Medicine has a long and complex past that mirrors the course of human history. Indeed, the major historical milestones of medicine cannot be understood outside of cultural context. A current of reductionist thought flows throughout the history of medicine, and has been pivotal in identifying and defining disease, and directing treatment into specialized, highly developed fields. However, this may have led to the creation of artificial boundaries around assessment and management, resulting in fractured, and at times, sub-optimal patient care. A more contemporary approach has reconceptualized the patient within a larger clinical and practical context. This transition demonstrates the value of an interdisciplinary approach, in which the patient, rather than the illness is the focus of treatment rather than the identified illness. There is also a transition toward a greater mechanistic understanding of illnesses. These developments have resulted in a greater appreciation of the overlap between physical and mental health, two areas which have at times occupied opposite poles of medical practice due to dualistic thinking, but which undeniably influence one another and can never be fully disentangled.

This textbook focuses its lens at this interface, examining the relationship between medical disorders and the most ubiquitous mental illness, depression. The associations between medical illness and depressive illness now appear to be more extensive and more intimate than previously appreciated. These associations may be considered coincidental, causal, or the result of a common underlying pathological process. The implications of these associations are shifting clinical practice in a new and more unified direction.

In this chapter, we will review differential diagnosis of depressive disorders within medically ill populations, including brief considerations of screening and treatment of depression in medical settings and an approach for stratification and treatment that can be implemented in both inpatient and outpatient settings. This discussion is followed by a closer examination of the relationship between depression and medical illness, reviewing diseases and treatments known to cause depression and examining depression as a final common pathway for both emotional and physiological disturbances. Finally, we review the synergistic effects of depression and medical illness, ranging from diminished functional status and decreased quality of life to increased rates of suicide and other forms of physical mortality. Although treatment is not a specific focus of this chapter and is covered in great depth later in this textbook, this chapter reiterates key themes of early intervention and collaborative care, as such principles of treatment can be implemented in the medical setting and are critical to optimizing outcomes.

In order to best appreciate the current understanding of depression in medically ill patients, it is helpful to begin with an historical perspective. This review reflects the natural evolution of man’s approach to “madness.” Early pioneers in the field produced rich descriptions of psychopathology, whereas later generations would propose causal mechanisms and modes of treatment.

Historical accounts of what constitutes a depressive disorder are long and varied. Yet as Stanley Jackson noted in his history of Melancholia and Depression, descriptions of depression date back over two millennia, yet have a remarkable consistency. Jackson describes the wide variety of terms for depression over the years, including feeling down, blue, unhappy, feeling dispirited, discouraged, disappointed, dejected, despondent, melancholy, sad, depressed, and despairing. For Jackson, depression is at the heart of being human.¹

The term melancholia dates back to the humoral theory during Greek and Roman times When Aristotle identified a “melancholic temperament” that he related to overproduction of “black bile”.² This early observation of the mind-body interaction in depression permeates our conceptualization of depression.

In the mid-nineteenth century, Griesenger described “stadium melancholicum” as the initial period of the disease and one that could “precede insanity,” which we would now term psychotic depression³ and various forms of major depression; he may have been the first to posit a hereditary predisposition for depression.³ At the same time, Falret identified the concept of “circular insanity” or bipolar disorder, and also noted that it was “very hereditary”.⁴ In the 1880s, Emil Kraepelin delineated “manic depressive insanity” as a new nosologic entity, distinguishing it from dementia praecox and Bleuler schizophrenia and suggesting that all were part of the same spectrum: “the classification of states by definite fundamental disorders is the experience that all morbid forms brought together here as a clinical entity, not only pass over the one into the other without recognizable boundaries, but they may even replace each other in one and the same case”.^5–8 In the mid-twentieth century, Karl Leonhard continued the Kraepelinian tradition and also introduced the concept of unipolar versus bipolar depression, that is, pure melancholia and pure depression.⁹ He identified five “pure depressions” subtypes, including agitated, hypochondriacal, self-tortured, suspicious and apathetic, again illustrating the diverse phenotypes of depressive disorder. Leonhard also looked toward genetics and heredity as the etiology of these disorders.¹⁰

In the 1970s, Akiskal and McKinney elucidated a unified hypothesis of depressive disorder¹¹ that included interactions with medical illness. They introduced a stress diathesis model in which the interactions between genetics, neurobiological development, and interpersonal factors all impact the diencephalic centers of reinforcement and conceptualized depression as a “psychobiological final common pathway” based on genetic vulnerability,¹¹ while emphasizing that physiologic stressors, including medical illness, could all be directly related to the emergence of depression. They also suggested acute and chronic stress, including chronic disease, could lead to depression.

In 1997, advances in our understanding of molecular neuroscience led Duman et al. to emphasize that depression is a heterogeneous illness that can result from the dysregulation of several neurotransmitters or metabolic systems.¹² They emphasized the need for a broader understanding of the biologic basis of depression including the role of growth factors, genetic predispositions related to monoamine enzymes, receptors and proteins and noted risk factors for depression including medical illnesses. They too emphasized a stress diathesis model that includes both responses to stress and genetic vulnerability, a model that is very germane to our focus on depression in medical illness.

Today it is postulated by Kendler et al.¹³ that major depression is a “prototypical multifactorial disorder” influenced by many factors including predisposing genetics, exposure to disturbed family environment, childhood sexual abuse, premature parental loss, predisposing personality traits, early-onset anxiety or conduct disorder, exposure to traumatic events and major adversities, low social support, substance misuse, prior history of major depression, low self-esteem and recent stressful life events. It has also been proposed by Parker¹⁴ that “neurobiological processes lead to an obligatory depressed mood component alone or via recruitment of other neurobiological processes determining the dimensional expression of, for example, anxiety, irritability, hostility, fatigue, with such features… joining depression to define in part, mood state parameters.” This diverges from a unitarian paradigm for depression toward an emphasis on subtypes that could eventually be defined by neuroimaging, and ultimately result in more specific treatment models. Chapter 2 focuses upon the brain circuit abnormalities that have been identified and are transforming the understanding of depression in medical illness.

Finally, though the theories of causality of depression have adopted a more integrative neurobiological model, the history of how to treat depression is also filled with competing models that reflect the historical paradigms of the day. During the psychoanalytic era, the guiding paradigm was Freud’s “Mourning and Melancholia”¹⁵ emphasizing the concept of loss in the affective state of grief and mourning in which the emotional world becomes “poor and empty” and distinguishing this from melancholia (depression) wherein it is the ego itself that is lost and becomes worthless. The grief stricken patient complains of the loss of a loved one whereas the melancholic focuses on his own inadequacies.

In the early 1950s, Bibring expanded this by focusing on the decrease in self-esteem seen in melancholic depression in contrast to grief. An “ego psychologist,” Bibring describes the role of lost self-esteem in depression, particularly helplessness of the ego, another consideration in individuals with medical illness.¹⁶ Aaron Beck then introduced the concept that early emotional deprivation leading to change in cognitive perceptions underlies depression and described the triad of hopeless, helpless, and worthless feelings that drive negative cognitive patterns and thoughts. Beck introduced cognitive-behavioral therapy as an evidence-based treatment modality for depression.¹⁷

CHALLENGES IN THE DIAGNOSIS OF DEPRESSION

The current nosology and classificatory schema for the diagnosis of depressive disorders can be found in the DSM-5, which aims to “capture the heterogeneity of depressive disorders by classifying them along two dimensions: severity and chronicity.¹⁸” Table 1-1 presents the DSM diagnostic criteria for various depressive disorders.

Historically, medicine has progressed through the development of objective, reproducible tests and measures of physiological and anatomical abnormality. However, psychiatry has remained dependent on phenomenological description and clinical judgment for diagnosis.¹⁹ While patients or their healthcare providers may recognize the emergence of mood changes or physical symptoms, such as fatigue, psychomotor retardation, anorexia, and insomnia, the specific diagnosis of such disorders entails many challenges. Unlike some other fields of medicine, there are currently no biomarkers or imaging findings to conclusively support or refute the diagnosis of depressive disorder. Thus, healthcare providers frequently rely on screening tools to diagnose and track depressive symptoms over time. However, these diagnostic tools are not a substitute for seasoned clinical assessment using a structured approach.²⁰ Also confounding the reliability of psychiatric diagnosis is the issue of dynamic fluctuation. A patient’s clinical presentation may change over brief periods of time in response to both biological and environmental factors. Without the aid of definitive biomarkers or other objective measures, clinicians are challenged with distinguishing “normal” dysphoria from pathological symptoms. This issue becomes especially problematic in the diagnostic assessment of patients who do not meet full criteria for DSM-5 disorders. In this context, there is a move from categorical toward dimensional approaches to the spectrum of mental illness.

DIFFERENTIAL DIAGNOSIS

Major Depressive Disorder

Major depressive disorder (MDD) has been increasingly well characterized. The illness almost always includes either persistent depressed mood and/or loss of interest in all usual pleasurable areas. Common psychological features include feelings of guilt and worthlessness, impairment in decision making, low motivation, hopelessness, and suicidal ideation or behavior. In addition, MDD typically includes various physical derangements, often referred to as neurovegetative symptoms. These may include appetite disturbance (anorexia or hyperphagia), sleep impairment (insomnia or hypersomnia), psychomotor disturbance (agitation or retardation), fatigue, and concentration problems.

Most medical providers are reasonably adept at recognizing MDD, although the neurovegetative symptoms may lead providers to focus exclusively on the physical symptoms and thus miss the diagnosis. However, other depressive illnesses are less well known to medical providers. They may confuse or obscure the diagnosis but are important to recognize for optimal management and outcome. While MDD is the most commonly diagnosed and treated depressive disorder, practitioners must also be able to recognize and treat depressive entities not meeting full criteria for MDD, including persistent depressive disorder (dysthymia), minor depression, adjustment disorder with depressed mood, and secondary mood disorder due to a general medical condition. Providers also need to recognize that depressive symptoms can occur in the context of other serious psychiatric illnesses, such as schizophrenia, bipolar disorder, and posttraumatic stress disorder.

Persistent Depressive Disorder (Dysthymia)

Persistent depressive disorder is the second most common depressive disorder likely to be encountered by medical professionals.²¹ It is estimated that 9.1% of the U.S. population meet criteria for current depression, and greater than one-third of them have persistent depressive disorder.²² While MDD has been extensively studied and has a solid evidence base to guide treatment, there are fewer data to guide treatment of persistent depressive disorder. This difference can be attributed in part to the early classification of dysthymic symptoms as “chronic depression” or “depressive personality disorder,” conditions which were characterological in nature and believed to respond only to psychotherapy.²³ However, numerous studies have established the effectiveness of antidepressant medications as well as cognitive and behavioral therapeutic interventions in the treatment of persistent depressive disorder.^21,24–26

Depression with Anxious Features

Anxiety symptoms frequently co-occur along with depressive symptoms,²⁷ with rates of significant anxiety symptoms in the 40% to 60% range. Similarly, anxiety and depressive disorders have been demonstrated to have high rates of comorbidity in the same range,²⁸ and depressive illness has been shown to have increased comorbidity with most subtypes of anxiety disorders. Thus, the rate of comorbidity for posttraumatic stress disorder and depression is quite high, approaching 40%.²⁹ Since serious traumatic events are associated with depression, this helps to explain the strong correlation between these two illnesses. Panic disorder has also been noted to be highly comorbid with depressive illness, with a nearly sevenfold increase compared to patients without panic disorder.³⁰

This frequent co-occurrence has led many researchers to study whether a depressive subtype, often called anxious depression, may best account for this syndrome rather than separate but comorbid anxiety and depressive disorders. Studies suggest that those patients with marked anxious features may have more severe mood disorders,³¹ and that their course and outcomes are often worse, than patients without an anxiety component, including an increased risk of suicide.³² Clinicians should evaluate any patient presenting with depressive illness for comorbid anxiety, and treatment approaches that include consideration of anxiety are more likely to be successful.

In the setting of comorbid medical illness, the co-occurrence of anxiety and depression may be particularly devastating to patients. Anxious symptoms may contribute to poor sleep, diminished appetite, and psychomotor acceleration, all of which may interfere with treatment and recovery from the medical condition. Anxiety may also affect the patient’s ability to make difficult treatment decisions, and to tolerate unpleasant tests and procedures; for instance, anxiety often interferes with the ability of intubated patients to wean from their ventilators. Finally, as with depression, anxiety may have a direct, deleterious effect on medical conditions. For example, it has been demonstrated that PTSD is a significantly independent risk factor for coronary artery disease.³³

Adjustment Disorder with Depressed Mood

Individuals may have some symptoms of depressive illness, particularly depressed mood, in response to an acute stressful event, and the diagnosis and/or development of a medical illness is a particularly stressful experience for many individuals. This response may include marked and persistent distress which appears out of proportion to the seriousness of the event, and may result in impairment of function in a variety of areas, including social, interpersonal, and occupational. In most cases, however, the symptoms do not rise to the level of major depression disorder, and is more accurately diagnosed as an adjustment disorder with primarily depressed mood.

Adjustment disorder with depressed mood is self-limited, almost always resolving within 6 months. It also has favorable outcomes when targeted with either psychotherapeutic interventions such as cognitive behavioral therapy, although at times may require a brief course of pharmacotherapy and close clinical monitoring.³⁴ However, practitioners frequently prefer to take a “watchful waiting” approach to such patients, as it is possible that their depressive symptoms may improve independently of specific, targeted treatment. While this conservative approach may be appropriate for certain cases, providers should have a structured plan for regular observation, with a low threshold to initiate treatment if the patient’s symptoms worsen, or there is no concomitant mood reactivity or improvement as the patient’s primary condition improves.

Complicated Grief and Bereavement

Grief is a common experience in elderly populations, due to the increased frequency of losses that occur later in life. By some estimates, over 70% of elderly individuals experience serious personal loss over a 2-year period.³⁵ Grief is typically associated with many depressive features. These may include sadness, decrease in pleasure, and interest in usual activities, social isolation, insomnia, and difficulty concentrating in occupational and interpersonal settings.

Although grief is a normative reaction to serious loss and is typically self-limited, some people may experience a more severe response. Such a response, which may occur in nearly 10% of bereaved older adults³⁶ is known as complicated grief or persistent complex bereavement disorder. The grief is both persistent and prolonged, lasting a year or more. Unrelenting yearning for the lost person, continued sadness and sorrow related to the loss, and excessive preoccupation with that person or the circumstances of the loss may be overwhelming. There may also be a tendency to avoid people and places associated with the loss.

Medical illness itself also may be experienced by many individuals as loss, and serious losses are associated with worsening of physical health, decline in function, and increase in mortality.³⁷ The loss of physical health and integrity may have many of the qualities of grief associated with interpersonal loss, as well as the feelings of loss of personal capacity, independence, and omnipotence over one’s world. Since both interpersonal losses and physical illnesses are more likely in older individuals, complicated grief may be a more significant condition in this population. However, it may be difficult to distinguish typical grief in response to the onset or progression of illness from a more complicated grief reaction. When the course of the grief over the illness is prolonged and progressive, it is appropriate to address the issue with the patient and to consider treatment. Cognitive therapy has been suggested to be effective in the management of complicated grief.³⁸

Secondary Mood Disorder Due to a Medical Condition

In patients for whom the primary medical illness does not simply precipitate depression, but is thought to be its pathophysiologic cause, clinicians should consider a diagnosis of secondary mood disorder due to a general medical condition.³⁹ In these cases, the depressive syndrome can be etiologically related to the patient’s medical condition either by history, physical examination, or laboratory findings. The diagnosis requires that the patient’s mood symptoms are not better accounted for by another mental disorder and do not occur exclusively in the course of delirium or dementia. Examples of medical illnesses that cause depressive syndromes range from hypothyroidism to pancreatic cancer to cerebrovascular lesions. Although pharmacotherapy can ameliorate certain mood or neurovegetative symptoms, complete remission of the depressive symptoms may not occur without effective treatment of the underlying medical condition. For example, depressive symptoms in Cushing disease may be resistant to antidepressant treatment but respond to steroid suppression.⁴⁰