Should the Randomized Withdrawal Design for Relapse Prevention Studies in Mood Disorders Be Updated?

Co-chairs: Atul Mahableshwarkar, MD / Gary Sachs, MD

Medications to treat mood disorders are most commonly first approved for treatment of acute episodes. This is followed by study/studies that treat acutely ill patients in an open-label manner till they reach remission, followed by a variable period of continued open-label treatment. Total duration of open-label treatment has ranged from 6-26 weeks for approved agents. This is followed by a placebo-controlled, double-blind randomized withdrawal period during which rates of relapse are compared between the drug and placebo groups.

This is a powerful design which has consistently demonstrated sensitivity in separating drug from placebo when the acute studies have shown efficacy. Even when acute efficacy was not replicated, benefit in preventing relapses was evident which lead to approval of lamotrigine. However the following issues with this design and advances in the field should be considered and updates to it may be considered: 1) The definition of a relapse in these trials often requires the patient to be hospitalized or have a rather significant clinical worsening. In routine clinical care treatments are often adjusted earlier in a clinical course without waiting for dramatic worsening of clinical status. This clinical reality is not reflected in the current design; 2) Since the inception of this design the field has advanced to include the concepts of “roughening” as smaller worsening of clinical status which could lead to relapses and “necessary clinical adjustments” which was studied as a novel end point in patients with bipolar disorder in the LiTMUS trial; 3) Inclusion of patient evaluation of their clinical status such as using the QIDS or use of multiple assessments in determining relapse.

The proposed session will consist of 4 presentations, one outlining the issues, the second discussing the approaches from the LiTMUS study followed by presentations utilizing data from two separate recently concluded industry sponsored relapse prevention trials followed by regulatory discussions.