Many patients with depression also have comorbid conditions. These additional conditions must be taken into account and treated accordingly.

Anxiety: The concomitant occurrence of anxiety and depression is common. Frequently used to treat anxiety, MAOIs are no longer commonplace in the treatment of depression. With the development of safer antidepressants, such as SSRIs, MAOIs have become less popular given their substantial risk of adverse effects with drug and diet interactions. However, MAOIs should not be entirely overlooked in treating depression, particularly when there is comorbid social anxiety. Research indicates MAOIs are at least as effective as SSRIs for treatment of social anxiety.45 Therefore, MAOIs could serve as a valuable second-line treatment for those who do not respond to SSRI therapy. Two large reviews have determined MAOIs to be the most effective therapy in improving outcomes on the Liebowitz Social Anxiety Scale.46,47 This suggests that MAOIs can be recommended confidently as first-line treatment for patients with social anxiety who are able to make the lifestyle changes necessary to avoid dangerous interactions.

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In addition to MAOIs, mirtazapine has proved to be useful in reducing several different types of anxiety, including social phobia,48 panic disorder,12 and anxiety in the elderly.10,49 Trazodone has also been shown to be effective in reducing anxiety50 when compared with bupropion51 or an SSRI.52

Used to augment standard antidepressant therapy, buspirone (Buspar) is another useful alternative in managing depressed patients with comorbid generalized anxiety.53,54 Buspirone lacks the rebound anxiety and withdrawal symptoms that may occur with other anxiolytics, such as benzodiazepines. Additionally, buspirone has been shown to be just as effective as lorazepam (Ativan).53 Minimal side effects and a delayed onset of action make buspirone an attractive alternative to traditional anxiolytics. Some evidence suggests that buspirone works well in severe cases of depression, particularly for improving symptoms of guilt and anhedonia,54,55 which might make it valuable in augmenting therapy of those with melancholic depression.

ADHD: The sustained-release form of bupropion may be of value for patients who have comorbid ADHD or whose depression causes problems with concentration.56 Bupropion SR is believed to be at least as effective as methylphenidate in improving concentration.57 This is an important treatment alternative for those who cannot tolerate or who have contraindications to stimulant therapy. While bupropion improves attention, it has not been found to decrease impulsive behavior that may be associated with ADHD.58

Sexual dysfunction (secondary to use of SSRIs): Sexual side effects are common with antidepressant therapy, particularly with SSRIs, and are a frequently cited reason for early discontinuation of medications. Addition of bupropion, buspirone, mirtazapine, nefazodone, yohimbine (Yocon), or cyproheptadine can reduce or eliminate sexual dysfunction.59-61 An alternative approach is to switch antidepressants. Bupropion is less likely than SSRIs to cause sexual dysfunction.3 Switching to mirtazapine has also shown efficacy in reducing sexual side effects.62 The problem of sexual dysfunction with SSRI therapy is fairly easy to correct, so be sure to follow up with patients to minimize this side effect.

Chronic pain: Physical complaints of pain are common in the depressed population. New classes of antidepressants, such as duloxetine (Cymbalta) and venlafaxine, target noradrenergic mechanisms in addition to serotonergic mechanisms. The use of serotonin-norepinephrine reuptake inhibitors may add benefit when compared with SSRIs in treating neuropathic pain, such as occurs in fibromyalgia and chronic pain syndromes.63-66 Similarly, comorbid anxiety may be better treated by these drugs compared with SSRIs.67 At high doses, venlafaxine may increase BP and should be monitored closely, especially in persons with hypertension. Milnacipran (Savella), a serotonin-norepinephrine reuptake inhibitor recently approved to treat fibromyalgia, is used to treat depression as well in other countries.

Obsessive compulsive disorder (OCD) The usual treatment for OCD is trials of high-dose SSRIs. Antipsychotics may be useful as augmentation to antidepressant therapy, particularly in populations with OCD. Second-generation antipsychotics reduce symptoms of inflexible thinking, as exhibited by those with OCD. Risperidone (Risperdal) and haloperidol (Haldol) have been shown to reduce compulsions and other symptoms associated with OCD.68,69

Additional treatments

Second-generation antipsychotics: Clearly, antipsychotic augmentation is warranted in those experiencing depression with psychotic features. The presence of psychotic features indicates severe impairment. As previously discussed, anti­psychotics may be of value in depressed populations with comorbid OCD, as well as other types of difficult-to-treat depression.

Risperidone has shown efficacy in reducing depressive symptoms.68,70 Haloperidol is also effective but to a lesser extent.68 Antipsychotics may also reduce manifestations of tic disorders.69 Aripiprazole (Abilify), another second-generation antipsychotic, is indicated as a potential augmenter in cases of treatment-resistant depression.71 Its use may be associated with significant side effects, including headache, fatigue, and akathisia.

Using antipsychotics as augmentation therapy in unipolar depression has some research support; unfortunately, these agents have not been evaluated as extensively in bipolar depression. Use of antipsychotics in bipolar mania is better understood; they are useful in reducing aggression and agitation during manic episodes.72 One study found that compared with lithium, quetiapine (Seroquel) yielded greater improvement in scores on the Hamilton Rating Scale for Depression and the Montgomery-Asberg Depression Rating Scale at both two and four weeks.73

Lithium: The use of lithium is not limited to bipolar patients. It should also be considered to augment therapy for unipolar depression. Lithium has been shown to enhance the effects of certain antidepressants without worsening adverse effects.74-77 Not only does lithium increase remission rates significantly, it also may be protective against relapse when used as continuation therapy.74

Stimulants: Ongoing research is evaluating whether stimulants can be useful in the treatment of depression in some populations, particularly among elderly patients. Few well-designed RCTs address the effectiveness of using stimulants as augmentation of antidepressant therapy. However, one large, well-designed study does indeed suggest that methylphenidate was effective in augmenting antidepressant therapy by reducing apathy and fatigue.78 Another smaller study found that methylphenidate used with citalopram improved depression in an elderly population compared with citalopram plus placebo.79 Emptage et al conducted a 10-year review of studies in elderly populations and concluded that methylphenidate was an effective agent in the augmentation of various antidepressant therapies.80

Pindolol: Pindolol may be beneficial for patients with bipolar depression and those experiencing their first episode of unipolar depression.81 However, this added benefit may only be evident early in the course of treatment. One study found that while the effect of adding pindolol to antidepressant therapy was significant at two weeks, the effect was equal to standard treatment by four weeks into the trial.82 Patients using pindolol, a beta blocker, should be monitored for hypotension and bradycardia. Pindolol should be avoided in those with a history of asthma or allergies.

Omega-3 fatty acids: Growing evidence suggests that levels of omega-3 fatty acids are deficient in at least some populations of depressed patients, i.e., those with perinatal or bipolar disease. At least one placebo-controlled RCT involving pregnant women indicates that supplementing the diet with omega-3 fatty acids may improve depression when used as monotherapy.83 A meta-analysis of 10 studies concluded that dietary supplementation with omega-3 fatty acids significantly improved depression in both unipolar and bipolar groups when used as monotherapy.84 Another study found efficacy of omega-3 fatty acids in bipolar individuals.85 However, given the small sample sizes, short study durations, and variable outcomes of these trials, larger studies replicating these findings are needed before omega-3 dietary supplementation can be recommended definitively, especially as monotherapy, for the treatment of depressed patients.

Testosterone: Little solid evidence supports the use of testosterone as an effective adjunct to treat depression. In men with hypogonadism, treatment-resistant depression, and HIV, testosterone may show promise, but further research is necessary.86

Dopamine agonists A number of studies, albeit small, have found that pramipexole (Mirapex) provides an antidepressant effect when used with a mood stabilizer in both bipolar and unipolar populations.87-90