What are the augmentation options and strategies to improve mood after failure of antidepressant monotherapy?

Augmentation Strategies After Antidepressant Monotherapy Failure

First-Line Augmentation Options

For patients who have failed initial antidepressant monotherapy, augmentation with atypical antipsychotics (aripiprazole, quetiapine, cariprazine, or olanzapine) or switching to a different antidepressant (bupropion, venlafaxine, or mirtazapine) represent the most evidence-based strategies, with atypical antipsychotics showing superior symptom reduction but higher dropout rates. 1, 2

Atypical Antipsychotic Augmentation (Strongest Evidence)

• Quetiapine augmentation reduces depressive symptoms significantly (SMD -0.32,95% CI -0.46 to -0.18) with high-quality evidence, though dropout rates increase to 10-39% versus 12-23% with monotherapy (RR 1.57,95% CI 1.14 to 2.17). 3

• Cariprazine augmentation demonstrates significant symptom reduction (MD on MADRS -1.50,95% CI -2.74 to -0.25) with high-quality evidence, but increases dropout risk (RR 1.68,95% CI 1.16 to 2.41). 3

• Olanzapine augmentation shows substantial benefit (MD on MADRS -12.4,95% CI -22.44 to -2.36) with low-quality evidence due to limited studies. 3

• Aripiprazole is recommended by the National Institute of Mental Health for partial responders, typically at doses of 2-15mg daily. 2

Switching to Alternative Antidepressants

• Mirtazapine is the preferred switch option when anxiety and insomnia are prominent, providing statistically faster symptom relief than SSRIs with sedating properties that address comorbid symptoms simultaneously. 2

• Venlafaxine (SNRI) is the alternative switch option for prominent anxiety symptoms, demonstrating superior efficacy compared to fluoxetine for treating anxiety in depressed patients. 2

• Bupropion can be used either as a switch or augmentation agent, with moderate-quality evidence showing no significant difference in response rates when switching between different second-generation antidepressants (bupropion vs. sertraline vs. venlafaxine). 1, 2

Second-Line Augmentation Strategies

Antidepressant Augmentation

• Bupropion augmentation of existing SSRI treatment decreases depression severity more than buspirone augmentation and has lower discontinuation rates due to adverse events (moderate-quality evidence). 1, 2

• Mirtazapine augmentation shows little clinically important benefit in symptom reduction (MD on BDI-II -1.7,95% CI -4.03 to 0.63) with high-quality evidence, making it a less preferred augmentation strategy. 3

• Mianserin augmentation improves depression symptom severity scores (MD on HAM-D -4.8,95% CI -8.18 to -1.42) with moderate-quality evidence. 3

Traditional Augmentation Agents

• Lithium augmentation remains one of the best-documented treatments for treatment-resistant depression, though it requires careful monitoring of blood levels, thyroid function, and renal function. 2

• Buspirone augmentation provides no evidence of benefit in reducing depressive symptoms (MD on MADRS -0.30,95% CI -9.48 to 8.88) with low-quality evidence. 3

• Thyroid hormone augmentation is an established off-label option for treatment-resistant depression, though specific efficacy data from the provided evidence is limited. 4

Novel Pharmacological Options

Ketamine and Esketamine (Reserved for Multiple Treatment Failures)

• Ketamine or esketamine should be suggested only after patients have failed several adequate pharmacologic trials, with evidence showing improvement in depressive symptoms for up to 7 days when added to ongoing antidepressant treatment. 1

• Esketamine (intranasal) as augmentation with twice-weekly dosing improves depressive symptoms and remission rates at up to 28 days in patients with treatment-resistant depression who have new or optimized antidepressant therapy. 1

• Critical limitation: Esketamine requires risk evaluation and mitigation strategy compliance, including pharmacy and health care setting certification, plus mandatory 2-hour post-treatment monitoring. 1

• Ketamine lacks long-term efficacy and safety data beyond 7 days, with bulk of evidence from patients who previously failed adequate antidepressant trials. 1

Treatment Algorithm

Step 1: Verify Adequate Trial

• Confirm each previous antidepressant was tried at therapeutic doses for minimum 4 weeks at a licensed dosage before declaring treatment failure. 2

Step 2: Choose Strategy Based on Clinical Presentation

For partial responders:

• Augment with bupropion 150-300mg daily 2
• Alternative: Augment with atypical antipsychotic (quetiapine 150-300mg or aripiprazole 2-15mg) 2, 3

For non-responders with prominent anxiety/insomnia:

• Switch to mirtazapine 15-45mg at bedtime 2

For non-responders with anxiety without significant insomnia:

• Switch to venlafaxine 75-225mg daily 2

For non-responders without specific symptom targets:

• Switch to different second-generation antidepressant (moderate-quality evidence shows no difference between bupropion, sertraline, or venlafaxine) 1
• Alternative: Augment with atypical antipsychotic 3

Step 3: After Second Failure

• Consider augmentation with lithium (requires monitoring) 2
• Consider second atypical antipsychotic trial if first failed—failure to respond to one atypical antipsychotic augmentation does not preclude response to another 5
• Low-quality evidence shows switching to cognitive therapy produces similar outcomes to switching antidepressants 1

Step 4: Multiple Treatment Failures

• Consider ketamine or esketamine augmentation after several adequate pharmacologic trials have failed 1
• Consider electroconvulsive therapy if pharmacological approaches continue to fail 2

Critical Considerations and Pitfalls

• Dropout rates with antipsychotics: Augmentation with atypical antipsychotics increases dropout risk by 57-68% compared to monotherapy, primarily due to side effects or adverse events. 3

• Switching versus augmentation: No direct comparison trials exist between switching strategies versus augmentation strategies, making evidence-based choice between these approaches impossible. 1

• Second-step treatment evidence gap: Only 2 trials address comparative benefits of second-step treatments, with none showing one strategy having greater efficacy than another. 1

• Combination therapy evidence: Low-quality evidence shows no difference in remission between antidepressant monotherapy and combination with exercise, suggesting combination may not provide additional benefit. 1

Integration of Psychotherapy

• Cognitive behavioral therapy (CBT) should be offered regardless of medication choice, as low-quality evidence shows no difference between switching to another antidepressant versus switching to cognitive therapy. 1, 2

• CBT is recommended as an essential component by the American College of Physicians for treatment-resistant depression. 2