Introduction

Notwithstanding their extraordinary popularity, the new classes of antidepressants introduced during the past decade have not solved the problem of refractory depression. If anything, challenges to the clinician have grown more daunting: more patients are receiving antidepressants, their expectations are higher, third-party payors are now actively involved in monitoring treatment cost and efficiency, and the proliferation of treatment options has made choices among those options more complicated. Moreover, for all of their advantages in terms of safety, tolerability, and efficacy across a range of non-affective disorders, the new agents are not substantially more effective as antidepressants than the older tricyclics and monoamine oxidase inhibitors (MAOIs) (Montgomery, 1995).

Three basic operational strategies have emerged in the pharmacologic management of refractory depression (Table 10.1): (i) optimization of the current drug regimen; (ii) substitution of the current drug with a different drug; and (iii) combination of two or more drugs, one of which may be the current drug. This chapter will review and evaluate various combination approaches through a consideration of the following factors: mechanism of action, evidence of efficacy (including study designs and patient samples), specificity and predictors of response, safety (including common adverse effects and potential major toxicity), and clinical use (including dosage and special requirements). Before turning to this, however, a brief discussion of the terminology of refractory depression and all three management strategies will place the role of combination approaches in proper clinical perspective.

Refractory depression: basic concepts

Numerous formal definitions of refractory depression have been proposed (Nierenberg, 1990; Thase & Rush, 1995; Fava & Davidson, 1996).