What is the next best medication for anxiety and depression if a patient is not tolerating Selective Serotonin Reuptake Inhibitors (SSRIs) like Lexapro (escitalopram)?

Next Best Medication for Anxiety and Depression After SSRI Intolerance

When a patient cannot tolerate escitalopram (Lexapro), switch to bupropion as the next best medication choice, as it has a distinctly different adverse effect profile with lower rates of sexual dysfunction, nausea, and other common SSRI side effects that typically cause intolerance. 1, 2

Primary Recommendation: Bupropion

• Bupropion is associated with significantly lower rates of sexual adverse events compared to SSRIs like fluoxetine or sertraline, making it the optimal choice when SSRI side effects (particularly sexual dysfunction, nausea, or somnolence) are the reason for intolerance 1
• Bupropion works through a different mechanism (dopamine and norepinephrine reuptake inhibition rather than serotonin), providing therapeutic benefit without the typical SSRI adverse effect profile 2
• The American College of Physicians guidelines explicitly recommend selecting antidepressants based on adverse effect profiles when efficacy is comparable across agents 1

Alternative Second-Line Options

SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors)

• Venlafaxine or duloxetine can be considered if the patient's intolerance to escitalopram was not related to serotonergic side effects (e.g., if intolerance was due to QT prolongation concerns specific to escitalopram) 3
• SNRIs may have modest efficacy advantages over SSRIs as a class (5-10% difference in remission rates), though this advantage has not been demonstrated versus escitalopram specifically 3
• Caution: SNRIs can cause hypertension at higher doses, so avoid in patients with cardiovascular disease 1

Other SSRIs (If Specific to Escitalopram)

• If the intolerance is specific to escitalopram (such as QT prolongation concerns), switching to sertraline is reasonable as it has been extensively studied, appears safer regarding QT effects, and has lower potential for drug-drug interactions 1
• Sertraline has demonstrated efficacy for both anxiety and depression with a well-established safety profile 1
• Avoid citalopram if QT prolongation was the issue, as it shares this risk with escitalopram and is contraindicated at doses exceeding 40 mg/day 1

For Anxiety-Predominant Presentations

If anxiety is the primary concern and SSRIs have failed due to intolerance:

• Pregabalin is recommended as a second-line agent for anxiety disorders when SSRIs/SNRIs fail 4
• Gabapentin can be considered, particularly if comorbid pain conditions exist 4
• Benzodiazepines (alprazolam, clonazepam) provide rapid anxiety relief but should be reserved for short-term use due to dependence risk 4

Critical Monitoring Requirements

• Begin monitoring within 1-2 weeks of starting any new antidepressant to assess for suicidal ideation, agitation, irritability, or unusual behavioral changes 1
• The risk for suicide attempts is greatest during the first 1-2 months of treatment with any antidepressant 1
• Regular assessment of therapeutic response and adverse effects should continue throughout treatment 1

Important Caveats

• Paroxetine should be avoided as it has higher rates of sexual dysfunction than other SSRIs and significant discontinuation syndrome risk 1
• Avoid tricyclic antidepressants and MAO inhibitors due to significant cardiovascular side effects and safety concerns 1
• Combination therapy with cognitive behavioral therapy (CBT) plus medication often yields superior results compared to either approach alone, particularly for moderate to severe presentations 1, 4

Practical Algorithm

1. First, identify the specific reason for SSRI intolerance:

   • Sexual dysfunction, GI symptoms, sedation → Switch to bupropion 1, 2
   • QT prolongation concerns → Switch to sertraline 1
   • Inadequate response rather than true intolerance → Consider SNRI (venlafaxine/duloxetine) 3

2. For anxiety-predominant cases where bupropion may be less ideal:

   • Try sertraline first (proven efficacy for both anxiety and depression) 1
   • If this fails, consider pregabalin as second-line 4

3. Always add or continue CBT regardless of medication choice, as combination therapy improves outcomes 1, 4