What's the next step for a patient with Major Depressive Disorder (MDD) and Obsessive-Compulsive Disorder (OCD) who is not responding to 200mg of Zoloft (sertraline) and 100mg of Lamotrigine daily?

Treatment-Resistant MDD and OCD: Next Steps

For this patient failing 200mg sertraline (maximum FDA-approved dose) and 100mg lamotrigine, the next step is to augment the sertraline with cognitive behavioral therapy (CBT) with exposure and response prevention (ERP) for the OCD component, while simultaneously considering switching or augmenting the antidepressant regimen for MDD—specifically either switching to a different SSRI/SNRI or augmenting with an atypical antipsychotic. 1

Understanding the Current Situation

This patient presents a complex dual-diagnosis scenario requiring separate but coordinated treatment strategies:

OCD Treatment Considerations

• Sertraline 200mg is at the maximum FDA-approved dose for OCD 2, and the patient has not responded adequately after what should be at least 8-12 weeks of treatment 1
• Approximately 50% of OCD patients fail to respond to initial SSRI monotherapy 1, 3, making this a common clinical scenario
• Lamotrigine has some evidence as a glutamatergic augmentation agent for treatment-resistant OCD 1, though 100mg may be subtherapeutic for this indication

MDD Treatment Considerations

• The American College of Physicians recommends modifying treatment if inadequate response occurs within 6-8 weeks 1, which appears to be the case here
• Response rates to initial antidepressant therapy are only 50%, with 54% failing to achieve remission 1

Recommended Treatment Algorithm

Step 1: Optimize OCD Treatment (Priority)

Add CBT with ERP immediately 1:

• This is the strongest evidence-based augmentation strategy for SSRI-resistant OCD
• Effect sizes are larger with SSRI + CBT augmentation compared to SSRI + antipsychotic augmentation 1
• Recommend 10-20 sessions of individual or group CBT with exposure and response prevention 1

If CBT is unavailable or not tolerated, consider these pharmacological options in order:

1. Switch to clomipramine (most evidence-based alternative) 1:

   • Start 25mg daily, titrate to 150-250mg daily over several weeks
   • More efficacious than SSRIs in some meta-analyses, though tolerability is lower 1
   • Critical warning: If combining with sertraline, there is serious risk of seizures, cardiac arrhythmia, and serotonin syndrome due to elevated drug levels 1

2. Augment sertraline with an atypical antipsychotic 1:

   • Risperidone or aripiprazole have the strongest evidence 1
   • Start risperidone 0.5mg daily, titrate to 2-4mg daily
   • Important caveat: Only one-third of SSRI-resistant OCD patients show clinically meaningful response 1
   • Monitor closely for metabolic side effects and weight gain 1

3. Consider glutamatergic augmentation 1:

   • Increase lamotrigine to 200-400mg daily (current 100mg is likely subtherapeutic)
   • Alternative: Add N-acetylcysteine 1200-2400mg daily (three of five RCTs showed superiority to placebo) 1
   • Memantine augmentation also has evidence in SSRI-resistant OCD 1

Step 2: Address MDD Component

For the depression, choose one of these evidence-based strategies:

Option A: Switch to a different antidepressant 1:

• Switch to venlafaxine XR 75mg daily, titrate to 150-225mg daily
• Alternative: Switch to another SSRI (though evidence shows no superiority of one SSRI over another) 1
• Rationale: The STAR*D trial showed 1 in 4 patients become symptom-free after switching, with no difference between bupropion, sertraline, or venlafaxine 1

Option B: Augment current sertraline 1, 4:

• Add bupropion SR 150mg daily, increase to 300mg daily after 1 week
• Advantage: Bupropion has lower rates of sexual dysfunction than SSRIs 1
• Alternative augmentation: Aripiprazole 2-5mg daily or lithium 150-300mg daily (targeting blood level 0.2-0.6 mEq/L) 1, 4

Option C: Augment with CBT for depression 1:

• If not already implementing CBT for OCD, this addresses both conditions
• Evidence shows no difference between switching antidepressants versus switching to cognitive therapy 1

Critical Pitfalls to Avoid

• Do not combine clomipramine with sertraline without careful monitoring and dose reduction due to dangerous drug-drug interactions 1
• Do not make dose changes more frequently than weekly given sertraline's 24-hour half-life 2
• Do not assume lamotrigine at 100mg is providing adequate augmentation—therapeutic doses for mood disorders are typically 200-400mg daily
• Do not use benzodiazepines as primary augmentation for OCD, as they lack evidence for core OCD symptoms 3
• Monitor closely for suicidality, especially in the first 1-2 weeks after any medication change 1

Monitoring Plan

• Reassess within 1-2 weeks of any medication change for adverse effects and suicidality 1
• Allow 8-12 weeks at therapeutic doses before declaring treatment failure for OCD 1
• Allow 6-8 weeks before declaring treatment failure for MDD 1
• If no response after these interventions, consider intensive outpatient treatment, residential treatment, or consultation for neuromodulation (rTMS is FDA-approved for OCD) 1