Anxiety and Depression Comorbidity: Implications and Intervention

Naomi M. Simon, MD; Jerrold F. Rosenbaum, MD


March 27, 2003

In This Article

Treatment of Comorbid Depression and Anxiety Disorders

General Principles

While data supporting treatment selection for anxiety disorders comorbid with depression are limited and specific to the type of anxiety disorder, there are a number of general principles of treatment of depression and anxiety disorder comorbidity. Often, adjunctive or alternative strategies are needed to optimize outcomes for comorbid anxiety and depression. Cognitive-behavioral therapy (CBT), if available, is one option with well-documented efficacy for both depression and anxiety disorders.[11] However, untreated severe depression may interfere with response to CBT for anxiety disorders,[12] and, at very least, additional sessions with strategies to target depressive symptoms and low motivation may be necessary.

Antidepressants are now first-line treatments for anxiety disorders, with or without comorbid depression, with a move away from tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) due to preferential use of selective serotonin reuptake inhibitors (SSRIs; citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) and the serotonin norepinephrine reuptake inhibitor (SNRI) venlafaxine due to their greater tolerability and safety profiles. However, patients who report symptoms of depression and anxiety should be carefully screened for a personal or family history of bipolar disorder before an antidepressant is initiated, as anxiety comorbidity is also greatly elevated in bipolar disorder[13] and the initiation of antidepressant may trigger the onset of a manic episode. Patients with anxiety are particularly sensitive to initiation side effects, such as jitteriness, that may occur early in antidepressant therapy. Thus, patients with anxiety disorders, and particularly those with panic symptoms, should generally be initiated at half the usual depression starting doses (eg, citalopram/escitalopram or paroxetine 10 mg, sertraline 25mg); however, at least as high doses as in depression are required for efficacy when an anxiety disorder is present and the medication should be titrated slowly to efficacy. Further, while benzodiazepines may result in earlier efficacy for anxiety, the benzodiazepine may not be necessary beyond the first few weeks of treatment.[14] Monotherapy with benzodiazepines in the presence of major depression should be avoided. Further, the selection of initial antidepressant based on a more sedating side effect profile has not been shown to improve tolerability and may increase side effect burden over time.

Comorbid Panic Disorder and Depression

There are minimal data specifically addressing pharmacotherapy outcomes for patients with panic disorder and MDD. However, one randomized trial of imipramine compared with sertraline for panic disorder comorbid with major depression found no difference in efficacy for the panic or MDD, but better tolerability with sertraline,[15] supporting the notion that the key reason to select the newer antidepressants over TCAs in panic disorder and depression is their greater tolerability and safety. Patients with panic disorder in particular are highly sensitive and fearful of physical sensations; thus, education about potential side effects such as early jitteriness, increased anxiety, tremulousness, or gastrointestinal symptoms, as well as expectations about the likelihood of side effect resolution are critical. Patients who report previous intolerance of antidepressant initiation should be titrated even more slowly, or may benefit from initial combined therapy with a benzodiazepine.[14] Although controlled data are lacking, clinical options for treatment for patients who do not respond fully and/or fail to tolerate initial SSRI include adjunctive treatment with CBT for depression aimed at residual depression and/or panic, benzodiazepines for residual panic, TCAs, buspirone, gabapentin, beta blockers, or valproic acid (particularly in the setting of bipolar symptoms). Alternatively, patients may be switched to a different SSRI, venlafaxine, a TCA, or atypical antidepressants such as nefazodone or mirtazapine; MAOIs are reserved for the most refractory patients, given their safety profile and dietary restrictions.

Comorbid SAD and Depression

Currently, we are unaware of any controlled trials for comorbid SAD and MDD. However, SSRIs remain first-line pharmacotherapy for each disorder. SAD is unlike panic disorder, however, in that TCAs have not been shown to be effective agents for SAD and should be avoided.[16] Further, patients with SAD generally have fewer concerns about sensitivity to early side effects, and the high rates of comorbid alcohol abuse and dependence should direct treatment away from benzodiazepines; at very least, patients should be carefully screened for alcohol and substance abuse prior to benzodiazepine initiation.[17] Despite lack of controlled data, other clinically useful options for adjunctive treatment of residual social anxiety symptoms include CBT, buspirone, gabapentin, and beta blockers (for performance anxiety). Alternatively, a switch to a second SSRI, venlafaxine, possibly bupropion SR, or MAOIs may be necessary. More research is needed.

Comorbid PTSD and Depression

One controlled trial examined outcomes for patients with PTSD with or without MDD; while the presence of depression did not affect PTSD response to sertraline or to placebo, patients with an additional anxiety comorbidity had lower placebo responsivity.[18] Depression symptoms have also been shown to improve in patients with PTSD treated with paroxetine.[19] The majority of patients with PTSD benefit from the addition of psychotherapy. In particular, there is demonstrated efficacy for exposure based therapies that aid the patient in imaginal exposure to trauma memories and in return to avoided situations or reminders of their trauma that are now safe but continue to trigger anxiety.[20] SSRIs are first-line pharmacotherapy, with emerging data for SNRIs, mirtazapine, and nefazodone.[21,22,23,24] Atypical antipsychotics such as risperidone, olanzapine, and quetiapine[25] may also have a role adjunctively; a small double-blind trial of olanzapine, at a mean dose of 15 mg/day, adjunctive for patients refractory to SSRI therapy, found significant reductions in symptoms of PTSD, depression, and improvements in sleep.[26] Adjunctive buspirone and anticonvulsants may also be useful for residual PTSD symptoms.

Comorbid Obsessive-Compulsive Disorder (OCD) and Depression

Serotonergic agents, such as the SSRIs and the TCA clomipramine, alone or in combination, are the cornerstone of pharmacotherapy for OCD. One randomized trial of desipramine compared with sertraline for OCD comorbid with MDD found a greater reduction in both OCD and MDD symptoms with the SSRI.[27] In general, higher doses of antidepressants are required for OCD, and when present, depressive symptoms often respond first. Response in OCD may be less affected by the presence of comorbid MDD than other anxiety disorders.[28]

Comorbid GAD and Depression

Antidepressants such as SSRIs (escitalopram/citalopram, sertraline, paroxetine) and SNRIs (venlafaxine) are first-line treatment for GAD, which commonly presents comorbid with depression. An analysis of a subset of patients with GAD comorbid with MDD in a randomized, placebo-controlled trial of venlafaxine XR(SNRI) compared with fluoxetine(SSRI) found greater response for depression and anxiety with the SNRI vs an SSRI.[29] Buspirone at a mean dose of 30 mg/day has demonstrated modest but statistically significant reductions of anxiety and depressive symptoms in patients with GAD and mild concomitant depressive symptoms[30]; the use of buspirone adjunctively at doses of 30 to 90 mg/day may be a useful strategy.


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