such subgroups would thus be defined based on biology first and only subsequently connected to specific behavioral symptoms. A practical example would be the use of anti-inflammatory agents. Over the past few years, several studies have shown increased levels of inflammatory and/or immune markers in patients with mood disorders [32]. As a result, the immune system has recently become a target of interest for the development of biomarkers and therapeutics for mood disorders. Under this rubric, an anti-inflammatory agent might not be effective when using a symptom-based categorization scheme (for instance, a diagnosis of MDD), but might be effective in a particular cluster whose etiology happens to be largely inflammatory in nature (for instance, an enriched biological subgroup) [33,34]. In this vein, Drysdale and colleagues used resting state fMRI rather than symptom rating scales to parse out subgroups [35]. Their study examined approximately 1500 subjects who had received resting state fMRI at different research centers that used the same methods. The researchers were able to identify several biotypes based on biology—in this case, brain activity. While specific clinical symptoms did not delineate the biotypes, they did differ in clinical-symptom profiles, for example, by anhedonia, anxiety, or insomnia. Building on this work, the researchers then tested the usefulness of clustering based on treatment response to rTMS. They found a larger effect size with one of the biotypes relative to the others; this resulted in a larger effect size than if all the patients had been lumped together based on their diagnosis of depression alone. Interestingly, it is possible that if DSM-5 criteria had been used instead, not even a detection of signal efficacy would have resulted from rTMS. Taken together, the evidence reviewed thus far suggests that delineation of depressive subgroups and their response to treatment can be defined by clinical measures (as, for instance, in our EFA of ketamine and treatment response) or by biology (as, for instance, with resting state fMRI and TRD). This, in turn, emphasizes the importance of incorporating both comprehensive clinical ratings and neurobiological techniques into clinical trials in order to better assess the scope of response to treatment.

Fig. 2 Illustration of how precision medicine might be used to parse more traditional diagnostic methods that center on symptom-based categories. In the case of mood disorders, individuals experiencing a range of symptoms could be studied with a broad variety of analytical tools, enabling researchers to group heterogeneous syndromes into more homogenous clusters. (Reproduced from [31]).

Similarly, both our laboratory and that of others have sought to address drug discovery and development strategies by incorporating biomarkers that are either used in treatment response paradigms or that signal drug effects (target or functional engagement) [27,28,36–38]. This strategy has been encouraged by many, including the Institute of Medicine [39]. Examples of the various technologies that have begun to be incorporated into treatment response studies include neuroimaging technologies such as positron emission tomography (PET) [37,40], functional magnetic resonance imaging (fMRI) [41], brain proton magnetic resonance spectroscopy (1H-MRS), neurophysiology measures (e.g., sleep electroencephalography, magnetoencephalography (MEG)) [42], peripheral blood, cerebrospinal fluid (CSF) [43], genetics, proteomics [44], metabolomics [43,45], actigraphy [46], transcriptomes [47], and microRNA [48,49]. In addition, parallel and translational efforts are taking place on the basic science side, using a multi-scale, systems biology approach to better understand TRD [9].

One paradigm now being used to enhance drug development efforts for depression and bipolar disorder is the study of interventions that are radically distinct from existing treatments in some clinically useful manner. The glutamatergic modulator ketamine is a critical example of this strategy. Ketamine is distinguished from other antidepressant therapies by several factors, including its rapid antidepressant and antisuicidal effects that occur within a few hours [38,50,51]; its effectiveness in patients who have failed to respond to multiple conventional antidepressants as well as ECT, which is the most effective treatment for MDD known to date [52]; and the fact that it modulates a distinct (glutamatergic) neurotransmitter system. Because of its rapid antidepressant effects, ketamine has become a useful tool for examining multiple biomarkers within a relatively short period of time, in distinct contrast to the complexity and cost of studying existing treatments (for a review, see [38]). This new paradigm for the study of biomarkers associated with rapid antidepressant effects is illustrated in Fig. 3. Broadly, the model investigates multiple biomarkers (e.g., fMRI, MEG, polysomnography (PSG), brain-derived neurotrophic factor (BDNF), single nucleotide polymorphisms (SNPs)), while interventions that produce rapid antidepressant clinical effects within 72 h are being administered. Bio-signatures of response, non-response, and relapse resulting from the integration of biological findings are generated. These results can then inform and guide drug discovery and development efforts. Indeed, early work has already begun to yield promising putative biomarkers to predict rapid antidepressant response [53,54]. With regard to ketamine, this approach was recently expanded to include more detailed information on the biology of the response and relapse process as well as the mechanistic processes underlying ketamine's effects [55–58]. Similar strategies are already being conducted at the preclinical level, identifying the molecular and cellular signatures of response to ketamine [59]. Overall, these strategies—which seek to longitudinally assess the efficacy of rapid-acting antidepressants at both the micro and macro levels in both patients and healthy controls—are likely to generate important insights for developing the next generation of treatments that both act more rapidly and are more effective than existing antidepressants.

Fig. 3 Schematic overview of the Ketamine Mechanism of Action (Ket-MOA) study. Multi-modal biomarkers obtained longitudinally before, during, and after an experimental intervention permit us to contrast biological factors in the same individual during the depressed or suicidal state and when in remission.

This new paradigm may ultimately also be able to advance personalized medicine for depression by matching a specific treatment to an individual [60]. In this respect, our extensive work with multi-modal biomarkers obtained longitudinally on our research unit in patients with TRD before, during, and after an experimental intervention has already permitted us to contrast biological factors in the same individual during the depressed or suicidal state and when in remission; our results have further allowed us to identify biologically defined subgroups of TRD and suicide that are etiologically heterogeneous [36,38,55–58]. The resulting data have led to important insights across units of analysis, from the cellular level to circuits to self-report measures. These rich data are anticipated to enhance our ability to identify biomarkers that distinguish patients based on distinct depressive subtypes relevant to clinical response. This, in turn, allows additional studies to be conducted where subjects are stratified based on specific biomarkers and facilitates the development of novel target interventions. Because of the complexity of the data and the need to integrate these different modalities, more sophisticated methods and analyses will need to be performed. Notably, a framework for developing biomarkers in psychiatry using network neuroscience has quite recently been proposed [61]. Indeed, similar efforts to identify biomarkers of response to ECT are underway [62–64].

This important paradigm shift with regard to the way we conduct psychiatric research, assess response, and explore avenues for personalized medicine is likely to put psychiatry on par with other areas of medicine. The ultimate goal is to be able to intervene with treatments that rapidly prevent major depressive episodes from fully manifesting or that prevent suicide by rapidly eliminating severe suicidal ideation. It is hoped that through such research methods, more effective treatments for depression can be developed that will alleviate the burden of symptoms and potentially prevent premature death and suicide.

Funding

Funding for this work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; ZIA MH002927); by a NARSAD Independent Investigator Award to Dr. Zarate; and by a Brain and Behavior Mood Disorders Research Award to Dr. Zarate.

Conflict of Interest

Dr. Zarate is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation; as a co-inventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydro and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as a co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. He has assigned his patent rights to the U.S. government, but will share a percentage of any royalties that may be received by the government. All other authors have no conflict of interest to disclose, financial or otherwise.

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Chapter 2

The Role of Environmental and Psychosocial Factors in Depression

Gordon Parker    School of Psychiatry, University of New South Wales and the Black Dog Institute, Sydney, NSW, Australia

Abstract

A representative set of candidates’ environmental and psychosocial factors that may predispose to or precipitate depression as distal and proximal risk factors, respectively, is noted. It is conceded that social factors may not be independent of genetic factors and several studies are overviewed to show that social factors range in their salience to differing mood disorders. Lowered self-esteem is positioned as central to the definition of depression, and such recognition allows distinction between stressors that induce depression as against those that shape grief or other responses. The capacity of stressors to have their impact modified by the individual's cognitive style and subsequent corrective social factors is detailed. The strong links between social stressors and certain personality styles in providing a risk to depression are emphasized and it is proposed that research and clinical work should recognize the individual's social and intrapsychic worlds as being strongly linked.

Keywords

Social stressors; Life events; Depression; Environmental factors; Psychosocial factors; Risk factors

Acknowledgments

I thank Kerrie Eyers and Tahlia Ricciardi for their assistance with manuscript preparation and acknowledge the support of an NHMRC Program Grant (1037196).

Introduction

The injunction to first define your terms is relevant to structuring this chapter. A focus on environmental and psychosocial factors suggests examining their independent impact and effectively excluding genetic and other nonsocial factors. However, we should concede interactions whereby genes might predispose and environmental and psychosocial factors then precipitate or otherwise advance the risk of depression. Such a diathesis-stress model is a common one in psychiatry, with the genetic contribution likely to be quite variable in terms of mechanisms, as recently elegantly reviewed by Uher and Zwicker [1]. One example is worth noting. In 2003, Caspi et al. [2] described how a functional polymorphism in the promotor region of the serotonin gene moderated the influence of stressful life events on the risk of depression, with individuals having one or two copies of the short allele being more likely to become depressed. Such a gene/environment interaction was a distinct paradigm change, mechanisms were explicated (e.g., those with short arm alleles having decreased cingulate control over dampening the amygdala response to stress), confirmatory replication studies were published and then, as often occurs in psychiatry, negative studies emerged. Nevertheless, we need to concede genetic—and epigenetic—contributions, although neither will be detailed in this chapter, which focusses on social factors.

The current topic is generally addressed by nominating and considering environmental and psychosocial factors that occur across the individual's early years (distal stressors) or those which more immediately precede and may precipitate onset (proximal stressors) of a depressive episode. Much of the key research was undertaken in the 80s and 90s, when psychiatric research focused on social factors, viewing them as the principal causes of psychiatric disorders. In recent years, research in that field has been minimal, as psychiatry has increasingly embraced a biological model. Recent research has made us aware that a number of environmental factors can have impact on the developing embryo and advance the risk of certain disorders in the child's developmental years or later, but other than conceding such influences they will not be addressed in this overview.

Some Consideration of Depression

In addition to issues in relation to the title's subject (i.e., psychosocial and environmental factors), there are many nuances to the title's predicate (i.e., depression), as depression can range from normative states of sadness and depressed mood to severe clinical depressive disorders and include disease states.

In recent decades, a dimensional model of the depressive disorders has been dominant, especially following DSM-III’s introduction of major depression and a set of more minor depressive disorders. Since its introduction, major depression has been the most common depressive category researched and many scientific papers commence with statements referring to major depression as a severe, impairing, and persistent disease, and thus ascribing entity status to it. In reality, major depression is more of a domain diagnosis (akin to a chest physician classifying a patient as having major breathlessness), which sweeps together a heterogeneous group of differing depressive conditions with varying biological, psychological, and social origins.

Prior to major depression's ascendency, a binary model for categorizing the depressive disorders dominated: one where endogenous (or melancholic, endogenomorphic, Type A, vital) depression was contrasted with a second (neurotic or reactive) type. The very naming of those types suggests the differential relevance of environmental and psychosocial factors. For example, endogenous indicates that the causes of such conditions are internal (and likely to be biological), while reactive depression imputes external environmental and psychosocial factors. Current research continues to demonstrate that the relevance and impact salience of environmental and psychosocial factors to depression are highly likely to be contingent on the depressive subtype.

Melancholic depression has long had a number of stable ascriptions. These include a relatively distinctive set of overrepresented clinical features (especially psychomotor disturbance), evidence of disturbed biological functioning, and a preferential response to physical treatments such as antidepressant medication and electroconvulsant therapy—and with psychosocial determinants being viewed as less relevant causal factors, thus emphasizing the role of genetic and other biological (i.e., endogenous) factors. And yet, some patients with an unequivocal melancholic depression will report an antecedent stressor. Two empirical studies are classics in this field. Frank et al. [3] studied 90 patients with Research Diagnostic Criteria-defined endogenous depression and assessed their life events over the preceding six months. While they were less likely to report antecedent stressors than those with non-endogenous depression (i.e., 43% vs 65%), nearly one half of the endogenous depressive group reported life event stressors. There was, however, a closer temporal association between severe events and depression in those with the non-endogenous type—suggesting that life events were far more likely to be precipitating factors rather than simply background stressors in the non-endogenous subset. Some in the endogenous group reporting such stressors may have nominated background stressors rather than ones that triggered the depressive episode.

In the second study, Brown et al. [4] assigned 127 depressed female patients to endogenous and non-endogenous categories via several subtyping measures. One (a melancholic/psychotic measure) quantified that 40% of the melancholic/psychotic as against 73% of the non-melancholic patients had experienced a severe life event. The finding—across these two studies—seems to indicate that life event stressors can predispose to and/or precipitate episodes of endogenous/melancholic depression in some individuals.

Such findings could reflect a number of explanations. Firstly, that the diagnostic measure was invalid and falsely assigned those with reactive depressive disorders to an endogenous/melancholic class. Secondly, the ad hoc post hoc ergo propter hoc principle, which encourages people to believe that, if two events occur together, one must have caused the other (as illustrated by one wag noting that It has been conclusively proved that the beating of tom toms will restore the sun after an eclipse). Here, the individual seeks to explain why they might have become depressed and nominates events that might have been completely irrelevant to the onset of depression, but which are interpreted and judged by the individual as explanatory and causal. Thirdly, that life event stressors can predispose to and/or precipitate episodes of endogenous/melancholic depression in some individuals.

In relation to the last possibility, some clinical nuances are worthy of consideration. In developing a measure of melancholia—the Sydney Melancholia Prototypic Index or SMPI [5]—two life event items were empirically established as weighted to melancholic depression (i.e., depressions sometimes coming out of the blue without any particularly clear reason, and the severity of depressive episodes appearing far worse than would be expected given the circumstances that preceded or appeared to cause the episode), while two converse items (i.e., there always being a cause for a depressive episode, and the severity of episodes being explained by the type of stressful events and their impact marrying with the individual's personality style) were weighted to a non-melancholic depression. Thus, those with melancholia are likely to report at least some episodes as being autonomous and without a preceding or explanatory life event, to judge the depressive reaction as more severe than explainable by the actual stressor, and with their episodes tending to last longer than might be expected from the life event circumstances, while for those with non-melancholic depression, the onset, severity, and impact of the depression appear consistent and plausibly linked to the antecedent stressors.

Thus, endogenous or melancholic depression is not always solely from within and the impact of environmental psychosocial and life events stressors must also be conceded in this type of depression. While such associations are less common and distinctive than for those with non-melancholic depression, how might such stressors increase the risk of a depressive episode? A Hooke's Law variant may be of relevance. In essence, patients often report their first melancholic episode as following a distinct stressor and then observe that relapses and recurrences occur ostensibly without distinctive stressors—becoming more autonomous—and perhaps reflecting less elasticity or a change in the threshold to episode. Alternately, as some medical disorders can be brought on by seemingly irrelevant psychosocial stressors (such as diabetes emerging after an individual has been involved in a car accident), melancholic episodes may similarly be induced by stressors, albeit with mediating mechanisms (e.g., compromised immunological functioning) yet to be clarified.

Psychotic depression is, like melancholia, best viewed as a categorical depressive disease type. Its base features are melancholic symptoms, but it differs from melancholia by the added mantle of psychotic features (i.e., mood congruent or mood incongruent delusions and/or hallucinations). As with melancholic depression, psychotic episodes can occur without apparent preceding stressors in a percentage of those with the condition. Intriguingly, episodes can be precipitated by supposedly quite minor stressors. A female patient of mine heard a broom fall over in a cupboard, a male patient thought he saw a speed camera light flash as he drove his car along a highway: both immediately moved from a euthymic state into an episode of psychotic depression with delusional preoccupations.

Depressogenic Factors

As a logical corollary, the relevance and contribution of certain depressogenic factors can vary across differing mood disorders. Shortly, we will consider how certain parental characteristics (i.e., low care and overprotection) can predispose to certain types of depression, but here we examine the varying specificity of such ingredients to differing mood disorders. For example, in one report [6], patients with a diagnosis of neurotic depression were significantly more likely to report their parents as low on care and high on overprotection (a combination termed affectionless control) compared to a nondepressed control group, while those with a manic-depressive diagnosis did not differ from controls on either parental dimensions. In another report [7], we examined parenting judgments made by 65 melancholic and 84 non-melancholic depressed patients compared to a sample of nondepressed control subjects. The melancholic patients did not differ from the controls in their scoring of parents along care and overprotection dimensions, while the non-melancholic patients returned significantly lower parental (i.e., maternal and paternal) care scores and higher overprotection scores. Thus, it is important to recognize that environmental and psychosocial factors can vary considerably in their relevance and specificity across differing subtypes of depression.

Impact of Cognitive Style

The next issue worth noting is the impact of cognitive style. Environmental factor X may, objectively, be minor and yet present a depressogenic enormity to one individual who has a vulnerable personality style, while the converse—an objectively severe depressogenic stressor may have little to no impact on a resilient individual—is also commonly observed. At the simplest level, individuals may deny or magnify the impact of stressors. The observation by Epictetus that Men are disturbed not by things but by the views which they take of them is commonly quoted and underpins many of the tenets of cognitive therapy. Beck [8] detailed a number of cognitive distortions (e.g., arbitrary inference, selective abstraction, magnification, overgeneralization, personalization) that underpin cognitive theories of depression. Thus, the attributions and cognitive distortions that individuals bring to appraise stressors will not only increase or decrease the chance of any such event causing depression or not (as well as its impact if inducing a depressive episode), but also risk compromising empirical studies that simply quantify the presumed salience of differing environmental and psychosocial stressors.

In relation to the last methodological nuance, Brown and Harris [9] sought to correct against subjective biases and cognitive distortions effected by participants—and also by external raters—by introducing a contextual method for rating life events. In assessing a reported stressor, this strategy required multiple raters to make a judgment as to what individuals in such circumstances would be likely to feel, taking into account the individual's history and current circumstances, and also relying on manuals providing strict definitions of events and their appropriate scale scores, while consensus meetings also enable a further check on any investigator biases. Such a strategy does allow the differential impact of varying depressogenic stressors to be quantified and graded more objectively, but ignores the Epictetus injunction and clinical reality that onset of any depression is not necessarily due to the event per se but more the impact of the event on the particular individual with their protective (e.g., denial) or vulnerability (e.g., magnification) filters for appraising stressors.

Mechanisms Linking Psychosocial Stressors With Depression: The Centrality of Self-Esteem

Turning to mechanisms accounting for developmental and psychosocial factors generating depressive states, according to Bibring [10] a key characteristic of a depressed state is a drop in the individual's self-esteem (with self-esteem capturing the degree to which an individual judges themselves as capable, significant, successful, and worthy) and with the extent of the drop correlating with the severity of the depressed state. Individuals with low self-esteem are at greater risk of depression, while those with a so-called lacunae or Swiss cheese self-esteem are at risk of depression only when facing certain salient stressors, as detailed shortly in relation to a key and lock model which links reactive depression to certain emotionally weighted stressors.

Such findings invite the question as to how individuals develop or fail to develop a healthy self-esteem. Most commonly, self-esteem is initially shaped by the extent to which parenting figures provide care and nurture and avoid being overprotective and controlling. Intriguingly, Hinde [11] has detailed how all-important human relationships (i.e., parent-child, husband-wife, teacher-pupil) are underpinned principally by those two dimensions of care and control. Decades back, we developed the Parental Bonding Instrument or PBI [6]. Parental care was expressed by items such as the parent speaking warmly to the child, understanding their problems and worries, enjoying talking things over with their child, frequently smiling at the child, and making the child feel better when upset. Parental control was evidenced by the parent seemingly not wanting the child to grow up, controlling everything the child did, invading the child's privacy, tending to baby the child, trying to make the child dependent on the parent, being overprotective, and not letting the child decide things for oneself.

In a number of studies (see [12]), we quantified that high self-esteem in subjects correlated with them perceiving their parents as highly caring and low on overprotectiveness during their first 16 years, and with the converse parenting being associated with low self-esteem and depression (of specific types). However, any baseline level of self-esteem reflecting such parental characteristics is obviously capable of modification (positively or negatively) by the impact of other and subsequent key interpersonal relationships (e.g., close friends, intimate partner), which in turn can modify the risk to depression. As noted by Brown et al. [13] self-esteem is, in part, the internal representation of social support. Intriguingly, those with low self-esteem as a consequence of early parental deprivation are more likely to enter into uncaring and dysfunctional close and intimate relationships (as a consequence of their low sense of self-worth) and thus reify their low self-esteem and further increase their risk of developing depression in response to problematic relationships and their attendant stressors [14]. Those who have experienced parental deprivation and who marry up in the sense of establishing relationships with caring and supportive partners reduce the risk of depression as a consequence of their raised self-esteem. In an empirical study of 63 women [15], the chance of depression in those who had experienced uncaring parenting and who later had an affectionate and caring husband was only marginally more likely than for those who had had caring parenting and an affectionate husband, while the benefits of caring parenting were largely undone by marriage to an unaffectionate husband. Thus, vulnerability to depressogenic stressors is increased by a low self-esteem, but the latter is modifiable by in vivo factors (i.e., the nature of later and current interpersonal relationships).

Depressogenic Stressors

Turning to depressogenic stressors, we can assemble a large list of psychosocial and environmental factors that may predispose as background factors and/or precipitate or provoke depression by lowering the individual's self-esteem and generating depression. Examples of distal and proximal stressors include:

•uncaring and/or overprotective parenting

•bullying in childhood or subsequently

•sexual abuse

•a critical and condemnatory partner

•being fired; criticism of personal or work performance

•responsibility for a major financial loss

•loss of one's roles in life.

In relation to distal stressors, Dahl et al. [16] analyzed data from national Danish registers involving nearly one million people. The risk of developing a moderate to severe depressive disorder in adolescence or adulthood was increased by exposure to all adverse events examined and ranked here in order: childhood abuse, out-of-home care in childhood, parental psychiatric disorder, parental death from unnatural causes, parental disability, family disruption, parental incarceration, parental death from natural causes, and parental somatic illness. Some of these variables would have achieved significance as a consequence of the large sample size, and some (e.g., parental death) may reflect adverse consequences of the event rather than the event itself—as considered shortly. In addition, the researchers quantified a dose-response relationship, with, for example, the risk of depression advanced by 54% following exposure to one stressor and an almost 300% increase for those who experienced four or more adverse events.

In addition to these stressors that have been consistently linked with an increased chance of adult depression, there are numerous examples of accidental life stressors that can be depressogenic. For example, the mother of a child born with a major and uncorrectable physical problem may develop depression. An active octogenarian who has a stroke that limits his mobility and results in him being placed in a dispiriting nursing home would be at high risk of depression.

Other social factors often nominated as causes of depression include drug and/or alcohol abuse, developing a major medical problem, or socioeconomic variables such as female gender and low social class. Caveats also need to be made in relation to low social class and/or poverty. Such factors are unlikely to cause depression by themselves. If everyone in the individual's community is also poor and socially deprived, then there is no social disjunction factor in operation and, if individuals feel that they are all in it together, depression should not of necessity be expected. Nevertheless, low social support is strongly linked with a greater risk of depression—especially in women [17].

Not all major accidental life event stressors necessarily increase the risk of depression. While neglectful and overprotective parenting does, as has been detailed, the death of a parent is not invariably such a factor. Decades back, Becker [18] concluded that there was "no consistent, substantial evidence for a relationship between early parental loss per se and either predisposition to depression or severity of depressive episode." While the death of a parent is likely to be highly distressing and depressing to the child at the time, if the remaining parent and other substitute parental support figures offer the child care, the risk to the child of depression in adulthood is averted.

Depression Versus Grief

It could also be expected that the death of one's spouse might cause depression. However, despite a move to position grief in DSM-5 as a depressive disorder, we view grief as closer to a normative state (and thus distinct from clinical depression), and its phenomenology differs. In grief, there is an initial impact phase and while the individual may be profoundly distressed, there is no loss of self-esteem; the individual is experiencing more the loss of the other—with grief being a response to a break in a social bond. Numerous studies have shown that depression only occurs in a minority of individuals who are grieving the death of their partner and, in such a minority, it generally only occurs late in the grief process.

It is conceded that distinction then invites consideration of the following vignette. A 23-year-old woman in a close relationship for over a year is told by her partner that he is leaving her. She becomes immediately distressed, is unable to sleep for more than an hour or two, has no appetite, and displays rapid weight loss, while she is hypervigilant (e.g., imagining that she has seen his magenta-colored Porsche in the distance) and her performance at work is compromised. Is the diagnosis grief or reactive depression? Clearly, it could be either or both. If the process parallels the stages of grief (e.g., impact phase, denial phase, searching behaviors, bargaining) and there is no loss of self-esteem or self-worth (and indeed there might more likely be retributive anger at the loss), then it may be more appropriate to make a diagnosis of grief. Conversely, if the woman then begins to feel worthless (whether in consequence of her intrinsic personality style, low self-esteem, or because her partner demeaned her in his reasons for leaving), then it may be more appropriate to diagnose a reactive depressive condition. Of course, if instead of developing the set of symptoms detailed earlier, the woman is delighted by her partner leaving (The jerk's gone. I can get on with my life.), neither grief nor reactive depression would be expected. The point here is that every environmental or social factor that might be viewed as intrinsically depressogenic does not lead inevitably to a clinically depressed state. If in doubt, read Man's Search for Meaning by Victor Frankl [19] and wonder at his spiritual survival and triumph in the Nazi death camps.

The Role of Personality

Thus, we return to Epicectus. Psychosocial and environmental factors do not, ineluctably, lead to depression. A diathesis-stress model is common to many psychiatric disorders, with, in this case, certain personality styles predisposing or providing a diathesis to depression in response to psychosocial stressors. The individual's personality is central in shaping perception and also contributes by showing some specificity to certain life events. It is the manner in which such events are perceived and their attributional meanings to the individual, which is all-important.

Parker and Manicavasagar [20] detailed a number of personality styles that predispose to episodes of non-melancholic depression and suggested degrees of specificity to certain social and environmental factors. For example, perfectionists are hypersensitive to scenarios involving loss of pride and, when overwhelmed by stress, may ruminate over past failures. People with high trait anxiety will, when faced with depressogenic stressors, develop high autonomic arousal, and either externalize with irritability and volatility, while those who internalize will take things very personally, be tense and nervy, and be at risk of depression as a consequence of a conviction that the worst will happen (i.e., they catastrophize). Those who are shy (or socially avoidant) will be at risk in social situations due to their high levels of anxiety and self-criticism, often ruminating about previous experiences of being bullied or humiliated. Those who have a personality style of personal reserve—and who are apprehensive about getting close to people at a personal or emotional level—are at risk of becoming depressed when others recognize and criticize their personality style (for instance, a colleague commenting that they are a cold fish). Those with atypical depression have a personality style marked by hypersensitivity to judgments by others (whether positive or negative, and with the latter most hurtful when others appear rejecting or abandoning). Those with a short-fuse temper and limited anger control will often behave in entitled and demanding ways and, when their needs are not met, may explode with anger and, if having any capacity for insight or remorse, then become depressed by recognizing the collateral damage in consequence of their outburst. And those with intrinsically low self-esteem are at risk of depression as a consequence of their harsh self-critical style and are often reliant on others for praise and reassurance, which, if ceased, can tip them into depressive episodes.

Keys and Locks: Swiss Cheese and a Lacunae Self-Esteem

While such descriptions indicate that certain personality styles provide an increased risk to certain types of stressors, there is another variant of the diathesis-stress paradigm that is worthy of consideration and which we have described as a key and lock [21] phenomenon. It relates to the lacunae or Swiss cheese model where a particular stressor appears to have specific salience to the individual (as if the stressor arrow is uncannily directed to the bullseye: the most vulnerable part of the individual's self-esteem). Even if outwardly minor, the stressor produces a disproportionately severe depression. The following vignette provides an example.

A woman in her late fifties developed her first episode of depression following an urgent but successful coronary bypass operation. Initial clinical assessment failed to identify any distinctive predisposing factors, established that she handled some quite perturbing life events (including a divorce) without any depression, and the link between the operation and her depression remained unclear. At the second interview, and when circumstances around the operation were pursued, she stated that the surgeon had been peremptory and curt and given her little explanation about the operation. She added quietly I felt violated. Following the surgery, she had been shocked by the sight of her chest wound and raged at the staff, telling them that her personal space had been trampled and her dignity lost. When her early years were reviewed again, she hesitatingly related a period of two years when her father had sexually abused her and had sworn her to secrecy under threat of death. She had never informed anyone about that traumatic period, stating that she had put it at the back of her memory. In retrospect, however, the clue lay in her statement that the surgeon had violated her, a highly emotive descriptor. In essence, sexual abuse had laid down a predispositional lock programmed to deconstruct on later occasions when she might feel violated, and the surgeon's authoritarian and paternalistic approach to her had acted like a key in unlocking the painful suppressed memories and thereby producing a severe clinical depressive episode.

A diagnosis of reactive depression argues generally for the therapist to empathically listen to the circumstances and assist the patient to neutralize or minimize the stressor's impact or help them to come to terms with it. In those with a reactive depression and where the key and lock mechanism is operative, there is considerable benefit in identifying for the patient the psychological links between the predisposing and precipitating circumstances, as the patient will rarely have joined the dots. After obtaining insight, such patients become less vulnerable to salient stressors and, when facing such stressors, are more able to apply corrective strategies.

Conclusions

This review of the contribution of environmental and psychosocial factors to depression indicates that any model suggesting direct causal links is unlikely to be valid, and that a number of modifying and specificity factors must be considered and conceded.

First, the impact of such social factors may not be independent of genetic factors that singly or in combination contribute vulnerability or resilience to adverse life event stressors. Second, such factors are likely to make quite differing contributions to differing types of mood disorders. Thus, for instance, when considering the impact of poor parenting in childhood, this review has shown that it is distinctly more likely to be overrepresented in those who develop non-melancholic depression, but is a minimal or nonexistent risk factor to those who develop melancholic depression and bipolar disorder. For those with the latter disorders, if episodes are not autonomous and occurring out of the blue, then the severity of the episode appears more profound than might be accounted for by the apparent size of the stressor and tends to persist longer than might be anticipated from such a stressor, suggesting that any