Medical comorbidities and functioning in depression: a clinical perspective

Pedro Antônio SCHMIDT DO
InsCer, Porto Alegre, BRAZIL

Medical comorbidities and functioning in depression: a clinical perspective

by P. A. Schmidt do Prado-Lima, Brazil

Although very common, the comorbidity between depression and various somatic illnesses is frequently neglected and undertreated in clinical practice. Those affected often consult a general practitioner, a medical professional that is usually ill-equipped to recognize depression or establish a hierarchy between the comorbid conditions, and so the somatic illness often becomes the main target of investigation and treatment. This difficulty in recognizing the comorbidity between a somatic illness and depression has consequences for the clinical outcome, since comorbidity between depression and somatic illnesses is a downward spiraling condition, where each illness (depression and the somatic illness) becomes a risk factor for the other. There is accumulating evidence implicating inflammation as a critical mediator in the pathophysiology of depression. In fact, depression can both trigger inflammatory processes and be triggered by inflammation. As many comorbid illnesses are also inflammatory in nature, it is likely that inflammation could be the common underlying mechanism in at least some of these comorbidities, like depression with cardiovascular illnesses or diabetes, among many others. This article briefly reviews the main aspects of the comorbidity between depression and somatic illnesses. In particular, it addresses the challenge represented by its recognition and reviews the available evidence showing the role played by inflammation.

Medicographia. 2014;36:464-469 (see French abstract on page 469)

Psychiatric disorders have a unique nature that makes them seem different from other medical conditions. They are often poorly understood, perhaps because they have both a biological and a psychological aspect, even though their psychological aspect actually has a biological basis. Physicians are trained in biology since the beginning of their medical studies, and for them understanding the nature of psychiatric disorders—depression among them—can be a challenge. This challenge is greater because some somatic medical illnesses can lead to depression, and depression can be a risk factor for the development of various medical illnesses. Moreover, depression can manifest through somatic symptoms and mimic other diseases. Comorbidity between depression and a somatic medical illness is very frequent and is a confounding factor that hampers and reduces the rate of diagnosis of depression—and consequently its treatment—thus contributing to increased health care costs. Understanding the nature of this higher-than-expected association is the first step to motivating the physicians that are most likely to see such patients—ie, general practitioners—to improve their skills in diagnosing and treating depression. On the other hand, from a psychiatric point of view, studying the comorbidity between depression and somatic illnesses offers an opportunity to address the possible mechanisms underlying not only this interaction, but also mood disorders. This review will briefly expose some important aspects of this comorbidity, in particular the challenge represented by its recognition and the evidence suggesting that inflammation is a possible mechanism underlying this interaction.

Medical comorbidity is common in depression

As expected, the co-occurrence between two very common conditions—depression and other nonpsychiatric medical diseases— is itself only common due to statistical chance. This fact alone is justification enough to study this subject, since these comorbidities change the prognosis and treatment of both conditions. But this is only part of the problem. In fact, through mechanisms that are still poorly understood, a variety of nonpsychiatric medical conditions are risk factors for the development of depression. Similarly, through mechanisms that are now beginning to be unravelled,1 depression is a risk factor for the development and progression of a variety of nonpsychiatric medical illnesses, like diabetes2 and cardiovascular diseases,3 among others. Therefore, these interactions increase the prevalence of these comorbidities.

To exemplify this, a large epidemiological study using data collected by three German statutory health insurers during the period 2005-2007 showed that 99.8% of “severe depressive patients” (defined as ICD-10 F32.2, F32.3, F33.2, and F33.3, n=110 462) also presented a “somatic comorbidity.”4 It is interesting to note that in these depressive patients there were higher rates of comorbidity with nonpsychiatric diseases (99.8%) than with other psychiatric disorders (88.5%).4

Some of the medical comorbidities associated with depression are well established. One of the most frequently reported is the comorbidity between depression and cardiovascular disease. In a case-control study, it was found that 46.1% of patients suffering from recurrent depressive disorder also had a cardiovascular disease, compared with 13.9% in the control group (P<0.001).3 On the other hand, looking from the cardiological perspective, another meta-analysis showed that clinically significant depression was found in 21.5% of patients with heart failure, which is higher than expected in the general population.5 Yet another meta-analysis found that depression was a risk factor for the development of myocardial infarction (odds ratio [OR] 1.60; 95% confidence interval [CI], 1.34-1.92).6

Another example is type 2 diabetes. Comorbidity between diabetes and depression was first described in the seventeenth century by the English physician and anatomist Thomas Willis, who stated that diabetes was caused by sorrow.7 A meta-analysis including 51 331 patients showed that the prevalence of depression was significantly higher in patients with type 2 diabetes than in those without (17.6% and 9.8% respectively, OR 1.6; 95% CI, 1.2-2.0). Although the prevalence of depression was higher in women (23.8%) than in men (12.8%) with type 2 diabetes, the increase in relative risk was greater in men (OR 1.9; 95% CI, 1.7-2.1) than in women (OR, 1.3; 95% CI, 1.2-1.4).8 Another meta-analysis attempted to identify whether depression is a risk factor for the development of type 2 diabetes or vice-versa. They found that the relative risk was 1.15 for the occurrence of depression after diabetes and 1.6 for the occurrence of diabetes after depression, demonstrating that depression is a stronger risk factor for the development of depression than the reverse.9

Chronic pain (of at least 6 months’ duration) has also been recognized as a common comorbidity with depression. A large survey including 18 980 subjects interviewed by telephone showed that at least one chronic painful physical condition occurred in 43.3% of subjects with major depression, four times more frequently than expected.10

Depression often goes unrecognized in depressive patients with a medical comorbidity

The first medical professional consulted for the diagnosis and treatment of patients showing depression and somatic illness comorbidity is often a general practitioner or another medical specialist with no psychiatric training. Often, these professionals investigate and treat the somatic illness, while depression is either unrecognized or considered secondary. This was demonstrated in a population-based survey in which only about half of the patients suffering from a major depressive disorder were diagnosed as such by a regular health care professional.11 Another study showed that only 23.1% of depressive patients received this diagnosis when consulting a primary care physician, patients with moderate depression being less likely to be diagnosed (17.8%) than those with moderately severe or severe depression (30.8% and 49.4%, respectively).12

Depression is more often the unrecognized “side” of the comorbidity when the physician consulted is a general practitioner, which seems logical because the training and experience of general practitioners are more directed toward diagnosing and treating somatic illnesses than psychiatric disorders. This problem cannot be solved easily. Of course, training in the recognition of depressive symptoms and syndromes could help improve the rate of diagnosis of depressive episodes. However, since many patients presenting with depression may, in fact, be suffering from bipolar disorder, prescribing the correct treatment requires the ability to differentiate between the two conditions. The use of antidepressants without mood stabilizers in patients with bipolar disorder could be harmful, which is why training in the diagnosis and treatment of depression must be balanced with training in the diagnosis and treatment of bipolar disorder in order to improve interventions and outcomes.

Somatic symptoms impair the recognition of depression

When they consult their physician, patients complain of signs and symptoms, which are then used by the physician to direct the investigation. Therefore, from a practical point of view it is important to study the relationship between somatic symptoms, and not only the somatic diagnosis, but also the co-occurrence of depression. Moreover, somatic symptoms are not synonymous with somatic illnesses, since they may be experienced by depressive patients in the absence of a somatic illness. This was exemplified in a large collaborative study organized by the World Health Organization involving 1146 major depressive patients who were consulting in primary care facilities in 15 different cities in 14 countries and underwent structured assessment for depressive and somatoform disorders.13 An average of 69% major depressive patients reported only somatic symptoms when consulting their general practitioner (ranging from 45% in Paris to 95% in Ankara), an average of 50% of them complained of unexplained somatic symptoms (ranging from 30% in Mainz to 62% in Bangalore), and an average of 11% denied having any psychological symptom (ranging from 2% in Rio de Janeiro to 26% in Athens and Berlin). Therefore, depression could mainly be described by patients through somatic symptoms, making its diagnosis more difficult, especially in the primary care setting, and leading these patients to use the health care system frequently.

Another variable that seems important is the number of somatic symptoms that appear to be associated with depressive and anxiety disorders. In primary care, the prevalence of mood disorders in patients with 0 to 1, 2 to 3, 4 to 5, 6 to 8, and 9 or more somatic symptoms was respectively 2%, 12%, 23%, 44%, and 60%.14

The majority of depressive patients will first consult a general practitioner. In general, such patients complain of somatic symptoms to their doctor not least because he/she is trained to inquire about and investigate somatic signs and symptoms. This scenario, together with the fact that depression may be accompanied by somatic symptoms, may lead to a failure to recognize depression and result in a time-consuming investigation that will not resolve the patient’s suffering and will increase health care use, and consequently, costs.

Comorbid depression increases the risk and worsens the outcome of medical conditions

Comorbidity is defined as two or more medical conditions existing simultaneously in the same patient. They can exist independently or interact, one being a risk factor that triggers or promotes further progression of the other. An example of such an interaction is the association of depression following myocardial infarction with mortality. A meta-analysis that included patients with myocardial infarction showed that depression was significantly associated with all causes of mortality (OR, 2.38; 95% CI, 1.76-3.22), cardiac mortality (OR, 2.59; 95% CI, 1.77-3.77), as well as new cardiovascular events (OR, 1.95; 95% CI, 1.33-2.85).15 Another meta-analysis studied different aspects of the relationship between depression and coronary heart disease. Depression was identified as a risk factor for the occurrence of coronary events in previously healthy subjects (OR, 1.81; 95% CI, 1.53-2.15) as well as a risk factor for a worse prognosis (OR, 1.8; 95% CI, 1.50-2.15).16

Another example is provided by comorbidity between depression and diabetes. In a study in which 10 704 patients with diabetes were surveyed over a 2-year period, it was shown that the occurrence of depression increased the risk of all-cause mortality by approximately 36%.17 In a prospective cohort 4184 patients were surveyed for approximately 5 years. Baseline major depression was associated with increased all-cause mortality (hazard ratio [HR], 2.26; 95% CI, 1.79-2.85), cardiovascular mortality (HR, 2.0; 95% CI, 1.37-2.94), and with noncardiovascular and noncancer mortality (HR, 3.35; 95% CI, 2.30-4.89), while minor depression showed a similar tendency.18 As explained above, the interaction between depression and somatic illness could be a “two-way street,” one being a risk factor for the other and vice-versa. In relation to this, a prospective 5-year follow-up study was conducted to identify risk factors for the occurrence of major depression in diabetic patients. It found that one or more coronary procedures during the follow-up period (OR, 1.92; 95% CI, 1.14- 2.25) or the number of diabetes symptoms at baseline (OR, 1.14; 95% CI, 1.05-1.22) were predictors of having major depression at the end of the follow-up.19 Thus, comorbidity could be viewed as a downward spiral, where both sides are risk factors for the other and can worsen the outcome.

Somatic diseases may lead to depression

Generally, the first approach regarding the high prevalence of depression associated with somatic diseases is based on the fact that illness can cause intense and constant stress and suffering capable of triggering and maintaining depression. The exception would be a disease whose biological mechanism has been found to cause depression, such as central nervous system and endocrine diseases. For example, it is easy to understand why Parkinson’s disease is associated with the development of major depression since, aside from the physical impairment associated with this disease, there is a decrease in dopamine levels that could provoke depression or some of its symptoms.20 It is important to note that the stress and hopelessness brought about by a chronic and progressive disease that alters one’s lifestyle, diminishes one’s capacity in many domains, causes limitations, and affects one’s self-esteem may itself trigger depression.

Perhaps a better example is hypothyroidism, which occurs in about 15% of patients with depression, a level of prevalence that is much higher than expected.21 Thyroid hormone treatment may accelerate and augment antidepressant pharmacotherapy and greatly influence brain function via genomic and nongenomic effects. The genomic action of triiodothyronine (T3) regulates genes encoding neurotrophins and other proteins that are involved in intracellular signaling pathways, while the nongenomic action of T3 involves activation of the phosphatidylinositol-3-kinase protein pathway, reduction of sensitivity of 5-HT1A autoreceptors (thereby increasing serotonergic neurotransmission) and increases 5-HT2 receptor sensitivity,21 all events linked to the neurobiology of depression. Even “subclinical” hypothyroidism, which imposes few or no “somatic-related” limitations, shows a higher prevalence of depression,22 demonstrating that the mechanisms involved are the direct effect of thyroid hormones.

Recently, other disease mechanisms capable of triggering and sustaining a depressive syndrome have been discovered. One example is the inflammatory mechanisms that are present in many somatic diseases.1 Historically speaking, the relationship between depression and tuberculosis is a classic example. More recently, a syndrome called “sickness behavior,” which is characterized by anhedonia, anorexia, cognitive impairment, decreased libido, fatigue, psychomotor retardation, social withdrawal, and hyperalgesia, symptoms that are present in depression and are also typical of viruses among other diseases, has been described. Sickness behavior is caused by the action of some proinflammatory cytokines in the central nervous system, such as tumor necrosis factor alpha (TNF-α), interleukin 1 (IL-1), and interleukin 6 (IL-6), among others.23 Many other conditions such as cardiovascular diseases, diabetes, cancer, asthma, or rheumatologic diseases, all of which are related to an increased prevalence of depression, also increase proinflammatory cytokines.

Stress induces inflammatory mechanisms

Some powerful risk factors for the development of depression, like early life stress and adulthood life stress, are associated with elevated inflammation.24 One example is provided by a study in which 135 adolescent girls were examined in relation to the production of IL-6 at baseline and following a major life event. Those subjects raised in a harsher family environment produced greater levels of IL-6 in comparison with those raised in a less harsh family environment.25 Moreover, stressful early life events are associated with higher levels of inflammation during a depressive episode. In a large cohort study, 1037 individuals were included from birth and surveyed for 32 years. Subjects with depression and no childhood maltreatment did not show any statistical difference in C-reactive protein (CRP) levels when compared with controls levels. However, subjects with childhood maltreatment as well as those with maltreatment plus depression showed a statistical increase in CRP when compared with controls.26

As mentioned above, a considerable amount of research shows that adulthood life stress is also associated with elevated inflammation. Both acute and chronic stress may elicit inflammation, particularly those events involving social stressors like conflict, threat, isolation, and rejection.24 This is exemplified by a study in which elderly adults who recently experienced the death of their spouse were shown to have higher levels of IL-1 and IL-6 activity than nonbereaved elderly adults. This response was moderated by a specific genotype of the IL-6 gene.27 Another example is provided by a study in which adolescent girls at high risk for depression were assessed regarding rejection-related life events and leukocyte levels of mRNA for proinflammatory transcription factor NF-&kppa;B (nuclear factor kappa-light-chain-enhancer of activated B cells) and inhibitor of κB (I-κB) (which regulates the effect of NF-κB). They found that the mRNA levels of both NF-κB and I-κB were higher in adolescents that had experienced a rejection situation than in those that had not.28

Depression can be triggered by inflammation

One argument that suggests that inflammation is a risk factor for the development of depression is the fact that about 50% of patients using interferon-α(INF-α) developed a major depressive episode.29 However, the other 50%, although they showed some neurovegetative symptoms like psychomotor retardation, fatigue, and disrupted appetite or sleep, cannot be said to have developed a major depressive episode because they did not develop affective or cognitive symptoms such as depressive mood, feelings of worthlessness, or guilt.29 In addition, having experienced a prior depressive episode has been shown to be a predictive factor for developing depression following INF-α use.29 Therefore, it seems that inflammation could trigger depression in vulnerable people.24

Depression could also be an inflammatory disease

In the last ten years we have observed increased interest in inflammatory mechanisms mediating the etiology and progression (related with prognosis) of mood disorders in general.1,23,24 There is now substantial data showing that different inflammatory processes are activated in depression. For example, the circulating levels of several proinflammatory cytokines including IL-1, IL-6, and TNF-&alph;, as well as CRP are higher, and there are increased numbers of T-cells bearing T-cell activation markers, including CD4+ and CD8+, increased production of interferon-γ (IFNγ), and elevated levels of the soluble receptors for IL-2 and TNF-α.23,24 It is important to point out that some of these inflammatory processes can diminish the availability of the serotonin precursor, tryptophan, a fact that may also contribute to triggering depression or to decreasing the effect of selective serotonin reuptake inhibitors for example.1,24

Do inflammatory mechanisms play a role in comorbidity?

As mentioned above, early life stress and adulthood stress elicit inflammatory processes; moreover, depression can both trigger inflammatory processes and be triggered by inflammation. Finally, many frequent comorbid illnesses are also inflammatory in nature. Therefore, inflammation could be at least one reason (among others, as yet unidentified) for the higher than- expected frequency of comorbidity between these somatic conditions and depression. In other words, inflammation (besides psychological stress) could play a key common role in the pathophysiology of some of these comorbidities and depression.24

Does medical comorbidity impair functioning and recovery from depression?

The short answer is yes. As mentioned above, inflammatory medical comorbidities can cause sickness behavior, the typical symptoms of which (anhedonia, anorexia, cognitive impairment, decreased libido, fatigue, psychomotor retardation, social withdrawal, and hyperalgesia) are also widely seen in depression. Sickness behavior is induced by some proinflammatory cytokines in the central nervous system—such as TNF-&lapha;, IL-1, and IL-6, among others23—and not only impairs functioning, but also hampers recovery from depression since it contributes to the maintenance of residual depressive symptoms. Moreover, the restraint and burden that somatic diseases entail may be a risk factor that can trigger and maintain depression and impair recovery. The mechanisms involved here are multiple and not fully understood, but may, in part, be due to activation of the hypothalamus-pituitary-adrenal axis, which is recognized as a key element for triggering depression. Given this, medical comorbidities could be considered as an element that worsens functioning and impairs full recovery from depression.


Comorbidity between depression and somatic illnesses is simultaneously highly prevalent and widely neglected. Those affected usually first consult general practitioners, who frequently fail to recognize depression or establish a hierarchy between the conditions. Therefore, the somatic illness usually becomes the main target of investigation and treatment. On the other hand, in addition to psychological distress, pain, and physical limitations, which have always been accepted as causes for the development of depression concomitantly to a medical disease, in the last ten years the role of inflammation as a common mechanism underlying some of these comorbidities has been investigated and identified. This leads us to ask why these interactions are so frequently encountered and why such comorbidities can be seen as a downward spiraling condition, where both depression and the somatic illness mutually contribute to the other as risk factors and ultimately worsen the outcome for the patient.

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Keywords: comorbidity; cytokine; depression; functioning; inflammation