Is a washout period necessary when switching between nortriptyline (tricyclic antidepressant) and sertraline (selective serotonin reuptake inhibitor)?

Washout Period When Switching Between Nortriptyline and Sertraline

A washout period is NOT necessary when switching from nortriptyline (TCA) to sertraline (SSRI), but IS required when switching from sertraline to nortriptyline. 1, 2, 3

Direction-Specific Switching Strategies

Switching FROM Nortriptyline TO Sertraline (No Washout Required)

Direct cross-taper is the preferred approach:

• Begin sertraline at a low dose (25-50 mg) while simultaneously tapering nortriptyline gradually over 1-2 weeks 1, 3
• This approach minimizes the risk of depressive symptom exacerbation during the transition period 4
• Monitor for serotonin syndrome during the first 24-48 hours after initiating sertraline, watching for mental status changes, neuromuscular hyperactivity, and autonomic hyperactivity 1
• Sertraline has minimal effect on cytochrome P450 2D6 at lower doses, reducing interaction concerns during overlap 2

Rationale: TCAs to SSRIs switches can be performed safely with cross-tapering because the risk of serotonin syndrome is low when adding an SSRI to a tapering TCA 3, 4

Switching FROM Sertraline TO Nortriptyline (Washout Recommended)

Conservative approach with washout period:

• Taper sertraline gradually over 1-2 weeks to minimize discontinuation syndrome (dizziness, fatigue, headaches, sensory disturbances) 1, 4
• Implement a washout period of at least 1 week after complete sertraline discontinuation before starting nortriptyline 3, 4
• This allows sertraline (half-life ~26 hours) to be eliminated, as the traditional recommendation is four times the terminal half-life for drug clearance 5

Rationale: Sertraline inhibits P450 2D6, which metabolizes nortriptyline 2. Starting nortriptyline while sertraline is still present could lead to elevated TCA levels and increased risk of cardiac conduction abnormalities, orthostatic hypotension, and anticholinergic toxicity 5, 2

Critical Safety Considerations

Serotonin Syndrome Risk

• The combination of TCAs with SSRIs increases serotonin syndrome risk, particularly problematic when initiating the SSRI 1, 2
• Avoid combining with MAOIs or other serotonergic drugs during any transition 1

TCA-Specific Toxicity Concerns

• Nortriptyline has a narrow therapeutic index with risks of cardiac conduction abnormalities, orthostatic hypotension, and anticholinergic effects 5
• Sertraline's inhibition of P450 2D6 can increase nortriptyline plasma concentrations by 30-50% if co-administered 2

Discontinuation Syndrome

• Sertraline has moderate risk for discontinuation syndrome; gradual tapering over days to weeks is essential 4
• If withdrawal symptoms occur, slow the tapering schedule 1

Monitoring During Transition

• First 48 hours: Vigilant monitoring for serotonin syndrome symptoms 1
• Weeks 1-4: Assess for withdrawal symptoms from the discontinued medication and emerging side effects from the new medication 1
• Ongoing: Monitor sleep, appetite, sexual function, and depressive symptoms as these may respond differently to each medication 1

Alternative Approach: When Rapid Switching is Necessary

If clinical circumstances require faster transition (severe symptoms, safety concerns):

• A moderate approach with 2-3 day overlap during cross-taper may be acceptable for nortriptyline-to-sertraline switches under close monitoring 3, 4
• This should only be attempted when expected benefits outweigh risks and with daily clinical monitoring 6
• Never use rapid switching when going from sertraline to nortriptyline due to pharmacokinetic interaction risks 2, 4