I am taking lamotrigine 150 mg daily and vortioxetine (Trintellix) 5 mg daily and still have anxiety, depression, and insomnia—what should I do?

Management of Persistent Anxiety, Depression, and Insomnia on Lamotrigine 150mg and Vortioxetine 5mg

Primary Recommendation: Optimize Vortioxetine Dose Before Adding Medications

Increase vortioxetine from 5mg to 10-20mg daily, as the current 5mg dose is subtherapeutic for treating anxiety and depression, and allow 8-12 weeks at the optimized dose before declaring treatment failure. 1

• The therapeutic dose range for vortioxetine in anxiety and depression is 10-20mg daily, with 5mg representing only a starting dose that lacks full efficacy 2, 3
• Vortioxetine demonstrates superior efficacy at 20mg compared to lower doses, with statistically significant reduction in anxiety symptoms (HAM-A score difference of -2.95 versus placebo) 1, 3
• Full therapeutic response to vortioxetine requires 4-6 weeks at the target dose, with some patients requiring up to 8-12 weeks 2, 1

Dosing Titration Protocol

• Week 1-2: Increase vortioxetine to 10mg daily 2
• Week 3-4: If tolerated and partial response observed, increase to 15mg daily 2
• Week 5-6: Titrate to maximum dose of 20mg daily if needed 1, 2
• Most adverse effects (nausea, vomiting) are mild-to-moderate and emerge within the first few weeks, then resolve with continued therapy 2, 3

Addressing Insomnia During Dose Optimization

For insomnia management while optimizing vortioxetine, consider low-dose trazodone 25-50mg at bedtime as a targeted sleep aid rather than an antidepressant dose. 4, 1

• Trazodone's hypnotic action at low doses (25-50mg) is attributed to 5-HT2A, H1, and alpha-1 adrenergic receptor antagonism 2
• Antidepressant doses of trazodone range from 50-400mg daily in divided doses, but 25-50mg at bedtime specifically targets insomnia without adding significant antidepressant effect 4, 2
• Benzodiazepines should be avoided due to tolerance, addiction risk, cognitive impairment, and paradoxical agitation in approximately 10% of patients 4

Lamotrigine Considerations

Continue lamotrigine 150mg as maintenance therapy, as it provides effective mood stabilization and prevention of depressive episodes in bipolar disorder. 5, 6

• Lamotrigine 150mg is within the therapeutic range (target 200mg/day after 6-week titration) and demonstrates efficacy in preventing depressive episodes 5, 6
• The combination of lamotrigine with vortioxetine has shown 73% response rates and 52% remission rates in bipolar depression in naturalistic studies 7
• Lamotrigine does not cause weight gain and is generally well tolerated, with common adverse events being headache, nausea, and insomnia 5, 6

If Symptoms Persist After Vortioxetine Optimization (8-12 Weeks at 20mg)

Augmentation Strategy (Preferred)

Add bupropion SR 150mg daily, titrating to 300-400mg daily over 3-7 days, as augmentation therapy to address residual anxiety, depression, and activation deficits. 1

• Bupropion's norepinephrine-dopamine reuptake inhibition complements vortioxetine's multimodal serotonergic activity, providing synergistic benefit 1, 2
• Bupropion specifically improves low motivation and energy deficits that often persist despite vortioxetine therapy 1
• Bupropion SR has significantly lower discontinuation rates due to adverse events (12.5%) compared to buspirone (20.6%, p<0.001) 1
• Contraindications: Do not use bupropion in patients with seizure disorders, eating disorders, or severe agitation 1, 2

Alternative Augmentation: Buspirone

If bupropion is contraindicated, initiate buspirone 5mg twice daily and titrate to 20mg three times daily over 2-4 weeks. 1

• Buspirone requires 2-4 weeks to become effective and is useful for mild-to-moderate agitation 4, 1
• Buspirone has higher discontinuation rates (20.6%) but remains an evidence-based option when bupropion cannot be used 1

Switching Strategy (If Augmentation Fails)

Switch to venlafaxine XR 37.5-225mg daily (SNRI) if combination therapy fails after 8-12 weeks. 1

• SNRIs demonstrate statistically significantly better response and remission rates than SSRIs in treatment-resistant depression with anxiety 1
• Venlafaxine's dual serotonin-norepinephrine action may provide superior efficacy for both depression and anxiety symptoms 1
• Allow 6-8 weeks at therapeutic venlafaxine dose (150-225mg daily) before declaring treatment failure 1

Critical Safety Monitoring

• Assess suicidal ideation at every visit during the first 1-2 months after any medication change, as suicide risk is greatest during this period 1
• Monitor for behavioral activation (agitation, restlessness, insomnia) within the first 24-48 hours after vortioxetine dose increases 1
• Watch for serotonin syndrome signs (mental status changes, neuromuscular hyperactivity, autonomic instability) when combining medications 1
• Do not combine vortioxetine with MAOIs or multiple serotonergic agents due to serotonin syndrome risk 1

Duration of Continuation Therapy

• Continue treatment for 4-9 months after first episode remission 4
• For recurrent depression (≥2 episodes), consider years to lifelong maintenance therapy to prevent relapse 4, 1

Common Pitfalls to Avoid

• Do not add augmentation agents before optimizing vortioxetine to 20mg for 8-12 weeks, as premature augmentation misses the opportunity for monotherapy response 1
• Do not switch medications before allowing adequate trial duration (8-12 weeks at therapeutic dose), as this leads to missed response opportunities 1
• Do not use benzodiazepines for chronic anxiety management due to tolerance, dependence, and cognitive impairment risks 4
• Do not exceed vortioxetine 20mg daily, as higher doses have not demonstrated additional benefit and may increase adverse effects 2, 3