What medications can be added to Lexapro (escitalopram) to enhance treatment of depression?

Augmentation Strategies for Lexapro (Escitalopram) in Depression

When Lexapro alone is insufficient for treating depression, bupropion is the preferred augmentation agent, offering superior reduction in depression severity compared to buspirone with fewer discontinuation rates due to adverse events. 1

Primary Augmentation Options

Bupropion (First-Line Augmentation)

• Bupropion demonstrates superior efficacy when augmenting SSRIs like escitalopram, decreasing depression severity more effectively than buspirone. 1
• Moderate-quality evidence shows discontinuation due to adverse events is lower with bupropion augmentation compared to buspirone augmentation. 1
• Bupropion works through a different mechanism (norepinephrine and dopamine reuptake inhibition) than escitalopram's serotonergic action, providing complementary neurotransmitter coverage. 2
• Initial dosing: Start at 37.5 mg every morning, increase by 37.5 mg every 3 days, up to maximum 150 mg twice daily. 1
• Critical precaution: Avoid bupropion in patients with seizure disorders, brain metastases, or elevated seizure risk (0.1% seizure risk). 1, 2
• Give the second dose before 3 p.m. to minimize insomnia risk, as bupropion is activating. 1

Buspirone (Alternative Augmentation)

• Buspirone can be safely combined with escitalopram for patients with comorbid anxiety and depression. 3
• Low-quality evidence shows no difference in response or remission rates when augmenting citalopram (escitalopram's parent compound) with buspirone versus bupropion, though bupropion reduces depression severity more. 1
• Initial dosing: 5 mg twice daily, titrate up to maximum 20 mg three times daily. 3
• Key advantage: Unlike benzodiazepines, buspirone does not cause tolerance, addiction, cognitive impairment, or paradoxical agitation. 3
• Important caveat: Buspirone requires 2-4 weeks to reach full therapeutic effect—do not expect immediate results. 3
• Theoretical risk of serotonin syndrome exists when combining with escitalopram; start low, increase slowly, and monitor especially in the first 24-48 hours after dose changes. 3

Additional Augmentation Considerations

Mirtazapine

• Mirtazapine (7.5 mg at bedtime, up to 30 mg) is potent, well-tolerated, and promotes sleep, appetite, and weight gain. 1
• Particularly useful for patients with agitated depression, insomnia, or poor appetite. 1

Lithium

• Lithium can augment antidepressant drugs at low doses (150 mg per day, targeting blood levels of 0.2-0.6 mEq/L). 1
• Elderly patients are prone to neurotoxicity at higher lithium dosages—use cautiously. 1

Monitoring and Safety

Serotonin Syndrome Surveillance

• When combining serotonergic medications (escitalopram with buspirone), monitor for mental status changes, neuromuscular hyperactivity, and autonomic hyperactivity. 3
• Highest risk occurs in the first 24-48 hours after initiating combination or dose adjustments. 3

Timeline Expectations

• Bupropion may produce rapid improvement in energy levels. 1
• Buspirone requires 2-4 weeks for full efficacy—patience is essential. 3
• Regular assessment of therapeutic response is necessary, as augmentation strategies may take several weeks to demonstrate benefit. 3

Common Pitfalls to Avoid

• Do not expect immediate results from buspirone—unlike benzodiazepines, it has delayed onset of action. 3
• Do not use bupropion in agitated patients or those with seizure risk factors. 1, 2
• Do not discontinue escitalopram abruptly—it is associated with discontinuation syndrome. 3
• Do not rely on buspirone for severe agitation—it is best for mild to moderate anxiety. 3
• Do not overlook early signs of serotonin syndrome, which can be mistaken for worsening anxiety. 3