Ten to 30 percent of patients taking antidepressants are partially or totally resistant to the treatment. Some patients also may experience breakthrough or recurrence of depression while taking the medication. Strategies for dealing with these problems include optimizing the dosage, switching medications, and adding combination or augmentation therapy, or electroconvulsive therapy.

An adequate trial of antidepressant therapy is commonly defined as four to six weeks. If the patient has a partial response, another four to six weeks of treatment and dosage titration should allow for a more complete response.

Patients who are unresponsive to treatment with antidepressants may become responsive by switching (45 percent) or augmentation (56 percent). Nonresponders are likely to respond if switched to an antidepressant with a different mechanism of action. Because SSRIs are structurally diverse, switching within the class of SSRIs may be useful. Patients must taper off of one agent before starting another to avoid the possibility of drug interactions, particularly serotonin syndrome.

Combination therapy involves the addition of a second antidepressant in patients who exhibit a partial response to one agent. This approach is frequently used to boost the response to initial treatment; however, no double-blind, placebo-controlled studies confirm the usefulness of this practice. In addition, it may lead to significant adverse effects or drug-drug interactions.

Augmentation, or the addition of another drug to an antidepressant, is a useful strategy in patients with a partial response. The second drug is usually not an antidepressant. The best documented options are lithium and triiodothyronine (T3). Lithium is administered in the usual dosages, keeping the lithium blood levels to the lower end of the range (0.4 to 0.8 mEq per L). The augmentation dosage of T3 is 25 mcg per day. [corrected]

Case reports and open studies indicate that augmentation with buspirone (Buspar, in a dosage of 15 to 30 mg per day), the psychostimulant methylphenidate (Ritalin, in a dosage of 10 to 15 mg per day), or pindolol (Visken, in a dosage of 2.5 to 7.5 mg per day with SSRIs) can be effective and tends to cause minimal adverse effects.

Electroconvulsive therapy is the most effective treatment in patients with severe resistance to medical antidepressant therapy or those with psychotic depression. Electroconvulsive therapy is safe under medically monitored conditions.

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Reviewed: 01/2006