What is the best approach to augment escitalopram (citalopram) treatment for anxiety in a patient with mixed depressive anxiety disorder?

Augmenting Escitalopram for Mixed Depressive-Anxiety Disorder

Add bupropion as first-line augmentation to escitalopram for mixed depressive-anxiety disorder, starting at 150 mg/day sustained-release formulation. 1

Primary Augmentation Strategy: Bupropion

• Bupropion demonstrates superior tolerability compared to buspirone when augmenting SSRIs, with significantly fewer discontinuations due to adverse events (12.5% vs. 20.6%; P < 0.001) in the STAR*D trial. 2, 1

• Bupropion provides mechanistic advantage by targeting dopamine and norepinephrine pathways rather than adding another serotonergic agent, which offers no additional benefit and increases serotonin syndrome risk. 1

• Start bupropion SR at 150 mg/day and allow 2-4 weeks for full therapeutic effect on both depressive and anxiety symptoms before considering dose escalation. 1

• The American College of Physicians found that bupropion augmentation produces similar response and remission rates to buspirone but with markedly better tolerability in patients with comorbid anxiety and depression. 2, 1

Alternative Pharmacologic Augmentation: Buspirone

• Buspirone augmentation showed equivalent efficacy to bupropion in the STAR*D trial when augmenting citalopram (escitalopram's parent compound), but with significantly higher discontinuation rates due to adverse events. 2, 1

• If bupropion is contraindicated (seizure history, eating disorders, abrupt alcohol/benzodiazepine withdrawal), buspirone becomes the preferred pharmacologic alternative. 1

• Start buspirone at 5 mg twice daily and titrate gradually to 10-30 mg twice daily (maximum 60 mg/day divided into three doses). 1

• Critical pitfall: Buspirone requires 2-4 weeks to reach full therapeutic effect—patients and providers often discontinue prematurely before the therapeutic window, mistakenly concluding it is ineffective. 1

• Buspirone has no addiction potential, tolerance development, or cognitive impairment, making it safer than benzodiazepines for long-term anxiety management. 1

Cognitive Behavioral Therapy Augmentation

• Add CBT to ongoing escitalopram rather than switching medications, as the STAR*D trial demonstrated equivalent efficacy between CBT augmentation and pharmacologic augmentation strategies. 2, 1

• CBT augmentation addresses both anxiety and depressive symptoms simultaneously with lower discontinuation rates due to adverse effects (9.2%) compared to medication augmentation (18.8%). 2, 1

• CBT should be offered as either an alternative to pharmacologic augmentation or as a combined approach with bupropion/buspirone for patients preferring multimodal treatment. 1

What NOT to Do

• Do not add another SSRI or SNRI as augmentation—this provides no mechanistic advantage over escitalopram alone and increases serotonin syndrome risk without improving efficacy. 1

• Avoid switching between different serotonergic antidepressants (SSRIs, SNRIs), as moderate-quality evidence from STAR*D showed no difference in response rates when switching between these agents. 2, 1

• Do not use benzodiazepines for long-term augmentation despite their immediate anxiety relief—they carry addiction potential and cognitive impairment risks that bupropion and buspirone avoid. 1

Critical Monitoring Parameters

• Monitor intensively during the first 24-48 hours after adding any augmentation agent, particularly when combining serotonergic medications. 1

• Assess for serotonin syndrome signs: mental status changes (agitation, confusion), neuromuscular hyperactivity (tremor, rigidity, myoclonus, hyperreflexia), and autonomic hyperactivity (tachycardia, hypertension, hyperthermia, diaphoresis). 1

• All antidepressants carry FDA black box warnings for increased suicidal thinking—monitor closely during treatment transitions, especially in patients under 25 years old. 1

• Allow minimum of one week at current escitalopram dose before adding augmentation to establish baseline tolerability. 3

If Augmentation Fails: Switching Strategy

• If bupropion or buspirone augmentation fails after adequate trial (4-6 weeks at therapeutic dose), switch to bupropion monotherapy rather than another serotonergic agent, as it avoids the same mechanistic pathway that failed with escitalopram. 1

• The STAR*D trial found no superiority when switching between different serotonergic antidepressants (bupropion vs. sertraline vs. venlafaxine), suggesting that staying within the same mechanistic class offers no advantage. 2

• When discontinuing escitalopram, taper gradually rather than abrupt cessation to minimize discontinuation symptoms; if intolerable symptoms occur, resume previous dose and taper more slowly. 3

• Allow at least 14 days between discontinuing escitalopram and starting an MAOI to prevent serotonin syndrome. 3

Evidence Quality Considerations

• The augmentation evidence comes primarily from the STAR*D trial, which provides moderate-quality evidence for bupropion and low-quality evidence for buspirone augmentation strategies. 2

• Comorbid anxiety did not affect the comparative efficacy of augmentation strategies in STAR*D subgroup analyses, supporting use of these strategies specifically in mixed anxiety-depressive presentations. 2

• Depression severity also did not significantly affect comparative efficacy of augmentation strategies, indicating these recommendations apply across the severity spectrum. 2