What are the appropriate next medication options for treating depression in a patient already taking escitalopram (Lexapro) who cannot use bupropion (Wellbutrin)?

Augment Lexapro with Bupropion SR

For a patient already on escitalopram (Lexapro) who cannot take bupropion (Wellbutrin), the next best medication option is to augment with buspirone, starting at 5 mg twice daily and titrating to 10-30 mg twice daily over 2-4 weeks. 1

Critical First Step: Optimize Current Escitalopram Dose

Before adding any medication, ensure the patient has been on escitalopram 20 mg daily for at least 8-12 weeks, as this is the minimum duration and dose needed to assess full antidepressant response. 2, 1 Premature switching or augmentation before allowing adequate trial duration leads to missed opportunities for response. 2

Primary Augmentation Strategy: Buspirone

Since bupropion is contraindicated or not tolerated, buspirone becomes the preferred augmentation agent for several reasons:

• The STAR*D trial demonstrated that buspirone augmentation of citalopram (a closely related SSRI) achieved similar efficacy to bupropion augmentation, with no difference in response or remission rates. 3, 1

• Buspirone has significantly lower discontinuation rates due to adverse events (12.5%) compared to other augmentation strategies, making it safer for long-term use. 1, 4

• Buspirone has no addiction potential, tolerance, or cognitive impairment, unlike benzodiazepines, making it appropriate for extended treatment. 1, 4

Buspirone Dosing Protocol

• Start at 5 mg twice daily and titrate gradually to 10-30 mg twice daily (maximum 20 mg three times daily). 1, 4

• Allow 2-4 weeks for full therapeutic effect—unlike benzodiazepines, buspirone is not immediately effective, and premature discontinuation before this window is a common pitfall. 1, 4

Alternative Strategy: Add Cognitive-Behavioral Therapy

Adding CBT to ongoing escitalopram demonstrates superior efficacy compared to medication alone for both anxiety and depression. 2, 1 Low-quality evidence shows no difference in response or remission when switching to CBT alone versus switching to another antidepressant, but CBT augmentation addresses both symptom domains simultaneously with lower discontinuation rates due to adverse effects compared to pharmacological augmentation. 1

Switching Strategy (If Augmentation Fails)

If buspirone augmentation fails after an adequate trial:

• Switch to an SNRI (venlafaxine 150-225 mg daily or duloxetine 40-120 mg daily), as SNRIs demonstrate statistically significantly better response and remission rates than SSRIs in treatment-resistant depression. 2

• Do not switch to another SSRI, as moderate-quality evidence from the STAR*D trial showed no difference in response when switching between serotonergic antidepressants, and no evidence supports superior efficacy of one SSRI over another. 2, 1

• Venlafaxine has slightly higher risks of discontinuation compared with SSRIs as a class, but its dual action on serotonin and norepinephrine may provide greater effect on both depression and anxiety symptoms. 2

Critical Safety Monitoring

Monitor intensively during the first 24-48 hours after any medication change, particularly when adding augmentation agents. 1

• Assess for serotonin syndrome signs: mental status changes, neuromuscular hyperactivity (tremor, hyperreflexia), and autonomic hyperactivity (fever, tachycardia). 1, 4 The risk is theoretical with buspirone but requires vigilance.

• Assess for suicidal ideation at every follow-up visit during the first 1-2 months after any antidepressant medication change, as all antidepressants carry black box warnings for increased suicidal thinking during treatment transitions. 2, 1

• Do not exceed escitalopram 20 mg daily without cardiac monitoring, as higher doses are associated with QT prolongation risk without additional benefit. 2

Common Pitfalls to Avoid

• Do not add another serotonergic agent (another SSRI or SNRI) as augmentation—this provides no mechanistic advantage and increases serotonin syndrome risk without demonstrated efficacy benefit. 2, 1

• Do not expect immediate results from buspirone—patients and providers often discontinue prematurely before the 2-4 week therapeutic window. 1, 4

• Do not use benzodiazepines for long-term augmentation—while they provide immediate anxiety relief, they carry addiction potential and cognitive impairment risks that buspirone avoids. 1, 4

Duration of Continuation Therapy

After achieving remission, continue treatment for 4-9 months for a first episode of major depression. 2 For patients with recurrent depression (≥2 episodes), consider maintenance therapy for years to lifelong to prevent relapse. 2