This chapter presents a discussion of the terminology of refractory depression, and three management strategies, namely optimization of the current drug, substitution of the current drug with a different drug, and combination of two or more drugs. It reviews and evaluates various combination approaches through a consideration of the following factors: mechanism of action, evidence of efficacy, specificity and predictors of response, safety, and clinical use. The chapter distinguishes three combination strategies on the basis of treatment objective: augmentation, acceleration, and stabilization. Augmentation refers to the simultaneous use of multiple agents to increase efficacy over what might be obtained with any one of the agents used. Some of the combination agents discussed in the chapter includes lithium, triiodothyronine (T3), buspirone, stimulants, neuroleptics, and 5-HT1A antagonists. Buspirone is an azapirone derivative which acts as an agonist at the 5-HT1A receptor.