What is the next step for a patient with a history of treatment-resistant depression, currently experiencing depression and anxiety, who is on Vyvanse (lisdexamfetamine) 50mg and has previously tried Prozac (fluoxetine), Zoloft (sertraline), and Wellbutrin (bupropion)?

Treatment Approach for Treatment-Resistant Depression with Comorbid Anxiety

Given this patient has failed three adequate antidepressant trials (Prozac, Zoloft, and Wellbutrin) from different classes, the next step should be augmentation with an atypical antipsychotic, specifically aripiprazole starting at 2 mg daily, which can be titrated up to 10-15 mg as tolerated. 1

Rationale for This Recommendation

This patient meets criteria for treatment-resistant depression (TRD), defined as failure of at least two adequate antidepressant trials from different classes. 2 The patient has failed three medications: fluoxetine (SSRI), sertraline (SSRI), and bupropion (NDRI), representing two distinct antidepressant classes. 3

After two treatment failures, the chances of remission decrease significantly with each subsequent antidepressant switch, making augmentation strategies more appropriate than further switching. 1, 4

Why Augmentation Over Switching

• Switching to another antidepressant monotherapy has limited effectiveness in achieving remission once TRD is established. 5
• Augmentation strategies build upon any partial improvements already achieved, rather than potentially losing gains by discontinuing current therapy. 5
• The patient is currently on Vyvanse (lisdexamfetamine), which may be providing some benefit for comorbid ADHD or residual depressive symptoms, making augmentation preferable to preserve this effect. 1

Specific Augmentation Strategy

Aripiprazole augmentation demonstrates superior remission rates of 55.4% in treatment-resistant depression, significantly better than other augmentation strategies like bupropion (34.0%). 1, 6

Dosing Protocol:

• Start aripiprazole at 2 mg daily to minimize tremor and akathisia risk. 1
• Increase by 2-3 mg every 1-2 weeks as tolerated. 1
• Target dose range: 10-15 mg daily maximum. 1
• Monitor for akathisia, weight gain, and metabolic side effects. 7

Alternative Augmentation Options if Aripiprazole Fails or Is Not Tolerated

Second-Line Augmentation:

• Quetiapine extended-release is another FDA-approved atypical antipsychotic for depression augmentation. 8, 7
• Lithium augmentation is one of the best-documented treatments for TRD, though it requires more intensive monitoring. 6, 8
  • Start lithium carbonate 300 mg twice daily. 1
  • Target blood level: 0.6-1.0 mEq/L. 1
  • Requires weekly lithium levels initially, then monthly thyroid and renal function monitoring. 1

Third-Line Options:

• Combination antidepressant therapy: Adding bupropion SR 150-300 mg to the current regimen decreases depression severity more than buspirone augmentation. 1, 6
• Switching to venlafaxine ER 150-225 mg daily may be particularly beneficial given the patient's comorbid anxiety, as venlafaxine demonstrates superior efficacy for anxiety symptoms in patients with depression and anxiety. 1, 6
• Mirtazapine offers rapid symptom relief and is particularly beneficial for comorbid anxiety and insomnia due to its sedating properties. 6

Important Monitoring Considerations

• Close monitoring for suicidal ideation is essential during medication changes, as patients on SSRIs are at increased risk for nonfatal suicide attempts. 6
• Monitor for serotonin syndrome risk, especially if combining multiple serotonergic agents. 1
• Watch for bleeding risk with SSRI/SNRI combinations. 1
• Assess for metabolic side effects (weight gain, glucose dysregulation) with atypical antipsychotics. 7

Common Pitfalls to Avoid

• Do not declare treatment failure prematurely: Ensure each prior antidepressant trial was adequate (minimum licensed dosage for at least 4 weeks). 6, 3
• Confirm medication adherence before diagnosing TRD, as up to 50% of patients with MDD have adherence issues. 2
• Consider plasma level monitoring if available to confirm adequate drug exposure and identify fast/slow metabolizers. 2
• Rule out bipolar disorder: Screen for previous episodes of mania, hypomania, or subthreshold bipolarity, as these patients require different treatment approaches. 2

If Multiple Augmentation Strategies Fail

Consider non-pharmacological interventions:

• Cognitive behavioral therapy (CBT) shows moderate certainty evidence for similar treatment effects as antidepressants. 6
• Electroconvulsive therapy (ECT) may be effective for severe TRD. 6, 3
• Ketamine or esketamine can be used for TRD and may help reduce suicidal ideation. 3, 8
• Repetitive transcranial magnetic stimulation is another evidence-based option. 3