Haloperidol and CYP2D6

Haloperidol (Haldol® and other brands/generics) is an antipsychotic medication approved for the treatment of schizophrenia, Tourette’s syndrome, and other behavioral disorders. Its mechanism is not completely understood, but it is known to target receptors in the brain to reduce hyperactivity and abnormal brain processes. Serious adverse events related to the use of haloperidol include heart issues known as QT prolongation and arrhythmias. Serious brain issues known as neuroleptic malignant syndrome and tardive dyskinesia may also occur.

CYP2D6 is an enzyme involved in the processing of many drugs, including haloperidol. Individuals with different genetic make-ups can produce slightly different versions of the CYP2D6 enzyme. This affects the body's ability to break down drugs because some of these variations will lead to increased or decreased functioning of the enzyme.

Patients with different combinations of CYP2D6 genes fall under three categories: poor metabolizers, intermediate metabolizers, and ultra-rapid metabolizers. Poor metabolizers will break down haloperidol slowly and may need their dosage reduced by 50% or medication changed to prevent drug buildup in the body. Intermediate metabolizers are "normal", and no special therapy modification is needed in these patients. Ultra-rapid CYP2D6 metabolizers are not fully understood as it relates to haloperidol metabolism. These patients may process the drug too quickly and may need a higher dose of haloperidol or an alternate drug.

Sue is a 79-year-old Asian female with chronic lymphocytic leukemia. Her cancer has spread to multiple areas of her body and she has decided to transition into a palliative care unit. In order to control her cancer, she was started on a chemotherapy regimen as well as ondansetron to control her nausea and vomiting. Since starting the medications, she started to experience progressive agitation due to the nausea and vomiting. In return, her doctor decided to prescribe her haloperidol. Ten days after Sue started taking the haloperidol as directed, she started to experience involuntary movements around her mouth and eye region in addition to uncontrollable spastic-like movements of her arms and legs. A family member concerned about the recent onset of these movements brought Sue to the local hospital, where a doctor ran a genetic test as part of the standard protocol. Sue was later diagnosed with tardive dyskinesia and the genetic test revealed that she is a poor metabolizer for the CYP2D6 enzyme.

CYP2D6 genetic testing does not completely eliminate the risk of developing tardive dyskinesia or the adverse side effects experienced by haloperidol, nor does it guarantee the medication will work for you. However, in the case of haloperidol it has been found that genotyping is as reliable predictor of adverse events as measuring serum drug concentrations. Genetic testing can be used in addition to other diagnostic testing in order to personalize the treatments of patients.

The links below provide access to important articles and information relative to haloperidol. The links are to external websites and will be checked regularly for consistency.

• Haloperidol Prescribing Information
• Haloperidol Pharmacogenomic Dosing Guidelines
• Pharmacogenomics Knowledge Base: Haloperidol

Brockmöller J, Kirchheiner J, Schmider J, Walter S, Sachse C, Müller-Oerlinghausen B, Roots I. The impact of the CYP2D6 polymorphism on haloperidol pharmacokinetics and on the outcome of haloperidol treatment. Clinical Pharmacology and Therapeutics. 2002 Oct;72(4):438–52.

DailyMed [Internet]. Bethesda (MD): U.S. National Library of Medicine; c1993-2015. Haloperidol; [updated 2011 Dec; cited 2015 Jan 7]; [about 2 screens]. Available from: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2626f810-0b74-4829-bffc-4a6a0bd1c387

PharmGKB [Internet]. Stanford (CA): U.S. Department of Health and Human Services; c2001-2017. Haloperidol; [updated 2011 Aug 10; cited 2015 May 2]; [about 2 screens]. Available from: https://www.pharmgkb.org/chemical/PA449841/.

Samer CF, Lorenzini KI, Rollason V, Daali Y, Desmueles JA. Applications of CYP450 testing in the clinical setting. Molecular Diagnosis and Therapy. 2013 Jun;17(3):165-84.

Shin JG, Khadidjatou K, Flockhart DA. Potent inhibition of CYP2D6 by haloperidol metabolites: stereoselective inhibition by reduced haloperidol. British Journal of Clinical Pharmacology. 2001 Jan;51(1):45–52.

Swen JJ, Nijenhuis M, de Boer A, et al. Pharmacogenetics: from bench to byte-- an update of guidelines. Clinical Pharmacology and Therapeutics. 2011 May;89(5):662-73.