Comorbid anxiety and depression: Epidemiology, clinical manifestations... http://www.uptodate.com/contents/comorbid-anxiety-and-depression-ep...

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Comorbid anxiety and depression: Epidemiology, clinical manifestations, and diagnosis Author Michael Van Ameringen, MD Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Oct 2013. | This topic last updated: Fev 28, 2013. INTRODUCTION Anxiety disorders and depressive disorders are highly prevalent conditions that frequently co-occur. Individuals affected by both anxiety and depressive disorders concurrently have generally shown greater levels of functional impairment, reduced quality of life, and poorer treatment outcomes compared with individuals with only one disorder. Study of the clinical presentation, course, assessment, and diagnosis of these conditions have largely focused on the co-occurrence of depression and generalized anxiety disorder. The diagnosis of these conditions is complicated by the presence of mixed anxiety and mood states as well as substantial overlap in physical and emotional symptoms of the disorders. This topic describes the epidemiology, pathogenesis, clinical manifestations, course, and diagnosis of comorbid anxiety and depression. The treatment of comorbid anxiety and depression is discussed elsewhere. The epidemiology, pathogenesis, clinical manifestations, course, diagnosis, and treatment of individual depressive and anxiety disorders are also described separately. (See "Unipolar depression in adults: Epidemiology, pathogenesis, and neurobiology" and "Clinical manifestations and diagnosis of depression" and "Unipolar depression in adults: Prognosis and course of illness" and "Generalized anxiety disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis" and "Social anxiety disorder: Epidemiology, clinical manifestations, and diagnosis" and "Obsessive-compulsive disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, and diagnosis" and "Panic disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis" and "Agoraphobia in adults: Epidemiology, pathogenesis, clinical manifestations, course, and diagnosis".) EPIDEMIOLOGY Population-based samples There is a high rate of comorbid anxiety and depressive disorders in population-based samples. The lifetime prevalence of anxiety disorders and major depression among adults in the United States (US) has been reported to be 28.8 percent and 16.6 percent, respectively [1]. Three international studies found that depression is significantly associated with every anxiety disorder [1-3], with the highest associations in patients with generalized anxiety disorder (GAD) and the lowest in those with agoraphobia and specific phobias. Lifetime prevalence of comorbid anxiety and depression in the general population is very high. In a recent study of 1783 individuals, 75 percent of those with depression met criteria for an anxiety disorder in their lifetime; 79 percent of those with an anxiety disorder met criteria for lifetime major depression (table 1) [4]. A study found that the 12-month prevalence of comorbid mood and anxiety disorders (3.5 percent) in the Netherlands was higher than the prevalence of a pure mood disorder (ie, a mood disorder without a co-occurring anxiety disorder, eating disorder, or schizophrenia; 3.1 percent) but lower than pure anxiety disorder (7.7 percent) [5]. Of patients with mood disorders, 60.5 percent were diagnosed as having another mental disorder. Anxiety disorders were the most common category of disorders, with a prevalence of 53.4 percent among patients with a co-occurring disorder. In a community sample of 915 women age 42 to 52 years, 10.7 percent reported lifetime history of an anxiety Section Editor Murray B Stein, MD, MPH Deputy Editor Richard Hermann, MD

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disorder and major depression concurrently, 53 percent reported no lifetime history of either disorder, 13.8 percent reported a history of an anxiety disorder alone, and 22.1 percent had a history of depression alone [6]. Clinical samples High rates of comorbidity between anxiety disorders and depression have been observed in samples of patients receiving mental health care. Studies of patients with anxiety disorders have yielded a point prevalence of comorbid depression ranging from 2 to 69 percent, with lifetime rates as high as 81 percent [7-10]. Examples include: In a sample of 1127 outpatients with anxiety disorders, current and lifetime prevalence rates of mood disorders were 57 and 81 percent, respectively [10]. In those with a primary anxiety disorder, 30 percent met criteria for a comorbid mood disorder (major depression and/or dysthymia). The prevalence of comorbid major depression ranged from 3 percent in specific phobia to 69 percent in posttraumatic stress disorder. In a sample of 468 patients with DSM-III-R anxiety disorders, 11 percent suffered from comorbid depression [9]. Prevalence ranged from 4 percent for specific phobias to 36 percent for severe panic disorder with agoraphobia. Small studies of samples of patients with depressive disorders have yielded variations in the point prevalence of comorbid anxiety of 44.7 to 92.1 percent [11-13]. In an analysis of 255 depressed outpatients, 44.7 percent met diagnostic criteria for an anxiety disorder [13]. In a sample of 72 inpatients with major depression, 54.1 percent met diagnostic criteria for at least one anxiety disorder [12]. In a sample of 120 depressed patients who were participating in a genetics study, the odds of having a comorbid anxiety disorder with familial MDD were 6.6 (95% CI, 3.811.4, p<0.001) [14]. Risk factors Analyses of data of 3021 individuals from the Early Developmental Stages of Psychopathology (EDSP) study have been used to assess risk factors, temporal patterns, and longitudinal outcomes of anxiety, depression, and co-occurring anxiety and depressive disorders [15]. A study examined the relationship between risk factors for anxiety disorders compared to depressive disorders and to co-occurring anxiety and depressive disorders [15]. Factors common to both disorder classes were: female gender, perinatal factors, and parental psychiatric history. Risk factors for the co-occurrence were a direct combination of the risk factors for either disorder alone. There were no risk factors detected specific to comorbid anxiety and depression that were not risk factors for the individual disorders as well. The risk of depression in individuals with anxiety disorders was significantly associated with female gender, number of anxiety disorder diagnoses, severity of anxiety disorder at baseline, and the presence of panic attacks [16]. A study found that individuals with social phobia were significantly more likely to develop depression compared to those without the disorder. This effect was greatest for individuals who developed social phobia before the age of 16 years [17]. An epidemiological study of a nationally representative sample of 7076 adults in the Netherlands found the following factors to be associated with co-occurring anxiety and mood disorders compared to either disorder in its pure form [5]: Female gender Younger age (25 to 34 years)

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Lower education level Living alone Unemployment Parental psychiatric history Childhood trauma PATHOGENESIS While our understanding of the etiology of co-occurring anxiety and depression is limited, research has identified similarities between the two disorders in their neurobiology, genetic structure, and presence of neuroticism and harm avoidance. Neurobiology Research findings suggest that mood and anxiety symptoms result from a disruption in the balance of impulses from the brains limbic system. Brain imaging studies have most consistently implicated the amygdala, anterior cingulate cortex, and insula in the pathophysiology of anxiety [18]. As examples, neuroimaging studies in PTSD, social phobia, and specific phobia found significant hyperactivity in the amygdala and insula across all three disorders [19]. Neuroimaging studies in depression have not been as consistent. Evidence suggests abnormal activity levels in the anterior cingulate, dorsolateral, medial and inferior prefrontal cortex, insula, superior temporal gyrus, basal ganglia and cerebellum. The most consistent abnormality across both disorder classes has been found to be hyperactivity within the amygdala. This hyperactivity appears to manifest differently in anxiety and depression. In depressed patients, baseline amygdalar activity is higher than healthy controls; however, in patients with anxiety disorders, amygdalar activation is higher only during provocation tasks [20]. Neuropsychological factors Personality traits and neuropsychological factors may play a role in the risk for co-occurring depression and anxiety disorders. In two, large-scale studies, neuroticism was found to be the strongest and most significant predictor of comorbidity between different disorders, particularly anxiety and depression [21,22]. One of the studies examined whether comorbid anxiety and depression differed from either disorder cluster alone on neuropsychological and genetic dimensions, finding that those with the co-occurring disorders had: Greater impairments in working memory and attention compared with those with an anxiety disorder alone. Higher levels of harm avoidance and neuroticism compared with patients with depression alone, anxiety alone, or substance and alcohol disorders alone. A greater likelihood of having two distinct genetic markers for harm avoidance (catecholO-methyltransferase [COMT] Met158 and brain derived neurotrophic factor [BDNF] Met66) compared with either disorder alone [23]. Genetics Two studies suggest that the comorbidity between anxiety (generalized anxiety disorder [GAD] in particular) and depressive disorder could be explained in part by similarities in genetic structure. A study of more than 5600 same-sex twin pairs attempted to decipher the heritability of common psychiatric disorders [24]. Multivariate twin modeling analysis was used to examine clustering of DSM-III-R symptoms. Vulnerability to these phenotypes could be grouped into two clusters for anxiety and depression. The first cluster described risk for depression and generalized anxiety disorder while the second cluster described a broad risk for phobic disorders. Risk for panic disorder was shared by both clusters. Another analysis of same-sex twin pairs from the Virginia Twin Study showed a similar two factor structure, with GAD, panic, agoraphobia and, to some extent, social anxiety disorder in one cluster and specific phobias in another [25]. Twin studies have suggested that the anxiety disorders and major depression were distinct entities and not simply phases of the same disease [26]. A possible explanation for the comorbidity between anxiety and depression is a common genetic etiology and the presence of neuroticism with environmental factors playing a small role [26]. Conceptual issues Anxiety and depression overlap in some cognitive components and clinical symptoms (table 2). In the tripartite model of emotion, a prevailing conceptual theory for emotional disorders, anxiety, and 3 de 24 02/12/2013 05:02

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depression can be deconstructed into three principal components: negative affect, physiologic hyperarousal, and low positive affect [27]. Negative affect encompasses a wide range of negative emotional responses from fear and distress to disgust and anger. Negative affect is seen in both anxiety and depression. Low positive affect describes a state lacking positive emotional responses, such as happiness or pleasure. Positive emotional responses are absent in depression, but not in anxiety disorders. Physiologic hyperarousal is characteristic of anxiety disorders but not depression. Signs and symptoms include excessive agitation, edginess, and feeling keyed up or tense. Overlap between anxiety and depression can be partially explained by the shared concept of negative affect. This conceptualization was supported in a study of outpatients with moderate levels of psychopathology and DSM-III diagnoses of major depression (262 patients), dysthymia (82), panic disorder (156), or generalized anxiety disorder (79) [28]. Factor analysis found 12 symptom components. Depression was best explained by the presence of: Negative self-view Anhedonia Dysphoria Anxiety was best explained by the presence of: Panic attacks Threatening thoughts Subjective worry and tension Negative affect (eg, anhedonia, worry, and tension) was shared by both depression and anxiety. Physiologic hyperarousal (panic attacks) was unique to anxiety. Low positive affect (dysphoria) was unique to depression. Among all the factors, negative self-view had the largest influence, accounting for 17.1 percent of the variance seen in anxiety and depression. The study showed areas of symptom overlap between anxiety and depression. Using the factor structure to predict each diagnosis, strong reliability was found for major depression and panic disorder. However, two-thirds of those diagnosed with GAD were misclassified as having panic disorder or major depression, indicating substantial overlap in symptoms. A similar pattern of symptom overlap in major depression and anxiety disorders has been seen in other outpatient samples. An analysis of mean scores on anxiety and depression rating scales in 126 outpatients referred to an anxiety specialty clinic found substantial overlap between the two disorder classes [29]. Patients with major depression scored significantly higher on the anxiety scale than those with social phobia. Patients with major depression and patients with OCD had the highest scores on the depression rating scale, with no differences observed among patients with one of the other anxiety disorders. CLINICAL MANIFESTATIONS Study of the clinical presentation of anxiety co-occurring with depression has largely focused on symptoms of generalized anxiety disorder (table 3). Co-occurring generalized anxiety disorder (GAD) and depression can present on a continuum, from principally anxiety symptoms to mixed anxiety and depression, to principally depressive symptoms. Some of the symptoms of GAD and depression are characteristic of both disorders, while others are specific to GAD or depression [30]: Symptoms specific to depression: Loss of interest Weight change Poor appetite

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Motor retardation Guilt or worthlessness Thoughts of death Symptoms common to GAD and depression: Dysphoric mood Irritability Agitation or restlessness Concentration difficulties Insomnia Fatigue Symptoms specific to GAD: Excessive worry Autonomic hyperactivity Exaggerated startle response Muscle tension COURSE Comorbid anxiety (symptoms of generalized anxiety disorders or GAD) and depressive disorders have been found to differ from the individual disorder categories in age of onset [1,13,31], life course [32], and treatment outcome. Presence of both disorders together significantly decreases the odds of recovery, increases the time to therapeutic onset for pharmacotherapy [1,15], and is associated with a more chronic course [33]. However, the course of the co-occurring conditions can be complex. Onset and life course Age of onset patterns for anxiety and mood disorders appear distinct. In a 2005 nationally representative epidemiological study in the US, the median age of onset was 11 years for anxiety disorders and 30 years for mood disorders [1]. Data from the Early Developmental Stages of Psychopathology (EDSP) study found that [15]: Onset of anxiety was most likely to occur early in life, with few new cases after age 20 Prevalence of major depression increased significantly after age 20 Age of onset for comorbid anxiety and depressive disorders varied depending on which disorder class was used as the indexing disorder. For an anxiety disorder with comorbid depression, age of onset for the comorbid conditions closely followed that of an anxiety disorder alone. The age of onset for a depressive disorder and comorbid anxiety disorder closely followed that of a depressive disorder alone. Age of onset appears to vary by anxiety disorder. Subsequent EDSP analysis with additional follow-up data found that age of onset for GAD, panic disorder, and agoraphobia was generally in adolescence and early adulthood (similar to depression), while social anxiety disorder and specific phobias began in early childhood [31]. In a study of 255 depressed outpatients, 44.7 percent met diagnostic criteria for an anxiety disorder. The onset of both social anxiety disorder and GAD was more likely to precede the development of major depression, with the opposite being true for obsessive-compulsive disorder, panic disorder, agoraphobia, and simple phobias [13]. Co-occurrence of anxiety and depression is associated with a more chronic course compared with either disorder alone [33]. Analysis of data from a nationally representative epidemiologic study in the US found that, compared with individuals without GAD, patients with a primary lifetime diagnosis of GAD had an increased likelihood of both subsequent onset and persistence of a major depressive episode (MDE). A primary lifetime diagnosis of a MDE predicted the onset but not persistence of GAD. The study found that a temporal association between a MDE and GAD was highest among respondents aged 15 to 24 years. More than one-third of individuals with co-occurring MDE and GAD experienced the onset of both disorders within the same year. Despite the more chronic

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presentation, few differences in functional impairment have been observed between comorbid anxiety and depression and either disorder alone [13]. Depression is generally episodic in nature with modest rates of recovery, but rates of relapse are high. Anxiety disorders conversely tend to be chronic and unremitting, with low levels of recovery and moderate levels of relapse [32]. Co-occurring anxiety disorders and depression may have a worse course than the anxiety disorder alone: In a 12-year prospective study of patients with GAD or panic disorder with or without agoraphobia, those with comorbid major depression were half as likely to recover, compared with either disorder alone [32]. Data from the National Epidemiologic Survey of Alcohol and Related Conditions study indicated that those with GAD and major depression were significantly more impaired in perceived mental health quality and social functioning, compared with those with GAD alone [34]. A 15-year prospective analysis found that prevalence of anxiety and depression together did not change over the course of the study, while prevalence of anxiety alone and depression alone increased over time [35]. This finding suggests that comorbid anxiety and depression is a more stable condition than either disorder alone. Once comorbidity develops, it is unlikely that an individual will experience a recurrence of either disorder alone, particularly anxiety. In a community sample of 915 women age 42 to 52 years, women with a lifetime history of a co-occurring anxiety disorder and major depression were more likely to report a history that included recurrent major depression, multiple lifetime anxiety disorders, higher rates of treatment-seeking, and current elevations in current anxiety and depressive symptoms, compared with women without a history of a anxiety disorder or major depression occurring concurrently or separately [6]. Treatment response The presence of both depression and anxiety appears to have a poorer response to treatment than either disorder individually: In the Sequenced Treatment Alternative to Relieve Depression (STAR*D) trial, outpatients with anxious depression (ie, a diagnosis of major depression and a anxiety/somatization subscale score greater than seven on the Hamilton Rating Scale for Depression) had significantly lower response and remission rates, compared with patients with non-anxious depression [36]. Depressed patients with anxiety took longer to improve than depressed patients without anxiety [37]. In multiple clinical trials of patients diagnosed with anxiety disorders (GAD, panic disorder, social anxiety disorder, and OCD), the presence of co-occurring depression has been associated with poorer response of the anxiety disorder to pharmacotherapy and psychotherapy, compared with those with the anxiety disorders alone [38-42]. These trials suffered from several methodologic limitations, including that participants with comorbid depression had more severe symptoms of anxiety at baseline in some of the trials. Findings on functional outcomes and change in depressive symptoms were mixed. ASSESSMENT AND DIAGNOSIS A diagnostic assessment for potential co-occurring anxiety disorders and depressive disorders should include careful patient history, a complete physical examination, and appropriate laboratory studies. The medical history should address medical illnesses, medication side effects, and substance abuse that can produce anxiety or anxiety-like symptoms (table 4 and table 5) or depressive symptoms. (See "Unipolar depression in adults: Epidemiology, pathogenesis, and neurobiology", section on 'Secondary depression'.) The psychosocial history should screen for stressful life events, family psychiatric history, current social history, substance abuse history (including caffeine, nicotine, and alcohol), and past sexual, physical, and emotional abuse, or emotional neglect. Diagnosis of co-occurring depressive and anxiety disorders is based on DSM-IV-TR criteria for the individual disorders [43]. Two syndromes mixed anxiety and depression, and anxious depression include symptoms of anxiety, depression or both that are beneath the threshold required by DSM-IV-TR criteria for individual anxiety or depressive disorders. These emerging constructs may prove to be clinically useful, but require further research.

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Co-occurring depression and anxiety Major depressive disorder (MDD) (table 6) Dysthymia (table 7) Generalized anxiety disorder (GAD) (table 3) Obsessive-compulsive disorder (table 8) Panic disorder (table 9) Social anxiety disorder (table 10) Posttraumatic stress disorder (table 11) Specific phobia (table 12) Agoraphobia (table 13) Mixed anxiety and depression Mixed anxiety and depression (MAD) has been defined in the International Classification of Diseases, 10th Revision (ICD-10) as a condition where the symptoms of both anxiety and depression are present for at least one month, with neither being clearly predominant nor sufficient to meet diagnostic criteria for either an anxiety or a depressive disorder [44]. ICD-10 does not provide additional criteria for diagnosing the disorder. Mixed anxiety and depression appears in the appendix of DSM-IV-TR as a proposed disorder for further study [45], with proposed diagnostic criteria including: A four-week history of dysphoric mood Four of 10 specific symptoms of anxiety or depression Significant impairment The symptoms are not induced by a medical condition, medication or substances Meeting current criteria for another mood or anxiety disorder or meeting past criteria for MDD, GAD or panic disorder would exclude an individual from a diagnosis of MAD While not frequently observed in clinical psychiatric settings [46], data on the prevalence of MAD in primary care settings are mixed. An epidemiologic study in Munich, Germany found a rate of 0.8 percent in the general population for MAD using diagnostic criteria based on ICD-10 principles [46]. The low rate was surprising given that the rates of subthreshold DSM-III anxiety and depression were 21.9 percent and 2.4 percent respectively. Patients with MAD had significantly more psychosocial impairments, remitted less, and showed greater help-seeking behavior compared with those with anxiety or depression alone. In 78 primary care patients without known psychiatric illness, assessment with a structured clinical interview showed that 12.8 percent of the sample met criteria for MAD [47]. The functional impairment associated with a diagnosis of MAD was comparable to the impairment experienced by individuals with full-syndromal anxiety or depressive disorders. In a sample of 1634 primary care patients, a structured assessment found that 0.2 percent met the DSM-IV-TR proposed criteria for MAD. The degree of functional impairment did not differ between individuals with MAD and those with an anxiety disorder only. At six and 12-month follow-up assessments of patients diagnosed with MAD, remission rates were 70 and 8 percent, respectively. The study suggests that the diagnosis of DSM-IV MAD may not be stable over time [48]. A study of 65 primary care patients who screened positive for symptoms of anxiety and depression at an office visit identified 37 patients who did not meet criteria for an anxiety or depressive disorder [49]. None of the 37 patients reported, when asked, that the symptoms of depression and anxiety significantly interfered with their functioning. These findings do not support the need for an additional diagnosis of mixed anxietydepression disorder beyond the mood and anxiety disorders in DSM-IV-TR. Anxious depression A proposed disorder, anxious depression, combines criteria of a major depressive episode with an anxiety/somatization subscale score greater than seven on the Hamilton Rating Scale for Depression (HAM-D). Analyses of data from the Sequenced Treatment Alternative to Relieve Depression (STAR*D) clinical effectiveness trial [36,50] support establishing this diagnosis. In an analysis of data on 1450 outpatients meeting DSM-IV-TR criteria for major depression, 46 percent had a

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HAM-D anxiety/somatization subscale score 7. Compared with depressed patients without high levels of anxiety, these patients were more likely to be [50]: Older Less educated Severely depressed Suicidal Their rates of treatment response and remission were significantly lower, with a greater time to the onset of a clinical response [37]. The absence of agreed upon diagnostic criteria for anxious depression has hindered study of this group. Further research is needed to determine whether anxious depression is a clinically relevant subtype of major depression. Differential diagnosis The differential diagnoses of individual anxiety disorders and depressive disorders are described separately. (See "Unipolar depression in adults: Epidemiology, pathogenesis, and neurobiology" and "Clinical manifestations and diagnosis of depression" and "Unipolar depression in adults: Prognosis and course of illness" and "Generalized anxiety disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis" and "Social anxiety disorder: Epidemiology, clinical manifestations, and diagnosis" and "Obsessive-compulsive disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, and diagnosis" and "Panic disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis" and "Agoraphobia in adults: Epidemiology, pathogenesis, clinical manifestations, course, and diagnosis".) A table distinguishes among symptoms shared by depression and GAD, symptoms specific to depression, and symptoms specific to GAD (table 2). Diagnostic reliability Given the overlap in DSM-IV diagnostic criteria for depression and anxiety disorders, the accuracy of diagnosis of these disorders has been questioned, and study findings have been mixed: A study of clinical diagnosis in 362 outpatients found good to excellent inter-rater reliability for the disorders [51]. Structured interviews were conducted by clinical psychologists and advanced graduate students. A cross-sectional study found evidence of poor diagnostic accuracy in clinical samples of 666 patients with pure GAD, 772 pure with a major depressive episode, and 278 with co-occurring GAD and major depression [52]. Primary care clinicians made accurate diagnoses in only 34 percent of patients with GAD and 64 percent of patients with a major depressive episode. Rating scales Scales that have demonstrated good reliability and validity in the assessment of anxiety and depression, either presenting individually or co-occurring, include the following: Depression and anxiety The Depression and Anxiety Stress Scale (DASS) is potentially the most useful instrument for the assessment of patients with co-occurring depression and GAD symptoms, or when discrimination among mixed anxiety and depressive symptoms is unclear [53]. DASS has been shown to be reliable, accurate in its assessment of global anxiety, and able to separate anxiety and depressive symptoms. Depression The Montgomery Asberg Depression Rating Scale (MADRS) has been shown to be superior to other clinician-administered instruments, best capturing DSM-IV-TR symptoms of depression [54]. It has demonstrated excellent discrimination between depressed and non-depressed individuals [55], and between self-assessed depression and personality disorders [56]. It has also demonstrated good reliability and validity in elderly populations [57]. Generalized anxiety The Hamilton Rating Scale for Anxiety (HAMA) is the gold standard measure for the assessment of GAD symptom severity. This scale is reliable and valid, particularly when used with a structured interview guide [58]. The HAMA has demonstrated good ability to discriminate between anxiety and depression [59]. OCD The Yale Brown Obsessive Compulsive Scale (YBOCS) has shown good discrimination between OCD and depression as well as other anxiety disorders in initial validation study, and good sensitivity to

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change [60,61]. The self-report adaptation of the 10-item YBOCS scale and symptom checklist has shown similar reliability patterns [62]. Panic disorder The most commonly used observer-rated scale for panic disorder is the seven-item Panic Disorder Severity Scale (PDSS), which has demonstrated good inter-rater reliability and internal consistency with favorable validity and sensitivity to change when compared to diagnostic interview [63,64]. PTSD The Clinician Administered PTSD Scale (CAPS) has emerged as the most widely used instrument in clinical trials and has proven to be both an effective assessment tool and severity measure, despite substantial correlation with other measures of depression and anxiety [65]. Despite their wide use, the State Trait Anxiety Inventory (STAI) and the Hamilton Rating Scale for Depression (HAMD) have been criticized for an inability to distinguish between anxious and depressive symptoms [66-69]. SUMMARY AND RECOMMENDATIONS Population-based studies conducted in several countries have shown high rates of co-occurrence between associations between anxiety disorders and mood disorders. Mood disorders have shown the highest correlations with generalized anxiety disorder (GAD) and the lowest with agoraphobia and specific phobias (table 1). (See 'Epidemiology' above.) Research has found that patients with co-occurring anxiety and mood disorders were more likely to be female, younger (25 to 34 years), have a lower education level, live alone, be unemployed, have a parental psychiatric history, and to have experienced childhood trauma than those with purely an anxiety or mood disorder. (See 'Risk factors' above.) While our understanding of the etiology of co-occurring anxiety and depression is limited, research has identified similarities between the two disorders in their neurobiology, genetic structure, and presence of neuroticism and harm avoidance. (See 'Pathogenesis' above.) Co-occurring anxiety and depressive disorders have been found to differ from the individual disorder categories in age of onset, life course, and treatment outcome. Presence of both disorders together significantly decreases the odds of recovery, increases the time to therapeutic onset for pharmacotherapy, and is associated with a more chronic course. (See 'Course' above.) Clinical manifestations of comorbid anxiety and depression are often complex. Both anxiety and depressive disorders present overlapping symptoms including irritability, agitation/restlessness, difficulties concentrating, insomnia, and fatigue (table 2). (See 'Clinical manifestations' above.) Diagnosis of co-occurring depressive and anxiety disorders is based on DSM-IV-TR criteria for the individual disorders. Further research is needed on two proposed disorders, mixed anxiety and depression, and anxious depression, both of which incorporate symptoms of anxiety or depression below thresholds required by individual DSM-IV-TR depressive and anxiety disorders. (See 'Assessment and diagnosis' above.) Use of UpToDate is subject to the Subscription and License Agreement. Topic 14623 Version 2.0

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GRAPHICS Prevalence of comorbid depression in anxiety disorders (data from large epidemiological surveys)
Author/year
Schneier et al. 1992 [1] Flint 1994 [2] Wittchen et al. 1994 [3] Kessler et al. 1995 [4] Magee et al. 1996 [5]

Population/study
ECA ECA SAD

Anxiety disorder

Prevalence of comorbid MDD

16.6% (lifetime) 21% (12-month) 60% (12-month) 38.6% (30 day GAD); 62.4% (lifetime) 47.9% (males, lifetime); 48.5% (females, lifetime) 37.2% (lifetime) 45.9% (lifetime) 42.3% (lifetime) 59% (12-month) 14.5% (all 12-month) 37.1% 7.8% 29.8% 15.5% 15.5% 30.4% (2 weeks) 9.4% (2 weeks) 7.7% (all 12-month) 15% 7.3% 9% 3% 14.4% 49.7% (12-month) 40.7% (lifetime) 58.1% (12-month) 69.7% (12-month)

All anxiety disorders GAD

NCS NCS

GAD PTSD

NCS

SAD AGOR SP

Lieb et al. 2005 [6] Alonso et al. 2007 [7]

ESEMeD ESEMeD

GAD SAD GAD PTSD PD AGOR SP

Eisenberg et al. 2007 [8]

WHO

GAD PD

Gabilondo et al. 2010 [9]

ESEMeD

AD GAD PTSD PD AGOR SP

Kessler et al. 2010 [10] 2010 [11] Ruscio et al. Kessler et al. 1999 [12]

WHO NCS-R NCS MDUSS

Any anxiety disorder OCD GAD

ECA: Epidemiologic Catchment Area Study; NCS: National Comorbidity Survey; ESEMeD: European Study of the Epidemiology of Mental Disorders; WHO: World Health Organization Mental Health Survey Initiative;

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NCS-R: National Comorbidity Survey-Replication; MDUSS: Midlife Development in the United States Survey; AGOR: agoraphobia; GAD: generalized anxiety disorder; PD: panic disorder; PTSD: posttraumatic stress disorder; OCD: obsessive-compulsive disorder; SP: specific/simple phobia; SAD: social anxiety disorder; %: percent. References: 1. Schneier FR, Johnson J, Hornig CD, Liebowitz MR, Weissman MM. Social phobia. Comorbidity and morbidity in an epidemiologic sample. Arch Gen 49:282, 1992. 2. Flint AJ. Epidemiology and Comorbidity of Anxiety Disorders in the Elderly. Am J Psychiatry 151:640, 1994. 3. Wittchen HU, Zhao SY, Kessler RC, Eaton WW. Dsm-Iii-R Generalized Anxiety Disorder in the NationalComorbidity-Survey. Arch Gen Psychiatry 51:355, 1994. 4. Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic-Stress-Disorder in the National Comorbidity Survey. Arch Gen Psychiatry 52:1048, 1995. 5. Magee WJ, Eaton WW, Wittchen HU, McGonagle KA, Kessler RC. Agoraphobia, simple phobia, and social phobia in the national comorbidity survey. Arch Gen Psychiatry 53:159, 1996. 6. Lieb R, Becker E, Altamura C. The epidemiology of generalized anxiety disorder in Europe. European Neuropsychopharmacology 15:445, 2005. 7. Alonso J, Lpine JP, ESEMeD/MHEDEA 2000 Scientific Committee. Overview of key data from the European Study of the Epidemiology of Mental Disorders (ESEMeD). J Clin Psychiatry 68 Suppl 2:3, 2007. 8. Eisenberg D, Gollust SE, Golberstein E, Hefner JL. Prevalence and correlates of depression, anxiety, and suicidality among university students. Am J Orthopsychiatry 77:534, 2007. 9. Gabilondo A, Rojas-Farreras S, Vilagut G, Haro JM, Fernandez A, Pinto-Meza A, et al. Epidemiology of major depressive episode in a southern European country: Results from the ESEMeD-Spain project. J Affect Disord 120:76, 2010. 10. Kessler RC, Birnbaum HG, Shahly V, et al. Age differences in the prevalence and co-morbidity of DSM-IV major depressive episodes: results from the WHO World Mental Health Survey Initiative. Depress Anxiety 27:351, 2010. 11. Ruscio AM, Stein DJ, Chiu WT, Kessler RC. The epidemiology of obsessive-compulsive disorder in the National Comorbidity Survey Replication. Mol Psychiatry 15:53, 2010. 12. Kessler RC, DuPont RL, Berglund P, Wittchen HU. Impairment in pure and comorbid generalized anxiety disorder and major depression at 12 months in two national surveys. Am J Psychiatry 156:1915, 1999.

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Distinctive and overlapping symptoms of depression and anxiety

Symptoms specific to depression
Depressed or hopeless Loss of interest Weight change Poor appetite Motor retardation Guilt/worthlessness Thoughts of death
Reproduced from: Kendall PC, Watson D. Anxiety and Depression: distinctive and overlapping features, Academic Press, San Diego, CA 1989. Table used with the permission of Elsevier Inc. All rights reserved.

Symptoms common to anxiety and depression

Irritability Agitation/restlessness Concentration difficulties Insomnia Fatigue

Symptoms specific to anxiety

Excessive worry Autonomic hyperactivity Exaggerated startle response Muscle tension

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Diagnostic criteria for generalized anxiety disorder

1. Excessive anxiety and worry about a number of events or activities, occurring more days than not for at least six months, that are out of proportion to the likelihood or impact of feared events. 2. The worry is pervasive and difficult to control. 3. The anxiety and worry are associated with three (or more) of the following six symptoms (with at least some symptoms present for more days than not for the past six months):
Restlessness or feeling keyed up or on edge Being easily fatigued Difficulty concentrating or mind going blank Irritability Muscle tension Sleep disturbance (difficulty falling or staying asleep, or restless unsatisfying sleep)

4. The anxiety, worry, or physical symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
Adapted from Diagnostic and Statistical Manual of Mental Disorders, 4th Ed, Primary Care Version (DSM-IV-PC). American Psychiatric Association, Washington, DC 1995.

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Physical causes of anxiety-like symptoms

Cardiovascular
Angina pectoris, arrhythmias, heart failure, hypertension, hypovolemia, myocardial infarction, syncope (multiple causes), valvular disease, vascular collapse (shock)

Dietary
Caffeine, monosodium glutamate (Chinese restaurant syndrome), vitamin-deficiency diseases

Drug-related
Akathisia (secondary to antipsychotic drugs), anticholinergic toxicity, digitalis toxicity, hallucinogens, hypotensive agents, stimulants (amphetamines, cocaine, related drugs), withdrawal syndromes (alcohol, sedative-hypnotics), bronchodilators (theophylline, sympathomimetics)

Hematologic
Anemias

Immunologic
Anaphylaxis, systemic lupus erythematosus

Metabolic
Hyperadrenalism (Cushing's disease), hyperkalemia, hyperthermia, hyperthyroidism, hypocalcemia, hypoglycemia, hyponatremia, hypothyroidism, menopause, porphyria (acute intermittent)

Neurologic
Encephalopathies (infectious, metabolic, toxic), essential tremor, intracranial mass lesions, postconcussive syndrome, seizure disorders (especially of the temporal lobe), vertigo

Respiratory
Asthma, chronic obstructive pulmonary disease, pneumonia, pneumothorax, pulmonary edema, pulmonary embolism

Secreting tumors
Carcinoid, insulinoma, pheochromocytoma
Adapted from: Rosenbaum, JF, N Engl J Med 1982; 306:401.

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Drugs that cause anxiety-like symptoms

Stimulants
Amphetamine Aminophylline Caffeine Cocaine Methylphenidate Theophylline

Anticholinergics
Benztropine mesylate (Cogentin) Diphenhydramine (Benadryl) Meperidine (Demerol) Oxybutynin (Ditropan) Propantheline (Pro-Banthine) Tricyclics Trihexyphenidyl (Artane)

Sympathomimetics
Ephedrine Epinephrine Phenylpropanolamine Pseudoephedrine

Dopaminergics
Amantadine Bromocriptine Levodopa (L-dopa) Levodopa-carbidopa (Sinemet) Metoclopramide Neuroleptics

Drug withdrawal
Barbiturates Benzodiazepines Narcotics Alcohol Sedatives

Miscellaneous
Baclofen Cycloserine Hallucinogens Indomethacin

Adapted from Goldberg, RJ. Practical Guide to the Care of the Psychiatric Patient. Mosby Year Book, St. Louis 1995.

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DSM-IV-TR diagnostic criteria for major depression

A. Five (or more) of the following symptoms have been present during the same 2-week period, and represent a change from previous functioning. At least one of the symptoms is either depressed mood or loss of interest or pleasure.
(Note: Do not include symptoms that are clearly due to a general medical condition, or mood-incongruent delusions or hallucinations.) Depressed mood most of the day, nearly every day (or alternatively can be irritable mood in children and adolescents) Markedly diminished interest or pleasure in all, or almost all, activities, nearly every day Significant weight loss while not dieting, weight gain, or decrease or increase in appetite Insomnia or hypersomnia nearly every day Psychomotor agitation or retardation nearly every day Fatigue or loss of energy nearly every day Feelings of worthlessness or excessive or inappropriate guilt nearly every day Diminished ability to think or concentrate, or indecisiveness, nearly every day Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide

B. The symptoms do not meet criteria for a Mixed Episode. C. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. D. The symptoms are not due to the direct physiological effects of substance or a general medical condition. E. The symptoms are not better accounted for by Bereavement, ie, after the loss of a loved one, the symptoms persist for longer than two months or are characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation.
Adapted from American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision. American Psychiatric Association, Washington, DC 2000.

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DSM-IV-TR diagnostic criteria for dysthymic disorder

A. Depressed mood for most of the day, for more days than not, as indicated either by subjective account or observation by others, for at least 2 years. NOTE: In children and adolescents, mood can be irritable and duration must be at least 1 year. B. Presence, while depressed, of two (or more) of the following: 1. Poor appetite or overeating 2. Insomnia or hypersomnia 3. Low energy or fatigue 4. Low self-esteem 5. Poor concentration or difficulty making decisions 6. Feelings of hopelessness C. During the 2-year period (1 year for children or adolescents) of the disturbance, the person has never been without the symptoms in criteria A and B for more than 2 months at a time. D. No major depressive episode has been present during the first 2 years of the disturbance (1 year for children and adolescents); ie, the disturbance is not better accounted for by chronic major depressive disorder, or major depressive disorder, in partial remission. NOTE: There may have been a previous major depressive episode provided there was a full remission (no significant signs or symptoms for 2 months) before development of the dysthymic disorder. In addition, after the initial 2 years (1 year in children or adolescents) of dysthymic disorder, there may be superimposed episodes of major depressive disorder, in which case both diagnoses may be given when the criteria are met for a major depressive episode. E. There has never been a manic episode, a mixed episode, or a hypomanic episode, and criteria have never been met for cyclothymic disorder. F. The disturbance does not occur exclusively during the course of a chronic psychotic disorder, such as schizophrenia or delusional disorder. G. The symptoms are not due to the direct physiological effects of a substance (eg, a drug of abuse, a medication) or a general medical condition (eg, hypothyroidism). H. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, (Copyright 2000). American Psychiatric Association.

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Diagnostic criteria for obsessive-compulsive disorder

1. Either obsessions or compulsions
Obsessions Recurrent thoughts, impulses or images that cause marked anxiety or distress, are experienced as intrusive, go beyond excessive worry about real-life problems, and are not related to another mental disorder (eg, are not limited to thoughts about food in a person with anorexia nervos a). Compulsions Ritualistic behaviors or mental acts that are performed in response to an obsession or need to be rigidly carried out. These behaviors are excessive and performed to decrease anxiety or distress or avoid some dreaded event, but they are not realistically connected to those dreaded events.

2. The obsessions or compulsions are time-consuming (more than one hour per day), cause clinically significant distress, or interfere with a person's daily routine and occupational or social functioning.
Adapted from Diagnostic and Statistical Manual of Mental Disorders, 4th Ed, Primary Care Version (DSM-IV-PC). American Psychiatric Association, Washington, DC 1995.

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Diagnostic criteria for panic attack and panic disorder

Panic attack (summary of DSM-IV criteria)
A discrete period of intense fear or discomfort, in which four (or more) of the following symptoms develop abruptly and reach a peak within ten minutes: Cardiopulmonary symptoms Chest pain or discomfort Sensations of shortness of breath or smothering Palpitations, pounding heart, or accelerated heart rate Neurological symptoms Trembling or shaking Parasthesias (numbness or tingling sensation) Feeling dizzy, unsteady, light-headed or faint Psychiatric symptoms Derealization (feelings of unreality) or depersonalization (being detached from oneself) Fear of losing control or going crazy Fear of dying Autonomic symptoms Sweating Chills or hot flushes Gastrointestinal symptoms Feeling of choking Nausea or abdominal distress

Panic disorder (summary of DSM-IV criteria)

With agoraphobia A. Recurrent, unexpected panic attacks. B. At least one of the attacks has been followed by a month or more of: persistent concern about having additional attacks; worry about the implications of the attack or its consequences; a significant change in behavior related to the attacks. C. The presence of agoraphobia, ie, anxiety about being in places or situations in which escape might be difficult (or embarrassing) or in which help might not be available in the event of having a panic attack. Without agoraphobia A. Both A and B above B. Absence of agoraphobia
Adapted from Diagnostic and Statistical Manual of Mental Disorders, 4th Ed, Primary Care Version (DSM-IV-PC). American Psychiatric Association, Washington, DC 1995.

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DSM-IV-TR criteria for social anxiety disorder

A marked and persistent fear of one or more social or performance situations involving exposure to unfamiliar people or possible scrutiny by others. The person fears that he or she will act in a way (or show symptoms of anxiety) that will be humiliating or embarrassing. Exposure to the feared social situation almost invariably provokes anxiety, which may take the form of a panic attack. The person recognizes that the fear is excessive or unreasonable. The feared social or performance situations are avoided or endured with intense anxiety or distress. The condition interferes significantly with the person's normal routine, occupational (or academic) functioning, or social activities or relationships, or there is marked distress about having the phobia. The fear or avoidance is not due to the direct physiological effects of a substance or a general medical condition and is not better accounted for by another mental disorder. If a general medical condition or another mental disorder is present, the social or performance fear is unrelated to it (eg, the fear is not of trembling in Parkinson's disease).

Specify the disorder as "generalized" if fears include most social situations.

Reprinted with permission from: the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (Copyright 2000). American Psychiatric Association.

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Diagnostic criteria for posttraumatic stress disorder

Criterion A: The person has been exposed to a traumatic event in which both of the following were present:
1. The person experienced, witnessed or was confronted with an event or events that involved actual or threatened death or serious injury, or a threat to the physical integrity of self or others. 2. The person's response involved intense fear, helplessness or horror. Note: in children this may be expressed instead by disorganized or agitated behavior.

Criterion B: The traumatic event is persistently reexperienced in one (or more) of the following ways:
1. Recurrent and intrusive distressing recollections of the event, including images, thoughts, or perceptions. Note: in young children, repetitive play may occur in which themes or aspects of the trauma are expressed. 2. Recurrent distressing dreams of the event. Note: in children there may be frightening dreams without recognizable content. 3. Acting or feeling as if the traumatic event were recurring (including a sense of reliving the experience, illusions, hallucinations and dissociative flashback episodes, including those that occur on wakening or when intoxicated). Note: in young children trauma-specific reenactment may occur. 4. Intense psychological distress and/or physiological reactivity on exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event.

Criterion C: Persistent avoidance of stimuli associated with the trauma and numbing of general responsiveness (not present before the trauma), as indicated by three (or more) of the following:
1. Efforts to avoid thoughts, feelings or conversations associated with the trauma 2. Efforts to avoid activities, places or people that arouse recollections of the trauma 3. Inability to recall an important aspect of the trauma 4. Markedly diminished interest in participating in significant activities 5. Feeling detached or estranged from others 6. Restricted range of effect (eg, unable to have loving feelings) 7. Sense of a foreshortened future (eg, does not expect to have a career, marriage, children, or a normal life span)

Criterion D: Persistent symptoms of increased arousal (not present before trauma), as indicated by two (or more) of the following:
1. Difficulty falling or staying asleep 2. Irritability or outbursts of anger 3. Difficulty concentrating 4. Hypervigilance 5. Exaggerated startle response

Criterion E: Duration of the disturbance (symptoms in criteria B, C, and D) is more than one month. Criterion F: Disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of

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functioning. Specify if:

Acute: if duration of symptoms is less than three months Chronic: if duration of symptoms is three months or more With delayed onset: if onset of symptoms is at least six months after the stressor
Adapted from: Diagnostic and Statistical Manual of Mental Disorders, 4th ed, American Psychiatric Association, Washington, DC 1994.

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DSM-IV-TR criteria for specific phobia

Marked and persistent fear that is excessive or unreasonable, cued by the presence or anticipation of a specific object or situation (eg, flying, heights, animals, receiving an injection, seeing blood). Exposure to the phobic stimulus almost invariably provokes an immediate anxiety response, which may take the form of a situationally bound or situationally predisposed panic attack. (Note: In children, the anxiety may be expressed by crying, tantrums, freezing, or clinging.) The person recognizes that the fear is excessive or unreasonable. (Note: In children, this feature may be absent.) The phobic situation(s) is avoided or else endured with intense anxiety or distress. The avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with the person's normal routine, occupational (or academic) functioning, or social activities or relationships, or there is marked distress about having the phobia. In individuals under age 18 years, the duration is at least 6 months. The anxiety, panic attacks, or phobic avoidance associated with the specific object or situation are not better accounted for by another mental disorder, such as obsessive compulsive disorder (eg, fear of dirt in someone with an obsession about contamination), separation anxiety disorder (eg, avoidance of school), social phobia (eg, avoidance of social situations because of fear of embarrassment), panic disorder with agoraphobia, or agoraphobia without history of panic disorder.
Reprinted with permission from: the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, (Copyright 2000). American Psychiatric Association.

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DSM-IV-TR criteria for agoraphobia

Anxiety about being in places or situations from which escape might be difficult (or embarrassing) or in which help may not be available in the event of having an unexpected or situationally predisposed panic attack or panic-like symptoms. Agoraphobic fears typically involve characteristic clusters of situations that include being outside the home alone; being in a crowd or standing in a line; being on a bridge; and traveling in a bus, train, or automobile. The situations are avoided (eg, travel is restricted) or else are endured with marked distress or with anxiety about having a panic attack or panic-like symptoms, or require the presence of a companion. The anxiety or phobic avoidance is not better accounted for by another mental disorder such as social phobia (eg, avoidance limited to social situations because of fear of embarrassment), specific phobia (eg, avoidance limited to a single situation like elevators), obsessive-compulsive disorder (eg, avoidance of dirt in someone with an obsession about contamination), posttraumatic stress disorder (eg, avoidance of stimuli associated with a severe stressor), or separation anxiety disorder (eg, avoidance of leaving home or relatives).
Reprinted with permission from: the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, (Copyright 2000). American Psychiatric Association.

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