What are the next steps for a patient on venlafaxine (Effexor) 150mg three times a day (TID) and bupropion (Wellbutrin) 150mg once a day (QD) who continues to experience symptoms of depression, low motivation, and low concentration?

Treatment-Resistant Depression: Next Steps for Venlafaxine-Bupropion Combination Failure

Your patient requires either augmentation with cognitive behavioral therapy (CBT) or switching to a different antidepressant, as the current high-dose combination has failed after adequate trial duration.

Immediate Assessment

First, verify this is true treatment resistance by confirming:

• Adequate dose and duration: Your patient is on venlafaxine 450mg/day (150mg TID) and bupropion 150mg/day for presumably >6-8 weeks 1
• Medication adherence: Confirm the patient is actually taking medications as prescribed
• Comorbid conditions: Rule out hypothyroidism, substance use, or other medical conditions mimicking or exacerbating depression 2

Critical caveat: The bupropion dose is suboptimal at 150mg QD. Standard therapeutic dosing is 300-450mg/day 3, 4. However, given persistent symptoms despite already being on combination therapy, optimization alone is unlikely sufficient.

Evidence-Based Next Steps

Option 1: Add Cognitive Behavioral Therapy (Preferred Initial Strategy)

Augment current medications with CBT rather than making medication changes 1. The evidence shows:

• Low-quality evidence demonstrates no difference between augmenting with another antidepressant versus augmenting with cognitive therapy for response, remission, or depression severity 1
• CBT augmentation avoids polypharmacy risks and addresses the cognitive symptoms (low concentration, low motivation) your patient specifically reports 1
• This approach maintains the partial benefit already achieved while adding a complementary mechanism 1

Option 2: Medication Switching Strategy

If CBT is unavailable or the patient prefers medication adjustment:

Switch to a different second-generation antidepressant (SGA) rather than adding a third agent 1. The STAR*D trial showed that approximately 25% of patients become symptom-free after switching medications, with no difference among bupropion, sertraline, and venlafaxine 1.

Specific switching options based on evidence:

• Sertraline or escitalopram: Moderate-quality evidence shows no difference in response when switching between SGAs 1
• Mirtazapine: Has faster onset of action than other SGAs, though response rates equalize after 4 weeks 1

Option 3: Augmentation Strategies (If Switching/CBT Fail)

If the above strategies fail, consider augmentation with:

Lithium augmentation (even at low doses):

• Low-dose lithium (300-450mg/day, plasma level ~0.33 mEq/L) showed 51% response rate when augmenting venlafaxine in treatment-resistant depression 5
• Does not require plasma level monitoring at low doses and minimizes side effects 5
• Rapid response typically occurs within 7 days in responders 5

Atypical antipsychotic augmentation:

• Quetiapine or aripiprazole have demonstrated efficacy for treatment-resistant depression 4
• However, this adds metabolic and neurological side effect risks in a young patient 4

Alternative antidepressant combinations:

• Adding an SSRI (sertraline, citalopram, or paroxetine) to venlafaxine has shown benefit in case reports 6
• The venlafaxine-bupropion combination your patient is already on has demonstrated synergistic effects in treatment-resistant depression 3

What NOT to Do

Do not simply increase the venlafaxine dose further - your patient is already at 450mg/day, which exceeds typical maximum dosing (225-375mg/day) 3, 5. Higher doses increase side effects without proven additional benefit.

Avoid augmentation with buspirone - evidence shows bupropion augmentation decreases depression severity more than buspirone, with lower discontinuation rates due to adverse events 1.

Monitoring Requirements

Regardless of strategy chosen:

• Assess response within 1-2 weeks of any intervention change, then regularly thereafter 1
• Monitor for suicidal ideation closely, especially given the patient's age (19 years) - SSRIs increase risk of suicide attempts in younger patients 1
• Evaluate for treatment response by 6-8 weeks; if inadequate response, modify treatment again 1

Clinical Algorithm

1. Optimize current regimen: Increase bupropion to 300mg QD minimum (if not already done)
2. Add CBT as first-line augmentation strategy
3. If no response after 6-8 weeks: Switch to different SGA monotherapy (sertraline, escitalopram, or mirtazapine)
4. If switching fails: Consider low-dose lithium augmentation (300-450mg/day)
5. If all above fail: Refer to psychiatry for consideration of atypical antipsychotic augmentation or other specialized interventions 4

Important consideration for this young patient: The combination of low motivation and concentration difficulties may respond better to augmentation strategies that address dopaminergic and noradrenergic systems, making the current venlafaxine-bupropion combination theoretically optimal 3. The failure suggests either inadequate dosing (bupropion) or need for non-pharmacological intervention (CBT) rather than additional medications 1.