Depression and Comorbid Anxiety: An Overview of Pharmacological Options

Treatment for specific comorbidities
Although almost all classes of antidepressants display some degree of efficacy in the treatment of depression with comorbid anxiety disorders, the evidence varies across the agents and type of anxiety disorder. Even more importantly, there are few randomized controlled trials (RCTs) of specific agents in depression with particular anxiety comorbidities. Thus, the evidence presented be­low is mostly based on the data from trials of these agents for specific anxiety disorders (Table 4).

Of the few studies on depression with comorbid GAD, benefits have been found with escitalopram(Drug information on escitalopram) and venlafaxine.^29,30 As such, these may be considered first-line treatment.^29,30 Several SSRIs and SNRIs have also shown strong efficacy in GAD alone. Venlafaxine has been found to have particular benefits for psychic anxiety (the ruminative worry associated with GAD).31 Preliminary evidence also exists for imipramine(Drug information on imipramine), bupropion, buspirone(Drug information on buspirone), pregabalin(Drug information on pregabalin), and tiagabine(Drug information on tiagabine) in GAD, as well as for atypical antipsychotics or mirtaza- pine.^19,21,32-37 While benzodiazepines may afford quick relief of anxiety symptoms, such benefit may wear off after a few weeks of treatment and may not relieve depression.^23,31

Most patients with comorbid depression and GAD of mild to moderate severity may be treated with SSRI or SNRI monotherapy. Those who have severe forms may benefit from augmentation with benzodiazepines, atypical antipsychotics, or anticonvulsants.

Reports from RCTs in depression and comorbid PD are sparse, but there is robust evidence that antidepressants have significant benefit in PD alone. Specifically, evidence supports the use of all SSRIs, venlafaxine, and TCAs in PD.^38,39 In addition, mirtazapine(Drug information on mirtazapine) and adjunctive atypical antipsychotics may also improve panic and agoraphobic symptoms.^23,40

As noted, benzodiazepines have no proven efficacy in moderate to severe depression; however, they have shown benefit in PD.⁴¹ In particular, clo­nazepam adjunctive to SSRI initiation can speed onset of response.⁴² Limited benefits for mono­therapy with phenelzine, moclobemide(Drug information on moclobemide), and dival­proex have been noted.^9,43,44 The efficacy of these antidepressant agents in PD alone suggests that they may also be useful in depression comorbid with PD. For most patients, initiation of treatment with SSRIs or SNRIs, in conjunction with clo­nazepam followed by a slow taper of the benzodiazepine after remission, appears to be effective.

There are no published RCTs of psychopharmacological agents specifically for comorbid depression and SAD. However, as in depression, SSRIs and venlafaxine have shown significant benefits in treating SAD alone, both in the short and long term.⁴⁵ Notably, a longer duration of treatment with SSRIs or SNRIs (ie, 6 months to 2 years) has been shown to produce greater and more sustained treatment response in SAD, which is likely to be even more applicable in those with depressive comorbidity.⁴⁶

Other antidepressants that have shown some efficacy in SAD alone include bupropion and phenelzine(Drug information on phenelzine).^47,48 There is also sufficient evidence for benzodiazepines and anticonvulsants as second-line treatments._^49,50 Evidence for mirtazapine and atypical antipsychotics in SAD is still limited, making them third-line alternatives, and while moclobemide has shown efficacy in depression, it has had mixed results for SAD.^51-54 For most patients with depression and SAD, monotherapy with SSRIs and SNRIs may produce remission; the augmentation strategies may be more beneficial in refractory cases.

There are no published studies of depression comorbid with specific phobias. The literature on the pharmacological treatment of specific phobias alone is also sparse, probably because patients with phobic symptoms respond well to cognitive-behavioral therapy.⁵⁵ Most available data are on the efficacy of SSRI monotherapy.⁵⁶ No benefit was noted for benzodiazepine augmentation of exposure therapy.⁵⁵ If significant phobic symptoms remain after remission of depression, the addition of cognitive-behavioral interventions appears to be the best option.

Unfortunately, most treatment studies of obsessive-compulsive disorder (OCD) use the significant presence of depression as an exclusion criterion. Thus, there are few reports of the ef­ficacy of pharmacological agents in depression with comorbid OCD. In OCD alone, the most robust evidence is for the efficacy of SSRIs as a class together with clomipramine(Drug information on clomipramine) and, secondarily, ven­lafaxine.^57,58 In refractory cases, mirtazapine may be useful as monotherapy, with MAOIs, adjunctive typical and atypical antipsychotics, and adjunctive anticonvulsants as other possible options.^11,59-63