What are the next steps for an adult patient with a history of depression and possible comorbid anxiety, currently on desvenlafaxine (pristiq) 100mg and buspar (buspirone) 15mg, who continues to struggle with depressive symptoms?

Treatment-Resistant Depression on Desvenlafaxine and Buspirone

For this patient failing desvenlafaxine 100mg with buspirone 15mg augmentation, either switch to a different antidepressant (bupropion, sertraline, duloxetine, escitalopram, or mirtazapine) or augment with bupropion, as both strategies show similar efficacy but buspirone augmentation has significantly higher discontinuation rates due to adverse events compared to bupropion augmentation. 1

Evidence-Based Second-Step Treatment Options

The American College of Physicians 2023 systematic review provides the strongest guidance for this clinical scenario, showing that various pharmacologic switch and augmentation strategies demonstrate similar efficacy for treatment-resistant depression 1.

Augmentation Strategy

Bupropion augmentation is superior to continuing buspirone augmentation:

• The STAR*D trial demonstrated that while response and remission rates were similar between bupropion and buspirone augmentation, discontinuation due to adverse events was significantly lower with bupropion (12.5%) versus buspirone (20.6%; P < 0.001) 1, 2
• Bupropion augmentation decreases depression severity more effectively than buspirone augmentation 3
• The current buspirone dose of 15mg daily is subtherapeutic; therapeutic dosing requires 20-60mg daily (10-30mg twice daily), though this would further increase adverse event risk 2

Switch Strategy

Switching to a different second-generation antidepressant is equally effective as augmentation:

• Multiple trials show no significant differences in efficacy between switching to bupropion SR, escitalopram, duloxetine, sertraline, venlafaxine XR, or mirtazapine 1
• Two large trials (1,231 participants) found no differences in efficacy or safety between switching versus augmenting strategies 1
• Desvenlafaxine demonstrates a flat dose-response curve typical of SNRIs, making dose escalation above 100mg unlikely to improve outcomes 4

Critical Safety Considerations

Monitor for serotonin syndrome if augmenting or cross-tapering:

• The FDA label explicitly warns that desvenlafaxine combined with buspirone increases serotonin syndrome risk 5
• If adding bupropion to desvenlafaxine, monitor closely during the first 24-48 hours for tremor, diarrhea, delirium, neuromuscular rigidity, and hyperthermia 6, 5
• Bupropion does not increase serotonin syndrome risk as it lacks serotonergic activity 7

Assess for bipolar disorder before proceeding:

• The FDA mandates screening for personal or family history of bipolar disorder, mania, or hypomania before adjusting antidepressant therapy 5
• Antidepressant monotherapy or augmentation may precipitate manic episodes in undiagnosed bipolar disorder 5

Recommended Clinical Algorithm

Step 1: Verify adequate trial duration and adherence

• Ensure the patient has completed at least 6-12 weeks on current regimen at therapeutic doses 1
• Confirm medication adherence and assess for substance use or medical comorbidities affecting response 1

Step 2: Choose between augmentation and switching

For augmentation (if partial response to desvenlafaxine):

• Add bupropion SR 150mg daily, titrate to 150mg twice daily after discontinuing buspirone 1, 7
• Alternative: Consider aripiprazole augmentation (higher remission rates than bupropion in one trial: 55.4% vs 34.0%) 1

For switching (if minimal/no response to desvenlafaxine):

• Switch to bupropion SR, escitalopram, duloxetine, sertraline, or mirtazapine using direct cross-taper without washout period 1, 6
• Mirtazapine may be particularly useful if comorbid insomnia or poor appetite 1

Step 3: Add cognitive behavioral therapy

• CBT shows equivalent efficacy to medication switches and augmentation strategies with lower discontinuation rates (9.2% vs 18.8% for medication augmentation) 1
• The American College of Physicians recommends CBT as a first-line treatment option with moderate-quality evidence 1

Common Pitfalls to Avoid

Do not increase desvenlafaxine dose above 100mg:

• SNRIs demonstrate flat dose-response curves; higher doses increase adverse effects without improving efficacy 4
• The FDA-approved maximum dose is 400mg, but doses above 100mg show no additional benefit for depression 5

Do not continue ineffective buspirone augmentation:

• At 15mg daily, the dose is below the therapeutic range (20-60mg daily) 2
• Even at therapeutic doses, buspirone shows higher discontinuation rates than bupropion augmentation 1, 2

Do not abruptly discontinue desvenlafaxine:

• Taper gradually to avoid discontinuation syndrome (nausea, sweating, dysphoric mood, irritability, dizziness, sensory disturbances) 5
• When switching, use cross-taper method rather than abrupt discontinuation 6

Monitoring During Treatment Transition

• Assess suicidality weekly during first month of any medication change, as risk increases in adults under age 25 5
• Monitor blood pressure if continuing or initiating SNRI therapy 5
• Evaluate response using standardized tools (PHQ-9 or HAM-D) at 2-4 week intervals 1
• Screen for emergent anxiety, agitation, panic attacks, insomnia, irritability, hostility, or akathisia as potential precursors to suicidality 5