Augmentation Strategies for Treatment-Resistant Depression

Introduction to Augmentation

The American College of Physicians recommends modifying treatment if the patient does not have adequate response within 6-8 weeks of initiating escitalopram monotherapy, with augmentation with aripiprazole being a reasonable and evidence-supported strategy 1, 2, 3

Begin monitoring therapeutic response and adverse effects within 1-2 weeks of starting escitalopram, and evaluate for suicidal ideation increases during the first 1-2 months 1, 2
Make treatment modifications at 6-8 weeks if response is inadequate, with the American College of Physicians emphasizing that the choice of second-step strategy is less important than trying a different evidence-based approach 1, 2, 3

The American College of Physicians guidelines note that augmenting with another antidepressant or adding cognitive therapy shows no significant difference in response or remission rates, with aripiprazole being one of only six augmentation strategies whose confidence intervals did not overlap with placebo 4, 5, 6
Low-quality evidence from the STAR*D trial showed no difference in response or remission when augmenting citalopram with bupropion compared to buspirone, although aripiprazole has been studied more extensively in larger, higher-quality trials 7

The American College of Physicians emphasizes that switching to another antidepressant, switching to cognitive therapy, or augmenting with medication or cognitive therapy are all reasonable options, with moderate-quality evidence showing no difference in response when switching from one SSRI to another 3, 4, 5, 6
Adding therapy has similar efficacy with potentially fewer adverse events, and cost considerations should be discussed with patients, including the fact that aripiprazole is now generic but still more expensive than switching antidepressants 1, 3, 5

Continue combination therapy for 4-9 months after achieving satisfactory response, with longer duration potentially beneficial for patients with 2 or more prior depressive episodes 1, 2

The American College of Physicians recommends augmenting with bupropion SR as the first-line strategy for patients with major depression who have not responded to vortioxetine, due to its superior tolerability profile and potential to address cognitive symptoms 8
Bupropion SR has a lower discontinuation rate due to adverse events (12.5%) compared to buspirone (20.6%; P < 0.001) 8
Aripiprazole is the only FDA-approved augmentation agent for treatment-resistant depression, with higher remission rates (55.4%) compared to bupropion (34.0%; P = 0.031) in a high risk-of-bias trial 8
Buspirone has similar efficacy to bupropion in augmenting citalopram, but with significantly higher discontinuation rates due to adverse events 8, 9

The American College of Physicians emphasizes that adding cognitive behavioral therapy (CBT) has similar efficacy to medication augmentation with potentially fewer adverse events 10
CBT augmentation has numerically lower discontinuation rates due to adverse events (9.2%) compared to medication augmentation (18.8%; P = 0.086) 10

Moderate-quality evidence shows no significant differences in efficacy when switching from one second-generation antidepressant to another (bupropion SR, escitalopram, duloxetine, sertraline, or venlafaxine extended-release) 8, 10
Two trials with 1,231 participants showed no differences in efficacy or safety between switching versus augmenting strategies 10

The American College of Physicians emphasizes that the choice of second-step strategy (switching vs. augmenting) is less important than trying a different evidence-based approach 8, 10, 11