Which medication can be added as an adjunct to escitalopram (Lexapro) for augmentation in a patient with a partial response?

Adjunctive Medications for Escitalopram (Lexapro)

Add bupropion SR 150 mg once daily (titrated to 150 mg twice daily after 3 days) to your current escitalopram regimen if you have achieved only partial response after 6–8 weeks at therapeutic doses (10–20 mg daily). This combination achieves remission rates of approximately 50% compared to the typical 30% with SSRI monotherapy alone, and demonstrates significantly lower discontinuation rates (12.5%) due to adverse events compared to buspirone augmentation (20.6%, P < 0.001). 1, 2

Primary Augmentation Strategy: Bupropion SR

Bupropion SR is the preferred pharmacological augmentation agent for escitalopram based on superior tolerability and comparable efficacy to other augmentation strategies. 1

Dosing Protocol

• Start bupropion SR at 150 mg once daily for 3 days, then increase to 150 mg twice daily if tolerated 1, 3
• Maximum dose is 400 mg daily for depression (do not exceed 450 mg/day to maintain seizure risk at 0.1%) 1, 3
• Administer the second dose before 3 PM to minimize insomnia risk 1, 3
• Allow 6–8 weeks at therapeutic doses before declaring treatment failure 1

Clinical Advantages of This Combination

• Complementary mechanisms: Bupropion's norepinephrine-dopamine reuptake inhibition complements escitalopram's serotonergic activity, addressing residual symptoms through different pathways 1, 2
• Reduced sexual dysfunction: Bupropion significantly lowers rates of SSRI-induced sexual dysfunction (occurs in ~40% of SSRI monotherapy patients), making this combination particularly valuable for patients experiencing this side effect 1, 4
• Weight neutrality: Bupropion causes minimal weight gain or even modest weight loss, counteracting potential SSRI-related weight gain 1
• Energy and motivation: Bupropion's activating properties specifically improve low motivation, energy deficits, and apathy that often persist despite SSRI therapy 1

Absolute Contraindications to Bupropion

• History of seizure disorders or any condition predisposing to seizures (brain tumor, stroke, head trauma) 1, 3
• Current or recent MAOI use (within 14 days) 1, 3
• Eating disorders (bulimia, anorexia nervosa) due to increased seizure risk 1, 3
• Abrupt discontinuation of alcohol, benzodiazepines, or antiepileptic drugs 1, 3
• Uncontrolled hypertension 1, 3
• Moderate to severe hepatic impairment (maximum 150 mg daily if mild impairment) 1, 3
• Moderate to severe renal impairment (reduce dose by 50% if GFR <90 mL/min; avoid in ESRD) 1, 3

Critical Safety Monitoring

• Blood pressure and heart rate: Monitor at baseline and periodically during the first 12 weeks, as bupropion can elevate both parameters 1, 3
• Suicidal ideation: Assess at every visit during the first 1–2 months after adding bupropion, as this period carries the highest risk for suicide attempts (FDA black-box warning for patients <24 years) 1
• Agitation and activation: Watch for increased restlessness, agitation, or behavioral changes, particularly in the first few weeks; avoid bupropion in highly agitated patients 1, 3
• Seizure risk factors: Verify absence of conditions that lower seizure threshold before prescribing 1, 3

Alternative Augmentation Strategy: Buspirone

If bupropion is contraindicated or not tolerated, buspirone 5 mg twice daily (titrated to 20 mg three times daily over 2–4 weeks) is an alternative augmentation option, though it has higher discontinuation rates due to adverse events. 1

• Buspirone achieves similar remission rates to bupropion (~30%) but has significantly higher discontinuation rates (20.6% vs 12.5%, P < 0.001) 1
• Therapeutic onset requires 2–4 weeks for buspirone's anxiolytic effect 1
• Target dose is 20 mg three times daily (60 mg total daily) 1

Psychotherapy Augmentation: Cognitive-Behavioral Therapy

Adding cognitive-behavioral therapy (CBT) to escitalopram demonstrates superior efficacy compared to medication alone and should be considered as first-line augmentation, particularly for patients with prominent anxiety symptoms. 1

• Combination of SSRI plus CBT shows greater efficacy than either modality alone for both depression and anxiety disorders 5, 1
• CBT can be initiated immediately while optimizing escitalopram dose, providing synergistic benefit 1
• Individual CBT following Clark-and-Wells or Heimberg models delivered by a trained therapist is the recommended approach 1
• Structured self-help CBT programs with therapist support are evidence-based alternatives when face-to-face therapy is not accessible 1

Critical Timing Considerations Before Augmentation

Ensure escitalopram has been optimized to 20 mg daily for a minimum of 6–8 weeks before adding augmentation therapy, as premature switching or augmentation leads to missed opportunities for response. 1

• Approximately 50% of patients who ultimately achieve remission with escitalopram do so between weeks 6 and 14 of treatment 1
• The maximum recommended daily dose of escitalopram is 20 mg; higher doses increase QT prolongation risk without additional benefit 1
• Assess treatment response every 2–4 weeks using standardized depression and anxiety rating scales (PHQ-9, HAM-D, or GAD-7) 1

Switching Strategy (If Augmentation Fails)

If combination therapy (escitalopram 20 mg + bupropion 300–400 mg) fails after 8 weeks, switch to an SNRI (venlafaxine 150–225 mg daily or duloxetine 60–120 mg daily) rather than trying another SSRI. 1

• SNRIs demonstrate statistically significantly better response and remission rates than SSRIs in treatment-resistant depression 1
• Switching to another SSRI after escitalopram failure yields remission in only 21–25% of cases, with no evidence favoring one SSRI over another 1
• Venlafaxine has slightly higher discontinuation rates compared to SSRIs but superior efficacy for anxious depression 1

Common Pitfalls to Avoid

• Do not combine escitalopram with other serotonergic agents (buspirone, triptans, tramadol, other antidepressants) before ensuring adequate dose and duration of SSRI monotherapy, as this increases serotonin syndrome risk 1
• Do not exceed escitalopram 20 mg daily without cardiac monitoring due to QT prolongation risk 1
• Do not make dose changes more frequently than every 2–4 weeks, as this prevents adequate assessment of therapeutic response and increases destabilization risk 1
• Do not combine bupropion with MAOIs or initiate within 14 days of MAOI discontinuation 1, 3
• Do not use naltrexone-bupropion combination products in patients on any opioid therapy (including buprenorphine/naloxone), as naltrexone will precipitate severe withdrawal 1, 3

Duration of Continuation Therapy

• Continue combination therapy for 4–9 months after achieving remission for a first episode of major depression 1
• For recurrent depression (≥2 episodes), maintain therapy for ≥1 year or longer, as relapse risk is 70% after two episodes and 90% after three episodes 1

Special Considerations for Specific Patient Populations

Patients with Comorbid Substance Use

• Bupropion may be particularly beneficial for patients with comorbid nicotine dependence, addressing both depression and smoking cessation simultaneously 1, 3
• For smoking cessation, start bupropion 1–2 weeks before the target quit date at 150 mg once daily for 3 days, then 150 mg twice daily (maximum 300 mg/day for smoking cessation) 1, 3
• Bupropion demonstrates efficacy for methamphetamine dependence, particularly in patients with low-to-moderate baseline use 1

Older Adults (≥65 years)

• Start bupropion at 37.5 mg every morning and increase by 37.5 mg every 3 days as tolerated, targeting a maximum of 150 mg twice daily (300 mg total) 1, 3
• Bupropion, escitalopram, sertraline, mirtazapine, and venlafaxine are preferred antidepressants for elderly patients due to favorable adverse-effect profiles 1
• Avoid paroxetine (high anticholinergic burden) and fluoxetine (greater agitation risk) in older adults 1

Patients with Hepatic or Renal Impairment

• Moderate to severe hepatic impairment: Maximum bupropion dose is 150 mg daily; for mild impairment, reduce dose and/or frequency 1, 3
• Moderate to severe renal impairment (GFR <90 mL/min): Reduce bupropion dose by 50% (e.g., 150 mg daily instead of 300 mg) 1, 3
• End-stage renal disease: Avoid bupropion entirely, as metabolites accumulate and hemodialysis does not effectively clear them 1, 3