Can clomipramine be used with Lexapro (escitalopram) for obsessive-compulsive disorder (OCD)?

Combining Clomipramine with Lexapro (Escitalopram) for OCD

This combination should generally be avoided due to dangerous pharmacokinetic drug interactions that significantly increase clomipramine blood levels, risking life-threatening adverse effects including seizures, cardiac arrhythmias, and serotonin syndrome. 1, 2

Why This Combination Is Problematic

The core issue is a bidirectional pharmacokinetic interaction where escitalopram (Lexapro) inhibits the metabolism of clomipramine, dramatically raising its blood levels and toxicity risk 2:

• Clomipramine has dose-dependent life-threatening adverse effects, particularly seizures and cardiac conduction abnormalities, that become more likely at elevated blood concentrations 2
• SSRIs like escitalopram can raise clomipramine blood levels through CYP450 enzyme inhibition, though escitalopram has relatively less effect on CYP450 isoenzymes compared to other SSRIs 3, 2
• Serotonin syndrome risk increases when combining two serotonergic medications, with symptoms potentially emerging within 24-48 hours including mental status changes, neuromuscular hyperactivity, autonomic instability, and in severe cases, seizures and death 3

The Clinical Context: When This Question Arises

This combination is sometimes considered for SSRI-refractory OCD after escitalopram monotherapy has failed 4, 1. However, the evidence and guidelines point to safer alternatives:

Better Alternatives to This Combination

First-line augmentation strategies for SSRI-resistant OCD:

• Risperidone or aripiprazole augmentation have the strongest evidence, with approximately one-third of SSRI-resistant patients achieving clinically meaningful response 4, 1
• Adding CBT with Exposure and Response Prevention (ERP) produces larger effect sizes than antipsychotic augmentation 4, 1

Second-line augmentation options:

• N-acetylcysteine has demonstrated superiority to placebo in three out of five randomized controlled trials 4, 1
• Memantine has shown efficacy in several trials 4, 1

Switching strategies:

• Consider switching from escitalopram to clomipramine monotherapy (not combining them) if multiple SSRIs have failed 4
• Clomipramine is reserved as second-line or third-line for treatment-resistant OCD after at least one adequate SSRI trial at maximum tolerated doses for 8-12 weeks 4

If This Combination Must Be Used (Rare Circumstances)

While guidelines explicitly warn against this combination 1, older case series suggest it may occasionally be considered in highly refractory cases with extreme caution and intensive monitoring 5, 6:

Mandatory Safety Protocols

Dosing must be dramatically reduced compared to monotherapy 5, 2, 6:

• Start clomipramine at 25 mg daily (not the typical 25-250 mg range used in monotherapy) 5, 6
• Maximum clomipramine dose typically 50 mg daily when combined with an SSRI 5, 6
• Escitalopram dose may need reduction as well 2

Intensive monitoring requirements 2, 6:

• Baseline and serial ECGs to monitor QTc interval prolongation and cardiac conduction abnormalities 6
• Clomipramine blood level monitoring (clomipramine plus desmethylclomipramine metabolite) 2, 6
• Vital signs at every visit, particularly heart rate and blood pressure 6
• Close monitoring for serotonin syndrome symptoms, especially in first 24-48 hours after any dose change 3

Cardiovascular side effects are the most common serious adverse effects, including QTc prolongation and tachycardia 6

Critical Pitfalls to Avoid

• Never use standard clomipramine dosing (up to 250 mg/day) when combining with SSRIs—this creates unacceptable toxicity risk 2, 6
• Do not combine with MAOIs—this is absolutely contraindicated due to severe serotonin syndrome risk 3
• Escitalopram may be a relatively safer SSRI choice for this combination compared to fluoxetine, paroxetine, or fluvoxamine due to less CYP450 inhibition, but risk still exists 3, 2
• Recent myocardial infarction is an absolute contraindication to clomipramine 4

The Bottom Line Algorithm

For SSRI-refractory OCD on escitalopram:

1. First, optimize the current regimen: Ensure escitalopram has been trialed at maximum tolerated dose for 8-12 weeks 4, 1

2. Add evidence-based augmentation: Risperidone or aripiprazole augmentation, or intensify CBT with ERP 4, 1

3. If augmentation fails: Consider switching to clomipramine monotherapy (discontinue escitalopram first with appropriate washout) rather than combining 4

4. Only in exceptional circumstances: Consider the combination with dramatically reduced doses and intensive monitoring as described above 5, 2, 6

5. Treatment duration: Maintain successful treatment for 12-24 months after achieving remission due to high relapse rates 4, 1