Zuclopenthixol

Zuclopenthixol blocks dopamine receptors, with high affinity for both D1 and D2 receptors. It also blocks alpha-adrenergic receptors strongly, serotonin receptors to some degree and histamine receptors slightly. The UK prescribing information lists it for psychoses, especially schizophrenia, in adults; it is not indicated for children [2].

Taken by mouth, it reaches its highest blood level in 3 to 6 hours, and its half-life is about one day. Blood levels track the dose closely. The liver breaks it down by sulphoxidation, N-dealkylation and glucuronidation, and most of it leaves the body in the feces [2]. The DPWG describes zuclopenthixol as mainly converted by CYP2D6 to inactive metabolites, while the UK prescribing information says it is partly metabolized by CYP2D6 [1] [2]. Either way, slower CYP2D6 activity leaves more of the active drug in circulation.

The most common side effects in the UK prescribing information are sleepiness, dry mouth and movement effects: akathisia (restlessness), extrapyramidal symptoms such as stiffness and tremor, and dystonia. QT prolongation on the ECG is rare, but the prescribing information asks for caution in people at risk and warns that drugs which raise zuclopenthixol levels may add to that risk [2].

CYP2D6 is a liver enzyme with many inherited variants. Each copy of the gene is given an activity value, and the two values are added to give an activity score. A score of 0 means a poor metabolizer (for example two no-function alleles such as *3, *4 or the *5 gene deletion), a score above 0 and below 1.25 an intermediate metabolizer, 1.25 to 2.25 a normal metabolizer, and above 2.25 an ultrarapid metabolizer, which requires extra copies of the gene [3].

CPIC estimates that about 6.5% of people of European ancestry are poor metabolizers, compared with about 2% to 3% of most other groups and under 1% of people of East Asian or Oceanian ancestry [4]. Intermediate metabolizers are much more common, so the DPWG's intermediate metabolizer advice applies to a large share of patients.

What the studies found

In the studies the DPWG reviewed, poor and intermediate metabolizers had higher zuclopenthixol levels and lower oral clearance, a finding repeated across several studies. One study reported lower levels in ultrarapid metabolizers. Clinical outcome data are sparse: the only direct sign of a practical effect was a higher number of dose changes among 11 intermediate metabolizers. The DPWG judged that the higher levels are likely to raise the risk of side effects in poor and intermediate metabolizers, and that lower levels are likely to reduce the effect in ultrarapid metabolizers [1].

The DPWG calculated its dose adjustments from the differences in drug levels between each group and normal metabolizers [1]. That is why intermediate metabolizers get a dose change here, unlike with haloperidol.

The DPWG, a group set up by the Royal Dutch Pharmacists Association, published its guideline on CYP2D6, CYP3A4, CYP1A2 and antipsychotics in 2024. For zuclopenthixol it advises a lower dose for poor and intermediate metabolizers and a cautious increase for ultrarapid metabolizers who do not respond. In its recommendations, "normal dose" means the dose the same person would be given without the gene variant [1]. A Gene2Rx report shows the DPWG recommendation for your CYP2D6 result.

The DPWG rates testing before treatment as "potentially beneficial" for zuclopenthixol. It does not recommend testing everyone who starts an antipsychotic, but advises following the guideline when a genotype is already known, and suggests testing case by case, for example when someone has had problems with several antipsychotics or other drugs cleared by CYP2D6 [1].

Other guidance

The UK prescribing information notes the CYP2D6 interaction with inhibiting drugs but gives no genotype-based dose [2]. CPIC has not published a zuclopenthixol guideline. Its gene-drug list gives CYP2D6 and zuclopenthixol a provisional level of B/C [5].

Bring the report to your prescriber with a full list of what you take, including over-the-counter products and supplements. A poor or intermediate metabolizer result is most useful when zuclopenthixol is started or its dose is being set. After months on a steady dose, the dose may already reflect how you responded.

Medicines that change the picture

The UK prescribing information warns that drugs that inhibit CYP2D6 may raise zuclopenthixol levels and increase the risk of side effects and heart rhythm problems [2]. This effect, where a medicine makes CYP2D6 behave as if your genes were different, is called phenoconversion. The FDA classes bupropion, fluoxetine, paroxetine, quinidine and terbinafine as strong CYP2D6 inhibitors [6]. Someone with normal CYP2D6 genes who takes one of them may clear zuclopenthixol more like a poor metabolizer.

The prescribing information also says to avoid other drugs that clearly prolong the QT interval, such as quinidine, amiodarone, sotalol, thioridazine, erythromycin and moxifloxacin, and to use caution with drugs that lower potassium, such as thiazide diuretics. It suggests a quarter to half the normal starting dose for frail or older people [2].

Do not start, stop or change zuclopenthixol or any other medicine because of a genetic result without talking to your prescriber.

Consumer arrays (23andMe, AncestryDNA, MyHeritage) are not clinical-grade tests, and their raw data is labeled not for medical use. They read fixed positions and can miss rare variants. Gene2Rx uses imputation to infer some variants that were not measured directly, but a variant at a position your data does not cover cannot be seen. A normal result means none of the assessed variants was found among the positions your data covers.

A genotype does not tell you whether zuclopenthixol will work for you or which side effects you will have; dose, age, other medicines and other conditions all count. If a clinical test (GeneSight, Genomind or another lab) has already reported your CYP2D6 genotype, those results can be entered for a Panel Report.

I am a CYP2D6 intermediate metabolizer. Why does my dose change for zuclopenthixol but not for haloperidol?

The DPWG looked at each drug separately. Intermediate metabolizers had higher zuclopenthixol levels, while for haloperidol the change was small and no clinically significant effects were found [1].

Does the advice apply to the depot injection?

The DPWG's recommendation is stated for zuclopenthixol without separating tablets from injections. How to apply it to a particular product is a decision for your prescriber.

1. Beunk L et al. Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6, CYP3A4 and CYP1A2 and antipsychotics. Eur J Hum Genet (2024). Zuclopenthixol metabolism, evidence summary, dose recommendations and testing advice.
2. Clopixol 10 mg film-coated tablets: summary of product characteristics. electronic medicines compendium (emc), UK. Indication, dosing, pharmacology, side effects and interactions.
3. Caudle KE et al. Standardizing CYP2D6 genotype to phenotype translation: consensus recommendations from the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group. Clin Transl Sci (2020). CYP2D6 activity scores and phenotype cut-offs.
4. CPIC. CYP2D6 frequency table (spreadsheet). Estimated phenotype frequencies by biogeographic group.
5. CPIC. Gene-drug pairs and CPIC levels (spreadsheet). Provisional level B/C for CYP2D6 and zuclopenthixol.
6. US Food and Drug Administration. For healthcare professionals: FDA's examples of drugs that interact with CYP enzymes and transporter systems. Strong CYP2D6 inhibitors.