Study to Answer What Comes Next When MDD Patients Don’t Respond

An ongoing study at more than 30 Veterans Administration (VA) medical centers will help provide clinicians with critical information about the best “next step” when patients with major depressive disorder (MDD) fail to respond to an initial antidepressant treatment.

The VA Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) study is a multi-site, prospective, randomized clinical trial of outpatients with nonpsychotic MDD. According to a paper describing the study’s rationale and design in Psychiatric Research (August 5), the study enrolled 1,522 veterans (approximately 50 subjects at each of 30 to 35 participating VA medical centers) including both men and women with a diversity of ethnic/racial and socioeconomic backgrounds. Participants were randomized to switching or augmenting arms of the study. Treatment arms included randomization to either switching to bupropion-sustained release (bupropion-SR) alone, augmenting current antidepressant therapy with bupropion-SR, or augmenting current antidepressant treatment with aripiprazole. Follow-up on the last subject will be completed in October.

The primary outcome for the VAST-D study is remission of depressive symptoms, defined by a score of 5 on the Quick Inventory of Depressive Symptomatology (QIDS-C16) for two consecutive visits during the 12 weeks of the acute treatment phase. Key secondary outcomes are response at the end of acute and continuation treatment, defined as 50 percent improvement from baseline on the QIDS-C16 and, as a separate response measure, a score of 1 or 2 indicating “much improved” or “very much improved” on the Clinical Global Impressions (CGI) Improvement Scale; percent change on the QIDS-C16 from baseline to end of acute and continuation treatment; and relapse, defined as having a QIDS-C16 score of greater than 11 after remission or during the continuation treatment.

Somaia Mohammed, M.D., Ph.D.

Somaia Mohamed, M.D., Ph.D., a co-principal investigator in the study, noted in comments to Psychiatric News that MDD is among the most disabling and widespread of mental disorders, causing as much or more functional impairment as chronic heart disease.

“Unfortunately, most research on antidepressant therapies is conducted by drug companies to win FDA marketing approval and compares new medications with placebo in short-term trials of about six weeks,” continued Mohamed, an associate clinical professor of psychiatry at Yale University School of Medicine. “What is really needed is research that compares approved medications over longer periods of time. These studies are often called hybrid efficacy-effectiveness studies because they use rigorous research methods and are designed to answer practical treatment questions in the setting of real-world practice. Only these kinds of studies can guide real-world clinical decision making in which the decision is almost never ‘should I use a medication or not?’, but rather ‘which medication will give the most long-term benefit for this particular patient?’ The field called comparative-effectiveness research has been developed to address this need throughout medicine.”

Mohamed said that VAST-D is unique in that it compares three FDA-approved treatment strategies to be used after a patient has already failed to benefit from a first treatment attempt. “It uniquely addresses a question of urgent practical relevance: what to do as a next-step therapy for major affective disorder,” she said. “In addition, it examines benefits over a far longer period than most clinical trials of antidepressants. For statistical reasons, such studies require many patients (1,500 in the case of VAST-D), and many clinics must be involved.”

She added that VAST-D results will provide an empirical basis for practice guidelines, replacing clinical consensus.

Michael Thase, M.D., an expert on depression and antidepressant treatment and one of the participating investigators at the Philadelphia VA Medical Center, said VAST-D is important because it follows on the findings of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. He is a professor of psychiatry at the Perelman School of Medicine at the University of Pennsylvania.

“VAST-D compares one of the better adjunctive treatment options studied in STAR*D—namely, adding the antidepressant bupropion to ongoing therapy with an SSRI or SNRI—with the most widely used strategy of the past decade, namely, adding the second-generation antipsychotic aripiprazole to ongoing antidepressant therapy,” Thase told Psychiatric News. “Because VAST-D is being conducted in VA clinics, it will provide valuable and needed information about difficult-to-treat depression in a predominantly male population, including a relatively high proportion with comorbidities such as substance and alcohol use disorders and PTSD.”

The VAST-D study is being supported by the U.S. Department of Veterans Affairs. ■