05. Antipsychotic Withdrawal Syndrome: Symptoms, Risks, and Prevention Strategies

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Antipsychotic Withdrawal: An Underestimated Issue

In this Quick Take, I’m going to talk about a topic that I think is probably underestimated by the profession, the issue of antipsychotic withdrawal.

Given that we have well-recognized withdrawal syndromes from benzodiazepines or SSRI antidepressants, for example, the lack of research delineating an antipsychotic withdrawal syndrome seems to be an oversight. So I thought I would bring you a pharmacovigilance study by Storck and colleagues from France published online in February of this year in the Journal of Psychopharmacology.

Withdrawal Dyskinesia and Psychosis: Familiar Phenomena

You’re probably familiar with one antipsychotic withdrawal phenomenon: withdrawal dyskinesia. This can happen if you stop a first-generation antipsychotic abruptly, particularly if the patient has underlying tardive dyskinesia.

It can be quite severe and may take several weeks to resolve. It is thought to be due to dopamine receptor supersensitivity that develops in some people as a result of dopamine blockade.

An interesting question is the possibility that in some patients there is not just withdrawal dyskinesia but also a withdrawal psychosis, although this is controversial. If true, it could get tricky when you try to stop an antipsychotic, as a psychotic relapse may be the result of a supersensitivity iatrogenic problem as opposed to a natural relapse.

VigiBase: The World’s Largest Drug Safety Database

The researchers from France took advantage of a large drug safety database called VigiBase to ask two questions:

1. What kind of side effects are reported when patients stop their antipsychotic?
2. Are there differences in reporting frequencies between antipsychotics?

VigiBase is the very large World Health Organization International Pharmacovigilance database with millions of reports from over 130 countries. It is the single largest drug safety data repository in the world.

The reports come in the form of individual case safety reports that were spontaneously submitted to their respective national safety databases by health professionals, patients, and sometimes the pharmaceutical industry before being sent on to VigiBase. They are usually reviewed to ensure that what is reported seems to be at least possible from the medication.

Insomnia, Anxiety, Depression: Common Withdrawal Symptoms

The authors identified almost 400,000 side effect reports from 26 antipsychotics in VigiBase over a two-year period from 2020 to 2022, of which about 2,000 were reports of withdrawal symptoms. They performed a disproportionality analysis to see if there was a different risk of reporting withdrawal with each antipsychotic compared to all other antipsychotics.

The main findings:

• Insomnia, anxiety and depression were the most common psychiatric side effects
• Tremor, headache and dizziness were the most common neurological symptoms
• The highest risk of reported side effects were for tiotixene, pimozide, quetiapine, thioridazine and ziprasidone
• Quetiapine had the most reported problems in absolute numbers, possibly related to frequent off-label prescribing and a different patient group perhaps more attuned to complaining about side effects and reporting them

Preventing Withdrawal: Go Slow If You Can

The prevention of antipsychotic withdrawal phenomena, even if mild, is straightforward in theory: go slow if you can. I understand that this is often not possible or patients simply stop their medications without telling you, in which case he or she may complain about non-specific symptoms like insomnia or anxiety.

Keep this possibility in mind when you see a patient. How slow to taper antipsychotics is a bit unclear and you need to strike a balance between what is desirable and what is feasible.

Don’t make it too complicated. Just remember to go slower at the end of a taper when even small dose changes lead to big changes in receptor occupancy.

Clinical Bottom Line: Avoid Withdrawal, Take Your Time

While not well described, antipsychotic withdrawal is real and it makes clinical sense to avoid antipsychotic withdrawal phenomena which are non-specific and could get confused with a psychotic relapse. Just take your time and support the patient well during this time period.

This is a time where you may want to see your patient more frequently and not just every two months. Something we probably are not doing well is warning patients about the possibility of withdrawal symptoms when they stop their medication. This is a discussion you should have at the beginning of treatment when you start an antipsychotic.

Abstract

Withdrawal syndrome after antipsychotics discontinuation: an analysis of the WHO database of spontaneous reports (Vigibase) between 2000 and 2022

Wilhelm Storck, Tanguy Taillefer de Laportalière, Antoine Yrondi, Hervé Javelot, Fabrice Berna, François Montastruc

RATIONALE

Withdrawal syndrome (WDS) has been described after discontinuation of antipsychotics. WDS could be the consequence of an over-activation of the dopaminergic pathway. Antipsychotics with a higher afnity for dopamine D2 receptors could be associated with a higher risk of WDS. This study aims to address this statement and evaluate the risk diference for withdrawal syndrome between antipsychotics based on pharmacovigilance data.

METHODS

We collected individual reports registered in Vigibase® between 01/01/2000 and 31/12/2022 of patients treated with antipsychotics and who had presented WDS. A disproportionality analysis was performed to evaluate the risk of reporting WDS with each antipsychotic compared to all other antipsychotics. We performed a correlation analysis to assess the correlation between the risk of reporting WDS for each antipsychotic in relation with their pKi for D2 and 5HT2A receptors.

RESULTS

The most frequent psychiatric withdrawal symptoms after antipsychotic discontinuation were insomnia, anxiety and depression. Tremor, headache and dizziness were among the most frequently reported neurologic withdrawal symptoms. Tiotixene had the highest risk of reporting WDS (ROR 7.08; 95%CI 3.49 – 14.35) followed by pimozide (ROR 4.35; 95%CI 1.93 – 9.77), quetiapine (ROR 4.24; 95%CI 3.87 – 4.64), thioridazine (ROR 4.17; 95%CI 2.50—6.98) and ziprasidone (ROR 2.98; 95%CI 2.41—3.67). We found a poor correlation between D2/5HT2A binding afnity and the risk of reporting withdrawal syndrome (R2=0,094). Conclusion Our results suggest that there might be a risk diference for WDS between antipsychotics. Tiotixene, pimozide and quetiapine were associated with a higher risk of reporting a WDS whereas this risk was lower with chlorpromazine, clozapine and fuphenazine. We could not address the issue of withdrawal psychosis, withdrawal dyskinesia, rebound psychosis or supersensitivity psychosis due to the lack of specifc WHO medDRA coded terms to identify potential cases.

Reference

Storck, W., Taillefer de Laportalière, T., Yrondi, A., Javelot, H., Berna, F., Montastruc, F. (2024). Withdrawal syndrome after antipsychotics discontinuation: an analysis of the WHO database of spontaneous reports (Vigibase) between 2000 and 2022. Volume 241, pages 1205–1212, (2024)