Introduction

The introduction of monoamine oxidase inhibitors (MAOIs) and imipramine in the 1950s for depression and the introduction of lithium for bipolar disorder in the 1970s transformed the biological understanding and treatment of mood disorders for millions worldwide. Methodologically sound meta-analyses and integration of scores of randomized clinical trials show that antidepressants and mood stabilizers are superior to placebo for both the acute and long-term treatment of unipolar and bipolar mood disorders, although some question the magnitude of the effect when taking into account unpublished trials that fail to differentiate active antidepressants from placebo (Hooper and Amsterdam 1998).

The methods used to demonstrate efficacy (i.e., superiority over placebo in tightly regulated randomized clinical trials) and achieve approval by the U.S. Food and Drug Administration (FDA) require that patients respond (usually defined as a 50% improvement in a standard baseline measurement of depression) more with active treatment than with placebo. A 50% improvement over baseline, however, leaves many patients with residual symptoms. These residual symptoms, in turn, are associated with suboptimal functioning (Miller et al. 1998) and a high risk of relapse into an episode of major depression (Judd et al. 1997, 1998). Alternatively, full remission of depressive symptoms improves functioning and lowers the risk of subsequent relapse.

The goal, therefore, is full remission of the depressive episode, a goal that is achieved in no more than 30%-50% of patients in most clinical trials of antidepressants and mood stabilizers. It is notable that failure to provide full remission in all patients occurs frequently in many medical treatments (e.g., angioplasty, coronary artery bypass grafts, antihypertensive treatments, analgesics, antiparkinsonian drugs, and insulin). In the broadest sense, the failure to achieve and maintain remission can be considered the definition of treatment-resistant depression.

Although many therapeutic options are available to manage resistant depression, few studies compare competing options at key decision points. The National Institute of Mental Health (NIMH) recognized the gap in knowledge and the critical need to obtain better data for clinicians to make informed decisions for both treatment-resistant unipolar depression and bipolar states (mania, rapid cycling, bipolar depression). To bridge this gap, two large NIMH studies that will evaluate competing treatment options along an algorithm are being conducted: the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) (http://www.edc.gsph.pitt.edu/stepbd) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) (http://www.edc.gsph.pitt.edu/stard). The results of these studies are pending. In the meantime, this chapter will critically review the available data for treating resistant mood disorders. First the data on the management of unipolar depression will be covered, and then the complex management of bipolar disorder will be reviewed.