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Alternatives for "difficult to treat" MDD

February 1, 2010
by William M. Glazer, MD
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Just 35 percent of MDD patients achieve remission with initial antidepressant monotherapy

A recent study published in a leading psychiatric journal used government data to find that use of multiple medications occurred in 60 percent of psychiatric office visits for patients receiving prescriptions.1 Adding a second (or third) antidepressant doubled in frequency during the study period between 1996 and 2006, yet guidelines promote the use of single antidepressants in a serial fashion. So do practicing clinicians know something that experts who write the guidelines do not?

Major depressive disorder (MDD) is a high volume and potentially costly condition that is treated widely with antidepressants in both behavioral and non-behavioral healthcare settings. These medications are, however, limited in their effectiveness. Studies show that only 50 percent of patients show improvement (response) after antidepressant trials. Even fewer patients reach remission, where they return to normal functioning.

There are two types of poorly responding patients that pose a particular challenge to clinicians and payers alike. The first group, which constitutes about 15 percent of all MDD patients, exhibits “treatment refractory depression.” No matter what is prescribed, they fail to respond. The second group consists of patients who show some symptomatic response to medication, but fail to remit adequately.

The importance of remission in MDD: The clock is ticking

According to the recent landmark “Star*D” study, only 35 percent of MDD patients reach remission, and of those that do, about one-third relapse within a year. To make matters worse, evidence suggests that patients whose MDD is only partially treated are more likely to experience worse outcomes over time than patients who have enjoyed remission. Specifically, studies have shown that they experience:

  • A greater risk of relapse and recurrence;

  • More chronic depressive episodes;

  • A shorter break between episodes;

  • More vocational and social dysfunction; and

  • Increased mortality rates from both medical conditions and suicide.

So the sooner these patients are treated effectively, the better their prognosis will be.

The fact that two-thirds of MDD patients require additional steps after an initial trial of a single antidepressant brings a certain drama to the treatment of MDD. “If I don't get my patient treated adequately from the start, they are going to suffer more severe consequences over time,” says Neil Liebowitz, MD, director of the Connecticut Anxiety and Depression Treatment Center in Farmington, Conn. “I like to work in a methodical fashion adjusting and/or adding treatments until remission is obtained.”

Questioning best practices for MDD: More aggressive treatment initially?

The current best practice for MDD is to “start a single ‘first-line’ agent and if it is not effective, then try other first-line agents,” says Stephen Stahl, MD, PhD, CEO of the Neuroscience Institute in Carlsbad, Calif. But this approach is time-consuming-the usual time frame for an antidepressant trial is six weeks. Two consecutive treatment trials will take up to three months, and we know that during this timeframe, half of these patients will stop their medications.

So the initial medication choice is a very important consideration in achieving decent clinical outcomes for the MDD patient. Over the past few years, the current MDD treatment guidelines are coming into question. According to Stahl, “A paradigm shift is afoot in which the chances of a first treatment working are maximized by giving combinations of treatments from the time the first antidepressant therapy is initiated.”2

Treatment options

In addition to selecting a single antidepressant at the start of treatment, there are two types of combination strategies that can be employed: augmenting the antidepressant with a non-antidepressant medication, or using two antidepressants at once.

Combining second generation antipsychotics with antidepressants

“Augmentation” involves the addition of another medication with the purpose of enhancing the effect of the antidepressant drug. There is an evidence base of the well-designed studies that have selected patients who have already exhibited failure to respond to antidepressant monotherapy. Within the last two years, three manufacturers have received FDA indications for use of second generation antipsychotics combined with antidepressants for treatment refractory MDD patients. But when one of the companies, AstraZeneca, attempted to extend the indication of its drug quetiapine (Seroquel XR) to a first-line monotherapy for MDD patients, FDA advisors balked, fearing that quetiapine's side effect burden-e.g., weight gain and metabolic problems-was too great for the increased numbers of persons that would be exposed to the drug. The review panel agreed that quetiapine by itself demonstrated clear efficacy for MDD symptoms. So for the time being, the augmentation strategies involving atypical antipsychotics will be limited to those MDD patients who have failed to respond adequately to individual antidepressants.

“My guess is that most clinicians would be more comfortable with antidepressant/antidepressant combination rather than adding a second generation antipsychotic from the start [in MDD],” said Dr. Leslie Citrome, Professor of Psychiatry, New York University School of Medicine.