How to Taper and Stop Clozapine
Clozapine should be tapered gradually over 1-2 weeks when discontinuation is planned and there is no evidence of moderate to severe neutropenia, with careful monitoring for psychotic relapse and cholinergic rebound symptoms including profuse sweating, headache, nausea, vomiting, and diarrhea. 1
Standard Tapering Protocol
The FDA-approved method involves reducing the dose gradually over a period of 1 to 2 weeks if termination of clozapine therapy is planned and there is no evidence of moderate to severe neutropenia. 1
The taper rate should be individualized based on the patient's ability to tolerate dose reductions, with consideration for slower tapers (potentially over months) in patients who have been on clozapine long-term, similar to principles used for other psychotropic medications. 2
For patients on clozapine for extended periods (years), consider applying the principle of 10% reductions per month or slower, as recommended for other long-term psychotropic medications. 2, 3
Some experts suggest hyperbolic tapering (reducing by one-quarter to one-half of the most recent dose sequentially) at 3-6 month intervals to allow neuroadaptations time to resolve, though this approach requires further validation for clozapine specifically. 4
Critical Monitoring Requirements
All patients must be monitored carefully for recurrence of psychotic symptoms and symptoms related to cholinergic rebound during and after discontinuation. 1
Cholinergic Rebound Symptoms to Monitor:
- Profuse sweating 1
- Headache 1
- Nausea and vomiting 1, 5
- Diarrhea 1, 5
- These symptoms typically appear within days of dose reduction. 3, 5
Additional Withdrawal Phenomena:
- Psychotic relapse (the most serious risk) 6, 5
- Catatonia 5
- Serotonergic discontinuation symptoms 5
- Anxiety and insomnia 3, 5
Neutropenia-Related Discontinuation
If abrupt clozapine discontinuation is necessary because of moderate to severe neutropenia, follow specific ANC monitoring protocols rather than gradual tapering. 1
For abrupt discontinuation unrelated to neutropenia, continue existing ANC monitoring until ANC is ≥1500/μL for general population patients or ≥1000/μL for patients with benign ethnic neutropenia. 1
Additional ANC monitoring is required for any patient reporting fever (≥38.5°C or 101.3°F) during the 2 weeks after discontinuation. 1
Managing Withdrawal Symptoms
If withdrawal symptoms become severe, pause the taper and restart when the patient is ready, potentially at a slower rate. 2
Consider supportive medications for specific symptoms: short-term trazodone for anxiety or irritability, sleep hygiene measures with possible short-term sleep aids for insomnia, and symptomatic treatments for gastrointestinal symptoms. 3
Monitor closely for depression, anxiety, and potential emergence of substance use, which may be revealed during tapering. 2
Withdrawal symptoms are not necessarily a sign that the patient needs to continue clozapine long-term. 3
Initiating Alternative Treatment
Antipsychotic switching should involve gradual cross-titration informed by the half-life and receptor profile of each medication. 2
If switching to another antipsychotic is planned, begin the new medication while gradually reducing clozapine to minimize risk of psychotic relapse. 2
For patients with treatment-resistant schizophrenia, carefully consider whether discontinuation is truly necessary, as clozapine remains the only antipsychotic effective for this population. 6
Common Pitfalls to Avoid
Never abruptly discontinue clozapine except in cases of serious medical toxicity (such as severe neutropenia), as this significantly increases the risk of psychotic relapse and severe withdrawal symptoms. 2, 1, 6
Do not mistake withdrawal symptoms for recurrence of the original psychiatric condition. 3
Avoid tapering too quickly, which increases both withdrawal symptom risk and psychotic relapse risk. 2, 6
Do not abandon patients during the tapering process—frequent follow-up (at least monthly) is essential. 2
Re-initiation Considerations
If clozapine needs to be restarted after even a brief interruption, the dose must be reduced to minimize risk of hypotension, bradycardia, and syncope. 1
If one day's dosing has been missed, resume at 40-50% of the established dose. 1
If two days have been missed, resume at approximately 25% of the established dose. 1
For longer interruptions, re-initiate at 12.5 mg once or twice daily, then increase more quickly than initial treatment if well-tolerated. 1