Oliver G. Cameron, MD, PhD

Comorbidity of psychiatric syndromes is quite common-in a 12-month period, almost 50% of adults in the United States with any psychiatric disorder had 2 or more disorders.

 The prevalence of comorbid anxiety disorder and major depressive disorder (MDD) is frequent and perhaps as high as 60%.

 It may be higher if significant but subsyndromal symptoms are included in analyses.

 This is far greater than the 2% or less co-occurrence that would be expected by chance. Although panic disorder (PD) and generalized anxiety disorder (GAD) have been most studied as part of an anxiety-depression comorbid state, all or almost all of the anxiety disorders appear to show comorbidity with at least depressive symptoms if not full MDD.

The National Comorbidity Survey Replication

 reported that in a 12-month period, the prevalence for an anxiety disorder was about 18%, and for a mood disorder it was 9.5%. Lifetime prevalences for any anxiety disorder and MDD were approximately 29% and 16.6%, respectively.

 Assuming a (perhaps conservative) 50% comorbidity rate, between 5% and 9% of the adult population has comorbid depression-anxiety in a 12-month period.

The impact of comorbid depression and anxiety is substantial. As demonstrated by the Global Burden of Disease study, neuropsychiatric disorders accounted for more than 13% of all medical disability worldwide and for more than 27% of all noncommunicable disease in 2005.

 Depression alone produced 10% to 12% of all disability from noncommunicable disease and approximately 5% of all disability (noncommunicable, communicable, injury). Thus, comorbid anxiety and depression may account for as much as 2% to 4% of all medical disability worldwide. In addition, depression (and, thus, comorbid depression and anxiety) is associated with other psychiatric and nonpsychiatric medical conditions (eg, cardiovascular disease, diabetes, HIV/AIDS, maternal and reproductive-related syndromes, and psychosomatic illnesses), with their resulting socioeconomic costs.

There has been little research on risk factors that predict the development of comorbid anxiety and depression compared with risk factors for either disorder alone. However, the high rate of comorbidity indicates that the simple occurrence of one disease state should be considered a predisposing factor for the development of the other. Psychosocial and situational difficulties also appear to be risk factors for the development of comorbid anxiety and depression.

 Familial/genetic studies reported different results, partly determined by the anxiety disorder under consideration.

 For example, MDD and GAD appear to be related to the same genetic factors, while MDD and PD are familially independent.

 Gender may also play a role, because women have a higher risk than men for both disorders.

Age is another consideration. Patients with anxiety disorders have a much earlier median age at onset than do those with mood disorders (age 11 years vs age 30 years).

 As would be expected, onset of anxiety usually predates onset of depression in patients with this comorbidity.

 However, the earlier onset of anxiety disorders does not necessarily infer causality.

The expected prognosis for patients with comorbid anxiety and depressive disorders is poorer than that for either disorder alone. These patients have greater severity of symptoms, increased risk of suicidality, a more chronic and persistent course, and more functional impairment. This syndrome is also more difficult to treat, with longer time to remission and need for increased medication.

There are several possible explanations for this high rate of comorbidity.

 diagnostic criteria tend to overlap, raising the likelihood that a person meeting criteria for one disorder has an increased probability of having the other. For example, depressive ruminations are similar to the obsessional thinking/worry seen in GAD; poor sleep quality and difficulty in concentrating occur in both depression and posttraumatic stress disorder; and phobic avoidance can be mistaken for depressive loss of energy or fatigue. A second possibility is that the disorders are etiologically different, but symptom episodes are provoked by related environmental events (ie, stressors), such as threat (anxiety) and loss (depression).

 The third possibility is that the underlying biologies of the disorders are the same or are highly overlapping; this is related to the first possible explanation. An understanding of the pathophysiology of depressive and anxiety disorders is necessary to address the first and third reasons.

A number of potential biological markers have been studied in people with comorbid depression and anxiety.

 Several markers have assessed noradrenergic or hypothalamic-pituitary-adrenocortical (HPA) axis function. Serotonergic (along with noradrenergic) function has also been of interest, because many medications with serotonergic and/or noradrenergic effects are beneficial for individuals with depression and/or anxiety.

 Other markers studied include sleep (which is abnormal in both types of disorders), thyroid axis activity (abnormal in depression), lactate infusion (abnormal in anxiety), and cardiovascular function (abnormal in both depression and anxiety). (Abnormality associated with sleep and cardiovascular functions presents differently in anxiety versus depression.)	

Earlier studies have not included nonpathological controls, patients with depression only, patients with anxiety only, and patients with both disorders. Interpretation of results has been somewhat hampered by the lack of inclusion of all 4 groups. Therefore, we recently designed and completed a study of HPA axis function and CNS noradrenergic function that included these 4 groups.

In order to determine the roles of each disorder as well as the comorbid state, we compared "pure" participants -those with anxiety only (social anxiety disorder or PD) or MDD only-with individuals who had comorbidity; these participants were also matched with controls. We used the Trier Social Stress Test (a reliable activator of the HPA axis) and the growth hormone response to the a

, anxiety was associated with a noradrenergic abnormality; depression was associated with a disruption of the normal negative correlation between the 2 systems. Most notably, hyperactivity of the HPA axis was uniquely associated with the comorbid state, indicating that there is something qualitatively (not just quantitatively) distinctly biological about the comorbid state. In other words, comorbid anxiety and depression might be a distinct disorder.

Both nonpharmacological and pharmacological treatments are effective for anxiety and depressive disorders. This is also true for patients with comorbid anxiety and depression,

 although more severely affected individuals tend to require medication.

 Cognitive-behavioral therapy (CBT) is the nonpharmacological approach most commonly used and most extensively studied.

 It has been demonstrated to be as effective as medication in most patients.

SSRIs have been considered the first-line medication treatment for comorbid individuals,

 although one review concluded that SSRIs were not demonstrably superior to other antidepressants for patients with comorbidity.

 Other pharmacological agents with some proven efficacy include benzodiazepines,

 buspirone, β-adrenergic blocking agents, anticonvulsants, and atypical antipsychotics.

 Benzodiazepines are typically recommended for a few weeks only, to be used while waiting for an antidepressant to become effective. They should then be gradually tapered. For a small number of patients who do not obtain satisfactory benefit from the antidepressant alone, extended use of benzodiazepines is appropriate.	

A few studies have compared specific pharmacological agents for treatment of patients with comorbidities. One study reported that these patients do not respond as well as those with non-anxious MDD to the tricyclic antidepressants (TCAs) imipramine and desipramine or the monoamine oxidase inhibitor (MAOI) phenelzine.

 Findings from a study that compared the TCA imipramine with the SSRI fluoxetine suggest that the SSRI would be more effective in individuals with comorbidity.

The results of another study that compared the SSRI paroxetine with the MAOI moclobemide showed that the SSRI was more beneficial for patients with comorbidity (MDD or dysthymia plus PD, GAD, or obsessive-compulsive disorder).

 Bupropion, an antidepressant with noradrenergic and dopaminergic effects, was comparable to sertraline in the treatment of MDD; effects included a reduction of anxiety symptoms.

 Mirtazapine, a noradrenergic and serotonergic agent, was found to be effective in patients with moderate to severe depression; it was particularly effective for patients with anxiety symptoms.

 Finally, in people with MDD and GAD, venlafaxine, an agent with serotonergic and noradrenergic effects, appeared superior to fluoxetine.

SSRIs are preferable to TCAs and MAOIs in comorbid (as well as noncomorbid) anxiety and depression based on safety and side-effect profiles. SSRIs might also be preferable for greater efficacy, but there is conflicting opinion, and TCAs and MAOIs should still be considered as second- or third-line choices for appropriate patients. Some data suggest that venlafaxine might be preferable to the SSRIs in patients with comorbid MDD and GAD, but that conclusion should be considered preliminary at best.

Anna, a woman in her 40s, experienced the development of anxiety at age 15; she feared having to speak in class and would spend several days before a presentation in frightened anticipation. Within several months, these fearful feelings developed at other times as well. Within a year of onset, sudden episodes of mental anxiety developed, with rapid heartbeat, shortness of breath, shaking, and sometimes an urge to defecate. At age 16, a public speaking phobia and GAD associated with panic attacks not reaching full PD criteria were diagnosed.

She was treated with in vivo desensitization and a

-adrenergic blocking agent, used "as needed." Her symptoms improved by 50%, but she had continued difficulty with GAD symptoms. At age 19, a benzodiazepine was prescribed and Anna experienced further relief but not remission.

In her late 20s, she noticed waxing and waning "depression, like my father had," with diminished interest in activities, increased sleep disturbance, loss of appetite with a 5-lb weight loss, daily fatigue, and anxious guilty ruminations about "anything and everything."

Some time later, she saw a psychiatrist, who diagnosed comorbid major depression and GAD and initiated CBT. An SSRI was prescribed at the highest recommended dose, and her benzodiazepine dosage was changed from as needed to a regular dose. At the end of the 4 months, Anna reported 80% improvement and felt the improvement was "good enough."

After about 15 months, the medication was gradually discontinued and CBT was stopped. She did well for almost a decade, but then her symptoms returned. A broad-spectrum antidepressant and a benzodiazepine were prescribed at a low daily dose with additional as-needed doses. Despite concerns, she never developed tolerance to the anxiolytic benefit of the benzodiazepine. She did very well on this regimen and it was decided to maintain it indefinitely. She did not feel the need to reenter CBT, but said she knew she could later if it seemed necessary.

This hypothetical case vignette illustrates a number of aspects of comorbid anxiety and depression. The patient is a woman with typical age at onset-early- to mid-teens for anxiety and late 20s for depression. (Some data suggest an earlier age at onset and/or a strong family history presages a more severe disorder, including comorbidity.) The initial anxiety treatment was only partially successful, and the ultimate complexity of her course of illness-significant relapse, need for different types of medications in maximal doses, more than one medication needed concurrently, and the ultimate requirement for open-ended treatment duration-are all consistent with the significant severity, chronic natural history, and somewhat poorer prognosis of comorbid depression and anxiety.

Ultimately, some patients require both ongoing use of a benzodiazepine anxiolytic and a broad-spectrum antidepressant with both noradrenergic and serotonergic effects. While it is premature to recommend such an antidepressant as being preferable to an SSRI as first-line treatment, it is clear that clinicians should be willing to try all types (and, sometimes, combinations) of medications until satisfactory relief is obtained. However, before any medication is judged to be ineffective, maximum allowable dosing to adverse effect tolerance should be attempted for at least 6 to 8 weeks, unless there is absolutely no symptom improvement in the first 3 to 6 weeks of treatment. In addition, nonpharmacological treatment should always be considered as part of a complete treatment approach.

The results of our biological study demonstrated that a central noradrenergic abnormality was associated with anxiety,

 while a loss of the negative correlation normally seen between noradrenergic and HPA axis functions occurred in major depression.

 The HPA axis hyperactivity observed only in patients with comorbidity suggested that comorbidity might be more than the sum of 2 coexisting syndromes.

 The presence of abnormalities in both systems, along with the loss of the functional association normally seen with these disorders, further suggested that the comorbid state might occur specifically when dysfunction is present in both systems. These findings require replication and await identification of potential clinical relevance.

 Kessler RC, Chiu WT, Demler O, et al. Prevalence, severity, and comorbidity of 12-month 

 disorders in the National Comorbidity Survey Replication. 

 Kaufman J, Charney D. Comorbidity of mood and anxiety disorders. 

 Gorman JM. Comorbid depression and anxiety spectrum disorders. 

 Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age-of-onset distributions of 

 Prince M, Patel V, Saxena S, et al. No health without mental health. 

 Pollack MH. Comorbid anxiety and depression. 

 Kendler KS, Neale MD, Kessler RC, et al. Major depression and generalized anxiety disorder: (partly) different environments? 

 Weissman MM. Family genetic studies of panic disorder. 

 Kendler KS, Walters EE, Neale MC, et al. The structure of the genetic and environmental risk factors for six major psychiatric disorders in women: phobia, generalized anxiety disorder, panic disorder, bulimia, major depression, and alcoholism. 

 Wittchen HU, Kessler RC, Pfister RC, Lieb M. Why do people with anxiety disorders become depressed? A prospective-longitudinal community study. 

 Roy-Byrne PP, Stang P, Wittchen HU, et al. Lifetime panic-depression comorbidity in the National Comorbidity Survey. Association with symptoms, impairment, course, and help-seeking. 

 Belzer K, Schneier FR. Comorbidity of anxiety and depressive disorders: issues of conceptualization, assessment, and treatment. 

 Cameron OG. Anxious-depressive comorbidity: effects on HPA axis and CNS noradrenergic functions. 

 Finley-Jones R, Brown GW. Types of stressful life event and the onset of anxiety and depressive disorders. 

 Baldwin DS, Evans DL, Hirschfeld RM, Kasper S. Can we distinguish anxiety from depression? 

 Young EA, Abelson JL, Cameron OG. Effect of comorbid anxiety disorders on the hypothalamic-pituitary-adrenal axis response to a social stressor in major depression. 

Oliver G. Cameron, MD, PhD

Articles

Understanding Comorbid Depression and Anxiety