Epidemiology

Key Points

Prevalence estimates of mental disorders in the United States continue to find that anxiety and mood disorders are the two most common mental disorders in the general population. Lifetime prevalence for anxiety disorders is estimated at 16.6% to 28.8% (Conway et al., 2006; Kessler et al., 2005a) and for major depression is 14.9% to 16.2% (Kessler et al., 2003). Recent 12-month prevalence rates show a similar stratification, with anxiety disorders most common (18.1%), followed by mood disorders (9.5%). Lifetime prevalence rates of panic disorder and GAD are 4.7% and 5.7%, respectively (Kessler et al., 2005a). Anxiety disorders make up approximately 2% of all office visits to physicians in the United States, but almost 50% occur in primary care settings. In comparison, approximately 40% of patients presenting with anxiety disorders are seen by psychiatrists (Harman et al., 2002).

Major depression remains a common disorder and is associated with substantial symptom severity and role impairment (Kessler et al., 2003). One-year prevalence rates for major depression are approximately 6% in the general population, followed by dysthymia (1.8%) and bipolar disorders (1%-2%). Rates in primary care settings remain substantially higher, with prevalence of 10% or greater (Spitzer et al., 1994), although many of these patients suffer from depressions that are unrecognized by their primary care physician (Schultheis et al., 1999).

Costs

Both anxiety and depressive disorders account for substantial health care costs and thus constitute a major public health and economic concern. Despite an increasing treatment rate of depression in the United States between 1990 and 2000, estimated costs from depression failed to decline and were calculated to be $83.1 billion in 2000, of which $26.1 billion were for direct medical costs, $5.4 billion for suicide mortality costs, and $51.5 billion for work-related costs (Greenberg et al., 2003). Similarly, estimates from the 1990s placed the annual economic burden of anxiety disorders at $63.1 billion (in 1998 dollars), of which nonpsychiatric direct medical costs accounted for 54% of the total, and direct psychiatric care accounted for 31% (Greenberg et al., 1999). Not surprisingly, patients with anxiety disorders are much more likely to see their primary care physicians or utilize emergency services. Patients with pure GAD (i.e., no comorbid medical illnesses), for example, were 1.6 times more likely to have seen a primary care physician four or more times in the past year than those without GAD or depression (Wittchen et al., 2002). Patients with panic disorder were almost twice as likely as controls to have visited an emergency room in the previous 6 months (Roy-Byrne et al., 1999).

Disease Course

Both anxiety and depressive disorders tend to run a chronic course, with waxing and waning symptomatology. Illness severity typically worsens the longer the illness remains untreated. The age of onset for anxiety disorders varies greatly, depending on the specific condition. Specific phobias and separation anxiety, for example, often begin in childhood (median age of onset, 7 years), while panic disorder (median age, 21) and GAD (median age, 31) are typically seen in early to mid-adulthood (Kessler et al., 2005b). In elderly persons (>65 years) the prevalence of all anxiety disorders appears to decline, except for GAD, which is maintained at 4% prevalence and may increase over time (Krasucki et al., 1998). GAD is often a recurring illness in which patients may experience periods of residual symptoms and occasional interepisode remissions (Angst et al., 2009). More than one third of patients with panic disorder have full remission with treatment, but about 20% have an unremitting and chronic course despite treatment (Katschnig and Amering, 1998).

The onset of major depression can occur at any age, although the median age of onset is 30 (Kessler et al., 2005b). Depression is a highly recurrent illness, and each episode increases the likelihood of future episodes. Patients with a single episode have a 50% lifetime chance of recurrence, whereas those with three or more episodes have an almost 100% chance of recurrence without treatment (Eaton et al., 2008). Untreated depressive episodes can last 6 months or longer (Kessler et al., 2003).The Sequenced Treatment Alternatives to Relieve Depression (STAR∗D) study found that a substantial number of patients receiving first-line treatment may require 8 weeks or more of treatment to achieve response or remission (Trivedi et al., 2006). Although most patients will recover from their depressive episode and return to normal functioning with treatment, approximately 15% of patients will continue to have an unremitting course, with worsening psychosocial functioning and higher risk for suicide (Eaton et al., 2008).

Neurobiology and Genetics

The neurobiology of both depressive and anxiety disorders is complex and incompletely understood. In contrast to illnesses such as Parkinson’s or Huntington’s disease, no single area of brain pathology or anatomic lesion has been implicated in the development of anxiety or depression; rather, these illnesses appear to be mediated by dysregulation of complex interactions between neural circuits (Nestler et al., 2002). In depression, most lines of investigation have involved dysregulation of the hypothalamic-pituitary axis (HPA) and hippocampus, along with investigations of neural circuitry mediating mood, reward, sleep, appetite, motivation, and cognition. In particular, hyperactivity of the HPA axis in some depressed patients has been found to lead to hippocampal volume reduction, likely by reduction of brain-derived neurotrophic factor (BDNF) and changes in the mechanisms that mediate BDNF expression. However, whether reduced hippocampal volume is a partial cause or merely a result of depression is currently unclear, and it is not seen in all patients diagnosed with depression. Although epidemiologic studies show that depression appears highly heritable, with some studies showing that 40 to 50% of the risk may be genetic, no one gene appears implicated, and depression likely is the phenotypic expression of multiple genetic vulnerabilities, coupled with environmental stresses (physical/emotional trauma, viral illness), physical factors (e.g., preexisting or comorbid medical illnesses such as hypothyroidism or stroke), and random processes during brain development (Nestler et al., 2002).

Neurobiologic research in anxiety disorders has focused on elucidating the neural networks involved in the fear response, but despite advances in neuroimaging, the exact mechanism of each anxiety disorder has yet to be completely understood. Strategies to understand the neuroanatomic underpinnings of panic disorder have focused on translational research, using conditioned fear in animals as a model for panic attacks in humans. Panic disorder patients may have an especially sensitive fear mechanism involving the central nucleus of the amygdala, the hippocampus, thalamus, hypothalamus, periaqueductal gray region, locus ceruleus, and other brainstem sites (Gorman et al., 2000). Other areas of focus in anxiety disorders have involved investigations into alterations of interoceptive processing of the anterior insula (Mathew et al., 2008). Both the insula and the anterior cingulate cortex (ACC) are thought to be the regions of the brain that form a representation of the visceral state of the body. A heightened sensitivity of this region may underlie the misinterpretation of bodily signals in panic disorder.

Genetic epidemiologic studies have clearly documented that anxiety disorders aggregate in families and that this familial link primarily results from genetic factors (Smoller and Faraone, 2008). First-degree relatives of probands with the major anxiety disorders (panic disorder, social anxiety disorder, specific phobias, OCD) have a fourfold to sixfold increased risk of the index disorders compared to relatives of unaffected probands (Hettema et al., 2001). Genetic studies of GAD suggest that a common genetic susceptibility may apply to “clusters” of anxiety disorders and other comorbid disorders (Norrholm and Ressler, 2009). An overlap of genes may play a role in the development of multiple psychiatric conditions, including anxiety and depression.

Interaction of Depression and Anxiety

Major depression and anxiety are often found together, and each illness complicates the course and outcome of the other. Studies have consistently shown that anxiety disorders are the most frequently occurring comorbid disorder with major depression, with 50% to 60% of major depressed patients with both illnesses (Zimmerman et al., 2002). Anxiety can lead to depression in almost 60% of patients, whereas depression leads to anxiety in only 15% of patients (Mineka et al., 1998). Not surprisingly, the more severe anxiety disorders are more likely to lead to subsequent depression; that is, panic disorder, agoraphobia, OCD, PTSD and GAD more frequently lead to depression compared to either social phobia or simple phobia. In addition, patients with both illnesses often have increased severity of symptoms, increased frequency of episodes (either mood or anxiety episodes), poorer response to treatment, higher suicide rates, a more chronic course, and overall poorer prognosis.

Treatment is complicated by the fewer studies on coexisting depression and anxiety, providing clinicians with a smaller evidence-base for treatment decisions. Patients with comorbid major depressive disorders are half as likely subsequently to recover from panic disorder with agoraphobia or GAD, and comorbid major depression almost doubles the likelihood of recurrence of panic disorder with agoraphobia (Bruce et al., 2005). In addition, children and adolescents with anxiety disorders are at eight times the risk of additional depression (Angold et al., 1999). Practitioners must therefore be aggressive in screening for anxiety disorders in patients reporting depressive symptoms, as well as screening for depression in patients reporting anxiety symptoms.

Interaction of Depression, Anxiety, and Medical Illness

A complex and reciprocal relationship exists between medical illnesses and comorbid anxiety and depressive disorders. Medical illnesses are associated with higher prevalence rates of anxiety and depression, and anxiety and depression are associated with higher rates of comorbid medical illnesses. Studies of patients with diabetes, cancer, stroke, myocardial infarction, HIV-related illness, and Parkinson’s disease have higher rates of depression compared to patients without such illnesses (Katon, 2003a). Common medical disorders seen in primary care settings have high comorbidity with anxiety disorders as well. Cardiovascular disease is associated with a 1.5 times greater risk of both GAD and panic disorder (Goodwin et al., 2008). Patients with back pain or arthritis are almost twice as likely to have panic attacks or GAD (McWilliams et al., 2004), whereas patients with asthma (pediatric or adult) may have a 30% increased likelihood of anxiety disorders (Katon et al., 2004). The prevalence of anxiety and depression in patients with diabetes is more than double that in the general population (Collins et al., 2009). Almost 100% of patients with irritable bowel syndrome will have major depression, GAD, or panic disorder (Lydiard et al., 1993).

Medical illnesses are associated with a higher risk for mood and anxiety disorders, so the presence of these disorders places patients at higher risk for multiple medical conditions. Patients with GAD or panic disorder are almost six times more likely to have a cardiac disorder, three times more likely to have a gastrointestinal (GI) disorder, twice as likely to have respiratory difficulties, and twice as likely to have migraine headaches compared to patients without anxiety disorders (Harter et al., 2003). Depression may be a predictor for the subsequent development of medical illness. Several studies found an association between history of major depression and subsequent development of type II diabetes (Eaton et al., 1996; Kawakami et al., 1999) and coronary artery disease (Rugulies, 2002).

Management of patients with comorbid medical illness and anxiety or depression is complex. Such patients have higher rates of unexplained symptoms than patients without these disorders, even after adjusting for the severity of medical illness (Katon and Walker, 1998). An increasing body of literature suggests that patients with medical illness and comorbid depression/anxiety adapt more poorly to chronic symptoms, such as fatigue or pain, and tend to focus on both symptoms of their physical illnesses and physical symptoms associated with other organ symptoms. Not surprisingly, patients with medical illness and comorbid depression have 50% higher medical costs than patients with medical illness alone (Katon, 2003). Comorbid patients are more functionally impaired and have more lost workdays, poorer quality of life, and higher rates of medical utilization (Simon, 2003). Disease management is also complicated by higher rates of nonadherence to treatment and self-care regimens, as well as higher rates of risk behaviors (e.g., smoking, overeating, sedentary lifestyle). Response to antidepressant treatment may be less robust, as evidenced by patients with cardiovascular disease, stroke, and diabetes (Katon, 2003).

Diagnosis of Mood Disorders

Mood disorders are divided into depressive disorders, bipolar disorders, and disorders based on etiology (i.e., mood disorders caused by general medical conditions and substance-induced mood disorders). For primary care physicians, identification, treatment, and management of depressive disorders are essential. Bipolar disorders, which are typically more complex to identify and treat, are best referred to mental health professionals for ongoing treatment. Therefore, this chapter concentrates on identifying bipolar disorder and distinguishing between unipolar and bipolar depression, but does not delve into the specifics of treating bipolar patients.

The essential feature of a major depressive episode is a period lasting at least 2 weeks during which the patient experiences depressed mood or loss of interest or pleasure in almost all activities, a distinct change in usual self, and clinically significant distress or changes in functioning. It is accompanied by a constellation of other symptoms, such as changes in sleep, eating, energy, motivation, and concentration; difficulty making decisions; and often feelings of hopelessness, worthlessness and guilt (Box 47-1). Patients may ruminate about death, feel that life is not worth living, have thoughts about suicide, may make plans to kill themselves, or make attempts. Many patients complain of memory difficulties, become easily distracted, and describe an inability to think clearly. Patients often pace, wring their hands or have an inability to sit still; conversely, they may become greatly slowed or immobilized. In some patients, irritable mood may predominate more than sadness, or they may have explosive, angry outbursts (Fava and Rosenbaum, 1999). Irritability is especially noted in depressed children and adolescents. In its most severe forms—major depression with psychotic features—patients may hear voices telling them to kill themselves or may develop delusional beliefs, such as having a serious illness despite numerous tests providing no evidence (APA, 2000).

The essential feature of dysthymia is a chronically depressed mood that occurs most days for at least 2 years. Patients may have a variety of other symptoms, such as feelings of inadequacy, generalized loss of interest or pleasure, social withdrawal, feelings of guilt or brooding about the past, and decreased activity, productivity, or effectiveness (Box 47-2). Neurovegetative symptoms such as insomnia or hypersomnia, poor appetite or overeating, low energy, and poor concentration may be present but are less common than in major depressive episodes. These patients may state that they have been depressed for as long as they can remember and cannot recall episodes of recovery or remission of symptoms. In addition, dysthymic patients may periodically have superimposed major depressive episodes, often called “double depression” (APA, 2000).

Bipolar disorder is a chronic mood disorder characterized by the presence of mania (bipolar I disorder) or hypomania and depression (bipolar II disorder). Manic episodes are distinct periods of abnormally and persistent moods that can be euphoric, expansive, or irritable. Although manic patients are often thought to be always euphoric, only about 20% of patients experience pure euphoria; most describe a mix of severe irritability, severe emotional lability, and volatility (Goodwin and Jamison, 2007). Manic patients often have greatly inflated self-esteem, confidence, decreased need for sleep, pressured speech, racing or crowded thoughts, distractibility, increased involvement in goal-directed activities (e.g., starting many projects but being unable to finish any), hypersexuality, and excessive involvement in pleasurable activities with a high potential for painful consequences (APA, 2000). Patients can exert great levels of physical activity, appear tireless, and may become extremely physically agitated. Approximately 60% of bipolar I patients will experience psychosis, which may involve delusions of grandeur (feeling omnipotent, having special powers or “gifts”), persecution, or hallucinations (more often auditory as opposed to visual) (Goodwin and Jamison, 2007). Despite mania being the defining characteristic of the disease, depressed moods tend to predominate, with bipolar I patients experiencing a 3:1 ratio of depression to mania over the course of the illness (Judd et al., 2003).

Primary care physicians are more likely to encounter patients with bipolar II disorder than bipolar I disorder. Bipolar II disorder is characterized by hypomanic and major depressive episodes, although over the course of the illness it is primarily a disease of depression, with depressive episodes predominating over hypomanic episodes by a 37:1 ratio (Judd et al., 2003). Symptoms of hypomanic episodes are similar to full manic episodes, but the severity of manic behaviors is attenuated, and the extreme functional, occupational, and social impairment evident in manic episodes is absent in hypomania. Current DSM-IV-TR criteria require that distinct elevations in mood must be present for at least 4 days, must be clearly different from the patient’s usual nondepressed mood, and must be accompanied by a change in the patient’s usual functioning. Because patients primarily seek help during their depressive episodes and typically do not report hypomanic episodes as abnormal, undiagnosed bipolar disorder remains a major difficulty in primary care settings (Manning et al., 1999). Moreover, bipolar disorder may be more common in primary care settings than in general populations. Of 649 patients being treated for depression in a primary care clinic, 21% screened positive for bipolar disorder (Hirschfeld et al., 2005), whereas 10% of patients screened positive for bipolar disorder in a general medical clinic, although 80% of these patients had been diagnosed with unipolar depression (Das et al., 2005).

Diagnosis of Anxiety Disorders

The essential feature of generalized anxiety disorder is excessive anxiety and worry about a number of events or activities, occurring most days over 6 months. Patients have difficulty controlling the worry, report subjective distress, and may experience difficulties in social or occupational functioning. The intensity, duration, or frequency of the worry is out of proportion to the actual likelihood or impact of the feared event. Patients must have at least three associated physical symptoms, including restlessness, irritability, muscle tension, disturbed sleep, fatigability, and difficulty concentrating. The list of associated symptoms can be thought of as symptoms of inner tension (restlessness or edginess, irritability, muscle tension) and symptoms associated with the fatiguing effects of chronic anxiety (fatigue, concentration difficulties, sleep disturbance) (Box 47-3).

Panic attacks, a collection of distressing physical, cognitive, and emotional symptoms, may occur in a variety of anxiety disorders, such as specific phobias, social phobias, PTSD, and acute stress disorder. Panic attacks are discrete periods of intense fear in the absence of real danger, accompanied by at least 4 of 13 cognitive and physical symptoms (Box 47-4). The attacks have a sudden onset, build to a peak quickly, and are often accompanied by feelings of doom, imminent danger, and a need to escape. Symptoms of panic attacks can include somatic complaints (e.g., sweating, chills), cardiovascular symptoms (pounding heart, accelerated heart rate, chest pain), neurologic symptoms (trembling, unsteadiness, lightheadedness, paresthesias), GI symptoms (choking sensations, nausea), and pulmonary symptoms (shortness of breath). In addition, patients with panic attacks may worry they are dying, “going crazy,” or have the sensation of being detached from reality.

Patients with panic disorder experience recurrent, unexpected panic attacks, followed by at least 1 month of persistent worry that they will suffer another panic attack. Panic disorder patients may begin to avoid places where a prior attack occurred or where help may not be available; such avoidance can lead to the development of agoraphobia and typically worsens their psychosocial functioning (Box 47-5).

Box 47-5 Diagnostic Criteria for Panic Disorder without Agoraphobia

From the American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed, text revision. Washington, DC, APA, 2000.

A. Both (1) and (2):

1. Recurrent and unexpected panic attacks

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