In an adult on vortioxetine (Trintellix) 20 mg daily with residual depressive symptoms, low motivation and mood lability, and no history of bipolar disorder, psychosis, uncontrolled hypertension, or seizure disorder, what medication can be added for augmentation?

Augmentation Options for Vortioxetine 20mg in Treatment-Resistant Depression

For a patient on vortioxetine 20mg with residual depressive symptoms and low motivation, add bupropion SR 150mg daily (titrating to 300-400mg based on response) as the preferred augmentation strategy, as it provides dual benefits of enhanced antidepressant efficacy and improved motivational symptoms with significantly lower discontinuation rates compared to other augmentation agents. 1

Primary Recommendation: Bupropion Augmentation

Bupropion SR augmentation achieves remission rates of approximately 50% compared to 30% with SSRI monotherapy alone, and has significantly lower discontinuation rates due to adverse events (12.5%) compared to buspirone (20.6%, p<0.001). 1

Dosing Protocol

• Start bupropion SR at 150mg every morning 1
• Increase by 150mg every 3-7 days as tolerated 2
• Target dose: 300-400mg daily (given as divided doses, with second dose before 3 p.m. to minimize insomnia) 2, 1
• Allow 6-8 weeks at optimized dose before declaring treatment failure 1

Rationale for Bupropion

• Activating properties specifically address low motivation and energy deficits 2
• Distinct mechanism (norepinephrine-dopamine reuptake inhibition) complements vortioxetine's multimodal serotonergic activity 2, 3
• Lower sexual dysfunction rates compared to continuing serotonergic monotherapy 1
• The STAR*D trial demonstrated similar efficacy between bupropion and buspirone augmentation, but bupropion had superior tolerability 1

Critical Contraindications

• Do not use bupropion in patients with seizure disorders or eating disorders 2
• Avoid in agitated patients, as bupropion is activating 2

Alternative Augmentation Strategy: Aripiprazole

If bupropion is contraindicated or ineffective after 8 weeks, aripiprazole 2-5mg daily represents the most evidence-based alternative augmentation strategy, with studies showing it can double remission rates compared to placebo. 4

Aripiprazole Dosing and Monitoring

• Start at 2mg daily, titrate to mean effective dose of 6.9mg/day 4
• Mandatory metabolic monitoring before initiation: baseline BMI, waist circumference, blood pressure, fasting glucose or HbA1c, lipid profile, liver function tests, renal function, and complete blood count 4
• Follow-up monitoring: weight, BMI, and blood pressure weekly for 6 weeks, then at 3 months, then annually; fasting glucose at 4 weeks, 3 months, then annually 4
• Comprehensive metabolic reassessment at 3 months and annually thereafter 4

When to Consider Aripiprazole Over Bupropion

• Patient has prominent anhedonia or psychomotor retardation not responding to bupropion 4
• History of seizures or eating disorders (bupropion contraindications) 2
• Patient requires additional mood stabilization 4

Third-Line Option: Switch to SNRI

If augmentation strategies fail after adequate trials (8-12 weeks each), switching to an SNRI such as venlafaxine (37.5-225mg daily) or duloxetine (40-120mg daily) demonstrates statistically significantly better response and remission rates than continuing failed SSRI-class therapy. 1

• SNRIs provide dual serotonin-norepinephrine action that may address both depression and motivational symptoms 1
• Venlafaxine and duloxetine have robust evidence for treatment-resistant depression 1
• However, SNRIs have higher rates of adverse effects (nausea, vomiting) compared to SSRIs 1

Critical Timing Considerations

Ensure the patient has been on vortioxetine 20mg for at least 8-12 weeks before declaring treatment failure, as this is the minimum duration needed to assess full antidepressant response. 1

• Vortioxetine has a mean terminal half-life of approximately 66 hours, with steady-state achieved within 2 weeks 5
• However, clinical response may take 8-12 weeks to fully manifest 1
• Premature switching before adequate trial duration leads to missed opportunities for response 1

Monitoring Requirements After Augmentation

• Assess for suicidal ideation during the first 1-2 months after any medication change, as suicide risk is greatest during this period 1
• Monitor for emergence of agitation, irritability, or unusual behavioral changes 1
• Use standardized depression rating scales (PHQ-9 or HAM-D) to objectively track symptoms every 2-4 weeks 1
• Evaluate treatment response at 6-8 weeks after augmentation initiation 1

Common Pitfalls to Avoid

• Do not add buspirone as first-line augmentation: while effective, it has significantly higher discontinuation rates (20.6%) compared to bupropion (12.5%, p<0.001) 1
• Do not combine vortioxetine with MAOIs or multiple serotonergic agents due to serotonin syndrome risk 1
• Do not neglect metabolic monitoring if using aripiprazole, as atypical antipsychotics carry significant cardiometabolic risks even at low doses 4
• Do not make dose changes more frequently than every 2-4 weeks, as this prevents adequate assessment of therapeutic response 1

Duration of Continuation Therapy

• Continue treatment for 4-9 months after satisfactory response in patients with first episode of major depressive disorder 1
• For patients with 2 or more episodes, consider years to lifelong maintenance therapy 1

Adjunctive Psychotherapy

Add cognitive-behavioral therapy (CBT) to medication, as combination therapy demonstrates superior efficacy compared to medication alone for depression. 1

• CBT can be initiated immediately while optimizing medication, providing synergistic benefit 1
• The combination addresses both neurobiological and psychological components of depression 1