What are the options when duloxetine (Cymbalta) and bupropion (Wellbutrin) fail to improve depression?

Treatment Options When Duloxetine and Bupropion Fail to Improve Depression

When duloxetine and bupropion have failed to improve depression, switching to a different antidepressant class (such as an SSRI like sertraline) or augmenting with cognitive therapy are equally effective strategies with similar remission rates. 1

Evidence-Based Treatment Algorithm for Treatment-Resistant Depression

First Step: Switch to Another Antidepressant

• Switch to an SSRI: Sertraline, escitalopram, or fluoxetine

  • Evidence shows no significant differences in response rates when switching between different second-generation antidepressants 1
  • The STAR*D trial demonstrated that approximately 25% of patients become symptom-free after switching medications 1

• Switch to an SNRI: Venlafaxine (if not previously tried)

  • Some limited evidence suggests venlafaxine may have greater response rates than other second-generation antidepressants in treatment-resistant cases 1
  • Low-quality evidence showed no difference in risk for adverse events between venlafaxine and citalopram 1

Second Step: Augmentation Strategies

• Add cognitive therapy to current medication

  • Low-quality evidence shows no difference in response, remission, or depression severity between augmenting with another medication versus cognitive therapy 1
  • May have fewer discontinuations due to adverse events compared to medication augmentation 1

• Add another antidepressant

  • Consider mirtazapine augmentation
    • Mirtazapine has a faster onset of action than many other antidepressants 1, 2
    • Unique mechanism targeting alpha-2 adrenergic receptors and multiple serotonin receptors 2

• Consider combination therapy

  • Preliminary evidence suggests the combination of venlafaxine and bupropion may be effective in treatment-resistant depression 3
  • Limited evidence also suggests duloxetine and bupropion combination may be beneficial in some cases 4

Third Step: Consider Alternative Approaches

• Try a medication with a novel mechanism

  • Vortioxetine: Acts on multiple serotonin receptors with potential cognitive benefits 2
  • Vilazodone: Combined SSRI and 5-HT1A partial agonist properties 2

• Non-pharmacological interventions

  • Third-wave CBT shows lower discontinuation rates compared to antidepressants 1
  • Evidence suggests CBT is as effective as medication switches for treatment-resistant depression 1

Important Clinical Considerations

Efficacy Expectations

• Approximately 38% of patients do not achieve treatment response during 6-12 weeks of treatment with second-generation antidepressants 1
• 54% do not achieve remission with initial treatment 1
• When switching medications after failure, expect about 25% of patients to achieve remission 1

Monitoring for Special Populations

• For patients with accompanying anxiety, consider venlafaxine which may have superior efficacy compared to fluoxetine 1
• For patients with psychomotor agitation, sertraline may have better efficacy 1
• For patients with insomnia, consider mirtazapine which has sedative properties 2

Common Pitfalls to Avoid

1. Inadequate dosing: Ensure previous medications were at therapeutic doses for adequate duration
2. Overlooking side effect profiles: Select medications with different side effect profiles than those that failed
3. Ignoring comorbidities: Address accompanying symptoms like anxiety or insomnia
4. Premature discontinuation: Allow 4-6 weeks for full therapeutic effect of new medication
5. Neglecting non-pharmacological options: Cognitive therapy shows similar efficacy to medication switches 1

The evidence consistently shows that when duloxetine and bupropion fail, switching to another antidepressant class or augmenting with cognitive therapy are equally viable options with similar efficacy outcomes. The decision between these approaches should be guided by the patient's previous medication experiences, side effect profiles, and specific symptom clusters.