What's the next step for a 53-year-old patient with ongoing depression despite being on 25mg of lamotrigine (lamotrigine)

Increase Lamotrigine Dose and Add an Antidepressant

For a 53-year-old patient with ongoing depression on 25mg lamotrigine, the most effective next step is to add an SSRI (escitalopram 10-20mg daily) or SNRI (venlafaxine 37.5-225mg daily) while continuing lamotrigine at the current dose, as lamotrigine at 25mg is a subtherapeutic dose for depression and combination therapy achieves remission rates of approximately 50% versus 30% with monotherapy alone. 1

Why 25mg Lamotrigine Alone Is Insufficient

• Lamotrigine 25mg is far below the therapeutic range for mood disorders—the typical target dose is 200mg daily for bipolar depression, with doses ranging from 50-300mg in clinical trials 2, 3, 4
• The American College of Psychiatrists recommends starting with an SSRI or SNRI while continuing lamotrigine due to its minimal drug interactions and safety for combination therapy 1
• Lamotrigine has demonstrated efficacy primarily as maintenance therapy for bipolar disorder and for preventing depressive episodes, but requires adequate dosing 2

Recommended Treatment Algorithm

Step 1: Add an Antidepressant Immediately

• Start escitalopram 10mg daily, titrating to 20mg after 2-4 weeks, OR venlafaxine 37.5-75mg daily, titrating to 150-225mg 1
• Do not wait to increase lamotrigine first—the evidence supports adding antidepressants to low-dose lamotrigine rather than increasing lamotrigine alone 1
• Escitalopram has the most favorable drug interaction profile with minimal CYP450 effects, making it safest for combination therapy 1

Step 2: Monitor Response Objectively

• Use standardized depression rating scales (PHQ-9) every 2-4 weeks to track symptoms 1
• Assess specifically for suicidal ideation during the first 1-2 months after adding the antidepressant, as suicide risk peaks during this period 1
• Allow 6-8 weeks at therapeutic antidepressant dose before declaring treatment failure 1

Step 3: If Inadequate Response After 8 Weeks

• Switch to a different antidepressant class (from SSRI to SNRI or vice versa) OR add bupropion SR 150-400mg to the SSRI 1
• SNRIs demonstrate statistically significantly better response and remission rates than SSRIs in treatment-resistant depression 1
• Augmentation with bupropion achieves approximately 50% remission versus 30% with SSRI monotherapy 1

Critical Safety Considerations

• Do not increase lamotrigine beyond 300mg daily without first adding an antidepressant, as higher doses increase seizure risk without established benefit for depression 1
• Do not exceed escitalopram 20mg daily, as higher doses increase QT prolongation risk without additional benefit 1
• Lamotrigine requires slow titration (25mg weekly increments) to minimize serious rash risk (0.1% incidence, including Stevens-Johnson syndrome) 2

Duration of Treatment

• Continue combination therapy for 4-9 months after achieving remission for first episode of major depression 1
• For recurrent depression (2+ episodes), consider years to lifelong maintenance therapy 1

Common Pitfalls to Avoid

• Do not continue lamotrigine 25mg monotherapy—this dose is inadequate for treating depression and delays recovery 1, 2
• Do not increase lamotrigine as monotherapy first—the guideline explicitly recommends adding an antidepressant to low-dose lamotrigine rather than titrating lamotrigine alone 1
• Do not wait longer than 8 weeks at therapeutic dose before modifying treatment, as continuing ineffective treatment worsens outcomes 1