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From the College of Medicine at the University of Cincinnati, Ohio, where Dr Aina is a resident in the Combined Family Medicine–Psychiatry Program and Dr Susman is the Fred Lazarus, Jr, professor and chairman of the Department of Family Medicine. Dr Susman serves as editor of the Journal of Family Practice and the American Academy of Family Physicians' (AAFP) FP essentials program.

Address correspondence to Jeffrey L. Susman, MD, Department of Family Medicine, Box 670582, College of Medicine, University of Cincinnati, Cincinnati, OH 45267-0582. E-mail: susmanjl{at}uc.edu

Comorbidity is the rule with anxiety and depressive disorders. Anxiety and major depressive disorder are often comorbid with each other; these disorders are commonly associated with other psychiatric disorders; and they are frequently found coexisting with long-standing chronic medical conditions such as cardiovascular disease and diabetes mellitus. The comorbidity of major depressive and anxiety disorders is associated with barriers to treatment and worse psychiatric outcomes, including treatment resistance, increased risk for suicide, greater chance for recurrence, and greater utilization of medical resources. Effective recognition and treatment of anxiety and depression may be associated with functional improvement in the medical disorders (eg, lower HbA_1c level in patients with diabetes). Paying careful attention to the development of anxiety and depression may also positively impact the economic burden of these disorders.

To help primary care physicians better understand the comorbidity of depression and anxiety and medical disorders, the authors describe three case scenarios.

	Case 1 Presentation

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"Mr Goldman," aged 55 years, has a chief complaint of back pain and poor sleep. These symptoms began after his wife died about 6 months before this visit. He has also had diffuse nonradicular lumbar pain. No "red flags" exist for serious underlying problems such as cancer or cauda equina. The patient sleeps fitfully and wakes up early in the morning with anxiety. He has had one episode during which his heart was pounding, he felt extremely fearful, and he thought he was going to die. He has mild benign prostatic hypertrophy, hypertension (for which he is treated with terazosin), and type 2 diabetes mellitus (controlled with metformin).

As with many patients, this individual has a history compatible with multiple medical and psychiatric disorders. Many patients with depression present with somatic symptoms such as backache. The beginning of symptoms after a loss of a spouse suggests a grief reaction, adjustment disorder, or major depressive disorder (MDD). Pain and psychiatric problems are often linked. Sleep disturbance, especially early-morning awakening, is suggestive of major depression. His anxiety symptoms are compatible to those of panic disorder. And finally, the interaction between possible psychiatric and medical illnesses should be considered. Thus, on the basis of Mr Goldman's history, his physician is faced with multiple possible etiologies for the patient's clinical picture.

Initial Diagnostic Approach
Many factors may conspire against the diagnosis of a mental health condition, particularly when patients present with a complicated history (Figure 1). The Diagnostic and Statistical Manual of Mental Disorders Text Revision (DSM-IV-TR)¹ underscores the importance of ruling out medical disorders and substance abuse as a cause of a patient's symptoms. Common considerations in the differential diagnosis of depression include thyroid disorders and other endocrinopathies, medication side effects, malignancy, and neurologic disorders. Anxiety may be caused by thyroid disorders, a variety of medications including over-the-counter preparations and herbal remedies, and substance abuse. Cardinal signs of depression (ie, mood disturbance or anhedonia) or anxiety (eg, fears, worries, compulsions, avoidance) may help initially suggest a psychiatric condition. But patients often present with somatic symptoms.^2,3

View larger version (46K): [in this window] [in a new window]   Figure 1. Barriers to accurate diagnosis of depression and anxiety.

A tool that specifically assesses for depression and anxiety with comorbid medical illness is the Hospital Anxiety and Depression Scale (HADS).⁵ The HADS is a self-assessment scale that has been found to be a reliable instrument for detecting and measuring the severity of depression and anxiety. The HADS cut-off scores of 7 to 8 identify possible depression or anxiety, and a score of 10 to 11 indicates probable depression or anxiety, or both. This tool can be administered in 2 to 5 minutes, and it has been validated in a wide range of populations and settings.

Distinguishing Between Anxiety and Depression
Physicians often attempt to separate depression from anxiety. Unfortunately, such distinctions are often challenging and artificial. Anxiety symptoms are common in patients with major depression: 72% worry, 62% present with psychic anxiety, 42% have somatic anxiety, and 29% have panic attacks.⁶ Factors that favor MDD include symptoms such as anergic hopelessness, feeling as if they "just can't go on," anhedonia, and early-morning awakenings, whereas problems such as initial insomnia, worry or fears, and specific behaviors such as avoidance or phobias point to anxiety. However, as the National Comorbidity Survey⁷ indicates, comorbid depression and anxiety is the rule rather than the exception in up to 60% of patients with MDD.⁷

Of greater importance is the need to identify symptoms and signs of alternative psychiatric disorders that require different or alternative treatment. For example, a history suggestive of posttraumatic stress disorder, such as the exposure to a traumatic life event, might greatly alter therapy. Likewise, physicians should be vigilant for factors suggesting bipolar disorder: a family history of bipolar disorder, manic symptoms with antidepressant treatment, prior history of mania or hypomania, or a decreased need for sleep.

	Case 1 Continued

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Mr Goldman's wife died of pneumonia. She had long suffered with probable Alzheimer disease, and the patient, though saddened by his wife's demise, thinks it was for the best. He denies alcohol or substance use. He is anxious about the future but denies any persistent worries or fears. He wonders if life is worth living, and he just cannot get motivated. He formerly had a great interest in golf, but he says, "At this point, I don't know why I'm continuing on." He has never had symptoms suggestive of bipolar disorder.

Although physicians may cleanly differentiate depression and anxiety, many symptoms overlap and many patients with MDD or anxiety disorders have multiple psychiatric disorders. For example, more than 50% of patients with generalized anxiety disorder and more than 30% of those with social anxiety disorder meet the criteria for MDD.^8,9 Typically, an anxiety disorder precedes the development of MDD.⁷ Anxiety disorders are often comorbid with each other.¹⁰ Thus, rather than conceptualizing MDD and anxiety as single, exclusive disorders, physicians are wise to expect significant overlap and comorbid psychiatric conditions.

Impact of Depression and Anxiety
Functioning and well-being are greatly diminished with comorbid MDD and anxiety. Health services research suggests that the impact of work loss has its greatest effect in patients with severe comorbid disease and that depression has the greatest economic impact.^11,12 Recent work suggests that for primary care outpatients with anxiety, MDD, panic, posttraumatic stress disorder, and social phobia, each disorder causes equal decrements of function.¹³ Thus, patients with clinically significant comorbidity suffer the greatest functional and economic burden.

Suicide Risk in Patients With Comorbid Depression and Anxiety
It is important to be vigilant to consider the risk for suicide. About one in 10 of depressed patients will attempt suicide, and although 70% of suicides revolve around depressive illness, anxiety disorders also pose a significant risk for suicide.¹⁴ Moreover, comorbid anxiety and depression portends an even greater chance of nonresponse to treatment, long-term poor outcome, and suicide. For example, with uncomplicated panic disorder, the risk of suicide is 7%, but if comorbid depression exists, the risk is increased to 23.6%. Likewise, MDD without anxiety was associated with a 7.9% risk of suicide, but when comorbid anxiety was present, this risk jumped to 19.8%.¹⁵

While physicians may be reluctant to ask about suicide, there is good evidence that asking patients about suicide and assessing their risk of suicide does not increase the risk of completed suicide. Does the patient have thoughts of self-harm? Has the patient made any specific plans to do so? If so, what are these plans? Are they available and potentially lethal? A person with vague symptoms responding: "Well you know, I occasionally think I would be better off if I was gone and dead. But then there are the grandchildren, and you know I couldn't leave them" would be less concerning than the patient confiding: "I oiled up my shotgun and have it loaded for me just like my grandfather did 50 years ago today."

An area of current controversy is the role of antidepressants, specifically selective serotonin reuptake inhibitors (SSRIs), in suicide (particularly in children and adolescents). It has been long recognized that antidepressants may increase agitation and activation, or improve a deeply depressed and suicidal patient just enough to carry out a plan. Thus, it is crucial not only to screen depressed and anxious patients for suicidal ideation, but also to follow up and carefully monitor the patient for treatment-emergent suicidality.¹⁶

	Case 2 Presentation

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"Mrs Poland," aged 45 years, was seen in the emergency department (ED) with chest pain. She said she had the sudden sense that she "couldn't catch her breath" and that she was going to die. Her symptoms escalated rapidly over 5 to 10 minutes and then abated. She was brought to the ED on the insistence of her husband. Findings of an initial examination are normal, including the electrocardiogram and creatine kinase MB subunit and troponin levels. Mrs Poland's primary care physician skillfully made the diagnosis of a panic attack and treated Mrs Poland for it.

Ten years later, the primary care physician is again called to the ED for Mrs Poland. Unfortunately, this time, the patient has clear evidence of an ST-elevation myocardial infarction. The physician follows up with Mrs Poland in the office 4 weeks after aggressive hospital management. Despite Mrs Poland's having preserved left ventricular function and excellent functional capacity, her husband reports that all his wife does is sit around and say she would be better off dead.

	Depression and Medical Illness

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One of the greatest challenges facing physicians today is managing MDD and anxiety disorders in the setting of acute and chronic medical illness (Figure 2). Increasingly, investigators are unraveling the interaction between depression, anxiety, and medical disease: anxiety and depression may negatively influence the outcomes of medical illness; and many medical problems increase the risk of suffering from depression and anxiety. The interaction of depression, anxiety, and three medical illnesses—heart disease, diabetes, and human immunodefiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS)—provides an example.

View larger version (54K): [in this window] [in a new window]   Figure 2. Medical disorders that commonly coexist with anxiety and depression.

One quantitative review concluded that depressive symptoms contribute a clinically significant independent risk for the onset of coronary disease, a relative risk (1.64) that is greater than that conferred by passive smoking (1.25) but less than that conferred by active smoking (2.5).¹⁷

In a classic study, depressive symptoms were found to be a clinically significant independent risk factor for cumulative mortality following heart attack.¹⁸ A recent meta-analysis concluded that post–myocardial infarction depression is associated with a 2.0- to 2.5-fold increased risk of a worse cardiovascular outcome.¹⁹ In the past, there has been concern about the risks of treating patients with cardiac disease for depression; however, the latest evidence suggests that SSRIs and other newer agents can be safely used. While both nortriptyline hydrochloride and paroxetine hydrochloride are effective for the treatment of patients with depression in the setting of ischemic heart disease, nortriptyline was associated with a higher dropout rate because of side effects and with variablility in increased heart rate and reduced heart rate.²⁰

In the largest intervention trial of treatment of patients who had depression post–myocardial infarction, the Sertraline Antidepressant Heart Attack Trial (SADHART),²¹ cardiovascular and stroke events and mortality were all positively influenced by antidepressant treatment. However, these results failed to achieve statistical significance. Nonetheless, early intervention in the treatment of patients with depression associated with ischemic heart disease holds promise²² Moreover, the negative effects of depression (ie, negative influence on morbidity, function, and medical outcomes) appear in a wide variety of heart problems, including heart failure.²³

Similar work has been done with anxiety and while the data are not as compelling or complete, anxiety symptoms appear to be associated with the incidence and progression of heart disease.^24,25. Thus, a large body of evidence supports the bidirectional link between heart disease and anxiety and depression.

	Case 3 Presentation

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"Mr Cummings," aged 65 years, has long-standing type 2 diabetes mellitus. During the past 5 years, his glycosylated hemoglobin (HbA_1c) level has risen from 6.9% to 9.9%. Although his physician has increased this patient's oral medication regimen and added insulin glargine, his HbA_1c level continues to climb. The patient's physician considers whether adding more insulin might be beneficial.

Comorbid Depression and Diabetes Mellitus
Although the link between heart disease and depression has become better known, the relation between depression and diabetes mellitus is perhaps less appreciated. Ten percent to 20% of individuals with diabetes suffer from depression, and this rate increases to almost 30% in those with a prior history of depression. Anxiety disorders are also highly prevalent.²⁶

Patients with diabetes and depression have been shown to have a greater number of risk factors, poorer compliance with personal diabetic care (adherence to diet, checking blood sugar levels), are at increased risk of retinopathy and macrovascular complications, and have a decreased quality of life and increased disability burden.²⁷ A meta-analysis of 24 studies showed that depression was associated with hyperglycemia in both type 1 and type 2 diabetes mellitus.²⁸

Again, a bidirectional relationship is apparent. In a prospective population-based similar study of 2764 Japanese men, those with MDD or depressive symptoms were at a higher risk of having type 2 diabetes mellitus develop.²⁹ Some studies have shown that insulin resistance accompanies depression, independent of its relation with weight gain. Interestingly, insulin resistance improves with treatment of depression. Remission of depression is also associated with reduced HbA_1c levels in diabetes. These observations were independent of diabetes risk factors of smoking, obesity, alcoholism, and family history of diabetes.

When treating patients with diabetes and depression, psychotherapeutic interventions may be effective. For example, cognitive behavioral therapy (CBT) may result in higher rates of remission of depression. In one study of CBT,³⁰ at 6-month follow-up, the mean HbA_1c level was significantly better in the group that had CBT than in the control group. The presence of diabetic complications and lower compliance with blood sugar monitoring in the CBT group were independent predictors of poor response to CBT. Persistence of depression was associated with higher HbA_1c levels and less adherence to self-management of blood glucose.³⁰

Practically speaking, physicians should be alert for depression when treating patients with diabetes and consider the development of diabetes in patients with depression.

HIV Infection and AIDS
The high prevalence of depression in persons with HIV/AIDS is also well documented. Individuals with HIV/AIDS fall into two groups: those with a primary (idiopathic) mood disorder and those with a secondary organic mood disorder thought to be a consequence of HIV/AIDS. Although depression can occur with any chronic medical illness, persons with HIV/AIDS are prone to depression as a result of the neurotropic effects of the HIV on the subcortical brain structures.³¹ Some authors believe that depressive symptoms increase in the few months before AIDS develops.

Other Medical Illnesses
Similar data demonstrate the link between anxiety, depression, and other common medical illnesses ranging from stroke and Parkinson disease to irritable bowel syndrome, cancer, and fibromyalgia. A recent study analyzing data from the US National Co-morbidity Survey Part II concluded that anxiety disorders were positively associated with medical disorders after adjusting for depression, substance-use disorders, and sociodemographics.³² This conclusion indicates a strong and unique association between anxiety disorders and medical disorders. Indeed, the study noted a stronger association of anxiety disorders and chronic pain syndromes than the association of depression and chronic pain.³³ Thus, depression, anxiety, and chronic medical illness are closely related.

	Case 3 Continued

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Mr Cummings' physician diagnoses MDD. How does he decide what options to use for treatment?

Treatment Considerations
Many factors influence treatment of patients with anxiety and depression comorbid with medical diseases (Figure 3). Effective nonpharmacologic interventions such as exercise for depression, CBT for most anxiety disorders and depression, and education should be offered. Support groups, both in person and via the Internet, may be effective. Although generalizations are difficult, medication choice should avoid drug-drug or drug-disease interactions and meet patient preferences. The SSRIs and selective norepinephrine reuptake inhibitors are thus cornerstones of most pharmacologic approaches.

View larger version (82K): [in this window] [in a new window]   Figure 3. Factors that influence treatment of medically ill patients with comorbid anxiety and depression.

	Comment

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Attention should be paid to enhancing the office environment of care and utilizing the most up-to-date models of collaborative care management of mental disorders and medical illness.³⁸ Physicians should provide regular follow-up through a full 6- to 9-month continuation phase of therapy and consider maintenance therapy. In general, anxiety disorders tend to be more chronic and achieving long-term remission is often challenging without life-long therapy, often with multiple medications, depending on the disorder.³⁹ Treatment of underlying medical problems, restoring function, long-term education of the patient and family, and addressing the complex web of comorbidity often yield outstanding outcomes for the patient and satisfying results for the physician.

	Footnotes

 
Dr Aina has no conflicts of interest to disclose. Dr Susman discloses that he serves as a consultant to and is a member of the speakers bureau of Wyeth Pharmaceuticals, Forest Pharmaceuticals, Inc, and Organon.

This continuing medical education publication is supported by an unrestricted educational grant from Forest Laboratories, Inc.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Aina, Y. Articles by Susman, J. L. Search for Related Content PubMed PubMed Citation Articles by Aina, Y. Articles by Susman, J. L.