The authors examine recent literature in order to assist psychiatrists in evaluating the findings and determining how to best put research findings into real-world practice.
Major depressive disorder (MDD) is a prevalent and debilitating chronic condition1 for which first-line standard antidepressant treatment modalities lead to remission in only one third of patients who experience it.2 As psychiatrists, we are faced with tough decisions on how to proceed in managing non-response to the remaining two thirds. Strategies include antidepressant switching or augmentation with various agents. To complicate matters, a highly co-morbid condition for those with MDD is posttraumatic stress disorder (PTSD) with national surveys showing a 0.5 correlation.3 Such co-occurrence is associated with greater disease burden severity and very different challenges in terms of management compared with MDD alone.4
In a secondary analysis of a 2017 study,5 Mohamed and colleagues6 tackled a timely question: Should a PTSD comorbidity affect our decision of how to manage MDD non-response to a first line antidepressant treatment?
1. Structured Question
Type of Question: Should a concurrent PTSD diagnosis affect whether to augment or switch medications when MDD has not responded to a prior antidepressant trial?
Type of study: Secondary analysis of a randomized, single-blind, parallel-assignment trial (ClinicalTrials.gov identifier: NCT01421342).5 [Note: This clinical trial is the 2017 study5 which generated the data based on which the 2020 secondary analysis6 was conducted].
Population: In a total of 35 study sites, from December 2012 to May 2015, that included a total of 1522 Veterans Health Administration (VA) patients, primarily men (85.2%) with a mean age of 54.4, who experienced suboptimal response to at least 1 course of SSRI/SNRI/mirtazapine antidepressant treatment meeting minimal standards for dose and duration.5 A total of 717 participants (47.1%) had a co-occurring PTSD diagnosis. Patients all had a diagnosis of non-psychotic MDD and were referred by their VA clinicians.
Exposures: Study assignment was random (1:1:1) to 3 treatment strategies: switch to bupropion (switch-BUP); augment current antidepressant with bupropion (aug-BUP); or augment current antidepressant with aripiprazole (aug-ARI).
Method: For 12 weeks the participants underwent treatment with either switch-BUP (n = 511), aug-BUP (n = 506), or aug-ARI (n = 505). Blinded ratings with the 16-item Quick Inventory of Depressive Symptomatology-Clinician Rated (QIDS-C16) determined remission (less than or equal to a score of 5) and response (reduction in score from baseline by 50% or more) by 12 weeks and relapse after remission (score of 11 or more for those who previously achieved remission). Long-term follow up lasted up to 24 weeks. Survival analyses compared treatment effects in patients with concurrent PTSD and those without it.
Statistical analysis: Remission and response outcomes for patients with and without comorbid PTSD were compared using Cox regression models with comorbid PTSD and treatment as independent variables with an interaction term for treatment and PTSD. Multivariable Cox regression models were developed using stepwise regression in which significant predictors of outcome that were associated with PTSD were added to the models to adjust estimates of PTSD and treatment effects for covariates. Comparisons were expressed by relative risk ratios (RR) estimated from hazard ratios from Cox models and 95% confidence intervals (CI), reporting the Wald test P values.
From the main study,6 among the 1522 randomized veterans, 1137 (74.7%) completed the treatment phase. Remission rates at 12 weeks (primary outcome) were 22.3% (n = 114) for the switch-BUP group, 26.9% (n = 136) for the aug-BUP group; and 28.9% (n = 146) for the aug-ARI group. Response (secondary outcome) was greater for the aug-ARI group (74.3%) than for either the switch-BUP (62.4%; RR, 1.19 [95% CI, 1.09-1.29]) or aug-BUP (65.6%; RR, 1.13 [95% CI, 1.04-1.23]). Anxiety was more frequent in the 2 bupropion groups (24.3% in switch-BUP [n = 124] vs 16.6% in the aug-ARI group [n = 84]; and 22.5% in aug-BUP group [n = 114]). Adverse effects were more frequent in the aug-ARI group and included somnolence, akathisia, and weight gain.
2.1. Comparing the impact of a PTSD comorbidity
A greater proportion of African American and Hispanic patients were found in the comorbid PTSD group and overall patients with comorbid PTSD had more severe depressive symptoms on the QIDS as well as global clinical severity indexes, and lower qualty of life scores.
In terms of retention, of the 717 participants with PTSD, 27.6% withdrew from the study before the 12 week completion compared to 23.2% without (difference=4.4% [95% CI, 0.001%–8.76%], P=.0495). The difference in dropout for those with PTSD vs. those without PTSD was greatest in the aug-BUP group (29.5% vs 21.4%, respectively; difference=8.1% [95% CI, 0.52%–15.7%], P=.035) but similar in the switch-BUP and aug-ARI groups.
In terms of remission, at 12 weeks there was a 43% lower risk of remissionfor those with comorbid PTSD (RR=0.567; 95% CI, 0.462–0.697), with all 3 treatments, irrespective of the severity of MDD. Kaplan-Meier plots of cumulative probability of remission for each treatment group by PTSD status show remission rates are lower in the PTSD group, and the switch-BUP treatment group had the lowest rate of remission.
Relative risk of response was also significant for those with PTSD (RR=0.745; 95% CI, 0.658–0.843) and for each of the 3 treatments, reflecting a 25% lower symptom improvement among those with PTSD. For relapse after remission, the risk was not significantly greater among those with PTSD (RR=1.30; 95% CI, 0.867–1.94). The results across treatment groups were mixed, with significantly greater likelihood of relapse among participants with PTSD in the aug-BUP group (RR=2.19; 95% CI, 1.13–4.25) but not among those in the switch-BUP or aug-ARI groups.
2.2. Comparing the impact of various treatment interventions
A comparison of the magnitude of treatment effects between pairs of treatments (risk ratios reflecting comparative effectiveness of paired treatments) among patients with and without PTSD showed no significant differences in comparative treatment effectiveness on remission between patients with and without PTSD. In the analysis of response, augmentation with aripiprazole was associated with significantly greater likelihood of achieving response (68.4%) than switching to bupropion (57.7%) in patients with PTSD (HR=1.26; 95% CI, 1.01–1.59) and also in patients without PTSD (HR=1.29; 95% CI, 1.05–1.57) (78.9% response with augment with aripiprazole vs 66.9% response with switching to bupropion).
There were no significant differences in response between augmentation with aripiprazole and augmentation with bupropion in either patients with PTSD or patients not diagnosed with PTSD. The analysis of relapse showed no significant differences between pairs of treatment groups with or without PTSD and minor interaction of treatment group and PTSD diagnosis (P=.15).
3. The bottom line
In this population of older veteran males with nonpsychotic moderate to severe MDD unresponsive to antidepressant treatment, those with comorbid PTSD showed greater disease burden at baseline and significantly lower remission and response with 3 next-step 12-week treatments.6 Augmentation with aripiprazole resulted in a small, yet statistically significant, increase in response likelihood at 12 weeks when compared with switching to bupropion irrespective of a comorbid PTSD diagnosis.
There were several limitations of the 2020 study. First, it was conducted within the VA system with a predominantly older male population with likely combat-related trauma histories. It is thus unclear whether results would generalize to the broader population with other underlying PTSD forms. Second, despite inclusion of a greater proportion of participants with non-psychotic psychiatric comorbidities, there were still a number of exclusion criteria, including active substance use which represents a significant comorbidity found in patients with MDD.
Third, all individuals included here experience a moderate degree of depression severity; hence, these findings cannot be extrapolated in the care of patients with mild and severe MDD. Fourth, 26% of participants did not complete the study, resulting in a fairly substantial dropout rate. It is also possible that the group that switched to bupropion may have experienced withdrawal from previous treatment, putting them at a disadvantage for dropout or other adverse outcomes. Fifth, only 1 antidepressant and 1 antipsychotic were evaluated. Generality to other agents is unknown, especially to factors such as behavioral interventions, tricyclic antidepressants, monoamine oxidase inhibitors, electroconvulsive therapy, transcranial magnetic stimulation, and lithium augmentation. Lastly, although there was no financial support from industry, authors did disclose some pharmaceutical affiliations, which may potentially lead to biases.
Dr Stanciu is Assistant Professor of Psychiatry at Dartmouth’s Geisel School of Medicine and Director of Addiction Services at New Hampshire Hospital, Concord, NH. He is Addiction Section Editor for Psychiatric TimesTM. Dr Gnanasegaram is Instructor in Psychiatry at Dartmouth’s Geisel School of Medicine and Attending Psychiatrist at New Hampshire Hospital, Concord, NH. The authors report no conflicts of interest concerning the subject matter of this article.
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