What is the next best medication to consider for a patient with anxiety and depression who has not responded to Lexapro (escitalopram) and citalopram?

Next Medication for Treatment-Resistant Anxiety and Depression

Direct Recommendation

For this 25-year-old female who has failed both escitalopram (Lexapro) and citalopram, you should switch to either bupropion sustained-release, sertraline, or venlafaxine extended-release, as these three medications show equivalent efficacy in treatment-resistant depression and no single agent demonstrates superiority over the others. 1

Your proposed plan to switch to fluoxetine (Prozac) is not supported by the evidence, as fluoxetine has a slower onset of action compared to other SSRIs and shows no advantage in treatment-resistant cases. 1, 2

Evidence-Based Switching Strategy

First-Line Options After SSRI Failure

The STAR*D trial—the highest quality evidence for treatment-resistant depression—demonstrated that when switching from an initial SSRI failure, the following three medications perform equally well: 1

• Bupropion sustained-release (up to 400 mg/day)
• Sertraline (up to 200 mg/day)
• Venlafaxine extended-release (up to 375 mg/day)

Approximately 21% of patients achieve remission and an additional 9% achieve response without remission when switching to any of these agents. 3

Why Not Fluoxetine?

• Fluoxetine has a significantly slower onset of action compared to other SSRIs (paroxetine, sertraline) and SNRIs. 1
• No evidence supports fluoxetine as superior for treatment-resistant cases. 1
• Since your patient has already failed two SSRIs (escitalopram and citalopram), switching to a third SSRI (fluoxetine) offers no mechanistic advantage. 1

Selection Among the Three Recommended Options

For anxiety and depression combined, the evidence shows: 1

• Venlafaxine (SNRI) showed statistically better response rates than fluoxetine in one trial for patients with MDD and anxiety symptoms, though other trials showed equivalence with sertraline and bupropion. 1
• Sertraline has the lowest discontinuation rate due to adverse effects among SSRIs and shows equivalent efficacy for anxiety symptoms. 1, 2
• Bupropion has the lowest rate of sexual side effects compared to SSRIs, which is particularly relevant for a 25-year-old female. 1

Practical Switching Protocol

Direct Switch Method

You can perform a direct switch without cross-tapering when moving from citalopram to any of the three recommended agents: 4

• Stop citalopram 20 mg on day 1
• Start the new medication at standard starting dose on day 2
• This approach is well-tolerated and avoids prolonged subtherapeutic dosing

Starting Doses

• Bupropion SR: Start 150 mg daily, increase to 150 mg twice daily after 3-4 days, maximum 400 mg/day
• Sertraline: Start 50 mg daily, increase to 100-200 mg/day as tolerated
• Venlafaxine XR: Start 37.5-75 mg daily, increase to 150-225 mg/day (maximum 375 mg/day)

Expected Timeline and Monitoring

Treatment Duration

• Minimum 12 weeks of adequate dosing is necessary to capture the maximum number of responders. 3
• Half of responses and two-thirds of remissions occur after 6 weeks of treatment. 3
• One-third of responses occur after 9 weeks or more. 3

Early Triage Point

• Assess symptom reduction at week 2: Patients with at least 20% reduction in depressive symptoms are 6 times more likely to ultimately respond or remit. 3
• If less than 20% improvement by week 2, strongly consider augmentation strategies or alternative approaches rather than waiting the full 12 weeks. 3

Monitoring Schedule

Begin monitoring within 1-2 weeks of initiation for: 1

• Suicidal ideation (highest risk in first 1-2 months)
• Agitation, irritability, or behavioral changes
• Treatment response and adverse effects

Critical Caveats

Realistic Expectations

• 58% of patients achieve no meaningful benefit when switching to a second monoaminergic antidepressant after SSRI failure. 3
• Only about 20% achieve remission with a second-step switch. 3
• If this switch fails, strongly consider augmentation strategies (adding bupropion or buspirone to an SSRI) or switching to cognitive behavioral therapy. 1

Combination Therapy Consideration

Given her anxiety symptoms, combination of medication plus CBT may be more effective than either alone, particularly for severe anxiety. 5

• CBT should be structured with approximately 14 sessions over 4 months
• Each session lasting 60-90 minutes
• Consider this if medication switching alone proves insufficient 5