Quetiapine

Quetiapine acts on many brain receptors at once, including dopamine D2, serotonin 5-HT2A, histamine H1 and alpha-1 adrenergic receptors. It binds histamine H1 and alpha-1 receptors much more tightly than dopamine D2 receptors. Sleepiness is common: in schizophrenia trials, 18% of people on Seroquel reported somnolence compared with 11% on placebo. Blocking alpha-1 receptors can cause a drop in blood pressure on standing, with dizziness or fainting, mostly while the dose is being raised [2].

Seroquel tablets are approved for schizophrenia and for manic and depressive episodes of bipolar disorder [2]. Seroquel XR, the extended-release form, has the same uses plus add-on treatment of major depressive disorder alongside an antidepressant [3].

Less than 1% of a dose leaves the body unchanged. The liver turns most of it into inactive products, and CYP3A4 is the enzyme behind the main inactive metabolite, quetiapine sulfoxide. One metabolite, N-desalkylquetiapine (norquetiapine), is active: it binds many receptors more strongly than quetiapine itself, and CYP3A4 also helps clear it. The half-life of quetiapine is about 6 hours [2]. The DPWG notes that norquetiapine seems to carry mainly antidepressant activity, and that CYP2D6 plays only a minor part in quetiapine's metabolism [1].

CYP3A4 takes part in the metabolism of more than half of prescribed drugs [4]. Unlike CYP2D6, most of the difference in CYP3A4 activity between people comes from other drugs that block or induce it rather than from genes, and the DPWG expects CYP3A4 variants to have smaller effects than CYP2D6 variants [1].

The best-studied reduced-function variant is CYP3A4*22, a change in an intron (rs35599367) that lowers how much enzyme the liver makes. Carriers of *22 had about 2.5 times lower CYP3A4 activity in a testosterone test, and the variant explains about 12% of CYP3A4 activity differences worldwide. The DPWG reports a *22 allele frequency of 3.2% to 10.6% in the Dutch population, with similar frequencies in the African American and Chinese American groups studied. Other alleles are rarer: *20, which has no function, is found almost only in people of Spanish and Latin American ancestry, and *16 only in certain countries [1].

What the study found

The evidence for quetiapine comes from a single Dutch study of 238 adults with measured quetiapine blood levels. The 31 carriers of *22 had 2.5 times higher quetiapine levels than non-carriers at a similar median dose of 300 mg a day, and 16.1% of carriers had levels above the therapeutic range, compared with 2.9% of non-carriers [4]. Analyzed by phenotype, as the DPWG did, the dose-corrected level was 1.2 times higher in the 29 intermediate metabolizers (one *22 copy) and 3.2 times higher in the 2 poor metabolizers (two copies) [1].

The DPWG judged the poor metabolizer effect large enough to be likely to cause more side effects, and expected the formation of norquetiapine, the probable source of the antidepressant effect, to be strongly reduced. It acknowledges that the evidence is limited, resting on that one study with 31 carriers and only 2 poor metabolizers [1].

The DPWG, a group set up by the Royal Dutch Pharmacists Association, published its guideline on CYP2D6, CYP3A4, CYP1A2 and antipsychotics in 2024. For quetiapine and CYP3A4 it advises a change only for poor metabolizers. The DPWG defines a CYP3A4 intermediate metabolizer as someone with one reduced-function or inactive allele (for example *1/*22), and a poor metabolizer as someone with two (for example *22/*22, *16/*22 or *16/*16). 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 CYP3A4 result.

The Gene2Rx report groups CYP3A4 results a little differently from the DPWG. It reports two decreased-function alleles, such as *22/*22, *16/*22 or *16/*16, as intermediate metabolizer, and gives poor metabolizer only when at least one allele has no function (*6, *20 or *26). The DPWG classes those three diplotypes as poor metabolizers, so its poor metabolizer advice for quetiapine applies to them. If your report lists one of these CYP3A4 diplotypes, show your prescriber the diplotype itself, not just the phenotype label.

The DPWG rates testing before treatment as "potentially beneficial" for quetiapine and CYP3A4. It does not recommend testing everyone who starts quetiapine, but advises following the guideline when a genotype is already known. It found no interaction between CYP2D6 and quetiapine, and lists quetiapine as a possible alternative for people whose CYP2D6 results affect other antipsychotics [1].

Other guidance

The FDA label for Seroquel does not mention CYP3A4 genotype, but it sets firm dose rules for CYP3A4 drug interactions (see Using your result) [2]. CPIC has not published a quetiapine guideline.

For most people, other medicines change quetiapine levels far more than CYP3A4 genes do. The Seroquel label says to cut the quetiapine dose to one sixth when a strong CYP3A4 inhibitor such as ketoconazole, itraconazole, indinavir, ritonavir or nefazodone is added, and to raise it back 6-fold when the inhibitor is stopped. With long-term use (more than 7 to 14 days) of a strong CYP3A4 inducer such as phenytoin, carbamazepine, rifampin or St John's wort, the dose may need to go up as much as 5-fold; phenytoin raised quetiapine clearance 5-fold. When the inducer is stopped, the dose goes back to its original level within 7 to 14 days [2]. These effects are larger than the 3.2-fold rise seen in CYP3A4 poor metabolizers, and they apply whatever your genotype. A person with *22 who also takes a strong CYP3A4 inhibitor may be affected by both.

Age and liver function matter too. Quetiapine clearance was 40% lower in people aged 65 and over, and the label suggests a lower starting dose and slower increases for older adults and for people with liver impairment [2].

Bring your report to your prescriber with a full list of what you take, including over-the-counter products and supplements. Do not start, stop or change quetiapine or any other medicine because of a genetic result without talking to your prescriber.

The quetiapine evidence is thin: the poor metabolizer estimate comes from 2 people in a single study. A CYP3A4 result says nothing about the drugs, foods or liver conditions that change CYP3A4 activity day to day, and those usually matter more.

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. Several CYP3A4 alleles have no agreed function, and a result that includes one of them is reported as indeterminate.

A genotype does not tell you whether quetiapine will work for you or which side effects you will have. Sleepiness and blood pressure changes depend on dose, other medicines and individual factors as well as on drug levels.

I carry one copy of CYP3A4*22. Do I need a lower quetiapine dose?

Not under the DPWG guideline. One copy raised levels by about 20%, and the DPWG recommends no action for intermediate metabolizers [1].

Why does the advice for depression differ from other uses?

The DPWG expects poor metabolizers to make much less norquetiapine, the metabolite thought to drive the antidepressant effect. For depression it advises a different drug rather than a lower dose [1].

Does my CYP2D6 result matter for quetiapine?

No. The DPWG found no interaction between CYP2D6 and quetiapine [1].

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). CYP3A4 phenotype definitions, *22 frequency, evidence summary, quetiapine recommendations.
2. Seroquel (quetiapine) tablets: prescribing information (AstraZeneca). DailyMed. Indications, metabolism, CYP3A4 interaction dosing, side effects, older adults.
3. Seroquel XR (quetiapine) extended-release tablets: prescribing information (AstraZeneca). DailyMed. Indications, including add-on treatment of major depressive disorder.
4. van der Weide K, van der Weide J. The influence of the CYP3A4*22 polymorphism on serum concentration of quetiapine in psychiatric patients. J Clin Psychopharmacol (2014). The study behind the DPWG recommendation.