Haloperidol

Haloperidol blocks dopamine D2 receptors in the brain. The injection label describes its effect in schizophrenia as unclear in mechanism but probably due to this D2 blockade; it binds alpha-1 adrenergic receptors less strongly and has little effect on muscarinic or histamine receptors [2]. In the US, the tablets are approved for psychotic disorders, for the tics and vocal utterances of Tourette's disorder in children and adults, and, after other treatments have failed, for some severe behavior problems and hyperactivity in children [3]. The short-acting injection is approved for schizophrenia [2].

The body clears haloperidol in the liver along several paths. According to the label, the main ones are glucuronidation (attaching a sugar group so the drug can be excreted) and ketone reduction. Cytochrome P450 enzymes also take part, mostly CYP3A4 and to a lesser extent CYP2D6 [2]. The DPWG describes the same picture: mainly glucuronidation, with smaller contributions from CYP2D6, CYP3A4 and carbonyl reduction [1]. Because CYP2D6 is only one route, losing it raises levels but does not stop clearance.

Haloperidol's best-known side effects are movement effects called extrapyramidal symptoms (stiffness, tremor, restlessness and muscle spasms) and tardive dyskinesia, a movement disorder that can be permanent. The label also reports QT prolongation, torsades de pointes and sudden death, and says doses above those recommended appear to carry a higher risk of QT prolongation [3]. The injection label warns that higher haloperidol levels, from whatever cause, may raise the risk of side effects, including QT prolongation [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 [4]. CPIC and the DPWG agreed on these cut-offs in 2020.

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 [5].

What the studies found

The DPWG reviewed the published studies for its 2024 guideline. Several found higher haloperidol levels in poor and in intermediate metabolizers. The clinical evidence is thinner. One study that included five poor metabolizers found higher scores for extrapyramidal symptoms, and one case report described a poor metabolizer with serious side effects. In intermediate metabolizers, no clinically significant effects were found [1].

At the other end, ultrarapid metabolizers had lower haloperidol levels. A study that included five ultrarapid metabolizers found that they had the lowest rate of symptom improvement of any group [1]. These are small numbers. The DPWG calculated its dose adjustments from the differences in drug levels between each group and normal metabolizers.

The label adds a point about combined effects: CYP3A4 inhibition and reduced CYP2D6 activity may add together, so a poor metabolizer who also takes a CYP3A4 inhibitor can reach higher levels than either factor alone would produce [2].

The DPWG, a group set up by the Royal Dutch Pharmacists Association, published its guideline on CYP2D6, CYP3A4, CYP1A2 and antipsychotics in 2024. For haloperidol it advises a dose change for CYP2D6 poor and ultrarapid metabolizers and no change for other results. 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 haloperidol. 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 US haloperidol labels say that reduced CYP2D6 activity or CYP2D6 inhibitors can raise haloperidol levels, but they give no dose based on genotype [2]. CPIC has not published a haloperidol guideline. Its gene-drug list gives CYP2D6 and haloperidol a provisional level of B/C [6].

Bring the report to your prescriber with a full list of what you take, including over-the-counter products and supplements. A poor metabolizer result is most useful when haloperidol is started or its dose is being set. Someone who has been on a steady dose for months may already be on a dose that reflects how they responded.

Medicines that change the picture

Other drugs can make CYP2D6 behave as if your genes were different, an effect called phenoconversion. The haloperidol label names CYP2D6 inhibitors that raised haloperidol levels: chlorpromazine, promethazine, quinidine, paroxetine, sertraline and venlafaxine. It names fluoxetine and fluvoxamine as inhibitors of both CYP3A4 and CYP2D6, and alprazolam, itraconazole, ketoconazole, nefazodone and ritonavir as CYP3A4 inhibitors. QTc increases were seen when haloperidol was given with ketoconazole and paroxetine together [2]. The FDA classes bupropion, fluoxetine, paroxetine, quinidine and terbinafine as strong CYP2D6 inhibitors [7].

Strong CYP3A4 inducers work the other way. The label lists carbamazepine, phenobarbital, phenytoin, rifampin and St John's wort. In 12 patients, adding rifampin lowered haloperidol levels by an average of 70%, and in 5 others, stopping rifampin raised them 3.3-fold [2]. When an inducer is stopped, haloperidol levels can climb back up over time.

Haloperidol itself inhibits CYP2D6, so it can raise levels of other CYP2D6 drugs, such as the tricyclic antidepressants desipramine and imipramine [2].

Other factors

The label says older adults generally need lower doses, and that levels may rise with liver impairment because the liver does most of the clearing [3] [2]. Low potassium or magnesium, other QT-prolonging drugs, heart disease, an underactive thyroid and inherited long QT syndrome all add to the heart rhythm risk regardless of genotype [3].

Do not start, stop or change haloperidol 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 haloperidol will work for you or which side effects you will have. Extrapyramidal symptoms, tardive dyskinesia and QT prolongation depend on dose, age, other medicines and other conditions as well as on drug levels. 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 poor metabolizer. Can I still take haloperidol?

Yes. The DPWG does not advise avoiding it in poor metabolizers; it advises a lower dose, 60% of the normal dose (see What the guidelines recommend).

I am an intermediate metabolizer. Does my dose need to change?

Not under the DPWG guideline. Levels are modestly higher, but studies did not find clinically significant effects, and the DPWG recommends no action [1].

Does the result apply to the long-acting injection?

The DPWG's 60% recommendation is stated for haloperidol 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). Haloperidol metabolism, evidence summary, dose recommendations and testing advice.
2. Haloperidol injection, USP (haloperidol lactate): prescribing information (Fresenius Kabi). DailyMed. Mechanism, metabolic routes, inhibitors, inducers and liver impairment.
3. Haloperidol tablets, USP: prescribing information (Mylan). DailyMed. Indications, cardiac warnings and dosing in older adults.
4. 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.
5. CPIC. CYP2D6 frequency table (spreadsheet). Estimated phenotype frequencies by biogeographic group.
6. CPIC. Gene-drug pairs and CPIC levels (spreadsheet). Provisional level B/C for CYP2D6 and haloperidol.
7. US Food and Drug Administration. For healthcare professionals: FDA's examples of drugs that interact with CYP enzymes and transporter systems. Strong CYP2D6 inhibitors.