Next Steps After Failed Trials of Bupropion and Sertraline for Depression
For patients who have failed treatment with bupropion (Wellbutrin) and sertraline (Zoloft), switching to venlafaxine (an SNRI) is recommended as the next step in treatment, based on evidence showing greater response rates with venlafaxine than with other second-generation antidepressants in treatment-resistant depression. 1
Understanding Treatment-Resistant Depression
Treatment-resistant depression (TRD) is defined as failure to respond to at least two adequate antidepressant trials within the current depressive episode 2. Your patient has already failed trials of:
- Bupropion (Wellbutrin) - a norepinephrine-dopamine reuptake inhibitor
- Sertraline (Zoloft) - a selective serotonin reuptake inhibitor (SSRI)
This represents two different medication classes with distinct mechanisms of action, confirming treatment resistance.
Treatment Algorithm for Failed Bupropion and Sertraline
Step 1: Switch to Venlafaxine (SNRI)
- Venlafaxine has shown superior efficacy in some studies for SSRI non-responders 1
- Start with 37.5-75mg daily and titrate gradually to 150-225mg daily
- Monitor for side effects including increased blood pressure, nausea, and potential withdrawal symptoms if missed doses occur
Step 2: If venlafaxine fails, consider these options:
Option A: Try Mirtazapine
- Offers faster onset of action compared to SSRIs 2, 1
- Particularly beneficial for patients with insomnia or appetite issues
- Start at 15mg at bedtime, can increase to 30-45mg
Option B: Medication Augmentation
- Add an atypical antipsychotic to the current antidepressant
- Consider lithium or thyroid hormone augmentation
- Bupropion augmentation has shown better outcomes than buspirone augmentation 1
Option C: Consider MAOI (if severe/refractory)
- MAOIs may be effective for treatment-resistant cases 3
- Requires strict dietary restrictions and medication precautions
- Should be prescribed by psychiatrists experienced with these medications
Important Clinical Considerations
Efficacy Expectations
- Approximately 25% of patients become symptom-free after switching medications, even after multiple failures 1, 4
- The STAR*D trial showed no significant difference in remission rates between bupropion-SR, sertraline, and venlafaxine-XR as second-line agents, but smaller studies suggest venlafaxine may be superior 2, 1
Monitoring and Safety
- Begin monitoring 1-2 weeks after initiating new therapy
- Assess for treatment response, adverse effects, vital signs, and suicidal thoughts
- Watch for signs of serotonin syndrome, particularly with medication combinations 5
Combination Therapy Cautions
- While combination therapy (e.g., bupropion + sertraline) has shown efficacy in some refractory cases 6, it carries increased risk of adverse effects
- Serotonin syndrome is a potential risk when combining serotonergic agents 5
- Only consider combinations under close supervision by experienced clinicians
Non-Pharmacological Approaches
- Consider adding Cognitive Behavioral Therapy (CBT), which has similar effectiveness to antidepressants with fewer adverse effects 1
- Exercise therapy and sleep hygiene interventions can provide additional benefit
Medication Changes
- Make medication changes gradually to minimize destabilization
- Allow 4-6 weeks at therapeutic doses to assess efficacy
- If switching from an SSRI to an MAOI, ensure appropriate washout periods to avoid serotonin syndrome
Remember that persistence is key in finding the right treatment approach, as many patients will eventually respond with the appropriate medication or combination.