Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder (MDD) Unresponsive to Antidepressant Treatment: the VAST-D Randomized Clinical Trial 

Major depressive disorder (MDD) is a chronic condition that affects millions of Americans. Unfortunately, first-line monotherapy does not adequately address depressive symptoms for some MDD patients. The VA Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) trial set out to determine the relative effectiveness and safety of 3 next-step treatments for MDD in patients who failed to respond adequately to at least 1 antidepressant treatment trial of adequate dose and duration. This clinical article summary shares the key findings of this landmark trial.

- Joan Kitten, ARNP

What do the findings of the VAST-D trial mean for a practicing PMHNP?

"Treating patients with MDD can be challenging and even frustrating, for both the patient and clinician, especially given that patients with MDD may not adequately respond to initial management. This trial is important in that it looks at 'next steps' for such patients and sheds light on responses to various second-line management strategies."

NP Psych Navigator contributors are paid consultants of AbbVie Inc.

Major depressive disorder (MDD) is a chronic, debilitating disorder that affects millions of American adults. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial showed that approximately 47% of patients respond to initial antidepressant pharmacotherapy for MDD, with only about 30% of patients achieving remission.1 With many patients with MDD requiring additional treatment strategies to achieve an adequate response, it is important to understand alternate or “next-step” treatments. The VA Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) study was a clinical trial designed to elucidate research-based “next steps” for outpatients with MDD who did not have an adequate response to standard “first-step” treatments.2 In VAST-D, patients were considered to have failed “first-step” therapy if they did not respond adequately to a treatment course with a selective-serotonin reuptake inhibitor (SSRI), serotonin and norepinephrine reuptake inhibitor (SNRI), or a particular atypical antidepressant of an adequate dose and duration.2

Why was the research needed?

Results from the STAR*D trial indicated that many patients with MDD are not adequately treated with initial monotherapy. That study looked at the effect of some switch and augmentation treatment strategies, but it did not include second-generation antipsychotics (SGAs), which are currently used as adjunctive treatment to an antidepressant in some adult patients with MDD. A more recent study that did include an SGA in its design is the VAST-D trial. The objective of the VAST-D trial was to determine the relative effectiveness and safety of 3 “next-step” treatments for MDD in patients who failed to respond adequately to at least 1 antidepressant treatment trial of adequate dose and duration. The patients were assessed for response in the acute treatment phase (12 weeks) and in longer-term follow-up (36 weeks).2

What did the researchers do?

The VAST-D study was a multi-site, randomized, single-blind, parallel-assignment trial.2 It enrolled 1522 adults (ages 18 to 75) diagnosed with MDD without psychosis who experienced inadequate response to at least 1 antidepressant treatment trial of adequate dose and duration.2 Participants were randomly assigned (1:1:1) to 1 of 3 treatments and evaluated for up to 36 weeks.2 The 3 “next steps” were to switch to a different antidepressant, a norepinephrine/dopamine-reuptake inhibitor (NDRI) (n = 511); to augment the patient’s current antidepressant with an NDRI (n = 506); or to augment the patient’s current antidepressant treatment with an SGA (n = 505). These “next-step” interventions were intended to last for 12 weeks for acute treatment phase assessment.2 Patients who achieved adequate response in the acute treatment phase were eligible for 24 additional weeks of follow-up to evaluate relapse and other outcomes.2

What were the key results of the study?

Assessment measures

The primary endpoint was remission of symptoms of MDD during the acute treatment phase as measured by the 16-item Quick Inventory of Depressive Symptomatology-Clinician Rated (QIDS-C16).2 Remission was defined as a QIDS-C16 score of 5 or less for 2 consecutive weeks during the acute treatment phase.2 Secondary endpoints included response, relapse, and adverse effects. Response was defined as a 50% reduction in QIDS-C16 score or improvement on the Clinical Global Impression Improvement (CGI-I) scale to a score of 2 or 1 at any scheduled visit through week 12.2


The primary outcome of remission at 12 weeks was significantly higher in the augment-SGA group (28.9%) compared with the switch-to-NDRI group (22.3%) but not compared with the augment-NDRI group (26.9%).2 Remission with the augment-NDRI group was not significantly different than in the switch group. Figure 1 illustrates that during this 12-week follow-up, 22% of patients achieved remission after switching to an NDRI, 27% of patients achieved remission on a combination of their current antidepressant plus an NDRI, and 29% of patients achieved remission after augmenting their current antidepressant with an SGA. 

Abbreviations: NDRI, norepinephrine and dopamine reuptake inhibitor; QIDS-C16, the 16-item Quick Inventory of Depressive Symptomatology, Clinician Rating; SGA, second-generation antipsychotic. 

The secondary outcome of response measured by the QIDS-C16 at 12 weeks was significantly higher in the augment-SGA group (74.3%) than for either the switch (62.4%) or the augment-NDRI groups (65.6%). There was no significant difference between the augment-NDRI group and the switch-to-NDRI group.2 Response measured by the CGI-I also favored the augment-SGA group (79%) compared with both the switch-to-NDRI group (70%) and the augment-NDRI group (74%).2 (Figure 2) Among patients achieving remission at 12 weeks, there were no significant differences in the secondary outcome of relapse among the 3 treatment groups.2 

 Abbreviations: NDRI, norepinephrine and dopamine reuptake inhibitor; SGA, second-generation antipsychotic.

Adverse events

Serious adverse events

Among 165 patients (10.8%), a total of 207 serious adverse events (SAEs) occurred. This included 8 deaths during follow-up or within 30 days of completion of the follow-up period. Investigators and the data safety monitoring committee agreed that the deaths were not related to the study medication.2

Nonserious adverse events

Nonserious adverse events associated with the switch-to-NDRI group included nausea, irritability, and hypomania.2 Nonserious adverse events associated with both the switch-to and augment-NDRI groups included anxiety, decreased appetite, dry mouth, and increased blood pressure.2 Nonserious adverse events associated with the augment-SGA group included fatigue, increased appetite, increased weight, akathisia, somnolence, and abnormal values for several laboratory tests.2 At week 12, weight gain of 7% or greater was more frequent in the augment-SGA group (9.5%) compared with the switch group (2.3%) and the augment-NDRI group (1.9%).2 For patients continuing through week 36, the proportion with weight gain of over 7% was similarly greater in the augment-SGA group (25.2%) compared with the augment-NDRI group (5.2%) and the switch group (5.2%).2

Additional VAST-D studies analyses

Identifying and providing safe and effective “next-step” treatments is important. In VAST-D, 47% of participants were diagnosed with MDD as well as concurrent posttraumatic stress disorder (PTSD).3 In 2020, the authors of the original study completed a secondary analysis looking at concurrent PTSD in patients with MDD.3 They wanted to determine if concurrent PTSD affected whether to augment or switch medications in patients with inadequate response to initial antidepressant monotherapy.3 The authors noted a 43% lower rate of remission within 12 weeks among patients with PTSD as compared to those without.3 Response rates were also noted to be lower among patients with concurrent PTSD across all 3 treatment groups, reflecting a 25% lower symptom improvement in that cohort.3


Limitations of this trial include the patient population studied; only Veterans Health Administration (VHA) patients were enrolled in this trial.4 Participants were largely male and White, with moderate to severe depressive symptoms, and about 30% of participants reported recent suicidal ideation. Participants also reported impairment in multiple domains and had negative self-worth.4 Many patients who were diagnosed with nonpsychotic MDD and failed initial pharmacotherapy still did not meet the inclusion criteria because they had already failed a trial of a medication used in the VAST-D trial or that was otherwise contraindicated.4 These limitations could make extrapolating results to the general population challenging.

Additionally, VAST-D used scales which are not used in clinical practice, including an adapted version of the Brief Grief Questionnaire, the Mixed Features Scale, and the Positive Mental Health Questionnaire.4 The latter 2 of these scales had not been validated or field-tested. The scientific leads of the study felt that there were no other alternative scales that met their objectives.4 VAST-D measures did not include age of onset of first major depressive episode or other key symptoms. These factors are both potentially useful prognostic indicators.4 Information was not collected on MDD “subtypes” (eg, atypical, anxious) or if onset was early, late, or seasonal. The authors did not feel, however, that such subtypes had been found to be reliable predictors of response in prior studies.4

Why are these results important?

Over half of patients with MDD do not achieve remission with initial antidepressant monotherapy.1,2 It is important that we recognize the urgency surrounding the unmet needs of MDD patients, especially regarding the poor clinical outcomes which may be experienced by patients with partial response to antidepressants.5,6 Thus, identifying and providing additional “next-step” treatment options are clinical imperatives.

VAST-D is noteworthy for its examination of the effects of augmenting with an SGA. The use of augmentation with an SGA has been shown to result in remission in some patients with MDD who did not have adequate response to first-line antidepressant monotherapy. Clinicians offering augmentation with an SGA should get baseline screenings and educate patients on the need for follow-up.2

What’s next?

Given the limitations cited above, it will be important to conduct similar trials among larger and more diverse populations of patients with MDD in the future. Further studies could provide more invaluable insights for developing personalized care for this patient population.

It is important to consider the heterogeneity of responses to antidepressant treatment and the value of continuing to develop evidence-based strategies to help most efficiently guide patient treatment journeys.   


  1. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163(1):28-40. doi:10.1176/appi.ajp.163.1.28
  2. Mohamed S, Johnson GR, Chen P, et al. Effect of antidepressant switching vs augmentation on remission among patients with major depressive disorder unresponsive to antidepressant treatment: the VAST-D randomized clinical trial. JAMA. 2017;318(2):132-145. doi:10.1001/jama.2017.8036
  3. Mohamed S, Johnson GR, Sevilimedu V, et al. Impact of concurrent posttraumatic stress disorder on outcomes of antipsychotic augmentation for major depressive disorder with a prior failed treatment: VAST-D randomized clinical trial. J Clin Psychiatry. 2020;81(4):19m13038.
  4. Zisook S, Tal I, Weingart K, et al. Characteristics of U.S. Veteran patients with major depressive disorder who require "next-step" treatments: a VAST-D report. J Affect Disord. 2016;206:232-240.
  5. Hung CI, Liu CY, Yang CH. Untreated duration predicted the severity of depression at the two-year follow-up point. PLoS One. 2017;12(9):e0185119.
  6. Kraus C, Kadriu B, Lanzenberger R, Zarate CA Jr, Kasper S. Prognosis and improved outcomes in major depression: a review. Transl Psychiatry. 2019;9(1):127. 

This resource is intended for educational purposes only and is intended for US healthcare professionals. Healthcare professionals should use independent medical judgment. All decisions regarding patient care must be handled by a healthcare professional and be made based on the unique needs of each patient. 

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