What is the preferred adjunctive medication for an adult with major depressive disorder who has an inadequate response to therapeutic-dose vortioxetine (Trintellix)?

Adjunctive Treatment for Inadequate Response to Vortioxetine (Trintellix)

For adults with major depressive disorder who have not achieved adequate response to therapeutic-dose vortioxetine, augmentation with bupropion SR (150 mg twice daily) or an atypical antipsychotic (aripiprazole 2–5 mg daily or brexpiprazole 1–3 mg daily) represents the most evidence-based next step, with bupropion offering superior tolerability and lower discontinuation rates compared to other augmentation strategies. 1, 2

Verify Adequate Vortioxetine Trial Before Augmentation

• Confirm that vortioxetine has been administered at 10–20 mg daily for at least 6–8 weeks before declaring treatment failure, as this duration is required to assess adequate response. 1, 2
• Document adherence to the current regimen; up to 50% of patients with MDD demonstrate non-adherence, which can masquerade as treatment resistance. 3
• Vortioxetine demonstrates efficacy comparable to SNRIs for acute MDD, with response rates of 42–49% at therapeutic doses. 4, 5

First-Line Augmentation Strategy: Bupropion SR

Augmenting vortioxetine with bupropion SR 150 mg twice daily (after a 3-day titration from 150 mg once daily) is the preferred initial augmentation strategy based on moderate-certainty evidence from the STAR*D trial showing comparable efficacy to switching strategies but with significantly lower discontinuation rates due to adverse events (12.5% vs 20.6% with buspirone, P < 0.001). 1, 2

Rationale for Bupropion Augmentation

• Bupropion augmentation of SSRIs/SNRIs achieves remission in approximately 30% of patients who failed initial antidepressant monotherapy. 2
• Bupropion works through complementary dopaminergic and noradrenergic mechanisms, addressing different neurotransmitter systems than vortioxetine's serotonergic modulation. 2, 6
• Bupropion has significantly lower rates of sexual dysfunction compared to serotonergic antidepressants and is associated with minimal weight gain or modest weight loss. 2, 7
• The combination is particularly beneficial for patients with prominent cognitive symptoms, low energy, or apathy. 2

Bupropion Dosing and Monitoring

• Start bupropion SR 150 mg once daily for 3 days, then increase to 150 mg twice daily (total 300 mg/day) if tolerated. 2, 7
• Administer the second dose before 3 PM to minimize insomnia risk. 2, 7
• Maximum dose is 300 mg/day for augmentation to maintain seizure risk at approximately 0.1%. 2, 7
• Assess response at 6–8 weeks after reaching therapeutic dose before considering further treatment modifications. 1, 2

Critical Bupropion Contraindications

• Seizure disorders or any condition predisposing to seizures (prior head trauma, brain tumor, stroke). 2, 7
• Current or recent MAOI use (within 14 days). 2, 7
• Eating disorders (bulimia or anorexia nervosa) due to increased seizure risk. 2, 7
• Abrupt discontinuation of alcohol, benzodiazepines, or antiepileptic drugs. 2, 7
• Uncontrolled hypertension, as bupropion can elevate blood pressure and heart rate. 2, 7

Monitoring Parameters for Bupropion

• Assess for suicidal ideation, agitation, or behavioral changes within the first 1–2 weeks, as suicide risk peaks during the initial 1–2 months of antidepressant therapy. 2
• Monitor blood pressure and heart rate periodically, especially during the first 12 weeks. 2, 7
• Watch for neuropsychiatric adverse effects including agitation, restlessness, and insomnia. 2, 7

Second-Line Augmentation Strategy: Atypical Antipsychotics

If bupropion is contraindicated or ineffective after 6–8 weeks, augmentation with aripiprazole (starting at 2–5 mg daily) or brexpiprazole (starting at 1 mg daily, titrating to 2–3 mg) represents the next evidence-based option, though these agents carry higher metabolic and extrapyramidal risks. 1, 2, 8

Aripiprazole Augmentation

• A high risk-of-bias trial reported higher remission rates with aripiprazole augmentation (55.4%) versus bupropion augmentation (34.0%), P = 0.031, though the quality of this evidence is limited. 1
• Aripiprazole is FDA-approved as adjunctive treatment for major depressive disorder with inadequate response to antidepressants. 8
• Start at 2–5 mg daily and titrate based on response and tolerability. 8
• Only about one-third of patients who failed an SSRI achieve clinically meaningful response with atypical antipsychotic augmentation. 2

Monitoring for Atypical Antipsychotics

• Monitor weight, fasting glucose, and lipid profile at baseline and quarterly to detect metabolic syndrome. 2
• Assess for extrapyramidal symptoms including akathisia and tardive dyskinesia. 2
• Watch for sedation and orthostatic hypotension, particularly during dose titration. 2

Alternative Augmentation: Cognitive-Behavioral Therapy

Adding cognitive-behavioral therapy to ongoing vortioxetine produces superior outcomes compared to medication monotherapy and should be strongly considered, particularly for patients with severe depression or work-functioning impairment. 1, 2, 3

• CBT combined with antidepressants nearly doubles remission rates (57.5% vs 31.0%, P < 0.001) in severe depression. 3
• CBT augmentation demonstrates efficacy comparable to pharmacologic augmentation in the STAR*D trial. 1
• CBT reduces relapse rates compared to antidepressant monotherapy. 2

Switching Strategies (If Augmentation Fails)

If augmentation strategies fail after 6–8 weeks, switching to a different antidepressant class (SNRI such as duloxetine 60 mg daily or venlafaxine XR 150–225 mg daily) yields remission in approximately 21–25% of cases. 1, 2

• Various switch strategies (to bupropion SR, escitalopram, duloxetine, sertraline, or venlafaxine XR) demonstrate similar efficacy with no significant differences in response or remission rates. 1
• Switching from one SSRI to another does not produce significant differences in response rates; therefore, switching to a different pharmacologic class is recommended. 2
• Duloxetine may be slightly more effective than vortioxetine based on head-to-head comparisons (response RR 0.86,95% CI 0.79–0.94). 5

Treatment-Resistant Depression Considerations

For patients meeting criteria for treatment-resistant depression (failure of ≥2 adequate antidepressant trials), consider advanced therapies including ketamine/esketamine, repetitive transcranial magnetic stimulation (rTMS), or electroconvulsive therapy (ECT). 2, 3

• Ketamine produces rapid symptom reduction within 24 hours with benefits persisting for 3–7 days in TRD. 2
• Esketamine is FDA-approved for treatment-resistant depression and depressive symptoms with acute suicidal ideation. 2
• rTMS and theta-burst stimulation are recommended for multiple treatment failures. 2
• ECT is indicated for multiple treatment failures or when rapid clinical improvement is required. 2

Common Pitfalls to Avoid

• Do not augment before confirming an adequate 6–8 week trial at therapeutic vortioxetine doses (10–20 mg daily). 1, 2
• Do not exceed bupropion 300 mg/day when used for augmentation, as seizure risk increases markedly above this threshold. 2, 7
• Do not combine bupropion with MAOIs or initiate within 14 days of MAOI discontinuation. 2, 7
• Do not skip intensive monitoring during weeks 1–2 after adding any augmentation agent, as suicide risk peaks during this period. 2
• Do not use tricyclic antidepressants as augmentation agents due to higher adverse-effect burden and overdose risk. 1, 2
• Do not assume all augmentation strategies are equivalent; bupropion demonstrates superior tolerability compared to buspirone and comparable efficacy to other options. 1, 2