Is a trial of escitalopram (Lexapro) supported for an adult patient with Major Depressive Disorder (MDD) and Generalized Anxiety Disorder (GAD) who did not improve on citalopram (Celexa) 15 years ago?

Escitalopram Trial After Prior Citalopram Failure

A trial of escitalopram is reasonable despite prior citalopram failure 15 years ago, though the evidence supporting this approach is limited and switching to a different class of antidepressant may be preferable.

Rationale for Considering Escitalopram

Pharmacologic Differences Between Citalopram and Escitalopram

• Escitalopram is the isolated S-enantiomer of racemic citalopram, making it more selective and potent at approximately half the dosage of citalopram 1
• The R-enantiomer present in citalopram is essentially pharmacologically inactive, and removing it may enhance therapeutic effects 1
• Limited evidence from pooled RCTs showed escitalopram demonstrated improvement in sleep scores over citalopram in patients with depression, suggesting some differential effects 2

Time Since Prior Treatment

• The 15-year interval since the failed citalopram trial is clinically significant, as the patient's neurobiological state, comorbidities, and medication metabolism may have changed substantially
• No guideline evidence directly addresses optimal timing for retrying medications from the same class after remote failures

Evidence Against This Approach

Guideline Recommendations for Treatment Failure

• American College of Physicians guidelines show no difference in efficacy when switching between second-generation antidepressants (SGAs) within the same class 2
• Moderate-quality evidence demonstrates similar efficacy whether switching from citalopram to sertraline, bupropion, or venlafaxine 2
• Switching to medications with dual noradrenergic and serotonergic action (such as venlafaxine) may be more rational after SSRI failure 3

Lack of Direct Comparative Evidence

• No studies specifically compare escitalopram efficacy in patients who previously failed citalopram 2
• The pharmacologic similarity between these agents suggests limited biological rationale for expecting dramatically different outcomes

Efficacy Evidence for Escitalopram in MDD and GAD

Major Depressive Disorder

• Escitalopram 10-20 mg/day demonstrated statistically significant superiority over placebo on MADRS scores in three 8-week trials 4
• Symptom improvement occurred rapidly, with some parameters improving within 1-2 weeks 1
• In long-term trials up to 36 weeks, escitalopram significantly prolonged time to relapse compared to placebo 4

Generalized Anxiety Disorder

• Escitalopram 10-20 mg/day showed statistically significant superiority over placebo on HAM-A scores in multiple 8-12 week trials 4, 5
• Pooled analysis of approximately 850 patients revealed significantly greater improvement beginning at week 1-2 and continuing through week 8 5
• In 24-week relapse-prevention studies, escitalopram recipients had 4.04 times lower risk of relapse than placebo 6
• Long-term treatment (24 weeks) led to continuing improvement with 92% of completers achieving response 7

Practical Recommendations

If Proceeding with Escitalopram

• Start at 10 mg/day for 4 weeks, then consider increasing to 20 mg/day if response is inadequate 4, 5
• Assess response by week 2, as early improvement predicts ultimate response 1
• Plan for at least 8-12 weeks of adequate trial before declaring treatment failure 4
• Monitor for common adverse events including nausea (15%), insomnia (9%), and sexual dysfunction (9% ejaculatory delay in males) 4

Alternative Strategies to Consider First

• Switching to venlafaxine or mirtazapine may be more appropriate given prior SSRI failure, as these target different or additional neurotransmitter systems 3
• Augmentation with cognitive behavioral therapy should be offered concurrently, as moderate-quality evidence shows similar efficacy between medication switches and CBT 3, 2
• Consider duloxetine for dual serotonergic/noradrenergic action if pain symptoms are present 2

Common Pitfalls

• Avoid assuming the 15-year interval automatically justifies retrying the same medication class without considering mechanistic alternatives - while time may change response, switching to a different mechanism of action is supported by stronger evidence 2, 3
• Do not use inadequate doses or duration - ensure full 10-20 mg dosing for minimum 8 weeks before declaring failure 4
• Recognize that escitalopram's main advantage over citalopram is improved tolerability and potency at lower doses, not necessarily superior efficacy in treatment-resistant cases 1