Version July 2025
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 either disorder alone.
Studies 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. Anxious distress is included as a subtype of major depression in the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) [1].
This topic describes the epidemiology, pathogenesis, clinical manifestations, course, and diagnosis of comorbid anxiety and depression. The epidemiology, pathogenesis, clinical manifestations, course, diagnosis, and treatment of individual depressive and anxiety disorders are described separately.
●(See "Major depression in adults: Epidemiology".)
●(See "Approach to the adult patient with suspected depression".)
●(See "Depression in adults: Course of illness".)
●(See "Social anxiety disorder in adults: Epidemiology, clinical features, assessment, and diagnosis".)
●(See "Panic disorder in adults: Epidemiology, clinical manifestations, and diagnosis".)
●(See "Agoraphobia in adults: Epidemiology, pathogenesis, clinical manifestations, course, and diagnosis".)
EPIDEMIOLOGY
Population-based samples — The lifetime prevalence of anxiety disorders and major depression among adults in the United States has been reported to be 28.8 percent and 16.6 percent, respectively [2].
Three international studies found that depression is significantly associated with every anxiety disorder [2-4], with the highest associations in patients with generalized anxiety disorder and the lowest in those with agoraphobia and specific phobias.
Lifetime prevalence of comorbid anxiety and depression in the general population is very high (table 1) [5-11]. For example, in a survey of 74,045 adults across 24 countries, the average lifetime prevalence of major depressive disorder was 11.2 percent; 45.7 percent of those individuals also had one or more lifetime anxiety disorders [7].
Another population based survey 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) [12]. 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 54.3 percent among patients with a co-occurring disorder.
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 [13-18].
For example:
●In a sample of 1127 outpatients with anxiety disorders, current and lifetime prevalence rates of mood disorders were 57 and 81 percent, respectively [16]. 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.
●Small studies involving patients with depressive disorders have yielded variations in the point prevalence of comorbid anxiety of 45 to 92 percent [19-21].
Risk factors — Analyses of data of 3021 individuals from the Early Developmental Stages of Psychopathology study have been used to assess risk factors, temporal patterns, and longitudinal outcomes of anxiety, depression, and co-occurring anxiety and depressive disorders [22]. 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.
Other studies have shown that the risk of depression in individuals with anxiety disorders is associated with female gender, younger age, lower education, unemployment, number of anxiety disorder diagnoses, severity of anxiety disorder at baseline, early traumatization, neuroticism, conscientiousness, socioeconomic stressors, parental psychiatric history, and the presence of panic attacks [12,23-25].
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 brain’s limbic system. A study reported that individuals with comorbid depression and anxiety have increased resting-state functional connectivity of the limbic network when compared with depression or anxiety alone [26].
Brain imaging studies have most consistently implicated the amygdala, anterior cingulate cortex, and insula in the pathophysiology of anxiety [27]. As examples, neuroimaging studies in social phobia and specific phobia have found significant hyperactivity in the amygdala and insula [28].
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. However, the hyperactivity appears to manifest differently in anxiety and depression. In depressed patients baseline amygdalar activity is higher than healthy controls while in patients with anxiety disorders, amygdalar activation is higher only during provocation tasks [29]. In addition, comorbid patients presented decreased activity in the cingulate gyrus, right perirhinal cortex, and right posterior parietal cortex, and increased activity in the left prefrontal cortex and left insular cortex [30].
Individuals with comorbid depression and anxiety have also been found to have lower levels of omega-3 polyunsaturated fatty acids. These levels appear to decrease as anxiety severity increases [31].
Neuropsychologic factors — Personality traits and neuropsychologic 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 [32,33].
Other studies have reported that individuals with comorbid disorders, as compared with either disorder alone, have greater impairments in working memory and attention, higher levels of harm avoidance and neuroticism, greater impairment in psychosocial functioning (eg, home management, work, socialization, relationships), increased impulsivity, and more severe suicidal ideation [7,17].
Genetics — Some studies suggest that the comorbidity between anxiety (ie, generalized anxiety disorder) and depressive disorder could be explained in part by similarities in genetic structure [34,35].
Twin studies have suggested that the anxiety disorders and major depression were distinct entities and not simply phases of the same disease [36]. 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 [36].
Conceptual issues — Distinctive and overlapping symptoms of depression and anxiety are found on the associated table (table 2).
In the tripartite model of emotion, a prevailing conceptual theory for emotional disorders, anxiety and depression can be deconstructed into three principal components: negative affect, physiologic hyperarousal, and low positive affect [37,38].
●Negative affect encompasses a wide range of negative emotional responses including fear, distress, disgust, anger, anhedonia, tension and is shared in both anxiety and depression.
●Physiologic hyperarousal is characteristic of anxiety disorders (eg, panic disorder) but not depression. Signs and symptoms include excessive agitation, edginess, and feeling “keyed up” or tense.
●Low positive affect (eg dysphoria) describes a state lacking positive emotional responses, such as happiness or pleasure. Positive emotional responses are absent in depression, but not in anxiety disorders.
Among all the factors, negative self-view had the largest influence, accounting for 17.1 percent of the variance seen in anxiety and depression [38].
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. A similar pattern of symptom overlap in major depression and anxiety disorders has been seen in other outpatient samples [39].
CLINICAL MANIFESTATIONS —
Study of the clinical presentation of anxiety co-occurring with depression has largely focused on symptoms of generalized anxiety disorder (GAD). Co-occurring 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 (table 2) [40]:
●Symptoms specific to depression:
•Loss of interest
•Weight change
•Poor appetite
•Bradykinesia
•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
There is some research to suggest that the order of which disorder presents first (ie, anxiety first versus depression first) may affect clinical presentation. In an analysis of data drawn from the National Institute of Health and Care Research (NIHR) BioResource Cohort (n = 63,411), individuals with first onset of anxiety were more likely to be female, less likely to have obtained university degrees, and less likely to self-report having been diagnosed with either depression or anxiety. “Anxiety-first” participants also had more severe symptoms, significantly higher recurrence rates, self-reported trauma, other self-reported mental health conditions, and current symptoms of depression when compared to those presenting with “depression-first” [41]
COURSE —
Comorbid anxiety (symptoms of generalized anxiety disorder [GAD]) and depressive disorders have been found to differ from the individual disorder categories in age of onset [2,7,21,42], life course [43], and treatment outcome.
Onset and life course — Age of onset patterns for anxiety and mood disorders appear distinct. In a nationally representative epidemiologic study in the United States, the median age of onset was 11 years for anxiety disorders and 30 years for mood disorders [2].
Data from the Early Developmental Stages of Psychopathology (EDSP) study found that [22]:
●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. Age of onset also appears to vary by anxiety disorder [21,42]. 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.
Co-occurrence of anxiety and depression as compared with either disorder alone is associated with a more chronic course [44,45], decreased odds of recovery, increased time to therapeutic onset for pharmacotherapy [2,22], higher symptom severity, and greater functional impairment [11,46] However, the course of the co-occurring conditions can be complex [8,11,21,43-48].
As examples:
●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 [43].
●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 [47].
●In a community sample of 915 females age 42 to 52 years, those with a lifetime history of a co-occurring anxiety disorder and major depression as compared with those with either disorder alone were more likely to report a history that included recurrent major depression, multiple severe lifetime anxiety disorders, greater symptoms of anxiety or depression, decreased social support, and higher rates of seeking treatment [8].
Analysis of data from a nationally representative epidemiologic study in the United States 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) [21]. A primary lifetime diagnosis of an MDE predicted the onset but not persistence of GAD. A temporal association between the onset of the disorders appears to be seen in individuals age 15 to 24, with more than one-third of individuals with co-occurring MDE and GAD experiencing the onset of both disorders within the same year.
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 trial, outpatients with anxious depression (ie, a diagnosis of major depression and an anxiety/somatization subscale score greater than seven on the Hamilton Rating Scale for Depression) had significantly lower response and remission rates and poorer outcomes, compared with patients with non-anxious depression [49,50]. Depressed patients with anxiety took longer to improve than depressed patients without anxiety [51].
●In multiple clinical trials of patients diagnosed with anxiety disorders (GAD, panic disorder, social anxiety disorder, and obsessive-compulsive disorder), 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 [52-56]. 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 —
Our diagnostic assessment of individuals with possible co-occurring anxiety disorders and depressive disorders includes a careful patient history, a complete physical examination, and appropriate laboratory studies. We assess for medical illness, side effect of medication, substance use, or substance withdrawal that can produce anxiety or anxiety-like symptoms (table 3 and table 4) or depressive symptoms. (See "Unipolar depression: Pathogenesis", section on 'Secondary depression'.)
We ask about stressful life events, family psychiatric history, social history, substance use history (including caffeine, nicotine, and alcohol), and past sexual, physical, and emotional abuse, or emotional neglect.
DIAGNOSIS —
Diagnoses of co-occurring depressive and anxiety disorders are based on DSM-5-TR criteria for the individual disorders [1]. Diagnostic criteria for mood disorders and specific anxiety disorders are found elsewhere.
●(See "Depression in adults: Clinical features and diagnosis", section on 'Major depressive disorder'.)
Differential diagnosis — We differentiate co-occurring anxiety and depression from other disorders with similar presentation by careful history. A table distinguishes among symptoms shared by depression and generalized anxiety disorder (GAD), symptoms specific to depression, and symptoms specific to GAD (table 2).
●Major depressive disorder with anxious distress – Anxious distress is included as a specifier of major depression [1]. Symptoms of anxiety are beneath the threshold required by DSM criteria for individual anxiety disorder. Anxiety symptoms that are part of a depressive syndrome are difficult to distinguish from primary anxiety disorders. Anxious distress is characterized by the presence of two or more of the following symptoms during most days of the depressive episode (see "Depression in adults: Clinical features and diagnosis", section on 'Specific symptom constellations'):
•Feeling keyed-up or tense
•Feeling unusually restless
•Difficulty concentrating because of worry
•Fear that something awful will happen
•Feeling that the individual might lose control of themselves
The following criteria are used to characterize the severity of the anxious distress:
•Mild: Two symptoms
•Moderate: Three symptoms
•Moderate-severe: Four to five symptoms
•Severe: Four to five symptoms with motor agitation
Analyses of data from the Sequenced Treatment Alternative to Relieve Depression clinical effectiveness trial [49,57] have supported the diagnosis of major depressive disorder with anxious distress. In an analysis of data on 1450 outpatients meeting criteria for major depression, 46 percent had a Hamilton Rating Scale for Depression anxiety/somatization subscale score ≥7. Compared with depressed patients without high levels of anxiety, these patients were more likely to be [57]:
•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 [51]. High levels of anxiety have generally been associated with increased suicide risk, longer duration of illness and greater likelihood of treatment nonresponse. These results support the addition of the anxious distress specifier to diagnostic criteria for major depression.
There is some concern that use of the anxious distress specifier may lead clinicians to forget about diagnosing comorbid anxiety disorders under the assumption that the “anxious distress” sufficiently characterizes the clinical presentation of the patient. We are careful to be prompted by the use of the specifier and carefully assess for the presence of a comorbid anxiety disorder, for which specific treatments may be indicated.
●Mixed anxiety and depression – Mixed anxiety and depression 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 [58]. ICD-10 does not provide additional criteria for diagnosing the disorder.
Diagnostic reliability — Given the overlap in 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 [59]. 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 (MDE), and 278 with co-occurring GAD and major depression [60]. Primary care clinicians made accurate diagnoses in only 34 percent of patients with GAD and 64 percent of patients with an MDE.
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 [61]. 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 has been shown to be superior to other clinician-administered instruments, best capturing symptoms of depression [62]. It has demonstrated excellent discrimination between depressed and nondepressed individuals [63], and between self-assessed depression and personality disorders [64]. It has also demonstrated good reliability and validity in older adult populations [65].
●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 [66]. The HAMA has demonstrated good ability to discriminate between anxiety and depression [67].
●Obsessive-compulsive disorder – The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) has shown good discrimination between obsessive-compulsive disorder and depression as well as other anxiety disorders in initial validation study, and good sensitivity to change [68,69]. The self-report adaptation of the 10-item YBOCS scale and symptom checklist has shown similar reliability patterns [70].
●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 [71,72].
●Posttraumatic stress disorder – 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 [73].
Despite their wide use, the State Trait Anxiety Inventory and the Hamilton Rating Scale for Depression have been criticized for an inability to distinguish between anxious and depressive symptoms [74-77].
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anxiety and anxiety disorders in adults".)
SUMMARY AND RECOMMENDATIONS
●Comorbid mood and anxiety disorders – Population-based studies conducted in several countries have shown high rates of co-occurrence 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.)
●Risk factors – Research has found that patients with co-occurring anxiety and mood disorders are 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.)
●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. (See 'Pathogenesis' above.)
●Clinical manifestations – Co-occurring GAD and depression can present on a continuum, from principally anxiety symptoms to mixed anxiety and depression, to principally depressive symptoms. Symptoms commonly present in either disorder include irritability, agitation/restlessness, difficulties concentrating, insomnia, and fatigue (table 2). (See 'Clinical manifestations' above.)
●Course – 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.)
●Assessment and diagnosis – Our diagnostic assessment for potentially co-occurring anxiety and depressive disorders includes a careful history and complete physical examination. We screen for stressful life events, family psychiatric history, social history, history of substance use and history of past sexual, physical, or emotional abuse.
