Study identifies greater improvement for ‘next step’ treatment

Texas A&M psychiatry professor helps lead VA study that finds benefit of adding to antidepressant regimen
August 9, 2017

A clinical trial from Department of Veterans Affairs (VA) of veterans with major depressive disorder, published this month in the Journal of the American Medical Association (JAMA), found that the addition of an atypical antipsychotic medication to an antidepressant regimen showed greater improvement in symptoms of depression than switching to another antidepressant among patients who were not responding to their current antidepressant treatment.

“This is the largest study ever performed of ‘next-step’ pharmacotherapy for patients who did not have an adequate response to initial antidepressant pharmacotherapy,” said Paul B. Hicks, MD, PhD, vice dean and professor of psychiatry and behavioral sciences at the Texas A&M College of Medicine in Temple and one of 12 people on the study’s executive committee. “This is the best and largest comparison of switching versus augmentation strategies for ‘next-step’ pharmacotherapy that has been published. This study looks at the safety and efficacy of the use of a second-generation antipsychotic as an augmentation strategy for treatment-resistant depression.”

Hicks served as the initial site investigator for the Central Texas Veterans Health Care System, one of 35 VA medical centers across the country participating in the research, but was replaced in this role by Solomon Williams, MBBS, assistant professor of psychiatry and behavioral science, when Hicks became vice dean for the Temple Campus. The study’s executive committee, which provided oversight for the implementation of the project, including key decisions about management of the project from its inception until data analysis, also included principal investigators Somaia Mohamed, MD, PhD, of the VA New England Mental Illness, Research, Education, and Clinical Center and Yale Medical School, and Sidney Zisook, MD, VA San Diego Healthcare System and University of California, San Diego. Mohamed, a neuropsychologist, is a former associate professor in the Texas A&M College of Medicine Department of Psychiatry and Behavioral Science.

“Failure of depression pharmacotherapy is a major public health problem affecting millions of Americans each year,” Mohamed said. “There is a tremendous need for evidence on which treatments work best for these patients, and we found that among the three strategies evaluated in this study, evidence of the greatest symptom benefit was provided by adding an antipsychotic to previous antidepressant therapy.”

Major depressive disorder is a chronic, disabling disorder that affects an estimated 13 to 14 million American adults, or 5 percent of the adult population, annually. Previous large studies have shown that fewer than one-third of patients achieve remission with their first course of antidepressant pharmacotherapy. Thus, each year, as many as 9 million Americans may need a new treatment for their depression. A treatment that helps only 1 percent of these patients reduce depressive symptoms more than commonly used alternatives could potentially bring important relief to almost 100,000 Americans annually. Past studies have also compared treatments commonly used as “next step” therapies in major depressive disorder, but found no treatment to be significantly more effective than others.

However, since 2007, several antipsychotic medications have been approved by the US Food and Drug Administration (FDA) to be used in addition to antidepressant medication for patients whose depression has not responded to antidepressant treatment alone. Antipsychotic augmentation therapy has been found to be more effective than a placebo, but until now, no large study has compared it to other approved antidepressant switching or augmentation strategies.

The VA Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) study enrolled 1,522 veterans who were not experiencing an adequate response from their current antidepressant treatment. Participants were randomly assigned to one of three treatments: switching to another antidepressant, bupropion, from their current antidepressant; adding the antidepressant, bupropion, to their current antidepressant; or adding the atypical antipsychotic, aripiprazole, to their current antidepressant.

The primary objective of the VAST-D study was to compare the two different augmentation strategies to the switching strategy and then also to compare the effects of the two augmentation strategies.

The results showed a significantly greater likelihood of “remission” (nearly complete relief of depressive symptoms) during the 12-week acute treatment phase in the augmentation with aripiprazole group compared to the group switching to bupropion, with 29 percent remission in the group augmenting with aripiprazole compared to 22 percent remission in the group switching to bupropion. However, remission for augmentation with aripiprazole was not significantly different than augmentation with bupropion, where 27 percent achieved remission in the acute treatment phase.

For a secondary outcome measure of treatment response, defined as at least 50 percent improvement in depression symptoms, the study showed a significantly greater likelihood of response in the augmentation with aripiprazole group (74 percent) compared to both switching to bupropion (62 percent) and augmenting with bupropion (66 percent) groups.

Because major depression is often a chronic or relapsing disorder, it is not enough to get patients well; it is at least equally important to keep them well. Thus, the study also sought to determine if there were differences in longer-term outcomes. Patients who achieved remission during the first 12 weeks of the study were followed for up to 36 weeks to see if there were differences in the risk of worsening depressive symptoms, or relapse. No differences were found in rates of relapse among the treatment groups, suggesting that benefits achieved in the acute phase were sustained to a similar degree across treatments.

Side effects were also carefully monitored and emerged with all treatments. Overall rates did not differ among treatments, but bupropion and aripiprazole had different adverse event profiles. Anxiety was more frequent in the two bupropion groups while sleepiness, weight gain and a kind of restlessness called akathisia were more frequent with aripiprazole. Due to these differences, Mohamed suggested that treatments should be selected by doctor and patient together to meet the individual needs and preferences of each patient.

VAST-D was sponsored by the VA Cooperative Studies Program.

— Christina Sumners

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