The problem of "hard to treat" MDD is both common and extremely important from a public health perspective. Even under conditions of well delivered care augmented by a "depression specialist" in either generalist or psychiatry specialist settings, only about one in three patients can be expected to achieve remission (i.e., relatively asymptomatic status) (+1), and many of these experience a relapse or recurrence within the next several months. Among those who do not achieve remission, neither switching to another antidepressant (+2) nor augmenting with another agent (+3) can be expected to result in remission in the majority of patients. Patients whose depressive episode fails to remit despite a well delivered trial of antidepressants plus at least one other well delivered trial of switching or augmenting medications may be considered "hard to treat". Such patients are at risk for all the untoward burdens of MDD including: chronicity and recurrence, comorbid and co-occurring disorders, increased morbidity and mortality associated with comorbid and co-occurring disorders, diminished quality of life, and increased suicide risk.

There is no simple best approach for handling hard to treat MDD. Clinicians, even "experts" in the field, have their own, often idiosyncratic, formulas for "the next best step". Their decisions are more often grounded in anecdotal data or recent past personal experience than in replicated, empirically-based data. Until very recently, there has been a dearth of randomized controlled trials (RCTs) on "hard to treat" MDD, and even the largest and best of the RCTs have failed to provide reliable algorithms.

I favor a systematic approach to help define the next best step for difficult to treat depressions that incorporates the six "Ds" of treatment resistant MDD: Diagnosis, dose, duration, different approaches, drugs and determination.

There is no easy solution to the problem of the difficult to treat depression. The approach outlined here systematically addresses diagnostic issues, dose, duration, different approaches, drug switching and augmentation strategies, and the determination not to give up. Although the challenge of treating such patients often seems daunting, the rewards of working with these patients can be enormous.

CME DisclosureSidney Zisook, M.D.; Advisory board/Speakers Bureau: GlaxoSmith Kline. Grant Support: Aspect Medical Systems, Pemlab, NIMH, Veterans Administration Health Care System. Speakers Bureau: Forest, Wyeth.