What are the recommended atypical antidepressant augmentation strategies for a patient with major depression, anxiety, and cognitive impairment who has not responded to initial treatment with Trintellix (vortioxetine)?

Augmentation Strategies for Treatment-Resistant Major Depression After Vortioxetine Failure

Direct Recommendation

For a patient with major depression, anxiety, and cognitive impairment who has not responded to vortioxetine, augment with bupropion SR as the first-line strategy, given its superior tolerability profile with significantly fewer discontinuations due to adverse events (12.5% vs. 20.6%; P < 0.001) compared to buspirone, and its potential to address cognitive symptoms while avoiding metabolic side effects. 1, 2

Evidence-Based Augmentation Options

First-Tier Pharmacologic Augmentation

Bupropion SR (Sustained Release)

• The STAR*D trial demonstrated that augmenting SSRIs/SNRIs with bupropion SR showed similar efficacy to other medication augmentation strategies in achieving response and remission, but with a clear safety advantage 1, 2
• Bupropion discontinuation rates due to adverse events were significantly lower (12.5%) compared to buspirone (20.6%; P < 0.001) 1
• This agent may be particularly beneficial for your patient given the cognitive impairment, as bupropion does not worsen cognition and may provide activating effects that counter apathy 3
• Start at 150 mg daily and increase to 300-400 mg daily based on response 4

Aripiprazole

• Aripiprazole is the only FDA-approved augmentation agent for treatment-resistant depression and is one of only six augmentation strategies whose confidence intervals did not overlap with placebo in network meta-analyses 2, 5
• A high risk-of-bias trial showed higher remission rates with aripiprazole augmentation (55.4%) compared to bupropion (34.0%; P = 0.031), though this should be interpreted cautiously given study quality 1
• Doses for augmentation are lower than those used in schizophrenia or bipolar disorder, typically 2-10 mg daily 5
• Critical caveat: Monitor closely for metabolic side effects (weight gain, glucose dysregulation, lipid abnormalities) which may be particularly problematic in long-term treatment 5, 3

Second-Tier Options

Buspirone

• The STAR*D trial showed no difference in response or remission when augmenting citalopram with buspirone compared to bupropion, but buspirone had significantly higher discontinuation rates due to adverse events 1
• Start at 5 mg twice daily and titrate up to maximum 20 mg three times daily 6
• Requires 2-4 weeks to reach full therapeutic effect, which is a disadvantage compared to other strategies 6
• Important consideration: Given your patient's anxiety, buspirone targets this symptom specifically, but the evidence shows no effect of comorbid anxiety on comparative efficacy of augmentation strategies 1

Other Atypical Antipsychotics

• Quetiapine and risperidone have controlled trial data supporting efficacy at low doses, though neither has FDA approval for this indication 5, 3
• Olanzapine combined with fluoxetine was one of the first approved combinations for treatment-resistant depression, but metabolic side effects significantly limit its use 3

Non-Pharmacologic Augmentation

Cognitive Behavioral Therapy (CBT)

• The STAR*D trial demonstrated that augmenting antidepressants with CBT showed similar efficacy to medication augmentation (bupropion or buspirone) for response and remission 1
• Key advantage: CBT augmentation had numerically lower discontinuation rates due to adverse events (9.2%) compared to medication augmentation (18.8%; P = 0.086) 1
• This approach may be particularly valuable for your patient with cognitive impairment, as CBT can directly address cognitive distortions and provide coping strategies 2
• The American College of Physicians emphasizes that adding therapy has similar efficacy with potentially fewer adverse events 2

Alternative Strategy: Switching vs. Augmentation

Switching to Another Antidepressant

• 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) 1
• Two trials with 1,231 participants showed no differences in efficacy or safety between switching versus augmenting strategies 1
• Clinical pearl: 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 2

Specific Considerations for Your Patient

Addressing Cognitive Impairment

• Vortioxetine's unique advantage is its demonstrated reversal of cognitive decline in depression through its multimodal mechanism (5-HT reuptake inhibition plus modulation of multiple 5-HT receptors) 7, 8
• Since vortioxetine has failed, consider that bupropion augmentation may provide additional noradrenergic and dopaminergic effects that could benefit cognition without the metabolic burden of atypical antipsychotics 3
• Avoid augmentation strategies that worsen cognition, such as benzodiazepines for anxiety management 6

Addressing Comorbid Anxiety

• The STAR*D analyses found no effect of comorbid anxiety on the comparative efficacy of augmentation strategies, meaning anxiety should not drive your choice between medication options 1
• If anxiety remains prominent, consider CBT augmentation which addresses both depression and anxiety without additional medication burden 2

Monitoring and Timeline

Initial Assessment (Weeks 1-2)

• Monitor for therapeutic response and adverse effects within 1-2 weeks of initiating augmentation 2
• Evaluate for any increase in suicidal ideation, particularly during the first 1-2 months 2
• If using bupropion, monitor for activation, insomnia, or increased anxiety 4
• If using aripiprazole, obtain baseline metabolic parameters (weight, glucose, lipids) 5

Treatment Modification Decision Point (Weeks 6-8)

• Make treatment modifications at 6-8 weeks if response remains inadequate 2
• The American College of Physicians emphasizes trying a different evidence-based approach rather than prolonging an ineffective strategy 2

Long-Term Management (4-9 months)

• Continue combination therapy for 4-9 months after achieving satisfactory response 2
• Consider longer duration for patients with 2 or more prior depressive episodes 2

Common Pitfalls to Avoid

Inadequate Trial Duration

• Buspirone requires 2-4 weeks to reach full therapeutic effect; expecting immediate results leads to premature discontinuation 6
• Conversely, waiting beyond 6-8 weeks without response wastes valuable time when other strategies could be tried 2

Overlooking Non-Pharmacologic Options

• CBT augmentation has similar efficacy with potentially fewer adverse events but is often not discussed with patients 2
• Cost considerations should be transparent: aripiprazole is now generic but still more expensive than switching antidepressants or adding CBT 2

Metabolic Monitoring Failures

• When using atypical antipsychotics for augmentation, failure to monitor metabolic parameters can lead to significant long-term morbidity 5, 3
• This is particularly important given that treatment may continue for many months 2

Ignoring the Evidence on Strategy Equivalence

• The moderate-quality evidence shows that various switching and augmentation strategies provide similar symptom relief 1
• The key is selecting an evidence-based approach and implementing it properly, rather than endlessly searching for the "perfect" option 2