Combining antidepressants to address treatment-resistant depression

As discussed in Chapter 1 , it is helpful to define treatment-resistant depression (TRD). Although one defines treatment resistance, it is clear that this is a very significant clinical problem. We now know from multiple randomized controlled clinical trials and years of clinical experience that only a minority of patients are able to attain remission after treatment with an adequate dose of an antidepressant ( ).

Definitions of treatment resistance range from inadequate response to at least one antidepressant trial of adequate doses and duration, to failure to respond to a minimum of four different antidepressant treatments, including medications, evidence-based psychotherapy, or electroconvulsive therapy, administered at adequate doses and duration during the episode. Response has traditionally been defined as a 50% improvement on a dimensional rating scale of depressive symptoms such as the Hamilton Rating Scale for Depression (HAM-D) or the Montgomery-Asberg Depression Rating Scale (MADRS). However, the holy grail of depression treatment is remission, defined as a complete return to premorbid functioning arbitrarily defined as a HAM-D of 7 or less or an MADRS score of 10 or less. One might argue that even these are too liberal definitions of remission as those cutoffs would include patients with considerable morbidity ( ; ).

Reasons for why the remission rates in major depressive disorder (MDD) range from 28% in STAR*D ( ) to 50% in the PReDICT study of never-treated depressed patients remain obscure except the most obvious explanation, as recently reviewed by Nemeroff, is our very poor understanding of the pathophysiology of this serious and common psychiatric disorder ( ). Be that as it may, clinicians have a variety of evidence-based treatments to choose from when presented with a clear antidepressant monotherapy failure. These evidence-based strategies comprise a substantial portion of this volume. There are also exciting new developments in terms of novel treatments including theta burst accelerated TMS and novel antidepressants ( ).

Conceptualization of treatment resistance and modeling the approach, as addressed in 2, 6 respectively, are first steps to aid the clinician in achieving the goal of remission. There are multiple facets to creating a person-centered approach and our subspecialty of medicine allows us a very open-ended journey to knowing and helping patients as individuals. An optimal treatment plan combines the complex matrices of the person and the treatments. Other chapters provide in depth discussions of subtype of depression (unipolar, bipolar, psychotic); the macro- and microtime dimensions (child and adolescent, geriatric, pregnancy and postpartum, chronotherapeutics), the more common comorbidities (anxiety disorders, personality disorders, substance abuse, and chronic pain), and the potential role of pharmacogenomics, the latter clearly not realized. Faced with the many evidence-based treatments for patients who have failed antidepressant monotherapy, the clinician has little to guide him/her as there are no validated predictors of treatment response. Thus lithium, T3, pramipexole, a variety of atypical antipsychotics and several neuromodulation modalities are all available, many FDA approved.

In this chapter, we focus on the extant data concerning the use of combination antidepressant therapy.