Pimozide

Pimozide blocks dopamine receptors in the brain, as other antipsychotics do; the label says its exact mode of action in suppressing tics is not established. The US label limits it to Tourette's disorder that seriously affects development or daily life and has not responded to standard treatment. It is not a first choice and is not for tics that are merely annoying [1].

The liver clears pimozide mainly by N-dealkylation, carried out mostly by CYP3A4 and to a lesser extent by CYP1A2 and CYP2D6. The mean half-life in one patient group was about 55 hours, and exposure varied 13-fold between patients given the same dose [1].

The main safety concern is the heart. Pimozide prolongs the QT interval, and the label reports sudden deaths in studies of other conditions at doses around 1 mg/kg, and two sudden deaths when clarithromycin, which blocks CYP3A4, was added. It requires an ECG before treatment and periodically during dose adjustment, and lists many drugs as contraindicated [1].

CYP2D6 is a liver enzyme with many inherited variants. People with two non-working copies are poor metabolizers; people with reduced function are intermediate metabolizers. CPIC estimates that about 6.5% of people of European ancestry are poor metabolizers, compared with about 2% to 3% in most other groups and under 1% of people of East Asian or Oceanian ancestry [3].

The label calls CYP2D6 a lesser route, but blocking it has a large effect. The label reports that adding paroxetine, a strong CYP2D6 inhibitor, raised pimozide exposure (AUC) by 151% and peak level by 62%. Poor metabolizers have higher pimozide levels, similar to those seen with strong CYP2D6 inhibitors, and take about 2 weeks to reach steady state because of the longer half-life [1].

FDA reviewers explained the label's numbers in a 2012 paper. Using data from a single-dose genotype study, they simulated repeated dosing and found that 4 mg a day was the highest dose at which poor metabolizers would not exceed the levels that extensive and intermediate metabolizers reach on 10 mg a day, the usual maximum [4]. The limit is based on simulated drug levels, not on observed heart rhythm events.

The FDA label builds genotyping into dosing [1]:

The FDA's Table of Pharmacogenetic Associations lists pimozide and CYP2D6 in its first section, where the data support therapeutic management recommendations [5]. CPIC's gene-drug list classes the label's pharmacogenetic information as "testing required" and gives the pair a provisional level of A/B; CPIC has not published a pimozide guideline [6]. A Gene2Rx report shows the FDA statement and the DPWG recommendation for your CYP2D6 result. The two differ for intermediate metabolizers: the FDA label makes no change, while the DPWG lowers the maximum dose.

Other guidance

The DPWG's 2024 antipsychotic guideline caps the dose for two groups. For poor metabolizers it sets 50% of the normal maximum: 10 mg a day from age 12, and 0.05 mg/kg a day up to 2 mg a day under 12. For intermediate metabolizers it sets 80%: 16 mg a day from age 12, and 0.08 mg/kg a day up to 3 mg a day under 12. It recommends no action for ultrarapid metabolizers [7]. The DPWG describes the extra QT risk as theoretical and considers testing before treatment potentially beneficial [2]. The Dutch adult figures are percentages of a higher maximum dose than the US label allows, which caps all adults at 10 mg a day; the US poor metabolizer limit of 4 mg is the stricter one.

Because the label asks for genotyping before doses above 4 mg a day in adults, a CYP2D6 result is directly relevant to pimozide. Bring the report to your prescriber, along with a full list of medicines, supplements and drinks (the label says to avoid grapefruit juice, which can block CYP3A4).

Drug interactions are the bigger danger. The label contraindicates pimozide with paroxetine and other strong CYP2D6 inhibitors, with sertraline, citalopram and escitalopram, with macrolide antibiotics such as clarithromycin and erythromycin, with the antifungals itraconazole and ketoconazole, with HIV protease inhibitors, with nefazodone, and with other drugs that prolong the QT interval [1]. Someone with normal CYP2D6 genes who takes a strong CYP2D6 inhibitor can clear pimozide like a poor metabolizer, an effect called phenoconversion. The FDA lists bupropion, fluoxetine, paroxetine, quinidine and terbinafine as strong CYP2D6 inhibitors [8].

Do not start, stop or change pimozide 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 Gene2Rx uses imputation to infer some variants that were not measured directly. A normal result means none of the assessed variants was found among the positions your data covers; it cannot rule out a variant at a position the data does not cover. Because the label makes genotyping part of dosing and the risk is to the heart, a clinical CYP2D6 test is the appropriate basis for going above 4 mg a day. If a clinical test (GeneSight, Genomind or another lab) has already reported your CYP2D6 genotype, those results can be entered for a Panel Report.

A genotype says nothing about other QT risks, such as congenital long QT syndrome, low potassium or other medicines. The ECG monitoring in the label measures the QT interval directly.

Can a Gene2Rx result count as the genotyping the label asks for?

It can flag common poor metabolizer genotypes, but it is not a clinical-grade test (see What this result cannot tell you). Your prescriber decides what testing is needed.

My report says I am an intermediate metabolizer. Does my dose change?

The FDA label makes no change for intermediate metabolizers. The DPWG sets a lower maximum, 80% of the normal maximum dose, and your report shows both. In US adults the label's usual ceiling of 10 mg a day is already below the Dutch limit of 16 mg a day [1] [7]. Your prescriber can weigh the two.

Why wait 14 days between dose increases?

Poor metabolizers take about 2 weeks to reach steady levels, so an earlier increase would be judged before the previous dose had taken full effect [1].

1. Pimozide tablets, USP: prescribing information (Par). DailyMed. Indication, dosing, CYP2D6 genotyping, contraindications and interactions.
2. ClinPGx. Annotation of DPWG Clinical Guideline for pimozide and CYP2D6. The Dutch recommendation text and testing advice.
3. CPIC. CYP2D6 frequency table (spreadsheet). Estimated phenotype frequencies by biogeographic group.
4. Rogers HL et al. CYP2D6 genotype information to guide pimozide treatment in adult and pediatric patients: basis for the U.S. Food and Drug Administration's new dosing recommendations. J Clin Psychiatry (2012). How the FDA set the 4 mg limit.
5. US Food and Drug Administration. Table of Pharmacogenetic Associations. The FDA statement for pimozide and CYP2D6 poor metabolizers.
6. CPIC. Gene-drug pairs and CPIC levels (spreadsheet). Provisional level A/B for CYP2D6 and pimozide; label testing classification.
7. 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). DPWG dose limits for pimozide.
8. US Food and Drug Administration. For healthcare professionals: FDA's examples of drugs that interact with CYP enzymes and transporter systems. Strong CYP2D6 inhibitors.