CHAPTER 7

Depression
Madeline Li, M.D., Ph.D., FRCPC
Joshua Rosenblat, M.D.
Gary Rodin, M.D., FRCPC

The risk of developing depressive disorders is increased in most chronic

medical conditions, and reciprocally, depression can be a risk factor for the
development of medical illnesses (Ramasubbu et al. 2012). There are
multiple nonspecific factors, such as disability and physical suffering, that may
increase the risk of depression in serious medical illnesses. There is also
speculation about whether specific biological mechanisms account for the
comorbidity of depression with particular medical conditions.
Depression is frequently underdiagnosed and untreated in medical settings,
despite its frequency, negative effects on health, and responsiveness to
treatment. This diagnostic and therapeutic neglect may be due to
underreporting of symptoms because of stigma, difficulty distinguishing
normative from pathological distress, physical symptom overlap between
depression and medical illness, and lack of sufficient caregiver training in or
comfort with mental health inquiry. There may also be mistaken beliefs
among both providers and patients about the untreatability of depression that
is “understandable.” Untreated depression is of concern in medical
populations because it is associated with greater somatic symptom burden
(Katon et al. 2007) and worse quality of life (Katon 2003) in common medical
disorders. Depression is also associated with higher rates of health care
utilization, such that the cost of medical care for depressed medical patients
is 50% higher than that for nondepressed medical patients; depressed
patients also tend to be less compliant with medical treatment and to have
less functional capacity and less occupational productivity (Unützer et al.
2009). Paradoxically, depression is also overdiagnosed in medical settings,
with unnecessary prescription of antidepressant medication for
nonpathological sadness or grief or diagnoses based solely on scores on
depression screening instruments.
In this chapter we review the prevalence and clinical features of depression
in the medically ill; discuss approaches to depression screening, diagnosis,
and treatment; and explore mechanisms that may account for the etiology,
course, and outcome of depression in the medical setting. We do not attempt
to provide in-depth information on depression in particular diseases; for
details on the effects of comorbid depression in various medical conditions,
readers are referred to the chapters on specific disorders in this textbook.

The Continuum of Depression: From Experience to

Disorder
Sadness is a normal, expectable response to the adverse effects of a
serious medical illness, including changes in bodily appearance and
functioning; pain and physical distress; limitations in the capacity to work and
to engage in pleasurable activities; perceived alteration in the anticipated life
trajectory; fears of disability and dependency; and alterations in intimate
relationships, family life, social relationships, and other activities.
Nonpathological sadness and grief lie at one end of the continuum of
depression in medical populations. In the middle lie subthreshold depressions
(Rodríguez et al. 2012), which are the most prevalent depressive
presentations among medically ill patients (Gellis 2010). At the more severe
end are depressive symptoms that clearly meet diagnostic criteria for major
depressive disorder as specified in DSM-5 (American Psychiatric Association
2013). These categorical distinctions have heuristic and communicative value,
although the boundaries that demarcate and distinguish them from one
another are somewhat arbitrary and often difficult to determine, particularly
in medically ill patients.
The eight major categories of depressive disorders specified in DSM-5 are
major depressive disorder (MDD), persistent depressive disorder (PDD;
formerly dysthymia), substance/medication-induced depressive disorder,
depressive disorder due to another medical condition, disruptive mood
dysregulation disorder (applicable only in children), premenstrual dysphoric
disorder, other specified depressive disorder (formerly minor or subsyndromal
depression), and unspecified depressive disorder (when insufficient
information is available to make a specific diagnosis). Subthreshold disorders,
including PDD and the other specified and unspecified depressive disorder
categories, may substantially reduce quality of life and result in moderate
functional impairment (Rowe and Rapaport 2006). At least 10%–20% of
subthreshold depressions progress to MDD (Lyness et al. 2006).
DSM-5 no longer excludes recent bereavement from a diagnosis of MDD,
although it should be noted that normative and nonpathological grief
following a loss may meet all diagnostic criteria for a depressive episode
(Horwitz and Wakefield 2007). Indeed, it may be argued that the onset,
exacerbation, or progression of a serious medical illness may be experienced
as a loss that can be at least as distressing as the loss of a loved one.
Notably, a diagnosis of adjustment disorder, which in DSM-5 is
reconceptualized as one of the trauma- and stressor-related disorders, can be
applied when a patient has symptoms of depression in reaction to a stressor,
such as medical illness, that do not meet criteria for MDD or PDD. The
operational criteria for this diagnosis, including what constitutes an
“excessive” response to the multiple and chronic stressors of medical illness,
are not clear. However, despite this ambiguity, the heuristic and
nonstigmatizing appeal of the category of adjustment disorder contribute to
its being one of the most common psychiatric diagnoses made in medical
patients (Li et al. 2010).

Epidemiology
Depressive disorders are extremely common in the general population,
with up to 17% of adults in the United States having had at least one episode
of MDD during their lifetime (Kessler et al. 2003) and 2%–4% suffering from
a current MDD (Ferrari et al. 2013). Medical illness has consistently been
shown to be a risk factor for depression (Patten et al. 2018). PDD and
subthreshold depression are the most common depressive syndromes in
medical populations, reported in up to 26% of medical outpatients, a rate
several times higher than that in the general population (Rowe and Rapaport
2006). The prevalence of MDD varies by population, with rates of 2%–4% in
community samples, 5%–10% in primary care settings, and 6%–14% in
medical inpatient settings; these progressive increases presumably are based
on differences in medical disease severity (Burvill 1995). Similarly, the risk of
a depressive episode in patients in primary care (Barkow et al. 2002) and in
the community (Wilhelm et al. 1999) rises with the number of comorbid
medical diseases. The reported prevalence rates of depressive disorders in
specific medical conditions, including cancer, diabetes, cardiovascular
disease, chronic obstructive pulmonary disease (COPD)/asthma, HIV/AIDS,
stroke, epilepsy, multiple sclerosis, Alzheimer’s disease, and Parkinson’s
disease, are listed in Table 7–1.

TABLE 7–1. Prevalence of depression in selected medical illnesses

MDD vs.
Prevalence of subthreshold
Medical illness MDD (%) depression (%) References
Cancer 8–24 15 vs. 22 Mitchell et al. 2011
Diabetes 9–26 14 vs. 32 Musselman et al. 2003; Roy and
Lloyd 2012
Type 2: 6–
33
Type 1: 6–
44

Heart disease 17–27 18 vs. 27 Rudisch and Nemeroff 2003;

Schleifer et al. 1989
COPD/asthma 20–50 28 vs. 40 Van Lieshout et al. 2009
HIV/AIDS 18–50 22 vs. 45 Arseniou et al. 2014
Stroke 15–31 14 vs. 18 Morris et al. 1990; Robinson and
Jorge 2016
Epilepsy 20–29 23 vs. 29 Fiest et al. 2013
Multiple 26–35 30 vs. 33 Boeschoten et al. 2017
sclerosis
Alzheimer’s 13–22 22 vs. 27 Chi et al. 2015; Lyketsos et al.
disease 1997
Parkinson’s 18–27 23 vs. 30 Goodarzi et al. 2016b
disease
Note. COPD=chronic obstructive pulmonary disease; MDD=major depressive disorder.

FIGURE 7–1. Pathways to depression.

Although depression is often regarded as a discrete disorder, it can also be considered as a final common
pathway of distress that arises from the interaction of biological, psychological and social factors. Biological
factors interact with the psychological impact of the disease which is filtered through the prism of individual
and interpersonal strengths to result in a range of depressive responses from normal sadness to major
depressive disorder.

Etiology
Increased rates of depressive symptoms and depressive disorders have
been found in virtually all chronic medical conditions in which depression has
been studied (Patten et al. 2018). It has been hypothesized that illness-
specific biological mechanisms lay the foundations for depression in certain
medical conditions, including hypothyroidism, stroke, Parkinson’s disease,
diabetes, and some types of cancer. Although specificity for depression has
not been substantiated in any of these conditions, each is associated with
multiple nonspecific risk factors that may increase the prevalence of
depression. In fact, depression in the context of medical illness is a prime
example of the biopsychosocial model of disease, with interacting
pathophysiological and psychosocial factors contributing to comorbidity. The
final common pathway to depression—resulting from the interaction of
disease-related, psychological, and social risk and protective factors—is
shown in Figure 7–1.
Potential biological contributors to depression in medical illness include the
physical effects of illness and treatment, medications, neurological
involvement, genetic vulnerability, and systemic inflammation. In this regard,
greater pain and treatment intensity (Patten et al. 2018), more advanced
disease (Manne et al. 2001), and proximity to death (Lo et al. 2011) have all
been shown to increase the risk of depression. Individuals with a genetic
vulnerability to depression are also more likely to develop it in the context of
medical illness (Levinson 2006), and common genetic vulnerabilities may
account for the frequent comorbidity of depression and Alzheimer’s disease
(Kim et al. 2002), Parkinson’s disease ( Mössner et al. 2001), and coronary
artery disease (Su et al. 2009). Immune-activated systemic inflammation
(Miller et al. 2009), manifesting as cytokine-induced “sickness behavior,” is
another proposed common pathophysiological mechanism that may underlie
depression in a wide range of medical disorders, including cancer (Raison and
Miller 2003), cardiovascular disease (Parissis et al. 2007), diabetes
(Musselman et al. 2003), Alzheimer’s disease (Leonard 2007), stroke
(Arbelaez et al. 2007), multiple sclerosis (Wallin et al. 2006), asthma (Van
Lieshout et al. 2009), and infectious diseases such as HIV/AIDS (Leserman
2003). This association has led some to posit the existence of a specific
subtype of depression—inflammatory cytokine-associated depression (ICAD)
(Lotrich 2015), characterized by more neurovegetative and fewer core
psychological symptoms (Capuron et al. 2009; Pasquini et al. 2008)—that is
more common in individuals with medical conditions associated with
inflammation (Dantzer et al. 2008).
It has been suggested that medication-induced depression is
symptomatically different from MDD, with less prominent and milder
depression and atypical features more characteristic of ICAD (Patten and
Barbui 2004). The association of depression with medications such as L-dopa,
calcium channel blockers, analgesics, nonsteroidal anti-inflammatory drugs,
isotretinoin, and phenobarbital has largely been based on case reports, with
few high-quality studies. Valid evidence linking medications to atypical
depressive syndromes has been found only for corticosteroids, interferon-α,
interleukin-2, gonadotropin-releasing hormone agonists, mefloquine, and
progestin-releasing implanted contraceptives (Patten and Barbui 2004). Most
of these drugs and their psychiatric side effects are discussed in other
chapters of this textbook.
Psychosocial factors that may contribute to the development of a comorbid
depressive disorder in medical illness include the stigma and personal
meaning of the medical condition, illness-related disability (Talbot et al.
1999), maladaptive coping styles (Wallin et al. 2006), low self-esteem,
impaired spiritual well-being (Rodin et al. 2007), and reduced capacity to
express affect (Classen et al. 2008). Low social support (Lewis 2001) and
poor communication with medical caregivers (Gurevich et al. 2004) also
increase the likelihood of a comorbid depressive disorder. Additionally,
expectations of support and the capacity for flexible use of social support,
captured in the construct of attachment security, may provide protection
against the emergence of depressive symptoms in medically ill patients
(Rodin et al. 2007).
Age is inversely related to the severity of depressive symptoms (Gottlieb et
al. 2004). Although depression in the general population has been strongly
associated with female gender (Lucht et al. 2003), this gender difference has
not been found consistently in depression in medical populations (Miller et al.
2011; Rodin et al. 2007). It may be that the overriding common stressors
related to the medical illness obliterate gender-related differences that would
otherwise emerge.

Clinical Features and Diagnosis

The diagnosis of depressive disorders in medical populations is fraught
with difficulties that include the following:
1. Many physical symptoms of medical illness (e.g., fatigue, anorexia, weight
loss, insomnia, psychomotor retardation, diminished concentration)
resemble those of depression. In addition, a variety of emotional
disturbances, such as “emotionalism,” pathological crying, apathy, and
fatigue in poststroke patients (Bogousslavsky 2003) or in patients with
multiple sclerosis (Chwastiak and Ehde 2007), can be mistaken for
depression. It may also be difficult to distinguish depression from the apathy
associated with hypoactive delirium or dementia, or from akinesia and
masked facies in Parkinson’s disease.
2. Thoughts of death and the desire for death in patients with advanced
medical disease have been associated with depression and demoralization in
the terminally ill (Breitbart et al. 2000). However, such thoughts must be
distinguished from adaptive death acceptance or an attempt at cognitive
mastery that does not reflect depression (Nissim et al. 2009).
3. Physical suffering and disability, in the absence of comorbid depression, may
diminish the capacity to experience pleasure in many formerly enjoyable
activities. Depressed mood or withdrawal from social or physical activities
that is disproportionate to physical disability increases the likelihood that the
loss of pleasure is secondary to depression.
4. In medical populations, depressive symptoms may manifest in atypical or
masked forms, including amplification of somatic symptoms (Katon et al.
2007) and noncompliance with or refusal of medical treatment (DiMatteo et
al. 2000). These symptoms or behaviors may not be recognized as
manifestations of depression, leading to underdiagnosis of depression.
5. The categories of MDD, substance/medication-induced depressive disorder,
and depressive disorder due to another medical condition may overlap in the
context of medical illness. The latter two diagnoses imply that the etiology
of the depression is a direct physiological consequence of the specified
general medical condition or substance, whereas the causation of depression
is most often multifactorial.

Various approaches have been proposed to diminish the confounding effect

of medical symptoms in the diagnosis of MDD. In DSM-5, it is acknowledged
that there are no “infallible guidelines” to follow in determining when
depression is secondary to another medical condition but that the index of
suspicion should be raised by 1) a temporal association between symptoms
and the onset, exacerbation, or remission of a medical condition, and 2) an
age at onset, course, or absence of family history that is atypical for a
primary mood disorder. The criteria for determining which symptoms are due
to a medical illness and which are due to other factors unrelated to the
medical illness are unclear and are left to “the clinician’s best judgment”
(American Psychiatric Association 2013).
A combined “exclusive” and “etiological” approach to the diagnosis of
depression in patients with medical illness was previously advocated, with
exclusion of symptoms judged by the clinician to be etiologically related to a
general medical condition or not more frequent in depressed than
nondepressed patients with such conditions (Bukberg et al. 1984). This
approach was intended to avoid attributing symptoms of physical illness to a
depressive syndrome. The exclusive approach is usually applied only to the
somatic symptoms of depression, although this does not take into account
that depressed medical patients report significantly more physical symptoms
than matched nondepressed medical patients (Fitzgerald et al. 2015).
Evaluating the rates of depression in hospitalized elderly medical patients
according to six different diagnostic schemes, Koenig et al. (1997) found no
overall advantage of one diagnostic scheme over others. In cases in which
the diagnosis remains unclear, a focus on the qualitative differences of
psychological features on the continuum of depression (Table 7–2), along
with a trial of treatment as appropriate, may be the most practical means of
resolving the question.

TABLE 7–2. Psychological features on the continuum of depression

DSM-5 major depressive
Normal sadness Subthreshold depression disorder
• Maintenance of intimacy and • Low mood • Feeling of isolation
connection presentation similar • Feeling of permanence
• Belief that things will get better to major depressive • Excessive guilt and regret
• Capacity to enjoy happy memories disorder but not • Self-critical
ruminations/loathing
• Sense of self-worth fluctuating with meeting full criteria
thoughts of cancer • Constant, pervasive, and
for symptom number nonreactive sadness
• Capacity to look forward to the future
or duration • Sense of hopelessness
• Retention of capacity for pleasure
• Maintenance of will to live • Potentially transient and • Loss of interest in activities
self-limited, including mood • Suicidal thoughts/behavior
episodes lasting <2 weeks
• Includes persistent
depressive disorder if
>2 years’ duration
Source.  Adapted with permission from Li M., Kennedy E.B., Byrne N., et al.: The Management of
Depression in Patients With Cancer: A Quality Initiative of the Program in Evidence-Based Care (PEBC),
Cancer Care Ontario (CCO). Guideline #19–4. Toronto, ON, Canada, Cancer Care Ontario, 2016.

Health Outcomes
The bidirectional comorbidity between depression and medical illness is
evidenced by the increased risk of acquiring certain medical conditions in
patients with a prior history of depression. MDD has been shown to increase
the risk of coronary artery disease 1.5- to 2-fold (Van der Kooy et al. 2007 ),
stroke 1.8-fold (Ramasubbu and Patten 2003), cancer 1.9-fold (Gross et al.
2010), diabetes 1.4-fold (Yu et al. 2015), epilepsy 4- to 6-fold (Hesdorffer et
al. 2000), and Alzheimer’s disease 2.1-fold (Green et al. 2003). These risk
increases may be mediated by biological mechanisms as well as by unhealthy
behaviors related to medical compliance, self-care, diet, or exercise (Katon
2003).
The World Health Organization (WHO) recently reported that depression is
the leading cause of disability worldwide, with more than 320 million people
affected globally (World Health Organization 2017). Remarkably, the WHO
World Health Survey (Moussavi et al. 2007) found that depression reduces
overall health significantly more than do chronic diseases such as coronary
artery disease, arthritis, asthma, and diabetes and that the comorbid state of
depression plus medical illness worsens health more than any combination of
chronic diseases without depression. Comorbid depression is associated with
a significant economic burden, including almost twofold higher rates of health
care utilization and workplace disability (Stein et al. 2006), longer inpatient
lengths of stay (Saravay et al. 1996), and at least a twofold increase in
emergency room visits (Himelhoch et al. 2004). Comorbid depression is also
associated with a threefold greater risk of nonadherence to medical
treatment, thereby contributing to increased morbidity and mortality
(DiMatteo et al. 2000). Such noncompliance may include not taking
treatments that are prescribed, not following diet or lifestyle
recommendations, and not appearing for medical appointments.
Comorbid depression and medical illness have been shown to be
associated with worse medical outcomes and higher mortality rates in a
number of medical conditions, but specific causal relationships between
depression and such outcomes have not been confirmed (Cuijpers et al.
2014). Depression has been associated with more rapid progression of HIV
disease (Leserman 2003) and with increased all-cause mortality in
cardiovascular disease (Carney and Freedland 2017), cancer (Batty et al.
2017; Pinquart and Duberstein 2010), organ transplant (Dew et al. 2015),
and diabetes (Park et al. 2013). This increased mortality rate, which persists
even after factors such as smoking, disease severity, and alcohol
consumption (Schulz et al. 2000) are controlled for, may be attributable to
several different factors. Biological mechanisms in depression may increase
mortality rates in the medically ill via effects on the autonomic nervous
system and on related cardiac outcomes. The association of suicide with
depression may also increase mortality rates in medical populations, a finding
that has been demonstrated in medical conditions such as cancer (Steel et al.
2007), multiple sclerosis (Stenager et al. 1996), and Huntington’s disease
(Almqvist et al. 1999). Depression may be associated with other health risk
behaviors—such as cigarette smoking, overeating, physical inactivity, obesity,
and excess alcohol consumption—that increase the prevalence of associated
medical illness and affect its course adversely.

Screening for Depression

Obstacles to Diagnosis in Medical Settings

Depression and other forms of distress are commonly underdiagnosed and
undertreated in medical settings (Fallowfield et al. 2001). A U.K. study
suggested that fewer than one-half of cases of depression are correctly
diagnosed by general practitioners (Mitchell et al. 2009). This finding
warrants concern, because a missed diagnosis of MDD may represent a lost
opportunity to improve quality of life, decrease the risk of suicide, shorten
hospital stay, and improve treatment compliance in the medically ill. There
are many explanations for the low rate of detection of clinical depression in
medical settings. The structure of medical care—with medical visits often
lasting less than 15 minutes, with multiple clinical concerns that may need to
be addressed during each visit, and the frequent lack of privacy in clinic and
hospital settings—may inhibit disclosure or elaboration of symptoms.
Furthermore, some clinicians avoid emotional inquiry because they fear that
they lack sufficient time or skill to manage emotional reactions. Some
patients are reluctant to disclose depressive symptoms because of perceived
stigma or anticipated lack of interest of their medical caregivers. However,
most patients welcome the opportunity to discuss psychosocial issues that
are raised by their health care providers (Rodin et al. 2009). In some cases,
both patients and clinicians have difficulty differentiating the somatic
symptoms of depression from those of medical disease. Even when clinically
significant depression is recognized as being present, it may be perceived as
an “understandable” reaction to medical illness and therefore not worth
treating.
Paradoxically, time-pressured medical clinic visits that preclude adequate
assessment of mood can lead to the overdiagnosis of depression and
unnecessary pharmacotherapy. This may be a result of misattribution of the
symptoms of physical illness to depression and use of low diagnostic
thresholds for depression, with an overreadiness to prescribe antidepressant
medications and/or to refer for specialized psychiatric assessment (Boland et
al. 1996) because of inadequate resources or training to explore or manage
psychological distress (Aragonès et al. 2006). More appropriate utilization of
limited specialized psychiatric resources may be facilitated by routine use of
validated depression screening tools in medical settings (Cahill et al. 2015;
Caruso et al. 2017; Gill et al. 2017; Hermanns et al. 2013; McCollister 2011;
Moraes et al. 2017; Quittner et al. 2016; Swartz et al. 2016), as has been
recommended for primary care by the U.S. Preventive Services Task Force,
“with adequate systems in place to ensure accurate diagnosis, effective
treatment, and appropriate follow-up” (O’Connor et al. 2016).

Screening Process
General Considerations
Screening for depression may be particularly helpful in medical settings,
where routine assessment of mood might otherwise not occur. The ideal
screening instrument would be easy to administer and score, acceptable to
patients, and, most importantly, accurate. However, the utility of screening
for depression depends not only on the measure used but also on whether
screening results are routinely assessed by medical caregivers and followed
up with appropriate and effective intervention. Failure to ensure that such a
response loop is implemented partially contributes to the paucity of evidence
that depression screening results in improved depression outcomes (Canadian
Task Force on Preventive Health Care et al. 2013 ; Thombs et al. 2014). The
WHO’s principles of screening for disease (Andermann et al. 2008) require
that medical screening tests demonstrate evidence of effectiveness, with
benefits outweighing harms. Screening for depression differs from screening
for conditions such as cancer because of the recurrent nature of depression,
where early identification may not necessarily reduce incidence in the context
of chronic medical illness. Furthermore, positive primary screening tests only
identify individuals with a high risk for a medical condition and must be
followed by appropriate secondary assessment to make a diagnosis. When
positive depression screens automatically trigger intervention, inappropriate
use of mental health resources or overprescription of antidepressants may
occur. The goal of depression screening should be to initiate a clinical
assessment by the health care provider (Li et al. 2016b).
Screening Instruments Commonly Used in Medical
Populations
There is no true gold standard for the diagnosis of depression, particularly
in the context of medical illness, but clinical interviews have traditionally
been used to confirm diagnoses and to establish prevalence rates. Such
interviews may be unstructured, utilizing an inclusive or substitutive approach
to counting symptoms, or more structured, utilizing diagnostic instruments
such as the Structured Clinical Interview for DSM-5 Disorders—Clinician
Version (SCID-5-CV; First et al. 2016), the Composite International Diagnostic
Interview (CIDI; World Health Organization 1997), the Mini-International
Neuropsychiatric Interview (MINI; Sheehan et al. 1998), the Present State
Examination (PSE; Hall et al. 1999), or the Primary Care Evaluation of Mental
Disorders (PRIME-MD; Spitzer et al. 1999).
Depression rating scales can be used to screen patients to identify those
who require clinical diagnostic assessment or to measure depression severity
and symptom change over time. Numerous psychometric measures have
been developed to measure depressive symptoms, with criterion validity and
optimal cutoff scores usually established with some form of clinical interview
(Wakefield et al. 2015). The cutoff scores selected determine the sensitivity
and specificity of the measure and, therefore, the proportion of false-negative
and false-positive cases. Use of higher cutoffs that avoid false positives may
be preferable for research purposes and for determining resource allocation in
more severe cases. Lower thresholds may be preferable in well-resourced
treatment settings in which a premium is placed on avoiding false negatives
and on detecting subthreshold disorders. In the following paragraphs we
briefly discuss four commonly used self-report instruments that have been
validated in medical populations: Center for Epidemiologic Studies—
Depression Scale (CES-D; Radloff 1977), Hospital Anxiety and Depression
Scale (HADS; Zigmond and Snaith 1983), Beck Depression Inventory–II (BDI-
II; Beck et al. 1996), and Patient Health Questionnaire–9 (PHQ-9; Kroenke et
al. 2001). The HADS and the BDI-II are copyrighted instruments, while the
CES-D and the PHQ-9 are available in the public domain.
The CES-D is a 20-item self-report measure of depressive symptoms, in
which only 4 of the 20 items are somatic. Originally designed as a measure of
depressive distress in community samples, the CES-D has also been
extensively used in medically ill samples, with evidence of good psychometric
properties. A cutoff score of 17 was originally recommended to identify
clinically significant depression (Radloff 1977), but the low positive predictive
value of the CES-D suggests that it might be a better measure of general
distress than of depression. Reported cutoff scores in a variety of medical
populations have varied between 14 and 23. Depending on cutoffs and
medical illness, sensitivity ranges from 73% to 100% and specificity from
61% to 89%.
The HADS is a 14-item self-report scale specifically designed for use in the
medically ill, with separate 7-item subscales for anxiety and depression. The
depression subscale emphasizes anhedonia and does not include somatic
items. The HADS is highly acceptable to patients and has been extensively
used in the medically ill, with reported cutoff scores ranging from 8 to 16.
Depending on cutoffs and medical illness, sensitivity ranges from 39% to
87% and specificity from 64% to 95%. The HADS does not discriminate well
between depression and anxiety, and like the CES-D, it may be better used
as a measure of emotional distress (Cosco et al. 2012; Norton et al. 2013).
The BDI-II was originally developed as a 21-item self-report measure of
symptom severity in psychiatric patients, but this instrument has been used in
numerous studies in the medically ill. Concerns have been raised about its
validity in patients with medical illness because of its preponderance of
somatic items and about the acceptability to patients of its forced-choice
format and complex response alternatives (Koenig et al. 1992). However,
there are many studies of the BDI-II as a screening instrument in medically ill
samples that have found it to be an accurate self-report measure (Wang and
Gorenstein 2013). The cutoff scores recommended in the medically ill have
ranged widely, from 7 to 22, providing sensitivity ranging from 45% to 100%
and specificity ranging from 64% to 100%, depending on the medical
condition (Wang and Gorenstein 2013).
The PHQ-9, the 9-item depression module of the self-administered Patient
Health Questionnaire, has been studied in thousands of primary care and
medical specialty outpatients in the United States, Europe, and China. The
PHQ-9 measures each of the nine DSM-5 criteria for a major depressive
episode, with scores ranging from 0 (not at all) to 3 (nearly every day).
Reported cutoff scores used in medical populations have ranged from 5 to 10.
Depending on cutoffs and medical illness, sensitivity ranges from 52% to
97% and specificity from 73% to 97% (Levis et al. 2017). Of note, Levis et
al. (2017) identified significant reporting bias in studies using the PHQ-9, as
primary study authors often only selectively report results from cutoffs that
perform well in their study.
Single-Item and Very Brief Screening Scales
Single-item screening tests for depression have wide appeal to health care
providers and patients, but not surprisingly, they have poor positive predictive
value in medical settings (Mitchell 2007; Mitchell and Coyne 2007).
Kroenke et al. (2001) evaluated the two-item PHQ-2, which was derived
from the PHQ-9. Meta-analytic studies using the PHQ-2 have reported
sensitivity and specificity estimates of 89.3% and 75.9%, respectively, in a
primary care population (Mitchell et al. 2016), and 91.8% and 67.7%,
respectively, in a geriatric population (Tsoi et al. 2017).
The lower specificity of single-item or ultra-brief self-report measures of
depression limits their utility, although measures such as the PHQ-2, which
focuses on the core features of depressed mood and/or anhedonia, may be
useful, particularly in a step-wise fashion. However, the most common
shortcoming in the detection of depression is not in the nature of the
instrument used or in the questions posed, but rather in the failure to screen
for depression using any method.

Treatment Outcomes
Although the negative impact of depression on illness is unequivocal and
the bidirectional relationship between depression and medical illness is
strong, evidence that treatment of depression improves disease-specific
medical outcomes is less clear. In an analysis of studies evaluating the
benefits of a screen-and-treat strategy for depression in diabetes, heart
failure, and coronary artery disease, Sharkey et al. (2013) found no evidence
of improved chronic disease outcomes. However, Katon et al. (2010)
demonstrated in a randomized controlled trial (RCT) that patients with
depression and chronic illness (poorly controlled diabetes, coronary artery
disease, or both) receiving collaborative care had greater overall 12-month
improvements in hemoglobin A1c, low-density lipoprotein cholesterol, systolic
blood pressure, and depression scores compared with those receiving usual
care. The question of whether treatment of depression improves medical
outcomes has been most extensively investigated in cardiovascular disease
and cancer, in which several studies have explored the relationship between
treatment of depression and survival.
In cardiovascular disease, no beneficial effects on cardiac outcomes were
found in studies of psychotherapeutic interventions such as the Montreal
Heart Attack Readjustment Trial (M-HART; Frasure-Smith 1995) and the
Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD; Berkman
et al. 2003) trial, although these studies may have been underpowered to
detected significant differences, given the modest effectiveness of treatment.
Randomized trials of pharmacological treatment for depression in
cardiovascular disease, such as the Sertraline Antidepressant Heart Attack
Randomized Trial (SADHART; Glassman et al. 2002) and a related trial
regarding congestive heart failure, SADHART-CHF ( O’Connor et al. 2010), and
the Myocardial INfarction and Depression—Intervention Trial (MIND-IT; van
den Brink et al. 2002) of mirtazapine, also failed to demonstrate a
statistically significant reduction in risk for cardiac events, although these
studies similarly demonstrated little reduction in depression. However, in a
subanalysis of subjects in the ENRICHD trial, there was reduced risk of death
or nonfatal myocardial infarction in subjects who received antidepressants,
particularly selective serotonin reuptake inhibitors (SSRIs) (adjusted hazard
ratio=0.57). Similarly, secondary analysis of the subgroup of patients in the
SADHART-CHF trial who achieved clinical remission of depression
demonstrated a statistically significant reduction in cardiovascular events
compared with the nonremission group (1.34±1.86 vs. 1.93±2.71; adjusted
P=0.01) (Jiang et al. 2011). Beneficial pleiotropic effects of SSRIs, such as
reduction in platelet activity (Serebruany et al. 2003) and improvement in
heart rate variability (Yeragani et al. 2002), may account for these findings.
Notably, one large study of enhanced depression treatment in patients with
acute coronary syndrome demonstrated a reduction in major adverse cardiac
events in intervention patients compared with usual-care patients (Davidson
et al. 2010). Unique aspects of this study were a flexible treatment model in
which patients could choose problem-solving therapy and/or antidepressants
and selection for persistent (>3 months) depression. A better understanding
of the temporal and mechanistic relationships between depression and
coronary artery disease is needed to clarify potential medical effects of
antidepressant treatment (Dickens et al. 2007; see also Chapter 17, “Heart
Disease”).
Studies have yet to be published on medical outcomes associated with
treatment of MDD in cancer patients, although such outcomes have been
assessed in studies in which threshold depression was not an inclusion
criterion. In an RCT of a 6-month course of fluoxetine versus placebo in early-
stage breast cancer patients undergoing adjuvant therapy, Navari et al.
(2008) reported that fluoxetine reduced depressive symptoms, improved
quality of life, and increased the likelihood of completion of adjuvant
treatment. The question of whether psychotherapy can improve survival in
cancer has been a hotly debated one (Coyne et al. 2009; Kraemer et al.
2009), with better-designed trials demonstrating that psychosocial
interventions that are effective in reducing depressive symptoms do not
confer a survival benefit in metastatic cancer patients (Jassim et al. 2015;
Kissane et al. 2007; see also Chapter 22, “Oncology”).
It may be that the effectiveness of currently available treatments for
depression in medical illness is too limited to shift the physiological disease
burden of advanced illness enough to alter survival outcomes. More effective
treatments may be needed to determine whether alleviation of depression in
medical illness has a significant impact on survival and to identify biologically
plausible mechanisms that could account for such an effect. Emphasis instead
should be on improving quality of life.

FIGURE 7–2. Stepped-care model of depression care, with treatment intensity corresponding
to depression severity.
aComplex depression includes depression that shows an inadequate response to multiple treatments, is
complicated by psychotic symptoms, and/or is associated with significant psychiatric comorbidity or
psychosocial factors.
Source. Reprinted from Li M, Kennedy EB, Byrne N, et al.: “Management of Depression in Patients With
Cancer: A Clinical Practice Guideline.” Journal of Oncology Practice 12(8):747–756, 2016; content from
National Institute for Health and Care Excellence 2015.
Treatment
Several studies have reported that both pharmacological and
psychotherapeutic interventions are effective in treating depression in
patients with medical disorders, although these effects may be less robust
than those in individuals with MDD without medical comorbidity (Iosifescu
2007). The latter finding may be due not only to a difference in the response
of MDD to treatment but also to the more prevalent subthreshold
presentations in medical populations, which tend not to respond to
antidepressant medications (Baumeister 2012) and for which optimal
treatment approaches are less clear (Rowe and Rapaport 2006).
The primary evidence base for the effectiveness of treatment of depression
in specific medical conditions is limited. Most systematic reviews and meta-
analyses have demonstrated modest benefit in illnesses including diabetes
(Baumeister et al. 2014), coronary artery disease (Baumeister et al. 2011),
COPD (Panagioti et al. 2016), cancer (Li et al. 2017), HIV infection and AIDS
(Sherr et al. 2011), chronic kidney disease (Grigoriou et al. 2015), stroke
(Nabavi et al. 2014), multiple sclerosis (Fiest et al. 2016), dementia (Ford
and Almeida 2017), and Parkinson’s disease ( Troeung et al. 2013 ). All such
reviews comment on the limited evidence base and the need for more RCTs
of depression treatments. Most current disease-specific depression treatment
guidelines recommend the use of both pharmacological and
psychotherapeutic interventions, based on pooled evidence of benefit in
medical populations and extrapolation from effectiveness in primary
psychiatric populations (Goodarzi et al. 2016a; Li et al. 2016a; Lichtman et al.
2008; Relf et al. 2013; Towfighi et al. 2017). The National Institute for Health
and Care Excellence (NICE) has synthesized the available evidence on the
treatment of depression in adults with a chronic physical health problem
(National Collaborating Centre for Mental Health [UK] 2010). Updated
guidelines published in November 2015 identified a few new treatment trials,
but none that altered NICE’s recommendations for a stepped-care approach
to depression management (National Institute for Health and Care Excellence
2015). Stepped care is a framework for care delivery in which treatment is
graded to the severity of depression (Figure 7–2). All patients with depression
are provided with basic assessment, support, psychoeducation, monitoring,
and referral (Step 1). Based on evidence that the risk–benefit ratio does not
support the use of antidepressant medications in subthreshold depression,
less intrusive and low-intensity psychological or psychosocial interventions
are provided first (Step 2), with progression to the next step of medications
and/or high-intensity psychological interventions (Step 3), which may be
delivered within a collaborative care model (Archer et al. 2012) if there is
inadequate response to initial treatment. Complex depression involving
suicide risk, psychosis, or severe psychosocial risk may require inpatient
admission and/or brain stimulation therapies. The components of these
interventions are described more fully below.

Psychotherapeutic Treatment
The full range of psychosocial interventions designed to treat depression in
medical populations is discussed in more detail in Chapter 37
(“Psychotherapy”) and in the chapters on specific disorders in this textbook.
The stepped-care model suggests use of low-intensity psychosocial
interventions for persistent subthreshold depressive symptoms or mild to
moderate depression. Low-intensity interventions include structured group
physical activity programs, group-based peer support or self-help programs,
individual guided self-help programs based on cognitive-behavioral therapy
(CBT), and computerized CBT. Such group-based therapies may protect
patients from depression by diminishing stigma and feelings of isolation and
by promoting self-efficacy and a sense of mastery. Patients with inadequate
response to treatment or with initial presentations of moderate to severe
depression should be offered high-intensity psychosocial interventions that
are professionally facilitated. Such interventions include individual or group
CBT or behavioral couples’ therapy. A Cochrane review of psychotherapy for
depression in patients with incurable cancer concluded that psychotherapy
was effective in decreasing depressive symptoms, although no studies were
identified that focused specifically on patients with MDD (Akechi et al. 2008).
Although the preponderance of research evidence supports cognitive-
behavioral approaches to treatment of depression in medical illness
(Baumeister et al. 2014; Hummel et al. 2017; Jassim et al. 2015; Orgeta et
al. 2015; Ski et al. 2016), such approaches are rarely adopted in routine
clinical practice. More commonly, an individualized eclectic approach is used,
combining elements of psychoeducation, behavioral activation, problem
solving, interpersonal therapy, mindfulness-based therapy, and supportive–
expressive psychotherapy delivered on an individual or a group basis. The
relationship with the primary medical caregiver may be the most important
psychotherapeutic tool to prevent or treat depression for many patients with
a serious medical illness. Specific psychological therapies may alleviate or
prevent depression, without the risk of physical side effects or drug
interactions, and may help to modify health behaviors that adversely affect
disease outcomes. The indication to refer to a mental health professional for
psychotherapy will depend on the severity of the depression and on the skill
and availability of practitioners. The specific psychotherapeutic intervention
selected should also take into account the available support network and the
patient’s capacity to learn new coping strategies and/or to engage in a
process that may involve introspection and the expression of feelings. Unique
features of psychotherapy in the medically ill are the importance of
collaborative relationships between the therapist and the medical caregivers,
the likelihood of frequent disruptions in treatment due to complications of the
disease, and the need for flexible treatment goals that accommodate shifts in
the patient’s physical well-being and capacity to participate. In more
advanced disease, issues related to hope, existential well-being, and advance
care planning may be prominent (Rodin et al. 2009).
Replicated evidence has demonstrated moderate antidepressant effects of
psychotherapeutic interventions for patients with cardiovascular disease (Ski
et al. 2016; Whalley et al. 2011), diabetes (Baumeister et al. 2012;
Musselman et al. 2003), cognitive impairment (Orgeta et al. 2015), HIV/AIDS
(van Luenen et al. 2018), multiple sclerosis (Fiest et al. 2016; Wallin et al.
2006), heart failure (Freedland et al. 2015), hemodialysis (Xing et al. 2016),
and stroke (Stalder-Lüthy et al. 2013). Numerous systematic reviews and
meta-analyses of psychosocial interventions in cancer have found treatment
effects for depressive symptoms (Williams and Dale 2006), and systematic
reviews of psychosocial interventions for categorical diagnoses of MDD (Li et
al. 2016a; Williams and Dale 2006) also demonstrate a treatment effect in
RCTs, although the number of studies in these reviews is small. Newly
emerging therapies, including Meaning-Centered Psychotherapy (Breitbart et
al. 2012), Dignity Therapy (Chochinov et al. 2011), and CALM Therapy (Lo et
al. 2014, 2016), have shown benefit in reducing depressive symptoms in
patients with advanced cancer, although the effectiveness of these therapies
in treating MDD has yet to be demonstrated.
In summary, studies of psychotherapeutic interventions to treat depression
in a variety of medical populations indicate some degree of effectiveness,
which is often improved in more severe depression when psychotherapy is
combined with antidepressant medication. Numerous other nonspecific
psychotherapeutic and educational interventions also may be effective in
reducing and preventing depressive symptoms.

Psychopharmacological Treatment
SSRIs, heterocyclic antidepressants and tricyclic antidepressants (TCAs),
novel antidepressants, and psychostimulants have been evaluated in the
treatment of depression comorbid with medical illness. All antidepressants
are discussed fully in Chapter 36 (“Psychopharmacology”); here we
summarize key points.
SSRIs are generally regarded as the first-line pharmacological treatment
for depression in medically ill patients because of their tolerability and
relative safety, although mixed-action antidepressants have become
increasingly popular in this population because of the potential for dual
benefits arising from their receptor-targeting profiles. Venlafaxine is effective
for hot flashes in breast cancer (Loprinzi et al. 2000); venlafaxine, duloxetine,
and milnacipran are effective for the treatment of pain syndromes (Jann and
Slade 2007); mirtazapine may be useful in treating nausea, insomnia, and
anorexia (de Boer 1996); and bupropion may be particularly useful in treating
patients with prominent neurovegetative symptoms, such as fatigue (Raison
et al. 2005). Vortioxetine and vilazodone are multimodal serotonin modulator
and stimulator antidepressants recently approved for use in the treatment of
MDD. Vortioxetine may have procognitive effects ( Rosenblat et al. 2015), but
they have yet to be evaluated in medical populations. TCAs such as
amitriptyline and nortriptyline have been shown to be effective as analgesics
in the treatment of chronic pain syndromes and insomnia (see Chapter 34,
“Pain”). Psychostimulants such as methylphenidate and modafinil (Ballon and
Feifel 2006) have been reported to rapidly alleviate depressive symptoms in a
range of medical conditions, including stroke (Grade et al. 1998), HIV disease
(Fernandez et al. 1995), and cancer (Andrew et al. 2017; Conley et al. 2016).
Many consider psychostimulants to be the antidepressants of choice in the
palliative care setting because of their rapid onset of action (Wilson et al.
2000); however, the evidence remains mixed, with both positive ( Ng et al.
2014) and negative (Centeno et al. 2012; Sullivan et al. 2017) trials in
palliative care. A Cochrane review (Candy et al. 2008) suggested that the
improvement in depression that occurs with psychostimulants may not be
clinically significant. Atypical antipsychotics such as olanzapine and
quetiapine are effective as augmenting agents in the treatment of MDD in the
general population, although this effect has not been studied in medical
populations. However, antipsychotics used for this purpose may have
additional benefits by stimulating appetite, relieving chemotherapy-induced
nausea, improving sleep, and alleviating perceptual disturbances associated
with delirium.

Brain Stimulation Therapies

Electroconvulsive therapy (ECT) is sometimes used in the medically ill to
treat severe or refractory depression (Beale et al. 1997). It has been shown
to be effective in improving depression in Parkinson’s disease and also may
improve the symptoms of the Parkinson’s disease itself ( Borisovskaya et al.
2016); it has also been shown to improve poststroke depression and
depression associated with multiple sclerosis, endocrine disorders, and renal
failure (Krystal and Coffey 1997). ECT has been associated with
improvements in cognition and mood in patients with dementia (Rao and
Lyketsos 2000) and is considered safe for epilepsy patients with severe or
refractory depression (Lambert and Robertson 1999). ECT should be
considered early in the course of depression with psychosis or catatonia, and
for depression associated with severe suicidal ideation or failure to maintain
adequate nutritional status. ECT and its risks are reviewed in detail in
Chapter 38 (“Electroconvulsive Therapy and Other Brain Stimulation
Therapies”).
Similarly, repetitive transcranial magnetic stimulation (rTMS), which does
not produce the short-term memory impairment associated with ECT, is
sometimes used as an alternative to pharmacotherapy, with growing
evidence supporting its use in the medically ill. Replicated evidence (i.e.,
more than 80 RCTs) supports a robust antidepressant effect of rTMS for
depression alone and in specific medical populations (Brunoni et al. 2017). In
a recent meta-analysis, Shen et al. (2017) identified 22 RCTs, all in China
(N=1,764 patients), of rTMS for poststroke depression. The results
demonstrated that rTMS had a positive effect, with high antidepressant
response and remission rates and improvement in activities of daily living.
Likewise, in a meta-analysis of eight RCTs ( N=312) evaluating the effects of
rTMS for depression in Parkinson’s disease, Xie et al. (2015) found a positive
pooled antidepressant effect for rTMS versus sham rTMS and an equivocal
antidepressant effect for rTMS versus SSRIs. Furthermore, patients who
received rTMS showed improvement in symptoms of Parkinson’s disease and
in performance of activities of daily living compared with patients who
received sham rTMS or SSRIs. Taken together, there is growing evidence to
support the use of rTMS for depression in medically ill patients, particularly
those with neurological disorders (McIntyre et al. 2016).

Collaborative Care
At a systems level of care, there is now strong evidence to support the
effectiveness of collaborative care models for the treatment of depression in
cancer (Sharpe et al. 2014; Walker et al. 2014), coronary artery disease
(Atlantis et al. 2014), diabetes (Tully and Baumeister 2015 ), multiple
sclerosis (Ehde et al. 2016), and hepatitis C (Kanwal et al. 2016). Whereas
the stepped-care model suggests use of collaborative care for either
refractory or moderate to severe depression, recent studies have supported
the clinical and cost effectiveness of collaborative care for subthreshold
depression as well (Gilbody et al. 2017; Lewis et al. 2017). (For further
information on collaborative care, see Chapter 37, “Psychotherapy.”)

Conclusion
Clinical depression is common in the medically ill and is associated with
impaired quality of life, decreased compliance with medical treatment, and
increased medical morbidity and mortality. The elevated prevalence of
depression in the medically ill is most often the result of multiple risk factors,
although there is continued speculation that specific biological mechanisms
operate in certain medical conditions. The diagnosis of depressive disorders
in medical patients is complicated by the frequent overlap between
symptoms of depression and those of medical illness. This overlap may
contribute to underdiagnosis when symptoms of depression are assumed to
be features of the medical condition, or to overdiagnosis when symptoms of a
medical illness are attributed to depressed mood. However, the neglect of
simple inquiry about the symptoms of depression may be the most common
reason that the diagnosis of depression is overlooked in medical patients.
Screening tests may be useful for drawing the attention of clinicians to these
symptoms and identifying patients in medical settings who are most likely to
have depressive disorders. Psychopharmacological and psychotherapeutic
approaches are both effective in the treatment of depressive disorders in the
medically ill and are often even more effective when used together in
collaborative care models.

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