PICO SEARCH ASSIGNMENT WORKSHEET              

Brief description of patient problem/setting (summarize the case very briefly):

Pt. A. P. Is a 55 y/o male currently unemployed and domiciled with a friend who initially presented to the hospital after a suicidal gesture in which he approached the train tracks with an intent to kill himself. Patient’s PMHx includes MDD, Alcohol use disorder (in remission), and a Brain aneurysm. Patient was previously prescribed sertraline and duloxetine for his depression but complains of persistent insomnia, low-appetite, and dysphoric mood. Upon evaluation patient’s affect is constricted but he appears to be emotionally stable. At the moment he does not wish to contact the friend he is currently domiciled with or his sister who he provided as collateral. Patient denies current suicidal or homicidal ideation and denies auditory or visual hallucinations.

Search Question: Clearly state the question (including outcomes or criteria to be tracked)

In adults with treatment resistant major depressive disorder who have had an inadequate response to multiple antidepressants, does augmenting the current antidepressant compared with switching antidepressants improve remission rates and depressive symptoms?

Question Type: What kind of question is this? (boxes now checkable in Word)

☐Prevalence                          ☐Screening                ☐Diagnosis

☐Prognosis                             X Treatment                ☐Harms

Assuming that the highest level of evidence to answer your question will be meta-analysis or systematic review, what other types of study might you include if these are not available (or if there is a much more current study of another type)? 

Please explain your choices. 

If meta-analyses or systematic reviews aren’t available to help answer a clinical question, I would then turn to randomized controlled trials like I’ve done with this PICO. These are excellent choices when you want to directly compare two interventions such as augmentation vs switching while minimizing any potential confounders, this is the benefit of randomization. The RCT’s that I’ve chosen were also pragmatic RCT’s which are a lot more applicable to real patient encounters and decision making. If an RCT was not available, I would then revert to prospective cohort studies which involves researchers tracking patient over time into the future to look at outcomes. These studies give you the benefit of looking at more long-term occurrences such as relapse rates, non-adherence resulting from AE’s and sustained remission. Another potential option would be retrospective cohort studies which classically are keen in detecting rare adverse events which are always a consideration with medications. Usually, such data can be pulled from claims data or EHR’s. More importantly these are another decent option because they are better suited for patient populations that are usually excluded from RCT’s such as those with polypharmacy or multiple comorbidities.

PICO search terms:

P	I	C	O
Major depressive disorder	Augmentation	Switchingantidepressant	Depression symptoms
Treatment-resistant depression	Adjunctive	Change antidepressant	Symptom severity
Adults with depression	Combination	Alternative antidepressant	Remission
Unipolar depression	Add-on	Different antidepressant	Treatment effectiveness
TRD

Search tools and strategy used:

I used 3 different databases, and these include: EBSCO (CINAHL), Pubmed, & the Nature journal. I wanted to note that the 2^nd study was found originally with Science Direct, but it was not the actual RCT which I could only find a full-text link to on the Nature journal. With each database I used different combination of my search terms and filters until I arrived at results of generally < 200. I made sure to include the key terms such “Treatment-resistant depression”, “Augmentation”, “Switching” etc. Some of the filters I used include within the last 10 years, full text, meta-analysis, randomized controlled trial, systematic review, English, USA, etc. Once I achieved an optimal number of results, I then looked for titles with clear relation to my topic, and I keenly reviewed the abstract information to get a general idea of the study’s contents. I made sure that each study was comparing augmentation to switching antidepressants which help to keep my research focused and relevant. Overall, this allowed me to find some intriguing studies that contribute to the evidenced-based thought process behind next steps in patients with depression not responding to initial treatments. Also, as my search strategy explains, I did consider systematic reviews and meta-analyses however the RCT’s that I found were more relevant to my PICO question and provided specific comparisons between augmentation and switching.

Database	Search Terms Used	Number of Results	Filters/Limiters Applied
EBSCO (CINAHL)	Depression AND Augmentation OR switching AND Depression symptoms	143	Within last 10 years, English language, USA
Nature (Molecular Psychiatry)	TRD AND Augmentation AND switching antidepressant AND treatment effectiveness	22	In the last 5 years
Pubmed	Depressed patients AND Augmentation OR Switching AND Remission	151	Last 10 years, free full text, full text, meta-analysis, randomized controlled trial, systematic review, English, medline

Results found:

1. Lenze, Eric J., et al. “Antidepressant Augmentation versus Switch in Treatment-Resistant Geriatric Depression.” New England Journal of Medicine, vol. 388, no. 12, 3 Mar. 2023, https://doi.org/10.1056/nejmoa2204462.

1. Study Type: Randomized Controlled Trial
2. Abstract:

1. Background: The benefits and risks of augmenting or switching antidepressants in older adults with treatment-resistant depression have not been extensively studied.
2. Methods: We conducted a two-step, open-label trial involving adults 60 years of age or older with treatment-resistant depression. In step 1, patients were randomly assigned in a 1:1:1 ratio to augmentation of existing antidepressant medication with aripiprazole, augmentation with bupropion, or a switch from existing antidepressant medication to bupropion. Patients who did not benefit from or were ineligible for step 1 were randomly assigned in step 2 in a 1:1 ratio to augmentation with lithium or a switch to nortriptyline. Each step lasted approximately 10 weeks. The primary outcome was the change from baseline in psychological well-being, assessed with the National Institutes of Health Toolbox Positive Affect and General Life Satisfaction subscales (population mean, 50; higher scores indicate greater well-being). A secondary outcome was remission of depression.
3. Results: In step 1, a total of 619 patients were enrolled; 211 were assigned to aripiprazole augmentation, 206 to bupropion augmentation, and 202 to a switch to bupropion. Well-being scores improved by 4.83 points, 4.33 points, and 2.04 points, respectively. The difference between the aripiprazole-augmentation group and the switch-to-bupropion group was 2.79 points (95% CI, 0.56 to 5.02; P=0.014, with a prespecified threshold P value of 0.017); the between-group differences were not significant for aripiprazole augmentation versus bupropion augmentation or for bupropion augmentation versus a switch to bupropion. Remission occurred in 28.9% of patients in the aripiprazole-augmentation group, 28.2% in the bupropion-augmentation group, and 19.3% in the switch-to-bupropion group. The rate of falls was highest with bupropion augmentation. In step 2, a total of 248 patients were enrolled; 127 were assigned to lithium augmentation and 121 to a switch to nortriptyline. Well-being scores improved by 3.17 points and 2.18 points, respectively (difference, 0.99; 95% CI, −1.92 to 3.91). Remission occurred in 18.9% of patients in the lithium-augmentation group and 21.5% in the switch-to-nortriptyline group; rates of falling were similar in the two groups.
4. Conclusions: In older adults with treatment-resistant depression, augmentation of existing antidepressants with aripiprazole improved well-being significantly more over 10 weeks than a switch to bupropion and was associated with a numerically higher incidence of remission. Among patients in whom augmentation or a switch to bupropion failed, changes in well-being and the occurrence of remission with lithium augmentation or a switch to nortriptyline were similar. Major depression is common in older adults1 and often persists despite appropriate treatment with first-line antidepressants.2 Treatment-resistant depression is typically defined as depression that does not remit despite two adequate trial uses of antidepressant medications3; in older adults, treatment failure is associated with decreased psychological well-being,4 disability,5 and cognitive decline.6-8 Pharmacologic strategies for treatment-resistant depression include augmentation, in which a medication is added to an existing antidepressant, and the replacement of an antidepressant with one from a different class (“switching”). The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial showed that augmenting with, or switching to, bupropion was as effective as or more effective than other strategies.9,10 In a randomized trial involving older adults, augmentation with aripiprazole was more effective than with placebo for reducing depression.11 In the Veterans Affairs Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) trial, augmentation with either aripiprazole or bupropion was slightly more effective than a switch to bupropion,12 but there are limited large comparative-effectiveness studies involving older adults with treatment-resistant depression that would clarify treatment strategies. There is increasing awareness of the importance of involving patients in the design of clinical trials.13 In a survey involving older adults with treatment-resistant depression, patient stakeholders recommended psychological well-being as an outcome that matters.14 Psychological well-being encompasses satisfaction, happiness, cognitive engagement, meaning, and purpose.15 There is also limited understanding of the comparative safety of antidepressant strategies in older adults,16 including risks of falls,17-21 cardiovascular risks,22 and risk of death23 with different agents used in trials. According to expert opinion, augmentation may lead to more adverse effects and a greater risk of drug interactions.24 There are also safety concerns with respect to using lithium or nortriptyline, approaches to treatment-resistant depression that are used in older adults.25,26 The current trial, Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM), was designed to investigate the benefits and risks of augmentation as compared with switching strategies for treatment-resistant depression in older adults.
5. Key Points:

1. This is a randomized controlled trial looking at adults ≥60 with treatment-resistant MDD. It directly compared two next step options which were augmentation of the current antidepressant vs. switching antidepressants.
2. Step 1 refers to the first randomized treatment change in which everyone who was enrolled into the study was compared on the basis of augmentation with either aripiprazole or bupropion vs. switching off the patient’s current antidepressant to bupropion. What they found was that augmentation with either agent produced greater improvement in depressive symptoms as measured by the change in MADRS (Montgomery-Asberg Depression Rating Scale).
3. Step 2 refers to the second randomized treatment consisting of people who didn’t benefit or progress into remission from Step 1 in addition to those deemed not eligible for Step 1 (for example having tried one of the Step 1 meds prior). This group was compared on the basis of augmentation with lithium vs. switching off the current antidepressant and beginning nortriptyline. This time there was no clear benefit to augmentation vs. switching.
4. The findings overall suggest that augmentation with medications such as aripiprazole or bupropion overall demonstrated greater efficacy in the initial next step, but when these options failed there were no significant differences between augmentation and switching.

4. Why I chose this study:

• This was a large multisite RCT across 5 academic centers in adults and its focus directly matched my PICO question in the sense that it compared augmentation of an existing antidepressant vs. patients being switched to an alternative antidepressant. What additionally added to the credibility of this study is its use of the MADRS which is an excellent measure of depressive symptoms as a secondary outcome. I thought it was also very clinically relevant in how they structured their research design into steps which is a lot like how treatment decisions would be made in real-life situations. The study even mentioned some points on safety which certainly plays a part in next step treatment decisions, it mentioned that bupropion augmentation was associated with higher rates of injurious falls than aripiprazole.

5. Link to study: https://www.proquest.com/docview/2789770833?accountid=15180&sourcetype=Scholarly%20Journals

2. Papakostas, George I., et al. “Comparative Effectiveness Research Trial for Antidepressant Incomplete and Non-Responders with Treatment Resistant Depression (ASCERTAIN-TRD) a Randomized Clinical Trial.” Molecular Psychiatry, 7 Mar. 2024, pp. 1–9, www.nature.com/articles/s41380-024-02468-x, https://doi.org/10.1038/s41380-024-02468-x

1. Study type: Randomized Controlled Trial
2. Abstract:

1. Background: Further research is needed to help improve both the standard of care and the outcome for patients with treatment-resistant depression. A particularly critical evidence gap exists with respect to whether pharmacological or non-pharmacological augmentation is superior to antidepressant switch, or vice-versa
2. Objective: to compare the effectiveness of augmentation with aripiprazole or repetitive transcranial magnetic stimulation versus switching to the antidepressant venlafaxine XR (or duloxetine for those not eligible to receive venlafaxine) for treatment-resistant depression.
3. Methods: In this multi-site, 8-week, randomized, open-label study, 278 subjects (196 females and 82 males, mean age 45.6 years (SD 15.3)) with treatment-resistant depression were assigned in a 1:1:1 fashion to treatment with either of these three interventions; 235 subjects completed the study. 260 randomized subjects with at least one post-baseline Montgomery-Asberg Depression Rating (MADRS) assessment were included in the analysis.
4. Results: Repetitive transcranial magnetic stimulation (score change (standard error (se)) = −17.39 (1.3) (p = 0.015) but not aripiprazole augmentation (score change (se) = −14.9 (1.1) (p = 0.069) was superior to switch (score change (se) = −13.22 (1.1)) on the MADRS. Aripiprazole (mean change (se) = −37.79 (2.9) (p = 0.003) but not repetitive transcranial magnetic stimulation augmentation (mean change (se) = −42.96 (3.6) (p = 0.031) was superior to switch (mean change (se) = −34.45 (3.0)) on the symptoms of depression questionnaire. Repetitive transcranial magnetic stimulation augmentation was shown to be more effective than switching antidepressants in treatment-resistant depression on the study primary measure.
5. Conclusion: In light of these findings, clinicians should consider repetitive transcranial magnetic stimulation augmentation early-on for treatment-resistant depression.
6. Key points:

1. This was another RCT done on adults with treatment resistant major depressive disorder. Much like the previous study it compared augmentation (this time either aripiprazole or rTMS) vs. switching (changing to venlafaxine XR or duloxetine).
2. The primary outcome that was examined was the change in the MADRS over a period of 8 weeks and what they found was that augmentation with rTMS produced a significantly greater reduction in depressive symptoms as compared to switching antidepressants.
3. Interestingly, this study found that augmentation with aripiprazole was not significantly better than switching antidepressants based on the MADRS results. However, on the symptoms of depression questionnaire which is a self-reported measurement of patient symptoms they found that there is a possible benefit when augmenting with aripiprazole.
4. Overall, this is another study that again shows that augmentation but this time with rTMS or aripiprazole has shown to be more effective in reducing depressive symptoms than switching.
5. Why I chose this study:

• Similar to the previous study this large RCT directly matches my PICO question as it compares augmentation vs switching in the setting of treatment resistant depression. The population in this study was also a lot larger as it included adults ages 18-80 which captures more of the typical outpatient adult population. This study also utilized the MADRS which again is well validated for reporting symptom changes. Another important reason in why I chose this study is because it evaluates augmentation in an interestingly different modality in the form of rTMS while still demonstrating superiority with aripiprazole augmentation despite not reaching full statistical significance.

5. Link to study: https://www.nature.com/articles/s41380-024-02468-x

3. Mohamed, Somaia, et al. “Effect of Antidepressant Switching vs Augmentation on Remission among Patients with Major Depressive Disorder Unresponsive to Antidepressant Treatment.” JAMA, vol. 318, no. 2, 11 July 2017, p. 132, https://doi.org/10.1001/jama.2017.8036.

1. Study Type: Randomized Controlled Trial
2. Abstract:

1. Background: Less than one-third of patients with major depressive disorder (MDD) achieve remission with their first antidepressant.
2. Objective: To determine the relative effectiveness and safety of 3 common alternate treatments for MDD.
3. Methods: From December 2012 to May 2015, 1522 patients at 35 US Veterans Health Administration medical centers who were diagnosed with nonpsychotic MDD, unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration, participated in the study. Patients were randomly assigned (1:1:1) to 1 of 3 treatments and evaluated for up to 36 weeks.
4. Interventions: Switch to a different antidepressant, bupropion (switch group, n = 511); augment current treatment with bupropion (augment-bupropion group, n = 506); or augment with an atypical antipsychotic, aripiprazole (augment-aripiprazole group, n = 505) for 12 weeks (acute treatment phase) and up to 36 weeks for longer-term follow-up (continuation phase).
5. Main outcomes & measures: The primary outcome was remission during the acute treatment phase (16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C16] score ≤5 at 2 consecutive visits). Secondary outcomes included response (≥50% reduction in QIDS-C16 score or improvement on the Clinical Global Impression Improvement scale), relapse, and adverse effects.
6. Results: Among 1522 randomized patients (mean age, 54.4 years; men, 1296 [85.2%]), 1137 (74.7%) completed the acute treatment phase. Remission rates at 12 weeks were 22.3% (n = 114) for the switch group, 26.9% (n = 136)for the augment-bupropion group, and 28.9% (n = 146) for the augment-aripiprazole group. The augment-aripiprazole group exceeded the switch group in remission (relative risk [RR], 1.30 [95% CI, 1.05-1.60]; P = .02), but other remission comparisons were not significant. Response was greater for the augment-aripiprazole group (74.3%) than for either the switch group (62.4%; RR, 1.19 [95% CI, 1.09-1.29]) or the augment-bupropion group (65.6%; RR, 1.13 [95% CI, 1.04-1.23]). No significant treatment differences were observed for relapse. Anxiety was more frequent in the 2 bupropion groups (24.3% in the switch group [n = 124] vs 16.6% in the augment-aripiprazole group [n = 84]; and 22.5% in augment-bupropion group [n = 114]). Adverse effects more frequent in the augment-aripiprazole group included somnolence, akathisia, and weight gain.
7. Conclusions & Relevance: Among a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach.
8. Key Points:

5. This is yet another RCT that appropriately addresses the question of whether or not augmentation or switching antidepressants is more efficacious. This study looked at augmentation with aripiprazole or bupropion as compared to switching to bupropion in adults with unresponsive MDD.
6. They found that augmentation with aripiprazole produced a statistically higher rate of remission as compared to switching to bupropion, however bupropion when compared to switching did not produce a statistically significant result.
7. With remission rates being the primary outcome, one of the secondary outcomes being measured was depression severity as measured by the Quick Inventory of Depressive Symptomatology. They found a ≥50% reduction rate with aripiprazole augmentation. This group also had the lowest rates of discontinuation.
8. Another important fact to consider is that there were no significant differences in relapse rates between groups amongst the individuals that achieved remission. In other words, the benefit of augmentation is mostly in reducing acute remission but not long-term.
9. Why I chose this study:

• This is yet another large population RCT in line with my PICO question. It directly compares switching vs augmentation in a population of 1522 patients. Furthermore, in comparison to the other studies the VAST-D study had the largest sample size by far. It was conducted across 35 VA medical centers which resulted in a great deal of variability and diversity but also an interesting population considering they were veterans. The study was also conducted with a clearly outlined primary outcome in the form of remission using the QIDS-C16 which is another widely validated tool.

5. Link to study: https://pmc.ncbi.nlm.nih.gov/articles/PMC5817471/

What is the clinical “bottom line” derived from these articles in answer to your question?

Considering the evidence from all 3 studies, it can be concluded that in patients with treatment-resistant depression augmentation of an existing antidepressant is generally more effective than switching to another antidepressant as monotherapy. Of course, the degree of efficacy is dependent on the therapeutic agent being used as augmentation but overall there is a clear advantage in augmentation as opposed to switching. Of the pharmacologic options, augmentation with Aripiprazole demonstrated the most consistent benefit in each of the studies as evidenced by its higher rates of remission and symptom improvement as compared to options such as bupropion and lithium. For example, in the VAST-D trial by (Mohamed et al.) Aripiprazole augmentation was associated with a 28.9% rate of remission meanwhile switching to bupropion yielded a 22.3% remission rate which is modest but still an advantage. In the OPTIMUM by (Lenze et al.) Aripiprazole again showed its efficacy in terms of well-being improvement scores of 4.83 compared to the 2.04 seen with switching to bupropion alongside remission rates of 28.9% and 19.3% respectively. As a result, Aripiprazole augmentation is a strong consideration in the setting of treatment-resistant depression. The ASCERTAIN-TRD RCT by (Papakostas et al.) also demonstrated that when appropriate patients can also greatly benefit from a non-pharmacologic option of augmentation with rTMS which showed greater efficacy than switching to venlafaxine XR or duloxetine.

Despite the promising evidence in these studies on the advantage of augmentation, it must also be recognized that the choice of Aripiprazole or any other augmentative therapy must be considered in the context of the patient’s comorbidities, preferences, and tolerability. As a dopamine blocking agent Aripiprazole understandably results in both extrapyramidal and metabolic effects ranging from akathisia to weight gain. Similarly, Bupropion which was also examined in these studies for its augmentative potential poses a concern for fall risks in the elderly. Nevertheless, the clinical approach of augmentation remains an effective next-step choice for patients presenting with treatment-resistant depression