What is the recommended washout period for a patient with bipolar II disorder switching from Emsam (selegiline) 9 mg/day to lamotrigine, given that lamotrigine has no serotonergic mechanism of action?

Washout Period When Switching from Emsam to Lamotrigine

A minimum 14-day washout period is required after discontinuing Emsam (selegiline) 9 mg/day before initiating lamotrigine, despite lamotrigine having no serotonergic mechanism of action. 1

Evidence-Based Rationale

The FDA label for selegiline explicitly states: "At least 14 days should elapse between discontinuation of selegiline and initiation of treatment with a tricyclic antidepressant or selective serotonin reuptake inhibitors." 1 While this guidance specifically addresses serotonergic agents, the 14-day washout represents the time needed for MAO-B enzyme regeneration and restoration of normal monoamine metabolism. 1

Why This Washout Applies Even for Non-Serotonergic Agents

• Selegiline at 9 mg/day approaches the threshold where MAO-B selectivity diminishes, and non-selective MAO inhibition may occur (selectivity is lost at doses of 30-40 mg/day, but partial loss begins at lower doses). 1
• The 14-day period allows for complete MAO enzyme regeneration, which is necessary regardless of whether the subsequent medication has serotonergic properties, as residual MAO inhibition can affect multiple neurotransmitter systems including dopamine and norepinephrine. 1
• Severe CNS toxicity with hyperpyrexia and death have been reported with combinations involving non-selective MAOIs, emphasizing the importance of adequate washout periods even when the pharmacological concern seems minimal. 1

Clinical Algorithm for the Switch

Week 1-2 (Days 1-14):

• Discontinue Emsam 9 mg/day completely
• Monitor for withdrawal symptoms or mood destabilization
• Do NOT initiate lamotrigine during this period
• Consider short-term symptomatic management if needed (non-serotonergic anxiolytics if appropriate for bipolar II)

Week 3 (Day 15 onward):

• Begin lamotrigine titration using the standard slow-titration protocol to minimize risk of serious rash including Stevens-Johnson syndrome 2, 3
• Start lamotrigine 25 mg/day for weeks 1-2
• Increase to 50 mg/day for weeks 3-4
• Increase to 100 mg/day for week 5
• Target maintenance dose of 200 mg/day by week 6 2, 3

Important Safety Considerations

• The 14-day washout is non-negotiable even though lamotrigine lacks serotonergic activity, as it represents the minimum time for MAO enzyme regeneration and prevents potential drug-drug interactions through non-serotonergic mechanisms. 1
• If the patient was taking any concomitant serotonergic medications with Emsam, the washout period becomes even more critical, though this appears not to be the case based on your question. 1
• Lamotrigine titration must be slow regardless of clinical urgency to minimize the 0.1% risk of serious rash including Stevens-Johnson syndrome. 2, 3
• If lamotrigine will be combined with valproate (common in bipolar disorder), start lamotrigine at 12.5 mg/day instead of 25 mg/day and use a slower titration schedule. 2, 3

Monitoring During Transition

• Assess mood stability weekly during the washout period, as discontinuation of Emsam may lead to depressive symptom emergence in bipolar II disorder. 4
• Monitor for signs of hypertensive crisis during the first week after Emsam discontinuation, particularly if the patient consumes tyramine-containing foods, as residual MAO inhibition persists. 1
• Watch for rash development during lamotrigine titration, particularly during the first 8 weeks, and discontinue immediately if serious rash develops. 2, 3

Common Pitfall to Avoid

Do not attempt to shorten the washout period to less than 14 days, even though lamotrigine is not serotonergic. The FDA guidance is based on the pharmacokinetics of MAO enzyme regeneration, not solely on serotonin syndrome risk. Premature initiation could theoretically result in unpredictable drug interactions through effects on dopamine and norepinephrine metabolism. 1