37 | DEPRESSION AND MEDICAL ILLNESS
TAMI D. BENTON, JOSHUA BLUME, PAUL CRITS-CHRISTOPH, BENOIT DUBÉ, AND DWIGHT L. EVANS
Increasing recognition of the impact of depression on physical health has prompted focused investigation on its diagnosis and treatment. The World Health Organization (WHO) projects that depression will be the leading cause of life lost to disability in 2030, imposing a greater health burden than ischemic heart disease (WHO, 2008). The report also emphasized depression’s contribution to morbidity and mortality. Depression is a risk factor for the onset and progression of both physical and social disability (Prince et al., 2007; WHO, 2008). Additionally, individuals with depression and other mental illnesses may develop their health conditions earlier due to behavioral and biological factors related to their mental illnesses, and they may die earlier from comorbid medical illness (Sullivan et al., 2012).
Evidence that adverse health risk behaviors and the presence of depression increases risk for medical disorders, and that the presence of a medical disorder may increase risk for depression has prompted examination of the bidirectional relationship between depression and medical illness (Evans et al., 2005). Further support for these observations has been provided by recent research identifying a potential role for inflammatory responses in the pathophysiology of depression, finding higher levels of pro-inflammatory cytokines, acute phase proteins, chemokines, and cellular adhesion molecules in depression (Blume et al., 2011; Dantzer et al., 2008).
In this chapter, we will review the relevant recent research linking depression and medical illness. We will present an overview of the bidirectional relationship between depression and medical illness. We will review existing research on the possible mechanism for the connection between depression and medical illness, focusing on the connection between depression and several specific medical illnesses (cardiac disease, diabetes, HIV/AIDS, cancer). We then outline basics of the assessment of depression in the context of medical illness. We conclude with a presentation of treatment considerations for depression in specific medically ill populations.
PREVALENCE OF DEPRESSION IN THE MEDICALLY ILL
Depressive disorders are more prevalent among the medically ill when compared to the general population of the United States. The average lifetime prevalence of depression is about 16.6% of the US population and is two times more prevalent in women when compared to men (Kessler et al., 2005). Those with chronic medical illnesses are two to three times more likely to be depressed than age- and gender-matched non-medically ill individuals in community-based primary care settings (Katon, 2011). The prevalence of depression among individuals who are medically ill ranges from 3% to 10% in community and primary care settings and up to 10–14% in inpatient medical settings (Katon, 2003). Prevalence estimates for depressive disorders among those populations with specific medical conditions are even higher, ranging from 20% to 55% (Evans et al., 2005) (Table 37.1).
MECHANISMS OF COMORBIDITY FOR DEPRESSION AND MEDICAL ILLNESS
Recent research examining depression among medically ill populations has sought to link the inflammatory processes underlying specific disorders such as cardiovascular disease, diabetes, and cancer, to those inflammatory processes underlying major depression. Emerging evidence suggests that depressive disorders may be conditions of immune dysregulation, specifically activation of the inflammatory response system (Dowlati et al., 2010; Raison et al., 2009). These theories gain support from the observation that the treatment of patients with cytokines can produce symptoms of depression, antidepressant treatments can reverse those symptoms, and immune system activation is present in some, but not all, individuals with depression. Additionally, cytokine mediated signaling to the brain can influence the production and metabolism of neurotransmitters relevant to mood disorders and its treatments including serotonin, dopamine, and catecholamines (Raison et al., 2009).
A decade of investigation has established the contribution of cytokines to the pathogenesis of depression. Cytokines are proteins and glycoproteins secreted by immune cells that function as signals among and between immune cells. Cytokines are the hormones of the immune system. They can be secreted by immune and nonimmune cells and can affect cells outside of the immune system. They function locally and systemically to modulate and regulate immune functions throughout the body, including those of the central nervous system.
The role of cytokines in the pathogenesis of depression has been confirmed by clinical and experimental observations. Several studies comparing cytokines in people with MDD have found increases in certain cytokines compared to people without MDD (Miller et al., 2009; Raison et al., 2009). Although association does not imply causality, there are many reasons to believe that the abnormalities of inflammation found in depression may contribute to its pathology. Medically ill patients who exhibit immune activation or inflammation secondary to infections, autoimmune diseases, and neoplastic diseases demonstrate higher rates of depression (Nemeroff and Vale, 2005). Cytokines have also been shown to be effective in the treatment of certain cancers, hepatitis C, viral infections, and multiple sclerosis. However, a behavioral syndrome similar to major depression has been observed among these individuals treated with cytokines for the treatment of infectious diseases or cancer. This syndrome referred to as “sickness behavior” is characterized by anhedonia, cognitive dysfunction, anxiety, irritability, psychomotor slowing, anergia, fatigue, anorexia, sleep alterations, and increased sensitivity to pain (Dantzer et al., 2008). Although the exact prevalence is unknown, studies suggest that the incidence of depression associated with cytokine therapy ranges from 0% to 45%, depending on the medical conditions and study designs (Dantzer et al., 2008). Moreover, the behavioral syndrome induced by cytokine treatment has been shown to be responsive to treatment with standard antidepressant medications, suggesting that the behaviors described as the “sickness syndrome” are related to major depression. However, antidepressant treatment has been noted to be more effective on the mood symptoms than on neurovegetative symptoms (Capuron et al., 2002; Constant et al., 2005).
TABLE 37.1. Depression in patients with comorbid medical illness
| Comorbid Medical Illness | Prevalence Rate (%) |
| Cardiac disease | 17–27 |
| Cerebrovascular disease | 14–19 |
| Alzheimer’s disease | 30–50 |
| Parkinson’s disease | 4–75 |
| Epilepsy | |
| Recurrent | 20–55 |
| Controlled | 3–9 |
| Diabetes | |
| Self-reported | 26 |
| Diagnostic interview | 9 |
| Cancer | 22–29 |
| HIV/AIDS | 5–20 |
| Pain | 30–54 |
| Obesity | 20–30 |
| General population | 10.3 |
Furthermore, cytokines have been found to influence all of the pathophysiologic domains relevant to depression. Cytokines have been shown to cause alterations in the metabolism of monoamine neurotransmitters relevant to depression, specifically serotonin, dopamine (DA), and norepinephrine (NE); to have stimulatory effects on HPA axis functioning through activation of corticotropin-releasing hormone (CRH) in the amygdala and the hypothalamus; to induce resistance of nervous, endocrine, and immune system tissues to circulating glucocorticoid hormones stimulating the glucocorticoid resistance found in patients with depression; to induce enzymes that metabolize tryptophan the primary precursor of serotonin, and may inhibit pathways involved in thyroid hormone metabolism and to activate NF-kB, a transcription factor that signals the inflammatory cascade in the brain (Dantzer et al., 2008; Irwin and Miller, 2007; Raison et al., 2009).
Despite growing evidence that dysregulation of the immune system may contribute to the pathogenesis of major depression, other studies have found conflicting results or no association between depression and immune parameters or inflammation (Blume et al., 2011; Whooley et al., 2007). One factor that might explain variations between studies is the type of immune system variable or inflammatory marker examined. Pike and Irwin found that, among patients with MDD relative to controls, there was evidence for decreases in NK cell activity (indicating impairment in the immune system) and higher levels of IL-6 (indicating immune activation) (Pike and Irwin, 2006). Furthermore, changes in NK cell activity were not correlated with levels of IL-6, suggesting that depression may have independent effects on these different aspects of the immune system. Alternatively, an emerging literature suggests that while acute inflammation boosts immune defenses, the chronic exposure of immune cells to proinflammatory cytokines may actually result in impaired cellular immunity (Medzhitov, 2008). Thus depression-associated chronic activation of the immune system may lead to immune deficiency resulting in increased vulnerability to cancer and infection (Blume et al., 2011). Miller points out that causality may also operate in the other direction: depression is associated with impaired regulatory T cells, which modulate innate immune responses (Miller, 2010). Thus, depression-associated cellular immune suppression may contribute to chronic inflammation, and the pathogenesis of diseases—such as atherosclerosis and cancer, in which inflammation has been implicated.
Further observations supporting the relationships between chronic inflammation and cellular immune suppression have been demonstrated among two of the most common rheumatologic disorders, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). SLE is an autoimmune disorder resulting in tissue and organ damage caused by abnormal immune complexes and T-lymphocytes as well as autoantibodies. RA is characterized by inflammation that primarily affects the synovial tissue of the joints. Both chronic inflammatory disorders have high rates of comorbid depression with prevalence estimates ranging from 13% to 42% in RA (Bruce, 2008) and 10.8% to 39.6% in SLE (Nery et al., 2007), depending on diagnostic methods. Both disorders are characterized by multiorgan systemic involvement affecting the cardiac, vascular, respiratory, and nervous systems. Direct CNS involvement is rare in RA, however neuropsychiatric manifestations are frequent in SLE. The mainstay of treatments for both disorders include anti-inflammatory agents and other immunosuppressant agents.
Chronic inflammation is present in RA and SLE, and both conditions are characterized by a high frequency of infection, possibly related to impaired circulating T-cells leading to immune suppression (Doran et al., 2002; Gladman et al., 2002; Koetz et al., 2000; La Cava, 2008). In addition, impaired T-cell function has been observed in the synovial fluid of individuals with RA, when the T-cells were chronically exposed to TNF alpha (Cope, 2003), and etanercept, an anti TNF-alpha therapy, has been shown to restore T-cell reactivity in patients with RA (Berg et al., 2001; Blume et al., 2011). Dysregulation of immune T-cell tolerance, and decreased numbers and/or functioning of suppressive CD4CD25 T-regulatory cells have been observed in peripheral blood in human models of SLE (La Cava, 2008). Thus, depression associated cellular immune suppression might contribute to inflammation and the pathogenesis of both SLE and RA, as well as atherosclerosis and cancer.
CARDIAC DISEASE
The intimate and clinically relevant connection between depression and cardiovascular disease has been well established. Depression is prevalent across the spectrum of cardiac diseases including coronary artery disease (CAD), unstable angina, acute myocardial infarction, congestive heart failure, and coronary artery bypass graft surgery. Current estimates suggest rates of depression that are significantly higher than in the general population, ranging from 17% to 27% (Rudisch and Nemeroff, 2003). Depressive symptoms increase the risk for the onset of CAD by 1.64-fold. Furthermore, the occurrence of depression within three to four months of a myocardial infarction (MI), predicts a three times greater likelihood of dying in the next year, when compared to individuals without depression following MI (Lett et al., 2004).
Depression appears to be an independent risk factor in cardiac disease, as the connection between depression and cardiac disease does not appear to be due to the association between depression and other known risk factors (e.g., smoking, history of MI). Depression has been found to be a significant predictor of mortality 6 and 18 months following Ml, even after adjusting for other risk factors such as left ventricular dysfunction and previous MI (Frasure-Smith et al., 1995).
MECHANISMS OF COMORBIDITY
Several possible mechanisms linking depression to cardiovascular diseases have been proposed. These include inflammation, hypothalamic-pituitary-adrenocortical dysregulation, sympathomedullary hyperactivity, increased platelet activity and aggregation, autonomic dysfunction causing reduced heart rate variability (HRV), and endothelial dysfunction (Celano and Huffman, 2011; Skala et al., 2006).
It is well known that HPA axis dysregulation occurs in depression and that administration of corticosteroids is associated with increases in cardiovascular disease risk factors, including hypercholesterolemia, hypertriglyceridemia, and hypertension. Consistent with this potential mechanism, elevated plasma cortisol has been found to be associated with moderate to severe coronary atherosclerosis in young and middle aged men.
Sympathoadrenal hyperactivity may mediate the relationship between depression and cardiovascular disease through an effect on platelets. Individuals with depression show increased levels of plasma NE in response to cold or orthostatic challenge, which may enhance platelet activity. Some, but not all studies have found platelet hyperactivity in those with MDD. Recent studies of depressed patients with ischemic heart disease show elevated platelet factor 4 and plasma b-thromboglobulin levels (Celano and Huffman, 2011).
Inflammatory responses may partly underlie the relationship between depression and cardiovascular disease. The inflammatory markers IL-6, TNF-a, and C reactive protein (CRP) are associated with cardiovascular and cerebrovascular events, specifically CHD, congestive heart failure, and stroke (Cesari et al., 2003). Increases in circulating levels of IL-6 and CRP are also found in depression (Dowlati et al., 2010). Other studies examining the relationships between depression and inflammation in cardiac disease have found elevations in CRP and serum amyloid A (SAA) in women treated for major depression who are in remission, suggesting a sustained proinflammatory state in women who have clinically recovered and who no longer take antidepressant medications. The authors suggest that the persistence of a “proinflammatory state” might contribute to the increased CAD risk associated with MDD (Kling et al., 2007).
Statins are drugs routinely administered to patients post-MI for their lipid lowering and anti-inflammatory properties. Stafford and Berk investigated the effect of statins on the onset of depression in hospitalized cardiac patients, hypothesizing that the anti-inflammatory effect of statins would serve as prophylaxis against depression. In support of a link among depression, inflammation, and cardiovascular disease, they found that over nine months postdischarge, statins were associated with a 79% reduction in the likelihood of depression (Stafford and Berk, 2011). Recent findings from the Heart and Soul Study suggest that statin use was associated with a 38% decreased odds of developing depression in their sample, further confirming this association (Otte et al., 2012).
Frasure-Smith and colleagues (2007) assessed 702 individuals (602 men) for depression and inflammatory markers (CRP), IL-6, and soluble adhesion molecules at two months postdischarge for an acute coronary syndrome, and then followed them for two years for major adverse cardiac events defined as cardiac death, survived MI or cardiac arrest, and nonelective revascularization. Of this sample, 102 individuals (78 men) experienced at least one major adverse cardiac event. Elevated scores on the Beck Depression Inventory-II (BDI-II) and current major depression were significantly related to major adverse coronary events over two years, and this association was stronger in men than women. The study also found an association between elevated depressive symptoms, CRP, and soluble intercellular adhesion molecules (sICAM-1), but not IL-6, providing some support for the association between depression and inflammation (Frasure-Smith et al., 2007).
Abnormalities of the autonomic nervous system may be another mechanism linking depression and CAD. HRV, a measure of the balance between sympathetic and parasympathetic inputs to the cardiac conduction system, is often reduced in patients with severe CAD or heart failure. Reduced HRV is associated with ventricular arrhythmias and sudden cardiac death (Dekker et al., 2000). Studies that found diminished HRV in depression raised the possibility that HRV might be the link between depression and CAD (Nahshoni et al., 2004; Stein et al., 2000). One study found that HRV partially mediates the relation between depression and increased risk for mortality after acute myocardial infarction (Carney et al., 2005). HRV has also been found to be associated with increased markers of inflammation in patients with heart failure and acute coronary syndromes.
Depression is also associated with endothelial dysfunction, a putative mechanism of atherosclerotic disease. A study of men and women ages 40 to 84 years old concluded that depressed individuals had impaired flow-mediated dilation of the brachial artery—a measure of endothelial function—compared to non-depressed individuals. The use of antidepressant medication was associated with improved endothelial function. Subsequent investigations have corroborated these findings (Cooper et al., 2010; Pizzi et al., 2008, 2009).
Evidence further suggests that depression may worsen the impact of other cardiac factors. In a study examining risks for cardiac mortality following MI, the highest death rates (60%) for patients at 18 months post-MI were found in a subgroup of patients with elevated depressive symptoms and increased numbers of premature ventricular contractions per hour (PVCs) (Frasure-Smith et al., 1995).
Depression can also indirectly increase the risk of CAD. The pessimism and low energy often found in clinical depression can lead individuals to be less adherent to exercise programs, smoking cessation, dietary changes, and pharmacological interventions for CAD (Glazer et al., 2002; Skala et al., 2006; Wang et al., 2002). Failure to adequately address these risk factors may then put the individual with depression at even greater risk for a future cardiac event.
DIABETES MELLITUS
Depression is common among individuals with diabetes. Among the 23.6 million people in the United States diagnosed with diabetes mellitus (DM), 5–15% have type I diabetes (CDC 2008), with type II diabetes (T2DM) being much more prevalent; however, research suggests that rates of depression are elevated in both. People with diabetes are twice as likely to have depression compared with those without diabetes. Prevalence estimates suggest that 10–15% of individuals with DM are currently affected by depression and that 24–29% of individuals with diabetes will be affected by depression during their lifetimes. The presence of depression has been associated with higher symptom burden; poor adherence to medication, diet, and exercise; and higher hemoglobin A1C levels (Markowitz et al., 2011). Depression has also been associated with increased frequency and severity of diabetes complications including retinopathy, nephropathy, neuropathy, macrovascular complications including coronary vascular diseases, and sexual dysfunction. Furthermore, depression has been associated with an increased risk of all cause mortality in diabetes, among individuals with and without previous cardiovascular disease (Sullivan et al., 2012). Depressive symptoms and heightened distress, absent a major depression diagnosis, have been found to adversely impact diabetes self-care and diabetes control (Markowitz et al., 2011). Depression with diabetes has been associated with increased health care costs (Katon, 2011).
MECHANISMS OF COMORBIDITY
The mechanisms underlying the well-established association between depression and diabetes remain unknown. Studies seeking to understand these associations have focused on the diagnosis and burden of disease management as a risk for the development of depression, suggesting that depression is a consequence of diabetes (Knol et al., 2007) Other studies have suggested that depression is a risk factor for diabetes (Campayo et al., 2010; Golden et al., 2008; Knol et al., 2007).
Studies examining the bidirectional associations between depression and diabetes have provided conflicting results. Longitudinal studies of clinically depressed older adults in the community found depression to be associated with a 65% increased risk for incident diabetes, and that this association was true for untreated depression and persistent and non-severe depression (Campayo et al., 2010). Golden and colleagues examined incident rates for T2DM in men and women with and without depressive symptoms over five years. They found incidence rates for T2DM of 22.0/1,000 person years for those with increased depression symptoms compared with 16.6/1000 person years for those without increased depressive symptoms. Incident rates for elevated depressive symptoms per 1,000 person years were 36.8 for those with normal fasting glucose; 27.9 for those with impaired fasting glucose; 31.2 for untreated T2DM and 61.9 for treated T2DM. They also found a modest association of baseline depressive symptoms with incident T2DM, which were partially attributed to lifestyle. Both untreated T2DM and impaired FG were inversely associated with incident depressive symptoms, but treated T2DM was positively associated with depressive symptoms (Golden et al., 2008).
The Vietnam experience study (Gale et al., 2010) explored the association between fasting glucose, T2DM (diagnosed and undiagnosed), and depression among middle aged men. Subjects with untreated diabetes had nearly double the odds (1.8 95% CI) of developing major depression compared with men with normal FBGs. Men with known diabetes had triple the odds of MDD (3.82 95% CI). Men with undiagnosed and diagnosed T2DM had higher depression scores, suggesting that there is a positive association between T2DM and depression, even for those who are unaware of their disease.
Several, but not all, studies support the hypothesis that increased depression is a consequence of diabetes. Some studies suggest that the psychosocial burden of diabetes may increase risk for depressive symptoms. Other investigators have found that the perceived disability and awareness of having a chronic illness may impose higher levels of psychologic burden for people with diabetes, particularly if they have low levels of social support (Knol et al., 2007). A meta-analysis by Mezuk and colleagues found that people with diabetes have a modest (15%) increased risk for depression compared to those without diabetes, but that depression is associated with a 60% increased risk for T2DM (Mezuk et al., 2008). Another meta-analysis examining depression and diabetes, found a 24% increased risk for incident depression among those diagnosed with diabetes compared to people without diabetes, and that rates of incident diabetes were greater for those with previous depressive episodes (Nouwen et al., 2010). However, investigators discovered that patients with chronic illnesses overall who were frequent users of medical care had similar rates of new depression diagnosis.
Further support for depression as a consequence of diabetes is provided by the Utrecht health project, a longitudinal study of a population of adults in the Netherlands. Knoll and colleagues investigated subjects with impaired fasting glucose and undiagnosed diabetes finding no association with increased depressive symptoms, suggesting that depression results from the diagnosis of diabetes. In this study, those diagnosed with diabetes had a 1.7 times risk for depressive symptoms. After adjusting for the number of chronic diseases, risk for depression was no longer significant (Knol et al., 2007).
Although the biological mechanisms underlying the association between depression and diabetes remain unclear, the evidence strongly suggests a bidirectional relationship.
Depression related physiologic alterations have been associated with increased vulnerability of depressed patients to develop T2DM. Efforts to understand the biological relationships underlying the depression-diabetes link have focused on three potential mechanisms: The hypothalamic pituitary adrenal axis (HPA), counter-regulatory effects of the sympathetic and parasympathetic nervous systems, alterations in glucose transport, and immune activation and inflammation (Musselman et al., 2003).
Psychological stress and depression stimulate activation of the HPA axis and sympathetic nervous systems (SNS), resulting in the release of cortisol and increased catecholamine and cytokine production (Dantzer et al., 2008). The release of these hormones (glucocorticoids, catecholamines, growth hormone, glucagon) stimulating both anabolic and catabolic processes involved in glucose regulation may lead to increased insulin resistance, by counteracting insulin’s hypoglycemic effects, thus raising blood glucose levels and increasing the risk for diabetes. Increasing levels of cortisol are associated with redistribution of fat from subcutaneous to increased visceral adipose tissue, which results in central adiposity and dyslipidemia (Champaneri et al., 2010).
Another potential mediator implicated in the relationship between depression and diabetes involves cellular glucose transporters. These transporters facilitate the entry of glucose, a necessary metabolic substrate for all mammalian cells, into cells. Entry of glucose into endothelial cells, astrocytes, and neurons are facilitated by GLUT1 and GLUT3 respectively (Musselman et al., 2003).
Studies using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), both methods for quantifying neuronal activity in the brain by measuring glucose utilization, have shown decreased glucose utilization in the left lateral prefrontal cortex. PET has also shown a correlation between reduction in LPFC function and depression severity. Further studies are needed to determine whether these alterations in neuronal activity are related to alterations in the glucose transporters. Additionally, since brain glucose consumption does not affect glucose transport, while alterations in plasma glucose does affect glucose transport, further studies will be needed to understand these relationships (Musselman et al., 2003).
Immune activation and cell mediated cytokine production have also been implicated in the relationship between depression and diabetes. Elevations in the proinflammatory cytokines, IL-1, IL-6, and TNF-alpha, have been found in some, but not all, depressed patients (Blume et al., 2011; Dowlati et al., 2010). Proinflammatory cytokine production is also increased in individuals with diabetes (Musselman et al., 2003). Cytokines IL1, IL6, TNF alpha, and IFN gamma, found to induce sickness, exert neural effects that mediate these symptoms.
HIV/AIDS
Meta-analyses of early prevalence studies revealed that those with HIV were nearly twice as likely to have a diagnosis of major depression compared to individuals who were HIV-negative (Ciesla and Roberts, 2001). Prevalence rates of major depression range from about 5% to 20% (Cruess et al., 2003). A number of studies have found that women who were HIV positive may be particularly susceptible to MDD, with rates of current MDD higher in women who are HIV-positive compared to women who were HIV-negative (Evans et al., 2005; Lewis et al., 2010). Large-scale studies of depressive disorders among pediatric patients who are HIV-positive are lacking, but a meta-analysis estimated the prevalence in this population at 25% (Scharko, 2006).
There is considerable evidence that depression impacts the clinical course and treatment of HIV/AIDS. Clinical depression, elevated levels of depressive symptoms, or general psychological stress are associated with poor adherence to antiretroviral treatment, deterioration in psychosocial functioning, more rapid progression of HIV/AIDS, and higher mortality in both men and women before and after the HAART era (Evans et al., 2005; Ickovics et al., 2001; Leserman et al., 2002; Leserman, 2008). One study of over 1,700 women who were HIV-positive followed for 7.5 years found that those with chronic depression had 1.7 times greater odds of dying compared to women without depression (Cook et al., 2004). The impact of depression on mortality remained even after controlling for antiretroviral therapy use, medication adherence, substance abuse, clinical indicators (baseline CD4 count, baseline viral load, baseline HIV symptoms), and demographic factors; the use of mental health services was associated with significantly less AIDS-related mortality.
MECHANISMS OF COMORBIDITY
Although there is now substantial evidence supporting a relationship between depression and HIV disease progression, less is known about the mechanisms underlying this relationship. It is possible that unhealthy lifestyle behaviors may play a mediating role in this relationship between depression and the course of HIV/AIDS, but support for this hypothesis is lacking (Ickovics et al., 2001; Leserman et al., 2002; Leserman, 2003).
Disruption of the HPA axis has been investigated as a possible mediator of the depression-immune relationship. Increased levels of cortisol have been linked to stress and depression in HIV (Gorman et al., 1991), and it is hypothesized that cortisol may adversely influence the immune response and thereby negatively impact HIV disease progression (Evans et al., 2005; Leserman, 2003). In addition, NE has been shown to affect HIV replication (Cole et al., 1998). Another possible mediator is the neuropeptide substance P, which upregulates HIV and is elevated in persons with HIV (Douglas et al., 2001; Ho et al., 1996). The diminished host defense against HIV infection that has been observed in depressed individuals, may result from depression associated alterations in the functioning of killer lymphocytes (NK and cytotoxic T-lymphocytes), thus hastening HIV disease progression (Evans et al., 2002; Ironson et al., 2001; Leserman, 2003). Consistent with this hypothesis, stressful life events, poor social support, and chronic depression have all been associated with more rapid declines in CD4 lymphocyte counts (Burack et al., 1993; Kemeny and Dean, 1995; Kemeny et al., 1995) and progression to AIDS (Ickovics et al., 2001; Leserman et al., 2002; Leserman, 2003, 2008). Recent evidence from ex vivo studies suggest that a SSRI or a substance P antagonist may enhance NK immunity in HIV/AIDS adding further evidence to the potential role for NK cells in the host defense against HIV and the role of depression and antidepressant treatment in HIV disease progression (Evans et al., 2008).
Depression also has an effect on adherence to treatment regimens. Patients with HIV and depressive disorders have greater difficulty in accessing antiretroviral therapy and adhering to treatment once accessed. (Rabkin, 2008).
CANCER
The prevalence of depression is higher among those with cancer than in the general population, and prevalence estimates vary across malignancy types and disease severity. Small sample sizes and non-standardized definitions of depression have also hindered research in this area. The general range of prevalence estimates for MDD among patients with cancer has been reported to be 1.5–50% across studies, with an overall rate of 22–29% (Evans et al., 2005; Raison and Miller, 2003).
The presence of depression in individuals with cancer has been associated with poorer prognosis and increased morbidity and mortality (Evans et al., 2005). A recent meta-analysis of 31 studies found that cancer patients with depressive symptoms had a 25% higher mortality and those with major depression had a 39% greater mortality (Satin et al., 2009). A more recent study by Giese-Davis et al. (2011) suggested that depression is an independent risk factor for survival in cancer and found that a decrease in depressive symptoms was associated with longer survival in a secondary analysis of women with metastatic breast cancer who were treated with supportive-expressive group therapy. An emerging preclinical and clinical literature suggests that immune suppression and immune activation in depression may help explain the effects of depression on cancer survival (Blume et al., 2011).
Recent evidence suggests that proinflammatory cytokines released during tissue damage and destruction resulting from cancer and its treatments may be associated with the onset of depressive symptoms. The inflammatory changes precipitated by these cytokines can have a substantial impact on neurotransmitter function, neuroendocrine function, and behavior, resulting in the “sickness syndrome.”
The observation that a significant percentage of patients with cancer treated with the cytokine IFN-a develop a behavioral syndrome with similarities to major depression has been an impetus for the investigations in this area. Cytokine therapies are well known to cause neurobehavioral symptoms including major depression in up to 50% of patients with cancer undergoing cytokine treatment with IFN-a (Capuron et al., 2002; Musselman et al., 2001a) and IL-2 (Capuron et al., 2004). Among patients with cancer, patients with depression and cancer were found to have significantly higher levels of IL-6 compared to patients with cancer and no depression and healthy controls (Musselman et al., 2001b). More recent studies have found associations between specific depressive symptoms and elevated cytokines; for example, some investigators have found elevated IL-6 concentrations in patients with cancer presenting with fatigue and impaired executive functioning (Collado-Hidalgo et al., 2006). Capuron and colleagues (Capuron et al., 2002, 2004) and Musselman et al. (2001a) have described two distinct behavioral syndromes that occur in individuals who become depressed with cytokine therapies. One syndrome is characterized by depressed mood, anxiety, irritability, and memory and attentional disturbances. This syndrome is reported to occur within the first three months of therapy in susceptible individuals (Capuron et al., 2002, 2004; Musselman et al., 2001a). The other syndrome, characterized by the neurovegetative symptoms of fatigue, psychomotor slowing, anorexia, and altered sleep patterns, occurs within the first few weeks of IFN-a therapy and persists at later stages of therapy (Capuron et al., 2002). These two different syndromes are thought to have different responsiveness to antidepressant treatment. The mood and cognitive symptoms were responsive to pretreatment with paroxetine (Capuron et al., 2002) whereas the neurovegetative symptoms were not, suggesting that these systems may have different pathophysiologic pathways.
Although depressive symptoms are very responsive to antidepressant treatment, the neurovegetative symptoms described in the “sickness syndrome” have been less responsive to antidepressant treatments, perhaps requiring a different treatment approach (Capuron et al., 2002; Raison and Miller, 2003).
ASSESSMENT OF DEPRESSION IN MEDICAL ILLNESS
Many psychological and physical factors can make the diagnosis of depression among those with medical illness challenging for the clinician. The classic signs and symptoms such as depressed mood, dysphoric affect, fatigue, pain, psychomotor retardation, anorexia, weight loss, cognitive impairment, and insomnia can represent demoralization or the medical illness itself. Thoughts of death or desire for a hastened death is not a reliable sign for depressive disorders in this population but may represent demoralization. In several studies, demoralization has been associated with lower quality of life and a desire for hastened death (Rackley and Bostwick, 2012). The loss of ability to experience pleasure in many activities may also be the result of physical suffering or disability and not a symptom of depression. Some acute medical conditions, such as hypoactive delirium, or progressive conditions, such as cancers and neurological conditions, have depressive symptoms that may change over time due to the illness or its treatments. Currently, no standardized approach exists for diagnosing depression among individuals who are medically ill. We continue to rely on the mental status examinations and DSM-IV criteria for depression (Evans et al., 2005). Investigators have examined the utility of excluding symptoms that can occur as part of the medical condition and the depressive condition (exclusive approach) versus the more favored inclusive approach that counts all symptoms when making a diagnosis of depression, but the findings have been inconclusive (Newport and Nemeroff, 1998; Raison and Miller, 2003). Fortunately, several well-validated instruments are available to assist the clinician in making the diagnosis of depression in the presence of medical symptoms (Rackley and Bostwick, 2012) (Table 37.2).
TREATMENT OF DEPRESSION IN MEDICAL ILLNESS
Well-controlled trials examining the efficacy of antidepressant treatments among individuals who are medically ill provide strong support for the effective use of antidepressant medications across many medical conditions (Evans et al., 2005). The challenge for the clinician is in choosing a medication that maximizes beneficial side effects while minimizing adverse effects. In the context of medical illness, identifying an effective agent and dosing regimen, whose mechanism of action and side-effect profile will not exacerbate the coexisting medical condition and minimizing polypharmacy can be challenging. The selective serotonin reuptake inhibitors (SSRIs) are widely used for treating depression in medical illness due to their safety and side-effect profiles. They may not only improve depressive symptoms but also result in positive effects on the co-occurring medical illness. For example, fluoxetine has been shown to improve glycemic control in patients with diabetes mellitus (Lustman et al., 2000). Caution in the use of SSRI or serotonin norepinephrine reuptake inhibitors (SNRIs) is warranted under certain circumstances to prevent exacerbation of the medical condition and to prevent the development of potentially serious side effects such as the syndrome of inappropriate antidiuretic hormone secretion (SIADH), platelet dysfunction that can lead to bleeding problems and serotonin syndrome (Turner et al., 2007).
Of greater concern is the potential for drug interactions. Patients with serious medical conditions, particularly the elderly, often receive multiple medications, increasing the risk of drug interactions. The presence of renal or hepatic disease with resulting fluid shifts and weight loss, for example, may affect metabolism and excretion of SSRIs and alter their pharmacokinetics (Beliles and Stoudemire, 1998). Tricyclic antidepressants (TCAs) are effective in the treatment of depression. Despite evidence of their efficacy in the treatment of depression among patients with medical conditions (Evans et al., 2005), SSRIs and SNRls have substantially reduced the clinical use of TCAs. SSRIs are more commonly used due to their efficacy, safety, and side- effect profiles. TCAs are strong antagonists of cholinergic, histaminic, and alpha-adrenergic receptors and can affect cardiac conduction, potentially exacerbating medical symptoms.
TABLE 37.2. Screening tools used for depression in patients who are medically ill
| Instrument | Description | Advantage/Disadvantage |
| Center for Epidemiological Studies Depression Scale (CES-D; Radloff, 1977) | 20-item self-report instrument of which only four are somatic; recommended cutoff score of 17. | Wide use in patients who are medically ill High sensitivity and specificity Lack of consensus on optimal cut scoresPositive predictive value low |
| The Hospital Anxiety and Depression Scale (HADS; Zigmond and Snaith, 1983) | 14-item self-report with separate 7-item subscale for depression and anxiety Cutoff scores range from 7 to 21 | Brief and highly acceptable to patients Not extensively validated as a screen Lack of consensus about utility of cutoff scores |
| Beck Depression Inventory-II (BDI-II; Beck et al., 1996) | 21-item self-report measure Cutoff scores: 10—mild; 20—moderate; 30—severe | Validated as an accurate self-report measure in patients who are medically ill Less acceptable to patients due to forced-choice format and complex response alternativesSensitivity and specificity high and positive predictive value high |
| The Patient Health Questionnaire-9 (PHQ-9; Kroenke and Spitzer., 2002) | 9-item self-report depression module of the PHQ Cutoff scores: 5-mild; 10-moderate; 15-moderately severe; 20-severe | Full PHQ well-validated in primary care/medical specialty clinic in United States, Europe, and China Good sensitivity and specificity |
| Zung Self-Rating Scale for Depression (Zung, 1965) | 20-item self report Likert-type scale scores 1–4 with highest possible score of 80 Cutoff scores: >50 for depression | Validated as an accurate self-report measure in patients who are medically ill Good sensitivity and specificity |
| Hamilton Depression Rating Scale (Hamilton, 1960) | 17-item scale; Clinician-administeredCutoff: 10–13 mild; 14–17 moderate; >17 severe | Validated as an accurate measure in patients who are medically illGood treatment change measure High specificity and sensitivity |
Like TCAs, monoamine oxidase inhibitors (MAOIs), while effective, are less commonly used due to their abilities to produce hypertensive reactions, drug-drug interactions with common agents such as over-the-counter sympathomimetics and stimulants, and need for tyramine restrictions. A potentially fatal serotonin syndrome, characterized by mental status changes, autonomic instability, and neurotransmitter hyperactivity, may occur when SSRIs or SNRIs are combined with MAOIs, and may be mistaken for disease in the medically ill (Rackley and Bostwick, 2012).
Psychostimulants (methylphenidate and amphetamine- based products) are used to treat depressed patients with medical conditions despite inconsistent data supporting efficacy. These agents have been used due to their ability to rapidly improve mood, motivation, and appetite, and diminish fatigue in patients who are debilitated (Hardy, 2009).
Emerging evidence suggests potential efficacy for other somatic therapies for depression in the medically ill. Neuromodulatory therapies such as electroconvulsive therapy (ECT) and transmagnetic stimulation (TMS) have shown promise for the treatment of depressive symptoms in medical illness. Recent preliminary data suggests IV ketamine, an N-methyl d-aspartate (NMDA) modulator, may rapidly ameliorate treatment-resistant depression in healthy, medically ill, and palliative care patients (Rackley and Bostwick, 2012).
ANTIDEPRESSANT TREATMENTS FOR DEPRESSION IN CARDIAC DISEASE, CANCER, AND HIV
CARDIAC DISEASE
The treatment of depression in the context of cardiac disease has been an area of great interest due to the well-established relationships between CAD, depression, and mortality. Several randomized controlled trials have been suggestive of efficacy and safety of antidepressants in the treatment of depressive disorders in patients with cardiac disease, though efficacy in regard to the progression of the cardiac disease has not been clearly established (Berkman et al., 2003; Glassman et al., 2002, 2009; Honig et al., 2007; Lesperance et al., 2007).
A Cochrane review and meta-analysis found that SSRIs and psychological approaches were effective for the treatment of depression in patients with coronary artery disease (Baumeister et al., 2011). There was no detectible difference in efficacy among various psychological treatments. Hospitalization rates and emergency room visits were reduced in patients treated with SSRIs compared to placebo, however this review was unable to conclude that there was any benefit in mortality, or cardiac events in active treatments compared to placebo. However, another recent meta-analysis did find that treatment with SSRIs is associated with a decrease in the rate of readmission and in the rate of mortality in patients with coronary heart disease (Pizzi et al., 2011).
DIABETES
The known associations of depression and diabetes, and the evidence supporting poor outcomes, have prompted trials examining the efficacy of therapeutic interventions for depression in diabetes. A recent meta-analysis from fourteen RCTs evaluating psychotherapy, pharmacologic interventions, and collaborative care in 1,724 subjects with type 1 and 2 diabetes and depression demonstrated clear effects with moderate effect size for depression treatment. Despite heterogeneity of study settings and treatment outcomes, depression treatments were effective (Markowitz et al., 2011; van der Feltz-Cornelis et al., 2010) for all three interventions in depression and diabetes.
Randomized placebo-controlled trials for fluoxetine, sertraline, paroxetine, and s-citalopram have demonstrated efficacy for the treatment of depression in diabetes (Markowitz et al., 2011). In a fluoxetine trial, significant reductions in depression severity were found for fluoxetine compared to placebo; however, there were no statistically significant differences in HbA1c (Lustman et al., 2000). In another trial with sertraline examining resolution of depression and glycemic control, hazard ratios for the risk of recurrence of depression for the sertraline treated group were significantly lower than for the placebo treated groups, suggesting a greater protection from recurrence of depression. Subjects under 55 years benefited from this prophylactic effect, when compared with a placebo group, but not those over 55 years. There were also improvements in HbA1c levels, however, they did not differ significantly between groups (Markowitz et al., 2011; Williams et al., 2007).
Two studies have examined paroxetine treatment for diabetes. In both studies, investigators studied depressed women who had not achieved optimal control of their type 2 diabetes for changes in depression severity and HbA1c levels, permitting observations of change in glycemic control. One study randomized mildly depressed postmenopausal women to either 10 weeks of a paroxetine or placebo condition. Although no differences were observed between groups with regard to depression scores, there was a statistical trend toward improved HbA1c in the paroxetine treated group when compared with placebo (Paile-Hyvarinen et al., 2007). The second study randomized mildly depressed subjects to six months of treatment with either paroxetine or placebo. HbA1c levels were significantly lower when compared to baseline for the paroxetine treated group when compared to placebo at three months. However, these gains were not maintained at six months. For both studies, depression severity was very low, with small sample sizes limiting power to detect changes in depression severity (Markowitz et al., 2011). There has been one study comparing the efficacy of different SSRIs. In this trial, subjects with T2DM and depression were randomized to either fluoxetine or paroxetine for 12 weeks. Both groups showed significant improvement on depression scores, while the fluoxetine group demonstrated a non-significant decrease in HbA1c levels (Gulseren et al., 2005).
There has been one double blind RCT of a TCA for depression in diabetes. Subjects with T1DM or T2DM and poor glycemic control were randomized to nortriptyline (NT) or placebo for eight weeks. Reductions in depression for the NT group were significantly greater than the placebo group, but not for reductions in HbA1c. NT was discovered to have a direct hyperglycemic effect on further analysis. However, improvements in depression improved glycemic control in both conditions mitigating differences (Markowitz et al., 2011).
An open trial of bupropion for depression with diabetes found that HbA1c levels, BMI, and body fat decreased significantly from baseline. Additionally, reduced BMI and depression severity predicted lower HbA1c levels during maintenance, while only decreased depression severity predicted lower HbA1c. This study, also measured pre- and posttreatment self-care with subjects reporting improvements in self-care during acute and maintenance phases (Markowitz et al., 2011; Williams et al., 2007).
Evidence supporting efficacy of antidepressant medications for depression in diabetes has resulted in increased utilization of SSRIs. However, several studies, but not all, suggest a link between the use of antidepressant medications (SSRIs and TCAs) and the risk for developing T2DM (Andersohn et al., 2009; Pan et al., 2012) while other studies found no association between antidepressant use and DM (Knol et al., 2007). Differing study designs may account for the inconsistencies in these findings.
Recent meta-analysis of treatments for depression in type 1 and type 2 diabetes concluded that psychosocial interventions, particularly cognitive behavioral therapies, are effective in improving depression in patients with diabetes, and in some but not all studies, effective at improving HbA1c levels (Markowitz et al., 2011; van der Feltz-Cornelis et al., 2010).
Collaborative care, an approach utilizing antidepressant and psychosocial interventions using a stepped care algorithm, has been studied in primary care populations. The evidence supports its effectiveness for the treatment of depression in the primary care setting similar to CBT and antidepressant treatments. Additionally, improvements of HbA1c levels and LDL cholesterol levels, were seen with the collaborative care model (Katon et al., 2010; Markowitz et al., 2011; van der Feltz-Cornelis et al., 2010). This approach may be a promising intervention for alleviating depression, and improving self-care and adherence for individuals with diabetes (Katon et al., 2010).
HIV/AIDS
A number of studies have supported the effectiveness of TCAs and SSRIs for treating depression in adults with HIV (Cruess et al., 2003; Rabkin, 2008; Repetto and Petitto, 2008). The TCAs and SSRIs have both shown equal efficacy in head to head studies. In one placebo-controlled study comparing imipramine, paroxetine, and placebo in 75 individuals who were HIV-positive, both agents were equally effective when compared to placebo. However, anticholinergic side effects with imipramine resulted in high dropout rates (48%) for imipramine, compared with 20% for paroxetine and 24% for placebo respectively (Elliott et al., 1998). One small open label study evaluated the efficacy of paroxetine, fluoxetine, and sertraline in HIV seropositive individuals. (Ferrando et al., 1997). Improvements were reported in depression and somatic symptoms related to HIV disease in most patients (83%), but the dropout rates were high (27%). Comparative effectiveness of the three SSRIs could not be evaluated due to the small sample size. One other small uncontrolled study found improvements among clinically depressed HIV seropositive individuals who were treated with paroxetine (Grassi et al., 1997). Preliminary data based on open trials suggests that sustained release bupropion (Theobald et al., 2002) and mirtazapine (Currier et al., 2003) may be effective. Although larger placebo-controlled studies are needed to confirm these findings, existing findings suggest the effectiveness of SSRIs in reducing symptoms of depression in HIV seropositive individuals. A protocol for a Cochrane review has recently been published (Lewis et al., 2010).
TCAs have been found to be ineffective in two studies of HIV-related neuropathy (Saarto and Wiffen, 2010). No data are available on the SNRIs venlafaxine and duloxetine in the treatments of HIV-related neuropathy.
Psychostimulants (methylphenidate and dextroamphetamine) have also been studied in placebo-controlled trials in patients with depression and HIV. There have been two small uncontrolled studies of psychostimulants in the treatment of depression in HIV/AIDS (Fernandez et al., 1995; Wagner et al., 1997), and one small, placebo-controlled study (Wagner and Rabkin, 2000) that showed efficacy. Reductions in depressive symptoms as early as two weeks after initiating treatment have been reported (Wagner et al., 1997). In another study, among patients who were HIV-positive who also had significant levels of fatigue, methylphenidate and pemoline were found to be significantly superior to placebo in decreasing fatigue, and improvement in fatigue was significantly associated with improved quality of life and decreased levels of depression (Breitbart et al., 2001).
Reductions in testosterone levels among individuals with HIV/AIDS can be associated with changes in mood, appetite, and sexual function. In one study enrolling symptomatic patients who were HIV-positive, testosterone treatment was significantly better than placebo at restoring libido and energy, alleviating depressed mood, and increasing muscle mass (Rabkin et al., 2000), and a recent meta-analysis found that testosterone was effective in treating depression in HIV/AIDS (Zarrouf et al., 2009). The adrenal steroid dehydroepiandrosterone (DHEA) has also been evaluated and was effective (Rabkin et al., 2006).
As with other medical and nonmedical populations, the choice of an antidepressant agent in patients with HIV must be guided by the potential for drug-drug interactions and a number of potential interactions have been noted for medications used to treat depression and HIV/AIDS (Watkins et al., 2011).
CANCER
The effectiveness of antidepressants agents, specifically SSRIs and TCAs, for the treatment of depression in individuals with cancer is supported by a number of clinical trials (Evans et al., 2005). In a small study of major depression among women with breast cancer, comparing the efficacy of an SSRI (paroxetine) to a TCA (desipramine), no differences were found in efficacy compared to placebo (Musselman et al., 2006). In addition to the SSRIs and TCAs, mirtazapine and mianserin have shown promising results in open trials (Costa et al., 1985; Theobald et al., 2002; van Heeringen and Zivkov, 1996). Mirtazapine’s potential to cause weight gain might be of benefit for anorexic-cachectic patients with cancer, but should be used cautiously in those already gaining weight from steroids or from chemotherapy (Theobald et al., 2002). SSRIs are generally preferred over TCAs in this population, because of fewer sedative and autonomic side effects. SSRIs and the SNRI venlafaxine have demonstrated positive effects for women without depression who become menopausal after chemotherapy for breast cancer or who have a recurrence of vasomotor symptoms when they discontinue hormone replacement therapy. They have been effective for reducing the number and intensity of hot flashes and night sweats. The potential for drug interactions must be considered in patients with cancer. Recent evidence indicates that antidepressants that inhibit CYP2D6 may adversely affect the metabolism of tamoxifen, and it is recommended that known CYP2D6 inhibitors such as fluoxetine, paroxetine, or buproprion, should be avoided in combination with tamoxifen (Desmarais and Looper, 2009).
As reviewed earlier, another consideration in patients with cancer is depression that can result from certain cancer treatments that activate the immune system. In particular, treatment with IFN-a can cause the onset of new depressive episodes or trigger a recurrence of a previous episode. In a placebo-controlled trial, the use of an antidepressant (paroxetine) at the time of IFN-a treatment was found to reduce the incidence of depressive episodes and reduce the rate of discontinuation of IFN-a treatment (Musselman et al., 2001a). Currently, prophylactic use of antidepressants for patients with cancer is not recommended.
Although studies supporting antidepressant efficacy for psychostimulants (methylphenidate, dextroamphetamine) are lacking, they have been used with patients with cancer to promote a sense of well-being, improve symptoms of depression, increase energy, and improve cognitive function (Rozans et al., 2002). Psychostimulants have also been used to potentiate the analgesic effects of opioids and to counteract their sedative effects (Rozans et al., 2002).
CONCLUSIONS
Depressive disorders are prevalent among those with chronic medical conditions and may increase symptom burden and functional disability, adversely affect self-care and adherence to treatment, and decrease quality of life. Depression is also associated with immune suppression and immune activation. Depression associated cellular immune suppression may be a mechanism whereby depression may adversely effect immune-based diseases such as cancer and AIDS. On the other hand, depression-associated immune activation may be a mechanism whereby depression may have an adverse effect on diseases such as cardiovascular disease and diabetes.
Antidepressant treatments and psychotherapies are effective in the treatment of many of the symptoms of depression in individuals who are medically ill. High rates of depression among the medically ill call for heightened attention to this comorbidity. Depression should be actively identified and targeted for intervention. A number of studies suggest that the treatment of depression in individuals who are medically ill might improve overall medical outcomes or disease progression. Further large- scale studies will be needed to confirm these findings. Future investigation should focus on understanding the immune mechanisms as well as other mechanisms underlying depression and comorbid medical illness. Understanding the mechanisms underlying the associations between depression and medical illness may stimulate the development of novel therapies that provide effective interventions for this complex patient population.
DISCLOSURES
The work of Drs. Benton, Crits-Christoph, Dubé, and Evans, and the training of Dr. Blume, has been funded, in part, by the National Institutes of Health. Dr. Dubé was on the Speaker Bureau of Boehringer Ingelheim in 2009, 2010, and 2011, and has received compensation.
REFERENCES
Andersohn, F., Schade, R., et al. (2009). Long-term use of antidepressants for depressive disorders and the risk of diabetes mellitus. Am. J. Psychiatry 166:591–598.
Baumeister, H., Hutter, N., et al. (2011). Psychological and pharmacological interventions for depression in patients with coronary artery disease. Cochrane Database Syst. Rev. CD008012.
Beck, A.T., Steer, R.A., et al. (1996). Comparison of Beck depression inventories-IA and –II in Psychiatric Outpatients. J. Pers. Assess. 67:588–597.
Beliles, K., and Stoudemire, A. (1998). Psychopharmacologic treatment of depression in the medically ill. Psychosomatics 39:S2–S19.
Berg, L., Lampa, J., et al. (2001). Increased peripheral T cell reactivity to microbial antigens and collagen type II in rheumatoid arthritis after treatment with soluble TNFalpha receptors. Ann. Rheum. Dis. 60:133–139.
Berkman, L.F., Blumenthal, J., et al. (2003). Effects of treating depression and low perceived social support on clinical events after myocardial infarction: the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD). Randomized Trial. JAMA 289:3106–3116.
Blume, J., Douglas, S.D., et al. (2011). Immune suppression and immune activation in depression. Brain Behav. Immun. 25:221–229.
Breitbart, W., Rosenfeld, B., et al. (2001). A randomized, double-blind, placebo-controlled trial of psychostimulants for the treatment of fatigue in ambulatory patients with human immunodeficiency virus disease. Arch. Intern. Med. 161:411–420.
Bruce, T.O. (2008). Comorbid depression in rheumatoid arthritis: pathophysiology and clinical implications. Curr. Psychiatry Rep. 10:258–264.
Burack, J.H., Barrett, D.C., et al. (1993). Depressive symptoms and CD4 lymphocyte decline among HIV-infected men. JAMA 270:2568–2573.
Campayo, A., de Jonge, P., et al. (2010). Depressive disorder and incident diabetes mellitus: the effect of characteristics of depression. Am. J. Psychiatry 167:580–588.
Capuron, L., Gumnick, J.F., et al. (2002). Neurobehavioral effects of interferon- alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacology 26:643–652.
Capuron, L., Ravaud, A., et al. (2004). Baseline mood and psychosocial characteristics of patients developing depressive symptoms during interleukin-2 and/or interferon-alpha cancer therapy. Brain Behav. Immun. 18:205–213.
Carney, R.M., Blumenthal, J.A., et al. (2005). Low heart rate variability and the effect of depression on post-myocardial infarction mortality. Arch. Intern. Med. 165:1486–1491.
CDC. (2008). National diabetes fact sheet: general information and national estimates on diabetes in the United States, 2007. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. Atlanta, GA.
Celano, C.M., and Huffman, J.C. (2011). Depression and cardiac disease: a review. Cardiol. Rev. 19:130–142.
Cesari, M., Penninx, B.W., et al. (2003). Inflammatory markers and onset of cardiovascular events: results from the Health ABC study. Circulation 108:2317–2322.
Champaneri, S., Wand, G.S., et al. (2010). Biological basis of depression in adults with diabetes. Curr. Diab. Rep. 10:396–405.
Ciesla, J.A., and Roberts, J.E. (2001). Meta-analysis of the relationship between HIV infection and risk for depressive disorders. Am. J. Psychiatry 158:725–730.
Cole, S.W., Korin, Y.D., et al. (1998). Norepinephrine accelerates HIV replication via protein kinase A-dependent effects on cytokine production. J. Immunol. 161:610–616.
Collado-Hidalgo, A., Bower, J.E., et al. (2006). Inflammatory biomarkers for persistent fatigue in breast cancer survivors. Clin. Cancer Res. 12:2759–2766.
Constant, E.L., Adam, S., et al. (2005). Effects of sertraline on depressive symptoms and attentional and executive functions in major depression. Depress. Anxiety 21:78–89.
Cook, J.A., Grey, D., et al. (2004). Depressive symptoms and AIDS-related mortality among a multisite cohort of HIV-positive women. Am. J. Public Health 94:1133–1140.
Cooper, D.C., Milic, M.S., et al. (2010). Adverse impact of mood on flow-mediated dilation. Psychosom. Med. 72:122–127.
Cope, A.P. (2003). Exploring the reciprocal relationship between immunity and inflammation in chronic inflammatory arthritis. Rheumatology (Oxford) 42:716–731.
Costa, D., Mogos, I., et al. (1985). Efficacy and safety of mianserin in the treatment of depression of women with cancer. Acta Psychiatr. Scand. Suppl. 320:85–92.
Cruess, D.G., Evans, D.L., et al. (2003). Prevalence, diagnosis, and pharmacological treatment of mood disorders in HIV disease. Biol. Psychiatry 54:307–316.
Currier, M.B., Molina, G., et al. (2003). A prospective trial of sustained-release bupropion for depression in HIV-seropositive and AIDS patients. Psychosomatics 44:120–125.
Dantzer, R., O’Connor, J.C., et al. (2008). From inflammation to sickness and depression: when the immune system subjugates the brain. Nat. Rev. Neurosci. 9:46–56.
Dekker, J.M., Crow, R.S., et al. (2000). Low heart rate variability in a 2-minute rhythm strip predicts risk of coronary heart disease and mortality from several causes: the ARIC Study. Atherosclerosis Risk In Communities. Circulation 102:1239–1244.
Desmarais, J.E., and Looper, K.J. (2009). Interactions between tamoxifen and antidepressants via cytochrome P450 2D6. J. Clin. Psychiatry 70:1688–1697.
Doran, M.F., Crowson, C.S., et al. (2002). Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study. Arthritis. Rheum. 46:2287–2293.
Douglas, S.D., Ho, W.Z., et al. (2001). Elevated substance P levels in HIV-infected men. AIDS 15:2043–2045.
Dowlati, Y., Herrmann, N., et al. (2010). A meta-analysis of cytokines in major depression. Biol. Psychiatry 67:446–457.
Elliott, A.J., Uldall, K.K., et al. (1998). Randomized, placebo-controlled trial of paroxetine versus imipramine in depressed HIV-positive outpatients. Am. J. Psychiatry 155:367–372.
Evans, D.L., Charney, D.S., et al. (2005). Mood disorders in the medically ill: scientific review and recommendations. Biol. Psychiatry 58:175–189.
Evans, D.L., Lynch, K.G., et al. (2008). Selective serotonin reuptake inhibitor and substance P antagonist enhancement of natural killer cell innate immunity in human immunodeficiency virus/acquired immunodeficiency syndrome. Biol. Psychiatry 63:899–905.
Evans, D.L., Ten Have, T.R., et al. (2002). Association of depression with viral load, CD8 T lymphocytes, and natural killer cells in women with HIV infection. Am. J. Psychiatry 159:1752–1759.
Fernandez, F., Levy, J.K., et al. (1995). Effects of methylphenidate in HIV-related depression: a comparative trial with desipramine. Int. J. Psychiatry Med. 25:53–67.
Ferrando, S.J., Goldman, J.D., et al. (1997). Selective serotonin reuptake inhibitor treatment of depression in symptomatic HIV infection and AIDS. Improvements in affective and somatic symptoms. Gen. Hosp. Psychiatry 19:89–97.
Frasure-Smith, N., Lesperance, F., et al. (1995). Depression and 18 month prognosis after myocardial infarction. Circulation 91:999–1005.
Frasure-Smith, N., Lesperance, F., et al. (2007). Depression, C-reactive protein and two-year major adverse cardiac events in men after acute coronary syndromes. Biol. Psychiatry 62:302–308.
Gale, C.R., Kivimaki, M., et al. (2010). Fasting glucose, diagnosis of Type 2 diabetes, and depression: the Vietnam experience study. Biol. Psychiatry 67:189–192.
Giese-Davis, J., Collie, K., et al. (2011). Decrease in depression symptoms is associated with longer survival in patients with metastatic breast cancer: a secondary analysis. J. Clin. Oncol. 29:413–420.
Gladman, D.D., Hussain, F., et al. (2002). The nature and outcome of infection in systemic lupus erythematosus. Lupus 11:234–239.
Glassman, A.H., Bigger, J.T., Jr., et al. (2009). Psychiatric characteristics associated with long-term mortality among 361 patients having an acute coronary syndrome and major depression. Arch. Gen. Psychiatry 66:1022–1029.
Glassman, A.H., O’Connor, C.M., et al. (2002). Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 288:701–709.
Glazer, K.M., Emery, C.F., et al. (2002). Psychological predictors of adherence and outcomes among patients in cardiac rehabilitation. J. Cardiopulm. Rehabil. 22:40–46.
Golden, S.H., Lazo, M., et al. (2008). Examining a bidirectional association between depressive symptoms and diabetes. JAMA 299:2751–2759.
Gorman, J.M., Kertzner, R., et al. (1991). Glucocorticoid level and neuropsychiatric symptoms in homosexual men with HIV infection. Am. J. Psychiatry 148:41–45.
Grassi, B., Gambini, O., et al. (1997). Efficacy of paroxetine for the treatment of depression in the context of HIV infection. Pharmacopsychiatry 30:70–71.
Gulseren, L., Gulseren, S., et al. (2005). Comparison of fluoxetine and paroxetine in type II diabetes mellitus patients. Arch. Med. Res. 36:159–165.
Hamilton, M. (1960). A rating scale for depression. J. Neurol. Neurosur. PS. 23:56–62.
Hardy, S.E. (2009). Methylphenidate for the treatment of depressive symptoms, including fatigue and apathy, in medically ill older adults and terminally ill adults. Am. J. Geriatr. Pharmacother. 7:34–59.
Ho, W.Z., Cnaan, A., et al. (1996). Substance P modulates human immunodeficiency virus replication in human peripheral blood monocyte-derived macrophages. AIDS Res. Hum. Retroviruses 12:195–198.
Honig, A., Kuyper, A.M., et al. (2007). Treatment of post-myocardial infarction depressive disorder: a randomized, placebo-controlled trial with mirtazapine. Psychosom. Med. 69:606–613.
Ickovics, J.R., Hamburger, M.E., et al. (2001). Mortality, CD4 cell count decline, and depressive symptoms among HIV-seropositive women: longitudinal analysis from the HIV Epidemiology Research Study. JAMA 285:1466–1474.
Ironson, G., Balbin, E., et al. (2001). Relative preservation of natural killer cell cytotoxicity and number in healthy AIDS patients with low CD4 cell counts. AIDS 15:2065–2073.
Irwin, M.R., and Miller, A.H. (2007). Depressive disorders and immunity: 20 years of progress and discovery. Brain Behav. Immun. 21:374–383.
Katon, W.J. (2003). Clinical and health services relationships between major depression, depressive symptoms, and general medical illness. Biol. Psychiatry 54:216–226.
Katon, W.J. (2011). Epidemiology and treatment of depression in patients with chronic medical illness. Dialogues Clin. Neurosci. 13:7–23.
Katon, W.J., Lin, E.H., et al. (2010). Collaborative care for patients with depression and chronic illnesses. N. Engl. J. Med. 363:2611–2620.
Kemeny, M.E., and Dean, L. (1995). Effects of AIDS-related bereavement on HIV progression among New York City gay men. AIDS Educ. Prev. 7:36–47.
Kemeny, M.E., Weiner, H., et al. (1995). Immune system changes after the death of a partner in HIV-positive gay men. Psychosom. Med. 57:547–554.
Kessler, R.C., Berglund, P., et al. (2005). Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch. Gen. Psychiatry 62:593–602.
Kling, M.A., Alesci, S., et al. (2007). Sustained low-grade pro-inflammatory state in unmedicated, remitted women with major depressive disorder as evidenced by elevated serum levels of the acute phase proteins C-reactive protein and serum amyloid A. Biol. Psychiatry 62:309–313.
Knol, M.J., Heerdink, E.R., et al. (2007). Depressive symptoms in subjects with diagnosed and undiagnosed type 2 diabetes. Psychosom. Med. 69:300–305.
Koetz, K., Bryl, E., et al. (2000). T cell homeostasis in patients with rheumatoid arthritis. Proc. Natl. Acad. Sci. USA 97:9203–9208.
Kroenke, K., and Spitzer, R.L. (2002). The PHQ-9: a new depression diagnostic and severity measure. Psychiatr. Ann. 32:509–515.
La Cava, A. (2008). T-regulatory cells in systemic lupus erythematosus. Lupus 17:421–425.
Leserman, J. (2003). HIV disease progression: depression, stress, and possible mechanisms. Biol. Psychiatry 54:295–306.
Leserman, J. (2008). Role of depression, stress, and trauma in HIV disease progression. Psychosom. Med. 70:539–545.
Leserman, J., Petitto, J.M., et al. (2002). Progression to AIDS, a clinical AIDS condition and mortality: psychosocial and physiological predictors. Psychol. Med. 32:1059–1073.
Lesperance, F., Frasure-Smith, N., et al. (2007). Effects of citalopram and interpersonal psychotherapy on depression in patients with coronary artery disease: the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE). trial. JAMA 297:367–379.
Lett, H.S., Blumenthal, J.A., et al. (2004). Depression as a risk factor for coronary artery disease: evidence, mechanisms, and treatment. Psychosom. Med. 66:305–315.
Lewis, I.S., Joska, J.A., et al. (2010). Antidepressants for depression in adults with HIV infection (Protocol). Cochrane Database Syst. Rev. CD008525.
Lustman, P.J., Freedland, K.E., et al. (2000). Fluoxetine for depression in diabetes: a randomized double-blind placebo-controlled trial. Diabetes Care 23:618–623.
Markowitz, S.M., Gonzalez, J.S., et al. (2011). A review of treating depression in diabetes: emerging findings. Psychosomatics 52:1–18.
Medzhitov, R. (2008). Origin and physiological roles of inflammation. Nature. 454:428–435.
Mezuk, B., Eaton, W.W., et al. (2008). Depression and type 2 diabetes over the lifespan: a meta-analysis. Diabetes Care 31:2383–2390.
Miller, A.H. (2010). Depression and immunity: a role for T cells? Brain Behav. Immun. 24:1–8.
Miller, A.H., Maletic, V., et al. (2009). Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol. Psychiatry 65:732–741.
Musselman, D.L., Betan, E., et al. (2003). Relationship of depression to diabetes types 1 and 2: epidemiology, biology, and treatment. Biol. Psychiatry 54:317–329.
Musselman, D.L., Lawson, D.H., et al. (2001a). Paroxetine for the prevention of depression induced by high-dose interferon alfa. N. Engl. J. Med. 344:961–966.
Musselman, D.L., Miller, A.H., et al. (2001b). Higher than normal plasma interleukin-6 concentrations in cancer patients with depression: preliminary findings. Am. J. Psychiatry 158:1252–1257.
Musselman, D.L., Somerset, W.I., et al. (2006). A double-blind, multicenter, parallel-group study of paroxetine, desipramine, or placebo in breast cancer patients (stages I, II, III, and IV). with major depression. J. Clin. Psychiatry 67:288–296.
Nahshoni, E., Aravot, D., et al. (2004). Heart rate variability in patients with major depression. Psychosomatics 45:129–134.
Nemeroff, C.B., and Vale, W.W. (2005). The neurobiology of depression: inroads to treatment and new drug discovery. J. Clin. Psychiatry 66(Suppl 7):5–13.
Nery, F.G., Borba, E.F., et al. (2007). Major depressive disorder and disease activity in systemic lupus erythematosus. Compr. Psychiatry 48:14–19.
Newport, D.J., and Nemeroff, C.B. (1998). Assessment and treatment of depression in the cancer patient. J. Psychosom. Res. 45:215–237.
Nouwen, A., Winkley, K., et al. (2010). Type 2 diabetes mellitus as a risk factor for the onset of depression: a systematic review and meta-analysis. Diabetologia 53:2480–2486.
Otte, C., Zhao, S., et al. (2012). Statin use and risk of depression in patients with coronary heart disease: longitudinal data from the heart and soul study. J. Clin. Psychiatry 73:610–615.
Pan, A., Sun, Q., et al. (2012). Use of antidepressant medication and risk of type 2 diabetes: results from three cohorts of US adults. Diabetologia 55:63–72.
Paile-Hyvarinen, M., Wahlbeck, K., et al. (2007). Quality of life and metabolic status in mildly depressed patients with type 2 diabetes treated with paroxetine: a double-blind randomized placebo controlled 6 month trial. BMC Fam. Pract. 8:34–41.
Pike, J.L., and Irwin, M.R. (2006). Dissociation of inflammatory markers and natural killer cell activity in major depressive disorder. Brain Behav. Immun. 20:169–174.
Pizzi, C., Mancini, S., et al. (2009). Effects of selective serotonin reuptake inhibitor therapy on endothelial function and inflammatory markers in patients with coronary heart disease. Clin. Pharmacol. Ther. 86:527–532.
Pizzi, C., Manzoli, L., et al. (2008). Analysis of potential predictors of depression among coronary heart disease risk factors including heart rate variability, markers of inflammation, and endothelial function. Eur. Heart J. 29:1110–1117.
Pizzi, C., Rutjes, A.W., et al. (2011). Meta-analysis of selective serotonin reuptake inhibitors in patients with depression and coronary heart disease. Am. J. Cardiol. 107:972–979.
Prince, M., Patel, V., et al. (2007). Global mental health 1—No health without mental health. Lancet 370:859–877.
Rabkin, J.G. (2008). HIV and depression: 2008 review and update. Curr. HIV/AIDS Rep. 5:163–171.
Rabkin, J.G., McElhiney, M.C., et al. (2006). Placebo-controlled trial of dehydroepiandrosterone (DHEA). for treatment of nonmajor depression in patients with HIV/AIDS. Am. J. Psychiatry 163:59–66.
Rabkin, J.G., Wagner, G.J., et al. (2000). A double-blind, placebo-controlled trial of testosterone therapy for HIV-positive men with hypogonadal symptoms. Arch. Gen. Psychiatry 57:141–147; discussion 155–156.
Rackley, S., and Bostwick, J.M. (2012). Depression in medically ill patients. Psychiatr. Clin. North Am. 35:231–247.
Radloff, L.S. (1977). The CES-D Scale: A self-report depression scale for research in the general population. Applied Psychological Measurement 1:385–401.
Raison, C.L., Borisov, A.S., et al. (2009). Activation of central nervous system inflammatory pathways by interferon-alpha: relationship to monoamines and depression. Biol. Psychiatry 65:296–303.
Raison, C.L., and Miller, A.H. (2003). Depression in cancer: new developments regarding diagnosis and treatment. Biol. Psychiatry 54:283–294.
Repetto, M.J., and Petitto, J.M. (2008). Psychopharmacology in HIV-infected patients. Psychosom. Med. 70:585–592.
Rozans, M., Dreisbach, A., et al. (2002). Palliative uses of methylphenidate in patients with cancer: a review. J. Clin. Oncol. 20:335–339.
Rudisch, B., and Nemeroff, C.B. (2003). Epidemiology of comorbid coronary artery disease and depression. Biol. Psychiatry 54:227–240.
Saarto, T., and Wiffen, P.J. (2010). Antidepressants for neuropathic pain: a Cochrane review. J. Neurol. Neurosurg. Psychiatry 81:1372–1373.
Satin, J.R., Linden, W., et al. (2009). Depression as a predictor of disease progression and mortality in cancer patients: a meta-analysis. Cancer 115:5349–5361.
Scharko, A.M. (2006). DSM psychiatric disorders in the context of pediatric HIV/AIDS. AIDS Care 18:441–445.
Skala, J.A., Freedland, K.E., et al. (2006). Coronary heart disease and depression: a review of recent mechanistic research. Can. J. Psychiatry 51:738–745.
Stafford, L., and Berk, M. (2011). The use of statins after a cardiac intervention is associated with reduced risk of subsequent depression: proof of concept for the inflammatory and oxidative hypotheses of depression? J. Clin. Psychiatry 72:1229–1235.
Stein, P.K., Carney, R.M., et al. (2000). Severe depression is associated with markedly reduced heart rate variability in patients with stable coronary heart disease. J. Psychosom. Res. 48:493–500.
Sullivan, M.D., O’Connor, P., et al. (2012). Depression predicts all-cause mortality: epidemiological evaluation from the ACCORD HRQL substudy. Diabetes Care 35:1708–1715.
Theobald, D.E., Kirsh, K.L., et al. (2002). An open-label, crossover trial of mirtazapine (15 and 30 mg) in cancer patients with pain and other distressing symptoms. J. Pain Symptom Manage. 23:442–447.
Turner, M.S., May, D.B., et al. (2007). Clinical impact of selective serotonin reuptake inhibitors therapy with bleeding risks. J. Intern. Med. 261:205–213.
van der Feltz-Cornelis, C.M., Nuyen, J., et al. (2010). Effect of interventions for major depressive disorder and significant depressive symptoms in patients with diabetes mellitus: a systematic review and meta-analysis. Gen. Hosp. Psychiatry 32:380–395.
van Heeringen, K., and Zivkov, M. (1996). Pharmacological treatment of depression in cancer patients. A placebo-controlled study of mianserin. Br. J. Psychiatry 169:440–443.
Wagner, G.J., Rabkin, J.G., et al. (1997). Dextroamphetamine as a treatment for depression and low energy in AIDS patients: a pilot study. J. Psychosom. Res. 42:407–411.
Wagner, G.J., and Rabkin, R. (2000). Effects of dextroamphetamine on depression and fatigue in men with HIV: a double-blind, placebo-controlled trial. J. Clin. Psychiatry 61:436–440.
Wang, P.S., Bohn, R.L., et al. (2002). Noncompliance with antihypertensive medications: the impact of depressive symptoms and psychosocial factors. J. Gen. Intern. Med. 17:504–511.
Watkins, C.C., Pieper, A.A., et al. (2011). Safety considerations in drug treatment of depression in HIV-positive patients: an updated review. Drug. Saf. 34:623–639.
WHO (2008). The Global Burden of Disease: 2004 Update. World Health Organization. Geneva, Switzerland: WHO Press.
Whooley, M.A., Caska, C.M., et al. (2007). Depression and inflammation in patients with coronary heart disease: findings from the Heart and Soul Study. Biol. Psychiatry 62:314–320.
Williams, M.M., Clouse, R.E., et al. (2007). Efficacy of sertraline in prevention of depression recurrence in older versus younger adults with diabetes. Diabetes Care 30:801–806.
Zarrouf, F.A., Artz, S., et al. (2009). Testosterone and depression: systematic review and meta-analysis. J. Psychiatr. Pract. 15:289–305.
Zigmond, A.S., and Snaith, R.P. (1983). The hospital anxiety and depression scale. Acta. Psychiatr. Scand. 67:361–370.
Zung, W.W. (1965). A self-rating depression scale. Arch. Gen. Psychiat. 12:63–70.