Lithium augmentation is the best- known and best-studied. The rationale for using lithium(Drug information on lithium) in treatment-resistant depression is that it potentiates the action of serotonin by reducing negative feedback through the serotonin (5-HT)-1A receptor. It may also modulate second-messenger systems that may not only enhance the actions of antidepressants but also confer intrinsic antidepressant effects. Lithium can be added to TCAs, MAOIs, and SSRIs; however, the majority of studies report the use of lithium augmentation of TCAs. The usual dosage of lithium is 600 to 1200 mg/d, with the goal of achieving a blood level of 0.4 to 0.8 mEq/L.
Response rates to lithium augmentation have been reported between 30% and 50%, and a review of 22 clinical reports listed response rates as high as 71%. A response may be seen as soon as 48 hours after the initial dose, but it usually takes about 2 weeks. Disad- vantages in using lithium include the need for monitoring blood levels and the risk of toxicity.1,4
Augmentation using thyroid hormone is another commonly employed strategy. The use of triiodothyronine (T3) to augment antidepressants has a response rate of 60% in patients with treatment-resistant depression.11 In contradistinction to lithium, thyroid hormone is thought to potentiate norepinephrine(Drug information on norepinephrine). It may also correct subclinical hypothyroidism that can contribute to depressive symptoms, or it may down-regulate thyroxine (T4). T3 lowers circulating levels of T4, the form of thyroid that enters the brain. Depressed patients may display relative hyperthyroidism because they have elevated T4 and most antidepressant treatments lower T4 levels. Level A evidence supports the use of thyroid augmentation but most controlled trials augmented TCAs. In most of the studies, patients who responded to thyroid augmentation were maintained on it for 2 to 3 weeks.12,13
Adding another antidepressant with a different mechanism can also enhance the response to the original treatment. Two agents commonly used for their addition of noradrenergic effects to SSRI treatment are bupropion and nortriptyline(Drug information on nortriptyline).14 Nortriptyline is the best- studied noradrenergic agent, and open-label response rates have been reported as 87% and higher when it is used as an augmentation agent.8 Bupropion augmentation in patients in whom citalopram(Drug information on citalopram) monotherapy had failed led to 30% to 40% remission rates.9 Another antidepressant used in augmentation is mirtazapine(Drug information on mirtazapine). It acts by blocking postsynaptic a-2 heteroceptors. This blockade prevents the normal feedback of serotonin inhibition by norepinephrine. It also blocks 5-HT2 and 5-HT3 receptors, which may decrease the side effects of increased serotonin, including nausea, anxiety, and sexual dysfunction. In at least 1 double-blind study, significant additive effects were observed.15
Another class of medication to use in augmentation is the stimulants. They are commonly used in the consultation-liaison service where depression may be interfering with the patient's ability to receive medical care and a rapid antidepressant response is needed while waiting for the SSRIs to take effect. Stimulants target somatic symptoms seen in medically ill patients with de- pression, such as fatigue, decreased appetite, decreased cognitive function, and pain.4 Unfortunately, most of the data are from case series or case reports, which points to the need for further studies. The dosages prescribed are usually 5 to 10 mg of methylphenidate(Drug information on methylphenidate) 3 times a day and 5 mg of dextroamphetamine 3 times a day. Modafinil(Drug information on modafinil) is similar to the stimulants and can also be used to augment antidepressants. In 1 study, SSRI-refractory depression had a response rate of 63% when 200 mg/d of modafinil was added versus a 45% response rate with placebo.16
An entirely different agent that is commonly used in clinical practice is buspirone(Drug information on buspirone). The rationale behind using buspirone to augment antidepressants is that it is a partial agonist at the 5-HT-1A autoreceptor. It not only blocks feedback inhibition of serotonin release but has some agonist activity in the setting of low serotonin. There are several open series studies with positive results. However, 2 large, double-blind placebo-controlled trials found buspirone augmentation to be equivalent to placebo.17,18 More recently, however, when buspirone was used for augmentation in patients in whom citalopram therapy had failed, about 30% of patients achieved remission, which was similar to the response achieved by patients receiving bupropion augmentation.19
Recently emerging data on the use of antipsychotic medication as augmentation agents for treatment-resistant depression afford clinicians another option. The rationale for using atypical antipsychotics is that they enhance antidepressant effects by blocking postsynaptic serotonin receptors and by increasing the release of monoamines in the prefrontal cortex. A study of the rat prefrontal cortex showed that when fluoxetine(Drug information on fluoxetine) and olanzapine(Drug information on olanzapine) are used together, the synergy produced a much greater increase in dopamine(Drug information on dopamine) and norepinephrine levels than when either agent was used alone.20
Initial results from clinical studies investigating atypical antipsychotic augmentation were positive. In one study, 28 patients with treatment-resistant depression in whom not only an SSRI but also a serotonin-norepinephrine reuptake inhibitor (SNRI) had failed, were given fluoxetine for 6 weeks. When this also failed to treat their depression, they were randomly assigned to treatment with fluoxetine and placebo, olanzapine and placebo, or the combination of olanzapine and fluoxetine for 8 weeks.21