Effective Next-Step Treatments Identified for Refractory Depression

Among patients with treatment-resistant major depressive disorder (MDD), two subgroups—patients aged 65 years and older and those with mixed hypomanic symptoms—may benefit from specific next-step treatments, according to a report published April 5 in AJP in Advance.

“Almost two-thirds of patients with major depressive disorder do not achieve remission with initial treatments,” according to Sidney Zisook, M.D., a distinguished professor of psychiatry at the University of California, San Diego, and colleagues. “Thus, identifying and providing effective, feasible, and safe ‘next-step’ treatments are clinical imperatives.”

The study involved more than 1,500 mostly older, white men with nonpsychotic MDD who were enrolled in the Veterans Affairs Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) study. To be included, participants must have previously failed to respond to at least one course of antidepressant treatment. The VAST-D study compared the effectiveness and safety of three next-step treatment strategies in a 12-week trial: switching to sustained-release bupropion, combining the current antidepressant with sustained-release bupropion, or augmenting the current antidepressant regimen with the antipsychotic aripiprazole.

In a 2017 JAMA article on VAST-D, researchers reported that aripiprazole augmentation significantly increased the likelihood of remission (29% of patients achieved remission) versus switching to bupropion monotherapy (22% achieved remission). Remission was defined as two or more consecutive visits during the 12 weeks with few or no depressive symptoms, as measured on the Quick Inventory of Depressive Symptoms. (The results of combining bupropion with the current antidepressant regimen did not differ significantly from the other results.)

Patients augmenting with aripiprazole also were less likely to experience anxiety than those in the bupropion treatment groups. However, adverse effects also were more frequent in the augmentation-aripiprazole group, including drowsiness, weight gain, and akathisia (a neurologic side effect characterized by a feeling of inner restlessness).

This latest study focused on identifying the most effective treatment strategies for patients based on sociodemographic or clinical features, a subject on which there has been very little research to date, Zisook told Psychiatric News. “We wanted to fine-tune earlier findings to help physicians determine, given an individual patient in your office, is there a rationale for giving one of these treatments over another? For the patient in front of you, when should you give drug X versus drug Y?”

To answer these questions, researchers evaluated participants’ response to the medications, as well as their age, ethnicity, and employment status; depression severity, duration, and subtype; level of anxiety; presence of mixed hypomanic symptoms; experiences with childhood adversity; symptoms of grief; co-occurrence of other medical and psychiatric conditions; mental health status; and quality of life.

The analysis revealed that augmentation with aripiprazole was more effective for specific patients—those aged 65 years and older—compared with the bupropion regimens. For patients with severe, mixed hypomanic symptoms, either augmentation with aripiprazole or combining the current treatment with bupropion was more effective than switching to bupropion alone.

“Although there is some advantage to aripiprazole, this needs to be weighed against the increase in potential side effects, including more weight gain, more daytime sedation, and neurologic side effects,” Zisook said. “Overall, it’s really a balancing act, and there’s no clear rule that’s going to apply to each patient. When considering what’s most likely to be effective versus potential side effects, you should always engage the patient when coming up with next-step treatments, because they’re the ones who need to be compliant taking the medication. So, they should be partners in making the decision.”

The researchers found that most patient demographic features did not predict overall remission at 12 weeks. Still, remission was more likely for individuals who were employed, less severely and chronically depressed, less anxious, andnot experiencing complicated grief symptoms and who had not experienced childhood adversity.

Participants with longer durations of the initial antidepressant treatment, better quality of life, and positive mental health status also were more likely to achieve remission, researchers reported.

“For patients with very severe depressions, high anxiety, or other features such as grief that are likely to predict a suboptimal response to antidepressants and antipsychotics, clinicians may need to be more patient because it may take longer for patients to respond,” Zisook said. “They should also consider adding other nonpharmacological treatments, such as cognitive-behavioral therapy, because these medications alone may not be enough.”

This study was supported and conducted by the Cooperative Studies Program in the Department of Veterans Affairs, VA Office of Research and Development. ■