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August, 2006--Volume 329, Number 11, pp 891-1047

Comorbid Depression and Anxiety: When and How to Treat

Robert H. Howland, MD and Michael E. Thase, MD

Depression Research and Treatment Program
University of Pittsburgh School of Medicine
Western Psychiatric Institute and Clinic
Pittsburgh, Pennsylvania


Source Information: Address correspondence and reprint requests to Robert H. Howland, MD, University of Pittsburgh School of Medicine; Western Psychiatric Institute and Clinic; 3811 O’Hara Street; Pittsburgh, PA 15213-2593 USA. Telephone: (412) 624-5330. Fax: (412) 624-3284;
Supported by an unrestricted educational grant from Wyeth Laboratories, Philadelphia, Pa.


Anxiety and depression are distinct disorders commonly seen in clinical practice, particularly in the primary care setting. Comorbid or mixed disorders are also encountered so frequently that a diagnostic category of "mixed anxiety-depressive disorder" appears in the appendix of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV).1 Many patients with diagnosable mood disorders have comorbid anxiety, characterized by a severe and persistent clinical course that makes diagnosis and treatment challenging.2,3 Higher rates of healthcare use and costs are also associated with comorbidity because these patients have more psychologic, physical, and social impairment than those with either disorder alone.2,3

It is crucial for clinicians to recognize both anxiety and depression early in the clinical course and institute appropriate therapy aimed at making the patient well (ie, achieving full remission) rather than merely improving symptoms. Patients with comorbid anxiety and depression tend to discontinue treatment earlier than those with depression alone, and they may not respond as robustly to conventional treatments.2,3 The introduction of newer classes of antidepressants that exhibit both robust antidepressant and anxiolytic effects has provided the ability to treat both disorders with a single medication.



Major depressive disorder (MDD), like the anxiety disorders, is one of the most common psychiatric disorders in the United States.4 Epidemiologic data indicate that the lifetime prevalence of MDD in adults is approximately 5.8%, although other studies have estimated it to be greater.4 Depressive disorders, which include MDD and dysthymia (Table 1),1 are associated with significant emotional and physical distress.

Table 1. DSM-IV Classification of Depressive Disorders
Major depressive disorder, single episode

Major depressive disorder, recurrent

Dysthymic disorder

Depressive disorder, not otherwise specified


DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Adapted from the American Psychiatric Association.1


Neurobiologic basis of depression

Depression was once postulated to result from dysregulation of the noradrenergic system alone. Hence, the pathophysiology focused on levels of norepinephrine and noradrenergic dysfunction.5 With the introduction of the selective serotonin reuptake inhibitors (SSRIs), attention shifted to the role of serotonin in depression. The exact mechanisms underlying depression, however, are more complex than is suggested simply by decreased levels of norepinephrine or serotonin. Newer hypotheses have emphasized the dysregulation of neurotransmitter systems.6

Implications for treatment

Drugs modify neurotransmitter systems by altering the sensitivity and downregulating the density of presynaptic and postsynaptic receptors. The changes occur over a period of weeks after drug therapy begins. The dysregulation hypothesis may explain more aptly why antidepressant effects are delayed after treatment is begun, even though many antidepressants rapidly block the reuptake of neurotransmitters.6 After an initial delay, SSRIs act to downregulate presynaptic serotonin autoreceptors, leading to an increased release of serotonin.

Although older tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) influence serotonergic and noradrenergic systems, both specialists and generalists generally prefer newer antidepressants such as SSRIs, mirtazapine, venlafaxine extended-release (XR), and nefazodone because of their overall safety and side effect profiles and convenient dosing.7,8



The primary anxiety disorders (Table 2) generally develop before the age of 30, are more common in women than men, and are associated with a family history of anxiety and depression.1,9,10 As a group, they are the most common of all psychiatric illnesses, with a 12-month prevalence rate estimated in the National Comorbidity Survey of 17.2% and a lifetime prevalence rate of 24.9%.10,11 Social phobia was the most common anxiety disorder, with a lifetime rate of 13.3%; other epidemiologic assessments have found that simple phobias were most common, with a lifetime prevalence of 9.8%.11

Table 2. DSM-IV Classification of Anxiety Disorders
Generalized anxiety disorder

Panic disorder

–With agoraphobia

–Without agoraphobia

Agoraphobia without a history of panic disorder

Phobic disorders



Obsessive-compulsive disorder

Posttraumatic stress disorder

Acute stress disorder

Anxiety disorder due to general medical condition

Anxiety disorder due to substance abuse

Anxiety disorder not otherwise specified

DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Adapted from the American Psychiatric Association.1

In contrast, generalized anxiety disorder (GAD) affects 1.6-5.1% of the general population at some time during their lives.12 Panic disorder and social phobia frequently coexist with GAD (comorbidity rates of 24% and 34%, respectively).12 Agoraphobia develops in approximately one third to one half of all cases of panic disorder.1 The estimated lifetime prevalence of posttraumatic stress disorder is approximately 1-14%, although survivors and combat-experienced war veterans have substantially higher prevalence rates.1

Neurobiologic basis of anxiety and implications for treatment

Abnormalities in the regulatory mechanisms of the norepinephrine, gamma-aminobutyric acid, and serotonin neurotransmitter systems play crucial roles in the genesis of anxiety.9 Benzodiazepines act by potentiating the effects of gamma-aminobutyric acid9 and have traditionally been the therapy of choice in anxiety disorders because they produce rapid relief of somatic symptoms. However, their use may not be recommended beyond 4 to 6 weeks because of side effects and possible drug-drug interactions.9

More recently, the role of serotonin in the development of anxiety has been emphasized. Augmentation of presynaptic serotonin function has been postulated to be anxiolytic, and postsynaptic potentiation to be anxiogenic.13 The role of serotonin in anxiety has been supported by the efficacy of SSRIs in panic disorder and obsessive-compulsive disorder14,15 as well as the efficacy of buspirone16 and, most recently, venlafaxine XR, in GAD.17,18 Both the dual serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine XR and the SSRI paroxetine are approved by the US Food and Drug Administration for the treatment of GAD.

Comorbid depression and anxiety


In the National Comorbidity Survey, 58% of MDD patients were found to have an anxiety disorder; among these patients, the rate of comorbidity with GAD was 17.2%, and with panic disorder, 9.9%.19 Patients with a diagnosed anxiety disorder also had high rates of comorbid depression, including 22.4% of patients with social phobia, 9.4% with agoraphobia, and 2.3% with panic disorder.19 For many, the symptoms of both depression and anxiety are not severe enough (ie, are subsyndromal) to justify a primary diagnosis of either MDD or an anxiety disorder.2 Patients can also be categorized as having mixed anxiety-depressive disorder,1 and they are at significantly increased risk of developing full-blown depression or anxiety. Appropriate treatment is necessary to alleviate symptoms and prevent the emergence of more serious disease.2 The more commonly used antidepressants for the treatment of comorbid depression and anxiety and their specific reuptake inhibition are shown in Table 3.7,20

Accumulating evidence indicates that patients with comorbid depression and anxiety tend to have greater illness severity and a lower treatment response than those with either disorder alone.21 In addition, social function and quality of life are more greatly impaired.21

Table 3. Specific Reuptake Inhibition of Antidepressants for the Treatment of Comorbid Depression and Anxiety

Antidepressant class









SNRI (venlafaxine XR)





TCAs, tricyclic antidepressants; ü , specific reuptake inhibition; MAOIs, monoamine oxidase inhibitors; SSRIs, selective serotonin reuptake inhibitors; SNRI, serotonin norepinephrine reuptake inhibitor; XR, extended-release formulation. Adapted from DeVane7 and Wells and Mandos.20


Neurobiochemical models for comorbid depression and anxiety

Genetic studies suggest a biologic link between depression and anxiety. Family members of patients with comorbid depression and panic disorder have higher incidences of mood and anxiety disorders and alcohol abuse than the relatives of patients with depression alone.22 Patients with depression and GAD have more relatives with depression than patients with either disorder alone.21

Neurobiochemical evidence also suggests that both conditions are related to disturbances in serotonergic and noradrenergic transmission and regulation.21 The involvement of these neurotransmitter systems in both normal and pathologic mood states suggests a continuum from normal arousal to anxious and depressive states. One hypothesis is that sustained hyperarousal may deplete these neurotransmitters in critical areas of the forebrain, which may in turn make a patient more vulnerable to developing the emotional and somatic manifestations of depression.21

Diagnosis of comorbid depression and anxiety

Screening. Patients with signs and symptoms of depression and anxiety should be screened carefully. It is important to determine if a primary diagnosis can be made, whether the patient has symptoms related to comorbidity or subsyndromal mixed anxiety-depression, or if the symptoms are secondary to an underlying disease or condition.

Diagnosis. In general, depressive disorders can be distinguished from anxiety disorders. A thorough review of the patient’s medical history may reveal frequent visits to a general practitioner with repeated, nonspecific, medically unexplained physical complaints. The DSM-IV criteria for mixed anxiety-depressive disorder (Table 4)1 may be helpful in establishing whether the patient has subsyndromal features.

Table 4. DSM-IV Diagnostic Criteria for Mixed Anxiety-Depressive Disorder
Presence of persistent or recurrent dysphoric mood lasting ³4 weeks and accompanied by ³4 of the following symptoms:

    –Concentration or memory difficulties

    –Sleep disturbances

    –Fatigue or low energy



    –Being easily moved to tears


    –Anticipating the worst

    –Hopelessness or pessimism about the future

    –Low self-esteem or feelings of worthlessness

Symptoms are not due to a medication, drug abuse, or a medical condition and cause significant distress or impairment in social, occupational, or other important areas of functioning

Symptoms do not meet criteria of any other mental disorder

DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Adapted from the American Psychiatric Association.1


Treatment of comorbid depression and anxiety

Pharmacotherapy. General guidelines recommend initiation of antianxiety measures as quickly as possible. Available medications like venlafaxine that show an onset of action within the first week of treatment23 can help accomplish this more easily. Resolution of anxiety early in the course of treatment improves patients’ compliance with their antidepressant regimen and reduces the likelihood of premature discontinuation from treatment.24

Improved compliance likewise increases the likelihood of resolution of depressive symptoms resulting in remission. Depressive symptoms may not respond to traditional anxiolytic medications (ie, benzodiazepines) and may respond only mildly to buspirone.2 Benzodiazepines are generally limited to short-term use because of the risk of psychomotor impairment, sedation, and tolerance.25 Buspirone has a slow onset of action and hence may not be the drug of choice if quick therapeutic effect is needed.

Extensive studies using venlafaxine in patients with comorbid MDD and anxiety26,27 have also shown the efficacy of this agent in this scenario. A recent post-hoc subset analysis of data from an earlier study assessing the efficacy and safety of venlafaxine XR and fluoxetine in outpatients with MDD and high symptomatic anxiety showed that, compared with fluoxetine (20–80 mg/day), venlafaxine XR (75–225 mg/day) had greater efficacy in patients with MDD and comorbid GAD.28 While short-term studies have shown the efficacy of paroxetine in the treatment of GAD,29,30 its utility in long-term treatment of GAD has yet to be established. Likewise, the efficacy of this SSRI in treating patients with comorbid depression and anxiety needs to be determined.

Depending on the patient’s level of anxiety, monotherapy with an antidepressant that has shown good anxiolytic effects (including TCAs, MAOIs, SSRIs, and the newer agents venlafaxine XR, paroxetine, and nefazodone)2,26,27,29,31-33 is an option for the clinician.34 Newer antidepressants have certain advantages over the TCAs and MAOIs, however, in that they have more favorable side effect profiles and are safer in the event of overdosage.35

Psychotherapy. Clear evidence exists that some forms of psychotherapy are effective in the treatment of anxiety disorders and MDD.

Cognitive behavior therapy and interpersonal psychotherapy are practical, structured, skills-oriented therapies developed specifically for the treatment of depression,36,37 but cognitive behavior therapy has also been effective in treating various anxiety disorders.38

Because comorbid anxiety is strongly associated with the development of chronicity in depression and treatment resistance, psychotherapy might have an especially important adjunctive role in managing patients with these comorbidities.39,40

Another important concept is using psychotherapy as an approach for treating the residual symptoms of depression and anxiety.41 Even after optimizing pharmacotherapy as described above, some patients, though improved, will continue to have residual symptoms, which pose a risk factor for relapse, chronicity, and treatment noncompliance. Hence, the use of sequential psychotherapy might be an especially valuable approach for treating residual symptoms and enhancing treatment compliance, leading to a better overall clinical outcome.


Significant advances have been made in the understanding of comorbid depression and anxiety disorders. More refined diagnostic criteria have provided more precise distinctions between the discrete depressive disorders, anxiety disorders, and mixed anxiety-depression seen in clinical practice. Studies of antidepressants and anxiolytic drugs are providing additional information about the underlying neurobiologic derangements responsible for these psychiatric illnesses. Recent evidence that serotonergic and noradrenergic mechanisms underlie anxiety and depression is providing support for the use of newer antidepressants; their use may enable clinicians to help patients achieve wellness or full remission instead of simply experiencing improvement with treatment.


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