What are the next steps for a patient with Major Depressive Disorder (MDD) and Generalized Anxiety Disorder (GAD) who remains symptomatic with feelings of worthlessness and lack of energy while on Wellbutrin (Bupropion) 150mg every 24 hours and Duloxetine (Cymbalta) 90mg?

Treatment-Resistant Depression: Next Steps for Combination Therapy Failure

Switch to a different antidepressant class rather than continuing the current combination, as this patient has failed adequate trials of both an SNRI (duloxetine 90mg) and NDRI (bupropion 150mg) without response after 6-8 weeks. 1

Immediate Assessment Required

Before making medication changes, verify the following:

• Confirm adequate trial duration: The patient needs 6-8 weeks at therapeutic doses to determine treatment failure 1
• Assess medication adherence: Non-adherence is a common cause of apparent treatment resistance
• Rule out substance use: Alcohol or benzodiazepine use can blunt antidepressant response 1
• Monitor for suicidality: Reassess within 1-2 weeks of any medication change, as risk increases during treatment transitions 1, 2

Recommended Medication Strategy

Primary Recommendation: Switch to Venlafaxine XR or Mirtazapine

Switch to venlafaxine extended-release 150-225mg daily, as it showed superior response rates compared to other second-generation antidepressants in treatment-resistant patients, particularly those with comorbid anxiety 1. The STAR*D trial demonstrated that approximately 25% of patients become symptom-free after switching to a different antidepressant class 1.

Alternative: Mirtazapine offers faster onset of action (1-2 weeks) compared to other antidepressants and may be particularly useful given the patient's lack of energy 1. Start at 15mg at bedtime and titrate to 30-45mg.

Why Not Continue Current Regimen

• Duloxetine at 90mg is already at maximum recommended dose for MDD (60mg once daily is standard; doses above 60mg show minimal additional benefit) 1, 3, 4
• Bupropion 150mg daily is subtherapeutic: Therapeutic dosing for MDD requires 300-450mg daily 5
• The combination has been adequately trialed: No evidence supports continuing failed combination therapy beyond 6-8 weeks 1

Specific Switching Protocol

If Choosing Venlafaxine XR:

1. Taper duloxetine: Reduce to 60mg for 1 week, then 30mg for 1 week to minimize discontinuation syndrome 1
2. Cross-taper bupropion: Can continue during duloxetine taper as no significant interaction 6
3. Start venlafaxine XR 37.5mg daily during final week of duloxetine taper
4. Titrate venlafaxine: Increase to 75mg after 1 week, then 150mg after another week 1
5. Target dose 150-225mg daily based on response and tolerability 1
6. Discontinue bupropion once venlafaxine reaches 150mg (unless partial response warrants continuation)

If Choosing Mirtazapine:

1. Similar duloxetine taper as above
2. Start mirtazapine 15mg at bedtime during final week of duloxetine taper
3. Increase to 30mg after 1 week, then 45mg if needed 1
4. Discontinue bupropion after 1-2 weeks on mirtazapine

Critical Safety Considerations

Serotonin Syndrome Risk

Do NOT combine duloxetine with venlafaxine without proper tapering, as both are SNRIs and increase serotonin syndrome risk 7. Complete duloxetine taper before reaching therapeutic venlafaxine doses.

Monitoring Requirements

• Weekly visits for first 2-4 weeks after medication change to assess suicidality and emerging symptoms 1, 2
• Blood pressure monitoring if using venlafaxine (can cause dose-dependent hypertension) 1
• Reassess at 6-8 weeks: If inadequate response, consider augmentation strategies or referral 1

Alternative Strategies if First Switch Fails

Augmentation Options (Second-Line):

• Add lithium or thyroid hormone to the new antidepressant 1
• Consider atypical antipsychotic augmentation (aripiprazole, quetiapine) 1

When to Refer:

Refer to psychiatry if:

• No response after 2-3 adequate antidepressant trials 1
• Severe suicidality or psychotic features emerge 1
• Comorbid bipolar disorder suspected (bupropion and antidepressants can trigger mania) 1, 5

Duration of Treatment After Response

Continue treatment for 4-9 months minimum after achieving remission for first episode MDD 1. Given this patient has both MDD and GAD (suggesting chronicity), consider indefinite maintenance therapy after remission 1.

Common Pitfalls to Avoid

• Don't increase duloxetine beyond 60mg daily: Higher doses show minimal additional efficacy but increased side effects 3, 4
• Don't add another serotonergic agent without proper washout: Risk of serotonin syndrome 7
• Don't assume treatment failure before 6-8 weeks at therapeutic dose 1
• Don't ignore comorbid GAD: Venlafaxine has demonstrated efficacy for both MDD and GAD 1, 8