What is the next best treatment for a 53‑year‑old man with severe anxiety and depression who discontinued escitalopram (Lexapro) and sertraline (Zoloft) because of side effects and is currently taking buspirone (Buspar) without benefit?

Next Best Treatment: Switch to Venlafaxine or Augment with Bupropion

For a 53-year-old man with severe anxiety and depression who has failed two SSRIs (escitalopram and sertraline) due to side effects and shows no response to buspirone, the most evidence-based next step is to switch to venlafaxine (SNRI) 75–225 mg daily or augment the failed SSRI trial with bupropion SR 150–300 mg daily. 1

Why Switch to an SNRI (Venlafaxine)

• Venlafaxine demonstrates statistically significantly better response and remission rates than SSRIs in treatment-resistant depression, particularly when patients have failed multiple SSRI trials. 1
• The American Academy of Family Physicians recommends switching to an SNRI such as venlafaxine after SSRI failure, as SNRIs have demonstrated greater efficacy for treatment-resistant depression compared to continuing with SSRI therapy. 1
• SNRIs may have a greater effect on both depression and anxiety symptoms due to their dual action on serotonin and norepinephrine reuptake, making venlafaxine particularly appropriate for this patient's comorbid severe anxiety and depression. 1
• Switching medication classes often provides better outcomes than trying another SSRI after failing two agents from the same class. 1

Venlafaxine Dosing Protocol

• Start venlafaxine XR at 37.5–75 mg daily and titrate to a therapeutic range of 150–225 mg daily over 2–4 weeks. 1
• Allow a full 6–8 weeks at therapeutic doses (150–225 mg daily) before declaring treatment failure. 1
• Venlafaxine has slightly higher discontinuation rates compared with SSRIs due to adverse effects such as nausea and vomiting, but the superior efficacy in treatment-resistant cases justifies this trade-off. 1

Alternative: Bupropion Augmentation Strategy

If the patient had any partial benefit from either escitalopram or sertraline, augmenting with bupropion SR is equally valid and may be preferred to avoid SSRI discontinuation symptoms. 1

Why Bupropion Augmentation Works

• Bupropion augmentation of SSRIs decreases depression severity more effectively than buspirone augmentation in patients who failed initial SSRI monotherapy. 2
• The STAR*D trial demonstrated that bupropion augmentation achieved remission rates of approximately 30%, with significantly lower discontinuation rates due to adverse events (12.5%) compared to buspirone (20.6%, P < 0.001). 1, 2
• Bupropion's norepinephrine-dopamine reuptake inhibition complements SSRI serotonergic activity, providing synergistic antidepressant effects through distinct mechanisms. 2, 3
• Bupropion has significantly lower rates of sexual dysfunction compared to SSRIs, which may have contributed to this patient's side effects with prior SSRI trials. 2

Bupropion Dosing Protocol

• Start bupropion SR at 150 mg once daily for 3 days, then increase to 150 mg twice daily (300 mg total) if tolerated. 2
• The second dose must be administered before 3 PM to minimize insomnia risk. 2
• Maximum dose is 400 mg daily for SR formulation (divided doses), though 300 mg daily is typically sufficient for augmentation. 2
• Allow 6–8 weeks at therapeutic doses before assessing response. 2

Critical Bupropion Contraindications to Screen

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

Why Buspirone Has Failed

• Buspirone monotherapy is ineffective for severe depression; it is primarily an anxiolytic with minimal antidepressant properties. 1
• The American College of Physicians found no significant difference between buspirone augmentation and placebo in overall treatment-resistant depression, though it may benefit patients with initially severe symptoms (MADRS >30). 1, 4
• Buspirone augmentation should only be considered after optimizing SSRI dose and duration (8–12 weeks at maximum tolerated dose), which was not done in this case since the patient discontinued SSRIs due to side effects. 1

Why Not Try Another SSRI

• No evidence supports superior efficacy of one SSRI over another after failing two SSRIs from the same class. 1
• The American College of Physicians explicitly states that switching to another SSRI yields remission in only approximately 21–25% of cases, which is inferior to switching to an SNRI. 1
• This patient has already failed escitalopram and sertraline due to side effects, making a third SSRI trial unlikely to succeed. 1

Monitoring Requirements for Either Strategy

For Venlafaxine:

• Assess for suicidal ideation during the first 1–2 months after switching, as suicide risk is greatest during this period. 1
• Monitor blood pressure periodically, as venlafaxine can cause modest elevations. 1
• Use standardized depression and anxiety rating scales (PHQ-9, GAD-7) every 2–4 weeks to track response. 1

For Bupropion:

• Monitor blood pressure and heart rate, especially in the first 12 weeks, as bupropion can cause elevations in both. 2
• Assess for suicidal ideation, agitation, irritability, or unusual behavioral changes during the first 1–2 months, particularly in patients under 24 years (though this patient is 53). 2
• Watch for neuropsychiatric adverse effects including agitation and restlessness. 2

Adjunctive Psychotherapy Consideration

• Adding cognitive-behavioral therapy (CBT) to medication demonstrates superior efficacy compared to medication alone for both depression and anxiety disorders. 1
• CBT can be initiated immediately while optimizing pharmacotherapy, providing synergistic benefit through complementary neurobiological and psychological mechanisms. 1
• The American Academy of Child and Adolescent Psychiatry recommends addressing both components simultaneously for optimal outcomes. 1

Common Pitfalls to Avoid

• Do not try another SSRI after failing two SSRIs—switch medication classes. 1
• Do not continue buspirone monotherapy for severe depression; it lacks sufficient antidepressant efficacy. 1
• Do not switch medications before allowing adequate trial duration (6–8 weeks at therapeutic dose), though this patient's side effects justified early discontinuation. 1
• Do not exceed bupropion 450 mg/day to maintain seizure risk at 0.1%. 2
• Do not combine venlafaxine with escitalopram or other SSRIs, as this markedly raises serotonin syndrome risk without demonstrated benefit. 1

Treatment Duration After Response

• Continue treatment for 4–9 months after satisfactory response for a first episode of major depression. 1
• For recurrent depression (≥2 episodes), consider maintenance therapy for ≥1 year or longer to prevent relapse. 1